Stereoselective iodocyclization of 3-acylamino-2-methylene alkanoates: Synthesis of analogues of N-benzoyl-syn-phenylisoserine

Article abstract of DOI:10.1021/ol049146j

(Matrix Presented) A convenient approach to racemic analogues of N-benzoyl-syn-phenylisoserine was realized via the stereoselective iodocyclization of amides obtained from Baylis-Hillman adducts.

Full text of DOI:10.1021/ol049146j

ORGANIC
LETTERS
2004
Vol. 6, No. 15
2571-2574
Stereoselective Iodocyclization of
3-Acylamino-2-methylene Alkanoates:
Synthesis of Analogues of
N-Benzoyl-syn-phenylisoserine
Roberta Galeazzi,* Gianluca Martelli, Giovanna Mobbili, Mario Orena,* and
Samuele Rinaldi
Dipartimento di Scienze dei Materiali e della Terra, UniVersita` Politecnica delle
Marche, Via Brecce Bianche, I-60131 Ancona, Italy
m.orena@uniVpm.it
Received May 10, 2004
ABSTRACT
A convenient approach to racemic analogues of N-benzoyl-syn-phenylisoserine was realized via the stereoselective iodocyclization of amides
obtained from Baylis−Hillman adducts.
â-Amino-R-hydroxy acids show important biological activi-
ties.1 In particular, N-benzoyl-syn-phenylisoserine 1, the C-13
side chain of paclitaxel (Taxol, 2a), has been the target of
numerous synthetic efforts, and many paclitaxel derivatives
have been prepared in the quest for new products with
broader activity and lower toxicity than the parent drug
(Figure 1).2 Thus, biological assays carried out with the C-2′-
between the conformations around the 2′-3′ bond.3b In
addition, the hydroxymethyl derivative 2c demonstrates
inhibitory activity in microtubule depolymerization but was
devoid of significant cytotoxicity against KB or KB-V1
(Figure 1).4
(1) For reviews, see: (a) Cardillo, G.; Tomasini, C. Chem. Soc. ReV.
1996, 25, 117-128. (b) EnantioselectiVe Synthesis of â-Amino Acids:
Juaristi, E., Ed.; Wiley-VCH: New York, 1996. (c) Seebach, D.; Mattews,
J. L. J. Chem. Soc., Chem. Commun. 1997, 2015-2022. (d) Gellman, S.
H. Acc. Chem. Res. 1998, 31, 173-180.
(2) (a) Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem., Int. Ed.
Engl. 1994, 33, 15-44. (b) Chen, S. H.; Farina, V. Paclitaxel (Taxol)
Chemistry and Structure-Activity Relationships. In The Chemistry and
Pharmacology of Taxol and its DeriVatiVes; Farina, V., Ed.; Elsevier:
Amsterdam, 1995; pp 165-253. (c) Georg, G. I. The Medicinal Chemistry
of Taxol. In Taxol: Science and Application; Suffnes, M., Ed.; CRC: Boca
Raton, FL, 1995; pp 317-375. (d) Wang, M.; Cornett, B.; Nettles, J.; Liotta,
D. C.; Snyder, J. P. J. Org. Chem. 2000, 65, 1059-1068.
(3) (a) Denis, J.-N.; Fkyerat, A.; Gimbert, Y.; Coutterez, C.; Mantellier,
P.; Jost, S.; Greene, A. E. J. Chem. Soc., Perkin Trans. 1 1995, 1811-
1815. (b) Kant, J.; Schwartz, W. S.; Fairchild, C.; Gao, Q.; Huang, S.; Long,
B. H.; Kadow, J. F.; Langley, D. R.; Farina, V.; Vyas, D. Tetrahedron
Lett. 1996, 37, 6495-6498. (c) Ojima, I.; Wang, T.; Delaloge, F.
Tetrahedron Lett. 1998, 39, 3663-3666. (d) Cardillo, G.; Gentilucci, L.;
Tolomelli, A.; Tomasini, C. J. Org. Chem. 1998, 63, 2351-2353. (e)
Cardillo, G.; Tolomelli, A.; Tomasini, C. Eur. J. Org. Chem. 1999, 155,
5-161. (f) Nocioni, A. M.; Papa, C.; Tomasini, C. Tetrahedron Lett. 1999,
40, 8453-8456.
Figure 1.
methylated derivative 2b revealed a significant enhancement
of potency in comparison with 2a.3 The increased inhibition
activity against microtubule depolymerization and cytotoxy-
city toward KB-V1 was ascribed to a higher energy barrier
(4) Ge´nisson, Y.; Massardier, C.; Gautier-Luneau, I.; Greene, A. E. J.
Chem. Soc., Perkin Trans. 1 1996, 2869-2872.
10.1021/ol049146j CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/24/2004

