Stereoselective synthesis of functionalized trans-2,5-disubstituted tetrahydrofurans

Article abstract of DOI:10.1021/ol991194u

(formula presented) The addition of the titanium enolates of N-acetyl, N-propionyl, and N-bromoacetyl (R)-oxazolidin-2-ones to γ-lactol 2, derived from (S)-glutamic acid, afforded trans-and cis-2,5-disubstituted tetrahydrofurans (trans/cis ratio: R = H, 2

Full text of DOI:10.1021/ol991194u

ORGANIC
LETTERS
2000
Vol. 2, No. 1
53-56
Stereoselective Synthesis of
Functionalized trans-2,5-Disubstituted
Tetrahydrofurans
,†
Ronaldo A. Pilli,* Vale´ria B. Riatto,† and Ivo Vencato‡
Instituto de Qu´ımica, Unicamp, Cx. Postal 6154, 13083-970 Campinas, SP, Brazil, and
Departamento de Qu´ımica, UFSC, 88040-900 Floriano´polis, SC, Brazil
pilli@iqm.unicamp.br
Received October 28, 1999
ABSTRACT
The addition of the titanium enolates of N-acetyl, N-propionyl, and N-bromoacetyl (R)-oxazolidin-2-ones to γ-lactol 2, derived from (S)-glutamic
acid, afforded trans- and cis-2,5-disubstituted tetrahydrofurans (trans/cis ratio: R ) H, 2:1; R ) Me, 8:1; R ) Br, 10:1) after desilylation with
aqueous HF/CH CN. Chromatographic separation and LiBH reduction allowed the efficient preparation of the corresponding trans-2,5-disubstituted
3
4
tetrahydrofuran diols and the recovery of the chiral auxiliary.
The stereoselective synthesis of 2,5-disubstituted tetrahy-
drofuran rings has received much attention since they occur
as building blocks in many interesting natural products such
as cytotoxic polyethers1 and acetogenins.2 The Lewis acid-
promoted substitution at the anomeric center of 5-substituted-
γ-lactols via an intermediate oxocarbenium ion is one of the
strategies explored;3 however, studies involving the stereo-
selective addition of chiral and prochiral nucleophiles to
cyclic oxocarbenium ions are scarce. The usefulness of the
stereochemically defined titanium enolate of chiral oxazoli-
dinones in aldol4 and in the addition to cyclic N-acyliminium
ions5 reactions led us to explore their reactions with chiral
oxocarbenium ion derived from lactol 2, a useful building
block for the asymmetric synthesis of tetrahydrofuran-
containing natural products. In this paper we report the utility
of chiral oxazolidin-2-ones in the stereoselective synthesis
of 2,5-disubstituted tetrahydrofuran rings with the simulta-
neous formation of two new stereogenic centers.
(Scheme 1). The chlorotitanium enolate was generated by
the sequential addition of 1.1 equiv of TiCl4 and 1.1 equiv
Scheme 1
Initially, we examined the addition of achiral titanium(IV)
enolate 3a6 to lactol 2, derived from (S)-glutamic acid7
† Unicamp.
‡ UFSC.
10.1021/ol991194u CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/10/1999

