Highly stereoselective synthesis of stereochemically defined polyhydroxylated propargylamines by alkynylation of N-benzylimines derived from (R)-glyceraldehyde

Article abstract of DOI:10.1002/ejoc.200601011

The addition of the lithium derivative of tert-butyldimethylsilyl propargyl ether to N-benzylimines derived from (R)-2,3-O-isopropylideneglyceraldehyde has been achieved with acceptable yields and high diastereoselectivities. The syn/anti diastereoselectivity of the addition reaction can be controlled and reversed by the appropriate use of Lewis acids as inline precomplexing agents. Double stereodifferentiation processes using imines derived from (R)-2,3-O-isopropylideneglyceraldehyde and (R)- or (S)-α-methylbenzylamine as starting materials occur with total stereocontrol to afford syn and anti vic-propargylamino alcohol derivatives with orthogonally protected hydroxymethyl groups on both sides of the central core. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200601011

FULL PAPER
DOI: 10.1002/ejoc.200601011
Highly Stereoselective Synthesis of Stereochemically Defined Polyhydroxylated
Propargylamines by Alkynylation of N-Benzylimines Derived from
(R)-Glyceraldehyde
Roberto Díez,[a] Ramón Badorrey,[a] María D. Díaz-de-Villegas,*[a] and José A. Gálvez*[a]
Keywords: Amino alcohols / Asymmetric synthesis / Diastereoselectivity / Schiff bases / Nucleophilic addition
The addition of the lithium derivative of tert-butyldimethylsi-
lyl propargyl ether to N-benzylimines derived from (R)-2,3-
O-isopropylideneglyceraldehyde has been achieved with ac-
ceptable yields and high diastereoselectivities. The syn/anti
diastereoselectivity of the addition reaction can be controlled
and reversed by the appropriate use of Lewis acids as imine
precomplexing agents. Double stereodifferentiation pro-
lyceraldehyde and (R)- or (S)-α-methylbenzylamine as start-
ing materials occur with total stereocontrol to afford syn and
anti vic-propargylamino alcohol derivatives with orthogo-
nally protected hydroxymethyl groups on both sides of the
central core.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
cesses using imines derived from (R)-2,3-O-isopropylideneg- Germany, 2007)
odologies to produce vicinal amino alcohols and their de-
Introduction
rivatives have been developed in recent years.[6] Among
them, the asymmetric addition of organometallic reagents
to C=N bonds in chiral protected α-hydroxyimines is one
of the most attractive and direct approaches affording these
substructures.[7] Surprisingly, the extension of this method-
ology to the use of organometallic reagents derived from
terminal alkynes for the synthesis of enantiomerically pure
vicinal propargylamino alcohol derivatives, an interesting
class of compounds thanks to their potential in synthesis,[8]
has hardly been developed. Indeed, to the best of our
knowledge, there are only four reports on stereoselective ad-
ditions of alkynylmetallics to protected chiral α-hydroxy
imines. Martin and co-workers[9] reported the addition of
trimethylsilylethynylmagnesium bromide to an imine de-
rived from -sorbose to give the syn product with total dia-
stereoselectivity, whilst Evans et al.[10] described the exclus-
ive formation of the anti diastereoisomer in the nucleophilic
addition of 3,3-diethoxy-1-lithiopropyne to a cyclic imine
derived from -ribitol. More recently, Trost et al.[11] re-
ported the reaction between an N-allylimine derived from
(R)-glyceraldehyde and an alkynyllithium trimethylalumi-
nate, giving the corresponding amino alcohol derivative of
anti configuration with high diastereoselectivity. This com-
pound has been used as a key intermediate in the stereose-
lective synthesis of the lipophilic antibiotic (+)-streptazolin.
Shimizu and co-workers[12] have described the reaction be-
tween an imine derived from meso-tartaric acid and lithium
trimethylsilylacetylide to give either the syn product – albeit
in a low yield (17%) – when the reaction was conducted in
the presence of BF3·Et2O, or the anti product in 55% yield.
Finally, during the preparation of this manuscript Díez and
Optically active α-substituted propargylamine units are
present in a variety of biologically active compounds[1] and
are versatile building blocks and intermediates for a large
number of synthetic applications.[2] In general, synthetic
routes that provide reliable and convenient access to this
scaffold in enantiomerically pure form are still scarce,[3] and
of these, nucleophilic addition of alkynylides to chiral im-
ines or related carbonyl derivatives is often the method of
choice for the asymmetric synthesis of α-substituted pro-
pargylamines.[4] Recently, catalytic enantioselective pro-
cedures have emerged as a very appealing alternative to the
asymmetric synthesis of these compounds.[5] Such addition
reactions are intrinsically efficient because a new ste-
reogenic centre and a new C–C bond are created in a single
operation.
Enantiomerically pure vicinal amino alcohol derivatives
represent another interesting family of nitrogenated com-
pounds as they play an important role in synthetic and me-
dicinal chemistry.[6] 1,2-Amino alcohols are widely used as
chiral auxiliaries and metal ligands in catalytic asymmetric
synthesis and they are crucial structural features in a large
number of natural products and synthetic compounds of
pharmacological interest. As a result of their synthetic sig-
nificance, quite a number of stereoselective synthetic meth-
[a] Departamento de Química Orgánica, Instituto de Ciencia de
Materiales de Aragón, Instituto Universitario de Catálisis
Homogénea, Universidad de Zaragoza-CSIC,
50009 Zaragoza, Spain
Fax: +34-976761202
E-mail: loladiaz@unizar.es
jagl@unizar.es
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Synthesis of Polyhydroxylated Propargylamines
FULL PAPER
co-workers[13] reported that the addition of the lithium Ketalisation of -mannitol was performed by the procedure
anion of tetrahydro-2-(2-propynyloxy)-2H-pyran to imine reported by Priestley,[16] which employed catalytic SnCl2
1a takes place with acceptable levels of diastereoselectivity and 2,2-dimethoxypropane, whilst the oxidative cleavage of
in the presence of cerium trichloride.