Within an ongoing project aimed at inducing conforma-
tional changes and then activity changes in bioactive oli-
gopeptides5 by introduction of conformationally restricted
â-amino acids,6 we disclose here an efficient method leading
to derivatives of racemic syn-2-substituted 2-hydroxy-3-
amino acids 3a-d, analogues of N-benzoyl-syn-phenyl-
isoserine 1 (Figure 2), starting from the Baylis-Hillman
adducts 4.
8 in high yield. The reaction proceeded with total diaste-
reoselection, leading to a single product, as shown from GC
analysis and 1H and 13C NMR spectra of the crude reaction
mixtures.
This behavior, which could be ascribed to structural
features of the starting amide, was different from the
previously reported cyclizations of acyclic amides, which
invariably led to diastereomeric mixtures of cis- and trans-
4,5-disubstituted dihydro-1,3-oxazoles.12 At first, the geom-
etry of products 8 was assigned as cis by means of NOE
experiments. Then the configuration at C-5 in 8a was
inverted by simple steps to give the corresponding isomer
1
13 (Scheme 1). The comparison of the H NMR spectra
Scheme 1 a
Figure 2.
At first, 3-acylamino-2-methylene-3-arylpropanoates 7
were prepared by treatment of N-acylcarbamates 6 with
DABCO in DCM at room temperature (Table 1)7 and one
Table 1. Preparation of 3-Acylamino Esters 7 and
4,5-Disubstituted 4,5-Dihydro-1,3-oxazoles 8a
a Reagents and conditions: (a) 3 M H2SO4 in MeOH, rt. (b) Dry
Na2CO3, MeOH, rt. (c) CsF, DMF, 90 °C. (d) TsCl, Et3N, DMAP,
0 °C. (e). NaI, DMSO, 100 °C.
evidenced a shielded ABq for CH2I in 8a at δ 3.00, whereas
the analogous signal was unshielded in compound 13 (3.84
(5) (a) Galeazzi, R.; Mobbili, G.; Orena, M. Tetrahedron 1996, 52, 1069-
1084. (b) Galeazzi, R.; Geremia, S.; Mobbili, G.; Orena, M. Tetrahedron:
Asymmetry 1996, 7, 79-88. (c) Galeazzi, R.; Geremia, S.; Mobbili, G.;
Orena, M. Tetrahedron: Asymmetry 1996, 7, 3573-3584. (d) Galeazzi,
R.; Mobbili, G.; Orena, M. Tetrahedron: Asymmetry 1997, 8, 133-137.
(e) Galeazzi, R.; Mobbili, G.; Orena, M. Tetrahedron 1999, 55, 261-270.
(f) Galeazzi, R.; Mobbili, G.; Orena, M. Tetrahedron 1999, 55, 4029-
4042. (g) Galeazzi, R.; Martelli, G.; Mobbili, G.; Orena, M.; Rinaldi, S.
Tetrahedron: Asymmetry 2003, 14, 3353-3358. (h) Fava, C.; Galeazzi,
R.; Mobbili, G.; Orena, M. Tetrahedron: Asymmetry 2003, 14, 3697-3703.
(6) Motorina, I. A.; Huel, C.; Quiniou, E.; Mispelter, J.; Adjadj, E.;
Grierson, D. S. J. Am. Chem. Soc. 2001, 123, 8-17.
entry
R1
R2
R3
Ph
Ph
Ph
Ph
t-Bu
Bn
CH2Cl
CCl3
yield 7 %b yield 8 %b
a
b
c
d
e
f
g
h
i
Me
Me
Et
t-Bu Ph
Et Ph
t-Bu Ph
t-Bu Ph
t-Bu Ph
Et
Et
Ph
79
93
78
94
75
83
79
84
71
78
92
85
88
91
86
87
78
87
75
84
4-O2N-C6H4
Ph
(7) Ciclosi, M.; Fava, C.; Galeazzi, R.; Orena. M.; Sepulveda-Arques,
J. Tetrahedron Lett. 2002, 58, 2199-2202.
(8) (a) Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321-3408. (b)
Orena, M. Amination Reactions Promoted by Electrophiles. In Houben-
Weyl, Methods of Organic Chemistry, StereoselectiVe Synthesis; Helmchen,
G., Hofmann, R. W., Mulzer, J., Schauman, E., Eds., Thieme: Stuttgart,
1995; Vol. E 2le, pp 5291-5355.
(9) For recent work on iodocyclization, see: (a) Jorda´-Gregori, J. M.;
Gonza´lez-Rosende, M. E.; Sepu`lveda-Arques, J.; Galeazzi, R.; Orena, M.
Tetrahedron: Asymmetry 1999, 10, 1135-1143. (b) Jorda`-Gregori, J. M.;
Gonzalez-Rosende, M. E.; Cava-Montesinos, P.; Sepu`lveda-Arques, J.;
Galeazzi, R.; Orena, M. Tetrahedron: Asymmetry 2000, 11, 3769-3777.
(10) All reactions were performed starting from racemic amides, but
â-amino acids can be obtained in the enantiomerically pure form by kinetic
resolution of their phenylacetamides with penicillin G acylase. So, by using
enantiomerically pure starting materials, our approach leads to enantio-
merically pure compounds. See: Cardillo, G.; Gentilucci, L.; Tolomelli,
A.; Tomasini, C. J. Org. Chem. 1998, 63, 2351-2353, and references
therein.
4-CH3O-C6H4 Ph
4-Cl-C6H4
j
Ph
a Reagents and conditions: (a) DCM, rt, quantitative yield. (b) DABCO,
DCM, rt. (c) NIS, CHCl3, rt. b Yield of pure product after isolation.
or two heteroatoms were subsequently introduced on the
carbon backbone of these compounds by means of an
iodocyclization reaction.8-11 In fact, use of NIS in chloroform
at room temperature in the cyclization of 3-acylamino
derivatives 7 gave the corresponding dihydro-1,3-oxazoles
2572
Org. Lett., Vol. 6, No. 15, 2004

