A short approach to trisubstituted γ-butyrolactones

Article abstract of DOI:10.1016/j.tetlet.2005.10.151

The dihydroxylation of unsaturated aldol adducts with catalytic OsO ₄ and NMO occurs under very mild conditions and with moderate to excellent levels of diastereoselectivity to give trisubstituted γ-butyrolactone derivatives.

Full text of DOI:10.1016/j.tetlet.2005.10.151

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 213–216
A short approach to trisubstituted c-butyrolactones
Luiz C. Dias,* Ilton B. D. de Castro, Leonardo J. Steil and Tatiana Augusto
Instituto de Quı´mica, Universidade Estadual de Campinas, UNICAMP C.P. 6154, 13084-971, Campinas, SP, Brazil
Received 20 October 2005; revised 26 October 2005; accepted 27 October 2005
Available online 16 November 2005
Abstract—The dihydroxylation of unsaturated aldol adducts with catalytic OsO4 and NMO occurs under very mild conditions and
with moderate to excellent levels of diastereoselectivity to give trisubstituted c-butyrolactone derivatives.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
N-propionyloxazolidinone 1 with acrolein to give the
corresponding aldol adduct 2 in 89% yield (ds >95:5)
(Scheme 1).4 The next step involved treatment of the
aldol adduct with catalytic amounts of osmium tetroxide
and NMO in acetone/H2O as solvent. We were very
pleased to find that dihydroxylation of aldol adduct 2
under these conditions led directly to c-butyrolactone
3 in 40% yield and 90:10 diastereoselectivity for the
two-step sequence (dihydroxylation and lactonization).
The chiral auxiliary 4 was easily recovered.
Chiral substituted c-butyrolactones are present in the
structures of a wide variety of natural products with
potential pharmacological applications. The diversity
of their biogenetic origins suggests that this structure
may be one of the key elements in their biosynthesis.1
Because of their importance as chiral building blocks for
the synthesis of compounds with important biological
activities, such as antimumor, antibiotic, antifungal,
and antibacterial, the stereocontrolled synthesis of tri-
substituted c-butyrolactones represent an attractive
objective for synthetic organic chemists.2,3
Silylation of aldol 2 with TBSOTf and 2,6-lutidine gave
5 in 89% yield (Scheme 2). Treatment of 5 with catalytic
amounts of osmium tetroxide and NMO in acetone/
H2O as solvent gave c-butyrolactone 6 in 42% yield
and 90:10 diastereoselectivity for the two-step sequence
(dihydroxylation and lactonization).
Here we report, a novel methodology for the construc-
tion of c-butyrolactones, via a diastereoselective osmyl-
ation of unsaturated syn-aldol adducts. This synthetic
methodology involves two steps: (i) the preparation of
the enantiopure aldol adduct and (ii) the dihydroxyl-
ation reaction followed by in situ lactonization. Despite
the widespread application of the aldol reaction in syn-
thesis, to the best of our knowledge, this is the first direct
application of unsaturated aldol adducts in the synthesis
of c-butyrolactones via an osmylation/lactonization
sequence.3
Both lactones 3 and 6 were smoothly converted to the
same lactone 7 on treatment with TBSOTf and 2,6-luti-
dine in good overall yields. This proved that the same
O
O
O
OH
O
1. n-Bu2BOTf
Et3N, CH2Cl2
Me
N
O
N
O
1
Me
°
-78 C, 89%
2
Bn
Bn
ds > 95:5
O
2. Results and discussion
2.
H
The synthesis of butyrolactones began with the asym-
metric aldol addition of the boron enolate derived from
O
O
Me
NMO, OsO4 cat.
O
HN
Bn
O
+
acetone-H2O (8:1)
Keywords: Dihydroxylation; c-Lactones; Osmylation reaction; Aldol
adducts.