1,2:5,6-di-O-isopropylidene--mannitol was carried out
In recent years we have been investigating reactions be- with NaIO4 as reported by Schmid.[17]
tween conveniently protected N-benzylimines derived from
Reactivity between the chiral imine 1a and 3-(tert-butyl-
(R)-glyceraldehyde and methyl, benzyl, allyl, vinyl and aryl dimethylsilyloxy)prop-1-ynylmagnesium bromide, generated
organometallic reagents, mainly Grignard-type organome- in situ from tert-butyldimethylsilyl propargyl ether and eth-
tallics. With all these reagents we have obtained the corre- ylmagnesium bromide, was investigated first. This reaction
sponding chiral amino alcohol derivatives in good yields was not effective, however, with a complex reaction mixture
and with total diastereoselectivity.[14] In some cases we have being obtained after the starting imine had been consumed.
even been able to develop efficient stereodivergent synthe- On the other hand, the reaction between chiral imine
ses, either (i) by changing the 1,2-dihydroxy protecting 1a and 3-(tert-butyldimethylsilyloxy)prop-1-ynyllithium
groups in the starting imine,[14a,14d] or (ii) by choosing ap- (1 equiv.), generated in situ by deprotonation of the ter-
propriate organometallic species with which to carry out minal alkyne with butyllithium[18] at –30 °C, afforded the
the chemical process.[14b] The resulting syn or anti vicinal desired vicinal propargylamino alcohol derivative 2a as an
amino alcohol derivatives are versatile synthetic intermedi- 80:20 syn/anti mixture of diastereoisomers, though in very
ates and we have used them in asymmetric syntheses of sev- low yield. The effects of the amount of reagent, tempera-
eral classes of biologically active molecules.[14,15] In this pa- ture, solvent and Lewis acid were subsequently explored
per we wish to disclose our results on the diasteeoselective and the results are summarised in Table 1.
alkynylation of N-benzylimines derived from (R)-2,3-O-iso-
In general, long reaction times were required to provide
propylideneglyceraldehyde with 3-(tert-butyldimethylsilyl- complete conversion of the starting imine and, after con-
oxy)prop-1-ynyllithium in the presence or absence of a siderable experimentation, we observed that in the absence
Lewis acid to afford syn and anti vicinal propargylamino of Lewis acids the optimal yield (50%) and diastereoselec-
alcohol derivatives, respectively, with orthogonally pro- tivity (syn/anti 91:9) were obtained when the imine was
tected hydroxymethyl groups on both sides of the central added at –30 °C to an excess of 3-(tert-butyldimethylsilyl-
core (Scheme 1). These compounds can be regarded as use- oxy)prop-1-ynyllithium (2 equiv.) in dry ether. Other reac-
ful new building blocks as they have five possible points for tion conditions such as the use of 1 or 3 equiv. of the orga-
further derivatisation: three hydroxy groups at C1, C2 and nometallic reagent, a decrease or an increase in the reaction
C6, one amino group at C3 and one CϵC triple bond.
temperature, or the use of toluene or THF as the solvent
usually decreased the reaction yield and did not increase
(or even reduced) the stereoselection.
The stereochemical outcome of the addition reaction was
shown to be dependent on the presence or absence of Lewis
acids as precomplexing agents and the ability of these sys-
tems to form chelates.[19] Consequently, amino alcohol syn-
2a was obtained preferentially in the absence of Lewis acid
(Table 1, Entries 1–9) or with use of diethylaluminium chlo-
ride as a precomplexing agent (Table 1, Entry 11). In con-
trast, the addition reaction in the presence of boron trifluo-
ride–diethyl ether resulted in the formation of anti-2a as the
major compound (Table 1, Entry 13). Moreover, the reac-
tion was found to depend on the order of addition of rea-
gents, such that when the imine was added to a mixture
of the organollithium reagent and boron trifluoride diethyl
etherate the addition was not diastereoselective and the
yield was very poor (Table 1, Entry 14). Separation of the
syn and anti isomers was easily effected by flash chromatog-
raphy.
The stereochemistry of the compound obtained in the
absence of Lewis acid or with use of diethylaluminium chlo-
ride as a precomplexing agent presumably arises as a result
of chelation control and can be explained by considering α-
chelate A (see Figure 1).
Scheme 1. Diastereoselective addition of alkynylmetallics to chiral
imines 1a–c.
Results and Discussion
In this chelate the metal (Li or Al) coordinates with the
The N-benzylimine derived from (R)-2,3-O-isopropylid- nitrogen of the imine group and the adjacent oxygen to
eneglyceraldehyde (1a) was easily prepared on a multigram form a five-membered ring intermediate. The nucleophile
scale from inexpensive -mannitol in a three-step process. then preferentially approaches anti to the large dioxolane
Eur. J. Org. Chem. 2007, 2114–2120
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R. Díez, R. Badorrey, M. D. Díaz-de-Villegas, J. A. Gálvez
FULL PAPER
Table 1. Diastereoselective addition of TBSOCH2CϵCLi to chiral imines 1a–c.
Entry
Imine
OM (equiv.) Lewis acid (equiv.)
T (°C)
–30
–30
–30
20
Solvent
Product
Yield (%)[a]
syn/anti[b]
[c]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1b
1c
1b
1c
1
2
4
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
–
–
–
–
–
–
–
–
–
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
toluene
THF
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
2a
2a
2a
2a
2a
2a
2a
2a
2a
20
50
40
44
40
42
38
36
40
–
40
–
55
18
–
80:20
91:9
88:12
75:25
81:19
79:21
90:10
68:32
74:26
–
91:9
–
12:88
50:50
–
[c]
[c]
[c]
[c]
[c]
[c]
[c]
[c]
0
–20
–40
–30
–30
–30
–30
–30
–30
–30
–30
–30
–30
–30
–30
–30
9
[f]
10
11
12
13
14
15
16
17
18
19
20
Et2AlCl (1)[d]
Et2AlCl (2)[d]
BF3·OEt2 (1)[d]
BF3·OEt2 (2)[d]
BF3·OEt2 (2)[e]
–
2a
[f]
–
2a
2a
[c]
[g]
–
–
[c]
[g]
–
–
–
–
–
80
65
–
–
–
Et2AlCl (2)[d]
Et2AlCl (2)[d]
BF3·OEt2 (2)[d]
BF3·OEt2 (2)[d]
–
[g]
[g]
–
2b
2c
Ͼ2:98
15:85
[a] Diastereomeric mixture, isolated yield after column chromatography. [b] The crude reaction mixture was directly analysed by 1H NMR
spectroscopy and the diastereomeric ratio was determined from the relative intensities of characteristic protons. [c] The reaction was
carried out by addition of the imine to TBSOCH2CϵCLi. [d] The reaction was carried out by addition of TBSOCH2CϵCLi to the
precomplexed imine. [e] Imine was added to a mixture of TBSOCH2CϵCLi and BF3·OEt2. [f] Complex reaction mixture. [g] No reaction,
even at room temperature.
