Stereoselective synthesis of aza analogues of isoaltholactone and goniothalesdiol - New applications of the Heck-Matsuda reaction

Article abstract of DOI:10.1002/ejoc.201100886

The stereoselective synthesis of nitrogen analogues of biologically active isoaltholactone and goniothalesdiol are described. The successful strategy employed a Heck-Matsuda reaction between a chiral endocyclic enecarbamate bearing an ester functionality

Full text of DOI:10.1002/ejoc.201100886

FULL PAPER
DOI: 10.1002/ejoc.201100886
Stereoselective Synthesis of Aza Analogues of Isoaltholactone and
Goniothalesdiol – New Applications of the Heck–Matsuda Reaction
Angélica Venturini Moro,[a] Marcelo Rodrigues dos Santos,[a] and
Carlos Roque D. Correia*[a]
Keywords: Natural products / Medicinal chemistry / Total synthesis / Lactones / Arenediazonium salts
The stereoselective synthesis of nitrogen analogues of biolo-
gically active isoaltholactone and goniothalesdiol are de-
scribed. The successful strategy employed a Heck–Matsuda
reaction between a chiral endocyclic enecarbamate bearing
an ester functionality and arenediazonium tetrafluoroborates
in a divergent approach at an early stage of the synthesis.
Several aspects related to this critical arylation reaction are
discussed to highlight structural features that affect the out-
come of the arylation process. The synthesis of (–)-aza-isoal-
tholactone 6 was successfully accomplished in nine steps
from the starting enecarbamate. We also performed the syn-
thesis of the new fully substituted pyrrolidine (–)-
(2R,3R,4S,5S)-1-(tert-butoxycarbonyl)-3,4-dihydroxy-5-phen-
ylpyrrolidin-2-ylacrylic acid 28, which is a potential ad-
vanced intermediate in the route to aza-altholactone. More-
over, the synthesis of a new nitrogen analogue of gonio-
thalesdiol (+)-33 was accomplished from the protected dihy-
droxypyrrolidine (–)-27, obtained from an attempted synthe-
sis of aza-altholactone.
In this context, a class of natural compounds that has
received increased attention are the styryllactones, a diverse
group of secondary metabolites, which show high toxicity
to a broad spectrum of human tumor cells, including breast,
colon, kidney, and pancreas.[3] Several of these compounds
also have anti-inflammatory and antibiotic activity, as well
as activity as immunosuppressants and antifertility
agents.[4]
Introduction
Throughout history, Nature has supplied the basic needs
of human beings, one of which is the provision of medi-
cation to treat a broad spectrum of diseases. Nature pro-
vides valuable contributions, not only as a source of poten-
tially chemotherapeutic agents, but also prototype com-
pounds, which function as inspiration for the total synthesis
or semisynthesis of new drugs.
Natural products can be considered as prevalidated bio-
logical structures, which were selected by evolution to inter-
act with biological systems such as enzymes and protein
receptors. Moreover, during their biogenesis natural com-
pounds are recognized and undergo structural modifica-
tions through interactions with many different enzymatic
systems. These bioprocesses are relevant for the develop-
ment of new drugs as most are intended to interact with
some type of protein target.[1] However, quite often the
original structure of the natural product has to undergo
several changes in order to achieve therapeutic application
as they were not originally intended as drugs by the produc-
ing organisms. Therefore, structure refinement through the
synthesis of analogues occupies a central role in optimizing
efficiency of action, bioavailability, stability, interaction
with the target, pharmacokinetic, and pharmacodynamic
properties.[2]
There are over 30 different styryllactones with different
structural patterns (Figure 1). Among them, isoaltholac-
tone and altholactone display an α,β-unsaturated furano-
pyranone unit and
a central tetrasubstituted tetra-
hydrofuran ring bearing four consecutive stereogenic cen-
ters. These molecules have a common structural unit dif-
[a] Instituto de Química, Universidade Estadual de Campinas,
UNICAMP,
C.P. 6154, CEP. 13084-971, Campinas, São Paulo, Brazil
Fax: +55-19-37883023
E-mail: roque@iqm.unicamp.br
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100886.
Figure 1. Examples of natural styryllactones.
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 7259
Eur. J. Org. Chem. 2011, 7259–7270

A. V. Moro, M. Rodrigues dos Santos, C. R. D. Correia
FULL PAPER
fering only in the configuration of the stereogenic centers time that studies on the syntheses of these unnatural com-
at C-2 and C-3. This configurational difference has driven pounds have been described. For reasons of practicality and
the development of flexible, stereoselective routes towards cost, studies were directed towards the synthesis of the ni-
the syntheses of both diastereomers.
trogen analogues as their unnatural enantiomers.
Due to the broad spectrum of biological activity of this
class of compounds, several groups have devoted efforts
towards the total synthesis of styryllactones.[5] We recently
reported the synthesis of isoaltholactone using the Heck re-
action of dihydrofuran 1 with benzenediazonium tetrafluo-
roborate as the key step (Scheme 1).[6] The reaction, cata-
lyzed by Pd2(dba)3, occurred rapidly at room temperature,
providing the arylated product with high stereoselectivity in
favor of the trans isomer. Successive deprotection reactions,
dihydroxylation, acetonide formation, Swern oxidation,
Horner–Wadsworth–Emmons (HWE) olefination, and de-
protection/lactonization led to isoaltholactone in 25% over-
all yield.
Synthetic Plan
Initially, our proposed synthesis was aimed at the prepa-
ration of nitrogen analogues of both isoaltholactone and
altholactone through a common route (Scheme 2). The con-
vergence of the two synthetic routes would be linked to the
Heck reaction between benzenediazonium tetrafluorobor-
ate and endocyclic enecarbamate 15. Based on our previous
results, we predicted that a Heck reaction would provide
the cis and trans isomers in similar amounts.[7] Therefore,
the aza-styryllactones 6 and 7 would be accessible from the
trans and cis Heck adducts 13a and 13b using distinct
routes, whereas aza-goniothalesdiol analogues could be ob-
tained from both routes.
Scheme 1. Synthesis of (–)-isoaltholactone.
Given the biological importance of this class of com-
pounds and the synthesis of analogues, we report herein the
synthesis of the nitrogen analogue of isoaltholactone, aza-
isoaltholactone 6, as well as studies towards the synthesis
of other aza analogues 7 and 8 (Figure 2). It should be
noted that, to the best of our knowledge, this is the first
Scheme 2. Synthetic plan.
In our synthetic plan the pyranone ring of the aza-isoal-
tholactone 6 would be obtained by lactonization after de-
protection of acetonide 9 (Scheme 2). On the other hand,
the pyranone ring of aza-altholactone 7 would be obtained
from 10 in a more challenging manner involving a selective
ester hydrolysis with concomitant intramolecular epoxide
opening. In both routes, Z-α,β-unsaturated esters 9 and 10
would be generated by HWE olefination of the transient
aldehydes produced by the oxidation of alcohols 11 and 12.
Diol 11 should be easily accessible from the trans Heck ad-
duct 13a by dihydroxylation, whereas epoxidation of the cis
isomer 13b should provide the anti epoxide 12. The arylated
Figure 2. Aza-styryllactones and aza analogue of goniothalesdiol.
7260
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7259–7270

Aza Analogues of Isoaltholactone and Goniothalesdiol
3-pyrrolines 14 can be obtained by a Heck reaction between Table 1. Conditions for attempted Heck arylation of 15.
benzenediazonium tetrafluoroborate and the chiral endo-
cyclic enecarbamate 15 (synthesized from l-pyroglutamic
acid). Completing the synthetic strategy, the aza-gonio-
thalesdiol analogues could be synthesized from unsaturated
Entry Cat. (mol-%)
Solvent Equiv. PhN2BF4 T [°C]
esters 9 and/or 10.
1
2
3
4
5
6
7
8
9
Pd2(dba)3 (2)
Pd2(dba)3 (4)
Pd2(dba)3 (4)
Pd2(dba)3 (4)
Pd2(dba)3 (4)
Pd2(dba)3 (4)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2/CO (10)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeOH
MeOH
MeCN
1
1
0.85
1.5
1
1
1
25
25
25
25
40
50
25
40
25
Results and Discussion
Heck–Matsuda Arylation of Endocyclic Enecarbamates
The palladium-catalyzed Heck–Matsuda reaction of ar-
enediazonium salts with different olefins has been an im-
portant tool in the synthesis of natural products and biolo-
gically important compounds.[8,9] Arenediazonium salts of-
fer several advantages over the more conventionally em-
ployed aryl halides; arylations are usually milder, easier to
manipulate, faster, and more economic.[10] Even more im-
portant is the fact that they undergo an extremely facile
oxidative addition with Pd0, operating under ligand-free
conditions, to generate a highly reactive cationic ArPdII
species.[11]
The Heck–Matsuda arylation of endocyclic enecarb-
amates with arenediazonium salts has been studied exten-
sively by our group.[7] However, the specific arylation of ole-
fin 15 with benzenediazonium tetrafluoroborate has not
been previously performed. In analogy to the synthesis of
1
1
Scheme 4. Attempted arylation of 16.
this reaction, and the results seemed to indicate that aryl-
ation is highly dependent on the substituent on the arenedi-
azonium salt and on the nature of the group at C-5 on the
enecarbamate. Arylation of 16 was only feasible with salts
bearing electron-donating substituents (Table 2).
isoaltholactone, this was the olefin of choice for the synthe- Table 2. Heck–Matsuda arylation of 16 with 17a–f.
sis of the aza analogues (Scheme 3). Surprisingly, when the
conditions described above [Pd2(dba)3, sodium acetate in
acetonitrile] were applied to enecarbamate 15, the expected
Heck adduct 14 was not obtained, and olefin 15 was reco-
vered almost quantitatively.
