Synthesis of a 5-oxo-2-Tetrahydrofuranyl Derivative of an Evans Auxiliary via a Novel Reaction Induced by Nucleophiles

Article abstract of DOI:10.1055/s-2003-43339

A 5-oxo-2-tetrahydrofuranyl derivative of an Evans auxiliary could be obtained through a previously unknown 'rearrangement' of the oxazolidinone moiety in an α-benzoxy-γ-aldehyde acyl oxazolidinone in 60-97% yields on treatment with a range of nucleophiles.

Full text of DOI:10.1055/s-2003-43339

LETTER
125
Synthesis of a 5-oxo-2-Tetrahydrofuranyl Derivative of an Evans Auxiliary via
a Novel Reaction Induced by Nucleophiles
A
Novel
D
erivativ
i
e
of an
k
E
vans Auxil
a
iary ng Wu,* Liang Li, Ya-Ping Sun
State Key Laboratory of Bio-Organic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai 200032, P. R. China
Fax +86(21)64166128; E-mail: yikangwu@mail.sioc.ac.cn
Received 12 October 2003
1
Careful analysis of the H NMR and 13C NMR, DEPT,
Abstract: A 5-oxo-2-tetrahydrofuranyl derivative of an Evans aux-
COSY and HMQC spectra along with the data of the ele-
iliary could be obtained through a previously unknown ‘rearrange-
mental analysis (which gave a molecular formula of
ment’ of the oxazolidinone moiety in an a-benzoxy-g-aldehyde acyl
oxazolidinone in 60–97% yields on treatment with a range of
C20H19NO5) led to assignment of the structure as 5a,2
nucleophiles.
which was also confirmed3 by single crystal X-ray crystal-
lography (Figure 1). By comparing the spectra, another
product4 was easily assigned as the C-4 epimer 5b. Thus,
instead of the intended benzylation at the aldehyde carbo-
nyl, the reaction actually occurred was a ‘rearrangement’
of the oxazolidinone auxiliary from the acyl to the alde-
hyde carbon accompanied by a lactonization.
Key words: chiral auxiliaries, rearrangements, lactones, ring clo-
sure, tandem reactions
In an on-going synthetic project, we needed to attach a
benzyl group to the aldehyde carbonyl in compound 1 to
form either 2 or 3 (Scheme 1). Using 1 equivalent of
PhCH2Li1 to execute this intended conversion in anhy-
drous THF at –78 ºC led to the formation of two com-
pounds in 60–66% total yield, along with ca. 40% of the
oxazolidinone auxiliary (4-H+). Very careful following up
the reaction with TLC revealed that the reaction proceed-
ed extremely fast (finished within 3 min at –78 ºC). The
1H NMR spectra showed that both compounds contained
only two phenyl groups, suggesting a lactonization might
have already occurred in situ. The presence of lactone
functionality in these compounds was also supported by
an intense peak at around 1764 cm–1 in the FT-IR spectra.
However, the MS spectra did not seem to be compatible
with the structure of 3.
4 CHO
O
O
O
O
Ph
O
3
1
O
N
OBn
O
N
O
OBn
OBn
OH
Ph
Ph
1
2
3
Ph
BnLi
Figure 1 The ORTEP view of 5a
O
O
O
Formation of 5a/5b is definitely not a predictable outcome
and we are unable to find any similar literature precedents,
in spite of the fact that oxazolidinones has been
extensively5 employed in synthesis since the 1980’s and
that much about oxazolidinone chemistry is well known.
According to the existing chemistry knowledge one
would well expect that the non-hindered free aldehyde
carbonyl in 1 reacts preferentially with PhCH2Li rather
than 4.
O
8
2
3
O
N
O
1
O
O
O
O
H
4
Ph
+
H
Ph
Ph
5
N
O
H
N
O
H
7
4
6
Ph
H
Ph
5a
5b
H
Scheme 1
The nitrogen atom in the oxazolidinone is an imido one
(strongly electron-deficient). It does not seem possible for
this nitrogen to attack the aldehyde before the acyl (C-1)
SYNLETT 2004, No. 1, pp 0125–0127
Advanced online publication: 26.11.2003
DOI: 10.1055/s-2003-43339; Art ID: U21203ST
© Georg Thieme Verlag Stuttgart · New York
0
5.
0
1.
2
0
0
4

