Azaenolates of 2-chloromethyl-4-methoxymethyl-5-phenyl-2-oxazoline - A highly diastereo- and enantioselective synthesis of oxazolinyloxiranes

Article abstract of DOI:10.1002/1099-0690(200106)2001:11<2035::AID-EJOC2035>3.0.CO;2-R

The oxazoline-derived titanium azaenolate 6 couples highly stereoselectively with aldehydes affording highly optically pure oxazolinyloxiranes 7. The epoxide 7a has been deblocked to form the optically pure formyl oxirane 9. In contrast, the corresponding boron azaenolates 2 and 3 couple with very poor or no stereoselectivity. Lithium, aluminum and tin azaenolates have also been shortly studied.

Full text of DOI:10.1002/1099-0690(200106)2001:11<2035::AID-EJOC2035>3.0.CO;2-R

SHORT COMMUNICATION
Azaenolates of 2-Chloromethyl-4-methoxymethyl-5-phenyl-2-oxazoline ؊ A
Highly Diastereo- and Enantioselective Synthesis of Oxazolinyloxiranes
Vito Capriati,[a] Saverio Florio,*[a] and Renzo Luisi[a]
Keywords: Heterocycles / Titanium / Asymmetric synthesis / Nitrogen heterocycles
The oxazoline-derived titanium azaenolate 6 couples highly
stereoselectively with aldehydes affording highly optically
pure oxazolinyloxiranes 7. The epoxide 7a has been de-
blocked to form the optically pure formyl oxirane 9. In con-
trast, the corresponding boron azaenolates 2 and 3 couple
with very poor or no stereoselectivity. Lithium, aluminum and
tin azaenolates have also been shortly studied.
Oxazoline-derived azaenolates have been proved to be was the development of a simple procedure to synthesize
useful intermediates in synthetic organic chemistry.[1] While stereodefined oxazolinyloxiranes suitable for elaboration to
those derived from alkyloxazolines have been extensively in- more substituted, optically pure formyl oxiranes and their
vestigated, azaenolates of α-heterosubstituted oxazolines derivatives.
(Figure 1), which are equally useful from the synthetic
standpoint, have not been studied with the same thor-
oughness and interest, despite the fact that the α-Y group
is expected to dictate the geometry, E or Z, of the azaenol-
ate, and consequently the stereochemistry of the reactions
with electrophiles.[2,3]
Figure 1. Heterosubstituted azaenolates
Lithiated α-amino-[4] and α-alkoxy-substituted[5] oxazol-
ines have been studied in some detail; however, we felt that
metallated α-haloalkyloxazolines, which have already re-
ceived some attention,[6] deserved a much deeper examina-
Scheme 1. Reaction of 1, via the boron azaenolates 2 and 3, with
aldehydes to give a mixture of four stereoisomeric chlorohydrins 4
tion. Lithiated chloroalkyloxazolines, some of which have
and the corresponding epoxides 5
also been investigated spectroscopically,[7] have been shown
to behave as Darzens reagents and couple with carbonyl
compounds and imines to give oxazolinyloxiranes and azir-
Treatment of oxazoline 1 with iPr2NEt and Bu2BOTf in
idines.[8] However, the reactions of lithiated chiral oxazol-
ines have been found to occur with poor diastereoselectivity
no matter what the electrophile and the experimental condi-
tions.[6a,9] In contrast, the corresponding boron[10] and tita-
nium[11] azaenolates react with ketones with excellent dias-
tereoselectivity affording highly optically pure oxazolinyl
and then formyl oxiranes by the elaboration of the oxazoli-
nyl ring.
CH2Cl2 at 0 °C provided the boron azaenolate 2, which was
then reacted with benzaldehyde to produce a mixture of
four stereoisomeric chlorohydrins 4 in a 28:6:42:24 ratio
(Scheme 1). These chlorohydrins were then converted
quantitatively into the oxiranes 5a upon treatment with
NaOH in iPrOH (stereoisomeric ratio: 28:6:42:24). Exactly
the same result was obtained when the reaction was carried
out at Ϫ80 °C. Similarly, the reaction of boron azaenolate
3, prepared from 1 and 9-BBNOTf/iPr2NEt in Et2O at 0
°C, with PhCHO proceeded with poor diastereoselectivity
affording a diastereomeric mixture of the oxiranes 5a (ste-
reoisomeric ratio: 24:26:25:25). Equally poorly diastereose-
lective was the reaction of boron azaenolate 2 (CH2Cl2, 0
°C) with iPrCHO that ended up with the formation of a
diastereomeric mixture of oxiranes 5b (stereoisomeric ratio:
12:5:66:17). This sounds rather surprising in view of the fact
Here we report on the coupling reaction of azaenolates
of (4S,5S)-2-chloromethyl-4-methoxymethyl-5-phenyl-2-ox-
azoline (1) with aldehydes (Scheme 1). The main purpose
[a]
Centro C.N.R. ‘‘M.I.S.O.’’, Dipartimento Farmaco-Chimico,
`
Universita di Bari,
Via E. Orabona 4, 70125 Bari, Italy
Fax: (internat.) ϩ39-080/544-2231
E-mail: florio@farmchim.uniba.it
Eur. J. Org. Chem. 2001, 2035Ϫ2039
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0611Ϫ2035 $ 17.50ϩ.50/0
2035

V. Capriati, S. Florio, R. Luisi
SHORT COMMUNICATION
that azaenolates 2 and 3 have been found to couple highly
diastereoselectively with ketones. Comparable results were
obtained when the lithiated oxazoline 1 (LDA, THF, Ϫ80
°C) was treated with PhCHO to give the mixture of oxir-
anes 5a with a reasonable diastereoselectivity (trans/cis ra-
tio ϭ 85:15) but with no enantioselection at all (dr ϭ50:50
in both the diastereomers).
