Highly Diastereoselective Synthesis of trans-2,5-Disubstituted Tetrahydrofurans

Article abstract of DOI:10.1021/jo035811a

trans-2,5-Disubstituted tetrahydrofurans were obtained as major diastereomers (trans / cis ratio 90:10-100: 0) when acetylated y-lactols derived from (S)-glutamic acid were treated with titanium enolates of N-acetyl (R)-oxazolidin-2-thiones. A simple tran

Full text of DOI:10.1021/jo035811a

SCHEME 1. Dia ster eoselective Ad d ition of th e
Tita n iu m En ola te of 1a (1.5 equ iv) to La ctol
Aceta tes 2a -c (for Cla r ity, On ly (R)-1a Is
Rep r esen ted )
High ly Dia ster eoselective Syn th esis of
tr a n s-2,5-Disu bstitu ted Tetr a h yd r ofu r a n s
Gae¨l J alce, Matar Seck, Xavier Franck,*
Reynald Hocquemiller, and Bruno Figade`re*
Laboratoire de Pharmacognosie, associe´ au CNRS (BioCIS),
Universite´ Paris-Sud, Faculte´ de Pharmacie, 5 rue
J ean-Baptiste Cle´ment, F-92296 Chaˆtenay-Malabry, France
xavier.franck@cep.u-psud.fr; bruno.figadere@cep.u-psud.fr
Received December 12, 2003
Abstr a ct: trans-2,5-Disubstituted tetrahydrofurans were
obtained as major diastereomers (trans/ cis ratio 90:10-100:
0) when acetylated γ-lactols derived from (S)-glutamic acid
were treated with titanium enolates of N-acetyl (R)-oxazo-
lidin-2-thiones. A simple transesterification allowed us to
obtain the corresponding methyl esters and recover the
chiral auxiliary.
ratio for the N-bromoacetyl derivative.8 It is interesting
to note that the N-acetyloxazolidin-2-ones give also low
asymmetric induction in the aldol reactions.9 We thus
decided to study the addition of the titanium enolate of
N-acetyl chiral oxazolidin-2-thiones to the same γ-lactol
derivatives because these oxazolidin-2-thiones were re-
ported to give better diastereoselectivity in aldol reac-
tions.10
During our work on the total synthesis of annonaceous
acetogenins,1 we were interested in preparing 2,5-disub-
stituted tetrahydrofurans of trans relationship with high
diastereoselectivity. Recently, we reported that Grignard
reagents add to acetyl γ-lactols derived from (S)-glutamic
acid in good yields and moderate trans/ cis ratios (e.g.,
65:35-78:22).2 These diastereomeric ratios are, neverthe-
less, usually obtained whatever the nucleophiles are (e.g.,
alkylsilanes3 and enolates4). To our best knowledge, the
best trans/ cis ratio reported so far concerns the addition
of trimethylsilyloxyfuran on an acetyl γ-lactol possessing
a long aliphatic chain, derived from (S)-glutamic acid,
in the presence of trityl perchlorate.5 Since 2,5-disubsti-
tuted tetrahydrofurans are also found in many natural
products such as polyethers,6 we would like to report
herein the preparation of such building blocks.7 Recently,
Pilli reported the interesting reaction of the titanium
enolate of N-acyl (R)-4-benzyloxazolidin-2-one with a
γ-lactol derived from (S)-glutamic acid, leading to the
trans/ cis expected adduct mixtures but in a low diste-
reomeric 2:1 ratio for the N-acetyl compound and 10:1
Therefore, N-acetyl (R)-4-benzyloxazolidin-2-thione 1a
was prepared as previously reported.10b Its chlorotita-
nium enolate was generated by sequential addition of 1
equiv of TiCl4 and 1 equiv of diisopropylethylamine
(DIPEA) to a cold (0 °C) solution of the oxazolidin-2-
thione 1a in CH2Cl2. Then to the solution containing 1.5