Entry
R
trans/cis
Yield [%]
1
2
3
4
5
6
H (17a)
–
48:52
40:60
–
–
–
–
95
80
–
–
–
OMe (17b)
NHCO2Me (17c)
Cl (17d)
Br (17e)
NO2 (17f)
Scheme 3. Unsuccessful Heck–Matsuda arylation.
Faced with this intriguing outcome, other experiments
were designed to arylate the endocyclic enecarbamate 15
Given the unexpected behavior of 15 and 16 with
with benzenediazonium tetrafluoroborate. Changes in the benzenediazonium tetrafluoroborate, we decided to replace
nature of the catalyst, temperature, and ratio of olefin to these with enecarbamate 18 containing an ester group at C-
arenediazonium salts were all evaluated (Table 1). Initially 5 (Scheme 5). Enecarbamate 18 was then subjected to the
the amount of palladium catalyst was doubled, but again Heck reaction with benzenediazonium tetrafluoroborate
there was no consumption of 15. Different ratios of the re- under Pd2(dba)3 catalysis, as described previously.[7] Grati-
actants, the use of other palladium catalysts, and changes fyingly, Heck arylation occurred rapidly, which provided
in the temperature proved fruitless.
Heck product 19 in 85% yield in a diastereoisomeric ratio
Aiming to remove any potential steric interference, the of 55:45 (cis:trans), evaluated by gas chromatography. As it
silicon protecting group of 15 was removed to yield the hy- was not possible to separate the stereoisomers by column
droxy enecarbamate 16 (Scheme 4). Attempts to arylate 16 chromatography, they were reduced to the corresponding
led to the recovery of the starting material.
alcohols by treatment with sodium borohydride in the pres-
These results were even more intriguing when compared ence of calcium chloride. At this stage we could efficiently
to the successful arylation of 16 with arenediazonium salts separate the two stereoisomers by flash chromatography.
17b and 17c as previously reported (Table 2).[7] In view of The trans adduct 13a was obtained in 37% isolated yield,
these surprising results, we briefly evaluated the scope of and cis adduct 13b in 45% yield.
Eur. J. Org. Chem. 2011, 7259–7270
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7261

A. V. Moro, M. Rodrigues dos Santos, C. R. D. Correia
FULL PAPER
Figure 3. Two plausible rationalizations for stereoselective dihy-
droxylation.
Scheme 5. Heck–Matsuda arylation of 18.
The exclusive formation of the five-membered ring was
unambiguously confirmed by 13C NMR spectroscopy,
where the methyl groups of 20 are observed at 24.7 and
26.1 ppm (six-membered ring acetonides display chemical
shifts for the methyl groups at approximately 19 and
25 ppm).[13] The difference in chemical shifts between the
two methyl groups is due to stereoeletronic effects, which
are more prevalent in a six-membered ring.
The hydroxy acetonide 20 was oxidized to its corre-
sponding aldehyde with catalytic amounts of tetrapro-
pylammonium perruthenate (TPAP) in the presence of
NMO (Scheme 7).[14] The oxidation reaction occurred
rapidly and cleanly at room temperature. Therefore, simple
filtration through a short pad of silica gel followed by re-
moval of the solvent allowed the product to be used directly
in the next step. The intermediate aldehyde was then sub-
jected to a HWE olefination reaction, using Ando’s phos-
phonate 21.[15] This was the reagent of choice as it provides
high stereoselectivity favoring the Z isomer. Olefination was
performed, using sodium hydride as the base, to generate
the desired Z-α,β-unsaturated ester 9 in 70% yield (Z:E ra-
tio of 6:1) over two steps.
From this point on, each stereoisomer was treated sepa-
rately in the synthesis of the corresponding aza-styryllac-
tones. The trans isomer 13a was used for the synthesis of
aza-isoaltholactone 6, and the cis isomer 13b was used for
the synthesis of aza-altholactone 7.
The reasons for the effectiveness of the Heck–Matsuda
reaction towards 18 seem to be related to the coordinating
power of the nearby carbonyl group and the nature of the
reactive cationic arylpalladium intermediate. A more de-
tailed investigation of the mechanism of these arylation re-
actions is underway.
Synthesis of Aza-isoaltholactone 6
With the trans isomer 13a in hand, it was dihydroxylated
using catalytic amounts of potassium osmate (K2OsO4) and
N-methylmorpholine N-oxide (NMO) as cooxidants in a
ternary mixture of solvents (water, acetone, and tert-butyl
alcohol, Scheme 6). The corresponding diol was obtained
with high yield and purity and was used in the next step
without further purification. The diol was protected as an
acetonide using 2,2-dimethoxypropane (2,2-DMP) and
catalytic amounts of p-toluenesulfonic acid (p-TSA) in
acetone. Under these conditions the five-membered acet-
onide 20 was selectively obtained in 87% yield over two
steps.
Scheme 7. Oxidation with TPAP followed by HWE olefination.
To obtain aza-isoaltholactone 6, the ester acetonide 9
was treated with trifluoroacetic acid (TFA) in water under
the same conditions previously described for the synthesis of
(–)-isoaltholactone (Scheme 8).[6] However, under these
conditions the starting material was completely consumed,
but no formation of the expected unsaturated lactone 6 was
observed. Treatment of 9 with a catalytic amount of p-TSA
Scheme 6. Dihydroxylation and protection reactions.
The stereoselectivity observed for the dihydroxylation re- in methanol and subsequent use of ultrasound in benzene
action is in agreement with previous reports.[12] It is be- resulted in 6 in low yield, together with several byproducts.
lieved to be controlled by the steric hindrance of the phenyl
We then decided to subject 9 to an alternative protocol
group combined with the coordinating effect of the primary for the removal of the protecting groups and formation of
hydroxyl group to the osmium reagent. This interaction the lactone (Scheme 9). Therefore, initial treatment of 9
probably occurs through a hydrogen bond (A) or by a direct with a catalytic amount of p-TSA in methanol under micro-
interaction of the oxygen with the osmium atom (B), which wave irradiation (60 °C for 30 min) resulted in the removal
leads to the selective formation of the cis triol. These two of the acetonide and lactonization. Subsequently, another
plausible rationalizations are shown in Figure 3.
microwave-assisted reaction (60 °C for 1 h) using 5 equiv. of
7262
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7259–7270

Aza Analogues of Isoaltholactone and Goniothalesdiol
Scheme 8. Deprotection and lactonization of 9.
p-TSA in acetonitrile led to the removal of the Boc group.
Neutralization of the salt with triethylamine led to aza-
isoaltholactone 6 in 64% yield over three steps.
Scheme 11. Stereochemical model for epoxidation.
be prevented, which should lead to oxidant approach from
the least hindered face of the double bond. Epoxidation of
the intermediate silyloxy compound with mCPBA provided
epoxide 22 in 70% isolated yield.
Scheme 9. Completion of the synthesis of 6.
Attempted Synthesis of Aza-altholactone 7
Scheme 12. Synthesis of 22.
As presented in the synthetic plan, the strategy for the
synthesis of aza-altholactone 7 should start from the cis
diastereoisomer generated in the Heck reaction. Therefore,
13b was oxidized with m-chloroperoxybenzoic acid
(mCPBA) in toluene to furnish epoxide 12 in a moderate
53% yield (Scheme 10). An alternative method employing
dimethyldioxirane as the epoxidation agent was also tested
and proved equally effective (60% yield). Dimethyldioxir-
ane was generated in situ from the reaction between
OXONE® and acetone in the presence of an aqueous buffer
solution of NaHCO3.[16]
As expected, deprotection of 22 with tetrabutylammo-
nium fluoride (TBAF) in THF gave the epoxy alcohol 12
previously prepared from 13b. This result confirms our ini-
tial assumption that substrate control during epoxidation is
prevented in the case of the cis alcohol 13b.
With the desired epoxide 12 in hand, it was subjected to
oxidation to aldehyde 23 (Scheme 13) using standard pro-
cedures. To our surprise, Swern oxidation [oxalyl chloride,
dimethyl sulfoxide (DMSO), and triethylamine in dichloro-
methane][17] did not provide the desired aldehyde 23, but 2-
formylpyrrole 24 in a typical overoxidation reaction.
Attempts to minimize pyrrole formation by conducting the
reaction in shorter times were unsuccessful.
Scheme 10. Epoxidation of 13b.
There are several precedents for epoxidations directed by
coordinating neighboring groups.[12] However, in our case,
hydrogen bond coordination of the hydroxy group with the
epoxidation agent might be easily disrupted or prevented
because of steric congestion by the phenyl group cis to the
hydroxymethyl group (Scheme 11).
Scheme 13. Proof of the stereochemistry of 12.