Completely different results were obtained when the tita-
nium azaenolate of 1 was used (Table 1). Oxazoline 1
(Scheme 2) was first lithiated with LDA at Ϫ100 °C in THF
and then added to Ti(OiPr)4. The putative titanium enolate
6 was then reacted with PhCHO to produce oxazolinyloxir-
ane 7a (trans/cis ratio Ͼ 95:5; Scheme 2, Table 1) highly
stereoselectively. The trans isomer, which was further puri-
fied by chromatography and assigned its configuration on
Scheme 2. Reaction of 1, via the titanium azaenolate 6, with alde-
hydes to give the oxazolinyloxiranes 7
1
the basis of H NMR spectroscopic data (3JH-H ϭ 1.9 Hz),
1
was optically pure (drtrans Ͼ 95%, by GC and H NMR,
[α]2D4 ϭ ϩ219 [c ϭ 1, CHCl3]). The newly created stereocen-
ters were assigned the 1S,2R configuration by comparison
of the formyl oxirane 9, obtained by deblocking (methyl-
ation-reduction-hydrolysis according to a known proto-
col[8a]) of the oxazolinyl ring of 7a ([α]2D4 ϭ Ϫ12.6 [c ϭ 1
CHCl3]), with a specimen prepared from the commercially
available epoxy alcohol 8, with the 2R,3R configuration,[12]
by Swern oxidation ([α]2D4 ϭ Ϫ12.8 [c ϭ 1 CHCl3]) (see typ-
ical procedure and Scheme 3).[13] This represents a conveni-
ent route to stereodefined formyl oxiranes with two stereo-
centers on the oxirane ring and adds to the reported syn-
thetic procedure based on the Sharpless oxidation of allylic
alcohols. Comparable results were obtained when the tita-
nium azaenolate 6 was treated with other aromatic alde-
hydes. The trans oxazolinyloxiranes formed in good yield
and excellent diastereoselectivity (Table 1). Moreover,
equally highly stereoselective was the coupling of 6 with
aliphatic enolizable aldehydes.
Scheme 3. Synthesis of optically active formyl oxirane 9 from
epoxyalcohol 8 and deblocking of the oxazolinyl ring of 7a
specifically to the 1S,2R oxazolinyloxirane, can be explained
by assuming that the aldehyde attacks the titanium azaenol-
ate according to an unlike (re,si) topicity from below via a
ZimmermanϪTraxler-type six-membered chair-like trans-
ition state which places the phenyl and chlorine substituents
both pseudo-equatorial (Scheme 4).
Table 1. Synthesis of oxazolinyl oxiranes 7aϪf
[c]
R
Yield drtrans/cis
Configuration [α]2D4
[%][a],[b]
(c ϭ 1, CHCl3)
Scheme 4. Reaction of PhCHO with the E configured titanium
azaenolate 6 via a favored ZimmermanϪTraxler-type transition
state
7a Ph
70
60
Ͼ95:5
95:5
95:5
88:12
90:10
90:10
1S,2R
ϩ219
7b p-Br-Ph
1S,2R[d]
1S,2R[d]
1S,2R[d]
1S,2R[d]
1S,2R[d]
ϩ90.4
ϩ156
Ϫ21.1
ϩ0.5
7c p-NO2-Ph 50
7d (CH3)2CH 75
7e CH3(CH2)6 60
7f CH3(CH2)7 60
The coupling reactions of aluminum and tin azaenolates
of oxazoline
1 have also been briefly investigated
Ϫ1.4
(Scheme 5). Oxazoline 1 was first lithiated with LDA at
[a]
[b]
Isolated yields. Ϫ All new oxazolinyloxiranes 7 showed satis-
factory H, 13C NMR, MS and IR spectroscopic data. Ϫ Dias-
1
[c]
tereomeric ratio determined by 1H NMR spectroscopy and GC.
[d]
The diastereomeric ratio for each trans isomer was Ͼ95%. Ϫ
Presumed configuration.
A plausible explanation for the observed stereoselectivity
relies on the assumption that the stereoselective-determin-
ing step is the azaenolate formation,[14] the E configured
titanium azaenolate is the more stable isomer[15] and there
is no Z o E interconversion.[3Ϫ5] The 1R,2R configuration
Scheme 5. Reaction of 1, via the aluminum azaenolate 10, with
of the intermediate chlorohydrin, which would lead stereo- PhCHO to give 7a
2036
Eur. J. Org. Chem. 2001, 2035Ϫ2039

A Highly Diastereo- and Enantioselective Synthesis of Oxazolinyloxiranes
SHORT COMMUNICATION
Ϫ100 °C in THF and then added to Et2AlCl. The resulting azolinyloxiranes is the one that uses titanium. The specifi-
azaenolate 10 (not isolated) was then reacted with PhCHO city of the role of the titanium azaenolate is evidenced by
to produce, in a moderately stereoselective manner, the ox- comparison with the corresponding lithium, boron, alumi-
azolinyloxirane 7a (overall yield: 65%, mixture of diastereo- num and tin derivatives, which react with poor stereoselect-
isomers separable by column chromatography on silica gel: ivity. More work is under way to provide a rationalization
hexane/AcOEt, 75:25; trans/cis ratio ϭ 80:20; drtrans
70:30; drcis ϭ 85:15).
