FULL PAPER

Novel Cyclic 1,2-Diacetals Derived from (2R,3R)-(ⴙ)-Tartaric Acid: Synthesis

and Application as N,O Ligands for the Enantioselective Alkylation of
Benzaldehyde by Diethylzinc

M. Teresa Barros,*[a] Christopher D. Maycock,[b] and Ana Maria Faı́sca Phillips[a]

Keywords: Alkylation / Asymmetric catalysis / Diacetals / Zinc / N,O ligands

A chiral cyclic 1,2-diacetal derived from tartaric acid was ric induction was examined in the enantioselective addition
used as the basic structural unit for novel ligands. Monoox- of diethylzinc to benzaldehyde. Up to 60% ee was observed
azoline carbinols in which the degree of substitution of the with a secondary or a tertiary alcohol as the metal-chelat-
alcohol and the nature of the stereocentre in the oxazoline ing group.
ring were varied were synthesized in moderate to good ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
yields. The influence of these structural factors on asymmet- Germany, 2004)

Introduction Some derivatives of the cyclic 1,2-diacetal 1 made by

other researchers have already found applications in enanti-
oselective synthesis: as bis(oxazolines) in cyclopropanation
1,2-Diacetals have been known for many years, but their reactions,[3] as diphosphanes in the hydrogenation of acry-
chemistry still remains largely unexplored.[1] Cyclic 1,2-di- late derivatives[4] and enamides,[5] as thioethers in the
acetals such as 1, derived from tartaric acid, have been the hydrogenation of enamides,[5] and as phosphonites in ke-
subject of several studies during the last few years.[1] They tone hydrosilylation.[6] All the chiral ligands based on the
have a rigid 1,4-dioxane ring in which two methoxy groups 1,4-dioxane skeleton reported so far have C2 symmetry.
are stabilized in a trans-diaxial relationship by a double an- This symmetry was long believed to be the most efficient
omeric effect, and four chiral centres, which make them feature for ligand-induced multiplication of chirality, but re-
good templates for chirality transfer. They are structurally cently more complex structures bearing different chelating
related to TADDOL 2, which is also prepared from tartaric groups and more than one element of chirality have proved
acid, contains a 1,3-dioxolane ring, and whose derivatives to be very useful.[7] We decided to do away with C2 sym-
have many applications in catalysis.[2] metry, and to synthesize ligands with oxazoline and
hydroxy units, i.e. with two different donor atoms, N and
O, capable of chelating to metals. It is a well-known fact
that in homogeneous catalysis there is an almost complete
lack of useful structure⫺activity relationship.[8] Since most
catalytic cycles consist of several consecutive discrete steps,
intermediates may be quite different and hence it is difficult
to predict which structural factors may be best suited to a
particular reaction. We synthesized a series of ligands with
different structural features which could influence the in-
duction of chirality, such as hydroxy group substitution and
the nature of the chiral substituent in the oxazoline ring,
aiming to have a useful series to add to the chiral pool.
In order to assess the ability of our new catalysts to in-
[a]
Departamento de Quı́mica, REQUIMTE, Faculdade de duce asymmetry in catalytic reactions we decided to study
Ciências e Tecnologia, Universidade Nova de Lisboa, the enantioselective addition of diethylzinc to benzaldehyde
2825 Monte de Caparica, Portugal to produce 1-phenylpropanol, commonly used as a chiral
Fax: (internat.) ⫹ 351-212948550
E-mail: [email protected] building block. This reaction has been widely studied since
[b]
Instituto de Tecnologia Quı́mica e Biológica, Universidade its discovery by Oguni and Omi in 1984,[9] and it has been
Nova de Lisboa,
Rua da Quinta Grande 6, Apartado 127, 2780 Oeiras, Portugal reviewed recently.[10] Amino alcohols constitute an import-
Fax: (internat.) ⫹ 351-214469789 ant part of the chiral ligands studied, and oxazoline-con-

1820  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/ejoc.200300750 Eur. J. Org. Chem. 2004, 1820⫺1829
Novel Cyclic 1,2-Diacetals Derived from (2R,3R)-(⫹)-Tartaric Acid FULL PAPER
taining catalysts have also received some attention. Simple way (vide infra), and heating to higher temperatures (deca-
hydroxymethyloxazolines,[11] pyridyloxazoline alcohols,[12] lin reflux) was necessary. The amides could, however, be
ferrocene-based systems[13] and a TADDOL analog[14] have readily converted into oxazolines by activation of the
been tried with success, but a systematic investigation of the hydroxy group as a tosylate and in situ ring closure in the
effect of altering the degree of substitution of the alcohol presence of excess triethylamine. This method works well
chelating group has not been made. The present study when there are other secondary or tertiary hydroxy groups
aimed to fill this gap as well as to explore further the chem- in a molecule.[19] Novel oxazolines 6a⫺c were synthesized
istry of 1,2-diacetals. in this manner. They were the only product of the reaction
and were obtained in good to high yields (65⫺79% from
the acid) after column chromatography.

Results and Discussion

B. Synthesis of the Catalyst Containing a Secondary
A. Synthesis of TADDOL Analogs Hydroxy Group
The C2-symmetric diester 1 used as starting material for Catalysts containing a primary or a secondary hydroxy
the preparation of all the catalysts was obtained from group required a different synthetic strategy. In these cases
(2R,3R)-(⫹)-tartaric acid by an acetal exchange reaction it was necessary to protect the carboxylic acid function
with 2,2,3,3-tetramethoxybutane and p-toluenesulfonic acid before transforming the ester into an alcohol (Scheme 2).
as catalyst as reported previously.[15] The diester was con- Corey’s orthoester protecting group was used to protect the
verted into unsymmetrical derivatives via the half-ester 3, acid against the attack of organometallic reagents (Grig-
obtained in good yield (85%) by partial hydrolysis with nard reagents, LiAlH4)[20] as its oxabicyclo[2,2,2]octyl or-
methanolic KOH[16] (Scheme 1). Reaction of the half-ester thoester (OBO ester 9). This strategy could be used success-
with an excess of Grignard reagent produced the tertiary fully because the base-stable cyclic orthoester is much more
alcohol directly, a strategy which has already been used with sensitive to acid than the cyclic 1,2-diacetal, and deprotec-
the TADDOL analogues.[17] Oxazolines 6a⫺c could be re- tion could be achieved under very mild conditions in which
adily obtained from the acid in good to high yields the cyclic acetal was not affected.
(65⫺79%) in a two-step process: amidation and dehydrative The OBO ester was prepared in two steps; acid 3 was
cyclization. Heating the acid in the presence of an amino initially esterified with 3-(hydroxymethyl)-3-methyloxetane
alcohol to 150 °C with concomitant azeotropic removal of and DCC/DMAP; higher yields of product 8 were obtained
the water formed with a Dean⫺Stark trap, produced am- (77%) when an excess (two-fold) of oxetane alcohol was
ides 5a⫺c. used. The ester was subsequently converted into the OBO
The products were pure enough to be used in the next ester 9 by a rearrangement reaction catalyzed by BF3·Et2O.
step without prior purification. When the activation energy The reaction was complete in 1 hour at room temperature,
for this process is low enough, oxazolines may form directly and the OBO ester was obtained as the only product in high
in this fashion by removal of another molecule of water,[18] yield (82%). Direct reduction of protected ester 9 to the
but in our case only one oxazoline was synthesized in this aldehyde was tried, but attempts with DIBAL-H or LiAlH4/

Scheme 1. Reagents and conditions: i) 1.2 equiv. KOH, MeOH, reflux; ii) 3 equiv. PhMgBr, THF, reflux; iii) amino alcohol, xylene,
reflux; iv) pTsCl, Et3N, CH2Cl2, reflux

Eur. J. Org. Chem. 2004, 1820⫺1829 www.eurjoc.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1821
FULL PAPER M. T. Barros, C. D. Maycock, A. M. Faı́sca Phillips

Scheme 2. Reagents and conditions: i) DCC, DMAP, CH2Cl2, 0 °C, 4 h; ii) BF3·Et2O, CH2Cl2, room temp., 1 h; iii) LiAlH4, THF, reflux;
iv) (COCl)2, DMSO, Et3N, CH2Cl2, ⫺60 °C; v) PhMgBr, THF, reflux, 1 h 30; vi) 1  HCl, pH 1, 0 °C, 40 min, then 1  LiOH, pH 11,
reflux; vii) amino alcohol, xylene, reflux, 17 h; viii) pTsCl, Et3N, CH2Cl2, reflux, 17 h

Et2NH were unsuccessful. Hence the ester was first reduced C. Synthesis of the Catalyst Containing a Primary
with LiAlH4 [21] to alcohol 10 in good yield (68%), and 10 Hydroxy Group
was then converted into the aldehyde 11 (in 87% yield) by
Swern oxidation under standard conditions.[22] The product The approach used for the synthesis of this catalyst is
was pure enough to be used in the next step without further shown in Scheme 3. Acid 3 was protected as the OBO ester,
purification. Grignard addition proceeded smoothly, and and the ester function was reduced to the alcohol. Depro-
the alcohol was obtained in 72% yield after chromatogra- tection was carried out as described for 12, to give 16 in
phy. There was no duplication of signals in spectra (1H good yield (88%). The oxazoline synthesis, however, re-
NMR, 13C NMR), suggesting that the product formed with quired a method different from that used for the other cata-
either full or very high stereocontrol.[23] The acid was then lysts. After the amidation of 16, there are two primary
deprotected[24] in a sequence of two one-pot reactions. hydroxy groups present in the molecule which can compete
Acidifying a THF/H2O solution of 12 at 0 °C with HCl to in the tosylation step, and mixtures can be produced. Hence
pH 1 and stirring for 30 min caused complete rearrange- a direct approach was used. Dehydration at 135 °C in xy-
ment of the OBO ester to an intermediate ester. Only one lene produced amide 17 together with small amounts of the
product formed in this step, as indicated by TLC. This ester oxazoline; even after long periods of heating the reaction
may be isolated if wished. Normally it was not isolated, but did not go to completion, and eventually other (unidenti-
the solution was treated with aqueous LiOH solution and fied) products formed. When the acid and the amino al-
the pH raised to 11. After a period of reflux (4:30 h), the cohol were heated to a higher temperature in decalin (bath
hydrolysis was complete and acid 13 could be obtained in temperature 210 °C) oxazoline 18 formed. The reaction
high yield (88%) by acidification and extraction. The amid- goes via the amide, which is the major component of the
ation and subsequent oxazoline formation were carried out reaction mixture after 17 h of reflux. If the amide is not
as described for catalysts 6aⴚc to give 15 in 63% yield. isolated but the mixture is refluxed for 3⫺4 days, about 75%

1822  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org Eur. J. Org. Chem. 2004, 1820⫺1829
Novel Cyclic 1,2-Diacetals Derived from (2R,3R)-(⫹)-Tartaric Acid FULL PAPER
of the starting material is converted into product. Refluxing
the mixture longer (i.e. 6 days) does not increase the conver-
sion, even though some amide is still present in the reaction
mixture after this time, as indicated by 1H NMR spec-
troscopy.