In order to verify this hypothesis, 13b was treated with
tert-butyldimethylsilyl chloride (TBSCl) in the presence of
Bearing in mind the successful oxidation of alcohol 20
imidazole in dichloromethane to yield the corresponding during the synthesis of aza-isoaltholactone 6 employing
silyloxy derivative in 87% yield (Scheme 12). Coordination TPAP,[14] we also tested this mild reagent for the oxidation
of this silyloxy substrate with the epoxidation agent should of 12 (Scheme 14). Unfortunately, even after 12 hours, the
Eur. J. Org. Chem. 2011, 7259–7270
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7263

A. V. Moro, M. Rodrigues dos Santos, C. R. D. Correia
FULL PAPER
formation of the desired aldehyde 23 was not observed. material was observed, even after long reaction times. TPAP
Other oxidants such py·SO3/DMSO,[18] PCC/NaOAc,[19] oxidation of 26 under microwave irradiation (300 W,
and 2-iodoxybenzoic acid[20] were also examined but all 30 min, 70 °C) was also unsuccessful.
attempts proved fruitless. With the Dess–Martin
periodinane (DMP)[21] the starting material 12 was quickly
consumed, however, a complex mixture of unidentified
products was obtained.
Scheme 16. Attempted oxidation of 26.
As oxidation of the primary alcohol could not be
achieved by the above approach, we chose another pathway
for the preparation of aldehyde 30. The desired aldehyde
Scheme 14. Attempted oxidation of 12.
could, in principle, be achieved by controlled reduction of
the ester 31b with diisobutylaluminium hydride (DIBAL-
H) at low temperature (Scheme 17).
In view of these surprising and disappointing results, a
new approach was evaluated (Scheme 15). In this revised
strategy we planned the diastereoselective synthesis of triol
25 from cis alcohol 13b, and regioselective protection of the
secondary hydroxy groups of 25 in the form of acetonide
26 followed by oxidation of the primary alcohol, thus avoid-
ing the aromatization problems encountered in previous
oxidation attempts. The aldehyde formed would be sub-
jected to HWE olefination, and the ester 27 hydrolyzed to
Scheme 17. Revised strategy for the synthesis of 30.
the corresponding carboxylic acid. The acetonide protect-
ing group would be removed and an intramolecular Mitsu-
nobu reaction would lead to the desired six-membered lac-
tone 29.
The methylester 31b was obtained in two steps starting
from the mixture of diastereoisomers 19 obtained from the
Heck reaction. Initially, the mixture of stereoisomers 19a/
19b was dihydroxylated affording the corresponding dia-
Scheme 15. New synthetic plan.
Putting this plan into practice, 25 was obtained in an
efficient and selective manner using catalytic amounts of
potassium osmate in the presence of NMO (83% yield)
(Scheme 16). Acetalization of 25 occurred uneventfully
using 2,2-DMP in acetone, in the presence of p-TSA to fur-
nish acetonide 26 in 80% yield. Intriguingly, alcohol 26 also
proved very resistant to oxidation to aldehyde 30 (DMP,
TPAP, and PCC). In all cases, no consumption of starting Scheme 18. Preparation of 32a and 32b.
7264 Eur. J. Org. Chem. 2011, 7259–7270
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Aza Analogues of Isoaltholactone and Goniothalesdiol
stereoisomeric mixture of diols 32a and 32b in 83% yield
After olefination, 27 was treated with catalytic amounts
(Scheme 18). As chromatographic separation was difficult of p-TSA in methanol, for the removal of the acetonide,
at this stage, the mixture of 32a/32b was used in the next and the α,β-unsaturated ester was hydrolyzed to the corre-
step.
sponding carboxylic acid 28 by treatment with a 1 m solu-
The mixture of 32a/32b was converted into the corre- tion of sodium hydroxide (52% yield over two steps). The
sponding diastereomeric acetonides 31a/31b in 64% yield ester diol 28 constitutes an acyclic analogue of aza-altholac-
(Scheme 19), which were separated by flash chromatog- tone 7, except for the stereochemistry at C-3.
raphy.
To form the lactone moiety and invert the stereochemis-
try at C-3, an intramolecular Mitsunobu reaction was per-
formed (Scheme 21).[23] Unfortunately, treatment of 28 with
triphenylphosphane and diethyl azodicarboxylate (DEAD)
resulted in no consumption of the starting material. It is
worth mentioning that at the end of all the attempted cycli-
zations, the DEAD reduction product, diethyl hydrazine-
1,2-dicarboxylate, was isolated, which indicated that the in-
termediate generated in situ by the reaction of PPh3 with
DEAD was formed.
Scheme 19. Preparation and separation of 31a and 31b.
Scheme 21. The intramolecular Mitsunobu reaction.
The next step involved reduction of 31b in a controlled
manner to aldehyde 30 (Scheme 20). This reaction was suc-
cessfully performed by slow and cautious addition of DI-
BAL-H to a solution of 31b in dichloromethane at –80 °C.
Gratifyingly, the reduction occurred cleanly providing 30,
which was immediately used in HWE olefination using
21.[15] The desired α,β-unsaturated ester 27 was obtained in
a Z:E ratio of 5:1 in 60% yield from 31b. The synthesis
of 30 by reduction of 31b circumvented one of the biggest
problems faced so far: the oxidation step, and even removed
a synthetic step. In spite of not being carried out in this
work, the trans ester 31a may also be subjected to same
reduction with DIBAL-H, followed by HWE olefination to
give intermediate 9, which was used for the synthesis of aza-
isoaltholactone 6.
Synthesis of an Aza Analogue of Goniothalesdiol
As the last step in the assembly of the lactone moiety
still requires further studies, we focused our attention on
the synthesis of aza analogues of related styryllactones with
a linear side chain connected to the THF ring instead of a
lactone group. In particular, one compound that caught our
attention was goniothalesdiol (Figure 4).[24] This natural
product exhibits significant cytotoxicity against P388 leuke-
mia cells, as well as pronounced insecticidal activity. In view
of its important biological profile and the absence of any
nitrogen-containing analogue in the literature, we decided
to direct our studies to the synthesis of pyrrolidine 33, tak-
ing advantage of the advanced intermediate 27 synthesized
as described above.
Figure 4. Goniothalesdiol and 33.
Thus, unsaturated ester 27 was cleanly hydrogenated un-
der a hydrogen atmosphere in the presence of Pd(OH)2/C,
which led to the saturated ester 34 (Scheme 22). To con-
clude the synthesis of pyrrolidine 33, the acetonide and Boc
protecting groups were removed in acidic media under mi-
crowave irradiation. The epi-aza analogue of goniothales-
diol 33 was thus obtained in 59% yield over four steps.
Scheme 20. Synthesis of 28.
Eur. J. Org. Chem. 2011, 7259–7270
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7265

A. V. Moro, M. Rodrigues dos Santos, C. R. D. Correia
FULL PAPER
silica gel GF254, 0.25 mm thickness. For visualization, TLC plates
were either placed under ultraviolet light or developed with phos-
phomolibdic acid followed by heating. Air- and moisture-sensitive
reactions were conducted in flame- or oven-dried glassware
equipped with tightly fitting rubber septa under a positive atmo-
sphere of dry argon. Reagents and solvents were handled using
standard syringe techniques.
Procedure for the Heck Arylation of 18 with Benzenediazonium Tet-
rafluoroborate. Synthesis of 19: To a round-bottomed flask (or a
test tube) were added 18 (1.13 g, 5 mmol) and acetonitrile (23 mL).
To the resulting suspension were added Pd2(dba)3·dba (4 mol-%,
200 mg), sodium acetate (3 equiv., 15 mmol, 1.6 g) and the
benzenediazonium salt (1.3 equiv., 6.5 mmol). The reaction was
stirred at room temperature, and the reaction progress was moni-
tored by the evolution of N2. After the nitrogen bubbling had
stopped, the crude reaction mixture was filtered through a plug of
silica and concentrated under reduced pressure. The product was
purified by flash chromatography (hexane/ethyl acetate as eluent)
to provide 19 in 85% yield (1.28 g), as an inseparable mixture of
diastereoisomers, which was used directly in the next step.
Scheme 22. Synthesis of 33.
Conclusions
We have described new synthetic applications of the
Heck–Matsuda arylation involving chiral, nonracemic, en-
docyclic enecarbamates and arenediazonium salts. This
method permitted the stereoselective synthesis of (–)-aza-
isoaltholactone 6 and the stereoselective syntheses of two
new highly substituted dihydroxypyrrolidines (–)-28 and
(+)-33. The latter compounds constitute optically active
epi-aza analogues of altholactone and goniothalesdiol. The
strategy relied on a divergent approach to illustrate the fea-
sibility and synthetic potential of the stereoisomers ob-
tained by an efficient Heck–Matsuda reaction of the chiral
endocyclic enecarbamate 18 with benzenediazonium tetra-
fluoroborate. The lack of reactivity displayed by endocyclic
enecarbamates 15 and 16 towards benzenediazonium tetra-
fluoroborate was intriguing, and further studies are in pro-
gress to understand the basis for these unusual results.