ϭ
of the experimentally observed titanium stereoselectivity.
In contrast, the reaction of the tin azaenolate 11
(Scheme 6), generated upon treatment of oxazoline 1 with
Sn(OTf)2 and diisopropylethylamine (DIPEA) in THF at
room temperature, with PhCHO furnished the Z-chloro-
(oxazolinyl)styrene 12 (50% yield),[16] while the reaction of
11 with benzophenone and cyclohexanone led to the oxazo-
linyloxiranes 13 and 14, respectively, with excellent stereo-
selectivity (80%, dr ϭ 97:3; 75%, dr ϭ 96:4).
Experimental Section
General: Tetrahydrofuran (THF) was freshly distilled under a nitro-
gen atmosphere over sodium benzophenone ketyl. Diisopropylam-
ine was distilled over finely powdered calcium hydride. Ti(iPrO)4
was distillated prior to use while all the other chemicals were of
commercial grade (Aldrich) and used without further purification.
Petroleum ether refers to the 40Ϫ60 °C boiling fraction. A com-
mercial solution of nBuLi (in hexanes) from Aldrich was titrated
with N-pivaloyl-o-toluidine prior to use.[17] Ϫ NMR: Bruker
1
1
(500 MHz and 50.3 or 125 MHz, for H and 13C, respectively); H
NMR: CDCl3 as solvent (δH ϭ 7.24); 13C NMR: CDCl3 as solvent
(δC ϭ 77.0). Ϫ FT-IR: PerkinϪElmer Spectrum One. Ϫ GC-MS
spectrometry analyses were performed on a gas chromatograph HP
6890 (HP-5MS capillary column, 30 m, 0.25 mm i.d.) equipped
with a mass-selective detector operating at 70 eV (EI). Ϫ Melting
points were uncorrected. TLC was performed on Merck silica gel
plates with F-254 indicator; visualization was accomplished by UV
light (254 nm). Column chromatography was performed with silica
gel (70Ϫ230 mesh) and petroleum ether (or hexane)/Et2O (or Ac-
OEt) mixtures as the eluent. All reactions involving air-sensitive
reagents were performed under nitrogen in oven-dried glassware
using syringe and septum cap technique.
Typical Procedure for the Synthesis of 7a and 9: A solution of 1
(120 mg, 0.50 mmol) in 3 mL of THF was added dropwise to a
solution of LDA [0.55 mmol; from 0.55 mmol of nBuLi (2.4 , 230
µL) and 0.55 mmol of iPr2NH (80 µL)] in 6 mL of THF precooled
to Ϫ98 °C under N2. To the resulting red mixture, a solution of
Ti(iPrO)4 (0.70 mmol, 210 µL) in 1 mL of THF was added directly
after 1 min. The mixture was stirred at Ϫ98 °C for 15 min. and a
solution of PhCHO (0.65 mmol, 66 µL) in 1 mL of THF was then
added. The mixture was allowed to warm to room temperature and
quenched with sat. aq. NH4Cl. The organic layer was separated
and the aqueous layer filtered and extracted with AcOEt (3 ϫ
20 mL). The combined organic extracts were dried (Na2SO4) and
evaporated in vacuo. The crude chlorohydrin thus obtained was
dissolved in iPrOH (5 mL) and reacted with NaOH 2% w/w
(10 mL). After conversion into the epoxide (monitored by TLC)
the crude product was purified by flash chromatography (petro-
leum ether/AcOEt, 7:3; Rf ϭ 0.4) to give (1S,2R,4ЈS,5ЈS)-trans-1,2-
epoxy-1-(4-methoxymethyl-5-phenyl-2-oxazolin-2-yl)-2-phenyl-
ethane (7a) (108 mg, 70% yield).
Scheme 6. Reaction of 1, via the tin azaenolate 11, with PhCHO,
Ph2CO and cyclohexanone to give the oxazolinylstyrene 12 and
oxazolinyl epoxides 13 and 14
The absolute configuration of the new stereocenter of
oxirane 13 was assigned by comparison with a specimen
prepared as reported previously.[11] The R configuration of
the oxirane 14, on the other hand, was established by com-
parison with its S stereoisomer 15,[11] whose structure was
determined by an X-ray analysis carried out on the α-hy-
droxyamide 16, which in turn was obtained by deblocking
of both the heterocyclic rings of 15 (Scheme 7).
Oil, drtrans/cis Ͼ 95:5, drtrans Ͼ 95%. Ϫ [α]2D4 ϭ ϩ219 (c ϭ 1, CHCl3).
