Synthesis of advanced intermediates for the preparation of aza-analogues of podophyllotoxin

Article abstract of DOI:10.1016/j.tetlet.2004.01.040

Some central intermediates useful for the synthesis of aza-analogues of the anti-cancer drug podophyllotoxin have been prepared starting from L-DOPA and (R)-Garner aldehyde.

Full text of DOI:10.1016/j.tetlet.2004.01.040

Tetrahedron
Letters
Tetrahedron Letters45 (2004) 2133–2136
Synthesis of advanced intermediates for the preparation of
aza-analogues of podophyllotoxin
Enrico Marcantoni, Marino Petrini* and Roberto Profeta
Dipartimento di Scienze Chimiche, Universitꢀa di Camerino, via S. Agostino, 1. I-62032 Camerino, Italy
Received 5 January 2004; accepted 12 January 2004
Abstract—Some central intermediates useful for the synthesis of aza-analogues of the anti-cancer drug podophyllotoxin have been
prepared starting from L-DOPA and (R)-Garner aldehyde.
Ó 2004 Elsevier Ltd. All rights reserved.
O
The interesting biological properties displayed by podo-
phyllotoxin 1 and its congeners, have spurred the
development of several synthetic approaches for the
assembling of this polycyclic molecule.1 A consistent
number of structural modifications have been intro-
duced in the original skeleton of 1 in order to overcome
some toxic side effects associated with its utilization as
anti-cancer drug. Among these derivatives, etoposide 2
seems the most effective one as topoisomerase II inhib-
itor.2 Aza-analoguesof 1 ascompounds 3 and 4,
O
O
HO
HO
O
H
H
O
OH
H
H
O
O
O
O
O
O
O
MeO
OMe
MeO
OMe
OMe
OH
R
1
2
F
H
O
O
incorporating
a nitrogen atom in the molecular
HN
4
1
3
N
H
O
O
O
framework, also show an enhanced pharmacological
profile.3
O
O
O
H
MeO
OMe
OMe
HO
OMe
OH
4
R = OH, H
3
OH
The assembling of aza derivatives of type 4 often
requiresaspivotal intermediate oxazolidin-2-one 5 that
can be prepared from a-amino acid 6 (Scheme 1).4
O
4
O
HN
O
O
5
CO H
O
O
2
Compound 6 in optically pure form wasoriginally pre-
pared by resolution of the corresponding racemic mix-
ture5 and only recently by asymmetric synthesis.6
NH
2
6
We have devised a new procedure to accede to derivative
5 that makesues of
Scheme 1.
L-DOPA methyl ester 7 aschiral
source. a-Amino acid derivative 7 istranfsormed into
carbamate 8 and then converted into methylene acetal 9
using CH2Cl2/CsF in DMF (Scheme 2).7 Reduction of
the ester function in 9 with NaBH4/CaCl2 and then base
induced cyclization givesoxazolidin-2-one 10.8 Benzylic
Keywords: Garner aldehyde; Iminium ions; Oxazolidinones; Podo-
phyllotoxin; Sulfones.
* Corresponding author. Tel.: +39-0737-402253; fax: +39-0737-4022-
97; e-mail: marino.petrini@unicam.it
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.040