(mismatched pair). Thus, treatment of boron trifluoride-
precomplexed imines 1b and 1c with the alkynyllithium pro-
duced compounds of anti relative configuration with com-
plete stereocontrol when imine 1b was the starting material.
On the other hand, an 85:15 mixture of compounds anti-
2c/syn-2c was obtained from imine 1c. The α-(S,S) combi-
nation was therefore the matched pair for this process, while
the α-(S,R) combination was the mismatched pair.
The assignment of the absolute configuration of the
Figure 1. Stereocorrelation models for the addition of alkynylmet-
newly formed stereogenic carbon in the addition reactions
was achieved by conversion of compounds anti-2a, anti-2b
and anti-2c into known (S)-glutamic acid, as shown in
Scheme 2.
allics to imines 1a–c.
substituent, giving rise to the observed syn major product.
In the presence of boron trifluoride, Felkin–Anh-type inter-
mediate B could account for the observed stereochemistry.
In order to achieve complete diastereoselectivity in the
nucleophilic addition, a double stereodifferentiation strat-
egy[20] was considered. In this approach, imines 1b and 1c
were prepared from (R)-isopropylideneglyceraldehyde and
(S)- or (R)-1-phenylethylamine, respectively (Scheme 1),
and their reactivities with 3-(tert-butyldimethylsilyloxy)-
prop-1-ynyllithium were assessed. Imines 1b and 1c did not
react with the lithium acetylide in the absence of Lewis acid
or in the presence of diethylaluminium chloride either at
low temperature or at room temperature. Precomplexation
of imines 1b and 1c with boron trifluoride proved to be
effective, however,[21] and compounds 2b and 2c were iso-
lated after addition of the lithium acetylide in acceptable
yields. The stereochemical course of these reactions was
mainly controlled by the α-stereogenic centre in the car-
bonyl moiety (1,2-asymmetric induction) and the Lewis
acid, while the stereogenic centre in the amine moiety (1,3-
Removal of the N-benzyl protecting groups with con-
comitant reduction of the CϵC triple bond was easily per-
formed by hydrogenation of the corresponding compound
anti-2a–c at atmospheric pressure in a methanolic solution
and in the presence of Pd/C as the catalyst, to afford com-
pound 3 in 87, 85 and 78% yields, respectively. Subsequent
conversion of compound 3 into the corresponding N-ben-
zyloxycarbonyl derivative was smoothly achieved by treat-
ment with benzyl chloroformate in the presence of diisopro-
pylethylamine to give compound 4 in 86% yield. Treatment
of 4 with trifluoroacetic acid resulted in hydrolysis of both
the ketal and the trialkylsilyloxy groups, and triol 5 was
obtained in 95% yield. Finally, oxidative cleavage of the
1,2-diol moiety by treatment with excess sodium periodate
and subsequent oxidation of the crude α-amino-δ-hydroxy-
aldehyde intermediate with sodium dichromate in aqueous
sulfuric acid (Jones’ reagent) gave Cbz-glutamic acid, which
was hydrogenated without purification in the presence of
asymmetric induction) modulated the diastereoselectivity of Pd/C as a catalyst to afford enantiomerically pure (S)-glu-
the process either upwards (matched pair) or downwards tamic acid 6 in an overall yield of 80% from 5. Compound
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Synthesis of Polyhydroxylated Propargylamines
FULL PAPER
Experimental Section
General Remarks: All manipulations with air-sensitive reagents
were carried out under dry argon by use of standard Schlenk tech-
niques. Whenever possible the reactions were monitored by TLC.
TLC was performed on precoated silica gel polyester plates and
products were viewed by use of UV light (254 nm) and anisal-
dehyde/sulfuric acid/ethanol (2:1:100). Column chromatography
was performed on silica gel (Kieselgel 60). Melting points were de-
termined in open capillaries with a Büchi capillary melting point
apparatus and are not corrected. HPLC was performed with a
Waters HPLC system consisting of a Waters 600-E pump with a
Waters 991 photodiode array detector; analytical resolutions were
carried out on a 250ϫ4.6 mm Chirobiotic T 5 µm column. NMR
spectra were recorded with Bruker ARX 300 or Bruker AV 400 in-
struments operating at 300 or 400 MHz for 1H NMR and 75 or
100 MHz for 13C NMR with a 5 mm probe. All chemical shifts are
relative to deuterated solvent signals, δ in ppm, J in Hz. The follow-
ing abbreviations are used: s, singlet; d, doublet; t, triplet; m, mul-
tiplet; brs, broad singlet; brd, broad doublet; dd, doublet of dou-
blets. Optical rotations were measured with a Jasco 1020 polarime-
ter at 20 °C with concentrations given in g/100 mL. High-Resolu-
tion Mass Spectra (HRMS) were recorded on a VG-autospec in-
strument. Elemental analyses were performed with a Perkin–
Elmer 200 CHNS elemental analyser.
Scheme 2. Conversion of compounds anti-2a–c into (S)-glutamic
acid.
Starting Materials: Chemicals for reactions were used as purchased
from commercial sources. 1,2:5,6-Di-O-isopropylidene--manni-
tol,[16] (R)-2,3-O-isopropylideneglyceraldehyde[17] and 3-(tert-butyl-
dimethylsilyloxy)-1-propyne[24] were prepared by literature pro-
cedures. Chiral imines 1a–c were obtained by a previously described
procedure for the synthesis of 1a[25] and used immediately.