1
Ϫ H NMR (500 MHz): δ ϭ 3.41 (s, 3 H, CH3O), 3.55 (dd, J ϭ
6.1, 9.7 Hz, 1 H, CHaHbOMe), 3.63 (dd, J ϭ 4.4, 9.7 Hz, 1 H,
CHaHbOMe), 3.75 (d, J ϭ 1.9 Hz, 1 H, CH oxirane), 4.20Ϫ4.23
(m, 1 H, CHCH2), 4.30 (d, J ϭ 1.9 Hz, 1 H, CH oxirane), 5.43 (d,
J ϭ 6.8 Hz, 1 H, CHPh), 7.30Ϫ7.38 (m, 5 H, ArH). Ϫ 13C NMR
(50.3 MHz, APT): δ ϭ 54.7 (CH3O), 57.9 (CH), 59.3 (CH), 73.7
(CH2), 74.7 (CH), 83.9 (CH), 125.4 (ArCH), 125.8 (ArCH), 128.3
(ArCH), 128.6 (ArCH), 128.8 (ArCH), 135.2 (ArC), 135.9 (ArC),
140.0 (CϭN). Ϫ GC-MS (70 eV): m/z (%) ϭ 309 (0.8) [Mϩ], 148
(100.0), 116 (32.7), 91 (61.1), 45 (95.0). Ϫ FT-IR (film): ν˜ ϭ 1667
Scheme 7. Synthesis of the hydroxyamide 16 from the oxazolinyl
epoxide 15
In conclusion, this paper illustrates that, among the aza-
enolates of a chiral oxazoline such as 1, the most useful
procedure for the preparation of highly optically pure ox- cmϪ1 (s, CϭN).
Eur. J. Org. Chem. 2001, 2035Ϫ2039
2037

V. Capriati, S. Florio, R. Luisi
SHORT COMMUNICATION
MeOTf (0.65 mmol, 73 µL) was added to a solution of 7a (100 mg,
Ϫ 45], 146 (2.6), 126 (100.0), 119 (3.8), 91 (4.3), 67 (4.8). Ϫ FT-IR
Ϫ1
˜
0.32 mmol) in 4 mL of CH2Cl2 at 0 °C under N2. The resulting (film): ν ϭ 1666 cm (s, CϭN).
mixture was stirred for 45 min., cooled to Ϫ78 °C and reacted with
(1S,2R,4ЈS,5ЈS)-trans-1,2-Epoxy-1-(4-methoxymethyl-5-phenyl-2-
NaBH4 (8 mg, 0.8 mmol) in EtOH/THF(1 ϩ 4 mL, respectively).
After 10 min. the reaction was quenched with sat. aq. NH4Cl and
extracted with Et2O (3 ϫ 20 mL). The crude mixture was purified
by flash chromatography (petroleum ether/AcOEt, 7:3) and finally
hydrolyzed with a solution of (COOH)2 (20 mg, 0.22 mmol) in
H2O/THF (1 ϩ 4 mL, respectively) at 0 °C. After 45 min. brine
was added and the mixture extracted with Et2O (3 ϫ 20 mL). Evap-
oration of the solvent left a residue that was purified by flash chro-
matography (hexane/Et2O 6:4) to give (2S,3R)-trans-2,3-epoxy-3-
phenylpropanal (9) (16.5 mg, 35% overall yield).
oxazolin-2-yl)nonane (7e): 60% yield. Oil, drtrans/cis ϭ 90:10, drtrans
1
Ͼ 95%. Ϫ [α]2D4 ϭ ϩ0.5 (c ϭ 1, CHCl3). Ϫ H NMR (500 MHz;
selected data): δ ϭ 0.84 (t, J ϭ 6.8 Hz, 3 H, CH3), 1.20Ϫ1.75 [3
m, 12 H, (CH2)6], 3.28Ϫ3.35 (m, 1 H, CH oxirane), 3.37 (s, 3 H,
CH3O), 3.40 (d, J ϭ 2.0 Hz, 1 H, CH oxirane), 3.49 (dd, J ϭ 6.3,
9.8 Hz, 1 H, CHaOCH3), 3.58 (dd, J ϭ 4.4, 9.8 Hz, 1 H,
CHbOCH3), 4.11Ϫ4.14 (m, 1 H, CHCH2), 5.32 (d, J ϭ 6.9 Hz, 1
H, CHPh), 7.19Ϫ7.35 (2 m, 5 H, ArH). Ϫ 13C NMR (125 MHz;
selected data): δ ϭ 13.7, 22.3, 25.4, 28.8, 28.9, 31.2, 31.4, 50.6, 58.0,
58.9, 73.5, 74.2, 83.5, 125.0, 127.9, 128.4, 139.8, 164.2. Ϫ GC-MS
(70 eV): m/z (%) ϭ 331 (2.2) [Mϩ], 286 (100.0), 230 (35.3), 196
Oil, ee Ͼ 95% by chiral GC analysis (β-DEX 120, Supelco, Det.:
FID, 300 °C. Column head pressure: 22 psi. Oven: 110 °C. tR
ϭ
(17.3), 146 (32.4), 126 (71.5), 91 (36.7), 67 (39.1). Ϫ FT-IR (film):
32.96 min.). Ϫ [α]2D4 ϭ Ϫ12.6 (c ϭ 1, CHCl3). Ϫ 1H NMR
(500 MHz): δ ϭ 3.42 (dd, J ϭ 1.7, 6.0 Hz, 1 H, CHCHO), 4.15 (d,
J ϭ 1.7 Hz, 1 H, CHPh), 7.26Ϫ743 (2 m, 5 H, ArH), 9.17 (d, J ϭ
6.0 Hz, 1 H, CHO). Ϫ 13C NMR (125 MHz): δ ϭ 56.6 (CH oxir-
ane), 62.9 (CH oxirane), 125.7 (ArCH), 128.7 (ArCH), 129.1
(ArCH), 134.1 (ArC), 196.8 (CHO). Ϫ GC-MS (70 eV): m/z (%) ϭ
Ϫ1
˜
ν ϭ 1666 cm (s, CϭN).
