Synthesis of Easy-to-Functionalize Azabicycloalkane Scaffolds as Dipeptide Turn Mimics en Route to cRGD-Based Bioconjugates

Article abstract of DOI:10.1002/ejoc.201501003

In this paper we report the synthesis of new azabicycloalkane scaffolds, which could be exploited to obtain cRGD-based bioconjugates that may find promising application for targeted drug delivery, theranostic, and general cancer-cell labeling. By exploiti

Full text of DOI:10.1002/ejoc.201501003

FULL PAPER
DOI: 10.1002/ejoc.201501003
Synthesis of Easy-to-Functionalize Azabicycloalkane Scaffolds as Dipeptide
Turn Mimics en Route to cRGD-Based Bioconjugates
Massimo Serra,*[a] Simone Maria Tambini,[a] Marcello Di Giacomo,[a]
Elena Giulia Peviani,[a] Laura Belvisi,[b] and Lino Colombo*[a]
Keywords: RGD integrin antagonists / Peptidomimetics / Amino acids / Lactams / Antitumor agents
In this paper we report the synthesis of new azabicycloalk-
ane scaffolds, which could be exploited to obtain cRGD-
based bioconjugates that may find promising application for
targeted drug delivery, theranostic, and general cancer-cell
labeling. By exploiting a Hosomi–Sakurai intramolecular
allylation reaction we efficiently converted a silylated alde-
hyde precursor into 7,5-fused lactam scaffolds endowed with
an exocyclic double bond. The presence of the vinyl function
should make it possible to conjugate bioactive compounds to
selectively carry them to tumor sites. The optimized synthetic
sequence allows the gram-scale preparation of the target
scaffolds in a few steps and good 39% overall yield from
readily accessible materials. The high reactivity of the exo-
cyclic olefin moiety was ascertained by performing a Heck
coupling reaction with 1-bromo-4-nitrobenzene, which gave
the corresponding functionalized derivatives in good (80–
91%) yields.
melanoma, breast cancer, and brain cancer, such as gliobla-
stoma (GBM).[3] The ανβ3 and ανβ5 recognize endogenous
ECM proteins and synthetic molecules that contain the tri-
peptide sequence Arg-Gly-Asp (RGD) that is therefore used
as a binding motif in the design and synthesis of integrin
antagonists.[4]
Some previous studies have investigated the functional
effects of small RGD-like molecules as integrin antagonists.
A prototype RGD-like molecule, Cilengitide, has been
mainly tested for treatment of GBM.[5] Despite promising
preliminary data, its use as an anticancer therapeutic has
been discontinued as a result of failure in phase-III clinical
trials.[6] As a consequence, in the last years, the use of RGD-
based antagonists alone as anticancer agents has been set
aside. Nevertheless, the availability of high-affinity ligands,
and the well-known biological roles of ανβ3 integrin sub-
types, has placed RGD-based ανβ3 antagonists under ex-
tensive studies for tumor targeting.[7]
Azabicyclolactam derivatives of type 1 can be viewed as
conformationally constrained mimics of dipeptide Phe-Pro
(Scheme 1). These 7,5-fused bicyclic scaffolds, which can be
structurally characterized by the presence of a quaternary
stereocenter at position 3 of the lactam ring, are useful in-
termediates in the synthesis of RGD-based cyclopentapept-
ides that are effective integrin inhibitors.[8] The most active
compound of the series, 1a-RGD, was shown to be a nano-
molar inhibitor of integrin receptors ανβ3 and ανβ5, which
are overexpressed on the cancer-cell surface and reported to
be involved in tumor-induced neoangiogenesis.[9] Moreover,
cyclopentapeptide 1a-RGD is one of the few RGD-like
antagonists that proved to be effective at inhibiting cell mi-
Introduction
A key issue related to cancer therapy is the control of
tumor-cell proliferation and aggressive behavior. Neoplastic
growth is a complex process that results from interactions
among different cell types present in the tumor mass, such
as tumor cells, and cells present in the tumoral niche, such
as fibroblast and endothelial cells, that contribute to the
composition of the extracellular matrix (ECM). ECM pro-
teins, such as fibronectin, laminin and collagen, regulate
cellular processes like cell migration, proliferation, and dif-
ferentiation, and exert their effect by binding cell surface
receptors, the integrins.[1] The most interesting feature of
integrins in oncology comes from the observation that
changes in the adhesion properties in cancer cells are deeply
involved in the early and final steps of metastasis forma-
tion.[2] Moreover, integrins represent an excellent target in
cancer therapy, because in some cancer cells they are over-
expressed relative to their non-cancer cell counterpart.
The αvβ3 and ανβ5 integrins appear to regulate metast-
asic processes in different cancer types like colon cancer,
[a] University of Pavia, Department of Drug Sciences, Medicinal
Chemistry and Pharmaceutical Technology Section
Viale Taramelli 12, 27100 Pavia, Italy
E-mail: massimo.serra@unipv.it
lino.colombo@unipv.it
http://dipsf.unipv.eu/site/home.html
[b] Università degli Studi di Milano, Dipartimento di Chimica
Via Golgi 19, 20133, Milan, Italy
Supporting information and ORCID(s) from the author(s) for
this article are available on the WWW under http://dx.doi.org/
10.1002/ejoc.201501003.
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Scheme 1.
gration and attachment, and inducing anoikis in glioblas- scaffolds of type 2. Indeed, alcohol 4 could be converted
toma cell lines.[10]
into aldehyde 3 through oxidation of the alcoholic function
In recent years, many efforts have been directed towards followed by introduction of the trimethylsilyl moiety.
the development of integrin ligands that can provide ad-
To obtain 4, we initially decided to explore the feasibility
vanced tools for drug delivery, imaging, or theranostics.[11] of the synthetic route depicted in Scheme 2, which exploits
Along these lines, and taking into account the relevant af- the condensation reaction between (S)-N-carboxybenzyl-
finity of 1a-RGD towards ανβ3 and ανβ5 receptors, we are (Cbz)-O-acetylbenzylserine 12 and cis-5-allylproline methyl
pursuing the idea to develop a synthetic strategy that would ester 13.
allow the synthesis of conjugate derivatives with potential
use in cancer therapy. To this aim, the introduction onto
bicyclolactam scaffolds 1 of a functional group to be ex-
ploited as an attachment point for the conjugation of bioac-
tive compounds is mandatory. Indeed, through the use of
an appropriate linker, it would be possible to covalently
conjugate these RGD-based cyclopentapeptides to either
therapeutic (cytotoxic) or imaging agents, such that they
could be selectively carried on the tumor-induced neovascu-
larization (Scheme 1). Because such a structural modifica-
tion could lead to an unpredictable influence on the confor-
mational properties of the cyclic peptide moiety, we as-
sumed that the most appropriate position to be function-
alized would be the one that resides on a carbon atom away
from both the RGD sequence and the proline ring. A vinyl
function seemed the most appropriate choice on grounds of
its ample synthetic versatility, robustness of the C–C bond,
and limited steric requirements.
This new synthetic approach uses, as a key reaction, an
intramolecular Sakurai allylation reaction of aldehyde 3.
This Lewis acid catalyzed cyclization reaction would allow
us to obtain, in one operation, the seven-membered lactam
ring and introduce an exocyclic vinyl unit.
Scheme 2. Reagents and conditions: (i) (Boc)2O, THF, 0 °C then
r.t., 24 h; (ii) LiOH, THF/H2O/MeOH, r.t., 2.5 h; (iii) PhCH2Br.,
CsCO3, 50 °C, 1 h; (iv) HCl/MeOH, 0 °C, 3 h; (v) (Cbz)2O, THF,
0 °C then r.t., 1 h; (vi) Ac2O, Et3N, DMAP, CH2Cl2, r.t., 1 h;
(vii) H2, Pd/C(en) (en
(viii) PyBroP, DIEA, DMAP, CH2Cl2, r.t., 24 h; (ix) HCl/MeOH,
0 °C, 5 h.
= ethylenediamine), EtOH, r.t., 3 h;
Results and Discussion
First-Generation Synthesis of Dipeptide 4
The retrosynthetic analysis (Scheme 1) shows that di-
This choice was mainly dictated by the easy accessibility
peptide 4 is a key intermediate to obtain new bicyclolactam of amino acidic precursors 5 and 13, the stereoselective
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Synthesis of Easily Functionalizable Azabicycloalkane Scaffolds
(asymmetric) synthesis of which was reported previously by the following reaction with 5-allylproline methyl ester gave
us.[12,13] Compound 5 is readily obtained from l-serine the desired dipeptide in yields not higher than 10% despite
through stereoselective alkylation reaction of Seebach’s ox- a thorough screen of the most common condensing agents.
azolidine, whereas (2S,5R)-5-allylproline methyl ester 13 It was therefore necessary to add an additional step, to
could be synthesized in a few steps from l-pyroglutamic acid. switch the N-protecting group of derivative 8 from Boc to
The unacceptable length of this seemingly trivial synthe- Cbz, to obtain intermediate 10. To obtain (S)-N-Cbz-O-
sis resulted, because the condensation reaction between acetylbenzylserine 12 we had to develop a selective benzyl
either N-tert-butoxycarbonyl- (Boc-) or N-Cbz-protected 2- ester hydrogenolysis reaction that would preserve the Cbz
benzylserine and cis-5-allylproline methyl ester was unsuc- protecting group. By performing the reaction in the pres-
cessful. Despite an extensive screen for condensing agents, ence of a Pd/C–ethylenediamine complex catalyst,[16] after
such as N,NЈ-dicyclohexylcarbodiimide, 1-[bis(dimethyl- careful optimization work, we were able to isolate free
amino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3- amino acid 12 in 50–60% yields. By exploiting PyBroP as
oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole, a condensing agent for the amide bond formation, we ob-
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa- tained dipeptide 14, which, after removal of the acetyl
fluorophosphate, isobutyl chloroformate, PyBroP, and group, was converted into desired dipeptide 4. The final de-
bis(2-oxo-3-oxazolidinyl)phosphinic chloride, at both room protection step proved rather troublesome. Attempts to se-
and reflux temperatures, we isolated only unreacted starting lectively cleave the acetate whilst keeping the methyl ester
materials along with traces of a by-product with a structure intact, e.g. by using a methanolic solution of potassium
consistent with (4-benzyl-2-oxo-4-oxazolidine)carboxylic carbonate, led to the isolation of lactone by-product I,
acid.[14] This compound arises probably through nucleo- which arises from intramolecular attack of the alcoholic
philic attack of the free hydroxy group to the carbamate function on the methyl ester carbonyl group. Under more
carbonyl group.
basic reaction conditions, it was possible to isolate only di-
The low nucleophilicity of the nitrogen atom in proline ketopiperazine II, possibly arising from previous hydrolysis
derivative 13 and the unavoidable steric requirements of the of the benzyl carbamate followed by intramolecular attack
α-benzylserine derivative hamper the formation of the di- of the amino group on the methyl ester.
peptide. To the best of our knowledge, only one similar di-
The difficulties encountered to restore the hydroxy group
peptide has been reported in the literature, Boc-NH-α- by saponification of the corresponding acetate, led us to
methyl-Ser-ProCO2Me, but neither experimental procedure attempt a transesterification reaction with methanolic HCl.
for its preparation nor spectroscopic data are detailed.[15] This reaction made it possible to obtain desired dipeptide
Moreover, only one example of condensation between N- 4 with yields close to 50%, but again we isolated significant
protected serine and 5-substituted proline esters is known, amounts of the previously described lactone by-product.
whereas proline or 4-substituted proline esters were shown
to couple in good yields under standard conditions.