6 was found to be identical with an authentic sample of (S)-
glutamic acid upon comparison of their spectroscopic data
and specific rotations,[22] which enabled the unambiguous
assignment of the configurations of compounds 2a–c. The
enantiomeric purity of compound 6 was determined by chi-
ral HPLC (Ͼ99:1), with use of rac-glutamic acid as the ref-
erence.[23] Amino acid 6 was detected as a single peak,
showing that racemisation had not occurred to any appreci-
able extent during the reaction sequence.
1
Compound 1a: H NMR (CDCl3, 400 MHz, 25 °C): δ = 1.43 (s, 3
H), 1.50 (s, 3 H), 3.99 (dd, J = 8.5, 6.2 Hz, 1 H), 4.23 (dd, J = 8.5,
6.8 Hz, 1 H), 4.64 (brs, 2 H), 4.64–4.68 (m, 1 H), 7.27–7.30 (m, 3
H), 7.34–7.40 (m, 2 H), 7.79 (dt, J = 5.0, 1.4 Hz, 1 H) ppm. 13C
NMR (CDCl3, 100 MHz, 25 °C): δ = 25.4, 25.5, 64.6, 67.4, 77.0,
110.2, 127.1, 127.9, 128.5, 138.3, 164.1 ppm.
1
Compound 1b: H NMR (CDCl3, 400 MHz, 25 °C): δ = 1.41 (s, 3
H), 1.47 (s, 3 H), 1.51 (d, J = 6.7 Hz, 3 H), 4.00 (dd, J = 8.4,
6.2 Hz, 1 H), 4.24 (dd, J = 8.4, 6.8 Hz, 1 H), 4.39 (q, J = 6.7 Hz,
1 H), 4.64 (ddd, J = 6.8, 6.2, 5.0 Hz, 1 H), 7.32–7.38 (m, 5 H), 7.75
(dd, J = 5.0, 0.6 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 MHz,
25 °C): δ = 24.3, 25.4, 26.5, 67.4, 69.3, 76.9, 110.2, 126.5, 127.0,
128.4, 144.0, 161.7 ppm.
Conclusions
In summary, we have shown that the syn and anti isomers
of propargylamine 2a can be obtained with high diastereo-
selectivity from the same starting material – N-benzylimine
1a, derived from (R)-2,3-O-isopropylideneglyceraldehyde –
by nucleophilic addition of LiCϵCCH2OTBS in the pres-
ence or absence of the appropriate Lewis acid. A double
stereodifferentiation process using boron-precomplexed N-
1
Compound 1c: H NMR (CDCl3, 400 MHz, 25 °C): δ = 1.42 (s, 3
H), 1.46 (s, 3 H), 1.53 (d, J = 6.6 Hz, 3 H), 3.90 (dd, J = 8.5,
6.3 Hz, 1 H), 4.20 (dd, J = 8.5, 6.8 Hz, 1 H), 4.39 (q, J = 6.6 Hz,
1 H), 4.65 (ddd, J = 6.8, 6.3, 5.2 Hz, 1 H), 7.30–7.38 (m, 5 H), 7.74
(dd, J = 5.2, 0.6 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 MHz,
25 °C): δ = 24.4, 25.4, 26.5, 67.4, 69.4, 77.1, 110.2, 126.5, 127.0,
(R)-α-methylbenzylimine 1b provided enantiomerically pure 128.5, 144.2, 161.7 ppm.
anti propargylamino alcohol derivative 2b with total dia-
General Procedures for the Addition of Alkynylmetallics to Chiral
Imines 1a–c
stereoselectivity. These compounds can be regarded as
multifunctional key intermediates for further derivatisation
since they possess an amino group, an ethynyl group and
several selectively protected hydroxy groups as substituents.
These groups can be easily transformed into a variety of
different functional groups. In particular, these compounds
could be useful as building blocks for the preparation of a
wide variety of biologically active compounds; research in
this area is underway and will be reported in due course.
Procedure A: A solution of butyllithium in hexanes (1 , 2 mL,
2 mmol) was slowly added at –78 °C under argon to a solution
of 3-(tert-butyldimethylsilyloxy)prop-1-yne (342 mg, 2 mmol) in the
corresponding dry solvent (2 mL). After having been stirred for 1 h
at –78 °C the solution was warmed to the desired temperature, a
solution of the corresponding chiral imine 1 (1 mmol) in the same
dry solvent (3 mL) was added dropwise, and stirring was continued
for 72 h at the same temperature. The reaction mixture was then
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R. Díez, R. Badorrey, M. D. Díaz-de-Villegas, J. A. Gálvez
FULL PAPER
treated with saturated aqueous NH4Cl (10 mL), the organic phase
was separated, and the aqueous layer was extracted with diethyl
ether (3ϫ10 mL). The combined organic layers were dried with
anhydrous MgSO4, filtered and concentrated to give an oily resi-
due, which was purified by silica gel column chromatography.
300 MHz, 25 °C): δ = 0.10 (s, 6 H), 0.89 (s, 9 H), 1.29 (d, J =
6.5 Hz, 3 H), 1.32 (s, 3 H), 1.43 (s, 3 H), 1.64 (brs, 1 H), 3.56 (dt,
J = 5.0, 1.7 Hz, 1 H), 3.97 (dd, J = 8.3, 6.5 Hz, 1 H), 4.03 (dd, J
= 8.3, 6.3 Hz, 1 H), 4.07–4.17 (m, 2 H), 4.31 (d, J = 1.7 Hz, 2 H),
7.18–7.38 (m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz, 25 °C): δ =
–5.1, 18.3, 22.2, 25.4, 25.8, 26.5, 50.5, 51.8, 55.1, 67.1, 77.6, 82.7,
Procedure B: A solution of butyllithium in hexanes (1 , 2 mL,
2 mmol) was slowly added at –78 °C under argon to a solution
of 3-(tert-butyldimethylsilyloxy)-1-propyne (342 mg, 2 mmol) in the
corresponding dry solvent (2 mL) and stirring was continued for
1 h at the same temperature. A solution of chiral imine 1 (1 mmol)
in dry diethyl ether (2 mL) was added under argon to a solution of
the corresponding Lewis acid (2 mmol) in dry diethyl ether. After
having been stirred for 5 min at room temperature, the solution was
cooled to –30 °C. An ethereal solution of 3-(tert-butyldimethylsily-
loxy)prop-1-ynyllithium (2 mmol), obtained as described above,
was slowly added and the reaction mixture was stirred for 24 h at
–30 °C. The reaction mixture was treated with saturated aqueous
NH4Cl (10 mL), the organic phase was separated, and the aqueous
layer was extracted with diethyl ether (3ϫ10 mL). The combined
organic layers were dried with anhydrous MgSO4, filtered and con-
centrated to give an oily residue, which was purified by silica gel
column chromatography.