(1S,2R,4ЈS,5ЈS)-trans-1,2-Epoxy-1-(4-methoxymethyl-5-phenyl-2-
oxazolin-2-yl)decane (7f): 60% yield. Oil, drtrans/cis ϭ 90:10, drtrans
1
Ͼ 95%. Ϫ [α]2D4 ϭ Ϫ1.4 (c ϭ 1, CHCl3). Ϫ H NMR (500 MHz;
selected data): δ ϭ 0.85 (t, J ϭ 6.7 Hz, 3 H, CH3), 1.20Ϫ1.75 [3
m, 14 H, (CH2)7], 3.30Ϫ3.34 (m, 1 H, CH oxirane), 3.38 (s, 3 H,
CH3O), 3.41 (d, J ϭ 2.0 Hz, 1 H, CH oxirane), 3.50 (dd, J ϭ 6.3,
9.7 Hz, 1 H, CHaOCH3), 3.59 (dd, J ϭ 4.4, 9.7 Hz, 1 H,
CHbOCH3), 4.10Ϫ4.18 (m, 1 H, CHCH2), 5.32 (d, J ϭ 6.9 Hz, 1
H, CHPh), 7.21Ϫ7.36 (2 m, 5 H, ArH). Ϫ 13C NMR (125 MHz;
selected data): δ ϭ 14.0, 22.6, 25.7, 29.1, 29.2, 29.4, 31.4, 31.7, 50.9,
58.3, 59.2, 73.8, 74.5, 83.7, 125.3, 125.9, 128.2, 128.7, 140.1, 164.4.
Ϫ GC-MS (70 eV): m/z (%) ϭ 345 (2.2) [Mϩ], 300 (100.0), 244
(32.9), 194 (17.6), 146 (31.6), 126 (64.8), 91 (33.7), 67 (36.5). Ϫ FT-
IR (film): ν˜ ϭ 1667 cmϪ1 (s, CϭN).
148 (12.6) [Mϩ], 147 (20.1), 119 (24.6), 105 (10.5), 91 (100.0), 77
Ϫ1
˜
(16.5). Ϫ FT-IR (film): ν ϭ 1725 cm (s, CO).
Oxazolinyl epoxides 7b؊f, 13؊14 and oxazolinylethene 12 showed
the following data:
(1S,2R,4ЈS,5ЈS)-trans-1,2-Epoxy-1-(4-methoxymethyl-5-phenyl-2-
oxazolin-2-yl)-2-p-bromophenylethane (7b): 60% yield. Oil, drtrans/
1
ϭ 95:5, drtrans Ͼ 95%. Ϫ [α]2D4 ϭ ϩ90.4 (c ϭ 1, CHCl3). Ϫ H
cis
NMR (200 MHz; selected data): δ ϭ 3.41 (s, 3 H, CH3O),
3.52Ϫ3.66 (m, 2 H, CH2OCH3), 3.70 (d, J ϭ 1.8 Hz, 1 H, CH
oxirane), 4.17Ϫ4.24 (m, 1 H, CHCH2), 4.25 (d, J ϭ 1.8 Hz, 1 H,
CH oxirane), 5.42 (d, J ϭ 7.0 Hz, 1 H, CHPh), 7.15Ϫ7.60 (3 m, 9
H, ArH). Ϫ 13C NMR (50.3 MHz; selected data): δ ϭ 54.7, 57.3,
59.3, 73.6, 74.6, 83.9, 122.8, 125.4, 127.4, 128.4, 128.8, 131.8, 139.8,
140.8, 163.1. Ϫ GC-MS (70 eV): m/z (%) ϭ 389 (0.5) [Mϩ ϩ 2], 387
(2R,4ЈS,5ЈS)-2-[3,3-Bis(phenyloxiranyl)]-4-methoxymethyl-5-
phenyl-2-oxazoline (13): 80% yield. Oil, dr ϭ 97:3. Ϫ [α]2D4 ϭ Ϫ31.0
(c ϭ 1, CHCl3). Ϫ 1H NMR (500 MHz; selected data): δ ϭ 3.13
(dd, J ϭ 6.8, 9.7 Hz, 1 H, CHaOCH3), 3.28 (s, 3 H, CH3O), 3.40
(dd, J ϭ 4.7, 9.7 Hz, 1 H, CHbOCH3), 4.01Ϫ4.18 (m, 1 H,
CHCH2), 4.22 (s, 1 H, CH oxirane), 5.17 (d, J ϭ 7.7 Hz, 1 H,
CHPh), 6.70Ϫ6.72 (m, 2 H, ArH), 7.15Ϫ7.37 (3 m, 11 H),
7.50Ϫ7.55 (m, 2 H, ArH). Ϫ 13C NMR (125 MHz; selected data):
δ ϭ 59.0, 59.4, 66.6, 73.7, 74.1, 84.3, 125.2, 126.7, 127.8, 128.0,
128.11, 128.15, 128.2, 128.28, 128.35, 128.4, 135.6, 138.8, 139.5,
162.2. Ϫ GC-MS (70 eV): m/z (%) ϭ 385 (5.8) [Mϩ], 368 (9.9), 238
(34.6), 208 (35.9), 165 (81.4), 148 (99.6), 147 (100.0), 105 (44.3), 77
(31.7), 45 (64.9). Ϫ FT-IR (film): ν˜ ϭ 1660 cmϪ1 (s, CϭN).