Scheme 3. Reagents and conditions: i) 1  HCl, pH 1, 0 °C, 30 min,

then 1  LiOH, pH 11, reflux; ii) amino alcohol, decalin, reflux Figure 1. Variation of the ee as a function of the reaction con-
ditions in the addition of diethylzinc to benzaldehyde catalyzed by
6a: a) the effect of the catalyst concentration on ee and on conver-
sion after 24 h; b) the effect of temperature observed after 24 h.[26]
D. Catalysis
The potential of the novel chiral oxazoline carbinols to
catalyze the asymmetric addition of Et2Zn to benzaldehyde Figure 1 (see a and b) illustrate some of the results. The
was investigated. Preliminary experiments showed that 2 reaction was slow; after 24 h at 12 °C there was more than
mol equivalents of Et2Zn were necessary, otherwise the re- 80% conversion, but small amounts of aldehyde remained
action would not go further than half-way, irrespective of unchanged. This also happened at room temperature, with
the length of time used. The addition was tried with 6a 9% unchanged aldehyde remaining even after 47 h, as deter-
as catalyst, at different temperatures and different catalyst mined by 1H NMR spectroscopy. It seems that the alkoxide
concentrations, to establish the best reaction conditions. formed inhibits the reaction, as reported to occur in some

Table 1. Enantioselective addition of diethylzinc to benzaldehyde catalyzed by various oxazoline carbinols

Entry[a] Catalyst R1 R2 R3 Substrate[b] [%] BzOH[b] [%] Conversion[c] [%] ee[d] [%]

1 6a Ph Ph Ph 16 ⬍ 9 67 54
2 6b Ph Ph iPr 11 ⬍ 5 nd[e] 46
3 6c Ph Ph Me 20 ⬍ 5 66 20
4 16 Ph H Ph nf[f] ⬍ 5 79 49
5 18 H H Ph 2 ⬍ 10 58 11
[a]
Reactions were carried out under argon, and a molar ratio of Et2Zn/benzaldehyde/catalyst ⫽ 2.1:1:0.1. Additions took place at 0 °C
and the mixtures were afterwards stirred for 24 h at 12⫺15 °C. [b] Determined from the 1H NMR spectrum. [c] Determined by HPLC
analysis, using 1-phenylethanol as internal standard. [d] Determined by HPLC analysis, on a Chiralcel OB-H column from Daicel. [e] Not
determined. [f] Not found.

Eur. J. Org. Chem. 2004, 1820⫺1829 www.eurjoc.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1823
FULL PAPER M. T. Barros, C. D. Maycock, A. M. Faı́sca Phillips

cases by other researchers. The highest enantiomeric excess change from the diphenylhydroxymethyl to the phenyl-
was obtained when the reaction was carried out at 0 °C hydroxymethyl group had little influence on induction de-
(61%), but at this temperature the reaction was even slower; spite an increase in the reaction rate, but a change from the
a benzaldehyde to alcohol ratio of 1:3.7 was obtained after diphenylhydroxymethyl to the hydroxymethyl group had a
42 h, and propiophenone also formed in large amounts large influence on induction. In the oxazoline unit, the nat-
(20%) as a by-product. Propiophenone results from a slow ure of the chiral substituent as well as steric effects had a
disproportionation reaction between the ethylation product strong influence on induction, which decreased in the order
ethylzinc 1-phenyl-1-propoxide and benzaldehyde.[25] Ph ⬎ iPr ⬎ Me.
At higher temperatures, i.e. 12⫺15 °C, no propiophenone
formed, as determined by 1H NMR spectroscopy, and the
enantiomeric excess was 54%. Raising the temperature
speeded up the reaction more, but the ee dropped slightly
Experimental Section
(41% was obtained after 24 h). Varying the catalyst concen-
General Remarks: All reactions were carried out under argon. Sol-
tration had a small effect on the enantioselectivity of the
vents were purified by standard procedures and distilled before use.
reaction, but a large effect on the rate. Hence changing the
2,2,3,3-Tetramethoxybutane,[27] dioxane dimethyl ester 1,[1] and the
catalyst concentration from 3.7 to 11.0 mmol equivalents hydroxymethyloxetane 7,[20a] were prepared according to literature
increased the ee from 44 to 55%, whereas the conversion procedures. Column chromatography was carried out on
changed from 63 to 97% in 24 h. When the final reaction Macherey⫺Nagel silica gel (230⫺400 mesh). Melting points were
conditions were selected, a compromise between these fac- measured with an Electrothermal Melting Point apparatus or with
tors was made, so that a good conversion could be reached a Reichert Thermovar apparatus, and are uncorrected. Elemental
at a low catalyst concentration. All the catalysts prepared analyses (C, H, N) were performed by the Laboratory for External
were then assessed under identical conditions, and the re- Services of CQFB-Lab Associado/REQUIMTE, of the Depart-
sults are presented in Table 1. ment of Chemistry, FCT, UNL, Monte de Caparica. NMR spectra
were obtained with a Bruker AR X400 NMR spectrometer. Chemi-
Benzyl alcohol, which forms by β-hydride reduction, is
cal shifts are reported relative to TMS. Signals in 13C NMR spectra
sometimes obtained as a major by-product of the reaction
were assigned with the aid of DEPT spectra. Two-dimensional
between benzaldehyde and diethylzinc. In our reactions un- spectra (COSY 45, HMQC, SECSY) were recorded whenever
der optimized conditions it was present as less than 10% of necessary for structure elucidation. IR spectra were obtained with
the crude reaction mixtures. The (R)-isomer was the pre- a Mattson Instruments Satellite FTIR spectrometer. Optical ro-
dominant product in all cases. The highest enantiomeric ex- tations (0.5-dm cell, 1-mL capacity) were measured with an
cess was obtained with catalyst 6a, the catalyst containing AA⫺1000 Polarimeter from Optical Activity Ltd. HPLC analyses
a tertiary alcohol group (54%), and the lowest (11%) with were carried out with a Merck Hitachi instrument equipped with
18, containing a primary hydroxy group. Catalyst 4 (con- a Chiralcel OB-H column, with hexane/iPrOH as eluent (flow
taining a secondary hydroxy group, and hence another chi- 0.9 mL/min), and a Merck⫺Hitachi -4250 UV⫺VIS detector.
ral centre near the active reaction centre) provided nearly (2R,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-1,4-dioxane-2,3-di-
the same induction as 6a (49%), but it also gave the largest carboxylic Acid Monomethyl Ester (3): The diester (5.33 g, 0.018
enhancement in rate (all the substrate had reacted after mol) was suspended in dry MeOH (12 mL). Potassium hydroxide
24 h). A separate experiment showed that after 16 h only ⬍ (1.25 g, 0. 022 mol) in MeOH (10 mL) was added dropwise, at room
2% of the starting material remained unchanged. These re- temperature, over a period of 1 h. The solution was afterwards re-
sults suggest that steric effects play an important role in fluxed for 2 h 30. The solvent was then evaporated off, and the
reducing the number of conformations possible in the tran- mixture was distributed between CHCl3 and water. The aqueous
sition state, and hence the catalyst containing a tertiary al- layer was extracted twice more with CHCl3. The combined chloro-
cohol group gave the best induction. form fractions were dried with anhydrous magnesium sulfate and
the solvent evaporated off. The residue was checked for the pres-
ence of unchanged diester. The diester obtained (0.349 g) was later
recycled. The remaining aqueous phase was acidified with HCl
Conclusion solution (2 ) to pH 1 and extracted with diethyl ether. The pH
was adjusted with HCl before each extraction. After drying, the
In the course of this work methods for the synthesis of solvent was evaporated off to give the product as a viscous colour-
D ⫽ ⫺132 (c ⫽ 2.03, CHCl3). H NMR
less liquid (4.34 g, 86%). [α]21 1
novel chiral oxazoline carbinols were developed. They were
obtained in good to moderate yields from a cyclic 1,2-diace- (400.1 MHz, CDCl3): δ ⫽ 1.36 (s, 3 H, CH3), 1.37 (s, 3 H, 2 ⫻
tal derived from tartaric acid. Structural features such as CH3), 3.32 (s, 3 H, OCH3), 3.33 (s, 3 H, OCH3), 3.78 (s, 3 H,
the degree of substitution of the alcohol as well as the nat- COOCH3), 4.49 (d, J ⫽ 5 Hz, 1 H, dioxane CH), 4.60 (d, J ⫽
ure of the chiral substituent in the oxazoline ring were va- 5 Hz, 1 H, dioxane CH), 9.00⫺9.25 (br. s, COOH) ppm. 13C NMR
(100.6 MHz, CDCl3): δ ⫽ 17.3 (2 ⫻ CH3), 48.6 (2 ⫻ OCH3), 52.6
ried. The effect of these modifications on the ability of these
(CH3), 68.3 (CH), 68.7 (CH), 99.2 (acetal C), 99.6 (acetal C), 168.2
ligands to induce chirality was investigated in a model reac- (CO), 171.7 (CO) ppm. IR (CHCl3): ν̃ ⫽ 3668, 3483, 3028, 3001,
tion, the enantioselective addition of diethylzinc to benzal- 2954, 2908, 2839, 2613, 2556, 1744, 1440, 1380, 1354, 1292, 1231,
dehyde. Steric effects near the hydroxy group seemed to be 1202, 1178, 1143, 1114, 1040, 898, 889, 855, 772, 664, 579, 428
more important than the presence of an extra stereogenic cm⫺1. C11H18O8 (278.26): calcd. C 47.48, H 6.52; found C 47.57,
centre near the coordination sphere of the metal. Thus, a H 6.87.