83.4, 109.7, 126.8, 127.1, 128.4, 145.8 ppm. IR (neat): ν =
˜
3405 cm–1. HRMS (FAB) for C23H38NO3Si [M + H]+: calcd.
404.2620; found: 404.2612.
Compound anti-2c: Treatment of imine 1c (500 mg, 2.15 mmol),
precomplexed with BF3·OEt2 (4.30 mmol), with 3-(tert-butyldi-
methylsilyloxy)prop-1-ynyllithium (4.30 mmol) as described in Pro-
cedure B yielded compound 2c as a 15:85 mixture of syn/anti dia-
stereoisomers, from which the major compound anti-2c (oil,
449 mg, 52 %) was isolated by silica gel column chromatography
(eluent: diethyl ether/hexane, 1:3). [α]2D0 = –25.20 (c = 1.0 in CHCl3).
1H NMR (CDCl3, 300 MHz, 25 °C): δ = 0.12 (s, 6 H), 0.91 (s, 9
H), 1.33 (d, J = 6.4 Hz, 3 H), 1.33 (s, 3 H), 1.39 (s, 3 H), 1.85 (brs,
1 H), 3.07 (dt, J = 4.5, 1.5 Hz, 1 H), 3.78 (dd, J = 8.2, 7.0 Hz, 1
H), 3.97 (dd, J = 8.2, 6.5 Hz, 1 H), 4.07–4.17 (m, 2 H), 4.36 (d, J =
1.5 Hz, 2 H), 7.18–7.38 (m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz,
25 °C): δ = –5.1, 18.2, 24.9, 25.4, 25.7, 26.3, 50.4, 51.6, 55.4, 67.1,
77.9, 82.9, 83.4, 109.4, 126.4, 127.0, 128.3, 144.5 ppm. IR (neat): ν
˜
Compound syn-2a: Treatment of imine 1a (1.5 g, 6.85 mmol) with
3-(tert-butyldimethylsilyloxy)prop-1-ynyllithium (13.70 mmol) as
described in Procedure A yielded compound 2a as a 91:9 mixture
of syn/anti diastereoisomers, from which the major compound syn-
2a (oil, 1.17 g, 44%) was isolated by silica gel column chromatog-
raphy (eluent: diethyl ether/hexane, 1:2). [α]2D0 = –51.20 (c = 1.0 in
CHCl3). 1H NMR (CDCl3, 400 MHz, 25 °C): δ = 0.01 (s, 6 H),
0.80 (s, 9 H), 1.19 (s, 3 H), 1.20 (s, 3 H), 1.79 (brs, 1 H), 3.30 (dt,
J = 7.4, 1.5 Hz, 1 H), 3.69 (d, J = 13.5 Hz, 1 H), 3.79 (dd, J = 8.4,
5.7 Hz, 1 H), 3.92 (dd, J = 8.4, 6.1 Hz, 1 H), 3.92 (d, J = 13.5 Hz,
1 H), 4.04 (ddd, J = 7.4, 6.1, 5.7 Hz, 1 H), 4.22 (d, J = 1.5 Hz, 2
H), 7.09–7.24 (m, 5 H) ppm. 13C NMR (CDCl3, 100 MHz, 25 °C):
δ = –5.3, 18.0, 25.2, 25.6, 26.5, 50.9, 51.5, 53.2, 66.8, 77.7, 82.2,
= 3340 cm–1. HRMS (FAB) for C23H38NO3Si [M + H]+: calcd.
404.2620; found: 404.2628.
Representative Procedure for the Synthesis of Compound 3: Pd/C
(10%, 150 mg) was added to a solution of compound anti-2a (1 g,
2.57 mmol) in absolute ethanol (15 mL) and the mixture was hydro-
genated at atmospheric pressure with stirring at room temperature
for 12 h. After completion of the reaction the catalyst was removed
by filtration and the filtrate was concentrated to dryness. The re-
sulting crude material was purified by silica gel column chromatog-
raphy (eluent: ethyl acetate/hexane, 6:1) to afford compound 3 (oil,
677 mg, 87% yield). [α]2D0 = –4.10 (c = 1.0 in CHCl3). 1H NMR
(CDCl3, 300 MHz, 25 °C): δ = 0.00 (s, 6 H), 0.85 (s, 9 H), 1.12–
1.22 (m, 1 H), 1.31 (s, 3 H), 1.38 (s, 3 H), 1.40 (brs, 2 H), 1.42–
1.70 (m, 3 H), 2.86–2.95 (m, 1 H), 3.59 (t, J = 6.0 Hz, 2 H), 3.75–
3.85 (m, 1 H), 3.91–4.01 (m, 2 H) ppm. 13C NMR (CDCl3,
75 MHz, 25 °C): δ = –5.3, 18.3, 25.2, 25.9, 26.5, 29.4, 30.1, 52.3,
83.4, 109.7, 126.8, 128.1, 128.1, 139.4 ppm. IR (neat): ν =
˜
3331 cm–1. HRMS (FAB) for C22H36NO3Si [M + H]+: calcd.
390.2464; found: 390.2475.