of diisopropylethylamine to a cold solution (-23 °C) of the
corresponding N-substituted oxazolidin-2-one in CH2Cl2
followed by the dropwise addition of a CH2Cl2 solution of
lactol 2. A 4:4:1:1 mixture of the four possible adducts
(trans-4a:trans-5a:cis-6a:cis-7a) was isolated in 61% yield
(Table 1). The major isomers trans-4a and trans-5a were
Table 1. Diastereoselective Reactions of Chlorotitanium
Enolates 3a-e with Lactol 2
adducts
(ratio)
yield (%)
(3J 2′,2 (Hz))
enolate
R
R1 R2 R3
3a
TBDPS
H
H
Me 4a :5a :6a :7a 61
(4:4:1:1)b
(4a , 6.8; 5a , 9.3)
58c,d
3b
3c
3d
3e
H
H
H
H
H
Bn Me 5b:7b
(8:1)a
Me 4c:6c
(5b, 9.3)
55c,d
Bn
H
H
(3.5:1)a
4/5d :6/7d
(2:1)b
(4c, 6.8; 6c, 9.3)
57c,d
Bn
H
H
Bn Br 5e:7e
57c,d
(10:1)b
(5e,9.5; 7e, 6.0)
a Determined by GC analysis. b Determined in the crude mixture by 1H
NMR spectroscopy (500 MHz) in CDCl3. c Yields (two steps) after
purification of the crude mixture by filtration through a pad of silica gel.
d TBDPS group deprotection with HF/CH3CN, except for 5e/7e where HF/
pyridine was used.
separated by column chromatography on silica gel, and their
configurations were determined after conversion to the
corresponding diols (TBDPS deprotection and reduction with
LiBH4, Table 2) and were compared with those of the diols
Table 2. Reduction of N-Acyloxazolidin-2-ones
adduct
R
R1 R2
R3
R4
diol
yield (%)a
4a b
4c
TBDPS
H
TBDPS
H
H
H
H
Bn
H
H
Bn
H
H
H
H
Bn
H
Me
Me
H
H
Me
H
H
H
(2′S,2S)-8
(2′S,2S)-8
90
87
89
88
88
89
5a b
Me (2′R,2S)-8
Me (2′R,2S)-8
H
H
5b
6c
4/5d
(2′S,2R)-8
(2S)-9
Bn
Figure 1. ORTEP drawing of 5b, 4c, 6c, and 5e.
a Chiral oxazolidin-2-ones recovered in good yields (85-95%). b Adducts
4a and 5a were desilylated (HF, CH3CN, H2O) prior to reduction with
LiBH4.
The lack of facial discrimination observed for achiral
titanium enolate 3a led us to examine the impact of chiral
derived from trans-4c and trans-5b (structure established by
X-ray diffraction analyses, Figure 1).
(3) Schmitt, A. S.; Reissig, H. U. Chem. Ber. 1995, 128, 871 and
references therein.
(4) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem.
Soc. 1991, 113, 1047.
(5) Pilli, R. A.; Alves, C. F.; Bo¨ckelmann, M. A.; Mascarenhas, Y. P.;
Nery, J. G.; Vencato, I. Tetrahedron Lett. 1999, 40, 2891.
(6) Ager, D. J.; Allen, D. R.; Schaad, D. R. Synthesis 1996, 1283.
(1) (a) Matsuo, Y.; Suzuki, M.; Masuda, M. Chem. Lett. 1995, 1043.
(b) Kang, S. H.; Lee, S. B. Chem. Commun. 1998, 761.
(2) (a) Keinan, E.; Sinha, A.; Yazbak, A.; Sinha, S. C. Pure Appl. Chem.
1997, 69, 423. (b) Hoppe, R.; Scharf, H. D. Synthesis 1995, 1447.
54
Org. Lett., Vol. 2, No. 1, 2000