As clearly highlighted by the experimental results de-
scribed so far, this first-generation synthesis was awkward
To avoid side reactions (vide supra), the hydroxy group and suffers from several weak points. In particular the selec-
of quaternary amino acid 6 was protected either as the tri- tive benzyl ester cleavage and the final hydrolysis, which
methylsilyl ether or tert-butyldiphenylsilyl ether. Unfortu- involves rather advanced and synthetically precious inter-
nately, any attempt of methyl ester saponification gave only mediates, required carefully controlled experimental condi-
starting material contaminated with trace amounts of desil- tions. Moreover, the 9 linear steps necessary to obtain key
ylated products.
intermediate 4, and the low 10% overall yield, do not meet
By assuming that the very low hydrolysis rate was mainly with our needs to synthesize final bicyclolactam scaffolds
due to steric factors, we tried to change the N-protecting of type 2 on a gram scale.
group by replacing tBoc with Cbz, but attempts to perform
the ester basic hydrolysis were unsuccessful. To further re-
duce the steric hindrance around the quaternary stereocen-
ter, we thought to adopt a less bulky protective group on
Second-Generation Synthesis of Dipeptide 4
the alcohol function by converting 6 into its corresponding
Efforts to reduce the length of the synthetic route and
O-acetyl derivative. Surprisingly, the acetylation reaction raise the overall yield that leads to 4, prompted us to ex-
with acetic anhydride or acetyl chloride did not provide the plore a second approach that involved the contemporary
desired product; similar results were obtained for attempts protection of the alcoholic and amino group of quaternary
to acetylate benzylserine 7. However, by starting from N- α-amino ester 5 (Scheme 3). The synthetic sequence started
Cbz-benzylserine, the acetylation reaction proceeded with protection of the amino group of compound 5 as its
smoothly, but the acetyl group cleaved easily during the Cbz derivative, followed by the almost quantitative conver-
subsequent saponification step. Attempts to restore the pro- sion of obtained (S)-N-Cbz-α-benzylserine methyl ester 15
tection on the hydroxy group met with failure, as reported into the corresponding N,O-aminal 16 by treatment with
for N-Boc analogue 7. To circumvent these drawbacks, 2,2-dimethoxypropane (DMP). Methyl ester saponification
mainly ester hydrolysis, we decided to synthesize benzyl es- with LiOH afforded carboxylic acid intermediate 17, which
ter 8, which was O-acetylated and, after hydrogenolysis, was coupled with cis-5-allylproline methyl ester to give di-
converted into the corresponding free acid. Unfortunately, peptide 18 in up to 85% yield. The last step, i.e. cleavage of
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the oxazolidine ring, turned out to be very arduous and reaction proceeded slowly (24–48 h), and alcohol 4 was ob-
required careful investigation. The first attempts, performed tained in low yields (40–50%) along with significant
with mixtures of MeOH/HCl (12 n) in different ratios, gave amounts of undesired products. Specifically, we isolated
dipeptide 4 in low yields with long reaction times (about lactone I and new side-product III (Scheme 4), analogous
96 h); moreover, in addition to the desired product, we iso- to II, but characterized by the presence of a benzyl carb-
lated similar amounts of by-product I. All methods for the onate instead of a free hydroxy group. This compound
selective cleavage of N,O-aminals, such as a catalytic could arise either by nucleophilic attack of the dipeptide 4
amount of p-toluensulfonic acid,[17] camphorsulfonic N-protected amino group on the methyl ester, followed by
acid,[18] and scandium triflate,[19] led to low conversion.
migration of the Cbz group on the alcohol moiety, or by an
unconventional first migration of the Cbz group from the
nitrogen atom to the oxygen atom of the primary alcohol,
followed by attack of the resulting free amino group on the
methyl ester. Despite thorough experimentation, that in-
cluded screens of various solvents [CH3CN, CH2Cl2, (CH3)2-
CO, tetrahydrofuran (THF)], various amounts of Lewis
acid (0.1–0.5 equiv.), different reaction concentrations
(0.05–0.3 m) and temperatures (from room temperature to
60 °C), and conventional and microwave-assisted heating,
we have never been able to repeat the results obtained even
with small amounts of compound 18. Although these re-
sults were difficult to rationalize, we thought that by acce-
lerating the oxazolidine ring-opening step, it might be pos-
sible to minimize the formation of the side-products and,
as a consequence, increase the yield of desired alcohol 4.
On the basis of this consideration, we took into account
Scheme 3. Reagents and conditions: (i) (Cbz)2O, THF, 0 °C,
15 min; (ii) DMP, TsOH, benzene, reflux, 4 h; (iii) LiOH, THF/
H2O/MeOH, r.t., 24 h; (iv) PyBroP, DIEA, DMAP, CH2Cl2, r.t.,
24 h; (v) Bi(OTf)3, CH3CN, r.t., 10 min.
The first encouraging result was obtained by employing the use of bismuth(III) triflate, already employed in the
BiBr3,[20] which catalyzed the hydrolysis of dipeptide 18 catalytic deprotection of acetals and ketals.[21] It is known
(100 mg; 0.2 mmol) in less than 4 h in 85–90% yields. Un- that metal centers of metal triflates are more cationic than
fortunately, our attempts to scale-up the reaction by tripling those of metal halides;[22] we therefore expected that bis-
the amount of starting material and keeping the other pa- muth(III) triflate, which is a stronger Lewis acid than bis-
rameters unchanged, gave disappointing results. Indeed, the muth(III) bromide, would lead to more efficient activation
Scheme 4. Reagents and conditions: (i) allyltrimethylsilane, G2, DBBQ, ethylene, CH2Cl2, reflux, 6 h; (ii) (COCl)2, DMSO, TEA, CH2Cl2,
–60 °C then 0 °C, 2 h; (iii) allyltrimethylsilane, HG2, DBBQ, CH2Cl2, reflux, 8 h; (iv) Sc(OTf)3, CH2Cl2, –10 °C then r.t., 5 h.
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Synthesis of Easily Functionalizable Azabicycloalkane Scaffolds
of the hemiaminal basic sites and consequently to a faster thetic approach. To further optimize the synthetic protocol
opening of the oxazolidine ring. In fact, by using commer- and minimize collateral reactions of alcohol 4, we decided
cial bismuth(III) triflate, the hydrolysis of the N,O-aminal to anticipate the oxidation step. The Swern reaction to give
was complete in only 10 min, with yields close to 90%, even 20 proceeded in a yield very similar to that previously re-
on a gram scale.
ported for the synthesis of 3, whereas the introduction of
The synthesis of target compound 4 was thus ac- the allylsilane moiety required a different experiment. The
complished in 60% overall yield from benzylserine methyl best CM catalyst proved to be HG2, which converted 20
ester 5, which is significantly higher than the yield obtained into trimethylsilyl derivative 3, as a 7:3 mixture of (E)/(Z)
with the first-generation approach. Moreover, the new isomers, in 84% yield. It is worthy to note that, in this case,
protocol is characterized by a limited number of steps and the use of ethylene did not lead to any benefit; it can there-
can be easily applied to a multi-gram scale synthesis.
fore be omitted, with significant cost savings and synthetic
With good amounts of alcohol 4 in hand, we decided to protocol simplification.
introduce the allylsilane unit by exploiting a cross metathe-
From the outset it was only possible to obtain a few mil-
sis (CM) reaction with allyltrimethylsilane. The experiment ligrams of diastereoisomeric pure compounds 3a and 3b,
was performed by applying typical metathesis reaction con- the chromatographic separation of which proved to be very
ditions, with the use of aprotic solvents, such as dichloro- difficult; therefore, the final cyclization was performed with
methane, dichloroethane, or toluene, and the Grubbs cata- the (E)/(Z) mixture of the two diastereoisomers. After an
lyst highlighted in Scheme 4.
extensive investigation of various Lewis acids able to pro-
In preliminary experiments, the Ru complex that turned mote this intramolecular Sakurai allylation, we found that
out to be the most effective was G2, but the CM reaction scandium triflate was the best one in terms of yield and
was sluggish and resulted in low conversion yields (Ͻ30%) mild reaction conditions. Among the Lewis acids tested,
even if the temperature was raised and the reaction time CuCl, ZnCl2, NiCl2, CeCl3, InCl3, and BiBr3 gave exclu-
extended. In addition, we isolated desired product 19 along sively proto-desilylation of dipeptide 3, whereas the use of
with the expected 1,4-bis(trimethylsilyl)but-2-ene, which BF3·Et2O, TiCl4, and NbCl5 also gave traces of three dia-
arises from homocoupling of allyltrimethylsilane, diketo- stereoisomeric alcohols 2a–2c. By employing In(OTf)3 it
piperazine III, and compound IV, which are generated by was possible to isolate alcohols 2 in 35% overall yield,
double-bond migration of the allyl moiety of alcohol 4. The whereas lanthanide triflates, such as La(OTf)3, Yb(OTf)3,
isomerization of terminal alkenes to internal alkenes pro- and Eu(OTf)3, were unable to catalyze the cyclization reac-
moted by ruthenium–carbene complexes is well known[23] tion.
and has found various synthetic applications.[24] It was pro-
The use of a stoichiometric amount of Sc(OTf)3 afforded
posed that the ruthenium species responsible for isomeriza- desired alcohols 2, as a mixture of 3 out of the potential 4
tion was a ruthenium hydride generated in situ either by diastereoisomers that arise from the generation of the
impurities[25] or decomposition of the Grubbs catalysts, e.g. seven-membered lactam ring, with an overall yield of 86%.
by silyl enol ethers,[26] hydrogen,[27] inorganic hydrides,[28] Attempts to reduce the amount of the Lewis acid resulted
and traces of alcohols.[29]
in lower conversion rates. By performing the reaction in the
A possible way to suppress the unwanted olefin isomer- presence of protic acids such as trifluoroacetic or meth-
ization reaction is by addition of a moderate pKa acid, such anesulfonic acid, rapid proto-desilylation of dipeptide 3 oc-
as acetic acid, or quinone-type compounds, such as 1,4- curred, which led to conversion of the (trimethylsilyl)allyl
benzoquinone.[30] These additives are able to prevent the moiety into a butenyl group. Finally, by employing molec-
formation of ruthenium hydride by reacting with hydride ular iodine, which is also reported to catalyze similar trans-
species generated under metathesis conditions. Among vari- formations, we obtained the same previously described dia-
ous benzoquinones, we decided to exploit the use of 2,6- stereoisomeric mixture of alcohols 2, but in yields not
dichloro-1,4-benzoquinone (DBBQ), an electron-deficient higher than 15%.
derivative reported to be highly effective in the prevention
of olefin migration in reactions catalyzed by G2. Moreover,
with the aim to reduce the amount of bis(silane) side prod-
Configurational Assignments
uct that arises from self-metathesis of allyltrimethylsilane,
Configurational assignments were performed by 2D-
we thought to take advantage of an ethenolysis, namely a NOESY experiments. Analysis of NOE correlations be-
CM reaction of an olefinic compound and ethene. By carry- tween relevant hydrogen atoms clearly evidenced that the
ing out the reaction under gaseous ethylene and in the pres- configuration of the C3 and C7 stereocenters was not affec-
ence of a catalytic amount of DBBQ we obtained 19 as a ted by the cyclization reaction. The quaternary C3 stereo-
7:3 mixture of (E)/(Z) isomers in a satisfactory 75% yield. center of the final products could, in principle, epimerize
Subsequent Swern oxidation of dipeptide 19 gave aldehyde through an acid-catalyzed retro-aldol reaction of the β-
3, the starting material for our intramolecular Sakurai reac- hydroxy amide group, followed by a subsequent aldol reac-
tion studies, in 90% yield.
tion between the amide enol and the newly created aldehyde
The formation of diketopiperazine side product III, in function (Scheme 5).
which the free hydroxy group of dipeptide 4 is strongly in-
All the diastereoisomers showed an evident NOE corre-
volved, remained one of the unresolved issues of this syn- lation between H7 and Hb (Figure 1), which suggests that
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Scheme 5. Possible mechanism for the acid-catalyzed epimerization of the C3 stereocenter.
Figure 1. Relevant NOE correlations exhibited by compounds 2a, 2b, and 2c (curved arrows).
the seven-membered ring has some favored conformations Functionalization of the C5 Exocyclic Vinyl Group
in which the benzyl moiety is folded into the inner side of
the lactam.