Compound anti-2a: Treatment of imine 1a (500 mg, 2.28 mmol) pre-
complexed with BF3·OEt2 (4.56 mmol) with 3-(tert-butyldimethyl-
silyloxy)prop-1-ynyllithium (4.56 mmol) as described in Pro-
cedure B yielded compound 2a as a 12:88 mixture of syn/anti dia-
stereoisomers, from which the major compound anti-2a (oil,
399 mg, 45%) was isolated by silica gel column chromatography
(eluent: diethyl ether/hexane, 1:2). [α]2D0 = +64.45 (c = 1.0 in
CHCl3). 1H NMR (CDCl3, 400 MHz, 25 °C): δ = 0.12 (s, 6 H),
0.91 (s, 9 H), 1.33 (s, 3 H), 1.42 (s, 3 H), 1.86 (brs, 1 H), 3.47 (dt,
J = 4.7, 1.7 Hz, 1 H), 3.80 (d, J = 13.1 Hz, 1 H), 3.96 (dd, J = 8.2,
6.7 Hz, 1 H), 4.03 (dd, J = 8.2, 6.5 Hz, 1 H), 4.04 (d, J = 13.1 Hz,
1 H), 4.18 (ddd, J = 6.7, 6.5, 4.7 Hz, 1 H), 4.37 (d, J = 1.7 Hz, 2
H), 7.19–7.39 (m, 5 H) ppm. 13C NMR (CDCl3, 100 MHz, 25 °C):
δ = –5.2, 18.1, 25.3, 25.7, 26.4, 51.2, 51.6, 51.7, 66.7, 77.6, 82.5,
63.0, 65.2, 79.4, 108.8 ppm. IR (neat): ν = 3356 cm–1. HRMS
˜
(FAB) for C15H33NO3Si [M + H]+: calcd. 304.2307; found:
304.2299.
Compound 4: Benzyl chloroformate (410 mg, 2.40 mmol) was added
to a solution of compound 3 (500 mg, 1.65 mmol) and diisopropy-
lethylamine (632 mg, 4.90 mmol) in dry dichloromethane (10 mL)
and the reaction mixture was stirred at room temperature for 15 h.
The reaction mixture was treated with water and extracted with
dichloromethane, and the organic layer was dried with anhydrous
MgSO4, filtered and concentrated in vacuo to afford a crude prod-
uct, which was purified by silica gel column chromatography (elu-
ent: diethyl ether/hexane, 1:4) to afford compound 4 (620 mg, 86%
yield). M.p. 58.5 °C. [α]2D0 = –6.56 (c = 1.0 in CHCl3). 1H NMR
(CDCl3, 400 MHz, 60 °C): δ = 0.03 (s, 6 H), 0.88 (s, 9 H), 1.32 (s,
3 H), 1.39 (s, 3 H), 1.48–1.69 (m, 3 H), 1.69–1.80 (m, 1 H), 3.57–
3.65 (m, 2 H), 3.66–3.76 (m, 1 H), 3.75 (dd, J = 8.3, 6.0 Hz, 1 H),
3.98 (dd, J = 8.3, 6.8 Hz, 1 H), 4.04–4.10 (m, 1 H), 4.73 (brs, 1 H),
5.04 (d, J = 16.0 Hz, 1 H), 5.07 (d, J = 16.0 Hz, 1 H), 7.25–7.36
(m, 5 H) ppm. 13C NMR (CDCl3, 100 MHz, 60 °C): δ = –5.3, 18.3,
25.2, 26.0, 26.4, 27.3, 28.9, 53.5, 62.7, 66.8, 78.3, 109.5, 128.1,
83.6, 109.5, 126.9, 128.2, 128.2, 139.6 ppm. IR (neat): ν =
˜
3352 cm–1. HRMS (FAB) for C22H36NO3Si [M + H]+: calcd.
390.2464; found: 390.2473.
Compound anti-2b: Treatment of imine 1b (1 g, 4.30 mmol) precom-
plexed with BF3·OEt2 (8.60 mmol) with 3-(tert-butyldimethylsilyl-
oxy)prop-1-ynyllithium (8.60 mmol) as described in Procedure B
yielded compound 2b as a single diastereoisomer. Purification of
the crude product by silica gel column chromatography (eluent:
diethyl ether/hexane, 1:3) yielded compound anti-2b (oil, 1.38 g,
80%). [α]2D0 = –15.93 (c = 1.0 in CHCl3). 1H NMR (CDCl3,
128.1, 128.5, 136.8, 156.3 ppm. IR (nujol):
ν =
˜
1655 cm–1.
C23H39NO5Si (437.6): calcd. C 63.12, H 8.98, N 3.20; found: C
63.06, H 9.07, N 3.12.
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2114–2120

Synthesis of Polyhydroxylated Propargylamines
FULL PAPER
rai, Y. Mutoh, Y. Ohta, M. Murakami, J. Am. Chem. Soc. 2004,
126, 5968–5969; e) S. N. Osipov, P. Tsouker, L. Henning, K.
Burger, Tetrahedron 2004, 60, 271–274; f) G. Z. Gao, F. Sanda,
T. Masuda, Macromolecules 2003, 36, 3932–3937; g) C. J. Bren-
nan, G. Pattenden, G. Rescourio, Tetrahedron Lett. 2003, 44,
8757–8760; h) A. Arcadi, S. Cacchi, L. Cascia, G. Fabrizi, F.
Marinelli, Org. Lett. 2001, 3, 2501–2504.
Compound 5: Trifluoroacetic acid (0.1 mL) was added to a solution
of compound 4 (300 mg, 0.68 mmol) in methanol/water (10 mL,
3:1) and the reaction mixture was stirred at room temperature for
15 h. On completion of the reaction the methanol was removed
under reduced pressure and the resulting solution was diluted with
water (15 mL) and washed with dichloromethane. Lyophilisation
of the aqueous layer gave compound 5 (184 mg, 95%) as a white
[3]
[4]
J. Blanchet, M. Bonin, L. Micouin, Org. Prep. Proced. Int.
2002, 34, 467–492.