titanium(IV) enolates 3b and 3c6 in the process. The addition
of a CH2Cl2 solution of lactol 2 to titanium(IV) enolates 3b
and 3c afforded only two diastereoisomers in 8:1 and 3.5:1
ratios, respectively (Table 1), revealing complete facial
control by the chiral titanium enolate (only products arising
from the addition to the re face of enolate 3b and to the si
face of enolate 3c were observed). After TBDPS group
deprotection with HF/CH3CN, the diastereoisomers trans-
5b, trans-4c, and cis-6c were separated by column chroma-
tography and fully characterized. The stereochemistry of the
minor isomer cis-6c was established by X-ray diffraction
analysis (Figure 1). The diastereoisomeric 2,5-disubstituted
Scheme 3
1
tetrahydrofurans were readily distinguishable by H NMR
spectroscopy as the vicinal coupling constants (3J2′,2) for the
protons in the newly created stereogenic centers were
diagnostic of their relative stereochemistry: J ) 9.3 Hz for
trans-5b and cis-6c and J ) 6.8 Hz for trans-4c (Table 1).
Unfortunately, low diastereoselection (2:1) was observed
in the addition of chiral titanium(IV) enolate derived from
N-acetyl oxazolidin-2-one 3d, revealing the importance of
the substitution pattern of the enolate in the stereochemical
course of the reaction.8 Preparatively useful access to trans-
4/5d was eventually secured in 84% yield through the
n-Bu3SnH reduction of bromo derivative trans-5e (structure
established by X-ray difraction analysis, Figure 1) formed
in 57% yield (10:1 diastereoisomeric mixture) from the
corresponding titanium enolate 3e (Scheme 2).
Scheme 2
(B) approach of the titanium enolate re face to the re face
of the oxocarbenium ion derived from 2. While the former
arrangement minimizes the steric interaction between the
methyl group of the enolate and the methylene groups of
the oxocarbenium ion, the latter one alleviates steric interac-
tion between the oxazolidinone ring and the oxocarbenium
ion.
The formation of the minor isomer cis-7b requires the
antiperiplanar approach of the titanium enolate re face to
the sterically hindered oxocarbenium ion si face (C). In this
case, the synclinal approach (D) seems to be less favored
due not only to steric interactions involving the methyl group
in the enolate and the -CH2OTBDPS group of the oxo-
carbenium ion but also to the electronically disfavored
interaction involving nonbonded electron pairs in closely
spaced oxygen atoms (Scheme 3).
The reaction of enolates 3a-e with the oxocarbenium ion
derived from 2 can produce up to four diastereoisomeric 2,5-
disubstituted tetrahydrofurans. The stereochemical outcome
of the reactions investigated seems to be ruled by an open
transition state with the favored approach of the less hindered
face of a Z-configured internally coordinated titanium enolate
to the more sterically available re face of the intermediate
oxocarbenium ion (Scheme 3).
The preferential formation of trans-5b can be rationalized
either through a synclinal (A, Scheme 3) or an antiperiplanar
The improved diastereoselection in the addition of bromo-
enolate 3e (trans-5e:cis-7e ) 10:1) results from severe steric
interaction between the bromine atom and the -CH2OTBDPS
group in the synclinal approach leading to cis-7e as well as
to the repulsive electronic interactions in the antiperiplanar
approach involving nonbonded electron pairs of the bromine
(7) (a) Blackwell, C. M.; Davidson, A. H.; Launchbury, S. B.; Lewis,
C. N.; Morrice, E. M.; Reeve, M. M.; Roffey, J. A. R.; Tipping, A. S.;
Todd, R. S. J. Org. Chem. 1992, 57, 3887. (b) Hanessian, S.; Grillo, T. A.
J. Org. Chem. 1998, 63, 1049.
(8) Low levels of asymmetric induction were also observed in the aldol
reaction of boron and titanium enolates of N-acetyloxazolidin-2-ones: (a)
Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127.
(b) Nerz-Stormes, M.; Thornton, E. R. J. Org. Chem. 1991, 56, 2489.
Org. Lett., Vol. 2, No. 1, 2000
55

atom and the oxygen atom of the oxocarbenium ion.
Accordingly, the decrease in the diastereoselection observed
for 3d is accounted for on the basis of the lack of a
discriminating group at the nucleophilic center of 3d (R )
H) and denotes the poor facial selectivity of the oxocar-
benium ion.
tion in the asymmetric synthesis of natural 2,5-trans-
disubstituted tetrahydrofurans is under investigation.
Acknowledgment. We acknowledge FAPESP for finan-
cial support and a fellowship (V.B.R.) and CNPq for a
fellowship (R.A.P.).
In summary, 2,5-disubstituted tetrahydrofuran rings were
prepared through the addition of titanium(IV) enolate 3a-e
to the oxocarbenium ion derived from lactol 2. We have
shown that the levels of the diastereoselection in the reactions
are modulated by the nature of the R3 group in the enolate
and by the intrinsic chirality of the oxazolidin-2-one.
Compounds trans-5b, trans-4/5d, and trans-5e were prepared
in good yields and diastereoisomeric ratio, and their utiliza-
Supporting Information Available: General procedures
and characterization data for compounds 4a, 5a, 5b, 4c, 6c,
4/5d, 5e, (2′R,2S,5S)-8, (2′S,2S,5S)-8, (2′S,2R,5S)-8, and
(2S,5S)-9. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL991194U
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Org. Lett., Vol. 2, No. 1, 2000