Stereoselective synthesis of chiral precursors to cyclobutane carbocyclic nucleosides and oligopeptides

Article abstract of DOI:10.1016/S0957-4166(02)00823-6

Versatile and highly efficient synthetic routes leading to optically active cyclobutanones, γ-amino acids and δ-amino alcohols are described. These compounds are relevant synthetic precursors to enantiopure cyclobutane carbocyclic nucleosides and oligopeptides. (-)-(S)-Verbenone is the chiral starting material used and the key synthetic steps involve concerted rearrangements in acidic medium.

Full text of DOI:10.1016/S0957-4166(02)00823-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 193–195
Stereoselective synthesis of chiral precursors to cyclobutane
carbocyclic nucleosides and oligopeptides
Pablo D. Rouge,a Albertina G. Moglioni,b,* Graciela Y. Moltrasiob and Rosa M. Ortun˜oc,*
aCentro de Investigacio´n y Desarrollo en Qu´ımica y Petroqu´ımica, INTI, Argentina
bDepartamento de Qu´ımica Orga´nica, Facultad de Farmacia y Bioqu´ımica, Universidad de Buenos Aires, Argentina
cDepartament de Qu`ımica, Universitat Auto`noma de Barcelona, 08193 Bellaterra, Spain
Received 18 November 2002; accepted 29 November 2002
Abstract—Versatile and highly efficient synthetic routes leading to optically active cyclobutanones, g-amino acids and d-amino
alcohols are described. These compounds are relevant synthetic precursors to enantiopure cyclobutane carbocyclic nucleosides and
oligopeptides. (−)-(S)-Verbenone is the chiral starting material used and the key synthetic steps involve concerted rearrangements
in acidic medium. © 2003 Elsevier Science Ltd. All rights reserved.
Amino acids containing small rings have been used to
mimic the skeleton or lateral chains of conformation-
ally restricted peptides. Cyclopentane,1 cyclobutane2,3
and cyclopropane derivatives,4 have been employed for
this purpose and several pertinent publications are
available. Nevertheless, the literature provides scarce
data related to the synthesis of optically active cyclobu-
tane amino acids and related oligopeptides.3 In nature,
cyclobutane amino acids such as 2,4-methanoglutamic
acid and 2,4-methanoproline5 have also been found, as
well as enantiomerically pure dipeptides containing the
same ring moiety as (1S,2S)-1-hydroxy-2-[(S)-valyl-
amino]cyclobutane-1-acetic acid, produced by Strepto-
myces species X-1092.6
1a10 involving an asymmetric cycloaddition. Compound
1a has been used as a substrate for the preparation of
enantiopure COXT-A and COXT-G. In 1995, two achi-
ral carbocyclic nucleosides bearing the guanine or the
adenine core were synthesized from cyclobutanone 2a
(Chart 1).11 Since then, numerous syntheses of COXT
have been documented.
Pursuing our ongoing research on the stereoselective
synthesis of cyclobutane-containing molecules from ter-
penes,12 we describe herein synthetic routes to g-amino
acid derivatives, convenient for incorporation into g-
oligopeptides, as well as amino alcohols and cyclobu-
tanones suitable for use as synthetic precursors to
COXT-type nucleosides. Such compounds were
obtained starting from (−)-cis-pinononic acid, 3, resul-
tant of the oxidative cleavage of the double bond in
(−)-(S)-verbenone.12a Concerted Baeyer–Villiger oxida-
tion (B–V) and Schmidt rearrangement were the chemi-
Otherwise, the usefulness of carbocyclic nucleosides in
the treatment of diverse diseases is well recognized.7 In
particular,
carbocyclic
analogs
(COXT)
of
oxethanocine A (OXT-A) have received considerable
attention due to their wide spectrum of antiviral and
antitumoral activity, and numerous syntheses have been
described. The earliest nucleoside was described in
19898 as a racemate, using cyclobutanone 1a as an
intermediate for the synthesis of COXT-A. That same
year Ichikawa et al.9 described the synthesis of optically
active COXT-A and COXT-G by using the enantiopure
cyclobutanone 1b as an intermediate. In 1991 Bristol-
Myers-Squibb developed an asymmetric synthesis of
* Corresponding authors. E-mail: amoglio@ffyb.uba.ar; rosa.ortuno
@uab.es
Chart 1.
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00823-6