Because the following objective of the project was the
For alcohol 2a, NOEs of H4 with Hb and Hv are particu- attachment to the exocyclic vinyl function of a suitable
larly diagnostic for the (S) absolute configuration of the C4 linker necessary to the obtainment of conjugate derivatives,
stereocenter. The opposite C5 configuration of alcohol 2b it seemed mandatory to ascertain the reactivity of the exo-
was deduced by the presence of an NOE between H5 and cyclic double bond. To this end, we decided to couple the
H7, whereas an NOE of H4 with Hv and the lack of a corre- less-substituted position of the vinyl function with a p-
lation signal between H4 and Hb are indicative of the (R) nitrophenyl moiety through a Heck reaction with 1-bromo-
configuration at C4. Further experimental evidence of the 4-nitrobenzene. The introduction of this aromatic moiety
(R) absolute configuration at C5 is the NOE between H5 can be regarded as a model of “adaptable linker”. Indeed,
and Hb. The fact that both, the H5 and the benzyl moiety, the p-nitro group could be exploited to directly conjugate
are oriented towards the same side of the bicyclic scaffold, the bioactive compound, e.g. through reduction of the nitro
1
is confirmed in the H NMR spectrum of 2b. Indeed, the group followed by formation of an amide bond. Alterna-
H5 resonance is shifted to higher frequency (δ = 2.8 versus tively, the aromatic amine that derives from reduction could
2.3 ppm for 2b and 2a, respectively), which suggests that be efficiently converted into an azide, and treated in a one-
in alcohol 2b the H5 proton is affected by the anisotropic pot “click” reaction with an alkynyl moiety.[31] To avoid the
deshielding effect of the aromatic ring. This effect is clearly formation of possible side products, the presence of the free
evident in alcohol 2c, in which the absolute configuration C4 hydroxy group must be considered with caution, be-
of the C5 stereocenter is the same as in 2b. Finally, the cause it could be reactive towards the adjacent Cbz-pro-
(S) configuration at C4 of the last diastereoisomer 2c was tected amino group. Indeed, the basic conditions needed for
attributed on the basis of an NOE signal correlating H4 and the coupling reaction could increase the nucleophilicity of
Hb.
the alcoholic function and lead to the formation of tricyclic
By following the hypothesis that scandium triflate could oxazolidinone side-products generated by intramolecular
be involved in the stereochemistry-determining step, we attack on the carbamate carbonyl group. On the basis of
were curious to see whether the use of chiral scandium(III) these assumptions, we decided to convert alcohols 2a–2c
bis(oxazoline) (box) or pyridyl-bis(oxazoline) (pybox) com- into the corresponding acetate esters 22a–22c that were
plexes could be exploited as valuable stereocontrolling then separately submitted to Heck coupling experiments
agents, which could enhance the low diastereoselection ex- (Scheme 6). We were particularly interested in the use of
erted by the Lewis acid alone. Among the various commer- immobilized transition metal catalysts as the palladium
cially available ligands tested, only (–)-2,6-bis[(4S)-iso- source, which offer the promise of easy handling, straight-
propyl-2-oxazolin-2-yl]pyridine furnished alcohol 2a as a forward separation from the reaction mixture, and de-
single diastereoisomer, albeit in low yield (20%) and re- creased product contamination as a result of metal leach-
duced reaction rate. The use of other box or pybox deriva- ing. The latter issue is particularly important in the field of
tives had a strong detrimental effect on the catalytic activity active pharmaceutical ingredients, in which the reduction of
of scandium(III) triflate, and only traces of diastereoisomer palladium content at the ppm level is required. The best
2a along with unreacted starting material were recovered.
results were obtained in the presence of commercially avail-
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Synthesis of Easily Functionalizable Azabicycloalkane Scaffolds
Scheme 6. Reagents and conditions: (i) Ac2O, DMAP, CH2Cl2, 60 °C (microwave), 1 h; (ii) 4-bromo-nitrobenzene, PdEnCat 30, Bu4NOAc,
EtOH, 120 °C (microwave); (iii) DBU, THF, 80 °C (microwave).
able PdEnCat 30, a polyurea-encapsulated Pd(OAc)2 cata- the Cαi-Cαi+3 distance (dα) confirms that the reverse-turn
lyst reported to be applicable to a variety of cross-coupling mimetic scaffolds induce rather “open” turns. Accordingly,
reactions, including the Heck coupling reaction.[32] By per- the lowest-energy conformer of 25 and 25a–25c features an
forming the reaction with microwave heating, we synthe- open turn, which induces the peptide backbone to reverse
sized the desired functionalized scaffolds 23a–23c without direction (Figure S4).
the need of any phosphine ligands in high yields (80–91%)
and relatively short reaction times (Ͻ1 h), thus confirming
the high reactivity of the exocyclic double bonds.
For the sake of completeness, we tested whether func-
tionalized scaffolds 23a–23c could be converted into the
same diene derivative 24, which allowed further optimiza-
tion of our synthetic strategy. The elimination reaction, re-
alized by heating each compound in the presence of DBU,
afforded 24 in satisfactory yields (75–78%). The same pro-
cedure could also be performed with comparable yields by
starting from a diastereoisomeric mixture of derivatives
23a–23c.
Conclusions
We have reported a new synthetic strategy to obtain 7,5-
fused 2-oxo-1-azabicycloalkane scaffolds characterized by
the presence of a vinyl moiety and a hydroxy group on the
seven-membered lactam ring at C5 and C4 positions,
respectively. These scaffolds are useful intermediates for the
synthesis of cRGD-based bioconjugates, which could find
potential applications in anticancer therapy. The key reac-
tion in the synthetic scheme is an intramolecular Hosomi–
Sakurai reaction, which allows the simultaneous generation
of both the lactam ring and the exocyclic double bond. The
synthetic sequence allows the gram-scale preparation of
scaffolds 2 in 8 steps and good 39% overall yield starting
from readily accessible materials. Even if the C5 exocyclic
double bond was designed as the privileged attachment
point for the conjugation of bioactive compounds, the
hydroxy group at C4 could be either a suitable conjugation
alternative, or a further conjugation site. In the case of ex-
clusive functionalization of the vinyl appendage, the OH
group should also be protected or eliminated, e.g. through
its conversion into an acetate or the formation of a C=C
double bond, by applying the reported functionalization
strategy. Finally, the C5 vinyl moiety has shown to be easily
functionalizable through a Heck-coupling reaction, thus
demonstrating it could be exploited as a point of attach-
ment for the synthesis of conjugate derivatives.
Computational Studies
Computational studies designed to investigate the ability
of the new azabicycloalkane scaffolds to adopt reverse-turn
conformations were performed on N-acetyl-NЈ-meth-
ylamide dipeptide analogues 25a–25c (Supporting Infor-
mation, Figure S3), featuring capping groups on the N- and
C-termini suitable for the definition of the various turn and
H-bond parameters. The preferred conformations of each
stereoisomeric scaffold were analyzed relative to the struc-
tures of the parent 7,5-fused azabicyclolactam derivative 25.
The turn propensity was quantitatively assessed by comput-
ing the percentage of conformations for which the afore-
mentioned parameters assume typical turn values. A sum-
mary of the reverse-turn mimetic properties of the calcu-
lated structures is reported in Table S1.
The quantitative characterization of the turn propensity
of the functionalized azabicycloalkane amino acid scaffolds
suggests that these systems are more effective as reverse-
turn mimetics than as β- or γ-turn mimics, in agreement
with the results obtained for the unsubstituted bicyclic
lactam. In fact, the percentages of conformers with a tor-
sion angle β (absolute value) of less than 60° are within a
range of 71–94%, whereas the percentages of conformers
that form intramolecular hydrogen bonds (by stabilizing
either a γ-turn or a β-turn) are significantly lower (20–37%
Experimental Section
General: All chemicals were of reagent grade and were used without
further purification. Solvents were purified in accordance with the
guidelines in Purification of Laboratory Chemicals.[33] All solvents
were freshly distilled from the appropriate drying agent. THF and
toluene were distilled from sodium/benzophenone ketyl, and trieth-
ylamine (TEA) and CH2Cl2 from CaH2. Reactions that required
anhydrous conditions were performed under N2. Yields were calcu-
lated for compounds purified by flash chromatography and judged
for γ-turn, 0% for β-turn, see Table S1). The analysis of homogeneous by thin-layer chromatography, NMR spectroscopy,
Eur. J. Org. Chem. 2015, 7557–7570
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7563

M. Serra, L. Colombo et al.
FULL PAPER
and mass spectrometry. Thin layer chromatography was performed
with Kieselgel 60 F254 (Merck) glass plates, and compounds were
visualized by a 254 nm UV lamp and stained with aqueous ceric
molybdate solution or iodine and a solution of 4,4Ј-methyl-
enebis(N,N-dimethylaniline), ninhydrin, and KI in an aqueous eth-
anolic solution of AcOH. Flash chromatography was performed
with Merck Kieselgel 60 (230–400 mesh). Optical rotations
[α]D were measured in a cell of 5 cm path length and 1 mL capacity
with a Jasco DIP-1000 polarimeter. IR spectra were recorded with
a Perkin–Elmer ATR-FTIR 1600 series spectrometer by using neat
samples. Mass spectra were recorded with a Finnigan LCQ-DECA
mass spectrometer. Elemental analyses were performed with a
Carlo Erba Elemental Analyzer Mod. 1106. Glassware for all reac-
tions was oven-dried at 110 °C and cooled in a desiccator, or flame-
dried and cooled under an inert gas prior to use. Liquid reagents
and solvents were introduced by oven-dried syringes through sep-
tum-sealed flasks under an inert gas.
drous Na2SO4, filtered, and the solvents evaporated in vacuo to
obtain compound 7 as an amorphous solid, without further purifi-
cation (92%). Rf = 0.30 (EtOAc). [α]2D2 –37.1 (c = 1.0, CDCl3). IR
(neat): ν = 3402 (br.), 1706, 1683, 1495, 1158 cm–1. 1H NMR ([D ]-
˜
6
DMSO, 90 °C, 400 MHz): δ = 1.44 (s, 9 H), 3.16 (d, J = 13.5 Hz,
1 H), 3.22 (d, J = 13.4 Hz, 1 H), 3.66 (d, J = 10.6 Hz, 1 H), 3.79
(d, J = 10.6 Hz, 1 H), 4.82–5.18 (br. s, 1 H, exchanges with D2O),
5.72 (s, 1 H), 7.13–7.30 (m, 5 H) ppm. 13C NMR ([D6]DMSO,
90 °C, 100 MHz): δ = 29.2, 37.4 (t), 64.1 (t), 65.5 (s), 79.2 (s), 127.1,
128.6, 131.0, 137.6 (s), 154.9 (s), 173.9 (s) ppm. MS (ESI): m/z =
296.3 [M + H]+, 318.3 [M + Na]+. C15H21NO5 (295.33): calcd. C
61.00, H 7.17, N 4.74; found C 60.84, H 7.23, N 4.65.
Synthesis of Benzyl (S)-2-Benzyl-2-(tert-butoxycarbonylamino)-3-
hydroxypropanoate (8): To a solution of 7 (5 g, 16.9 mmol) in dry
CH3CN (170 mL) under nitrogen were added sequentially CsCO3
(20.3 mmol) and benzyl bromide (20.3 mmol). The reaction mix-
ture was warmed to 50 °C and stirred for 1 h. After the reaction
Spectroscopic Methods: NMR spectra were acquired at 400 MHz was complete (TLC analysis), the CH3CN was removed under re-
for H and 100 MHz for 13C with a Bruker Avance 400 MHz spec-
trometer equipped with Bruker’s TopSpin 1.3 software package.
The abbreviatons s, d, t, q, br. s, and m stand for the resonance
multiplicities singlet, doublet, triplet, quartet, broad singlet, and
multiplet, respectively. The coupling constant values of complex
multiplets (e.g. dddd, ddddd) were confirmed by using multiplet
simulation procedures. In the peak listing of 13C spectra abbrevi-
ations s and t refer to zero and two protons attached to the carbon
atoms, respectively, as determined by DEPT-135 experiments.
Phase-sensitive 2D-NOESY experiments were performed at 298 K
by using the noesygpph pulse program from the Bruker library
(mixing time of 0.5 s). Sample temperatures were controlled with
the variable-temperature unit of the instrument.
duced pressure. Deionized water was added, and the aqueous phase
was extracted with CH2Cl2. The organic phases were collected,
dried with anhydrous Na2SO4, filtered, and the solvents evaporated
in vacuo. The crude mixture was purified by flash chromatography
to obtain pure compound 8 as an amorphous solid (84%). Rf =
0.34 (hexane/EtOAc, 75:25). [α]2D2 = +4.0 (c = 1.0, CDCl3). IR
1
(neat): ν = 3415, 1738, 1710, 1495, 1163 cm–1. 1H NMR ([D6]-
˜
DMSO, 90 °C, 400 MHz): δ = 1.42 (s, 9 H), 3.18 (d, J = 13.5 Hz,
1 H), 3.31 (d, J = 13.5 Hz, 1 H), 3.64 (d, J = 13.5 Hz, 1 H), 3.67
(d, J = 13.5 Hz, 1 H), 4.51–4.89 (br. s, 1 H, exchanges with D2O),
5.11 (d, J = 12.7 Hz, 1 H), 5.15 (d, J = 12.6 Hz, 2 H), 6.07 (s, 1
H), 7.09–7.16 (m, 2 H), 7.17–7.27 (m, 3 H), 7.29–7.40 (m, 5 H)
ppm. 13C NMR ([D6]DMSO, 90 °C, 100 MHz): δ = 29.1, 37.5 (t),
63.7 (t), 65.3 (s), 67.0 (t), 79.4 (s), 127.2, 128.6 (2 C), 128.7, 129.1,
131.1, 136.9 (s), 137.2 (s), 155.1 (s), 172.6 (s) ppm. MS (ESI): m/z
= 408.4 [M + Na]+. C22H27NO5 (385.46): calcd. C 68.55, H 7.06,
N 3.63; found C 68.78, H 7.22, N 3.68.