equiv of chlorotitanium enolate of 1a was added dropwise
a CH2Cl2 solution of acetate 2a , 2b, or 2c at -20 °C
(Scheme 1). After 30 min, usual workup gave the corre-
sponding adducts which were directly trans-esterified to
the methyl esters by basic methanol treatment (K2CO3
in MeOH), giving the nonseparable mixtures of trans/
cis esters 5a -c/6a -c (the chiral auxiliary was recovered
at this stage in typical 70-80% yield, after two steps, in
a pure optical form). The configurations were determined
on 5a -c and 6a -c by NMR methods (NOESY, COSY).
It is worth noting that in our case the lactols were
unreactive.8 Interestingly, the oxazolidin-2-thione (R)-1a
gave both a better trans/ cis ratio and a better yield than
the corresponding oxazolidinone.8 The reaction of chlo-
rotitanium enolate of (S)-1a , with 2c under the same
reaction conditions, gave the expected adducts methyl
esters 5c and 6c in lower overall yield (40%) and lower
diastereoselectivity (60:40 dr) (entry 4, Table 1). Interest-
ingly, 1.2 equiv of chlorotitanium enolate of (R)-1a also
reacts with a methoxy lactol to give the adducts in 62%
yield and 85/15 dr (results not shown).
* To whom correspondence should be addressed. Tel: (33) 146
835592. Fax: (33) 146 835399.
(1) (a) Cave´, A.; Figade`re, B.; Laurens, A.; Cortes, D. In Progress in
the Chemistry of Organic Natural Products; Herz, W., Kirby, G. W.,
Moore, R. E., Steglich, W, Tamm, Ch., Eds.; Springer-Verlag: Wien-
New York, 1997; Vol. 70, pp 81-288. (b) Zeng, L.; Oberlies, N. H.; Shi,
G.; Gu, Z.-M.; He, K.; McLaughlin, J . L. Nat. Prod. Rep. 1996, 275. (c)
Alali, F. Q.; Liu, X. X. J . Nat. Prod. 1999, 62, 504-540. (d) Figade`re,
B. Acc. Chem. Res. 1995, 28, 359.
(2) Franck, X.; Hocquemiller, R.; Figade`re, B. Chem. Commun.,
2002, 160-161.
(3) (a) Schmitt, A.; Reissig, H.-U. Eur. J . Org. Chem. 2000, 3893.
(b) Pilli, R. A.; Riatto V. B. Tetrahedron: Asymmetry 2000, 11, 3675.
(c) Larsen, K. C.; Ridgway, B. H.; Shaw, J . T.; Woerpel, K. A. J . Am.
Chem. Soc. 1999, 121, 12208-12209.
These first results are encouraging and show that the
chiral N-acetyl 4-benzyloxazolidin-2-thione 1a adds onto
an intermediate oxocarbenium (generated in situ from
the lactol acetates 2a -c) with a good diastereoselectivity.
(4) Koert, U.; Stein, M.; Harms, K. Tetrahedron Lett. 1993, 34, 2299.
(5) (a) Figade`re, B., Chaboche, C., Peyrat, J .-F., Cave´, A. Tetrahedron
Lett. 1993, 34, 8093. (b) Figade`re, B., Peyrat, J .-F., Cave´, A. J . Org.
Chem. 1997, 62, 3428.
(6) (a) Mori, K. Tetrahedron 1989, 45, 3233. (b) Matsuoto, Y.; Suzuki,
M.; Masuda, M. Chem. Lett. 1995, 1043.
(8) Pilli, R. A.; Riatto, V. B.; Vencato, I. Org. Lett. 2000, 2, 53.
(9) Nerz-Stormes, M.; Thornton, E. R. J . Org. Chem. 1991, 56, 2489.
(10) (a) Crimmins, M. T.; King, B. W.; Tabet, E. A. J . Am. Chem.
Soc. 1997, 119, 7883-7884. (b) Crimmins, M. T.; King, B. W.; Tabet,
E. A.; Chaudhary, K. J . Org. Chem. 2001, 66, 894-902. (c) Guz, N. R.;
Philipps, A. J . Org. Lett. 2002, 4, 2253-2256. (d) Velazquez, F.; Olivo,
H. F. Curr. Org. Chem. 2002, 6, 1-38.
(7) Harmange, J .-C.; Figade`re, B. Tetrahedron: Asymmetry 1993,
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10.1021/jo035811a CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/03/2004
3240
J . Org. Chem. 2004, 69, 3240-3241