194
P. D. Rouge et al. / Tetrahedron: Asymmetry 14 (2003) 193–195
of the one described by Burgess,3a which was prepared
as an N-Boc and benzyl ester derivative, starting from
(+)-(R)-verbenone in five steps and in 25% overall yield.
cal transformations involved in the respective key syn-
thetic steps. These reactions were studied with sub-
strates 3,12a 3a12a and 3b12f (Scheme 1).
16
Reduction of compound 7 with NaBH4 and CaCl2 led
to alcohol 8, which is a valuable synthetic precursor to
carbocyclic nucleosides. Otherwise, when t-butyl ester
3b underwent Schmidt rearrangement, increasing the
acidity of the medium led to ester hydrolysis, yielding a
mixture of products which were difficult to isolate.
Under B–V conditions (m-chloroperbenzoic acid in
CH2Cl2, rt, 2 days), compound 3a rearranged to the
corresponding acetate 4a13 (90% yield). The same reac-
tion applied to 3b showed random behavior and proved
to be poorly reproducible, 4b being only sporadically
obtained in ca. 10% yield. By controlling the reaction
conditions (2.5 M KOH in MeOH at 0°C for 3 h, TLC
monitoring),14 selective saponification of acetate 4a in
the presence of the methyl ester was achieved, leading
to alcohol 513 in 82% yield. Subsequent oxidation of 5
with ruthenium oxide afforded ketone 6.13 Compound
6, an analogue of 1 and 2, was thus prepared from
(−)-(S)-verbenone in five steps and 55% overall yield.
Compounds 5 and 6 are suitable chiral building blocks
for the preparation of cyclobutane carbocyclic
nucleosides.
In order to prepare partially protected g-amino acids,
several transformations were tried. Attempts to remove
the acetamide group by treatment of 7 with hydrazine
proved fruitless. On the other hand, (−)-cis-pinononic
acid, 3, was submitted to Schmidt rearrangement condi-
tions affording 9 in very poor yield. In contrast, mild
saponification of 7 by using 1.2 M K2CO3 in 3:1
MeOH–H2O provided, in 91% yield, N-acetyl g-cis
amino acid 9,13 homochiral as regards the Burgess
compound,3a but differently protected. Compound 9 is
convenient for incorporation into g-oligopeptides.
Moreover, 9 is one of the enantiomers of the racemate
described by Avotins.2
According to a second divergent route, compound 3a
underwent Schmidt rearrangement15 (NaN3/MeSO3H/
DME, −30°C to rt, 12 h) to afford the fully protected
g-amino acid 713 (75% yield), which was thus synthe-
sized in three steps from (−)-(S)-verbenone in 67%
overall yield. This amino acid is the formal enantiomer
Finally, the synthesis of the enantiopure free amino
acid 10 was achieved by hydrolysis of 7 with boiling 2
N aqueous HCl (83% yield). The synthesis of this
Scheme 1.

P. D. Rouge et al. / Tetrahedron: Asymmetry 14 (2003) 193–195
195
compound in racemic form has also been described by
Avotins.2
5. Bell, E. A.; Qureshi, M. Y.; Pryce, R. J.; Janzen, D. H.;
Lemke, P.; Clardy, J. J. Am. Chem. Soc. 1980, 102, 1409.
6. Baldwin, J. E.; Adlington, R. M.; Ting, H. Tetrahedron
1986, 42, 2575.
7. For a recent review on the synthesis and bioactivity of
carbocyclic nucleosides, see: Ichikawa, E.; Kato, K. Syn-
thesis 2002, 1.
Thus, in this work, highly versatile and efficient syn-
thetic routes from (−)-(S)-verbenone, involving con-
certed rearrangements in acid medium as the key steps,
have been accomplished for the preparation of cyclobu-
tanones, amino acids, and amino alcohols. These com-
pounds are relevant precursors to enantiopure
nucleosides and oligopeptides and active investigation
oriented to the synthesis of such products is being
carried out in our laboratories.
8. Honjo, M.; Maruyama, T.; Sato, Y.; Horii, T. Chem.
Pharm. Bull. 1989, 37, 1413.
9. Ichikawa, Y.; Narite, A.; Shiozawa, A.; Hayashi, Y.;
Narasaka, K. J. Chem. Soc., Chem. Commun. 1989, 1919.
10. Ahmad, S. Tetrahedron Lett. 1991, 32, 6997.
11. Kaiwar, V.; Reese, C. B.; Gray, E. J.; Neidle, S. J. Chem.
Soc., Perkin Trans. 1 1995, 2281.
Acknowledgements
12. (a) Moglioni, A. G.; Garc´ıa-Expo´sito, E.; Aguado, G. P.;
Parella, T.; Branchadell, V.; Moltrasio, G. Y.; Ortun˜o, R.
M. J. Org. Chem. 2000, 65, 3939; (b) Moglioni, A. G.;
The authors thanks Dr. Alicia Lagomarsino for her
generous support and for access to facilities. Financial
support from SECYT-UBA, CONICET, AGENCIA
PICT 0400600, ANTORCHAS (Argentina), and DGI
(BQU2001-1907) and AECI (Q2812001B) (Spain) is
gratefully acknowledged.
´
Garc´ıa-Expo´sito, E.; Alvarez-Larena, A.; Branchadell,
V.; Moltrasio, G. Y.; Ortun˜o, R. M. Tetrahedron: Asym-
´
metry 2000, 11, 4903; (c) Aguado, G. P.; Alvarez-Larena,
A.; Illa, O.; Moglioni, A. G.; Ortun˜o, R. M. Tetrahedron:
Asymmetry 2001, 12, 25; (d) Moglioni, A. G.; Muray, E.;
´
Castillo, J. A.; Alvarez-Larena, A.; Moltrasio, G. Y.;
Branchadell, V.; Ortun˜o, R. M. J. Org. Chem. 2002, 67,
2402; (e) Moglioni, A. G.; Brousse, B. N.; Alvarez-
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