Procedure for the Reduction of Heck Adducts. Synthesis of 13a and
13b: In a flask under an argon atmosphere, a solution of 19 (0.53 g,
1.74 mmol) in THF (5 mL) and ethanol (10 mL) was prepared. Dry
CaCl2 (0.56 g, 5.1 mmol) was added and, after complete dissolution
of CaCl2, NaBH4 (0.46 g, 12 mmol) was introduced. The mixture
was stirred at room temperature for 3 h before a solution of 2 m
K2CO3 (12 mL) was added. Soon after, saturated NaHCO3 (12 mL)
was added and the organic phase was extracted into ethyl acetate
(3ϫ20 mL). The organic phases were dried with MgSO4 and fil-
tered, and the solvent was removed under reduced pressure. The
crude product was purified by flash chromatography using hexane/
ethyl acetate (70:30) as eluent, providing the trans diastereoisomer
13a in 37% yield (0.176 g) and the cis product 13b in 45% yield
(0.214 g).
tert-Butyl (2S,5S)-2-(Hydroxymethyl)-5-phenyl-2,5-dihydro-1H-pyr-
role-1-carboxylate (13a): [α]2D0 = –203.4 (c = 1.14, AcOEt). 1H
NMR (250 MHz, CDCl3): δ = 1.13 (s, 6 H), 1.26 (s, 4 H), 3.72 (dd,
J1 = 11.8, J2 = 6.5 Hz, 1 H), 3.91 (dd, J1 = 11.8, J2 = 1.8 Hz, 1
H), 5.00–5.06 (m, 1 H), 5.37–5.41 (m, 1 H), 5.68 (dt, J1 = 6.3, J2
= 1.8 Hz, 1 H), 5.76 (dt, J1 = 6.3, J2 = 2.0 Hz, 1 H), 7.14–7.35 (m,
5 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 27.9, 67.2, 68.7,
69.5, 80.6, 125.5, 126.5, 127.4, 128.3, 132.2, 142.0, 155.9 ppm. IR
Experimental Section
Materials and Methods: 1H NMR spectra were obtained at 250 and
500 MHz. Spectra were recorded in CDCl3, CD3CN, and CD3OD
solutions. Chemical shifts are reported in ppm and referenced to
the residual solvent peak or tetramethylsilane. Data are reported
as follows: chemical shift (δ), multiplicity, coupling constant (J) in
Hertz and integrated intensity. 13C NMR spectra were obtained at
62.5 MHz and 125 MHz. Chemical shifts are reported in ppm and
referenced to the residual solvent peak. Abbreviations to denote
the multiplicity of a particular signal are s (singlet), br. s (broad
singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), dt
(double triplet), td (triple doublet), ddd (double double doublet)
and m (multiplet). Microwave reactions were conducted with a
CEM Discover® Microwave synthesizer. The machine consists of a
continuous focused microwave power delivery system with se-
lectable power output from 0–300 W. Reactions were performed in
glass vessels (capacity 10 mL) sealed with a septum. Temperature
measurements were conducted using an infrared temperature sen-
sor mounted under the reaction vessel. All experiments were per-
formed with a stirring. All experiments were carried out with simul-
taneous cooling by passing compressed air through the microwave
cavity while heating (option PowerMAX enabled). Column
chromatography was performed with silica gel (230–400 mesh) fol-
lowing the methods described by Still. TLC was performed with
(film): ν = 3349, 2975, 2930, 1656, 1411, 1135 cm–1. MS (EI): m/z
˜
= 276 [M + 1]+, 244, 188, 144, 115, 57.
tert-Butyl (2S,5R)-2-(Hydroxymethyl)-5-phenyl-2,5-dihydro-1H-pyr-
role-1-carboxylate (13b): [α]2D0 = +76.1 (c = 1.0, AcOEt). H NMR
1
(250 MHz, CDCl3): δ = 1.31 (s, 9 H), 3.75–3.97 (m, 2 H), 4.85 (d,
J = 8.5 Hz, 1 H), 5.04 (d, J = 8.5 Hz, 1 H), 5.47 (s, 1 H), 5.69–5.76
(m, 2 H), 7.24–7.37 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 28.1, 68.1, 68.5, 69.7, 81.1, 125.4, 127.0, 127.5, 128.3, 131.5,
141.1, 156.8 ppm. IR (film): ν = 3418, 2976, 1696, 1669, 1394, 1367,
˜
1170 cm–1. MS (EI): m/z = 275, 244, 188, 144, 57.
tert-Butyl (3aS,4R,6R,6aR)-4-(Hydroxymethyl)-2,2-dimethyl-6-phen-
yldihydro-3aH-[1,3]dioxolo[4,5-c]pyrrole-5(4H)-carboxylate
(20).
First Step: Olefin 13a (0.2 g, 0.727 mmol) was dissolved in mixture
of H2O/acetone/tBuOH (6:3:1, 2.5 mL) and N-methylmorpholine
N-oxide monohydrate (0.28 g, 2.07 mmol) was added.
K2OsO4·2H2O (0.015 g, 0.04 mmol) was introduced and the reac-
tion mixture was stirred at room temperature for 12 h. After this
time, a saturated aqueous solution of NaHSO3 was added and the
mixture was stirred for 30 min. The aqueous phase was extracted
into ethyl acetate and the organic phase was dried with anhydrous
7266
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7259–7270

Aza Analogues of Isoaltholactone and Goniothalesdiol
Na2SO4, filtered, and the solvents removed under reduced pressure.
Purification was performed by flash chromatography using hexane/
ethyl acetate (20:80) as eluent providing the desired triol.
(0.5 mL) was added and the solvent was removed. Purification by
flash chromatography eluting with ethyl acetate (triethylamine was
used to dope the column) provided 6 in 64% yield for the three
steps (0.016 g). [α]2D0 = –31 (c = 0.53, MeOH). 1H NMR (500 MHz,
CD3CN): δ = 4.02 (d, J = 7.5 Hz, 1 H), 4.10 (t, J = 6.5 Hz, 1 H),
4.17 (ddd, J1 = 6.0, J2 = 4.5, J3 = 1.5 Hz, 1 H), 4.93 (t, J = 6.0 Hz,
1 H), 6.02 (dd, J1 = 10.0, J2 = 1.5 Hz, 1 H), 6.83 (dd, J1 = 10.0, J1
= 4.0 Hz, 1 H), 7.20–7.46 (m, 5 H) ppm. 13C NMR (125 MHz,
CD3CN): δ = 50.5, 66.3, 78.7, 79.6, 121.0, 127.1, 127.6, 128.7,
Second Step: In a flask under an argon atmosphere, was prepared
a solution of the triol (0.218 g, 0.62 mmol), p-TSA (0.01 g,
0.053 mmol), and 2,2-DMP (2.5 mL) in dry acetone (5 mL). The
reaction mixture was stirred for 1 h. After this time, the reaction
was quenched with a saturated aqueous solution of NaHCO3 and
extracted into ethyl acetate. The organic phase was washed with
aqueous saturated NaCl, dried with anhydrous Na2SO4, filtered,
and concentrated under vacuum. Purification by flash chromatog-
raphy eluting with a mixture of hexane/ethyl acetate afforded 20 in
87% yield for the two steps (0.189 g). [α]2D0 = –43 (c = 1.0, MeOH).
1H NMR (250 MHz, CDCl3): δ = 1.19 (s, 9 H), 1.30 (s, 3 H), 1.52
(s, 3 H), 3.87–4.05 (m, 2 H), 4.10–4.20 (m, 1 H), 4.55 (dd, J1 = 6.0,
J2 = 1.0 Hz, 1 H), 4.86 (t, J = 6.0 Hz, 1 H), 4.99 (s, 1 H), 7.05–
7.45 (m, 5 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 24.7, 26.1,
27.9, 62.9, 65.5, 68.2, 79.9, 80.9, 85.2, 111.8, 125.6, 127.5, 128.8,
142.1, 146.4, 162.5 ppm. IR (KBr): ν = 3415, 3252, 2959, 2928,
˜
2856, 1728, 1458, 1381, 1270, 1123, 1073 cm–1. HRMS (ESI): calcd.
for C13H13NO3 [M + H+] 232.0974; found 232.0960.
tert-Butyl (1R,2R,4S,5S)-2-(Hydroxymethyl)-4-phenyl-6-oxa-3-aza-
bicyclo[3.1.0]hexane-3-carboxylate (12). Condition i: To a solution
of 13b (0.055 g, 0.2 mmol) in toluene (2.5 mL) was added mCPBA,
and the mixture was stirred at room temperature for 24 h. A satu-
rated solution of sodium bisulfide (5 mL) was added, and the mix-
ture was stirred for 30 min. The aqueous phase was extracted into
ethyl acetate (5 mL), and the organic phases were dried with
Na2SO4, filtered, and the solvents were removed under reduced
pressure. Purification by flash chromatography using as eluent hex-
ane/ethyl acetate (60:40) provided 12 in 53% yield (0.031 g).
140.8, 156.3 ppm. IR (film): ν = 1054, 1136, 1165, 1213, 1243, 1366,
˜
1398, 1453, 1675, 2936, 2980, 3425 cm–1. HRMS (ESI): calcd. for
C19H27NO5 [M + H+] 350.1967; found 350.1967.
tert-Butyl (3aS,4R,6R,6aR)-4-[(Z)-3-Ethoxy-3-oxoprop-1-enyl]-2,2-
dimethyl-6-phenyldihydro-3aH-[1,3]dioxolo[4,5-c]pyrrole-5(4H)-carb-
oxylate (9). First Step: In a flask under an argon atmosphere, 20
(0.027 g, 0.078 mmol) was dissolved in dry dichloromethane
(1.5 mL) containing finely macerated molecular sieves (40 mg) and
NMO (0.017 g, 0.126 mmol). The reaction mixture was stirred for
10 min before TPAP (5 mol-%) was added. The reaction was kept
at room temperature for 20 min and then filtered through a short
column of silica using ethyl acetate as eluent. The filtrate was evap-
orated under reduced pressure, and the aldehyde obtained was used
in the next step without further purification.