1824  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org Eur. J. Org. Chem. 2004, 1820⫺1829
Novel Cyclic 1,2-Diacetals Derived from (2R,3R)-(⫹)-Tartaric Acid FULL PAPER
(2R,3R,5R,6R)-3-(Hydroxydiphenylmethyl)-5,6-dimethoxy-5,6-di- 1529, 1495, 1450, 1378, 1201, 1143, 1132, 1121, 1039, 911, 701
methyl-1,4-dioxane-2-carboxylic Acid (4): A flame-dried two- cm⫺1. C30H35NO7 (521.61): calcd. C 69.08, H 6.76, N 2.69; found
necked flask was charged with a phenylmagnesium bromide solu- C 69.25, H 6.75, N 2.68.
tion (21.5 mL of a 1  solution in THF, 21.5 mmol). Half-ester 3
(1.99 g, 0.716 mmol) in dry THF (2.9 mL) was added dropwise at (2R,3R,5R,6R)-N-[(S)-1-Hydroxymethylisopropyl]-3-(hydroxy-
room temperature over 1 h while the solution was stirred under diphenylmethyl)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-carb-
argon. Afterwards the mixture was refluxed for 17 h. The reaction oxamide (5b): Prepared from (S)-(⫹)-2-amino-3-methyl-1-butanol
mixture was then cooled in an ice bath, and ice (3 g) was added. (0.103 g, 0.989 mmol) and acid 4 (0.398 g, 0.989 mmol), as de-
The pH was lowered to 1 with 1  HCl and the product was ex- scribed under the general procedure for amidation. It may be puri-
tracted with diethyl ether. The combined extracts were washed with fied by chromatography on silica gel (EtOAc/hexane, 6:4). M.p.
a saturated salt solution, filtered through anhydrous sodium sulfate 149⫺150 °C. [α]22
D ⫽ ⫹28.9 (c ⫽ 0.52, CHCl3). The assignments of

and the solvent was removed using a rotary evaporator. The sample the NMR signals were made by HMBC. 1H NMR (400.1 MHz,
was dried. The product was purified by column chromatography CDCl3): δ ⫽ 0.89 [d, J ⫽ 6.8 Hz, 3 H, CH(CH3)2], 0.93 [d, J ⫽
on silica gel treated with 1% Et3N in hexane (EtOAc/MeOH, 8:2). 6.4 Hz, 3 H, CH(CH3)2], 1.13 (s, 3 H, CH3), 1.30 (s, 3 H, CH3),
Some product eluted as a salt, which was converted into the free 1.88⫺1.97 [m, 1 H, CH(CH3)2], 2.19 (t, J ⫽ 5.6 Hz, 1 H, CH2OH),
acid after dissolution in water, acidification to pH 艐 1 with 2  2.64 (s, 3 H, OCH3), 3.20 (s, 3 H, OCH3), 3.65⫺3.78 (m, 3 H, CHN
HCl and extraction with diethyl ether. The product was obtained ⫹ CH2), 4.10 (d, J ⫽ 9.2 Hz, 1 H, dioxane CH), 4.58 (d, J ⫽ 9.2
as a white solid. Total yield: 1.16 g, 40%. M.p. 163⫺164 °C. [α]27 Hz, 1 H, dioxane CH), 6.01 (s, 1 H, OH), 7.14 (t, J ⫽ 7.2 Hz, 2
D ⫽
⫺26.6 (c ⫽ 2.00, CHCl3). 1H NMR (400.1 MHz, CDCl3): δ ⫽ 1.18 H, Ph-H), 7.21 (t, J ⫽ 7.2 Hz, 2 H, Ph-H), 7.29 (t, J ⫽ 7.2 Hz, 2
(s, 3 H, CH3), 1.33 (s, 3 H, CH3), 3.13 (s, 3 H, OCH3), 3.29 (s, 3 H, Ph-H), 7.36⫺7.40 (m, 3 H, 2 H of Ph ⫹ NH), 8.00 (d, J ⫽ 7.6
H, OCH3), 4.46 (d, J ⫽ 9.0 Hz, 1 H, CH), 4.84 (d, J ⫽ 9.0 Hz, 1 Hz, 2 H, Ph-H) ppm. 13C NMR (100.6 MHz, CDCl3, DEPT): δ ⫽
H, CH), 7.10 (t, J ⫽ 7.3 Hz, 1 H, Ph), 7.18 (t, J ⫽ 7.8 Hz, 2 ⫻ H, 17.3 (2 ⫻ CH3), 18.6 [CH3, CH(CH3)2], 19.5 [CH3, CH(CH3)2],
Ph-H), 7.25 (t, J ⫽ 7.3 Hz, 1 H, Ph-H), 7.35 (t, J ⫽ 7.8 Hz, 2 ⫻ 28.7 [CH, CH(CH3)2], 48.0 (CH3 of OCH3), 48.2 (CH3 of OCH3),
H, Ph-H), 7.42 (d, J ⫽ 7.5 Hz, 2 ⫻ H, Ph-H), 7.72 (d, J ⫽ 7.5 Hz, 57.1 (CHN), 63.3 (CH2), 70.0 (dioxane CH), 76.4 (dioxane CH),
2 ⫻ H, Ph-H) ppm. 13C NMR (100.6 MHz, CDCl3): δ ⫽ 17.3 126.6 (CH, Ph), 127.1 (4 ⫻ CH, Ph), 127.6 (CH, Ph), 127.8 (4 ⫻
(CH3), 17.4 (CH3), 48.5 (OCH3), 48.9 (OCH3), 68.8 (CH), 72.7 CH, Ph), 143.6 (Cquat, Ph), 146.0 (Cquat, Ph), 166.7 (CONH), 172.3
(CH), 78.1 (COH), 98.6 (acetal C), 99.1 (acetal C), 126.6 (4 ⫻ CH, (CONH) ppm. IR (CHCl3): ν̃ ⫽ 3409, 3062, 2995, 2965, 2898,
Ph), 126.9 (4 ⫻ CH, Ph), 127.0 (2 ⫻ CH, Ph), 127.4 (CH, Ph), 2836, 1648, 1531, 1493, 1449, 1377, 1265, 1205, 1143, 1131, 1122,
127.6 (4 ⫻ CH, Ph), 127.9 (4 ⫻ CH, Ph), 142.1 (CH, Ph), 144.5 (2 1044, 925, 908, 745, 722, 702 cm⫺1. C27H37NO7 (487.59): calcd. C
⫻ CH, Ph), 173.2 (CO) ppm. IR (CHCl3): ν̃ ⫽ 3671, 3550, 3415, 66.51, H 7.65, N 2.87; found C 66.38, H 7.67, N 2.95.
3062, 3027, 3010, 2950, 2837, 1727, 1600, 1493, 1450, 1377, 1144, (2R,3R,5R,6R)-N-[(S)-2-Hydroxy-1-methylethyl]-3-(hydroxy-
1128, 1119, 1038, 977, 912, 891, 876, 703, 664 cm⫺1. diphenylmethyl)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-carb-
C22H26O7·MeOH (434.49): calcd. C 63.58, H 6.96; found C 63.80,
oxamide (5c): Prepared from (S)-(⫹)-2-amino-1-propanol (0.053 g,
H 6.90.
0.692 mmol) and acid 4 (0.281 g, 0.699 mmol), as described in the
general procedure for amidation. 1H NMR (400.1 MHz, CHCl3):
General Procedure for Amidation: A reaction flask topped with a
δ ⫽ 1.12 (s, 3 H, CH3), 1.17 (d, J ⫽ 6.8 Hz, 3 H, CH3), 1.31 (s, 3
Dean⫺Stark apparatus and a condenser was charged with acid 4
H, CH3), 2.66 (s, 3 H, OCH3), 3.20 (s, 3 H, OCH3), 3.58 (dd, J ⫽
(1.00 mmol), the amino alcohol (1.00 mmol) and xylene (4.60 mL).
4.8, 10.8 Hz, 1 H, CHaHbOH), 3.69 (dd, J ⫽ 4.0, 11.2 Hz, 1 H,
The mixture was refluxed for 17 h under argon. The solvent was
CHaHbOH), 4.02 (m, 1 H, CHN), 4.10 (d, J ⫽ 9.2 Hz. Hz, 1 H,
then removed in vacuo, and the product was dried. Amides 5a⫺c
CH), 4.53 (d, J ⫽ 9.6 Hz, 1 H, CH), 6.20 (br. s, 1 H, OH), 7.16 (t,
were prepared in this way and were obtained as solids which were
2 H, Ph), 7.21 (t, 2 H, Ph), 7.29 (t, 1 H, Ph), 7.39 (t, 3 H, Ph), 8.00
used in the next step without further purification.
(d, J ⫽ 7.6 Hz, 2 H, Ph) ppm. 13C NMR (100.6 MHz, CDCl3,
(2R,3R,5R,6R)-N-[(S)-2-Hydroxyl-1-phenylethyl]-3-(hydroxy- DEPT): δ ⫽ 16.8 (CH3), 17.3 (2 ⫻ CH3), 47.5 (CHCH3), 48.0
(OCH3), 48.4 (OCH3), 65.9 (CH2OH), 69.8 (CH), 76.2 (CH), 78.3
diphenylmethyl)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-carb-
(CquatOH), 98.8 (acetal C), 99.1 (acetal C), 126.6 (CH, Ph), 127.1
oxamide (5a): Prepared from (S)-(⫹)-2-amino-2-phenylethanol
(CH, Ph), 127.6 (CH, Ph), 127.8 (CH, Ph), 128.9 (CH, Ph), 143.5
(0.200 g, 1.41 mmol) and acid 4 (0.569 g, 1.41 mmol) as described
(Cquat, Ph), 145.2 (Cquat, Ph), 171.7 (CONH) ppm. IR (CHCl3):
under the general procedure for amidation. It may be purified by
ν̃ ⫽ 3690, 3409, 3061, 3010, 2950, 2837, 1647, 1602, 1534, 1493,
chromatography on silica gel (EtOAc/hexane, 7.4:2.6) and recrys-
tallized from EtOAc/hexane to give white crystals. M.p. 166 °C. 1450, 1378, 1214, 1143, 1131, 1043, 913, 774, 744, 702, 665 cm⫺1.
D ⫽ ⫹63.9 (c ⫽ 0.26, CHCl3). H NMR (400.1 MHz, CHCl3):
[α]21 1
General Procedure for Oxazoline Synthesis: The oxazolines 6a⫺c
δ ⫽ 1.06 (s, 3 H, CH3), 1.25 (s, 3 H, CH3), 2.60 (s, 3 H, OCH3), were prepared from the corresponding amides 5a⫺c as follows: the
3.12 (s, 3 H, OCH3), 3.80 (dd, Jvic ⫽ 5.6, Jgem ⫽ 11.2 Hz, amide (1.00 mmol) was dissolved in CH2Cl2 (3.0 mL). Dry triethyl-
CHaCHb), 3.86 (dd, Jvic ⫽ 4.0, Jgem ⫽ 11.2 Hz, 1 H, CHaCHb), amine (4.99 mmol) and p-toluenesulfonyl chloride (1.06 mmol)
4.10 (d, J ⫽ 9.6 Hz, 1 H, dioxane CH), 4.51 (d, J 10 Hz, 1 H, were added, and the mixture was refluxed under argon for 17 h.
dioxane CH), 4.98 (m, 1 H, CHN), 7.06⫺7.32 (m, 14 H, Ph-H), After cooling to room temp. water (1.00 mmol) was added, and the
7.64 (d, J 8 Hz, 1 H, CONH), 7.92 (d, J ⫽ 7.2 Hz, 2 H, Ph-H) mixture was refluxed for 40 min. It was then cooled and extracted
ppm. 13C NMR (100.6 MHz, CDCl3; DEPT): δ ⫽ 17.3 (2 ⫻ CH3), four times with water. The organic layer was dried through anhy-
48.0 (OCH3), 48.3 (OCH3), 55.2 (CH or NHCH), 65.8 (CH2), 69.9 drous sodium sulfate, and the product was obtained as a solid after
(CH or NHCH), 76.1 (CH or NHCH), 78.3 (Ph2COH), 98.9 (acetal evaporation of the solvent.
C), 99.1 (acetal C), 126.5 (CH, Ph), 126.6 (CH, Ph), 127.1 (CH,
Ph), 127.5 (CH, Ph), 127.8 (CH, Ph), 128.9 (CH, Ph), 138.4 (Cquat, {(2R,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-3-[(S)-4-phenyl-4,5-
Ph), 143.4 (Cquat, Ph), 145.1 (Cquat, Ph), 171.8 (CONH) ppm. IR dihydrooxazol-2-yl]-1,4-dioxan-2-yl}diphenylmethanol (6a): White
(CHCl3): ν̃ ⫽ 3666, 3597, 3408, 3301, 3065, 3010, 2950, 2837, 1650, solid (76% based on the amide); purification by chromatography