126
Y. Wu et al.
LETTER
Table 1 The Main Results of Reaction of 1 with Nucleophiles
Nucleophile (Nu)
PhCH2Li
PhCH2ZnBr
PhCH2ZnBr
2-Bn-1,3-dithian-2-Li
4-Li
Solvent
Nu/1 (molar ratio)
Temp/time
Product [yield (%)]
Toluene/THF
1:1
1.5:1
6:1
1:1
1:1
5:8
1:1
1:1
1:1
6:7
–78 °C/5 min
0 °C/2 h
5a and 5b (66)
5a and 5b (80)
5a and 5b (60)
5a and 5b (66)
5a and 5b (97)
5a and 5b (84)
5a and 5b (86)
6 (90)
THF
THF
0 °C /2 h
THF
–78 °C /10 min
–78 °C/10 min
–78 °C /50 min
–78 °C to –30 °C /2 h
–78 °C /30 min
–78 °C /30 min
r.t./1 h
THF
Et2Zn
THF
MeONa
THF
MeONa
THF (and 10 equiv MeOH)
THF (and 10 equiv EtSH)
THF
EtSLi
7 (30)
KCN
5a and 5b (72)
is cleaved. Treatment of 1 with anhydrous ZnBr2 (1 equiv) all 1 fully consumed), giving7 unstable methyl ester 6 in
in dry THF at 0 ºC for hours did not result in any reaction 90% yield but no traces of 5a/5b.
at all. It appeared that 5a/5b must form through an initial
nucleophilic addition of 4 to the aldehyde carbonyl group
followed by an intramolecular attack of the resulting
alkoxide at the C-1, with the chiral auxiliary leaving as an
anion ready for attacking another aldehyde. Reaction of
added 4 (either 1 or 0.1 equivalents) with 1 in anhydrous
THF at –78 ºC for 30 min indeed led to 5a/5b in 97%
yield.
Similarly, treatment of 1 in dry THF with EtSLi in the
presence of EtSH (also an acidic proton source) at –78 ºC
for 30 minutes did not afford any 5a/5b at all although all
the starting 1 disappeared. The only isolable component in
the product mixture was 7 (in ca. 30% yield as a mixture
of two epimers, Scheme 2). The remainder consisted of a
number of minor components of low polarity that were
very difficult to separate from each other. Finally, KCN (1
We also tested some weaker nucleophiles on 1 and the equivalent) in anhydrous THF could also induce the rear-
main results are listed in Table 1. For instance, reaction rangement. Although at temperatures below 0 ºC no reac-
with PhCH2ZnBr6 (THF/0 °C/2 h) gave 5a/5b in 80% tion occurred, stirring at 20 ºC for 1 hour afforded 5a/5b
total yield (again as observed with PhCH2Li, with more in 72% yield (along with 18% of recovered ozaxolidinone
than half being 5a). More or less the same results were 4-H+).
also obtained with Et2Zn.
In brief, on treatment with a proper nucleophile, the chiral
auxiliary in 1 may migrate from the acyl carbon to the
O
CHO
aldehyde one, leading to a 5-oxo-2-tetrahydrofuranyl
derivative of an Evans auxiliary and thus illustrating a
previously unknown reaction for the oxazolidinones.
NaOMe
MeO
MeOH
–78 °C
90%
O
O
CHO
OBn
6
O
N
O
Acknowledgment
OBn
OBn
30%
Ph
This work has been supported by the National Science Foundation
of China (20025207, 20272071, 20372075), the Chinese Academy
of Sciences (Knowledge Innovation Project, KGCX2-SW-209),
and the Major State Basic Research Development Program
(G2000077502).
EtSLi
1
O
EtSH
–78 °C
EtS
7
Scheme 2
References
Addition of powdered NaOMe (1 equiv) to 1 in dry THF
at –78 ºC did not result in any reaction after a few hours
stirring. Raising the temperature from –78 ºC to –30 ºC
over 2 hours, however, afforded 5a/5b in 86% total yield.
The ratio between 5a and 5b in this case was inverted,
with more than half being 5b instead of 5a as observed
with e.g. PhCH2Li at –78 ºC. Presence of MeOH in the re-
action mixture obviously altered the reaction course (with
(1) Fuber, M.; Herbert, J. M.; Taylor, R. J. K. J. Chem. Soc.,
Perkin Trans. 1 1989, 683.
(2) Data for 5a: A white solid, mp 107–109 °C; [a]D15 –190.0 (c
1.0, CHCl3). 1H NMR (300 MHz, CDCl3): d = 7.50–7.20 (m,
10 H, aromat), 5.34 (dd, J = 9.0, 3.3 Hz, 1 H, H-2), 5.03 (t,
J = 8.9 Hz, 1 H, H-7), 4.94 (d, J = 11.2 Hz, 1 H, H-8), 4.65
(d, J = 11.4 Hz, 1 H, H-8), 4.64–4.58 (m, 2 H, H-4 and H-6),
4.13 (t, J = 9.1 Hz, 1 H, H-6), 3.08 (ddd, J = 3.2, 8.6, 14.1
Synlett 2004, No. 1, 125–127 © Thieme Stuttgart · New York