TABLE 1. Dia ster eoselective Ad d ition of th e Tita n iu m
En ola te of 1a (1.5 equ iv) to La ctol Aceta tes 2a -c,
F ollow ed by Meth a n olysis
SCHEME 3
chiral
lactol
yield (%)
auxiliary
acetate
T (°C)
(two steps)
dr (trans/cis)
(R)-1a
(R)-1a
(R)-1a
(S)-1a
2a
2b
2c
2c
-20
-20
-40
-40
52 (5a + 6a )
55 (5b + 6b)
77 (5c + 6c)
40 (5c + 6c)
70:30
77:23
90:10
60:40
5b and 6b in 56% yield (in two steps) and 100:0 dr (Table
2). It is important to note that this is the first time that
such a diastereoselectivity has been observed with this
lactol derivative. Finally, when the reaction was per-
formed at lower temperature (-40 °C), yields were lower
(not shown). In the case of lactol acetates 2c, with more
sterical demands due to the CH(OTBDMS)C4H9 side
chain, both chlorotitanium enolates of (R)-1b and (S)-1b
(generated as described above) gave the trans esters 5c
as the major diastereomer (100:0 and 90:10, respectively)
and in 75 and 48% yield, respectively, when the reactions
were run at -40 °C. In these cases, higher temperatures
gave lower diastereoselectivities (results not shown).
These results highlight again the substrate control of the
reaction.
It is important to note that the trans/cis intermediate
adducts 3 and 4 could also be isolated and further
transformed into the primary alcohols and aldehydes. For
instance, the LiBH4 reduction8 of the trans adduct 3,
obtained from addition of the titanium enolate of (R)-1b
to lactol acetates 2c, afforded the single primary alcohol
7 in 83% yield with 91% recovery of the chiral auxiliary.
The corresponding aldehyde 8 could also be prepared in
high yield (90%) from the same adduct 3 by Dibal-H
reduction,11 with recovery of the chiral auxiliary in 93%
yield (Scheme 3).
SCHEME 2. Ad d ition of th e Tita n iu m En ola te of
1b (1.5 equ iv) to La ctol Aceta tes 2a -c (for Cla r ity,
On ly (R)-1b Is Rep r esen ted )
TABLE 2. Dia ster eoselective Ad d ition of th e Tita n iu m
En ola te of 1b (1.5 equ iv) to La ctol Aceta tes 2a -c,
F ollow ed by Meth a n olysis
chiral
lactol
yield (%)
auxiliary
acetate
T (°C)
(two steps)
dr (trans/cis)
(R)-1b
(S)-1b
(R)-1b
(R)-1b
(S)-1b
2a
2a
2b
2c
2c
-20
-20
-20
-40
-40
51 (5a + 6a )
51 (5a + 6a )
56 (5b + 6b)
75 (5c + 6c)
48 (5c + 6c)
90:10
75:25
100:0
100:0
90:10
However both enantiomers of 1a gave the same major
trans diastereomer (with (R)-1a leading to a better
diastereoselectivity and higher yields than (S)-1a ). This
means that the reaction is not auxiliary but substrate
controlled and that the oxazolidin-2-thione 1a acts mainly
via its bulk and not only via its absolute configuration.
We thus decided to prepare a more bulky oxazolidin-2-
thione and synthesized for the first time the N-acetyl (R)-
5,5-diphenyl-4-benzyloxazolidin-2-thione 1b, and its enan-
tiomer (S)-1b, and studied their reactivity with the lactol
acetates 2a -c (Scheme 2 and Table 2). (R)-1b and (S)-
1b were prepared from the corresponding chiral (R)- and
(S)-R-amino acid methyl esters of phenylalanine by
double phenyl Grignard addition, followed by cyclization
of the 1,2-amino alcohols so obtained with thiophosgene.10c
Acetylation of the oxazolidin-2-thiones was then per-
formed by treatment with acetyl chloride in the presence
of NaH, leading to (R)-1b and (S)-1b in 55% overall yield
(three steps).
When 1.5 equiv of the chlorotitanium enolate of (R)-
1b (generated by 1 equiv of TiCl4 and 1 equiv of DIPEA)
reacted at -20 °C with lactol acetate 2a (1 equiv), the
adducts were obtained and directly transesterified to the
methyl esters 5a and 6a in 51% yield (two steps) and in
90:10 dr (Scheme 2, Table 2). Reaction of the chlorotita-
nium enolate of (S)-1b, with 2a , under the same reaction
conditions gave the methyl esters 5a and 6a in 51% yield
(in two steps) and 75:25 dr. With lactol acetate 2b, which
possesses the more bulky TBDPS protecting group, the
chlorotitanium enolate of (R)-1b gave the methyl esters
In conclusion, this study shows that chiral N-acetyl-
oxazolidin-2-thiones are much better nucleophiles than
their N-acetyloxazolidin-2-one counterparts, and the di-
astereoselective addition of their chlorotitanium enolates
to 2-acetoxytetrahydrofurans allows one to prepare the
trans compounds in good yields and excellent diastere-
omeric ratios (up to 100:0). The adducts so obtained may
be used in the asymmetric synthesis of 2,5-trans-disub-
stituted tetrahydrofurans with excellent recovery of the
chiral auxiliary.
Ack n ow led gm en t. This paper is dedicated to Prof.
William H. Okamura on the occasion of his retirement.
We thank the CNRS for a financial support and J . C.
J ullian for NMR experiments. We gratefully acknowl-
edge Mr. O. Langrene (ISOCHEM, Paris, France) for a
generous gift of D-phenylalanine. G. J . thanks the
Conseil Ge´ne´ral de Guadeloupe for financial support
through a fellowship.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 1b, des-acetyl 1b, 3, 5b,c, 7, and 8.
Experimental procedures and characterization data for des-
acetyl 1b, 1b, 3, 5b,c, 7, and 8. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O035811A
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Bardia, M.; Solans, X. Org. Lett. 2001, 3, 615-618.
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