2134
E. Marcantoni et al. / Tetrahedron Letters 45 (2004) 2133–2136
CO Me
2
HO
HO
CO Me
2
HO
HO
CO Me
O
O
2
CH Cl CsF
2 2
EtOCOCl
NHCO Et
2
NHCO Et
2
i Pr EtN, CH Cl
DMF , 110°C
68%
NH
2
2
2
2
78%
8
8
7
OAc
1. NaBH CaCl
4
THF-MeOH
2
O
O
O
DDQ
AcOH, 60°C
86%, d.r. = 3:2
O
+
epimer
O
HN
2. NaOH, MeOH ∆
HN
O
80%
O
O
10
11
Scheme 2.
O
M
Nu (re)
O
O
5
O
NBoc
CHO
+
H
H
O
O
N
13
12
O
O
Scheme 3.
BocNH
1. HCl, THF
2. MeO OMe
Ar
oxidation of compound 10 iscarried out with 2,3-di-
chloro-5,6-dicyano-1,4-benzoquinone (DDQ) in AcOH
giving acetoxy derivative 11 and itsepimer in 3:2 dia-
stereomeric ratio and 86% yield.9
16
O
O
TsOH, CH Cl , 52%
2
2
18
O
O
Ar =
The low diastereoselectivity observed in the last step
prompted usto elaborate an alternative protocol for the
preparation of compound 11. A possible solution could
be found in the diastereoselective addition of an orga-
nometallic reagent 12 to aldehyde 13 (Scheme 3).
Scheme 5.
the nucleophile from the re-side of the substrate (Scheme
5).12
Unfortunately, every attempt to prepare aldehyde 13 by
reduction of the corresponding ester or oxidation of the
primary alcohol failed. Therefore, we decided to reverse
this synthetic strategy creating the benzylic stereocenter
before the oxazolidin-2-one ring. For thispurpose, ( R)-
Garner aldehyde 14 ismade to react with commercially
available organomagnesium reagent 15 to give adduct
16 in good yield and satisfactory diastereoselectivity
(anti:syn ¼ 9:1) (Scheme 4).
The assignment of the newly formed stereocenter has
been made transforming alcohol 16 into the corre-
sponding 1,3-dioxane derivative 18. Evaluating the
coupling constants between H-4 and H-5 a value
J4–5 ¼ 9:3 Hz wasobtained and thisrevealsa trans
relationship between the aryl and carbamoyl groups.13
Recently, we have demonstrated that chiral oxazolidin-
2-onescan be converted into a-amidoalkylphenyl sulf-
onesby condensation with an appropriate aldehyde and
benzenesulfinic acid.14 These sulfones react with Lewis
acidsat low temperature giving the correpsonding
N-acyliminium ion derivatives.15 These electrophilic
intermediatesrapidly add with nucleophilic reagentsand
electron rich aromaticsboth inter- and intra-molecu-
larly.
Acetylation and hydrolysis of the oxazolidine ring10
providesalcohol 17 that isconverted into oxazolidin-2-
one 11 using SOCl2.11
The anti-diastereoselectivity observed in the formation
of alcohol 16 can be rationalized taking into account for
a Felkin–Ahn transition state that involves the attack of
O
O
1. Ac O, DMAP
2
pyridine
MgBr
NBoc
O
O
O
H
O
THF
+
NBoc
O
-78°C to rt, 90%
anti:syn 9:1
2. 80% AcOH
65%
HO
15
14
16
O
O
O
O
BocHN
HO
NH
SOCl
2
O
O
THF 0°C 80%
OAc
OAc
11
17
Scheme 4.

