Stereochemical control on the Michael addition of chiral 1,3-oxazolidine-2-thiones to N-crotonyl 1,3-oxazolidin-2-ones

Article abstract of DOI:10.1016/j.tetlet.2012.12.074

Addition of both antipodes of 4-phenyl 1,3-oxazolidine-2-thione to 4-substituted N-crotonyl 1,3-oxazolidin-2-ones furnished Michael addition products. A perfect match occurred when both Michael donor and acceptor possessed the same stereochemistry and a mismatch when they had opposite stereochemistries. The newly created stereochemical center was shown to be governed by the Michael donor and not by the acceptor.

Full text of DOI:10.1016/j.tetlet.2012.12.074

Tetrahedron Letters 54 (2013) 1230–1232
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereochemical control on the Michael addition of chiral
1,3-oxazolidine-2-thiones to N-crotonyl 1,3-oxazolidin-2-ones
⇑
Laura Munive, Sena A. Dzakuma, Horacio F. Olivo
Medicinal and Natural Products Chemistry, The University of Iowa, Iowa City, IA 52242, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Addition of both antipodes of 4-phenyl 1,3-oxazolidine-2-thione to 4-substituted N-crotonyl 1,3-oxazoli-
din-2-ones furnished Michael addition products. A perfect match occurred when both Michael donor and
acceptor possessed the same stereochemistry and a mismatch when they had opposite stereochemistries.
The newly created stereochemical center was shown to be governed by the Michael donor and not by the
acceptor.
Received 17 October 2012
Revised 17 December 2012
Accepted 19 December 2012
Available online 7 January 2013
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Michael addition
Stereochemical control
Oxazolidinethiones
N-Enoyl oxazolidinone
Thione-based chiral auxiliaries are gaining popularity because
they have many highly desirable characteristics; they are easy to
prepare, to attach to an acyl group, and to remove after conveying
stereochemical transfer in a transformation.1 N-Enoyl thione-based
auxiliaries are good Michael acceptors with organocuprates,2 but
in the presence of a Lewis acid they can also undergo a stereoselec-
tive intramolecular conjugate addition by the sulfur atom.3
N-Enoyl oxazolidinones have proved excellent Michael
acceptors in both catalyzed4 and chiral auxiliary based additions.
Diastereoselective conjugate additions of organocuprates,5 alkyl-
zirconocenes,6 and free radicals7 to N-enoyl oxazolidinones have
been reported in the presence of a Lewis acid. Davies et al. have
studied the double diastereoselective Michael addition of chiral
lithium amides to chiral oxazolidinones.8 They determined that
the active conformation of the N-enoyl oxazolidinone is the anti-
s-cis form.
We reported recently, that oxazolidinethiones and thiazolidin-
ethiones act as excellent nucleophiles on the diastereoselective
conjugate addition to N-crotonyl imides (oxazolidinones, thiazoli-
dinethiones, and oxazolidinethiones), Scheme 1.9 We found that
a diastereoselective conjugate addition takes place when oxazoli-
dinethione is added to N-crotonyl oxazolidinethione. A similar
conjugate addition occurs when a thiazolidinethione is added to
N-crotonyl thiazolidinethione. However, when a thiazolidinethione
is added to N-crotonyl oxazolidinethione, or an oxazolidinethione
is added to N-crotonyl thiazolidinethione, a concomitant trans-
acylation occurs and a complex mixture of products is achieved.
Interestingly, no trans-acylation occurs with the conjugate addition
of the thione-based heterocycle to the more robust N-crotonyl oxa-
zolidinone, and again a high diastereoselective conjugate addition
took place with both thiazolidinethiones and oxazolidinethiones.
We observed that the conjugate addition occurs when the nitro-
gen of the sulfur-containing heterocycle attacks C-3 of the N-croto-
nyl imide on the less hindered side of its anti-s-cis conformation. In
this Letter, we report our findings when both antipodes of 4-phe-
nyl-oxazolidinethiones are added to chiral N-crotonyl
oxazolidinones.
Initially, we investigated the conjugate addition of non-substi-
tuted oxazolidinethione 8 to N-crotonyl 4-substituted oxazolidi-
nones 7a–c, Table 1. Desired products were obtained in good to
very good yields. We observed no diastereoselectivity when the
substituted oxazolidinone carried a small isopropyl group, a slight
diastereoselectivity when the substituent was a phenyl ring, and
better diastereoselectivity when the substituent was a benzyl
group. Diastereomers could be separated by column chromatogra-
phy and fully characterized. Relative stereochemistry of major Mi-
chael adduct 9b was determined by X-ray analysis, Figure 1.10
The stereochemical assignment for the compounds 9a and 9c
was based on the similarities of hydrogen chemical shifts on C2
on the 1H NMR spectra with those of 9b. Interestingly, the major
diastereomer observed is not the syn-adduct (entries 2 and 3), as
observed previously when the stereochemistry of the Michael
acceptor (C4) and the stereochemistry of the Michael donor (C4)
⇑
Corresponding author. Tel.: +1 319 335 8849; fax: +1 319 335 8766.
E-mail address: horacio-olivo@uiowa.edu (H.F. Olivo).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.074