Synthesis of Methyl (S)-2-Benzyl-2-(tert-butoxycarbonylamino)-3-
hydroxypropanoate (6): To a solution of Boc2O (6.8 g, 31.1 mmol)
in dry THF (95 mL) under nitrogen and at 0 °C compound 5
(23.9 mmol) was added. The reaction mixture was then warmed to
room temperature and stirred for 24 h. A saturated solution of
NaCl (100 mL) was added to quench the reaction, and the aqueous
phase was extracted with Et2O and CH2Cl2. The organic phases
were collected, dried with anhydrous Na2SO4, filtered, and the sol-
vents evaporated in vacuo. The crude mixture was purified by flash
chromatography (hexane/EtOAc, 6:4) to obtain pure compound 6
as a pale yellow oil (88%). Rf = 0.4 (hexane/EtOAc, 60:40).
Synthesis of Benzyl (S)-2-Amino-2-benzyl-3-hydroxypropanoate (9):
A solution of compound 8 (1 g, 2.60 mmol), in saturated HCl
methanol (5 mL) was stirred at 0 °C for 3 h. After the reaction was
complete (TLC analysis), the MeOH was removed under reduced
pressure. The crude mixture was dissolved in deionized water
(15 mL) and washed with Et2O (3ϫ 5 mL). After basification with
solid K2CO3, the aqueous phase was carefully extracted with
CH2Cl2. The organic phases were collected, dried with anhydrous
[α]2D2 –50.6 (c = 1.0, CDCl ). IR (neat): ν = 3423 (br.), 1741, 1710,
˜
3
1495, 1159 cm–1. 1H NMR ([D6]DMSO, 90 °C, 400 MHz): δ = 1.44 Na2SO4, filtered, and the solvents evaporated in vacuo to obtain
(s, 9 H), 3.16 (d, J = 13.5 Hz, 1 H), 3.25 (d, J = 13.5 Hz, 1 H), compound 9 as an amorphous solid without further purification.
3.60 (dd, J = 5.2, 10.8 Hz, 1 H), 3.63–3.67 (m, 4 H), 4.64 (app t, 1
Rf = 0.31 (EtOAc/hexane, 7:3). [α]2D2 = +35.4 (c = 1.0, CDCl3). IR
H, exchanges with D2O), 5.97 (s, 1 H), 7.10–7.17 (m, 2 H), 7.18– (neat): ν = 3336, 3294, 3163 (br.), 1734, 1494, 1172 cm–1. 1H NMR
˜
7.30 (m, 3 H) ppm. 13C NMR ([D6]DMSO, 90 °C, 100 MHz): δ = ([D6]DMSO, 90 °C, 400 MHz): δ = 1.62–2.30 (br., 2 H, exchanges
29.1, 37.5 (t), 52.4, 63.7 (t), 65.4 (s), 79.4 (s), 127.2, 128.6, 131.0, with D2O), 2.77 (d, J = 13.3 Hz, 1 H), 2.98 (d, J = 13.3 Hz, 1 H),
137.3 (s), 155.1 (s), 173.2 (s) ppm. MS (ESI): m/z = 332.4 [M +
Na]+. C16H23NO5 (309.36): calcd. C 62.12, H 7.49, N 4.53; found
C 62.33, H 7.27, N 4.42.
3.45 (d, J = 10.3 Hz, 1 H), 3.75 (d, J = 10.3 Hz, 1 H), 4.38–4.89
(br., 1 H, exchanges with D2O), 5.10 (s, 2 H), 7.11–7.16 (m, 2 H),
7.18–7.24 (m, 3 H), 7.31–7.39 (m, 5 H) ppm. 13C NMR ([D6]
DMSO, 90 °C, 100 MHz): δ = 42.7 (t), 64.4 (s), 66.8 (t), 68.5 (t),
127.2, 128.6, 128.7 (2 C), 129.1, 130.9, 137.0 (s), 137.4 (s), 175.5 (s)
ppm. MS (ESI): m/z = 286.3 [M + H]+, 308.3 [M + Na]+.
C17H19NO3 (285.34): calcd. C 71.56, H 6.71, N 4.91; found C
71.41, H 6.54, N 4.82.
Synthesis of (S)-2-Benzyl-2-(tert-butoxycarbonylamino)-3-hydroxy-
propanoic Acid (7): To a solution of 6 (350 mg, 1.13 mmol) in THF
(11.3 mL) were added sequentially a solution of LiOH·H2O
(2.26 mmol) in water (5.3 mL) and MeOH until a homogeneous
solution was obtained. The reaction mixture was stirred at room
temperature for 2.5 h. After the reaction was complete (TLC analy-
sis), THF and MeOH were removed under reduced pressure, and
aqueous NaHCO3 was added. The aqueous phase was washed
twice with EtOAc, acidified with HCl (1 n) to pH = 1 and extracted
with CH2Cl2. The organic phases were collected, dried with anhy-
Synthesis of Benzyl (S)-2-Benzyl-2-(benzyloxycarbonylamino)-3-
hydroxypropanoate (10): To
a solution of Cbz2O (920 mg,
3.21 mmol) in dry THF (10.5 mL) under nitrogen at 0 °C, com-
pound 9 (705 mg, 2.47 mmol) was added. The reaction mixture was
then warmed to room temperature and stirred for 1 h. After the
7564
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7557–7570

Synthesis of Easily Functionalizable Azabicycloalkane Scaffolds
reaction was complete (TLC analysis), a saturated NaCl solution
was added to quench the reaction, and the aqueous phase was ex-
tracted once with Et2O and twice with CH2Cl2. The organic phases
were collected, dried with anhydrous Na2SO4, filtered, and the sol-
vents evaporated in vacuo. The crude mixture was purified by flash
chromatography (hexane/EtOAc, 60:40) to obtain the pure com-
pound as a yellow oil (92%, 2 steps). Rf = 0.28 (hexane/EtOAc,
ppm. 13C NMR ([D6]DMSO, 90 °C, 100 MHz): δ = 21.2, 38.4 (t),
63.4 (s), 64.6 (t), 66.5 (t), 127.6, 128.5, 128.6, 128.8, 129.1, 130.8,
136.2 (s), 137.9 (s), 155.3 (s), 170.4 (s), 172.4 (s) ppm. MS (ESI):
m/z = 372.4 [M + H]+, 394.4 [M + Na]+. C20H21NO6 (371.39):
calcd. C 64.68, H 5.70, N 3.77; found C 64.81, H 5.65, N 3.89.
Synthesis of Methyl (2S,5R)-1-[(S)-3-Acetoxy-2-benzyl-2-(benzyl-
oxycarbonylamino)propanoyl]-5-allylpyrrolidine-2-carboxylate (14):
To a solution of 12 (150 mg, 0.40 mmol) in dry CH2Cl2 (1.6 mL)
under nitrogen were added sequentially N,N-diisopropylethylamine
(DIEA; 0.44 mmol) and PyBroP (0.44 mmol). The reaction mixture
was stirred at room temperature for 2 h; then a solution of 13
(68 mg, 0.40 mmol) in dry CH2Cl2 (1.6 mL) and DMAP
(0.04 mmol) were added. After 24 h, the organic phase was concen-
trated under reduced pressure, and the crude mixture was purified
by flash chromatography (hexane/EtOAc, 70:30) to obtain com-
pound 14 as a pale yellow oil (60%). Rf = 0.37 (hexane/EtOAc,
60:40). [α]2D2 –10.1 (c = 1.0, CDCl ). IR (neat): ν = 3409 (br.), 1712,
˜
3
1495, 1213 cm–1. 1H NMR ([D6]DMSO, 90 °C, 400 MHz): δ = 3.19
(d, J = 13.5 Hz, 1 H), 3.31 (d, J = 13.5 Hz, 1 H), 3.68 (d, J = 5.2,
11.2 Hz, 1 H), 3.71 (d, J = 5.2, 11.2 Hz, 1 H), 4.76 (app t, J =
5.2 Hz, 1 H, exchanges with D2O), 5.06 (d, J = 12.6 Hz, 1 H), 5.09
(d, J = 12.6 Hz, 1 H), 5.11 (s, 2 H), 6.61 (s, 1 H), 7.04–7.12 (m, 2
H), 7.15–7.23 (m, 3 H), 7.22–7.42 (m, 10 H) ppm. 13C NMR ([D6]-
DMSO, 90 °C, 100 MHz): δ = 37.5 (t), 63.4 (t), 65.6 (s), 66.4 (t),
67.1 (t), 127.2, 128.5, (3 C), 128.6 (3 C), 128.7 (2 C), 129.1 (2 C),
131.1, 136.8 (s), 136.9 (s), 137.9 (s), 155.7 (s), 172.4 (s) ppm. MS
(ESI): m/z = 442.5 [M + Na]+. C25H25NO5 (419.48): calcd. C 71.58,
H 6.01, N 3.34; found C 71.82, H 6.08, N 3.42.
70:30). [α]2D2 –59.1 (c = 1.0, CDCl ). IR (neat): ν = 3308, 1790,
˜
3
1742, 1633, 1214 cm–1. H NMR ([D6]DMSO, 90 °C, 400 MHz): δ
1
= 1.66 (m, 1 H), 1.79 (m, 1 H), 1.88–2.02 (m, 2 H), 2.03 (s, 3 H),
2.25 (m, 1 H), 2.64 (m, 1 H), 3.23 (s, 2 H), 3.66 (s, 3 H), 4.08 (d, J
= 11.5 Hz, 1 H), 4.38 (m, 1 H), 4.48 (d, J = 11.5 Hz, 1 H), 4.64
(app t, J = 6.3 Hz, 1 H), 4.98–5.12 (m, 4 H), 5.81 (m, 1 H), 7.10–
7.19 (m, 3 H), 7.20–7.28 (m, 3 H), 7.29–7.41 (m, 5 H) ppm. 13C
NMR ([D6]DMSO, 90 °C, 100 MHz): δ = 21.2, 28.4 (t), 29.1 (t),
39.0 (t), 39.2 (t), 52.4, 59.5, 61.2, 63.4 (s), 64.0 (t), 66.8 (t), 117.4
(t), 127.6, 128.6, 128.8, 129.0, 131.0, 131.2, 136.0 (s), 136.2, 137.7
(s), 155.3 (s), 169.6 (s), 170.4 (s), 173.3 (s) ppm. MS (ESI): m/z =
523.6 [M + H]+, 545.6 [M + Na]+. C29H34N2O7 (522.60): calcd. C
66.65, H 6.56, N 5.36; found C 66.79, H 6.44, N 5.29.
Synthesis of Benzyl (S)-3-Acetoxy-2-benzyl-2-(benzyloxycarbonyl-
amino)propanoate (11): To a solution of 10 (1.98 g, 4.30 mmol) in
dry CH2Cl2 (17.2 mL) under nitrogen were added sequentially
Et3N (4.30 mmol), Ac2O (12.87 mmol) and 4-(dimethylamino)pyr-
idine (DMAP; 0.86 mmol). The reaction mixture was stirred at
room temperature for 1 h. After the reaction was complete (TLC
analysis), a saturated solution of NH4Cl was added to quench the
reaction, and the aqueous phase was extracted with CH2Cl2. The
organic layers were collected, dried with anhydrous Na2SO4, fil-
tered, and the solvents evaporated in vacuo. The crude mixture was
purified by flash chromatography (hexane/EtOAc, 75:25) to obtain
pure compound 11 as an oil (93%). Rf = 0.40 (hexane/EtOAc,
Synthesis of Methyl (2S,5R)-5-Allyl-1-[(S)-2-benzyl-2-(benzyloxy-
carbonylamino)-3-hydroxypropanoyl]pyrrolidine-2-carboxylate (4).
Starting from Compound 14: A solution of 14 (100 mg, 0.19 mmol),
in HCl-saturated methanol (0.5 mL) was stirred at 0 °C for 5 h.
After complete consumption of the starting material, the reaction
mixture was added to a saturated aqueous solution of NaHCO3
until neutralized, and extracted with EtOAc. The organic phases
were collected, dried with Na2SO4, filtered, and the solvents evapo-
rated in vacuo. The crude mixture was purified by flash chromatog-
raphy (hexane/EtOAc, 6:4) to obtain 4 as an oil (47%). Starting
from Compound 18: To compound 18 (2.15 g, 4.13 mmol) solubi-
lized in dry CH3CN under nitrogen was added bismuth triflate
(1.35 g, 2.06 mmol). After 10 min, a saturated solution of NaHCO3
was added to quench the reaction, until neutral pH was reached;
75:25). [α]2D2 –38.8 (c = 1.0, CDCl ). IR (neat): ν = 3419, 1741,
˜
3
1718, 1495, 1214 cm–1. H NMR ([D6]DMSO, 90 °C, 400 MHz): δ
1
= 2.00 (s, 3 H), 3.18 (d, J = 13.7 Hz, 1 H), 3.29 (d, J = 13.7 Hz, 1
H), 4.22 (d, J = 11.3 Hz, 1 H), 4.37 (d, J = 11.3 Hz, 1 H), 5.06 (d,
J = 12.6 Hz, 1 H), 5.09 (d, J = 12.4 Hz, 1 H), 5.10 (d, J = 12.6 Hz,
1 H), 5.12 (d, J = 12.4 Hz, 1 H), 7.01–7.07 (m, 2 H), 7.15 (br. s, 1
H), 7.20–7.25 (m, 3 H), 7.29–7.41 (m, 10 H) ppm. 13C NMR ([D6]-
DMSO, 90 °C, 100 MHz): δ = 21.1, 38.7 (t), 63.4 (s), 64.0 (t), 66.6
(t), 67.5 (t), 127.7, 128.5, 128.6, 128.9 (3 C), 129.1, 129.2, 131.0,
135.8 (s), 136.5 (s), 137.8 (s), 155.6 (s), 170.4 (s), 171.2 (s) ppm.