Condition ii: Compound 13b (0.041 g, 0.15 mmol) dissolved in acet-
one (2.5 mL) was cooled to 0 °C and an aqueous solution of
NaHCO3 (0.24 g in 1 mL of H2O, 2.8 mmol) was added. A solution
of Oxone® in water (0.48 g in 1.6 mL of H2O, 1.6 mmol) was added
and the reaction was kept at 0 °C for 3 h. The reaction was left at
room temperature for 2 h and a saturated solution of sodium chlor-
ide (5 mL) was added. The aqueous phase was extracted into ethyl
acetate (5 mL), and the combined organic phases were dried with
Na2SO4, filtered, and the solvents removed under reduced pressure.
Purification by flash chromatography using as eluent hexane/ethyl
acetate (60:40) provided 12 in 60% yield (0.034 g). [α]2D0 = +19.7 (c
Second Step: In a flask under an argon atmosphere, a suspension
of sodium hydride (0.004 g, 60% dispersion in mineral oil) in dry
THF (0.5 mL) was prepared at 0 °C. Then, 21 (0.035 g,
0.105 mmol) diluted in dry THF (0.5 mL) was added. The reaction
mixture was stirred for 15 min before a solution of the aldehyde
prepared in the first step in dry THF (0.5 mL) was added, and the
reaction was stirred for 1 h. The reaction mixture was then treated
with aqueous saturated ammonium chloride and extracted into
ethyl ether. The solvent was removed under reduced pressure, and
purification by flash chromatography eluting with a mixture of hex-
ane/ethyl acetate (70:30) provided 9 in 70% yield for the two steps
(0.023 g). [α]2D0 = –90 (c = 1.0, CHCl3). 1H NMR (250 MHz,
CDCl3): δ = 1.15 (s, 9 H), 1.26–1.33 (m, 6 H), 1.52 (s, 3 H), 4.18
(q, J = 7.0 Hz, 2 H), 4.61 (d, J = 5.7 Hz, 1 H), 5.01 (s, 1 H), 5.14
(t, J = 6.0 Hz, 1 H), 5.76 (t, J = 6.2 Hz, 1 H), 5.96 (d, J = 11.5 Hz,
1 H), 6.35 (dd, J1 = 11.5, J2 = 7.25 Hz, 1 H), 7.10–7.40 (m, 5 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 14.5, 25.0, 26.5, 28.2, 60.3,
61.4, 68.1, 80.3, 80.5, 86.1, 112.0, 118.8, 126.1, 127.7, 128.9, 141.4,
1
= 0.8, EtOAc). H NMR (250 MHz, CDCl3) presence of rotamers:
δ = 1.30 (s, 7 H), 1.46 (s, 2 H), 2.55 (br. s, 1 H), 3.63 (br. s, 1.6 H),
3.72–3.85 (m, 0.6 H), 3.88–3.91 (m, 1.8 H), 4.21 (t, J = 5.8 Hz, 0.2
H), 4.36 (t, J = 5.5 Hz, 0.8 H), 5.05 (s, 0.8 H), 5.20 (s, 0.2 H),
7.28–7.41 (m, 5 H) ppm. 13C NMR (125 MHz, CDCl3) presence of
rotamers: δ = 28.2, 28.4, 57.4, 58.1, 59.4, 60.2, 61.1, 61.3, 61.9,
62.8, 62.9, 63.9, 80.9, 81.3, 126.6, 126.8, 127.8, 127.9, 128.7, 128.8,
137.9, 138.0, 154.9, 156.7 ppm. 1H NMR (500 MHz, CD3CN) pres-
ence of rotamers: δ = 1.29 (s, 4.5 H), 1.43 (s, 4.5 H), 3.18 (t, J =
5.5 Hz, 0.5 H), 3.41 (t, J = 5.5 Hz, 0.5 H), 3.53–3.67 (m, 1.5 H),
3.75–3.86 (m, 1.5 H), 4.04 (dd, J1 = 8.3, J2 = 4.0 Hz, 0.5 H), 4.09
(dd, J1 = 7.3, J2 = 5.5 Hz, 0.5 H), 4.99 (s, 0.5 H), 5.02 (s, 0.5 H),
7.29–7.39 (m, 5 H) ppm. 13C NMR (125 MHz, CD3CN) presence
of rotamers: δ = 28.1, 28.2, 58.8, 59.5, 60.5, 61.2, 62.3, 62.4, 62.7,
62.8, 63.3, 63.9, 81.2, 81.4, 128.2, 128.3, 128.9, 129.0, 129.7, 129.8,
139.9, 140.0, 156.1, 156.7 ppm. 1H NMR (250 MHz, CD3CN,
70 °C) presence of rotamers: δ = 1.39 (s, 9 H), 3.10 (br. s, 1 H),
3.66–3.69 (m, 2 H), 3.77 (d, J = 2.8 Hz, 1 H), 3.82–3.89 (m, 1 H),
4.10–4.15 (m, 1 H), 5.04 (s, 1 H), 7.28–7.44 (m, 5 H) ppm. 13C
NMR (62.5 MHz, CD3CN, 70 °C) presence of rotamers: δ = 28.9,
59.1, 60.9, 62.6, 63.1, 63.9, 81.4, 128.3, 128.9, 130.0, 140.2,
149.3, 155.2, 166.6 ppm. IR (film): ν = 1171, 1373, 1465, 1652,
˜
1699, 1714, 2935, 2980 cm–1. HRMS (ESI): calcd. for C23H31NO6
[M + H+] 418.2230; found 418.2256.
(2R,3R,3aS,7aR)-3-Hydroxy-2-phenyl-1,2,3,3a-tetrahydropyrano-
[3,2-b]pyrrol-5(7aH)-one Aza-isoaltholactone (6): Into a flask con-
taining 9 (0.044 g, 0.106 mmol) was added a solution of p-TSA in
methanol (2 mL, 0.002 g/mL of p-TSA). This solution was transfer-
red to a microwave tube and reacted for 30 min at 60 °C under
microwave irradiation. The solvent was evaporated under reduced
pressure, and the crude reaction was dissolved in acetonitrile
(4 mL). p-TSA (0.1 g, 0.53 mmol) was added, and the mixture was
heated at 60 °C for 1 h under microwave irradiation. Triethylamine
156.7 ppm. IR (film): ν = 3433, 2977, 1694, 1674, 1415, 1368, 1169
˜
cm–1. EM (EI): m/z = 292 [M + 1]+, 248, 160, 142, 75, 57. HRMS
(ESI): calcd. for C16H21NO4 [M + Na]+ 314.1368; found 314.1320.
tert-Butyl (2S,5R)-2-[(tert-Butyldimethylsilyloxy)methyl]-5-phenyl-
2,5-dihydro-1H-pyrrole-1-carboxylate: To a flask under an argon at-
mosphere were added 13b (0.378 g, 1.37 mmol) and dry dichloro-
methane (5.5 mL) followed by imidazole (0.128 g, 1.91 mmol) and
tert-butyldimethylsilyl chloride (0.24 g, 1.63 mmol), which formed
Eur. J. Org. Chem. 2011, 7259–7270
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7267

A. V. Moro, M. Rodrigues dos Santos, C. R. D. Correia
FULL PAPER
a white suspension. The mixture was stirred for 12 h at room tem-
perature. The organic phase was washed with saturated ammonium
chloride (10 mL) and the aqueous phase extracted into dichloro-
methane (3ϫ15 mL). The organic phases were dried with MgSO4,
filtered, and the solvent was removed under reduced pressure. The
crude product was purified by flash chromatography using as elu-
ent hexane/ethyl acetate (95:05), which provided the protected
product in 87% yield (0.463 g). [α]2D0 = +28.8 (c = 1.58, AcOEt).
1H NMR (250 MHz, CDCl3) presence of rotamers: δ = 0.09 (s, 6
H), 0.92 (s, 9 H), 1.27 (s, 6 H), 1.46 (s, 3 H), 3.58 (t, J = 8.8 Hz,
0.4 H), 3.79 (t, J = 7.5 Hz, 0.6 H), 4.05–4.18 (m, 1 H), 4.56–4.65
(m, 1 H), 5.41 (br. s, 0.6 H), 5.57 (br. s, 0.4 H), 5.70–5.80 (m, 1 H),
5.96–5.98 (m, 1 H), 7.20–7.33 (m, 5 H) ppm. 13C NMR (62.5 MHz,
CDCl3) presence of rotamers: δ = –5.3, –5.2, 18.4, 28.2, 28.5, 29.7,
65.0, 66.2, 66.7, 68.9, 69.3, 79.7, 79.9, 127.1, 127.2, 127.3, 127.9,
ppm. 13C NMR (62.5 MHz, CD3OD, 57 °C): δ = 28.6, 63.4, 67.7,
68.5, 73.5, 79.9, 81.5, 127.5, 128.0, 129.3, 143.7, 157.7 ppm. IR
(film): ν = 3309, 1666, 1413, 1148, 1105 cm–1. EM (EI): m/z = 310
˜
[M
+
1]+, 254, 210. HRMS (ESI): calcd. for C16H23NO5
[M + H]+ 310.1654; found 310.1665.
tert-Butyl
(3aR,4R,6S,6aS)-4-(Hydroxymethyl)-2,2-dimethyl-6-
phenyldihydro-3aH-[1,3]dioxolo[4,5-c]pyrrole-5(4H)-carboxylate
(26): Under an argon atmosphere, was prepared a mixture of 25
(0.052 g, 0.17 mmol), anhydrous p-TSA (0.003 g, 0.017 mmol), and
2,2-DMP (0.73 mL) in dry acetone (1 mL) at room temperature.