δ), where the effect of the phenyl group is missing. The
opposite trend was observed for the COOMe signal (8a, 3.93
δ; 13, 3.19 δ), thus allowing definite assignment of the cis
configuration to 8a and trans configuration to 13.
methyl ester 3a, whose spectral data were in total agreement
with that of the reported compound.3h Conversely, treatment
of 14 with 6 M HCl/methanol 1:1 led to the corresponding
acid 15 (Scheme 2).
To explain the observed stereoselection, a full conforma-
tional analysis was carried out for the amide 7a, by using
molecular mechanics methods.13 Calculations showed that
a conformational equilibrium takes place for this compound,
and rotamer A, leading to cis isomer 8a, lies at lower energy
by 2.2 kcal/mol with respect to rotamer B, which would lead
to the trans isomer, 13 (Figure 3).14-16 Due to this difference
Scheme 2 a
a Reagents and conditions: (a) 1-Ethylpiperidinium hypophos-
phite, AIBN, refluxing toluene. (b) 3 M HCl in MeOH, rt. (c) 6 M
HCl in refluxing MeOH.
Figure 3. Conformational equilibrium for 7a leading to 8a.
Furthermore, the nucleophilic substitution at the iodo-
methyl group of 8d, directed toward preparation of the hy-
droxymethyl derivative 3b, was not trivial, and the introduc-
tion of the acetoxy group proved to be troublesome, due to
the low reactivity of the iodine, probably due to steric
hindrance.20 In fact, reaction of 8d with either acetate anion
on IRA 120 in refluxing toluene, and potassium acetate in
DMF at 80 °C, failed and starting material was recovered
along with some decomposition. However, when cesium
acetate was employed as a source of acetate anion in DMF
at 110 °C, the substitution proceeded in moderate yield,
leading to the 5-acetoxymethyl derivative 16, which was
subsequently cleaved on treatment with 1 M HCl in refluxing
MeOH to give the ester 3b. In analogy with 14, treatment
of 16 with 6 M HCl in refluxing MeOH led to the acid 17
in good yield (Scheme 3).
in energy, it appears that only rotamer A is significantly
populated, and this causes the reaction outcome. Thus, con-
formational stability seems to be the driving force leading
to the cis isomers 8, although synergic effects at the transition
state could not be discarded.17
With compounds 8 in hand, at first the synthesis of 3a
began with cleavage of the C-I bond of 8a, performed with
1-ethylpiperidinium hypophosphite,18,19 to give the 5-methyl
derivative 14 in high yield.
Subsequent cleavage of the heterocyclic ring, carried out
with 3 M HCl in methanol, afforded the corresponding
(11) A single example of iodocyclization of Baylis-Hillman adducts
was found in the literature: Drewes, S. E.; Njamela, O. L.; Roos, G. H. P.
Chem. Ber. 1990, 123, 2455-2456.
(12) (a) Cardillo, G.; Orena, M.; Sandri, S. J. Chem. Soc., Chem.
Commun. 1983, 1489-1490. (b) Cardillo, G.; Orena, M.; Sandri, S.;
Tomasini, C. Tetrahedron 1985, 41, 163-167. (c) Bongini, A.; Cardillo,
G.; Orena, M.; Sandri, S.; Tomasini, C. J. Chem. Soc., Perkin Trans. 1
1986, 1345-1349.
Scheme 3 a
(13) Molecular mechanics calculations were performed using the imple-
mentation of Amber all-atom force field (AMBER*) within the framework
of Macromodel version 5.5. The solvent effect was included by using the
implicit chloroform GB/SA solvation method of Still et al. The torsional
space of each molecule was randomly varied with the usage-directed Monte
Carlo conformational search of Chang-Guida-Still. For each search, at
least 1000 starting structures for each variable torsion angle were generated
and minimized until the gradient was less than 0.01 kcal Å-1 mol-1
.
Duplicate conformations and conformations with an energy excess of 5
kcal/mol above the global minimum were discarded.
(14) Weiner, S. J.; Kollman, P. A.; Nguyen, D. T.; Case D. A. J. Comput.
Chem. 1986, 4, 230-252.
(15) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caulfield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J.
Comput. Chem. 1990, 11, 440-452.
(16) (a) Still, W. C.; Tempczyk, A.; Hawley, R. C.; Hendrickson, T. J.
Am. Chem. Soc. 1990, 112, 6127. (b) Chang, G.; Guida, W. C.; Still, W. C.
J. Am. Chem. Soc. 1989, 111, 4379-4386.
a Reagents and conditions: (a) CsOAc, dry DMF, 110 °C. (b) 1
M HCl, MeOH, 60 °C. (c) 6 M HCl in refluxing MeOH.
(17) Chamberlin, A. R.; Mulholland, R. L., Jr.; Kahn, S. E.; Hehre, W.
J. J. Am. Chem. Soc. 1987, 109, 672-677.
(18) Graham, S. R.; Murphy, J. A.; Coates, D. Tetrahedron Lett. 1999,
40, 2415-2416.
(19) When Bu3SnH was employed, tin derivatives unseparable from 3a
were produced in the reduction reaction.
On the other hand, substitution of the iodine atom of
8d, with the aim of preparing the analogue 3c, proceeded
Org. Lett., Vol. 6, No. 15, 2004
2573