Eur. J. Org. Chem. 2004, 1820⫺1829 www.eurjoc.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1825
FULL PAPER M. T. Barros, C. D. Maycock, A. M. Faı́sca Phillips

on silica gel (CH2Cl2/EtOAc, 8:2). M.p. 79⫺80 °C (sublimes). ν̃ ⫽ 3556, 3061, 3009, 2970, 2953, 2905, 2837, 1676, 1600, 1492,
D ⫽ ⫺99.0 (c ⫽ 2.00, CHCl3). The assignments of the NMR
[α]32 1473, 1450, 1377, 1143, 1129, 1036, 986, 946. C25H31NO6 (441.52):
signals were made by HMBC. 1H NMR (400.1 MHz, CDCl3): δ ⫽ calcd. C 68.01, H 7.08, N 3.17; found C 68.06, H 7.18, N 3.16.
1.07 (s, 3 H, CH3), 1.26 (s, 3 H, CH3), 3.00 (s, 3 H, OCH3), 3.22
3-Methyl (2-Methyloxetan-2-yl)methyl (2R,3R,5R,6R)-5,6-Dimeth-
(s, 3 H, OCH3), 3.85 (t, J ⫽ 8.3 Hz, 1 H, OCHaHb), 4.27 (t, J ⫽
oxy-5,6-dimethyl-1,4-dioxane-2,3-dicarboxylate (8): Half-ester 3
10.3 Hz, 1 H, OCHaHb), 4.60 (t, J 9 Hz, 1 H, CHN), 4.80 (AB
(0.664 g, 2.39 mmol), 3-hydroxymethyl-3-methyloxetane (0.526 g,
system, J 艐 0 Hz, 2 H, 2 ⫻ dioxane CH), 6.95 (d, J ⫽ 7.0 Hz, 2
5.15 mmol) and 4-dimethylaminopyridine (0.032 g, 0.262 mmol)
H, Ph-H), 7.07 (t, J ⫽ 7.2 Hz, 1 H, Ph-H), 7.17 (m, 6 H, Ph-H),
were dissolved in CH2Cl2 (4.6 mL), and the solution was cooled to
7.22 (t, J ⫽ 7.4 Hz, 2 H, Ph-H), 7.46 (d, J ⫽ 7.7 Hz, 2 H Hz, Ph-
H), 7.70 (d, J ⫽ 7.7 Hz, 2 H, Ph-H) ppm. 13C NMR (100.6 MHz, 0 °C. 1,3-Dicyclohexylcarbodiimide (0.592 g, 2.87 mmol) dissolved
in CH2Cl2 (2.3 mL) was added dropwise. The urea started to pre-
CDCl3, DEPT): δ ⫽ 17.2 (CH3), 17.4 (CH3), 48.3 (OCH3), 48.8
cipitate within a few minutes. The solution was then stirred at 0 °C
(OCH3), 65.6 (CH), 68.3 (NCHPh), 73.3 (CH), 74.4 (CH2), 78.0
(CPh2OH), 98.7 (acetal C), 99.3 (acetal C), 126.5 (CH, Ph), 126.7 under argon for 4 h. The precipitated urea was filtered off with the
aid of CH2Cl2. The solvent was removed using a rotary evaporator,
(CH, Ph), 126.8 (2 ⫻ CH, Ph), 127.1 (CH, Ph), 127.3 (CH, Ph),
127.5 (CH, Ph), 127.7 (CH, Ph), 128.5 (CH, Ph), 141.0 (Cquat, Ph), the solid residue was redissolved in CH2Cl2 and filtered. The solu-
tion was then washed successively with water, HCl (0.2 ) and satu-
143.3 (Cquat, Ph), 144.6 (Cquat, Ph), 165.4 (OCN) ppm. IR (CHCl3):
rated sodium hydrogencarbonate solution. The solvent was re-
ν̃ ⫽ 3676, 3559, 3089, 3066, 3034, 3026, 3010, 2964, 2951, 2907,
2837, 1753, 1673, 1600, 1494, 1471, 1450, 1377, 1262, 1217, 1176, moved using a rotary evaporator. The crude product was purified
1165, 1217, 1176, 1165, 1143, 1129, 1118, 1035, 987, 786, 767, 749, by flash chromatography on silica gel pre-treated with 1% Et3N in
hexane (hexane/EtOAc, 1:1) to give a viscous liquid (0.593 g, 77%).
737, 701, 670, 664 cm⫺1. C30H33NO6 (503.60): calcd. C 71.55, H
D ⫽ ⫺111.1 (c ⫽ 2.01, CHCl3). H NMR (400.1 MHz, CDCl3):
[α]27 1
6.61, N 2.78; found C 71.27, H 6.64, N 2.73.
δ ⫽ 1.34 (s, 3 H, CH3), 1.35 (s, 6 H, 2 ⫻ CH3), 3.33 (s, 6 H, 2 ⫻
{(3R,3R,5R,6R)-3-[(S)-4-Isopropyl-4,5-dihydrooxazol-2-yl]-5,6- OCH3), 3.77 (s, 3 H, CO2CH3), 4.25 (virtual q, J ⫽ 8 Hz, 2 H,
dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl}diphenylmethanol (6b): CH2OCO), 4.37 (d, J ⫽ 6 Hz, 2 H, CH2O), 4.52 (d, J ⫽ 6 Hz, 2
White solid (79% based on acid 4); purification by chromatography H, CH2O), 4.55 (s, 1 H, CH), 4.56 (s, 1 H, CH) ppm. 13C NMR
on silica gel (CH2Cl2/EtOAc, 8.5:1.5). M.p. 58⫺59 °C. [α]25 (100.6 MHz, CDCl3, DEPT): δ ⫽ 17.1 (CH3, 2 ⫻ CH3), 20.9
D ⫽
⫺84.7 (c ⫽ 2.02, CHCl3). 1H NMR (400.1 MHz, CDCl3): δ ⫽ 0.77 (CH3), 38.9 (Cquat, C⫺CH3), 48.1 (CH3, 2 ⫻ OMe), 52.3 (CH3, 2
(d, J ⫽ 6.8 Hz, 3 H, CH3 of iPr), 0.84 (d, J ⫽ 7.2 Hz, 3 H, CH3 ⫻ CO2Me), 68.1 (CH), 68.2 (CH), 69.2 (CH2, CH2OCO), 79.0
of iPr), 1.10 (s, 3 H, CH3), 1.29 (s, 3 H, CH3), 1.58 [m, 1 H, (CH2, 2 ⫻ CH2O), 98.9 (Cquat, 2 ⫻ acetal C), 167.6 (Cquat, CO2),
CH(CH3)2], 2.96 (s, 3 H, OCH3), 3.25 (s, 3 H, OCH3), 3.61 (m, 1 168.0 (Cquat, CO2) ppm. IR (CHCl3): ν̃ ⫽ 3010, 2956, 2879, 2838,
H, CHN), 3.83 (t, J ⫽ 8.0 Hz, 1 H, CHaHbO), 4.07 (dd, J ⫽ 8.4 1749, 1460, 1440, 1380, 1289, 1230, 1178, 1144, 1113, 1039, 984,
Hz, 1 H, CHaHbO), 4.67 (AB system, J 艐 0 Hz, 2 H, 2 ⫻ dioxane 890, 755, 664. C16H26O9 (362.38): calcd. C 53.03, H 7.23; found C
CH), 7.13 (t, J ⫽ 7.2 Hz, 1 H, Ph-H), 7.23 (m, 3 H, Ph-H), 7.34 53.28, H 7.17.
(t, J ⫽ 7.2 Hz, 2 H, Ph-H), 7.48 (d, J ⫽ 8.4 Hz, 2 H, Ph-H), 7.86 Methyl (2R,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-3-(4-methyl-
(d, J ⫽ 7.2 Hz, 2 H, Ph-H) ppm. 13C NMR (100.6 MHz, CDCl3, 2,6,7-trioxabicyclo[2.2.2]oct-1-yl)-1,4-dioxane-2-carboxylate (9): A
DEPT): δ ⫽ 17.1 (CH3), 17.3 (CH3), 18.0 (CH3 of iPr), 18.4 (CH3 suspension of the oxetanyl ester 8 (3.50 g, 9.61 mmol) in dry
of iPr), 32.1 (CH of iPr), 48.2 (OCH3), 48.6 (OCH3), 65.7 (dioxane CH2Cl2 (12.4 mL) was stirred at room temp. under argon. Boron
CH), 70.3 (CH2), 70.8 (CHN), 74.1 (dioxane CH), 77.9 (CPh2OH), trifluoride⫺etherate (0.307 mL, 2.48 mmol) was added dropwise.
98.7 (acetal C), 99.2 (acetal C), 126.6 (CH, Ph), 126.8 (CH, Ph), The resulting solution changed from colourless to yellow brown in