°
HO
0 C, 40%
4
3
ds = 90:10
OH
*
Corresponding author. Tel.: +55 019 3788 3021; fax: +55 019 3788
3023; e-mail: ldias@iqm.unicamp.br
Scheme 1. Dihydroxylation/lactonization sequence.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.151

214
L. C. Dias et al. / Tetrahedron Letters 47 (2006) 213–216
O
O
TBS
O
OH
O
O
O
O
O
TBSOTf
Me
HO
Me
O
O
Cl3CO
OCCl3
2,6-lutidine
CH2Cl2
N
O
N
O
THF, rt, 61%
2
Me
5
Me
O
O
°
0 C, 89%
3
Bn
Bn
16
OH
O
O
O
O
Ha
Me
Me
Me
Ja,b = 8.9 Hz
NMO, OsO4 cat.
TBSOTf
O
O
O
J
J
J
b,c = 8.9 Hz
c,d = 3.1 Hz
c,e = 4.4 Hz
acetone-H2O (8:1)
Hb
Hc
Hd
He
2,6-lutidine
CH2Cl2
0 C, 89%
°
0 C, 42%
O
O
TBSO
TBSO
6
7
°
O
OTBS
OH
ds = 90:10
Scheme 2. Synthesis of lactones 6 and 7.
Scheme 4. Synthesis of cyclic carbonate 16.
as well as the cis relationship between Hb and Hc. The
small vicinal coupling constants between Hc with both
Hd (3.4 Hz) and He (4.4 Hz) confirmed that there is
no trans-diaxial relationship between these hydrogens
and unambiguously established the relative stereochem-
istry of the major isomers (Scheme 4).
major stereoisomer was obtained with both aldol
adducts 2 and 5.
Treatment of aldol adducts 8–11 with catalytic amounts
of osmium tetroxide and NMO in acetone/H2O as sol-
vent led to lactones 12–15, respectively, in good overall
yields and moderate to high diastereoselectivities for the
two-step sequence (Scheme 3).
The relative stereochemistry for lactones 12–15 was
determined by coupling constant analysis in their
1H NMR spectra as well as by NOESY experiments
(Fig. 1).5 The illustrated NOESY interactions between
Ha/Hd, and Hd with the hydrogens of the tert-butyl
group (OTBS) together with the coupling constants for
Ha/Hb (5.9 Hz) and Hb/Hc (0.7 Hz) confirmed the ste-
reochemistry of lactone 12.
It is noteworthy that aldol adducts 9–11 led to lactones
13–15, respectively, with a quaternary stereogenic center
being created. The use of anti-aldol adduct 11 led only to
moderate selectivity (ds = 75:25).
The observed relative stereochemistry of the major iso-
mers 3 and 6 was proved by conversion to the cyclic car-
bonate 16, after treatment of lactone 3 with triphosgene
(61% yield) followed by coupling constant analysis of its
1H NMR spectrum (Scheme 4). The large vicinal cou-
pling constant of Hb with both Ha and Hc (8.9 Hz) con-
firmed the trans-diaxial relationship between Hb and Ha
The NOESY interaction between Ha/Hc, together with
the coupling constant for Ha/Hb (9.5 Hz) confirmed the
stereochemistry of lactone 13. NOESY experiments per-
formed on lactones 14 and 15 also supported their rela-
tive stereochemistries. For lactone 14, a NOESY cross-
peak was observed for the Ha/OH signals and, for lac-
tone 15, a NOESY cross-peak was observed for the
Ha/Hb and Hb/Hc signals.
TBS
O
O
O
O
O
In these stereochemical assignments, both the C2–
methyl and the C3–OTBS (or OTMS in the case of lac-
Me
O
+
OH
H
4
NMO, OsO4 cat.
H
Ph
N
N
N
N
O
O
acetone-H2O (8:1)
8
Me
TBSO
°
0
C, 45%
12
ds >95:05
Bn
Ph
TBS
O
O
O
O
Me
O
Ha
Ha
Me
Me
O
O
NMO, OsO4 cat.