E. Marcantoni et al. / Tetrahedron Letters 45 (2004) 2133–2136
Table 1. Synthesis of derivatives 19 and 20 from oxazolidin-2-one 11
2135
20
D
Entry
R
19
Yield (%)a
20
Yield (%)a
½aꢀ (c, CHCl3)
1
2
3
4
Ph
19a
19b
19c
19d
80
60
61
64
20a
20b
20c
20d
75
73
70
75
)35.1 (0.35)
)81.2 (0.25)
25.1 (0.40)
32.6 (0.50)
cC6H11
Me2CHCH2
PhCH2CH2
a Yields of pure, isolated products.
OAc
Tetrahedron 1990, 46, 5029–5041; (d) Reynolds, A. J.;
Scott, A. J.; Turner, C. I.; Sheburn, M. S. J. Am. Chem.
Soc. 2003, 125, 12108–12109; (e) Engelhardt, U.; Sarkar,
U.; Linker, T. Angew. Chem., Int. Ed. 2003, 42, 2887–2889;
(f) Berkowitz, D. B.; Choi, S.; Maeng, J.-H. J. Org. Chem.
2000, 65, 847–860.
1
O
O
R CHO, PhSO H
2
O
11
N
MgSO , CH Cl , rt
4
2
2
O
R1
60-80%
SO2Ph
19
OH
2. Damayanthi, Y.; Lown, J. W. Curr. Med. Chem. 1998, 5,
205–252.
O
O
TiCl
4
O
N
CH Cl -78°C
2
2
3. (a) Kamal, A.; Kumar, B. A.; Arifuddin, M. Tetrahedron
Lett. 2003, 44, 8457–8459; (b) Poli, G.; Giambstiani, G.
J. Org. Chem. 2002, 67, 9456–9459; (c) Tratrat, C.; Giorgi-
Renault, S.; Husson, H.-P. Org. Lett. 2002, 4, 3187–3189;
(d) Ida, A.; Kano, M.; Kubota, Y.; Koga, K.; Tomioka,
K. Chem. Pharm. Bull. 2000, 48, 486–489.
4. (a) Tomioka, K.; Kubota, Y.; Koga, K. Tetrahedron 1993,
49, 1891–2000; (b) Compound 5 has been also used as a
central intermediate for the synthesis of aza-steganes:
Kubota, Y.; Kawasaki, H.; Tomioka, K.; Koga, K.
Tetrahedron 1993, 49, 3081–3090.
70-75%
O
R1
20
Scheme 6.
Reaction of compound 11 with different aldehydesand
PhSO2H givesthe correpsonding a-amidoalkylphenyl
sulfones 19 asan epimeric mixture in moderate to good
yield (Scheme 6).
5. Yamada, S.-I.; Fujii, T.; Shioiri, T. Chem. Pharm. Bull.
1962, 10, 680–688.
6. (a) Belokon, Y. N.; Bespalova, N. B.; Churkina, T. D.;
Sulfones 19 react with TiCl4 at )78 °C to produce an
N-acyliminium ion that undergoesa rapid ring clous re
to afford derivative 20 in fairly good yield asa isngle
isomer (Table 1).16
ꢁ
Cisarova, I.; Ezernitskaya, M. G.; Harutyunyan, S. R.;
Hrdina, R.; Kagan, H. B.; Kocovsky, P.; Kochetkov, K.
ꢂ
ꢁ
ꢂꢁ
A.; Larionov, O. V.; Lyssenko, K. A.; North, M.; Polasek,
The acidic conditionsalso produce a deacetylation at the
benzylic position and upon quenching with water the
corresponding alcohol of opposite configuration is
obtained.17 The nature of the stereocenter at C-4 was
ascertained through the analysis of the coupling constants
between H-3 and H-4 (J3–4 ¼ 1:8 Hz) that clearly indicate
a cis relationship of the corresponding hydrogens.
ꢁ
M.; Peregudov, A. S.; Prisyazhnyuk, V. V.; Vyskocil, S.
ꢁ
J. Am. Chem. Soc. 2003, 125, 12860–12871; (b) Gulliena,
ꢂ
G.; Najera, C. J. Org. Chem. 2000, 65, 7310–7322; (c)
Ollero, L.; Castedo, L.; Domınguez, D. Tetrahedron 1999,
ꢂ
55, 4445–4456.
7. Pedersen, M. L.; Berkowitz, D. B. J. Org. Chem. 1993, 58,
6966–6975.
8. Lewis, N.; McKillop, A.; Taylor, R. J. K.; Watson, R.
J. Synth. Commun. 1995, 25, 561–568.
9. Tomioka et al.4a report a yield of 70% for the same
conversion. The yield reported by us has been obtained
using a freshly opened bottle of DDQ (Aldrich).
10. Kumar, J. S. R.; Datta, A. Tetrahedron Lett. 1997, 38,
473–476.
In conclusion, a novel approach to the synthesis of some
useful intermediates for the preparation of aza-ana-
loguesof podophyllotoxin hasbeen devised. Compound
11 hasbeen finally converted by a two-tsep procedure
into 4-epi-aza-podophyllotoxin derivatives 20. Further
work devoted to maintain the correct stereochemistry at
C-4 during the cyclization step is currently in progress in
our laboratory.
11. Matsunaga, H.; Ishizuka, T.; Kumeda, T. Tetrahedron
20
D
1997, 53, 1275–1294, Compound 11: waxy solid; ½aꢀ 12.7°
(c 1, CHCl3); 1H NMR (CDCl3, 300 MHz) d: 2.13 (s, 3H),
4.03–4.31 (m, 2H), 4.38 (dd, 1H, J ¼ 9:1, 9.2 Hz), 5.74 (d,
1H, J ¼ 7:6 Hz), 5.99 (s, 2H), 6.82 (s, 2H); 13C NMR
(CDCl3, 75 MHz) d: 21.1, 56.2, 66.6, 75.4, 101.5, 107.1,
108.7, 120.8, 121.4, 148.2, 148.3, 159.5, 170.0.
Acknowledgements
ꢂ
12. William, L.; Zhang, Z.; Shao, F.; Carroll, P. J.; Joullie,
Financial support from University of Camerino (Na-
M. M. Tetrahedron 1996, 52, 11673–11694.
13. Radunz, H.-E.; Devant, R. M.; Eiermann, V. Liebigs.
Ann. Chem. 1988, 1103–1105.
14. (a) Mecozzi, T.; Petrini, M.; Profeta, R. Tetrahedron:
Asymmetry 2003, 14, 1171–1178; (b) Marcantoni, E.;
Mecozzi, T.; Petrini, M. J. Org. Chem. 2002, 67, 2989–
ꢀ
ꢀ
tional Project ÔSintesi e Reattivita-attivita di Sistemi
Insaturi FunzionalizzatiÕ) isgratefully acknowledged.
R. P. thanksC.I.N.M.P.I.S. (Bari) for a potsgraduate
fellowship.
ꢀ
2994; (c) Giardina, A.; Mecozzi, T.; Petrini, M. J. Org.
Chem. 2000, 65, 8277–8282.
References and notes
15. Reviews: (a) Petrini, M. In Targets in Heterocyclic
ꢀ
Systems; Attanasi, O. A., Spinelli, D., Eds.; Societa
Chimica Italiana: Rome, 2002; Vol. 6, pp 99–135; (b)
1. (a) Ward, R. S. Nat. Prod. Rep. 1999, 161, 75–96; (b)
Ward, R. S. Synthesis 1992, 719–730; (c) Ward, R. S.