127.2 (CH, Ph), 127.4 (CH, Ph), 127.6 (CH, Ph), 144.1 (Cquat, Ph), less than 10 min. One hour later Et3N (1.4 mL) was added, the
164.7 (OCN) ppm. IR (CHCl3): ν̃ ⫽ 3558, 3090, 3062, 3009, 2964, solution was stirred for 5⫺10 min and diethyl ether was added to
2908, 2875, 2837, 1676, 1600, 1492, 1464, 1449, 1375, 1212, 1202, precipitate the boron trifluoride⫺triethylamine complex. After stir-
1142, 1129, 1120, 1035, 987, 946, 911, 892, 881 cm⫺1. C27H35NO6 ring for about 10 min, the precipitate was filtered off and the sol-
(469.56): calcd. C 69.06, H 7.51, N 2.98; found C 69.12, H 7.51, vent was removed using a rotary evaporator. The product was puri-
N 2.95. fied by column chromatography on silica gel pre-treated with 1%
Et3N in hexane[28] (EtOAc) to give a white solid (2.87 g, 82%). M.p.
{(2R,3R,5R,6R)-5,6-Dimethoxy-3-[(S)-4-methyl-4,5-dihydrooxazol- 78 °C. [α]31
D ⫽ ⫺131.9 (c ⫽ 0.81, CHCl3). H NMR (400.1 MHz,
1
2-yl]-5,6-dimethyl-1,4-dioxan-2-yl}diphenylmethanol (6c): White
CDCl3): δ ⫽ 0.79 (s, 3 H, CH3), 1.32 (s, 3 H, CH3), 1.37 (s, 3 H,
solid (65% based on acid 4); purification by chromatography on
CH3), 3.29 (s, 3 H, OCH3), 3.31 (s, 3 H, OCH3), 3.73 (s, 3 H,
silica gel (EtOAc/CH2Cl2, 1:1). M.p. 124 °C (sublimes). [α]27 D ⫽
CO2CH3), 3.89 (s, 6 H, 3 ⫻ CH2), 4.06 (d, J ⫽ 10 Hz, 1 H, CH),
⫺88.9 (c ⫽ 2.01, CHCl3). 1H NMR (CDCl3): δ ⫽ 1.08 (d, J ⫽ 6.6
4.44 (d, J ⫽ 10 Hz, 1 H, CH) ppm. 13C NMR (100.6 MHz, CDCl3):
Hz, 3 H, oxazoline CH3), 1.13 (s, 3 H, CH3), 1.30 (s, 3 H, CH3),
δ ⫽ 14.3 (CH3), 17.3 (CH3), 17.5 (CH3), 30.5 (Cquat-CH3), 48.1 (2
3.08 (s, 3 H, OCH3), 3.26 (s, 3 H, OCH3), 3.59 (t, J ⫽ 7.9 Hz, 1 ⫻ OCH3), 53.2 (CO2CH3), 69.5 (CH), 69.9 (CH), 72.4 (3 ⫻ CH2O),
H, CHaHb), 3.69 (m, 1 H, CHCH3), 4.06 (t, J ⫽ 8.7 Hz, 1 H,
98.5 (acetal C), 99.1 (acetal C), 106.5 (orthoester C), 169.0 (CO2)
CHaHb), 4.67 (d, J ⫽ 9.7 Hz, 1 H, dioxane CH), 4.82 (d, J ⫽ 9.7
ppm. IR (CHCl3): ν̃ ⫽ 3009, 2952, 2885, 2837, 1746, 1471, 1460,
Hz, 1 H, dioxane CH), 5.69 (br. s, 1 H, OH), 7.12 (t, J ⫽ 7.2 Hz,
1439, 1404, 1379, 1353, 1289, 1199, 1141, 1119, 1076, 1043, 993,
1 H, Ph-H), 7.23 (q, J ⫽ 7.7 Hz, 1 H, CH, Ph-H), 7.33 (t, J ⫽ 7.4
892, 854, 821, 767, 739, 664, 562, 540, 440 cm⫺1. C16H26O9
Hz, 2 H, Ph-H), 7.51 (d, J ⫽ 7.7 Hz, 2 H, Ph-H), 7.77 (d, J ⫽ 7.7
(362.19): calcd. C 53.06, H 7.18; found C 52.84, H 7.24.
Hz, 2 H, Ph-H) ppm. 13C NMR (CDCl3, DEPT): δ ⫽ 17.2 (CH3),
17.4 (CH3), 20.7 (oxazoline CH3), 48.2 (OCH3), 48.8 (OCH3), 60.5 [(2R,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-3-(4-methyl-2,6,7-
(CHN), 65.5 (dioxane CH), 73.3 (dioxane CH), 73.6 (CH2), 78.0 trioxabicyclo[2.2.2]oct-1-yl)-1,4-dioxan-2-yl]methanol (10): A two-
(Cquat-OH), 98.6 (acetal C), 99.2 (acetal C), 126.7 (CH, Ph), 126.8 necked round-bottom flask was flame dried and charged with Li-
(CH, Ph), 127.1 (CH, Ph), 127.3 (CH, Ph), 127.6 (CH, Ph), 143.4 AlH4 (51.0 mg, 1.34 mmol) and dry THF (0.48 mL). Protected
(Cquat, Ph), 144.7 (Cquat, Ph), 163.8 (O⫺C⫽N) ppm. IR (CHCl3): half-ester 9 (0.396 g, 1.09 mmol) dissolved in dry THF (2.6 mL)

1826  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org Eur. J. Org. Chem. 2004, 1820⫺1829
Novel Cyclic 1,2-Diacetals Derived from (2R,3R)-(⫹)-Tartaric Acid FULL PAPER
was added dropwise at room temperature. The resulting suspension in an ice bath, and stirred under argon. Aldehyde 11 (0.214 g,
was refluxed for 3 h or until a TLC plate showed that the starting 0.521 mmol) dissolved in dry THF (1.75 mL), was added dropwise
material had all been consumed. The mixture was then warmed to over a period of 40 min. The solution was then placed in a oil bath
room temperature and an aqueous solution of KOH (10%) was and heated to reflux. After 1 h 20 it was cooled to room tempera-
added dropwise. The flask was stirred vigorously after each ad- ture, ammonium chloride solution (5%) was added, and the prod-
dition until the mixture turned white. Refluxing was continued for uct extracted three times with diethyl ether. The combined extracts
another hour. The solution was filtered and the product extracted were dried with anhydrous sodium sulfate, and the solvent removed
a few times with boiling THF. The pooled extracts were dried with using a rotary evaporator. The product was purified by column
anhydrous sodium sulfate, and the solvent removed using a rotary chromatography on silica gel pre-treated with 1% Et3N in hexane
evaporator. The solid obtained was purified by column chromatog- EtOAc/hexane, 1:1) to give a white solid (0.153 g, 72%). M.p.
raphy on silica gel pre-treated with 1% Et3N in hexane[28] (EtOAc/ 161⫺162 °C. [α]27D ⫽ ⫺141.0 (c ⫽ 0.58, CHCl3). The assignments
hexane, 8:2) to give the product as a white hygroscopic solid of the NMR signals were made by COSY. 1H NMR (400.1 MHz,
(0.250 g, 68%). [α]22 D ⫽ ⫺112.2 (c ⫽ 2.00, CHCl3). H NMR CDCl3): δ ⫽ 0.85 (s, 3 H, orthoester CH3), 1.14 (s, 3 H, CH3), 1.30
1