straightforwardly by using sodium azide in DMSO
(CAUTION!) (Scheme 4).
Scheme 5 a
Scheme 4 a
a Reagents and conditions: (a) Anhydrous Na2CO3, MeOH, rt.
(b) DAST, dry DCM, rt. (c) 3 M HCl in MeOH, rt.
a Reagents and conditions: (a) NaN3, DMSO, 80 °C. (b) 3 M
HCl in MeOH, rt. (c) Zn, NH4Cl, MeOH, rt. (d) BzCl, Et3N, DMAP,
0 °C.
In summary, starting from the Baylis-Hillman adducts
4, we developed a practical, stereoselective synthesis of
racemic analogues of syn-phenylisoserine 1. The preparation
of derivatives 3a-d in the enantiomerically pure form and
evaluation of biological activity data for new compounds
3c-d are currently underway and will be reported in due
course.
Thus, the azidomethyl derivative 18 was obtained in good
yield, and cleavage of the heterocyclic ring led to the azido
ester 19.
After conversion into the amino ester 3c, performed by
using Zn-NH4Cl, subsequent benzoylation gave 20.21
The reaction of the acetoxymethyl derivative 16 with
Na2CO3 in MeOH provided the hydroxymethyl derivative
21. Treatment with DAST in DCM gave 22 in good yield,
which was then converted into the ester 3d (Scheme 5).
Acknowledgment. We thank M.I.U.R. (Rome, Italy) for
financial support within PRIN 2002 framework.
Supporting Information Available: Experimental pro-
cedures and spectral data are given for all compounds,
1
together with H NMR and 13C NMR spectra of 3a-d, 8a,
(20) Compound 8d was employed, in place of 8a, since cleavage of the
ester function of 8a was observed under nucleophilic substitution reaction
conditions.
(21) Hydroxyamination of Baylis-Hillman adducts was already re-
ported: Pringle, W.; Sharpless, K. B. Tetrahedron Lett. 1999, 40, 5151-
5154.
13, 14, 16, 18, and 22 and charts of optimized geometries
and NACs for compound 7a. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL049146J
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Org. Lett., Vol. 6, No. 15, 2004