2136
E. Marcantoni et al. / Tetrahedron Letters 45 (2004) 2133–2136
Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56,
J ¼ 1:8, 8.4 Hz), 5.06 (dd, 1H, J ¼ 1:8, 8.0 Hz), 5.98 (d,
1H, J ¼ 1:5 Hz), 6.00 (d, 1H, J ¼ 1:2 Hz), 6.41 (s, 1H),
6.81 (s, 1H); 13C NMR (CDCl3, 75 MHz) d: 53.1, 56.4,
59.2, 65.7, 102.0, 108.8, 109.1, 127.0, 128.6, 128.8, 129.1,
132.6, 141.6, 147.7, 149.2, 159.8.
3817–3856; (c) De Koning, H.; Speckamp, W. N. In
Stereoselective Synthesis (Houben-Weyl); Helmchen, G.,
Hoffman, R. W., Mulzer, J., Schaumann, E., Eds.; Georg
Thieme: Stuttgart, 1995; Vol. E21, pp 1953–2009.
20
D
16. Compound 20a: waxy solid; ½aꢀ )35.1° (c 0.35, CHCl3);
17. A similar trend has been reported by Tomioka et al.4a
using triflic acid in dichloromethane–methanol for the
final cyclization step.
1H NMR (CDCl3, 300 MHz) d: 2.21 (br s, 1H), 4.34–4.40
(m, 1H), 4.46 (dd, 1H, J ¼ 2:2, 8.4 Hz), 4.62 (dd, 1H,