(400.1 MHz, CDCl3): δ ⫽ 0.82 (s, 3 H, CH3 of OBO ester), 1.30 (s, 3 H, CH3), 2.60 (s, 3 H, OCH3), 2.94 (d, J ⫽ 8 Hz, 1 H, CH⫺C,
(s, 3 H, CH3), 1.36 (s, 3 H, CH3), 2.27 (br. s, OH), 3.25 (s, 3 H, orthoester), 3.28 (s, 3 H, OCH3), 3.99 (s, 6 H, 3 ⫻ orthoester CH2),
OCH3), 3.28 (s, 3 H, OCH3), 3.76 (m, 3 H, 1 CH ⫹ CH2OH), 3.92 4.06 (m, 1 H, CHOH), 5.22 (d, J ⫽ 8.4 Hz, 1 H, dioxane CHCPh),
(br. s, 7 H, 3 ⫻ orthoester CH2 ⫹ CH) ppm. 13C NMR 7.21 (t, J ⫽ 7.2 Hz, 1 H, Ph), 7.30 (t, J ⫽ 7.4 Hz, 2 H, Ph-H), 7.39
(100.6 MHz, CDCl3; DEPT): δ ⫽ 12.9 (CH3), 17.4 (2 ⫻ CH3), 30.4 (d, J ⫽ 7.5 Hz, 2 H, Ph-H) ppm. 13C NMR (100.6 MHz, CDCl3,
(Cquat, Cquat-CH3), 47.8 (OCH3), 48.0 (OCH3), 62.7 (CH2, DEPT): δ ⫽ 14.4 (orthoester Me), 17.3 (CH3), 17.4 (CH3), 30.6
CH2OH), 69.0 (CH), 69.8 (CH), 72.4 (CH2, 3 ⫻ CH2O of OBO (orthoester Cquat), 47.3 (OCH3), 47.9 (OCH3), 69.5 (CH), 71.4
ester), 98.6 (Cquat, acetal C), 99.1 (Cquat, acetal C), 107.1 (orthoes- (CH), 72.1 (CH), 72.5 (3 ⫻ CH2), 98.9 (acetal C), 99.2 (acetal C),
ter C) ppm. IR (KBr): ν̃ ⫽ 3574, 3487, 2983, 2939, 2833, 1617, 107.4 (orthoester Cquat), 126.0 (CH, Ph), 126.6 (CH, Ph), 127.6
1474, 1459, 1404, 1316, 1299, 1285, 1256, 1198, 1123, 1038, 979, (CH, Ph), 141.8 (Cquat, Ph) ppm. IR (KBr): ν̃ ⫽ 3557.1, 3436.0,
940, 912, 888, 863, 752, 745, 736, 643, 660, 607 cm⫺1. C15H25O8 3083, 3057, 3031, 2991.3, 2947.5, 2882.9, 2832.7, 1495.7, 1469.0,
(333.36): calcd. C 54.05, H 7.56; found C 53.81, H 7.66. 1453.1, 1403.7, 1377.3, 1282.8, 1197.2, 1133.2, 1071.7, 1052.0,
1022.5, 993.0, 903.9, 887.1, 853.2, 828.3, 753.8, 738.6, 753.8, 738.8,
(2R,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-3-(4-methyl-2,6,7- 701.4, 571.2 cm⫺1. C21H30O8 (410.46): calcd. C 61.45, H 7.37;
trioxabicyclo[2.2.2]oct-1-yl)-1,4-dioxane-2-carbaldehyde (11): A re- found C 61.23, H 7.40.
action vessel was purged with argon, flame-dried and charged with
(2R,3R,5R,6R)-3-(Hydroxyphenylmethyl)-5,6-dimethoxy-5,6-
dry CH2Cl2 (3.2 mL) and (COCl)2 (0.152 mL, 1.75 mmol). The
dimethyl-1,4-dioxane-2-carboxylic Acid (13): Monoalcohol 12
solution was cooled to ⫺60 °C. Dry DMSO (0.264 mL, 3.72 mol)
(0.491 g, 1.20 mmol) was dissolved in THF/H2O (40:1, 6.16 mL).
dissolved in dry CH2Cl2 (0.77 mL) was added dropwise at a good
The solution was cooled to 0 °C and the pH was adjusted to 1 with
rate. The temperature was kept between ⫺50 and ⫺60 °C. Five
HCl (2 ). The mixture was then stirred at this temperature for
minutes later alcohol 10 (0.513 g, 1.53 mmol) dissolved in dry
40 min, by which time the OBO ester had been fully converted into
CH2Cl2 (2.2 mL) was added over 10 min. The mixture was stirred
the ester as indicated by a TLC plate. The pH was then raised to
for 40 min at ⫺50 to ⫺60 °C, then Et3N (1.1 mL) was added drop-
11 with LiOH solution (1 ) and the mixture was heated and re-
wise. The mixture was stirred for 5 min at this temperature, then it
fluxed for 4 h 40, or until the ester could no longer be detected by
was placed in an ice⫺NaCl bath and stirred for 30 min at 0 °C.
TLC. During this time the pH was checked two or three times, and
CH2Cl2 was added to the cold solution, and the mixture was
adjusted again with LiOH to pH 11 if the solution was found to
washed successively with ice-cold NH4Cl (5% solution) and a satu-
have become neutral. After cooling, the pH of the solution was
rated NaCl solution. It was filtered through anhydrous magnesium
adjusted to 1 and the product was extracted four times with diethyl
sulfate and the solvent was evaporated to give a solid (0.374 g,
ether. The combined diethyl ether extracts were filtered through
87%), which was used in the next reaction without purification.
anhydrous sodium sulfate and the solvent was removed using a
For analytical determinations the product was purified by column
rotary evaporator to give a white crystalline product (0.343 g, 88%),
chromatography on silica gel treated with 1% Et3N in hexane
which was used as it was in the next step. The product may be
(EtOAc/hexane, 8:2). M.p. 73⫺74 °C. [α]30 D ⫽ ⫺117.0 (c ⫽ 2.04,
recrystallized from diethyl ether/hexane to give white crystals. M.p.
CHCl3). 1H NMR (400.1 MHz, CDCl3): δ ⫽ 0.81 (s, 3 H, CH3 of
142⫺143 °C. [α]22 D ⫽ ⫺148.0 (c ⫽ 2.01, CHCl3).
1
H NMR
OBO ester), 1.33 (s, 3 H, CH3), 1.38 (s, 3 H, CH3), 3.26 (s, 3 H,
(400.1 MHz, CDCl3): δ ⫽ 1.23 (s, 3 H, CH3), 1.34 (s, 3 H, CH3),
OCH3), 3.30 (s, 3 H, OCH3), 3.91 (s, 6 H, 3 ⫻ orthoester CH2),
2.78 (s, 3 H, OCH3), 3.32 (s, 3 H, OCH3), 3.98 (dd, J ⫽ 1.6, 10.0
4.01 (d, J ⫽ 10 Hz, 1 H, CH), 4.32 (dd, J ⫽ 3.2, 9.6 Hz, 1 H, CH),
Hz, CH), 4.66 (d, ABX system, J ⫽ 10.0 Hz, 1 H, CHOH), 5.20
9.53 (d, J ⫽ 3.2 Hz, 1 H, CHO) ppm. 13C NMR (100.6 MHz,
(AB system, 1 H, CHCOO), 7.26 (d, J ⫽ 7.2 Hz, 1 H, Ph-H), 7.33
CDCl3): δ ⫽ 14.3 (orthoester CH3), 17.3 (CH3), 17.4 (CH3), 30.6
(t, J ⫽ 6.4 Hz, 2 H, Ph-H), 7.40 (d, J ⫽ 7.2 Hz, 2 H, Ph-H) ppm.
(orthoester C-CH3), 48.1 (2 ⫻ OCH3), 69.1 (CH), 72.4 (3 ⫻ ortho- 13
C NMR (100.6 MHz, CDCl3, DEPT): δ ⫽ 17.3 (2 ⫻ CH3), 47.8
ester CH2), 72.9 (CH-CHO), 98.6 (acetal C), 99.2 (acetal C), 106.4
(OCH3), 48.6 (OCH3), 68.4 (CHOH or dioxane CH), 71.6 (CHOH
(orthoester C), 195.2 (CHO) ppm. IR (CHCl3): ν̃ ⫽ 3010, 2960,
or dioxane CH), 71.8 (CHOH or dioxane CH), 98.9 (acetal C),
2949, 2885, 2837, 1735, 1472, 1459, 1403, 1460, 1403, 1378, 1353,
99.4 (acetal C), 126.1 (CH, Ph), 127.4 (CH, Ph), 128.0 (CH, Ph),
1241, 1139, 1122, 1072, 1049, 1024, 999, 932, 889, 875, 756, 741,
140.8 (Cquat, Ph), 171.2 (COOH) ppm. IR (CHCl3): ν̃ ⫽ 3674, 3556,
593, 563 cm⫺1. C15H24O8 (332.35): calcd. C 54.21, H 7.28; found
3426, 3026, 3012, 2951, 2837, 1772, 1739, 1604, 1453, 1378, 1230,
C 54.17, H 7.45.
1198, 1143, 1130, 1037, 907, 890, 855, 826, 781, 778, 770, 766, 760,
755, 750, 746, 742, 734, 701, 666, 634 cm⫺1. C16H22O7 (326.35):
[(2R,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-3-(4-methyl-2,6,7-
calcd. C 58.89, H 6.80; found C 58.99, H 6.88.
trioxabicyclo[2.2.2]oct-1-yl)-1,4-dioxan-2-yl]phenylmethanol (12):
Phenylmagnesium bromide (0.78 mL, 0.78 mmol of a 1  solution (2R,3R,5R,6R)-N-[(S)-2-Hydroxy-1-phenylethyl]-3-(hydroxy-
in hexanes) was added to a round-bottom two-necked flask, cooled phenylmethyl)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-carb-