After stirring for 12 h, a saturated solution of sodium hydrogen
carbonate (5 mL) was added, and the product extracted into ethyl
acetate (3ϫ5 mL). The organic phases were dried with Na2SO4,
filtered, and concentrated under reduced pressure. The crude prod-
uct was purified by flash chromatography using as eluent hexane/
ethyl acetate (50:50), which provided 26 in 80% yield (0.047 g).
128.2, 128.3, 130.3, 141.5, 142.2, 154.7 ppm. IR (film): ν = 3008,
˜
2967, 1741, 1372, 1222 cm–1. MS (EI): m/z = 389 [M]+, 276, 244,
[α]2D0 = –5 (c = 1.0, CHCl3). H NMR (250 MHz, CDCl3, 55 °C):
1
188, 144, 73, 57.
δ = 1.31 (s, 9 H), 1.33 (s, 3 H), 1.56 (s, 3 H), 3.72–3.85 (m, 2 H),
4.27 (td, J1 = 5.1, J2 = 2.0 Hz, 1 H), 4.52 (dd, J1 = 5.6, J2 = 2.0 Hz,
1 H), 4.62 (dd, J1 = 5.6, J2 = 2.0 Hz, 1 H), 5.04 (br. s, 1 H), 7.19–
7.35 (m, 5 H) ppm. 13C NMR (62.5 MHz, CDCl3, 55 °C): δ = 25.5,
27.5, 28.1, 64.5, 66.6, 68.8, 80.8, 81.6, 86.6, 112.2, 125.7, 127.2,
tert-Butyl (1R,2R,4S,5S)-2-[(tert-Butyldimethylsilyloxy)methyl]-4-
phenyl-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (22): To
a
solution of 13b (0.222 g, 0.57 mmol) in toluene (7 mL) was added
mCPBA (0.85 g, 2.8 mmol), and the reaction mixture was stirred at
room temperature for 24 h. A saturated solution of sodium bisulfite
(20 mL) was added, and the mixture was stirred for 30 min. The
aqueous phase was extracted into ethyl acetate (3ϫ20 mL), and the
organic phases were dried with Na2SO4, filtered, and the solvents
removed under reduced pressure. Purification by flash chromatog-
raphy using as eluent hexane/ethyl acetate (90:10) provided 22 in
70% yield (0.160 g). [α]2D0 = +17.2 (c = 1.56, AcOEt). 1H NMR
(250 MHz, CDCl3) presence of rotamers: δ = 0.09 (s, 3 H), 0.10 (s,
3 H), 0.89 (s, 5 H), 0.91 (s, 4 H), 1.29 (s, 5 H), 1.45 (s, 4 H), 3.56–
4.22 (m, 5 H), 4.99 (s, 0.5 H), 5.15 (s, 0.5 H), 7.25–7.39 (m, 5
H) ppm. 13C NMR (62.5 MHz, CDCl3) presence of rotamers: δ =
–5.45, –5.37, 18.2, 25.8, 28.2, 28.2, 58.4, 58.5, 59.4, 60.2, 60.5, 60.7,
62.0, 62.0, 62.5, 62.9, 80.1, 80.4, 126.7, 126.8, 127.5, 127.6, 128.4,
128.5, 141.1, 155.9 ppm. IR (film): ν = 3452, 1694, 1674, 1394 cm–1.
˜
EM (EI): m/z = 372 [M + Na]+, 316, 272. HRMS (ESI): calcd. for
C19H27NO5 [M + Na]+ 372.1787; found 372.1783.
Syntheses of 31a and 31b. First Step: To a solution of 19 (0.1 g,
0.33 mmol) in H2O/acetone/tBuOH (0.69:0.3:0.12 mL) was added
N-methylmorpholine N-oxide (0.116 g, 0.99 mmol) and K2OsO4
(0.013 g, 10 mol-%). The reaction mixture was stirred at room tem-
perature for 48 h. A saturated solution of sodium bisulfite (3 mL)
was added and the mixture was stirred for 30 min. The aqueous
phase was extracted into ethyl acetate (3ϫ5 mL), and the organic
phases were dried with Na2SO4, filtered, and the solvents removed
under reduced pressure. The crude product was purified by flash
chromatography using as eluent hexane/ethyl acetate (40:60), which
provided a mixture of 32 in 64% yield (0.071 g). As it was not
possible to efficiently separate the diastereoisomers by flash
chromatography, the mixture was used directly in next step.
128.6, 138.1, 138.7, 154.8 ppm. IR (film): ν = 3014, 2969, 2949,
˜
1738, 1367, 1228, 1216 cm–1. MS (EI): m/z = 306, 260, 248, 160,
142, 132, 73.
Second Step: Under an argon atmosphere was prepared a mixture
of 32 (0.071 g, 0.21 mmol), dry p-TSA (0.0038 g, 0.022 mmol), and
2,2-DMP (0.91 mL) in dry acetone (2 mL) at room temperature.
After stirring for 12 h, a saturated solution of sodium hydrogen
carbonate (5 mL) was added, and the product was extracted into
ethyl acetate (3ϫ10 mL). The organic phases were dried with
Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was purified by flash chromatography using as elu-
ent hexane/ethyl acetate (80:20). The two isomers were separated,
and 31b was obtained in 0.031 g with 31a in 0.017 g (64% yield for
the formation of two acetonides).
tert-Butyl (1R,2R,4S,5S)-2-(Hydroxymethyl)-4-phenyl-6-oxa-3-aza-
bicyclo[3.1.0]hexane-3-carboxylate (12): To
a solution of 22
(0.128 g, 0.32 mmol) in THF (2 mL) was added a 1.0 m solution of
TBAF in THF (0.38 mL, 0.38 mmol) at 0 °C. After 2 h at room
temperature, water (5 mL) was added, and the reaction mixture was
extracted into ethyl acetate (3ϫ5 mL). The organic phases were
dried with MgSO4, filtered, and the solvents removed under re-
duced pressure. Purification by flash chromatography using as elu-
ent hexane/ethyl acetate (60:40) provided 12 in 86% yield (0.079 g).
tert-Butyl (2R,3R,4S,5S)-3,4-Dihydroxy-2-(hydroxymethyl)-5-phen-
ylpyrrolidine-1-carboxylate (25): To 13b (0.057 g, 0.2 mmol) dis-
solved in H2O/acetone/tBuOH (0.42:0.18:0.07 mL) was added N-
methylmorpholine N-oxide (0.07 g, 0.6 mmol) and K2OsO4
(0.004 g, 5 mol-%). The reaction mixture was stirred at room tem-
perature for 48 h. A saturated solution of sodium bisulfite (3.0 mL)
was added, and the mixture was stirred for 30 min. The aqueous
phase was extracted into ethyl acetate (3ϫ5 mL), and organic
phases were dried with Na2SO4, filtered, and the solvents removed
under reduced pressure. The crude product was purified by flash
chromatography using as eluent hexane/ethyl acetate (20:80), which
provided 25 in 83% yield (0.052 g). [α]2D0 = –43 (c = 0.7, MeOH).
1H NMR (250 MHz, CD3OD, 57 °C): δ = 1.21 (s, 9 H), 3.77–3.90
(m, 3 H), 4.03 (dd, J1 = 6.3, J2 = 4.0 Hz, 1 H), 4.10 (dd, J1 = 4.1,
J2 = 2.5 Hz, 1 H), 4.55 (d, J = 6.3 Hz, 1 H), 7.17–7.37 (m, 5 H)
5-tert-Butyl 4-Methyl (3aS,4S,6R,6aR)-2,2-dimethyl-6-phenyldihy-
dro-3aH-[1,3]dioxolo[4,5-c]pyrrole-4,5(4H)-dicarboxylate (31a): 1H
NMR (250 MHz, CDCl3) presence of rotamers: δ = 1.13 (s, 6 H),
1.27 (s, 3 H), 1.37 (s, 3 H), 1.48 and 1.50 (2s, 3 H), 3.80 (s, 3 H),
4.57–4.62 (m, 1 H), 4.80 (d, J = 8.0 Hz, 0.45 H), 4.88 (d, J = 8.0 Hz,
0.55 H), 5.04–5.12 (m, 1 H), 5.14 (s, 0.55 H), 5.28 (s, 0.45 H), 7.10–
7.16 (m, 2 H), 7.27–7.38 (m, 3 H) ppm.