(0.5) [Mϩ], 342 (4.8), 148 (100.0), 116 (25.9), 89 (15.4), 67 (17.5). Ϫ
Ϫ1
˜
FT-IR (film): ν ϭ 1667 cm (s, CϭN).
(1S,2R,4ЈS,5ЈS)-trans-1,2-Epoxy-1-(4-methoxymethyl-5-phenyl-2-
oxazolin-2-yl)-2-p-nitrophenylethane (7c): 50% yield. Oil, drtrans/cis ϭ
1
95:5, drtrans Ͼ 95%. Ϫ [α]2D4 ϭ ϩ156 (c ϭ 1, CHCl3). Ϫ H NMR
(200 MHz; selected data): δ ϭ 3.40 (s, 3 H, CH3O), 3.50Ϫ3.65 (m,
2 H, CH2OCH3), 3.70 (d, J ϭ 2.4 Hz, 1 H, CH oxirane), 4.10Ϫ4.25
(m, 1 H, CHCH2), 4.37 (d, J ϭ 2.4 Hz, 1 H, CH oxirane), 5.40 (d,
J ϭ 8.2 Hz, 1 H, CHPh), 7.20Ϫ7.50 (2 m, 7 H, ArH), 8.05Ϫ8.25
(m, 2 H, ArH). Ϫ 13C NMR (50.3 MHz; selected data): δ ϭ 55.1,
56.7, 59.3, 73.4, 73.7, 74.7, 84.0, 123.9, 125.4, 126.6, 128.5, 128.9,
139.6, 142.6, 148.2, 162.6. Ϫ GC-MS (70 eV): m/z (%) ϭ 354 (0.9)
[Mϩ], 309 (74.8), 253 (37.4), 146 (68.3), 118 (41.1), 91 (54.9), 67
(100.0). Ϫ FT-IR (film): ν˜ ϭ 1667 cmϪ1 (s, CϭN).
(2R,4ЈS,5ЈS)-2-(4-Methoxymethyl-5-phenyl-2-oxazolin-2-yl)-1-
oxaspiro[2,5]octane (14): 75% yield. Oil, dr ϭ 96:4. Ϫ [α]2D4 ϭ Ϫ64.0
(c ϭ 1, CHCl3). Ϫ 1H NMR (500 MHz; selected data): δ ϭ
1.40Ϫ1.80 (2 m, 10 H, cyclohexyl), 3.36 (s, 3 H, CH3O), 3.47 (s, 1
H, CH oxirane), 3.50 (dd, J ϭ 6.9, 10.0 Hz, 1 H, CHaOCH3), 3.61
(dd, J ϭ 5.2, 10.0 Hz, 1 H, CHbOCH3), 4.10Ϫ4.18 (m, 1 H,
CHCH2), 5.35 (d, J ϭ 6.8 Hz, 1 H, CHPh), 7.20Ϫ7.40 (2 m, 5 H,
ArH). Ϫ 13C NMR (125 MHz; selected data): δ ϭ 24.9, 25.1, 25.4,
28.9, 35.0, 56.9, 59.3, 65.5, 73.9, 84.3, 125.8, 128.5, 128.8, 140.3,
163.6. Ϫ GC-MS (70 eV): m/z (%) ϭ 353 (2.9) [Mϩ], 336 (65.7),
(1S,2R,4ЈS,5ЈS)-trans-1,2-Epoxy-1-(4-methoxymethyl-5-phenyl-2-
oxazolin-2-yl)-3-methylbutane (7d): 75% yield. Oil, drtrans/cis
ϭ
1
88:12, drtrans Ͼ 95%. Ϫ [α]2D4 ϭ Ϫ21.1 (c ϭ 1, CHCl3). Ϫ H NMR
(200 MHz; selected data): δ ϭ 0.98 (d, J ϭ 6.6 Hz, 3 H, CH3), 1.00
(d, J ϭ 6.6 Hz, 3 H, CH3), 1.64 [octet, J ϭ 6.7 Hz, 1 H, CH(CH3)2],
3.15 (dd, J ϭ 1.9, 6.4 Hz, 1 H, CH oxirane), 3.37 (s, 3 H, CH3O),
308 (2.2), 252 (24.9), 206 (55.8), 148 (100.0), 16 (45.1), 105 (28.8),
Ϫ1
˜
91 (62.0), 45 (56.3). Ϫ FT-IR (film): ν ϭ 1660 cm (s, CϭN).