L. Munive et al. / Tetrahedron Letters 54 (2013) 1230–1232
1231
X
S
O
O
N
S
S
O
S
S
O
S
N
O
O
O
Ph
Et3N
Et3N
O
NH
N
X
NH
Ph
X
+
N
O
N
O
N
X
+
CH2Cl2, reflux
CH2Cl2
Ph
Ph
R
R
1 X = S
2 X= O
3 X = S
4 X = O
5 X = S
6 X = O
7a R = i-Pr
7b R = Ph
7c R = Bn
11a R = i-Pr (X-ray), 80%
11b R = Ph, 80%
11c R = Bn (X-ray), 85%
(S)-4
Scheme 1. Conjugate addition of thiazolidinethiones and oxazolidinethiones.9
Scheme 2. Conjugate addition of (4S)-phenyl oxazolidinethione to N-crotonyl
oxazolidinones.
Table 1
Conjugate addition of oxazolidinethione to N-crotonyl oxazolidinones
O
N
O
S
S
O
O
O
S
O
O
N
O
Et3N
O
N
+
O
NH
+
O
N
O
N
CH2Cl2
R
R
R
8
7a-c
10a-c
9a-c
Entry
Acceptor
R
Products
dra
1:1
1.2:1
2:1
Yielda (%)
1
2
3
7a
7b
7c
i-Pr
Ph
Bn
9a, 10a
9b, 10b
9c, 10c
76
85
82
a
As determined by 1H NMR peak integrations with crude product.
are the same (Fig. 1). These results show that the substituent of the
Michael acceptor does not play such an important role to control
the stereochemistry of the newly formed stereocenter.
Both enantiomers of phenylglycine are relatively inexpensive;
therefore we prepared both enantiomers of 4-phenyl-1,3-oxazoli-
dine-2-thione (4). We added the (S)-enantiomer of phenyl-oxazoli-
dinethione (S)-4 to the three N-crotonyl oxazolidinones 7a–c,
Scheme 2. Interestingly, one diastereomeric product was exclu-
sively observed in all three reactions. Michael products were ob-
tained in good isolated yields (80–85%). X-ray crystallographic
analysis of 11a and 11c confirmed unambiguously the stereochem-
istry of the new stereocenter at C3, Figure 2.
Figure 2. Ortep drawing of product 11a.
a match between the chiral Michael acceptor and the chiral nucle-
ophile when both substrates possess the same chirality.
We then proceeded to carry out the conjugate addition with the
opposite enantiomer of phenyl-oxazolidinethione (R)-4 to the
same three N-crotonyl oxazolidinethiones 7a–c, Table 2. This time,
we observed a high diastereoselectivity, and two products were
obtained in excellent ratios for the oxazolidinones with the isopro-
pyl and the phenyl substituents (entries 1 and 2). A lower diastere-
oselectivity (4:1 ratio) was achieved when the oxazolidinone
carried a benzyl group (entry 3). Diastereomers were separated
by column chromatography. X-ray analysis of the minor diastereo-
mer 13c revealed the stereochemistry of the newly formed stereo-
center, Figure 3.
Only the diastereomer with the syn-stereochemistry (C3, C40)
was obtained. From these experiments, we conclude that there is
Assignment of the C3 stereochemistry was made by comparing
the 1H NMR signals of 13c with those of 13a and b. This time, the
Table 2
Conjugate addition of oxazolidinethione to N-crotonyl oxazolidinones
O
N
O
N
S
O
S
S
O
O
O
O
Et3N
O
Ph
Ph
O
NH
Ph
O
N
+
+
O
N
O
N
CH2Cl2, reflux
R
R
R
7a-c
(R)-4
Major diastereomer
Minor diastereomer
12a-c
13a-c
Entry
Acceptor
R
Products
dra
Yielda (%)
1
2
3
7a
7b
7c
i-Pr
Ph
Bn
12a, 13a
12b, 13b
12c, 13c
12:1
30:1
4:1
70
90
85
a
As determined by 1H NMR peak integrations with crude product.
Figure 1. Ortep drawing of product ent-9b.