LETTER
Hz, 1 H, H-3), 2.38 (ddd, J = 6.5, 8.9, 14.7 Hz, 1 H, H-3). 13
A Novel Derivative of an Evans Auxiliary
127
C
J = 5.5, 7.8, 19.1 Hz, 1 H), 1.81 (dt, J = 13.4, 10.0 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 172.66, 157.93, 139.27,
136.35, 129.60, 129.22, 128.49, 128.22, 128.13, 126.14,
81.36, 73.08, 72.51, 71.06, 55.40, 32.99. FT-IR(film): 1767
cm–1. MS (EI): m/z (%) = 218(48) [M+ – BnOCHCH], 190
(21), 164 (30), 146 (29), 130 (27), 104 (49), 91 (100).
(5) See for example: (a) Evans, D. A. Science 1988, 240, 420.
(b) Compendium of Chiral Auxiliary Applications, Vol. 1–3;
Roos, G., Ed.; Academic Press: San Diego, 2002, and many
references cited therein.
(6) Wissing, E.; Kleijn, H.; Boersma, J.; van Koten, G. Recl.
Trav. Chim. Pays-Bas 1993, 112, 618; and references
therein..
(7) It is interesting to note that treatment of 6 in anhydrous THF
at –78 ºC with 4 did not give any 5 at all but a complicated
product mixture.
NMR (75 MHz, CDCl3): d = 173.96 (C-1), 156.41 (C-5),
136.86 (q, aromat), 135.83 (q, aromat), 129.70, (aromat,
CH), 129.57 (2 C, aromat), 128.42 (2 C, aromat), 128.08 (2
C, aromat), 128.01(aromat), 127.30 (2 C, aromat), 81.95 (C-
2), 72.59 (C-4), 72.52 (C-8), 70.08 (C-6), 60.69 (C-7), 32.47
(C-3). FT-IR (film of highly conc. solution in CH2Cl2): 1764
cm–1. MS (EI): m/z (%) = 218(77) [M+ – BnOCHCH],
190(32), 164(33), 146(41), 130(27), 104(46), 91(100).
(3) The crystallographic data (CCDC 207744) can be obtained
free of charge via from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; e-mail:
deposit@ccdc.cam.ac.uk.
(4) Data for 5b(oil): [a]D15 –113.8 (c 0.6, CHCl3). 1H NMR (300
MHz, CDCl3): d = 7.50–7.20 (m, 10 H), 5.04 (dd, J = 9.1, 5.2
Hz, 1 H), 4.82 (d, J = 11.7 Hz, 1 H), 4.69 (t, J = 9.0 Hz, 1 H),
4.59 (d, J = 11.8 Hz, 1 H), 4.21–4.10 (m, 2 H), 2.24 (ddd,
Synlett 2004, No. 1, 125–127 © Thieme Stuttgart · New York