3.46 (d, J ϭ 1.9 Hz, 1 H, CH oxirane), 3.48 (dd, J ϭ 6.2, 9.7 Hz, (4S,5S)-1-Chloro-1-(4-methoxymethyl-5-phenyl-2-oxazolin-2-yl)-2-
1 H, CHaOCH3), 3.58 (dd, J ϭ 4.5, 9.7 Hz, 1 H, CHbOCH3), phenylethene (12): 50% yield. M.p. 69 °C Ϫ [α]2D4 ϭ ϩ84.5 (c ϭ 1,
1
4.10Ϫ4.16 (m, 1 H, CHCH2), 5.31 (d, J ϭ 6.9 Hz, 1 H, CHPh),
CHCl3). Ϫ H NMR (300 MHz; selected data): δ ϭ 3.44 (s, 3 H,
7.21Ϫ7.34 (m, 5 H, ArH). Ϫ 13C NMR (50.3 MHz; selected data): CH3O), 3.65 (dd, J ϭ 6.3, 9.8 Hz, 1 H, CHaOCH3), 3.74 (dd, J ϭ
δ ϭ 18.2, 18.5, 30.0, 49.9, 59.3, 63.2, 73.8, 74.5, 83.8, 125.3, 128.2, 4.1, 9.8 Hz, 1 H, CHbOCH3), 4.32Ϫ4.36 (m, 1 H, CHCH2), 5.56
128.7, 140.0, 164.5. Ϫ GC-MS (70 eV): m/z (%) ϭ 230 (3.0) [Mϩ (d, J ϭ 7.1 Hz, 1 H, CHPh), 7.30Ϫ7.47 (m, 8 H, ArH), 7.71 (s, 1
2038
Eur. J. Org. Chem. 2001, 2035Ϫ2039

A Highly Diastereo- and Enantioselective Synthesis of Oxazolinyloxiranes
SHORT COMMUNICATION
[2b]
H, CHϭC), 7.08Ϫ7.60. Ϫ 13C NMR (75 MHz; selected data): δ ϭ
56.9, 74.0, 75.3, 85.3, 119.1, 125.9, 128.7, 128.7, 129.1, 130.0, 130.6,
313Ϫ327. Ϫ
1996, 37, 359Ϫ362.
For a review on the chemistry of oxazolines, see: A. I. Meyers,
A. Rottmann, J. Liebscher, Tetrahedron Lett.
[3]
133.5, 124.8, 140.5, 162.4. Ϫ GC-MS (70 eV): m/z (%) ϭ 327 (2.9)
J. Heterocyclic Chem. 1998, 35, 991Ϫ1002.
[Mϩ], 282 (100.0), 182 (14.7), 154 (23.8), 119 (75.3), 91 (80.7), 77
[4a] M. Le Bail, D. J. Aitken, F. Vergne, H. P. Husson, J. Chem.
[4]
Ϫ1
˜
(17.4), 45 (56.3). Ϫ FT-IR (film): ν ϭ 1636 cm (s, CϭN), 1607
[4b]
Soc., Perkin Trans. 1 1997, 1681Ϫ1689. Ϫ
P. Breton, C.
(CϭC). Ϫ C19H18ClNO2 (327.80): calcd. C 69.62, H 5.53, N 4.27;
found C 69.86, H 5.74, N 4.29.
´
`
Andre-Barres, Y. Langlois, Synthetic Commun. 1992, 22,
2543Ϫ2554.
[5]
T. R. Kelly, A. Arvanitis, Tetrahedron Lett. 1984, 25, 39Ϫ42.
[6] [6a]
Synthesis of (2S,1ЈS,2ЈS)-(؉)-2-(Cyclohexen-1-yl)-2-hydroxy-N-(2-
hydroxy-1-methoxymethyl-2-phenylethyl)acetamide (16): To a solu-
tion of oxazolinyl epoxide 15 (408 mg, 1.35 mmol) in 10 mL of
MeOH, was added 3  HCl (3 mL) and the resulting mixture re-
fluxed for 1.5 h. The mixture was then cooled to room temp.,
treated with a satd. solution of NaHCO3 (pH ϭ 7) and finally
extracted with CH2Cl2 (3 ϫ 20 mL). The combined organic layers
were dried (Na2SO4) and concentrated in vacuo. The crude product
was purified by flash chromatography (silica gel; CH2Cl2/AcOEt,
7:3) to give 16 (366 mg, 85%). M.p. 107Ϫ108 °C (CH2Cl2/hexane)
Ϫ [α]2D4 ϭ ϩ74.2 (c ϭ 1, CHCl3). Ϫ 1H NMR (500 MHz): δ ϭ
1.18Ϫ2.0 (5 m, 8 H, cyclohexyl), 3.36 (s, 3 H, CH3O), 3.46Ϫ3.48
A. I. Meyers, G. Knaus, P. M. Kendall, Tetrahedron Lett.
[6b]
1974, 3495Ϫ3498. Ϫ
K. Kamata, H. Sato, E. Takagi, I.
Agata, A. I. Meyers, Heterocycles 1999, 51, 373Ϫ378. Ϫ [6c] R.