MS (ESI): m/z = 462.5 [M + H]+, 484.5 [M + Na]+. C27H27NO6
(461.51): calcd. C 70.27, H 5.90, N 3.03; found C 70.39, H 5.83, N
2.97.
Synthesis of (S)-3-Acetoxy-2-benzyl-2-(benzyloxycarbonylamino)- then the mixture was quickly extracted with CH2Cl2. The organic
propanoic Acid (12): To a solution of 11 (961 mg, 2.08 mmol) in
absolute EtOH (8.3 mL), under H2 (balloon), was added Pd/C(en)
(en = ethylenediamine) (961 mg). The reaction mixture was stirred
at room temperature for 3 h. After complete consumption of the
phases were collected, dried with Na2SO4, filtered, and the solvents
evaporated in vacuo. The crude mixture was purified by flash
chromatography (CH2Cl2/Et2O, 9:1) to obtain 4 as an oil (86%).
Rf = 0.36 (hexane/EtOAc, 6:4), Rf = 0.30 (CH2Cl2/Et2O, 9:1).
starting material, the reaction mixture was filtered through a pad [α]2D2 –10.4 (c = 1.0, CDCl ). IR (neat): ν = 3376 (br.), 1720, 1621,
˜
3
of Celite, and the organic phase was removed under reduced pres-
sure. The residue was taken up with a saturated aqueous solution
of NaHCO3 and washed with Et2O. The aqueous phase was cooled
to 0 °C, acidified to pH = 1 with HCl (12 n), and extracted with
CH2Cl2. The organic phases were collected, dried with anhydrous
Na2SO4, filtered, and the solvents evaporated in vacuo to obtain
the pure compound as an amorphous solid without further purifi-
cation (60%). Rf = 0.44 (EtOAc/MeOH, 80:20). [α]2D2 –43.4 (c =
1495, 1395 cm–1. 1H NMR ([D6]DMSO, 90 °C, 400 MHz): δ = 1.64
(m, 1 H), 1.78 (m, 1 H), 1.90 (m, 1 H), 2.01 (m, 1 H), 2.22 (m, 1
H), 2.65 (m, 1 H), 3.17 (d, J = 13.8 Hz, 1 H), 3.25 (d, J = 13.8 Hz,
1 H), 3.62 (dd, J = 5.3, 11.3 Hz, 1 H), 3.64 (s, 3 H), 3.73 (dd, J =
5.3, 11.3 Hz, 1 H), 4.31–4.41 (br., 1 H), 4.42 (app t, J = 5.3 Hz, 1
H, exchanges with D2O), 4.64 (m, 1 H), 4.96–5.11 (m, 4 H), 5.79
(m, 1 H), 6.78 (s, 1 H), 7.12–7.25 (m, 5 H), 7.29–7.42 (m, 5 H)
ppm. 13C NMR ([D6]DMSO, 90 °C, 100 MHz): δ = 28.2 (t), 29.1
(t), 38.1 (t), 39.1 (t), 52.4, 59.4, 61.2, 62.5 (t), 65.3 (s), 66.5 (t), 117.3
(t), 127.1, 128.6 (2 C), 128.7, 129.1, 131.4, 136.5, 137.2 (s), 137.8
(s), 155.4 (s), 170.8 (s), 173.6 (s) ppm. MS (ESI): m/z = 481.5 [M
+ H]+, 503.5 [M + Na]+. C27H32N2O6 (480.56): calcd. C 67.48, H
1.0, CDCl ). IR (neat): ν = 3412 (br.), 1738, 1714, 1495, 1214 cm–1.
˜
3
1H NMR ([D6]DMSO, 90 °C, 400 MHz): δ = 2.02 (s, 3 H), 3.19 (d,
J = 13.6 Hz, 1 H), 3.25 (d, J = 13.6 Hz, 1 H), 4.37 (AB system, J
= 11.3 Hz, 2 H), 5.09 (AB system, J = 13.2 Hz, 2 H), 6.63 (br. s, 1
H), 7.07–7.16 (m, 2 H), 7.18–7.29 (m, 3 H), 7.30–7.49 (m, 5 H) 6.71, N 5.83; found C 67.24, H 6.73, N 5.91.
Eur. J. Org. Chem. 2015, 7557–7570
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7565

M. Serra, L. Colombo et al.
FULL PAPER
Synthesis of 3-Benzyl 4-Methyl (S)-4-Benzyl-2,2-dimethyloxazolid-
4.04 (d, J = 9.3 Hz, 1 H), 4.23 (m, 1 H), 4.32 (d, J = 9.3 Hz, 1 H),
ine-3,4-dicarboxylate (16): To compound 15 (307 mg, 0.89 mmol) 4.71 (dd, J = 4.0, 7.8 Hz, 1 H), 4.99–5.16 (m, 4 H), 5.82 (m, 1 H),
solubilized in dry benzene (10.2 mL) under nitrogen were sequen-
tially added 2,2-dimethoxypropane (4.47 mmol) and p-toluen-
sulfonic acid (PTSA·H2O; 0.06 mmol). The reaction mixture was
heated to reflux with a Dean–Stark apparatus for 2 h to remove
H2O. After the reaction was complete (TLC analysis), a saturated
aqueous solution of NaHCO3 was added to quench the reaction.
The aqueous phase was extracted with EtOAc, and the organic
phases were collected, dried with anhydrous Na2SO4 filtered, and
the solvents evaporated in vacuo. The crude mixture was purified
by flash chromatography (hexane/EtOAc, 8:2) to obtain 16 as a
pale yellow oil (94%). Rf = 0.36 (hexane/EtOAc, 8:2). [α]2D2 = +91.6
7.11–7.28 (m, 5 H), 7.29–7.53 (m, 5 H) ppm. 13C NMR ([D6]
DMSO, 120 °C, 100 MHz): δ = 24.7, 25.6, 29.1 (t), 29.7 (t), 39.4
(t), 39.8 (t), 52.7, 60.4, 61.8, 67.1 (t), 71.3 (t), 72.2 (s), 96.6 (s),
117.2 (t), 127.3, 128.5, 128.6, 128.8, 129.1, 131.6, 136.2, 137.4 (s),
137.5 (s), 153.1 (s), 170.5 (s), 173.3 (s) ppm. MS (ESI): m/z = 521.6
[M + H]+, 543.6 [M + Na]+. C30H36N2O6 (520.62): calcd. C 69.21,
H 6.97, N 5.38; found C 69.33, H 7.08, N 5.42.
Synthesis of Methyl (2S,5R)-1-[(S)-2-Benzyl-2-(benzyloxycarbonyl-
amino)-3-hydroxypropanoyl]-5-[4-(trimethylsilyl)but-2-enyl]pyrrolid-
ine-2-carboxylate (19): G2 catalyst (18 mg, 0.02 mmol) was loaded
in a round-bottomed flask under argon. Compound 4 (100 mg,
0.21 mmol), solubilized in dry CH2Cl2 (2.1 mL), 2,6-dichloro-1,4-
benzoquinone (0.02 mmol), and allyltrimethylsilane (1.05 mmol)
were sequentially added, and the reaction mixture was heated to
reflux. Ethylene was bubbled into the reaction flask for 15 min, and
then a balloon was filled to maintain an atmosphere of ethylene.
After 2 h, a second portion of G2 (0.006 mmol) was added, and
the reaction mixture was heated to reflux for a further 6 h. After
the reaction was complete (TLC analysis), the solvent was removed
under reduced pressure. The crude mixture was purified by flash
chromatography (100 % hexane to remove the excess of allyltri-
methylsilane, then hexane/EtOAc, 65:35 to recover 19) to obtain
(c = 1.0, CDCl ). IR (neat): ν = 1739, 1696, 1399, 1380, 1343, 1244,
˜
3
1068 cm–1. H NMR ([D6]DMSO, 120 °C, 400 MHz): δ = 0.83 (s,
1
3 H), 1.49 (s, 3 H), 3.13 (d, J = 13.9 Hz, 1 H), 3.49 (d, J = 13.8 Hz,
1 H), 3.65 (s, 3 H), 4.04 (d, J = 9.4 Hz, 1 H), 4.15 (d, J = 9.4 Hz,
1 H), 5.11 (d, J = 12.3 Hz, 1 H), 5.20 (d, J = 12.3 Hz, 1 H), 7.10–
7.16 (m, 2 H), 7.19–7.27 (m, 3 H), 7.33–7.44 (m, 5 H) ppm. 13C
NMR ([D6]DMSO, 100 °C, 100 MHz): δ = 25.0, 25.5, 38.6 (t), 53.2,
67.3 (t), 69.6 (s), 71.5 (t), 96.9 (s), 127.5, 128.6, 128.8, 128.9, 129.2,
131.7, 136.9 (s), 137.3 (s), 152.5 (s), 173.0 (s) ppm. MS (ESI): m/z
= 384.4 [M + H]+, 406.4 [M + Na]+. C22H25NO5 (383.44): calcd.
C 68.91, H 6.57, N 3.65; found C 69.07, H 6.45, N 3.60.
Synthesis of (S)-4-Benzyl-3-(benzyloxycarbonyl)-2,2-dimethylox- compound 19 (oil) as a 7:3 mixture of (E) and (Z) isomers (75%).
azolidine-4-carboxylic Acid (17): To a solution of 16 (316 mg,
0.82 mmol) in THF (9 mL) were added sequentially a solution of
LiOH·H2O (3.29 mmol) in water (2 mL) and MeOH until a homo-
geneous solution was obtained. The reaction mixture was stirred at
room temperature for 24 h. After the reaction was complete (TLC
analysis), THF and MeOH were removed under reduced pressure,
and a saturated solution of NaHCO3 was added. The aqueous
phase was washed with Et2O, acidified with HCl (1 n) to pH = 1,
and extracted with CH2Cl2. The organic phases were collected,
dried with anhydrous Na2SO4, filtered, and the solvents evaporated
in vacuo to obtain compound 17 as an amorphous solid without
Rf = 0.36 (hexane/EtOAc, 65:35). [α]2D2 = +5.3 (c = 1.0, CDCl3). IR
(neat): ν = 3375.8 (br.), 1722, 1621, 1495, 1395 cm–1. 1H NMR
˜
([D6]DMSO, 120 °C, 400 MHz, mixture of diastereoisomers): δ =
(–0.03)–0.07 (m, 9 H), 1.43 (d, J = 7.9 Hz, 1.35 H), 1.50 (d, J =
8.5 Hz, 0.55 H), 1.56–1.82 (m, 2 H), 1.88 (m, 1 H), 2.00 (m, 1 H),
2.07–2.19 (m, 0.67 H), 2.22–2.35 (m, 0.33 H), 2.64 (m, 1 H), 3.13–
3.30 (m, 2 H), 3.59–3.68 (m, 4 H), 3.73 (m, 1 H), 4.25–4.46 (br., 1
H), 4.63 (m, 1 H), 5.02 (d, J = 12.6 Hz, 1 H), 5.07 (d, J = 12.6 Hz,
1 H), 5.24 (m, 1 H), 5.46 (m, 1 H), 6.75 (br. s, 1 H), 7.10–7.25 (m,
5 H), 7.27–7.43 (m, 5 H) ppm. 13C NMR ([D6]DMSO, 120 °C,
100 MHz mixture of diastereoisomers): δ = –1.0, –0.9, –0.3, 19.2
further purification (92%). Rf = 0.3 (CH2Cl2/MeOH, 9:1, 0.1% (t), 23.2 (t), 29.1 (t), 29.3 (t), 32.5 (t), 38.0 (t), 38.1 (t), 38.2 (t),
AcOH). [α]2D2 = +96.3 (c = 1.0, CDCl ). IR (neat): ν = 3172 (br.),
52.3, 52.4, 60.1, 61.2, 61.3, 62.5 (t), 65.3 (s), 65.4 (s), 66.5 (t), 124.7,
˜
3
1740, 1699, 1346 cm–1. H NMR ([D6]DMSO, 120 °C, 400 MHz): 126.1, 127.1, 128.0, 128.5 (2 C), 128.6 (2 C), 129.0 (2 C), 129.2,
δ = 0.87 (s, 3 H), 1.50 (s, 3 H), 3.13 (d, J = 13.9 Hz, 1 H), 3.53 (d, 131.3 (2 C), 131.4; 137.1 (s), 137.2 (s), 137.8 (s, 2 C), 155.3 (s),
J = 13.9 Hz, 1 H), 4.07 (d, J = 9.2 Hz, 1 H), 4.14 (d, J = 9.2 Hz, 170.8 (s, 2 C), 173.6 (s), 173.7 (s) ppm. MS (ESI): m/z = 567.8 [M
1
1 H), 5.17 (AB system, 2 H), 7.11–7.16 (m, 2 H), 7.17–7.25 (m, 3
+ H]+, 589.8 [M + Na]+. C31H42N2O6Si (566.77): calcd. C 65.69,
H), 7.30–7.46 (m, 5 H) ppm. 13C NMR ([D6]DMSO, 120 °C, H 7.47, N 4.94; found C 65.47, H 7.50, N 4.86.