Eur. J. Org. Chem. 2004, 1820⫺1829 www.eurjoc.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1827
FULL PAPER M. T. Barros, C. D. Maycock, A. M. Faı́sca Phillips

oxamide (14): (S)-(⫹)-2-Amino-2-phenylethanol (0.064 g, a rotary evaporator to give a white crystalline product (1.01 g,
0.457 mmol), acid 13 (0.149 g, 0.457 mmol) and xylene (2.1 mL) 88%), used in the next reaction without further purification. It may
were heated to reflux and treated as described for amides 5a⫺c. be recrystallized from diethyl ether/hexane mixtures. M.p. 132 °C.
D ⫽ ⫺148.7 (c ⫽ 1.95, MeOH). H NMR (400.1 MHz, CDCl3):
[α]28 1
The product obtained was purified by column chromatography on
silica gel (CH2Cl2/EtOAc, 3:2) to give a white solid (0.087 g, 43%). δ ⫽ 1.32 (s, 3 H, CH3), 1.39 (s, 3 H, CH3), 3.27 (s, 3 H, OCH3),
M.p. 153 °C. [α]21
D ⫽ ⫺67.2 (c ⫽ 1.75, CHCl3). The assignments of 3.30 (s, 3 H, OCH3), 3.81⫺3.93 (m, 3 H, 2 ⫻ H of CH2 ⫹ CH),
the NMR signals were made by HMBC. 1H NMR (400.1 MHz, 4.44 (d, J ⫽ 9.9 Hz, 6 Hz, 1 H, CH) ppm. 13C NMR (100.6 MHz,
CDCl3): δ ⫽ 1.23 (s, 3 H, CH3), 1.31 (s, 3 H, CH3), 1.67 (br. s, CDCl3): δ ⫽ 17.3 (CH3), 17.4 (CH3), 48.2 (OCH3), 48.6 (OCH3),
OH), 2.49 (br. s, OH), 2.82 (s, 3 H, OCH3), 3.21 (s, 3 H, OCH3), 62.2 (CH2OH), 68.5 (CH), 68.9 (CH), 98.8 (acetal C), 99.5 (acetal
3.90 (dd, J ⫽ 1.6 Hz, 1 H, 10 Hz, 1 H, dioxane CH), 3.94 (m, 2 C), 170.6 (COOH) ppm. IR (KBr): ν̃ ⫽ 3401, 2996, 2959, 2841,
H, 2 ⫻ H of CH2), 4.50 (d, J ⫽ 10 Hz, dioxane CH), 5.13 (m, 1 2685, 1755, 1458, 1405, 1382, 1354, 1336, 1312, 1210, 1130, 1069,
H, CHN), 5.26 (br. s, CHOH), 7.23 (t, J ⫽ 7.2 Hz, 2 H, Ph-H), 1046, 966, 946, 890, 866, 773, 739, 670, 650 cm⫺1. C10H18O7
7.31 (m, 5 H, Ph-H), 7.38 (d, J ⫽ 7.2 Hz, 1 H, CONH), 7.43 (m, (250.25): calcd. C 48.00, H 7.25; found C 48.20, H 7.41.
3 H, Ph-H) ppm. 13C NMR (100.6 MHz, CDCl3, DEPT): δ ⫽ 17.3
(CH3), 17.4 (CH3), 47.9 (OCH3), 48.4 (OCH3), 55.5 (CH, CHPh), (2R,3R,5R,6R)-N-[(S)-2-Hydroxy-1-phenylethyl]-3-(hydroxy-
methyl)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-carboxamide
66.5 (CH2), 69.3 (CH, dioxane CHCON), 72.0 (CH, CHPh(OH),
(17): A two-necked round-bottom flask was charged with acid 16
73.0 (CH, dioxane CH), 98.9 (acetal C), 99.3 (acetal C), 126.4 (2
⫻ CH, Ph), 126.6 (2 ⫻ CH, Ph), 127.0 (CH), 127.8 (2 ⫻ CH, Ph), (0.253 g, 1.00 mmol), (S)-(⫹)-2-amino-2-phenylethanol (0.134 g,
128.1 (CH), 129.0 (2 ⫻ CH, Ph), 138.5 (Cquat, Ph), 141.1 ( Cquat, 0.098 mmol) and xylene (0.32 mL). The resulting suspension was
Ph), 170.0 (CONH) ppm. IR (CHCl3): ν̃ ⫽ 3676, 3412, 3066, 3012, stirred and refluxed under argon for 17 h. The solvent was removed
under reduced pressure and the product was dried to give the crude
2951, 2837, 1668, 1522, 1496, 1454, 1378, 1233, 1197, 1143, 1132,
amide. The assignments of the NMR signals were made by decoup-
1037, 948, 908, 891, 827, 782, 778, 774, 768, 764, 755, 750, 744,
ling. 1H NMR (400.1 MHz, CDCl3): δ ⫽ 1.31 (s, 3 H, CH3), 1.37
738, 702 cm⫺1. C24H31NO7 (445.51): calcd. C 64.70, H 7.01, N
(s, 3 H, CH3), 2.62 (br. s, OH), 3.25 (s, 3 H, OCH3), 3.28 (s, 3 H,
3.14; found C 64.47, H 6.73, N 3.04.
OCH3), 3.71 (s, 1 H, OH), 3.71⫺3.81 (m, 3 H, dioxane CH ⫹
[(2R,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-3-[(S)-4-phenyl-4,5- CH2), 3.89⫺3.93 (m, 2 H, PhCHCH2), 4.30 (d, J ⫽ 9.2 Hz, 1 H,
dihydrooxazol-2-yl)-1,4-dioxan-2-yl]phenylmethanol (15): Amide 14 CHCO), 5.07⫺5.11 (m, 1 H, CHN), 7.21⫺7.33 (m, 5 H, Ph-H),
(0.263 mmol) was dissolved in CH2Cl2 (0.80 mL) and p-toluenesul- 7.54 (d, J ⫽ 7.2 Hz, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3,
fonyl chloride (0.051 g, 0.269 mmol) and dry triethylamine DEPT): δ ⫽ 17.40 (2 ⫻ CH3), 48.1 (OCH3), 48.3 (OCH3), 55.1
(0.18 mL, 5.00 mmol) were added. The mixture was refluxed for (CH), 63.0 (CH2), 65.5 (CH2), 70.1 (CH), 70.9 (CH), 98.7 (Cquat,
17 h and treated as described for oxazolines 6aⴚc. The product acetal C), 99.3 (Cquat, acetal C), 126.5 (2 ⫻ CH, Ph), 127.7 (CH,
was purified by chromatography on silica gel (EtOAc/hexane, 7:3) Ph), 128.7 (2 ⫻ CH, Ph), 138.8 (Cquat, Ph), 169.8 (CONH) ppm.
to give a white solid (0.071 g, 63%). M.p. 47⫺48 °C. [α]22
D ⫽ ⫺129.0 [(2R,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-3-[(S)-4-phenyl-4,5-
(c ⫽ 0.77, CHCl3). The assignments of the NMR signals were made dihydrooxazol-2-yl]-1,4-dioxan-2-yl]methanol (18): Acid 16 (0.253 g,
by COSY and HMBC. 1H NMR (400.1 MHz, CDCl3): δ ⫽ 1.32 1.00 mmol) and (S)-(⫹)-2-amino-2-phenylethanol (0.144 g,
(s, 3 H, CH3), 1.35 (s, 3 H, CH3), 3.07 (s, 3 H, OCH3), 3.31 (s, 3 1.02 mmol) were mixed in decalin (2.98 mL) and refluxed for 94 h
H, OCH3), 4.05 (d, J ⫽ 8 Hz, 1 H, OH, exchanges with D2O), 4.07 with a Dean⫺Stark trap, under argon, using a sand bath kept at
(t, J ⫽ 8.8 Hz, 1 H, CHaHb), 4.30 (dd, J ⫽ 3.2, 9.6 Hz, 1 H, 210 °C. After this time the solvent was removed under reduced
CHCOH), 4.44 (dd, J ⫽ 8.4 Hz, 10 Hz, 1 H, CHaHb), 4.61 (d, J ⫽ pressure to give a crude mixture consisting of oxazoline, starting
10 Hz, 1 H, CH), 4.92 (dd, J ⫽ 2.8, 7.6 Hz, 1 H, CHPhOH), 5.03 material and one unidentified product, with the oxazoline being
(app. t, J ⫽ 10 Hz, 1 H, NCHPh), 7.20 (d, J ⫽ 6.8 Hz, 2 H, Ph- the major component. Refluxing the mixture longer did not im-
H), 7.33 (m, 6 H, Ph-H), 7.42 (d, J ⫽ 7.2 Hz, 2 H, Ph-H) ppm. prove the outcome. The solid was stirred in EtOH with charcoal
13
C NMR (100.6 MHz, CDCl3): δ ⫽ 17.3 (CH3), 17.5 (CH3), 48.01 and filtered through Celite. After column chromatography on silica
(OCH3), 48.3 (OCH3), 65.3 (dioxane CH), 69.2 (CHPhN), 72.5 gel (CHCl3/EtOAc, 1:5) the product was obtained as a pale-yellow
(CHCPh), 72.6 (CHPhOH), 74.6 (CH2), 99.08 (acetal C), 99.09
D ⫽ ⫺107.4 (c ⫽ 0.51, CHCl3). The assign-
solid (0.046 g, 15%). [α]19
(acetal C), 126.7 (2 ⫻ CH, Ph), 127.4 (CH, Ph), 127.8 (CH, Ph), ments of the NMR signals were made by HMBC. 1H NMR
127.9 (CH, Ph), 128.7 (CH, Ph), 140.8 (Cquat, Ph), 141.4 (Cquat, (400.1 MHz, CDCl3): δ ⴝ 1.33 (s, 3 H, Me), 1.39 (s, 3 H, Me), 3.30
Ph), 164.6 (O⫺C⫽N) ppm. IR (KBr): ν̃ ⫽ 3542, 3431, 3087, 3062, (s, 3 H, OMe), 3.35 (s, 3 H, OMe), 3.75 (dd, J ⫽ 4.4, 12.4 Hz, 1
3029, 2993, 2950, 2834, 1668, 1495, 1454, 1377, 1199, 1183, 1142, H, CHaHbOH), 3.82 (dd, J ⫽ 4.8, 12.4 Hz, 1 H, CHaHbOH), 4.16
1128, 1037, 922, 857, 759, 746, 701 cm⫺1. C24H29NO6 (427.50): (m, oxazoline H of CH2 ⫹ dioxane CH), 4.59 (d, J ⫽ 10 Hz, diox-
calcd. C 67.43, H 6.84, N 3.28; found C 67.16, H 6.86, N 3.24. ane CH), 4.70 (dd, J ⫽ 8.8 Hz, 10 Hz, 1 H, oxazoline H of CH2),
5.24 (t, J ⫽ 10 Hz, 1 H, oxazoline NCH), 7.21 (d, J ⫽ 6.8 Hz, 1 H,
(2R,3R,5R,6R)-3-(Hydroxymethyl)-5,6-dimethoxy-5,6-dimethyl-1,4- Ar-H), 7.37⫺7.27 (m, Ar-H) ppm. 13C NMR (100.6 MHz, CDCl3,
dioxane-2-carboxylic Acid (16): Monoalcohol 10 (1.519 g,
DEPT): δ ⫽ 17.4 (CH3), 17.5 (CH3), 48.1 (CH3), 48.4 (CH3), 62.9
4.54 mmol) was dissolved in THF/H2O (40:1, 23.6 mL). The solu-
(CH2OH), 66.0 (CHN), 69.3 (dioxane CH), 69.8 (dioxane CH),
tion was cooled to 0 °C and the pH was adjusted to 1 with HCl (2
74.8 (oxazoline CH2), 98.9 (acetal C), 99.1 (acetal C), 126.5 (2 ⫻
). The mixture was then stirred at this temperature for 30 min, by
CH, Ph), 127.8 (CH, Ph), 128.8 (2 ⫻ CH, Ph), 141.3 (Cquat, Ph),
which time the OBO ester had been fully converted into the acid
165.1 (O⫺C⫽N) ppm. IR (CHCl3): ν̃ ⫽ 3671, 3587, 3406, 3010,
as indicated by a TLC plate. The pH was then raised to 11 with a 2964, 2949, 2837, 1667, 1604, 1495, 1455, 1378, 1232, 1142, 1132,
solution of LiOH (1 ) and the mixture was heated and refluxed
1120, 1036, 924, 890, 869, 700, 664 cm⫺1. C18H25NO6 (351.40):
for 2 h, or until the ester could no longer be detected by TLC. After
calcd. C 61.52, H 7.17, N 3.99; found C 61.51, H 6.97, N 4.18.
cooling, the pH of the solution was adjusted to 1 and the product
was extracted four times with diethyl ether. The sample was dried General Procedure for the Catalyzed Enantioselective Addition of
with anhydrous sodium sulfate and the solvent was removed using Diethylzinc to Benzaldehyde: A Schlenk flask was flame-dried in