Liddell, C. G. Whiteley, J. Chem. Soc., Chem. Commun. 1983,
1535Ϫ1537. Ϫ
S. Afr. J. Chem. 1987, 40, 39Ϫ43. Ϫ
[6d]
R. B. English, J. R. Liddell, C. G. Whiteley,
[6e]
J. R. Liddell, C. G.
Whiteley, S. Afr. J. Chem. 1991, 44, 35Ϫ41.
A. Abbotto, S. Bradamante, S. Florio, V. Capriati, J. Org.
Chem. 1997, 62, 8937Ϫ8940.
[7]
[8] [8a]
S. Florio, V. Capriati, R. Luisi, Tetrahedron Lett. 1996, 37,
[8b]
4781Ϫ4784. Ϫ
Tetrahedron 1999, 35, 9859Ϫ9866. Ϫ
Capriati, G. Ingrosso, Tetrahedron Lett. 1999, 40, 6101Ϫ6104.
S. Florio, V. Capriati, R. Luisi, A. Abbotto, D. J. Pippel, un-
published results.
S. Florio, V. Capriati, R. Luisi, A. Abbotto, Tetrahedron Lett.
1999, 40, 7421Ϫ7425.
S. Florio, L. Troisi, V. Capriati, G. Coletta,
[8c]
S. Florio, L. Troisi, V.
[9]
(m,
1 H, exchanges with D2O, OH), 3.55Ϫ3.61 (m, 2 H,
CH2OCH3), 3.63Ϫ3.68 (br s, 1 H, exchanges with D2O, OH),
4.20Ϫ4.23 (m, 1 H, CHCH2), 4.31 (d, J ϭ 2.7 Hz, 1 H, CHOH),
5.04 (d, J ϭ 3.1 Hz, 1 H, CHPh), 5.78Ϫ5.80 (m, 1 H, CHϭC), 6.58
(br d, J ϭ 8.1 Hz, 1 H, exchanges slowly with D2O, NH),
7.23Ϫ7.32 (2 m, 5 H, ArH). Ϫ 13C NMR (125 MHz): δ ϭ 21.9,
22.1, 22.2, 25.1, 54.6, 59.3, 76.7, 77.0, 77.2, 127.6, 128.3, 128.5,
136.4, 140.7, 172.9. Ϫ GC-MS (70 eV): m/z (%) ϭ 319 (7.0) [Mϩ],
301 (7.0), 212 (30.0), 181 (100.0), 164 (32.8), 111 (97.3), 74 (80.1).
Ϫ FT-IR (film): ν˜ ϭ 3416 cmϪ1, 3152, 1637 (s, CϭO), 1529. Ϫ
C18H25NO4 (319.40): calcd. C 67.69, H 7.89, N 4.39; found C
68.07, H 8.26, N 4.44.
[10]
[11]
S. Florio, V. Capriati, R. Luisi, Tetrahedron Lett. 2000, 41,
5295Ϫ5298.
[12] [12a]
It might be useful to point out that the priority of the
groups linked to the C2 carbon changes on going from the
epoxy alcohol to the epoxy aldehyde. See: R. M. Hanson,
Chem. Rev. 1991, 91, 437Ϫ475. Ϫ
oxirane 9 was prepared according to the procedure reported in
ref.[8a] and its enantiomers showed the following retention times
by chiral GC analysis: 32.80 and 33.83 min.
U. M. Lindstrom, P. Somfai, Synthesis 1998, 109Ϫ117.
That the azaenolate formation is the stereoselective determin-
ing step has been proposed for α-heterosubstituted oxazoline
azaenolates. See refs.[4,5,9]
[12b]
Racemic trans formyl
[13]
[14]
[15]
[16]
Acknowledgments
Semiempirical and ab initio calculations carried out on
lithiated chloromethyloxazolines indicate that the E isomer is
much more stable than the Z one. This has been ascribed to
an intramolecular chelation of the lithium cation between the
nitrogen of the aza group and the α-chlorine atom. See refs.[7,9]
The Z configuration of 12 could be tentatively assigned by
Work carried out in the framework of the National Project ‘‘Stereo-
selezione in Sintesi Organica. Metodologie ed Applicazioni’’ sup-
`
ported by the Ministero dell’Universita e della Ricerca Scientifica
e Tecnologica, Rome, and by the University of Bari. We also thank
the Italian CNR for financial support.
1
comparing H chemical shift of the vinylic proton with those
of related cis- and trans-α-chlorocinnamic acids. The value
found in our case (δ ϭ 7.71) was very close to that of the Z
isomer (δ ϭ 7.87 vs. 7.18). L. A. Singer, N. P. Kong, J. Am.
Chem. Soc. 1967, 89, 5251Ϫ5256.
J. Suffert, J. Org. Chem. 1989, 54, 509Ϫ512.
Received January 2, 2001
[1]
P. Fey, i n Stereoselective Synthesis (Eds.: G. Helmchen, R. W.
Hoffmann, J. Mulzer, E. Schaumann), Houben-Weyl, Methods
in Organic Chemistry. Vol. E21b, 1995; pp 1749Ϫ1775, Thi-
eme, Stuttgart.
[17]
[2] [2a]
A. Rottmann, M. Bartoczek, J. Liebscher, Synthesis 1997,
[O01003]
Eur. J. Org. Chem. 2001, 2035Ϫ2039
2039