100 MHz): δ = 25.1, 25.6, 38.8 (t), 67.2 (t), 69.6 (s), 71.8 (t), 96.8
Synthesis of Methyl (2S,5R)-5-Allyl-1-[(S)-2-benzyl-2-(benzyloxy-
(s), 127.3, 128.5, 128.7 (2 C), 129.1, 131.6, 137.4 (s, 2 C), 152.7, (s),
173.8, (s) ppm. MS (ESI): m/z = 370.4, [M + H]+, 392.4, [M +
Na]+. C21H23NO5 (369.42): calcd. C 68.28, H 6.28, N 3.79; found
C 68.53, H 6.18, N 3.87.
carbonylamino)-3-oxopropanoyl]pyrrolidine-2-carboxylate (20): Ox-
alyl chloride (2 m) in CH2Cl2 (4.23 mL) was cooled to –60 °C under
nitrogen, and a solution of freshly distilled DMSO (0.8 mL,
11.28 mmol) in dry CH2Cl2 (3.76 mL) was added dropwise. After
Synthesis of Benzyl (S)-4-[(2R,5S)-2-Allyl-5-(methoxycarbonyl)- 30 min, a solution of 4 (1.36 g, 2.82 mmol) in dry CH2Cl2
pyrrolidine-1-carbonyl]-4-benzyl-2,2-dimethyloxazolidine-3-carb- (17.1 mL) was added, and the reaction mixture was stirred for a
oxylate (18): Compounds 17 (1.78 g, 4.84 mmol) and 13 (1 g, further 30 min. Then, a solution of Et3N (2.28 mL, 22.56 mmol) in
5.91 mmol) were solubilized in dry CH2Cl2 (52.8 mL) under nitro- dry CH2Cl2 (6.8 mL) was added, and the reaction mixture was
gen. After 5 min, DIEA (5 mmol), PyBroP (5 mmol), and DMAP slowly warmed to 0 °C. After the reaction was complete (TLC
(1.82 mmol) were added sequentially. The reaction mixture was
stirred at room temperature for 24 h. After the reaction was com-
plete (TLC analysis), the solvent was removed under reduced pres-
sure, and the crude mixture was purified by flash chromatography
(hexane/EtOAc, 75:25) to obtain compound 18 as a pale yellow oil
(85%). Rf = 0.36 (hexane/EtOAc, 75:25). [α]2D2 = +20.5 (c = 1.0,
analysis, CH2Cl2/Et2O, 95:05), phosphate buffer (pH = 7) was
added to quench the reaction, and the aqueous phase was extracted
with CH2Cl2. The organic phases were collected, dried with anhy-
drous Na2SO4, filtered, and the solvents evaporated in vacuo. The
crude mixture was purified by flash chromatography (CH2Cl2/
Et2O, 95:05) to obtain 20 as an oil (88%). Rf = 0.38 (CH2Cl2/Et2O,
CDCl ). IR (neat): ν = 1748, 1703, 1638, 1341 cm–1. 1H NMR ([D ]-
95:05). [α]2D2 –21.1 (c = 1.0, CDCl ). IR (neat): ν = 3373, 3316,
˜
˜
3
6
3
DMSO, 120 °C, 400 MHz): δ = 0.86 (s, 3 H), 1.45 (s, 3 H), 1.62
1734, 1715, 1634, 996, 915 cm–1. 1H NMR ([D6]DMSO, 120 °C,
(m, 1 H), 1.92–2.14 (m, 3 H), 2.23 (m, 1 H), 2.68 (m, 1 H), 3.15 400 MHz): δ = 1.62 (m, 1 H), 1.81 (m, 1 H), 1.88–2.01 (m, 2 H),
(d, J = 13.4 Hz, 1 H), 3.56 (d, J = 13.4 Hz, 1 H), 3.68 (s, 3 H), 2.18 (m, 1 H), 2.53–2.65 (br., 1 H), 3.37 (d, J = 14.2 Hz, 1 H), 3.42
7566
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7557–7570

Synthesis of Easily Functionalizable Azabicycloalkane Scaffolds
(d, J = 14.2 Hz, 1 H), 3.64 (s, 3 H), 4.13 (m, 1 H), 4.58 (app t, J =
6.3 Hz, 1 H), 4.99–5.10 (m, 2 H), 5.04 (d, J = 12.5 Hz, 1 H), 5.10
(d, J = 12.5 Hz, 1 H), 5.78 (dddd, J = 6.4, 7.6, 10.3, 17.2 Hz, 1 H),
7.05–7.15 (m, 3 H), 7.19–7.28 (m, 3 H), 7.29–7.41 (m, 5 H), 9.80
(s, 1 H) ppm. 13C NMR ([D6]DMSO, 120 °C, 100 MHz): δ = 28.8
(t, 2 C), 38.9 (t), 39.1 (t), 52.5, 59.9, 60.9, 67.3 (t), 70.9 (s), 117.4
(t), 127.8, 128.7 (2 C), 128.9, 129.1, 131.2, 135.2 (s), 136.0, 137.3
(s), 155.6 (s), 166.9 (s), 172.9 (s), 197.8 ppm. MS (ESI): m/z = 501.3
[M + Na]+. C27H30N2O6 (478.54): calcd. C 67.77, H 6.32, N 5.85;
found C 67.93, H 6.42, N 5.85.
128.3, 128.6, 128.7 (2 C), 128.9 (2 C), 129.1, 129.5, 131.2, 135.1 (s),
137.3 (s), 155.6 (s, 2 C), 166.7 (s), 167.0 (s), 172.9 (s, 2 C), 198.0,
198.1 ppm. C31H40N2O6Si (564.75): calcd. C 65.93, H 7.14, N 4.96;
found C 66.08, H 7.23, N 5.01.
Synthesis of Methyl (3S,6S,9aR)-6-Benzyl-6-(benzyloxycarbonyl-
amino)-7-hydroxy-5-oxo-8-vinyloctahydro-1H-pyrrolo[1,2-a]azepine-
3-carboxylate (2): Compound 3 [mixture of (E)/(Z) isomers, 1.01 g,
1.79 mmol] was solubilized in dry CH2Cl2 (17.9 mL) under nitro-
gen and cooled to –10 °C. Sc(OTf)3 (2.15 mmol) was added; after
30 min, the reaction mixture was warmed to room temperature.
Synthesis of Methyl (2S,5R)-1-[(S)-2-Benzyl-2-(benzyloxycarbonyl- After 5 h, the reaction mixture was filtered through a pad of Celite.
amino)-3-oxopropanoyl]-5-[4-(trimethylsilyl)but-2-enyl]pyrrolidine- CH2Cl2 was removed under reduced pressure. The crude mixture
2-carboxylate [3, (E) + (Z) Mixture). Starting from Compound 19: was purified by flash chromatography (hexane/EtOAc, 65:35) to
Oxalyl chloride (2 m) in CH2Cl2 (0.32 mL, 0.64 mmol) was cooled
to –60 °C under nitrogen, and a solution of freshly distilled DMSO
obtain compounds 2a (49%), 2b (16%), and 2c (21%) as foamy
solids. Compound 2a: Rf = 0.36 (hexane/EtOAc, 65:35). [α]2D2 –34.9
(0.06 mL, 0.85 mmol) in dry CH2Cl2 (0.25 mL) was added drop- (c = 0.5, CDCl ). IR (neat): ν = 3364, 3361 (br.), 1745, 1700,
˜
3
wise. After 30 min, a solution of 19 (121 mg, 0.21 mmol) in dry
CH2Cl2 (1.27 mL) was added, and the reaction mixture was stirred
for a further 30 min. Then, a solution of Et3N (0.23 mL,
1.71 mmol) in dry CH2Cl2 (0.51 mL) was added, and the reaction
mixture was slowly warmed to 0 °C. After the reaction was com-
plete (TLC analysis, hexane/EtOAc, 6:4), phosphate buffer (pH =
7) was added to quench the reaction, and the aqueous phase was
extracted with CH2Cl2. The organic phases were collected, dried
with anhydrous Na2SO4, filtered, and the solvents evaporated in
vacuo. The crude mixture was purified by flash chromatography
(hexane/EtOAc, 85:15) to obtain 3 (pale yellow oil) as a 7:3 mixture
of (E)/(Z) isomers (90%). Starting from Compound 20: HG2 cata-
lyst (0.04 mmol) was loaded in a dry round-bottomed flask under
1637 cm–1. 1H NMR ([D6]DMSO, 400 MHz): δ = 1.57 (m, 1 H,
H6), 1.69 (m, 1 H, H6), 1.79 (m, 1 H, H8), 1.91 (m, 1 H, H9), 2.22–
2.38 (m, 3 H, H5, H8, H9), 2.99 (d, J = 14.0 Hz, 1 H, Hb), 3.51 (d,
J = 14.0 Hz, 1 H, Hb), 3.57 (s, 3 H, CO2CH3), 4.18 (t, J = 7.6 Hz,
1 H, H10), 4.28 (d, J = 5.7 Hz, 1 H, H4, singlet after exchange with
D2O), 4.59 (m, 1 H, H7), 4.92–5.06 (m, 3 H, OCH2Ph, HC, HT),
5.21 (d, J = 12.5 Hz, 1 H, OCH2Ph), 5.90 (ddd, J = 7.8, 10.2,
17.7 Hz, 1 H, HV), 5.98 (d, J = 5.7 Hz, 1 H, OH, exchanges with
D2O), 6.19 (s, 1 H, NH), 6.73 (app d, J = 6.7 Hz, 2 H, ArH), 7.04–
7.16 (m, 3 H, ArH), 7.32–7.46 (m, 5 H, ArH) ppm. 13C NMR ([D6]
DMSO, 75 MHz): δ = 26.5 (t), 30.7 (t), 33.3 (t), 34.7 (t), 42.9, 51.8,
53.9, 60.8, 65.4 (t), 68.4 (s), 73.7, 114.0 (t), 126.2, 127.7, 128.0 (2
C), 128.4, 129.9, 136.4 (s), 136.9 (s), 141.6, 153.8 (s), 168.3 (s), 172.3
argon. Compound 20 (200 mg, 0.42 mmol), solubilized in dry (s) ppm. MS (ESI): m/z = 493.6 [M + H]+, 515.6 [M + Na]+. MS
CH2Cl2 (4.2 mL), 2,6-dichloro-1,4-benzoquinone (0.042 mmol),
and allyltrimethylsilane (2.09 mmol) were then sequentially added,
and the reaction mixture was heated to reflux. After 3 h, a second
portion of HG2 (0.021 mmol) was added, and the reaction mixture
was heated to reflux for a further 8 h. After the reaction was com-
(ESI): m/z = 501.3 [M + Na]+. C28H32N2O6 (492.57): calcd. C
68.28, H 6.55, N 5.69; found C 68.41, H 6.49, N 5.57. Compound
2b: Rf = 0.30 (hexane/EtOAc, 65:35). [α]2D2 –55.8 (c = 0.6, CDCl3).