1828  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org Eur. J. Org. Chem. 2004, 1820⫺1829
Novel Cyclic 1,2-Diacetals Derived from (2R,3R)-(⫹)-Tartaric Acid FULL PAPER
[13] [13a]
vacuo and filled with argon when cool. The catalyst was added (10 C. Bolm, K. Muñiz-Fernández, A. Seger, G. Raabe, K.
mol %) and then dry distilled toluene (0.96 mL). The solution was Günther, J. Org. Chem. 1998, 63, 7860⫺7867. [13b] W.-P. Deng,
degassed three times by freeze⫺pump⫺thaw, it was returned to an X.-L. Hou, L.-X. Dai, Tetrahedron: Asymmetry 1999, 10,
4689⫺4693. [13c] W. Zhang, H. Yoshinaga, Y. Imai, T. Kida, Y.
argon line and the flask was refilled with argon. The solution was
Nakatsuji, I. Ikeda, Synlett 2000, 10, 1512⫺1514.
cooled to 0 °C and a solution of diethylzinc in hexane (2.16 mL, [14]
D. Seebach, A. Pichota, A. K. Beck, A. B. Pinkerton, T. Litz,
1.0 , 2.2 equiv.) was added dropwise. The mixture was stirred for J. Karjalainen, V. Gramlich, Org. Lett. 1999, 1, 55⫺58.
10 min and freshly distilled benzaldehyde (0.100 mL, 0.984 mmol) [15]
M. T. Barros, A. J. Burke, C. D. Maycock, Tetrahedron Lett.
was added dropwise. The flask was then closed, placed in a covered 1999, 40, 1583⫺1586.
[16]
bath at the temperature required, and stirred for the period indi- For a related method used in the synthesis of 2,3-O-isopro-
cated in each experiment. Afterwards 1  HCl solution was added pylidene see: J. A. Musich, H. Rapoport, J. Am. Chem. Soc.
dropwise, the product was extracted with CH2Cl2, dried with anhy- 1978, 100, 4865⫺4872.
[17]
drous MgSO4 and the solvent removed using a rotary evaporator. D. A. Seebach, E. Devaquet, A. Ernst, M. Hayakawa, F. N.
M. Kühnle, W. B. Schweizer, B. Weber, Helv. Chim. Acta 1995,
Determination of Enantiomeric Excesses: HPLC analysis on a chiral 78, 1636⫺1650.
[18]
column was used under the following conditions: column, Daicel See, for instance, ref.[11]
[19] [19a]
For examples in which this route was applied to the synth-
Co. CHIRALCEL OB-H; eluent, hexane/2-propanol 85.5:1.5;
eses of oxazolines, see: C. Giordano, S. Caviocchioli, S. Levi,
flow-rate, 0.9 mL/min; detection, 254 nm. Under these conditions M. Villa, Tetrahedron Lett. 1988, 29, 5561⫺5564. [19b] M. Peer,
racemic 1-phenyl-1-propanol exhibited baseline separation of J. C. De Jong, M. Kiefer, T. Langer, H. Rieck, H. Schell, P.
peaks: (S) isomer tR 13 min, (R) isomer tR 16 min.[29] Peaks were Sennhenn, J. Sprinz, H. Steinhagen, B. Wiese, G. Helmchen,
assigned on the basis of the known order of elution of the enanti- Tetrahedron 1996, 52, 7547⫺7583.
[20] [20a]
omers on this column. For quantitative determinations, racemic 1- E. J. Corey, N. Raju, Tetrahedron Lett. 1983, 24,
phenylethanol was used as internal standard. 5571⫺5574. [20b] H. Kunz, H. Walman, in Comprehensive Or-
ganic Synthesis (Eds.: B. M. Trost, I. Fleming, L. A. Paquette),
Pergamon Press, 1991, vol. III, p. 673.
[21]
See, for example: D. Haag, H.-D. Scharf, J. Org. Chem. 1996,
Acknowledgments 61, 6127⫺6135.
[22]
The financial support given by Fundação para a Ciência e Tecnolo- E. J. Leopold, Org. Synth. Coll. Vol. VII, John Wiley & Sons,
gia to A. M. F. P. is gratefully acknowledged. New York, 1990, p. 258⫺263.
[23]
An attempt was made to determine the configuration of the
newly created chiral centre by Mosher⬘s method, but this was
[1]
S. V. Ley, D. K. Baeschlin, D. J. Dixon, A. C. Foster, S. J. Ince, unsuccessful. The determination will be attempted at a later
H. W. M. Priepke, D. J. Reynolds, Chem. Rev. 2001, 101, stage when more material is available.
[24]
53⫺80. For examples of OBO ester removal by treatment with acid
[2]
D. Seebach, A. K. Beck, A. Heckel, Angew. Chem. Int. Ed. followed by base to remove the intermediately formed ester see,
2001, 40, 92⫺138. for example: [24a] M. P. Atkins, B. T. Golding, D. A. Howes, P.
[3]
M. T. Barros, A. J. Burke, C. D. Maycock, C. R. Santos, Tenth J. Sellars, J. Chem. Soc., Chem. Commun. 1980, 207⫺208. [24b]
IUPAC symposium on organometallic chemistry directed towards E. J. Corey, B. De, J. Am. Chem. Soc. 1983, 105, 1662.
[25]
organic synthesis, Versailles, 1999. See, for example: R. Noyori, M. Kitamura, Angew. Chem. Int.
[4]
U. Berens, R. Selke, Tetrahedron: Asymmetry 1996, 7, Ed. Engl. 1991, 30, 49⫺69.
2055⫺2064. [26]
The result at 0 °C was obtained after a reaction time of 42 h.
[5] [27]
W. Li, J. P. Waldkirk, X. Zhang, J. Org. Chem. 2002, 67, J.-L. Montchamp, F. Tian, M. E. Hart, J. W. Frost, J. Org.
7618⫺7623. Chem. 1996, 61, 3897⫺3899.
[6] [28]
D. Haag, J. Runsink, H. D. Scharf, Organometallics 1998, 17, The OBO esters prepared in this study were very sensitive to
398⫺409. acid. For example, treated silica gel was necessary in all cases
[7]
K. Muñiz, C. Bolm, Chem. Eur. J. 2000, 6, 2309⫺2316. and samples for NMR spectroscopy were prepared routinely
[8]
J. G. De Vries, A. H. M. De Vries, Eur. J. Org. Chem. 2003, just prior to recording spectra, because it was found that the
799⫺811. OBO ester rearranged easily to an ester if left standing in
[9]
N. Oguni, T. Omi, Tetrahedron Lett. 1984, 25, 2823⫺2824. CDCl3 solution for prolonged periods. Similar findings have
[10]
L. Pu, H.-B. Yu, Chem. Rev. 2001, 101, 757⫺824. been reported by others, i.e.: M. A. Blaskovich, G. A. Lajoie,
[11]
J. V. Allen, J. M. J. Williams, Tetrahedron: Asymmetry 1994, J. Am. Chem. Soc. 1993, 115, 5021⫺5030.
[29]
5, 277⫺282. M. Kitamura, H. Oka, S. Suga, R. Noyori, Org. Synth. 2001,
[12]
E. Macedo, C. Moberg, Tetrahedron: Asymmetry 1995, 6, 79, 139⫺145.
549⫺558. Received November 28, 2003

Eur. J. Org. Chem. 2004, 1820⫺1829 www.eurjoc.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1829