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L. Munive et al. / Tetrahedron Letters 54 (2013) 1230–1232
and 5 equiv of dimethylcarbonate in dichloromethane to deliver
the methyl ester 15 in 90% yield, Scheme 4.11 The same product
15 was also reduced with sodium borohydride to deliver the corre-
sponding alcohol 16 in 70% yield.12
In summary, we have shown that the conjugate addition of non-
chiral oxazolidinethiones to chiral N-crotonyl oxazolidinones oc-
curs with no diastereoselectivity or very poor stereocontrol.
Chiral oxazolidinethiones are good Michael donors and control
the stereochemistry of the new stereocenter formed. There is a
match when the stereochemistries of Michael donor and acceptor
are the same. This exercise in double asymmetric induction should
be an important contribution to gain a better understanding of chi-
ral Michael donor molecules in conjugate additions.
Acknowledgments
We acknowledge Dr. Dale Swenson (University of Iowa) for
obtaining the X-ray analysis of compounds 9b, 11a, 11c, and 13c.
We thank CONACyT (Mexico) for a predoctoral fellowship (L.M.).
Supplementary data
Supplementary data (experimental procedures and compound
characterization, copies of NMR spectra (1H, 13C, DEPT, COSY and
HMQC) for all products) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tet-
let.2012.12.074. These data include MOL files and InChiKeys of
the most important compounds described in this article.
Figure 3. Ortep drawing of product 13c.
O
N
S
O
S
O
O
Et3N, CH2Cl2
O
R
O
NH
R
+
O
N
reflux
References and notes
O
N
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M.; Ortíz, A.; Olivo, H. F. Org. Lett. 2012, 14, 238–240.
7d
4a R = i-Pr
4b R = Ph
4c R = Bn
14a R = i-Pr, 70%
14b R = Ph, 85%
14c R = Bn, 80%
Scheme 3. Addition of chiral oxazolidinethiones to N-crotonyl oxazolidinone.
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O
S
O
O
N
O
N
O
N
S
O
S
NaOMe
NaBH4
O
N
DMC, CH2Cl2
90%
THF-H2O
70%
MeO
HO
15
16
Ph
9a
Scheme 4. Removal of oxazolidinone auxiliary.
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C40, compounds 12a–c).
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excellent match when the two stereocenters possess the same
absolute stereochemistry and the syn-product is formed exclu-
sively (Scheme 2). There is a mismatch when the stereochemistry
of the Michael acceptor and the donor is opposite, but a high dia-
stereoselectivity is still observed and the anti-product is formed in
major amount.
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To demonstrate these conclusions, the three chiral oxazolidin-
ethiones 4a–c were added to unsubstituted N-crotonyl oxazolidi-
none 7d (Scheme 3). As expected, we observed the formation of
only one diastereomeric product in very good yields in these three
conjugate additions.
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The oxazolidinone auxiliary of Michael addition product 15 was
easily removed by treatment with 5 equiv of sodium methoxide