Me +
4
O
acetone-H2O (8:1)
Hc
Hb
Me
Hc
Hc
OH
Me Me
TBSO
Hb
OH
Hd
°
0
C, 43%
13
Bn
TBSO
9
TBSO
12
OH
ds = 78:22
13
Ph
TBS
O
NOESY: Ha/Hc
Ja,b = 9.5 Hz
NOESY: Ha/Hd; Hd/t-Bu
O
O
O
O
Me
Ja,b = 5.9 Hz
Jb,c = 0.7 Hz
NMO, OsO4 cat.
O
+
4
4
Me
Me
O
O
acetone-H2O (8:1)
OH
H
O
Me Me
TBSO
°
0
C, 47%
O
14
Ha
Bn
O
10
Ha
Me
O
Me
Me
ds = 94:06
O
Hb
Me
Hc
Hc
Me
Hb
TMS
O
OH
TMSO
O
TBSO
H
15
HO
14
Me
NMO, OsO4 cat.
O
Me
+
Me
acetone-H2O (8:1)
NOESY: Ha/OH
Ja,b = 8.8 Hz
NOESY: Ha/Hb; Hb/Hc
Ja,b = 6.6 Hz
Me Me
TMSO
°
0
C, 44%
15
Bn
11
OH
ds = 75:25
Figure 1. NOESY interactions and coupling constants for lactones 12–
15.
Scheme 3. Synthesis of lactones 12–15.

L. C. Dias et al. / Tetrahedron Letters 47 (2006) 213–216
215
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3. Conclusions
In summary, we have demonstrated that dihydroxyl-
ation of unsaturated syn-aldol adducts occurs under
very mild conditions and with good levels of diastereo-
selectivity to give trisubstituted c-butyrolactone deriva-
tives. The relative and absolute stereochemistries of
C2–C3 stereocenters is then established by the nature
of the aldol reaction (syn or anti) and by the resident
chirality of the chiral auxiliary as, probably, the oxazo-
lidinone ring plays a dominant role in controlling the
conformation of these compounds. This research, in
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adducts, may represent a useful entry into the field of
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Acknowledgements
5. For conformational studies of c-lactones by MM2 calcu-
lations and coupling constant analysis, see (a) Jaime, C.;
We are grateful to FAEP-UNICAMP, FAPESP (Fun-
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Segura, C.; Dinares, I.; Font, J. J. Org. Chem. 1993, 58,
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dac¸ao de Amparo a Pesquisa do Estado de Sao Paulo)
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6. Lactone 3: 1H NMR (CD3OD, 300 MHz): d (ppm): 1.31 (d,
J 7.3 Hz, 3H), 2.66 (dq, J 8.8, 7.3 Hz, 1H), 3.72 (dd, J 12.8,
4.6 Hz, 1H), 3.94 (dd, J 12.8, 2.4 Hz, 1H), 4.01 (dd, J 8.8,
7.3 Hz, 1H), 4.18 (ddd, J 7.3, 4.6, 2.4 Hz, 1H); 13C NMR
(CD3OD, 75 MHz): d (ppm): 12.8, 44.9, 61.4, 74.7, 86.0,
179.3; Lactone 6: 1H NMR (CDCl3, 300 MHz): d (ppm):
0.10 (s, 3H), 0.11 (s, 3H), 0.89 (s, 9H), 1.28 (d, J 7.3 Hz,