1
solid. M.p. 136–138 °C. H NMR ([D6]DMSO, 400 MHz, 25 °C):
δ = 1.23–1.38 (m, 2 H), 1.39–1.56 (m, 1 H), 1.57–1.66 (m, 1 H),
3.22–3.46 (m, 6 H), 4.30 (dd, J = 6.1, 4.8 Hz, 1 H), 4.39 (dd, J =
6.0, 4.8 Hz, 1 H), 4.57 (d, J = 4.5 Hz, 1 H), 4.98 (d, J = 13.0 Hz,
1 H), 5.03 (d, J = 13.0 Hz, 1 H), 6.90 (d, J = 8.7 Hz, 1 H), 7.27–
7.39 (m, 5 H) ppm. 13C NMR ([D6]DMSO, 100 MHz, 25 °C): δ =
26.0, 29.2, 52.6, 60.8, 63.3, 65.0, 73.7, 127.6, 127.7, 128.3, 137.4,
Recent examples of diastereoselective additions: a) R. B. Let-
tan II, K. A. Scheidt, Org. Lett. 2005, 7, 3227–3230; b) G. Ma-
gueur, B. Crousse, D. Bonnet-Delpon, Tetrahedron Lett. 2005,
46, 2219–2221; c) B. Jiang, Y. G. Si, Tetrahedron Lett. 2003, 44,
6767–6768; d) R. Fässler, D. E. Frantz, J. Oetiker, E. M. Car-
reira, Angew. Chem. Int. Ed. 2002, 41, 3054–3056; e) N. Le-
bouvier, C. Laroche, F. Huguenot, T. Brigaud, Tetrahedron
Lett. 2002, 43, 2827–2830; f) J. Blanchet, M. Bonin, L. Mic-
ouin, H. P. Husson, J. Org. Chem. 2000, 65, 6423–6426.
Recent examples of enantioselective additions: a) F. Colombo,
M. Benaglia, S. Orlandi, F. Usuelli, G. Celentano, J. Org.
Chem. 2006, 71, 2064–2070; b) A. Bisai, V. K. Singh, Org. Lett.
2006, 8, 2405–2408; c) T. R. Wu, J. M. Chong, Org. Lett. 2006,
8, 15–18; d) N. Gommermann, P. Knochel, Tetrahedron 2005,
61, 11418–11426; e) T. E. Knöpfel, P. Aschwanden, T. Ichi-
kawa, T. Watanabe, E. M. Carreira, Angew. Chem. Int. Ed.
2004, 43, 5971–5973; f) C. Wei, Z. Li, C. J. Li, Synlett 2004,
1472–1483; g) C. Wei, J. T. Mague, C. J. Li, Proc. Natl. Acad.
Sci. USA 2004, 101, 5749–5754; h) P. G. Cozzi, R. Hilgraf, N.
Zimmermann, Eur. J. Org. Chem. 2004, 4095–4105; i) J. F. Tra-
verse, A. H. Hoveyda, M. L. Snapper, Org. Lett. 2003, 5, 3273–
3275; j) C. Koradin, N. Gommermann, K. Polborn, P. Kno-
chel, Chem. Eur. J. 2003, 9, 2797–2811; k) B. Jiang, Y. G. Si,
Angew. Chem. Int. Ed. 2004, 43, 216–218.
156.1 ppm. IR (neat): ν = 3360, 1680 cm–1. C H NO (283.3):
˜
14 21
5
calcd. C 59.35, H 7.47, N 4.94; found: C 59.19, H 7.36, N 5.03.
[5]
Compound 6: Small portions of NaIO4 (302 mg, 1.41 mmol) were
added to a stirred solution of compound 5 (100 mg, 0.35 mmol)
in methanol (10 mL) and the mixture was stirred for 3 h at room
temperature. On completion of the reaction the mixture was filtered
and concentrated under reduced pressure. The resulting residue was
dissolved in diethyl ether (15 mL), filtered and concentrated under
reduced pressure. Jones’ reagent (10 mL) was added at 0 °C to a
solution of the residue in acetone (10 mL) and the reaction mixture
was stirred at 0 °C for 4 h. The solution was concentrated under
reduced pressure and the residue was dissolved in dichloromethane,
diluted with water and extracted with dichloromethane. The com-
bined organic extracts were dried with anhydrous MgSO4, filtered
and concentrated in vacuo to afford a crude product, which was
dissolved in dichloromethane and hydrogenated at atmospheric
pressure by stirring at room temperature for 24 h in the presence
of Pd/C (10%, 10 mg). After completion of the reaction the catalyst
was removed by filtration and the filtrate was concentrated to dry-
ness to afford (S)-glutamic acid (41 mg, 80%) as a white solid. M.p.
204.5 °C (dec) [ref.[22] m.p. 205 °C. (dec)]. [α]2D0 = +31.0 (c = 2.0 in
5  HCl) [ref.[22] [α]2D0 = +31.5 (c = 2.0 in 5  HCl)]. 1H NMR
(D2O, 400 MHz, 25 °C): δ = 1.97–2.11 (m, 2 H), 2.31–2.50 (m, 2
H), 3.70 (t, J = 6.4 Hz, 1 H) ppm. 13C NMR (D2O, 100 MHz,
[6]
[7]
S. C. Bergmeier, Tetrahedron 2000, 56, 2561–2576.
a) H. Ding, G. K. Friestad, Synthesis 2005, 2815–2829; b) R.
Bloch, Chem. Rev. 1998, 98, 1407–1438; c) D. Enders, U. Rein-
hold, Tetrahedron: Asymmetry 1997, 8, 1895–1946.
[8]
For some recent examples, see: a) M. Achmatowicz, L. S. Heg-
edus, J. Org. Chem. 2004, 69, 2229–2234; b) F. Bernaud, E.
Vrancken, P. Mangeney, Org. Lett. 2003, 5, 2567–2569; c) J. J.
Fleming, K. W. Fiori, J. D. Bois, J. Am. Chem. Soc. 2003, 125,
2028–2029; d) H. Yoda, T. Uemura, K. Takabe, Tetrahedron
Lett. 2003, 44, 977–979; e) A. Dondoni, D. Perrone, Tetrahe-
dron 2003, 59, 4261–4273; f) P. Merino, E. Castillo, S. Franco,
F. L. Merchan, T. Tejero, Tetrahedron: Asymmetry 1998, 9,
1759–1769.
25 °C): 28.0, 32.5, 56.3, 176.3, 179.6 ppm. IR (nujol): ν = 3400,
˜
1675 cm–1.
[9]
G. Godin, P. Compain, G. Masson, O. R. Martin, J. Org.
Chem. 2002, 67, 6960–6970.