5-tert-Butyl 4-Methyl (3aR,4S,6S,6aS)-2,2-dimethyl-6-phenyldihy-
dro-3aH-[1,3]dioxolo[4,5-c]pyrrole-4,5(4H)-dicarboxylate (31b): 1H
NMR (250 MHz, CDCl3) presence of rotamers: δ = 1.22 and 1.40
(2s, 9 H), 1.32 (s, 3 H), 1.61 (s, 3 H), 3.82 (s, 3 H), 4.41–4.60 (m, 2
H), 4.80–4.83 (m, 1 H), 5.00 (br. s, 0.6 H), 5.17 (br. s, 0.4 H), 7.22–
7.38 (m, 3 H), 7.52 (d, J = 7.5 Hz, 2 H) ppm. 13C NMR (62.5 MHz,
7268
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7259–7270

Aza Analogues of Isoaltholactone and Goniothalesdiol
CDCl3) presence of rotamers: δ = 25.4, 27.5, 27.9, 52.5, 66.4, 67.1,
67.8, 80.7, 81.1, 81.8, 86.4, 86.9, 112.8, 126.2, 127.3, 128.4, 139.4,
140.3, 153.4, 153.9, 171.6 ppm.
H), 4.14 (br. s, 2 H), 4.83 (br. s, 1 H), 5.34 (t, J = 6.5 Hz, 1 H),
6.07 (d, J = 11.5 Hz, 1 H), 6.46 (dd, J1 = 11.5, J2 = 8.0 Hz, 1 H),
7.20–7.43 (m, 5 H) ppm.
tert-Butyl (3aR,4R,6S,6aS)-4-(3-Ethoxy-3-oxopropyl)-2,2-dimethyl-
6-phenyldihydro-3aH-[1,3]dioxolo[4,5-c]pyrrole-5(4H)-carboxylate
(34): To a solution of 27 (0.030 g, 0.072 mmol) in dry methanol
(2 mL) under a hydrogen atmosphere was added Pd(OH)2/C 10%
(20% w/w). The reaction was stirred at room temperature for 24 h.
The crude reaction mixture was filtered through a plug of Celite
and concentrated under reduced pressure. The resulting product 34
was used without further purification. 1H NMR (250 MHz,
CDCl3): δ = 1.25 (t, J = 7.2 Hz, 3 H), 1.33 (s, 3 H), 1.38 (br. s, 9
H), 1.54 (s, 3 H), 1.68–1.83 (m, 1 H), 1.88–2.15 (m, 1 H), 2.47 (t,
J = 7.7 Hz, 2 H), 4.13 (q, J = 7.2 Hz, 2 H), 4.15–4.19 (m, 1 H),
4.43 (dd, J1 = 5.5, J2 = 0.8 Hz, 1 H), 4.60–4.77 (m, 1 H), 5.12 (br.
s, 1 H), 7.18–7.37 (m, 5 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ
= 14.2, 25.5, 27.4, 28.2, 29.0, 31.4, 60.5, 64.1, 68.2, 80.2, 84.1, 86.8,
112.2, 125.5, 127.1, 128.5, 140.8, 154.9, 172.8 ppm.
(3aR,4R,6S,6aS)-tert-Butyl-4-[(Z)-3-ethoxy-3-oxoprop-1-enyl]-
2,2-dimethyl-6-phenyldihydro-3aH-[1,3]dioxolo[4,5-c]pyrrole-
5(4H)-carboxylate (27). First Step: In a long tube under an argon
atmosphere was prepared a solution of 31b (0.151 g, 0.4 mmol) in
dry dichloromethane (2 mL). The system was cooled to –80 °C, and
DIBAL-H (0.42 mmol, 1.5 m solution in toluene) was cautiously
added. It is worth pointing out that in order to avoid overreduction,
the reducing agent must run down the walls of the tube to cool
before reaching the reaction mixture. The reaction was maintained
at that temperature for 30 min, then 5 mL of a saturated solution
of Rochelle salt (K,Na tartrate) was added. The mixture was stirred
for 1 h at room temperature and extracted into diethyl ether. The
combined organic phases were dried with MgSO4, filtered, and the
solvents evaporated. The crude reaction was used in the next step
without prior purification.
Ethyl 3-[(2R,3R,4S,5S)-3,4-Dihydroxy-5-phenylpyrrolidin-2-yl]prop-
anoate (33): To crude 34 was added a solution of p-TSA (catalytic
amount) in methanol (2 mL). The solution was transferred to a
microwave tube and reacted for 30 min at 60 °C under microwave
irradiation. The solvent was evaporated under reduced pressure,
and the residue dissolved in acetonitrile (2 mL). p-TSA (0.013 g,
0.072 mmol) was added to the mixture, which was heated at 60 °C
for 1 h under microwave irradiation. Triethylamine (0.5 mL) was
added, and the solvent was removed. Purification by flash
chromatography eluting with ethyl acetate (triethylamine was used
to dope the column) provided 33 in 59% yield for the four steps
(0.011 g). [α]2D0 = +4 (c = 0.6, CHCl3). 1H NMR (250 MHz,
CDCl3): δ = 1.26 (t, J = 7.0 Hz, 3 H), 1.79–1.94 (m, 1 H), 1.96–
2.10 (m, 1 H), 2.37 (br. s, 3 H), 2.50 (t, J = 7.5 Hz, 2 H), 3.13–3.20
(m, 1 H), 3.80–3.88 (m, 2 H), 4.08 (d, J = 6.0 Hz, 1 H), 4.14 (q, J
= 7.0 Hz, 2 H), 7.26–7.43 (m, 5 H) ppm. 13C NMR (62.5 MHz,
CD3CN): δ = 14.2, 29.7, 31.3, 60.5, 63.0, 67.1, 75.5, 78.0, 126.8,
127.5, 128.5, 141.9, 173.9 ppm. HRMS (EI): calcd. for C15H21NO4
[M – H2O]+ 261.1365; found 261.1394.
Second Step: To
a suspension of sodium hydride (0.008 g,
0.184 mmol, 60% dispersion in mineral oil) in dry THF (1 mL) at
0 °C under an argon atmosphere was added 21 (0.064 g,
0.184 mmol) in THF (0.5 mL). After stirring for 10 min, 30
(0.016 g, 0.046 mmol) dissolved in dry THF (1 mL) was added, and
the mixture was stirred for 1 h. The reaction mixture was treated
with a saturated solution of ammonium chloride and extracted into
ethyl ether. The combined organic phases were dried with MgSO4
and concentrated under reduced pressure. The product was purified
by flash chromatography using as eluent hexane/ethyl acetate
(75:25), which provided 27 in 60% yield for the two steps (0.013 g).
1H NMR (250 MHz, CDCl3): δ = 1.31 (t, J = 7.3 Hz, 3 H), 1.35
(s, 9 H), 1.59 (s, 3 H), 1.62 (s, 3 H), 4.22 (q, J = 7.3 Hz, 2 H), 4.56
(dd, J1 = 5.5, J2 = 1.8 Hz, 1 H), 4.71 (dd, J1 = 5.5, J2 = 1.8 Hz, 1
H), 5.13 (br. s, 1 H), 5.75 (d, J = 8.3 Hz, 1 H), 5.87 (dd, J1 = 11.5,
J2 = 1.5 Hz, 1 H), 6.11–6.19 (m, 1 H), 7.20–7.40 (m, 5 H) ppm.
MS (EI): m/z = 418 [M + 1]+, 374, 372, 360, 328, 314. HRMS
(ESI): calcd. for C23H31NO6 [M + Na]+ 440.2049; found 440.2050.
HRMS (ESI): calcd. for C23H31NO6 [M + H]+ 418.2229; found
418.2228.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of NMR spectra of selected compounds.
tert-Butyl (2R,3R,4S,5S)-2-[(Z)-3-Ethoxy-3-oxoprop-1-enyl]-3,4-di-
hydroxy-5-phenylpyrrolidine-1-carboxylate: To a flask were added
27 (0.058 g, 0.135 mmol), p-TSA (approximately 0.003 g), and
methanol (2 mL). The reaction was heated to 60 °C for 5 h. The
reaction mixture was treated with a saturated solution of sodium
chloride and extracted into ethyl acetate. The combined organic
phases were dried with MgSO4 and concentrated at reduced pres-
sure. The product was purified by flash chromatography using as
Acknowledgments
The authors thank Conselho Nacional de Desenvolvimento Ci-
entífico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento
de Pessoal de Nível Superior (Capes), and Fundação de Amparo à
Pesquisa do Estado de São Paulo (FAPESP) for financial support
of this work. FAPESP, Capes, and CNPq are also acknowledged
for a PhD fellowship to A. V. M., an M.Sc. fellowship to M. R. S.,
and a research fellowship to C. R. D. C.
1
eluent hexane/ethyl acetate (50:50). H NMR (250 MHz, CDCl3):
δ = 1.17–1.45 (m, 12 H), 3.13 (br. s, 1 H), 4.08 (br. s, 2 H), 4.22 (q,
J = 7.3 Hz, 2 H), 4.90–5.40 (m, 3 H), 6.05 (d, J = 11.8 Hz, 1 H),
6.61 (br. s, 1 H), 7.20–7.40 (m, 5 H) ppm.
(Z)-3-[(2R,3R,4S,5S)-1-(tert-Butoxycarbonyl)-3,4-dihydroxy-5-phen-
ylpyrrolidin-2-yl]acrylic Acid (28): To a solution of ester described
above (0.020 g, 0.053 mmol) in ethanol (0.3 mL) was added a solu-
tion of NaOH (1 m, 0.13 mL). The mixture was stirred at room
temperature for 1 h and HCl (1 m, 0.053 mL) was added. The reac-
tion mixture was evaporated to remove ethanol, and HCl (1 m,
0.071 mL) was added. The aqueous phase was extracted into ethyl
acetate, and the combined organic phases were dried with MgSO4
and concentrated at reduced pressure. The product was purified by
flash chromatography using as eluent ethyl acetate/methanol/acetic
acid (94:5:1). Compound 28 was obtained in 52% yield for two
[1] a) A. Ganesan, Curr. Opin. Chem. Biol. 2008, 12, 306; b) A. L.