3H), 2.62 (m, 1H), 2.76 (br s, 1H), 3.67 (d, J 13.0 Hz, 1H),
3.98 (d, J 13.0 Hz, 1H), 4.14 (m, 2H); 13C NMR (CDCl3,
75 MHz): d (ppm): À4.6, À4.1, 12.8, 17.9, 25.6, 44.3, 60.1,
74.2, 84.1, 176.5. Lactone 7: 1H NMR (CDCl3, 300 MHz): d
(ppm): 0.07 (s, 3H), 0.08 (s, 3H), 0.10 (s, 3H), 0.11 (s, 3H),
0.89 (s, 9H), 0.90 (s, 9H), 1.29 (d, J 7.4 Hz, 3H), 2.60 (q, J
7.4 Hz, 1H), 3.75 (dd, J 12.1, 2.6 Hz, 1H), 3.92 (dd, J 12.1,
2.2 Hz, 1H), 4.10 (dt, J 6.6, 2.2 Hz, 1H), 4.20 (dd, J 8.1,
6.6 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d (ppm): À5.6,
À5.4, À4.8, À4.4, 13.0, 17.8, 18.2, 25.6, 25.8, 44.2, 60.4,
74.1, 84.4, 176.8. Lactone 12: 1H NMR (CDCl3, 300 MHz):
d (ppm): À0.14 (s, 3H), À0.07 (s, 3H), 0.83 (s, 9H), 1.16 (d,
J 7.3 Hz, 3H), 2.56 (dq, J 7.3, 5.9 Hz, 1H), 4.30 (dd, J 5.9,
0.7 Hz, 1H), 4.37 (dd, J 5.9, 0.7 Hz, 1H); 4.72 (d, J 5.9 Hz,
1H), 7.30–7.50 (m, 5H); 13C NMR (CDCl3, 75 MHz): d
(ppm): À5.2, À5.1, 8.8, 17.9, 25.6, 39.6, 71.4, 73.6, 89.5,
126.8, 128.8, 128.9, 138.8, 178.4. Lactone 13: 1H NMR
(CDCl3, 300 MHz): d (ppm): 0.10 (s, 3H), 0.12 (s, 3H), 0.90
(s, 9H), 1.24 (s, 3H), 1.28 (d, J 7.3 Hz, 3H), 2.15 (br s, 1H),
2.67 (dq, J 9.5, 7.3 Hz, 1H), 3.47 (d, J 12.8 Hz, 1H), 3.72 (d,
J 12.8 Hz, 1H), 4.25 (d, J 9.5 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d (ppm): À4.8, À4.3, 12.7, 16.7, 17.8, 25.6, 42.3,
65.0, 74.5, 86.5, 176.2. Lactone 14: 1H NMR (CDCl3,
300 MHz): d (ppm): 0.08 (s, 3H), 0.10 (s, 3H), 0.88 (s, 9H),
1.21 (s, 3H), 1.26 (d, J 7.3 Hz, 3H), 1.28 (d, J 6.4 Hz, 3H),
1.95 (br s, 1H), 2.61 (dq, J 8.8, 7.3 Hz, 1H), 3.60 (q, J
´
´
Cientıfico e Tecnologico), for financial support. We also
thank Professor Carol H. Collins, for helpful sugges-
tions about English grammar and style.
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L. C. Dias et al. / Tetrahedron Letters 47 (2006) 213–216
6.4 Hz, 1H), 4.35 (d, J 8.8 Hz, 1H); 13C NMR (CDCl3,
3.59 (d, J 12.1 Hz, 1H), 3.69 (d, J 12.1 Hz, 1H), 4.33 (d, J
6.6 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d (ppm): 0.10,
9.6, 17.9, 41.3, 67.4, 73.4, 88.5, 179.0.
75 MHz): d (ppm): À4.6, À4.0, 12.9, 16.5, 17.7, 17.9, 25.6,
1
42.3, 69.4, 75.7, 84.6, 176.3. Lactone 15: H NMR (CDCl3,
300 MHz): d (ppm): 0.14 (s, 9H), 1.15 (d, J 7.3 Hz, 3H),
1.28 (s, 3H), 2.40 (br s, 1H), 3.04 (dq, J 7.3, 6.6 Hz, 1H),
7. Yields refer to chromatographically and spectroscopically
homogeneous materials.