IR (neat): ν = 3415, 3296 (br.), 1735, 1687, 1625 cm–1. 1H NMR
˜
([D6]DMSO, 400 MHz): δ = 1.57–1.76 (m, 2 H, H6, H8), 1.82–1.96
plete (TLC analysis), CH2Cl2 was removed under reduced pressure. (m, 2 H, H6, H9), 2.07 (m, 1 H, H9), 2.24 (m, 1 H, H8), 2.76 (m, 1
The crude mixture was purified by flash chromatography (hexane/ H, H5), 3.34 (d, J = 14.1 Hz, 1 H, Hb), 3.41 (d, J = 14.1 Hz, 1 H,
EtOAc, 85:15) to obtain compound 3 as a 7:3 mixture of (E)/(Z) Hb) 3.59 (s, 3 H, CO2CH3), 4.06 (dd, J = 5.7, 10.1 Hz, 1 H, H4,
isomers (84%). Compound 3a: Rf = 0.33 (hexane/EtOAc, 85:15). 1H doublet after exchange with D2O), 4.16 (d, J = 8.7 Hz, 1 H, H10),
NMR ([D6]DMSO, 120 °C, 400 MHz): δ = 0.02 (s, 9 H), 1.51 (app
d, J = 8.5 Hz, 2 H), 1.59 (m, 1 H), 1.80 (m, 1 H), 1.87–1.99 (m, 2
H), 2.20 (m, 1 H), 2.55 (m, 1 H), 3.38 (AB system, 2 H), 3.63 (s, 3
4.32 (m, 1 H, H7), 4.93 (d, J = 12.5 Hz, 1 H, OCH2Ph), 4.97–5.18
(m, 4 H, OH, OCH2Ph, HC, HT, 1 H exchanges with D2O), 5.86–
6.09 (m, 2 H, HV, NH), 6.94–7.08 (m, 2 H, ArH), 7.15–7.26 (m, 3
H), 4.08 (m, 1 H), 4.58 (app t, J = 6.2 Hz, 1 H), 5.04 (d, J = H, ArH), 7.28–7.41 (m, 5 H, ArH) ppm. 13C NMR ([D6]DMSO,
12.6 Hz, 1 H), 5.08 (d, J = 12.6 Hz, 1 H), 5.24 (ddddd, J1 = J2 =
100 MHz): δ = 27.5 (t), 32.9 (t), 34.3 (t), 39.2 (t), 46.3, 52.7, 57.4,
1.5, J3 = 6.3 Hz, J4 = 7.9 Hz, J5 = 10.2 Hz, 1 H), 5.49 (ddddd, J1 63.4, 66.2 (t), 70.2 (s), 74.3, 114.9 (t), 127.6, 128.6 (2 C), 129.1 (2
= J2 = 1.7, J3 = J4 = 8.5 Hz, J5 = 10.2 Hz, 1 H), 7.04–7.14 (m, 3 C), 130.7, 136.5 (s), 137.8 (s), 143.3, 156.1 (s), 168.9 (s), 173.0 (s)
H), 7.19–7.27 (m, 3 H), 7.30–7.41 (m, 5 H), 9.79 (s, 1 H) ppm. MS
(ESI): m/z = 565.7 [M + H]+, 587.7 [M + Na]+. Compound 3b: Rf
= 0.31 (hexane/EtOAc, 85:15). [α]2D2 –12.4 (c = 1.0, CDCl3). IR
ppm. MS (ESI): m/z = 493.6 [M + H]+, 515.6 [M + Na]+.
C28H32N2O6 (492.57): calcd. C 68.28, H 6.55, N 5.69; found C
68.34, H 6.43, N 5.61. Compound 2c: Rf = 0.27 (hexane/EtOAc,
(neat): ν = 3380, 2840, 2720, 1736, 1716, 1635 cm–1. 1H NMR ([D ]- 65:35). [α]2D2 –81.9 (c = 1.4, CDCl ). IR (neat): ν = 3349 (br.), 1738,
˜
˜
6
3
DMSO, 120 °C, 400 MHz): δ = 0.18 (m, 9 H), 1.44 (app d, J = 1700, 1623 cm–1. 1H NMR ([D6]DMSO, 400 MHz): δ = 1.62 (br.
7.9 Hz, 2 H), 1.57–1.69 (m, 1 H), 1.70–1.82 (m, 1 H), 1.85–2.00 (m, d, J = 13.0 Hz, 1 H, H6), 1.78 (m, 1 H, H8), 1.90 (m, 1 H, H9),
2 H), 2.02–2.14 (m, 1 H), 2.50–2.58 (m, 1 H), 3.36 (d, J = 14.3 Hz, 2.05–2.21 (m, 2 H, H6, H9), 2.26 (m, 1 H, H8), 2.82 (br. t, J =
1 H), 3.41 (d, J = 14.3 Hz, 1 H), 3.63 (s, 3 H), 4.00–4.09 (m, 1 H),
4.54 (app t, J = 6.6 Hz, 1 H), 5.04 (d, J = 12.5 Hz, 1 H), 5.09 (d,
9.6 Hz, 1 H, H5), 3.35 (d, J = 13.6 Hz, 1 H, Hb), 3.40 (d, J =
13.6 Hz, 1 H, Hb), 3.58 (s, 3 H, CO2CH3), 4.28 (d, J = 8.9 Hz, 1
J = 12.5 Hz, 1 H), 5.16–5.26 (ddddd, J1 = J2 = 1.3 Hz, J3 = 7.6 Hz, H, H10), 4.38 (m, 1 H, H7), 4.48 (d, J = 5.3 Hz, 1 H, H4, singlet
J4 = 9.0 Hz, J5 = 15.4 Hz, 1 H), 5.41–5.51 (ddddd, J1 = J2 = 1.3, after exchange with D2O), 4.90 (d, J = 12.6 Hz, 1 H, OCH2Ph),
J3 = J4 = 7.9 Hz, J5 = 15.4 Hz, 1 H), 7.01–7.12 (m, 3 H), 7.17–7.27 5.05 (dd, J = 1.5, 10.3 Hz, 1 H, HC), 5.11–5.23 (m, 2 H, OCH2Ph,
(m, 3 H), 7.29–7.41 (m, 5 H), 9.77 (s, 1 H) ppm. MS (ESI): m/z = HT), 5.30 (d, J = 5.3 Hz, 1 H, OH, exchanges with D2O), 5.94 (ddd,
565.7 [M + H]+, 587.7 [M + Na]+. 13C NMR ([D6]DMSO, 120 °C, J = 7.5, 10.3, 17.5 Hz, 1 H, HV), 6.31 (s, 1 H, NH), 6.73–6.83 (m,
100 MHz mixture of diastereoisomers): δ = –1.1, –0.9, –0.3, 19.2
(t), 23.3 (t), 28.8 (t), 32.2 (t), 37.8 (t), 39.0 (t), 39.1 (t) 52.6 (3 C), ppm. 13C NMR ([D6]DMSO, 100 MHz): δ = 27.5 (t), 33.6 (t), 33.8
60.5, 60.8, 67.2 (t, 2 C), 70.7 (s, 2 C), 124.2, 125.6, 127.8 (2 C), (t), 34.5 (t), 43.9, 52.6, 58.6, 63.5, 65.8 (t), 69.6 (s), 70.6, 115.1 (t),
2 H, ArH), 7.07–7.19 (m, 3 H, ArH), 7.30–7.44 (m, 5 H, ArH)
Eur. J. Org. Chem. 2015, 7557–7570
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7567

M. Serra, L. Colombo et al.
FULL PAPER
127.3, 128.6, 128.7 128.8, 129.2, 130.3, 136.9 (s), 138.0 (s), 143.1,
153.9 (s), 169.7 (s), 172.9 (s) ppm. MS (ESI): m/z = 493.6 [M +
H]+, 515.6 [M + Na]+. C28H32N2O6 (492.57): calcd. C 68.28, H
6.55, N 5.69; found C 68.13, H 6.51, N 5.76.
0.36 (CH2Cl2/Et2O, 93:07); PhCH3/EtOAc, 80:20; Rf = 0.35.
[α]2D2 –73 (c = 0.75, CDCl ). IR (neat): ν = 3376, 1740, 1720, 1630,
˜
3
1483, 1424, 1198, 698 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 1.91
(m, 1 H), 2.03 (s, 3 H), 2.06–2.32 (m, 4 H), 2.38 (m, 1 H), 2.98 (m,
1 H), 3.28 (d, J = 13.6 Hz, 1 H), 3.74 (s, 3 H), 3.87 (d, J = 13.6 Hz,
1 H), 4.36 (m, 1 H), 4.59 (app d, J = 7.5 Hz, 1 H), 5.00 (d, J =
12.4 Hz, 1 H), 5.13 (d, J = 10.4 Hz, 1 H), 5.17 (d, J = 17.0 Hz, 1
H), 5.27 (d, J = 12.4 Hz, 1 H), 5.87 (ddd, J = 6.1, 10.5, 17.0 Hz, 1
H), 6.21 (s, 1 H), 6.45 (s, 1 H), 6.79–6.85 (m, 2 H), 7.09–7.15 (m,
2 H), 7.15–7.22 (m, 1 H), 7.30–7.41 (m, 5 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 21.0, 27.7 (t), 33.6 (t), 33.9 (t), 34.5 (t),
42.1, 52.6, 58.5, 63.4, 66.4 (t), 67.6 (s), 72.1, 116.1 (t), 127.4, 128.2,
128.5, 128.7 (2 C), 129.9, 135.3 (s),137.5 (s), 139.3, 154.5 (s), 168.6
(s), 170.3 (s), 172.6 (s) ppm. MS (ESI): m/z = 557.4 [M + Na]+.
C30H34N2O7 (534.61): calcd. C 67.40, H 6.41, N 5.24; found C
67.29, H 6.44, N 5.33.
Synthesis of Methyl (3S,6S,9aR)-7-Acetoxy-6-benzyl-6-(benzyloxy-
carbonylamino)-5-oxo-8-vinyloctahydro-1H-pyrrolo[1,2-a]azepine-
3-carboxylate (22). General Procedure: To a solution of compounds
2a–2c in dry CH2Cl2 (0.1 m), Ac2O (5 equiv.) was added dropwise,
followed by DMAP (1 equiv.). The pH was monitored (litmus test)
and, if necessary, Et3N was added to basify the solution. The reac-
tion mixture was heated by using microwaves and, after the reac-
tion was complete (TLC analysis), a saturated solution of NH4Cl
was added to quench the reaction. The aqueous phase was ex-
tracted with CH2Cl2, and the organic phases were collected, dried
with anhydrous Na2SO4, filtered, and the solvents evaporated in
vacuo. The crude mixture was purified by flash chromatography.
Compound 22a: Compound 22a was synthesized from 2a (100 mg,
0.2 mmol) by applying the above general procedure. After 30 min
of microwave heating at 60 °C, additional Ac2O (5 equiv.) was
added, and the reaction mixture was irradiated at 60 °C for 1 h.
The crude mixture was purified by flash chromatography (hexane/
EtOAc, 60:40) to obtain 22a as a foamy solid (93%). Rf = 0.34
Synthesis of Methyl (3S,6S,9aR)-7-Acetoxy-6-benzyl-6-(benzyl-
oxycarbonylamino)-8-(4-nitrostyryl)-5-oxooctahydro-1H-pyrrolo-
[1,2-a]azepine-3-carboxylate (23). General Procedure: To a solution
of 22a–22c in EtOH 99% (0.1 m) under nitrogen were added se-
quentially 1-bromo-4-nitrobenzene (1.1 equiv.), PdEnCat 30
(0.05 equiv.) and Bu4NOAc (3 equiv.). The reaction mixture was
heated in a microwave oven; after the reaction was complete (TLC
(hexane/EtOAc, 6:4). [α]2D2 –50 (c = 1.5, CDCl ). IR (neat): ν =
˜
3
3363, 1744, 1719, 1639, 1421, 1198, 699 cm–1. 1H NMR (CDCl3, analysis), the reaction mixture was separated by filtration and
400 MHz): δ = 1.78 (m, 1 H), 1.89 (m, 1 H), 2.00 (m, 1 H), 2.10 washed with EtOH. The crude mixture was purified by flash
(m, 1 H), 2.24 (s, 3 H), 2.29–2.48 (m, 2 H), 2.83 (m, 1 H), 3.06 (d,
chromatography. Compound 23a (E): Compound 22a (E) was syn-
J = 13.9 Hz, 1 H), 3.62 (d, J = 13.9 Hz, 1 H), 3.70 (s, 3 H), 4.38 thesized from 22a (50 mg, 0.09 mmol) by applying the general pro-
(t, J = 7.5 Hz, 1 H), 4.64 (m, 1 H), 5.03 (d, J = 12.2 Hz, 1 H), 5.06 cedure. After 30 min of microwave heating at 120 °C, the reaction
(d, J = 10.2 Hz, 1 H), 5.10 (d, J = 17.0 Hz, 1 H), 5.36 (d, J =
12.2 Hz, 1 H), 5.87 (ddd, J = 6.9, 10.2, 17.1 Hz, 1 H), 5.91 (s, 1 raphy to obtain 23a as an amorphous solid (91%). Rf = 0.37 (hex-
H), 6.47 (s, 1 H), 6.79 (d, J = 7.1 Hz, 2 H), 7.07–7.23 (m, 3 H),
ane/EtOAc, 65:35). [α]2D2 –8.5 (c = 0.50, CDCl ). IR (neat): ν =
7.30–7.45 (m, 5 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 21.5, 2923, 2852, 2690, 1756, 1716, 1649, 1482, 1340, 1193, 699 cm–1. 1H
was complete. The crude mixture was purified by flash chromatog-
˜
3
27.3 (t), 32.2 (t), 34.1 (t), 35.6 (t), 42.8, 52.7, 54.7, 61.7, 66.6 (t),
68.1 (s), 76.4, 115.5 (t), 127.5, 128.4, 128.5, 128.6, 128.8, 130.3,
135.5 (s), 137.1 (s), 139.5, 154.9 (s), 168.2 (s), 169.4 (s), 173.0 (s)
NMR (CDCl3, 400 MHz): δ = 1.85 (m, 1 H), 1.94–2.20 (m, 3 H),
2.29 (s, 3 H), 2.35–2.53 (m, 2 H), 3.04–3.15 (m, 2 H), 3.64 (d, J =
13.6 Hz, 1 H), 3.73 (s, 3 H), 4.43 (app t, J = 7.5 Hz, 1 H), 4.71 (m,
ppm. MS (ESI): m/z = 557.4 [M + Na]+. C30H34N2O7 (534.61): 1 H), 5.01 (d, J = 12.3 Hz, 1 H), 5.36 (d, J = 12.3 Hz, 1 H), 5.98
calcd. C 67.40, H 6.41, N 5.24; found C 67.59, H 6.47, N 5.31.