Harvey, Drug Discovery Today 2008, 13, 894.
[2] a) R. M. Wilson, S. J. Danishefsky, J. Org. Chem. 2006, 71,
8329; b) K. Hübel, T. Leßmann, H. Waldmann, Chem. Soc.
Rev. 2008, 37, 136.
[3] Z. Tian, S. Chen, Y. Zhang, M. Huang, L. Shi, F. Huang, C.
Fong, M. Yang, P. Xiao, Phytomedicine 2006, 13, 181.
[4] A. de Fatima, L. V. Modolo, L. S. Conegero, R. A. Pilli, C. V.
Ferreira, L. K. Kohn, J. E. de Carvalho, Curr. Med. Chem.
2006, 13, 3371.
[5] For reviews on syntheses of styryllactones, see: a) G. Zhao, B.
Wu, X. Y. Wu, Y. Z. Zhang, Mini-Rev. Org. Chem. 2005, 2, 333;
b) M. Mondon, J.-P. Gesson, Curr. Org. Synth. 2006, 3, 41.
1
steps (0.024 g). H NMR (250 MHz, CDCl3): δ = 1.10–1.50 (m, 9
Eur. J. Org. Chem. 2011, 7259–7270
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7269

A. V. Moro, M. Rodrigues dos Santos, C. R. D. Correia
FULL PAPER
[6] P. R. R. Meira, A. V. Moro, C. R. D. Correia, Synthesis 2007,
2279.
Correia, M. N. Eberlin, Angew. Chem. 2004, 116, 4489; Angew.
Chem. Int. Ed. 2004, 43, 4389.
[7] a) E. A. Severino, C. R. D. Correia, Org. Lett. 2000, 2, 3039;
b) E. A. Severino, E. R. Costenaro, A. L. L. Garcia, C. R. D.
Correia, Org. Lett. 2003, 5, 305; c) A. V. Moro, E. R. T. Tiek-
ink, J. Zukerman-Schpector, D. S. Lüdtke, C. R. D. Correia,
Eur. J. Org. Chem. 2010, 3696.
[12]
[13]
[14]
[15]
A. H. Hoveyda, D. A. Evans, G. C. Fu, Chem. Rev. 1993, 93,
1307.
C. F. Tormena, L. C. Dias, R. Rittner, J. Phys. Chem. A 2005,
109, 6077.
W. P. Griffith, S. V. Ley, G. P. Whitcombe, A. D. White, J.
Chem. Soc., Chem. Commun. 1987, 1625.
a) K. Ando, J. Org. Chem. 1997, 62, 1934; b) K. Ando, J. Org.
Chem. 2000, 65, 4745; c) K. Ando, Tetrahedron Lett. 1995, 36,
4105.
H. M. C. Ferraz, R. M. Muzzi, T. O. Vieira, H. Viertler, Tetra-
hedron Lett. 2000, 41, 5021.
[8] For other applications of Heck arylation using aryldiazonium
salts, see: a) M. J. S. Carpes, C. R. D. Correia, Synlett 2000,
1037; b) M. J. S. Carpes, C. R. D. Correia, Tetrahedron Lett.
2002, 43, 741; c) A. C. B Montes de Oca, C. R. D. Correia, Ar-
kivoc 2003, x, 390; d) A. L. L. Garcia, M. J. S. Carpes,
A. C. B. M. de Oca, M. A. G. dos Santos, C. C. Santana,
C. R. D. Correia, J. Org. Chem. 2005, 70, 1050; e) A. C. B. Bur-
toloso, A. L. L. Garcia, K. C. Miranda, C. R. D. Correia, Syn-
lett 2006, 3145; f) J. C. Pastre, C. R. D. Correia, Org. Lett.
2006, 8, 1657; g) R. L. Barreto, L. B. L. R. Nascimbem,
C. R. D. Correia, Synth. Commun. 2007, 37, 2011; h) K. P.
da Silva, M. N. Godói, C. R. D. Correia, Org. Lett. 2007, 9,
2815; i) A. V. Moro, F. S. P. Cardoso, C. R. D. Correia, Tetra-
hedron Lett. 2008, 49, 5668; j) J. C. Pastre, C. R. D. Correia,
Adv. Synth. Catal. 2009, 351, 1217; k) A. V. Moro, F. S. P. Car-
doso, C. R. D. Correia, Org. Lett. 2009, 11, 3642; l) A. H. L.
Machado, M. A. de Sousa, D. C. S. Patto, L. F. S. Azevedo,
F. I. Bombonato, C. R. D. Correia, Tetrahedron Lett. 2009, 50,
1222; m) F. A. Siqueira, J. G. Taylor, C. R. D. Correia, Tetrahe-
[16]
[17]
[18]
A. J. Mancuso, D. Swern, Synthesis 1981, 165.
a) H. Sugiyama, F. Yokokawa, T. Shioiri, Org. Lett. 2000, 2,
2149; b) A. Solladié-Cavallo, K. Azyat, M. Schmitt, R. Welter,
Tetrahedron: Asymmetry 2005, 16, 1055.
[19] A. P. Kozikowski, T. R. Nieduzak, T. Konoike, J. P. Springer, J.
Am. Chem. Soc. 1987, 109, 5167.
[20] J. D. More, N. S. Finney, Org. Lett. 2002, 4, 3001.
[21] A. B. Smith III, Q. Lin, V. A. Doughty, L. Zhuang, M. D.
McBriar, J. K. Kerns, C. S. Brook, N. Murase, K. Nakayama,
Angew. Chem. 2001, 113, 202; Angew. Chem. Int. Ed. 2001, 40,
196.
[22] Y. Gao, K. B. Sharpless, J. Am. Chem. Soc. 1988, 110, 7538.
dron Lett. 2010, 51, 2102; n) F. de Azambuja, C. R. D. Correia, [23] a) O. Mitsunobu, M. Yamada, Bull. Chem. Soc. Jpn. 1967, 40,
Tetrahedron Lett. 2011, 52, 42; o) J. G. Taylor, C. R. D. Correia,
J. Org. Chem. 2011, 76, 857.
2380; b) O. Mitsunobu, Synthesis 1981, 01.
[24] Isolation: S.-G. Cao, X.-H. Wu, K.-Y. Sim, B. K. H. Tan, J. T.
Pereira, S.-H. Goh, Tetrahedron 1998, 54, 2143. Synthetic ap-
proaches: a) H. Yoda, Y. Nakaseko, K. Takabe, Synlett 2002,
1532; b) M. Babjak, P. Kapitan, T. Gracza, Tetrahedron Lett.
2002, 43, 6983; c) J. Murga, P. Ruiz, E. Falomir, M. Carda, G.
Peris, J. A. Marco, J. Org. Chem. 2004, 69, 1987; d) J. S. Yadav,
A. K. Raju, P. P. Rao, G. Rajaiah, Tetrahedron: Asymmetry
2005, 16, 3283; e) M. Babjak, P. Kapitan, T. Gracza, Tetrahe-
dron 2005, 61, 2471; f) M. C. Carreno, G. Hernandez-Torres,
A. Urbano, F. Colobert, Org. Lett. 2005, 7, 5517; g) K. R. Pra-
sad, S. L. Gholap, J. Org. Chem. 2006, 71, 3643; h) S. Ghosh,
C. N. Rao, S. K. Dutta, Synlett 2007, 1464; i) M. Brichacek,
L. A. Batory, J. T. Njardarson, Angew. Chem. Int. Ed. 2010, 49,
1648; j) J. Li, H. Zheng, Y. Su, X. Xie, X. She, Synlett 2010,
2283.
[9] a) P. Baumeister, W. Meyer, K. Oertle, G. Seifert, U. Siegrist,
H. Steiner, Chimia 1997, 51, 144; b) P. Baumeister, W. Meyer,
K. Oertle, G. Seifert, U. Siegrist, H. Steiner, Stud. Surf. Sci.
Catal. 1997, 108, 37; c) S. Cacchi, G. Fabrizi, A. Goggiamani,
A. Sferrazza, Synlett 2009, 1277; d) B. Schmidt, F. Holter, A.
Kelling, U. Schilde, J. Org. Chem. 2011, 76, 3357; e) B.
Schmidt, R. Berger, F. Holter, Org. Biomol. Chem. 2010, 8,
1406.
[10] a) J. G. Taylor, A. V. Moro, C. R. D. Correia, Eur. J. Org.
Chem. 2011, 1403; b) F. X. Felpin, L. Nassar-Hardy, F. Le Cal-
lonnec, E. Fouquet, Tetrahedron 2011, 67, 2815; c) A. Roglans,
A. Pla-Quintana, M. Moreno-Mañas, Chem. Rev. 2006, 106,
4622.
[11] a) A. A. Sabino, A. H. L. Machado, C. R. D. Correia, M. N.
Eberlin, Angew. Chem. 2004, 116, 2568; Angew. Chem. Int. Ed.
2004, 43, 2514; b) A. A. Sabino, A. H. L. Machado, C. R. D.
Received: June 17, 2011
Published Online: September 15, 2011
7270
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7259–7270