Acknowledgments
[10]
G. B. Evans, R. H. Furneaux, G. J. Gainsford, J. C. Hanson,
G. A. Kicska, A. A. Sauve, V. L. Schramm, P. C. Tyler, J. Med.
Chem. 2003, 46, 155–160.
B. M. Trost, C. K. Chung, A. B. Pinkerton, Angew. Chem. Int.
Ed. 2004, 43, 4327–4329.
This work was supported by the Spanish Ministerio de Cienca y
Tecnología (MCYT) and Fondo Europeo de Desarollo Regional
(FEDER) (project PPQ2001-1834) and the Gobierno de Aragón.
R. D. was supported by a Spanish MCYT Predoctoral Fellowship.
[11]
[12]
[13]
M. Shimizu, M. Kawamoto, Y. Niwa, Chem. Commun. 1999,
1151–1152.
D. Díez, A. B. Antón, P. García, M. G. Nuñez, N. M. Garrido,
R. F. Moro, I. S. Marcos, P. Basabe, J. G. Urones, Tetrahedron:
Asymmetry 2006, 17, 2260–2264.
a) R. Badorrey, C. Cativiela, M. D. Díaz-de-Villegas, R. Díez,
J. A. Gálvez, Eur. J. Org. Chem. 2003, 2268–2275; b) R. Bador-
rey, C. Cativiela, M. D. Díaz-de-Villegas, R. Díez, J. A. Gálvez,
Eur. J. Org. Chem. 2002, 3763–3767; c) R. Badorrey, C. Cativi-
ela, M. D. Díaz-de-Villegas, J. A. Gálvez, Tetrahedron 2002, 58,
341–354; d) R. Badorrey, C. Cativiela, M. D. Díaz-de-Villegas,
J. A. Gálvez, Tetrahedron 1997, 53, 1411–1416; e) R. Badorrey,
C. Cativiela, M. D. Díaz-de-Villegas, J. A. Gálvez, Synthesis
1997, 747–749; f) C. Cativiela, M. D. Díaz-de-Villegas, J. A.
Gálvez, Tetrahedron: Asymmetry 1996, 7, 529–536.
[1] For representative examples, see: a) G. S. Kauffman, G. D.
Harris, R. L. Dorow, B. R. P. Stone, R. L. Parsons, J. A. Pesti,
N. A. Magnus, J. M. Fortunak, P. N. Confalone, W. A. Nugent,
Org. Lett. 2000, 2, 3119–3121; b) R. M. Scarborough, D. D.
Gretler, J. Med. Chem. 2000, 43, 3453–3473; c) M. E. Maier, F.
Boβe, A. J. Niestroj, Eur. J. Org. Chem. 1999, 1–13; d) A. G.
Myers, S. B. Cohen, N. J. Tom, D. J. Madar, M. E. Fraley, J.
Am. Chem. Soc. 1995, 117, 7574–7575; e) B. M. Nilsson, H. M.
Vargas, B. Ringdahl, U. Hacksell, J. Med. Chem. 1992, 35, 285–
294; f) P. H. Yu, B. A. Davis, A. A. Boulton, J. Med. Chem.
1992, 35, 3705–3713.
[2] For recent examples, see: a) F. Rivault, V. Schons, C. Liébert,
A. Burger, E. Sakr, M. A. Abdallah, I. J. Schalk, G. L. A. Mis-
lin, Tetrahedron 2006, 62, 2247–2254; b) M. H. Davidson, F. E.
McDonald, Org. Lett. 2004, 6, 1601–1603; c) P. Wipf, Y. Aoy-
ama, T. E. Benedum, Org. Lett. 2004, 6, 3593–3595; d) T. Mu-
[14]
[15]
a) R. Badorrey, C. Cativiela, M. D. Díaz-de-Villegas, J. A.
Gálvez, Synlett 2005, 1734–1736; b) R. Badorrey, C. Cativiela,
Eur. J. Org. Chem. 2007, 2114–2120
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2119

R. Díez, R. Badorrey, M. D. Díaz-de-Villegas, J. A. Gálvez
M. D. Díaz-de-Villegas, R. Díez, J. A. Gálvez, Tetrahedron [20] For a review of multiple stereoselectivity, see: O. J. Kolodiazh-
FULL PAPER
Lett. 2004, 45, 719–722; c) R. Badorrey, C. Cativiela, M. D.
Díaz-de-Villegas, J. A. Gálvez, Tetrahedron 1999, 55, 14145–
14160.
nyi, Tetrahedron 2003, 59, 5953–6018.
[21] K. B. Aubrecht, M. D. Winemiller, D. B. Collum, J. Am. Chem.
Soc. 2000, 122, 11084–11089.
[22] Aldrich Chemical Catalogue, 2005–2006, p. 1290.
[23] Chirobiotic T; UV detector 210 nm; 1 mLmin–1; 80:20 EtOH/
0.1% aqueous Et3NHAcO, pH4.0; room temp. for (S)-glu-
tamic acid 5.1 min; room temp. for (R)-glutamic acid 7.4 min.
[24] M. D. Cliff, S. G. Pyne, Tetrahedron 1996, 52, 13703–13712.
[25] R. Badorrey, C. Cativiela, M. D. Díaz-de-Villegas, J. A.
Gálvez, Tetrahedron 1999, 55, 7601–7612.
[16] M. J. Earle, A. Abdur-Rashid, N. D. Priestley, J. Org. Chem.
1996, 61, 5697–5700.
[17] C. R. Schmid, J. D. Bryant, M. Dowlatzedah, J. L. Phillips,
D. E. Prather, R. D. Schantz, N. L. Sear, C. S. Vianco, J. Org.
Chem. 1991, 56, 4056–4058.
[18] M. W. Logue, K. Teng, J. Org. Chem. 1982, 47, 2549–2553.
[19] For a review of chelation and non-chelation control in addition
reactions of chiral α-alkoxy carbonyl compounds, see: M. T.
Reetz, Angew. Chem. Int. Ed. Engl. 1984, 23, 556–569.
Received: November 22, 2006
Published Online: March 13, 2007
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2114–2120