Compound 22b: Compound 22b was synthesized from 2b (100 mg,
0.2 mmol) by applying the general procedure. After 30 min of mi-
crowave heating at 60 °C, additional Ac2O (5 equiv.) was added,
and then the solution was irradiated at 60 °C for 30 min. The crude
mixture was purified by flash chromatography (CH2Cl2/Et2O,
94:06) to obtain 22b as a foamy solid (92%). Rf = 0.36 (CH2Cl2/
(s, 1 H), 6.40 (dd, J = 7.1, 16.0 Hz, 1 H), 6.48 (s, 1 H), 6.52 (d, J
= 16.0 Hz, 1 H), 6.79 (d, J = 7.2 Hz, 2 H), 7.08–7.24 (m, 3 H),
7.30–7.44 (m, 5 H), 7.48 (d, J = 8.5 Hz, 2 H), 8.16 (d, J = 8.5 Hz,
2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 21.4, 27.2 (t), 32.0 (t),
34.3 (t), 35.5 (t), 42.6, 52.7, 54.5, 61.5, 66.6 (t), 67.9 (s), 76.1, 124.1,
127.2, 127.4, 128.3, 128.4, 128.6, 128.7, 129.9, 130.1, 135.1 (s),
136.4, 136.8 (s), 144.0 (s), 147.0 (s), 154.8 (s), 167.9 (s), 169.5 (s),
173.1 (s) ppm. MS (ESI): m/z = 678.4 [M + Na]+. C36H37N3O9
Et2O, 94:06). [α]2D2 –79 (c = 1.75, CDCl ). IR (neat): ν = 3314, 1752,
˜
3
1737, 1725, 1635, 1491, 1197, 699 cm–1
400 MHz): δ = 1.91 (m, 1 H), 1.89 (s, 3 H), 1.97–2.08 (m, 4 H), 6.44. Compound 23b (E): Compound 23b (E) was synthesized from
2.32 (m, 1 H), 2.92 (m, 1 H), 3.35 (d, J = 14.5 Hz, 1 H), 3.73 (s, 3 22b (50 mg, 0.09 mmol) by applying the general procedure. After
H), 4.26–4.37 (m, 2 H), 4.38 (d, J = 14.5 Hz, 1 H), 4.99 (d, J = 1 h of microwave heating at 120 °C, the reaction was complete. The
.
1H NMR (CDCl3, (655.70): calcd. C 65.94, H 5.69, N 6.41; found C 65.72, H 5.62, N
12.7 Hz, 1 H), 5.05 (dd, J = 1.3, 10.1 Hz, 1 H), 5.10 (d, J = 12.7 Hz,
1 H), 5.15 (d, J = 17.0 Hz, 1 H), 5.20 (d, J = 10.6 Hz, 1 H), 5.63
(ddd, J = 8.8, 10.1, 17.0 Hz, 1 H), 6.64 (s, 1 H), 6.97–7.05 (m, 2 H),
crude mixture was purified by flash chromatography to obtain 23b
as an amorphous solid (80%). Rf = 0.28 (hexane/EtOAc, 60:40).
[α]2D2 = +27.7 (c = 1.4, CDCl ). IR (neat): ν = 3341, 1738, 1636,
˜
3
1
7.10–7.22 (m, 3 H), 7.26–7.38 (m, 5 H) ppm. 13C NMR (CDCl3, 1596, 1492.6, 1415 cm–1. H NMR (CDCl3, 400 MHz): δ = 1.79 (s,
100 MHz): δ = 21.2, 27.5 (t), 30.8 (t), 34.3 (t), 39.6 (t), 46.9, 52.8,
57.7, 63.7, 66.2 (t), 67.8 (s), 76.3, 117.0 (t), 127.4, 128.0 (2 C), 128.7
(2 C), 129.7, 135.6 (s), 137.7 (s), 139.5, 155.2 (s), 168.6 (s), 170.6
(s), 172.7 (s) ppm. MS (ESI): m/z = 557.4 [M + Na]+. C30H34N2O7
(534.61): calcd. C 67.40, H 6.41, N 5.24; found C 67.32, H 6.46, N
5.19. Compound 22c: Compound 22c was synthesized from 2c
(100 mg, 0.2 mmol) by applying the general procedure. After
3 H), 1.93 (m, 1 H), 2.03–2.18 (m, 4 H), 2.37 (m, 1 H), 3.17 (m, 1
H), 3.39 (d, J = 14.4 Hz, 1 H), 3.75 (s, 3 H), 4.31–4.48 (m, 3 H),
4.99 (d, J = 12.7 Hz, 1 H), 5.09 (d, J = 12.6 Hz, 1 H), 5.35 (m, 1
H), 6.22 (dd, J = 9.0, 15.8 Hz, 1 H), 6.58 (d, J = 15.8 Hz, 1 H),
6.62 (s, 1 H), 6.99–7.05 (m, 2 H), 7.12–7.23 (m, 3 H), 7.27–7.36 (m,
5 H), 7.44 (d, J = 8.7 Hz, 2 H), 8.17 (d, J = 8.7 Hz, 2 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 20.5, 27.0 (t), 29.6 (t), 33.7 (t), 38.6
30 min of microwave heating at 60 °C, additional Ac2O (5 equiv.) (t), 45.7, 52.3, 56.9, 63.1, 65.8 (t), 67.1 (s), 75.8, 124.0, 126.7, 127.0,
was added, and then the solution was irradiated at 60 °C for
30 min. The crude mixture was purified by flash chromatography
(CH2Cl2/Et2O, 93:07) to obtain 22c as a foamy solid (93%). Rf =
127.6 (2 C), 128.2, 129.2, 129.8, 134.9 (s), 135.5, 137.0 (s), 143.1
(s), 146.9 (s), 154.7 (s), 168.0 (s), 169.9 (s), 172.1 (s) ppm. MS (ESI):
m/z = 678.4 [M + Na]+. C36H37N3O9 (655.70): calcd. C 65.94, H
7568
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7557–7570

Synthesis of Easily Functionalizable Azabicycloalkane Scaffolds
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5.69, N 6.41; found C 65.76, H 5.75, N 6.49. Compound 23c (E):
Compound 23c (E) was synthesized from 22c (50 mg, 0.09 mmol)
by applying the general procedure. After 1 h of microwave heating
at 120 °C, the reaction was complete. The crude mixture was puri-
fied by flash chromatography to obtain 23c as an amorphous solid
(84%). Rf = 0.28 (CH2Cl2/Et2O, 95:5). Rf = 0.32 (toluene/EtOAc,
85:15). [α]2D2 –36 (c = 1.7, CDCl ). IR (neat): ν = 3361, 1739, 1713,
˜
3
1630, 1594, 1480, 1421 cm–1. 1H NMR (CDCl3, 400 MHz): δ =
2.03 (s, 3 H), 2.04–2.28 (m, 4 H), 2.33–2.50 (m, 2 H), 3.22 (m, 1
H), 3.33 (d, J = 13.5 Hz, 1 H), 3.75 (s, 3 H), 3.90 (d, J = 13.5 Hz,
1 H), 4.43 (m, 1 H), 4.64 (app d, J = 7.3 Hz, 1 H), 5.01 (d, J =
12.4 Hz, 1 H), 5.25 (d, J = 12.4 Hz, 1 H), 6.31 (s, 1 H), 6.39 (dd,
J = 6.4, 16.1 Hz, 1 H), 6.47 (s, 1 H), 6.58 (d, J = 16.1 Hz, 1 H),
6.80–6.87 (m, 2 H), 7.09–7.16 (m, 2 H), 7.20 (m, 1 H), 7.30–7.42
(m, 5 H), 7.47 (d, J = 8.8 Hz, 2 H), 8.19 (d, J = 8.8 Hz, 2 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 21.1, 27.7 (t), 34.0 (t), 34.5 (t),
41.9, 52.7, 58.3, 63.4, 66.5 (t), 67.6 (s), 72.0, 124.4, 127.3, 127.6,
128.3, 128.5, 128.8 (2 C), 129.2, 129.9, 135.1 (s), 136.1, 137.4 (s),
143.9 (s), 147.4 (s), 154.6 (s), 168.4 (s), 170.3 (s), 172.6 (s) ppm.
MS (ESI): m/z = 678.4 [M + Na]+. C36H37N3O9 (655.70): calcd. C
65.94, H 5.69, N 6.41; found C 66.05, H 5.76, N 6.54.
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amino)-8-(4-nitrostyryl)-5-oxo-2,3,5,6,9,9a-hexahydro-1H-pyrrolo-
[1,2-a]azepine-3-carboxylate (24): To a solution of 23a–23c (50 mg,
0.076 mmol) in dry THF (0.1 m) under nitrogen DBU (0.15 mmol)
was added dropwise. The reaction mixture was heated in a micro-
wave oven at 80 °C for 1 h, then additional DBU (0.15 mmol) was
added, and the reaction mixture was irradiated at 80 °C for 1 h.
After the reaction was complete, a solution of HCl (1 m) was added
to quench the reaction. The aqueous phase was extracted with
EtOAc, the organic phases were collected, dried with anhydrous
Na2SO4, filtered, and the solvents evaporated in vacuo. The crude
mixture was purified by flash chromatography to obtain 24 as an
amorphous solid. Yield: 75% starting from 23a, 75% starting from
23b, and 78% starting from 23c. Rf = 0.36 (CH2Cl2/Et2O, 90:10).
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˜
3
1591, 1480, 1428 cm–1. H NMR (CDCl3, 400 MHz): δ = 2.01 (m,
1
1 H), 2.09–2.25 (m, 2 H), 2.41 (m, 1 H), 2.65–2.88 (m, 2 H), 3.27
(d, J = 13.9 Hz, 1 H), 3.73 (s, 3 H), 3.91 (d, J = 13.9 Hz, 1 H),
4.22–4.41 (br., 1 H), 4.54 (dd, J = 3.0, 7.8 Hz, 1 H), 5.12 (d, J =
12.4 Hz, 1 H), 5.26 (d, J = 12.4 Hz, 1 H), 6.57 (d, J = 16.2 Hz, 1
H), 6.58–6.65 (br., 1 H), 6.69 (s, 1 H), 6.90–6.96 (m, 2 H), 7.00 (d,
J = 16.2 Hz, 1 H), 7.16–7.27 (m, 3 H), 7.31–7.45 (m, 5 H), 7.55 (d,
J = 8.8 Hz, 2 H), 8.21 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 27.9 (t), 33.2 (t), 34.7 (t), 52.9, 55.8, 62.8, 65.0 (s),
66.7 (t), 124.6, 125.8, 127.2, 127.8, 128.4 (2 C), 128.7, 128.9, 130.1,
133.9, 135.1 (s), 135.3 (s), 137.2 (s), 138.3, 144.1 (s), 147.2 (s), 155.0
(s), 168.9 (s), 172.8 (s) ppm. MS (ESI): m/z = 618.2 [M + Na]+.
C34H33N3O7 (595.65): calcd. C 68.56, H 5.58, N 7.05; found C
68.79, H 5.68, N 7.13.
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Acknowledgments
Financial support from the Italian Ministry of Education, Univer-
sity and Research (Ministero dell’Università e della Ricerca,
MIUR) is gratefully acknowledged (PRIN project 2010NRREPL).
We thank Dr. Donatella Potenza for her valuable NMR advice.
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