Diastereoselective functionalisation of Baylis-Hillman adducts: A convenient approach to α-methyl-α-amino acids

Article abstract of DOI:10.1007/s00726-009-0465-y

The N-tosyl carbamates 4a-e, easily prepared starting from the Baylis-Hillman adducts 3a-e, underwent cyclization carried out with I ₂/NIS in the presence of NaH, to give the corresponding 2-oxo-1,3-oxazolidines 5a-e in good yield and total stereoselection when the substituent at C-5 is Ar. After the removal of tosyl group, followed by the cleavage of the heterocyclic ring, the α-methyl-α-amino acids 8a,b and 10 were obtained in good yield as hydrochlorides. Springer-Verlag 2010.

Full text of DOI:10.1007/s00726-009-0465-y

Amino Acids (2010) 39:489–497
DOI 10.1007/s00726-009-0465-y
ORIGINAL ARTICLE
Diastereoselective functionalisation of Baylis–Hillman adducts:
a convenient approach to a-methyl-a-amino acids
•
•
•
Gianluca Martelli Mario Orena Samuele Rinaldi
Piera Sabatino
Received: 18 September 2009 / Accepted: 24 December 2009 / Published online: 6 March 2010
ꢀ Springer-Verlag 2010
Abstract The N-tosyl carbamates 4a–e, easily prepared
starting from the Baylis–Hillman adducts 3a–e, underwent
cyclization carried out with I2/NIS in the presence of NaH,
to give the corresponding 2-oxo-1,3-oxazolidines 5a–e in
good yield and total stereoselection when the substituent at
C-5 is Ar. After the removal of tosyl group, followed by the
cleavage of the heterocyclic ring, the a-methyl-a-amino
acids 8a,b and 10 were obtained in good yield as
hydrochlorides.
important in bio-organic chemistry, since their incorpora-
tion introduces conformational restrictions into peptide
chains and increases constraints within the peptidomimetic
structures, consequently stabilizing the helical confor-
mations. In some cases they force peptides into their
biologically active conformations, often leading to pep-
tidomimetics with remarkable resistance to enzymatic
degradation (Toniolo et al. 2006). Moreover, a-methyl-
a-amino acids are frequently employed in bio organic
synthesis, so that a versatile route to these compounds in
the enantiomerically pure form is desirable (Wirth 1997;
Cativiela and Diaz-De-Villegas 1998; Xu et al. 2005; Vogt
and Brase 2007; Davies et al. 2007; Balducci et al. 2009).
Keywords a-Methyl-a-amino acid ꢀ Functionalisation ꢀ
Diastereoselection ꢀ Baylis–Hillman adducts
Introduction
Results and discussion
Quaternary stereocenters are common structural motifs in
bioactive natural products such as a-methyl-a-amino acids
(Mosey et al. 2008; Balducci et al. 2009), which are part of
molecules such as neurotropic lactacystin (Pattenden and
Rescourio 2008; Li et al. 2009), the immunosuppressive
agent myriocin (Imai et al. 2008; Jones and Marsden 2008)
and the antifungal agents sphingofungins (Trost and Lee
2001). These constrained building blocks have become
Within this topic, we devised that the stereocontrolled
intramolecular addition of a nucleophile to a gem-disub-
stituted double bond activated by an electrophile can give
rise to a one-step construction of such highly congested
motif (Orena 1995b). In addition, when an enantiomeri-
cally pure starting material is available, functionalization
allows to introduce stereocenters with the appropriate
configuration (Cardillo and Orena 1995), and the approach
we report here is particularly attractive since Baylis–Hill-
man adducts can be obtained with high enantiomeric purity
according to a lot of synthetic procedures (Basavaiah et al.
2003; Basavaiah et al. 2007). Directed towards this goal,
the imidate 1, arising from a Baylis–Hillman adduct, was
treated with NIS in CHCl3, and diastereomeric 4,5-dihy-
dro-1,3-oxazoles 2a and 2b were obtained in good yield but
80:20 d.r, the cis-isomer being the major component of the
reaction mixture. The diastereomers were separated by sil-
ica gel chromatography and configurations were assigned
G. Martelli ꢀ M. Orena (&) ꢀ S. Rinaldi (&)
`
Dipartimento I.S.A.C, Universita Politecnica delle Marche,
Via Brecce Bianche, 60131 Ancona, Italy
e-mail: m.orena@univpm.it
S. Rinaldi
e-mail: s.rinaldi@univpm.it
P. Sabatino
Dipartimento di Chimica ‘‘G. Ciamician’’,
`
Universita di Bologna, Via Selmi 2,
40126 Bologna, Italy
123

490
M. Orena et al.
O
OH
i
O
NHTs
R2
R2
COOR1
3
4
COOR1
O
ii
O
NTs
COOR1
R2
I
5
Scheme 2 a R1 = CH3, R2 = C6H5; b R1 = CH3, R2 = (CH3)2
CHCH2; c R1 = t-C4H9 R2 = C6H5; d R1 = C2H5, R2 = 2-naphthyl;
e, R1 = C2H5, R2 = 4-Cl-C6H4. i. TsNCO, DCM, rt, 30 min: 4a 94%
yield; 4b 93% yield; 4c 96% yield; 4d 98% yield; 4e 95% yield. ii.
NaH, THF, then I2/NIS, rt: 5a 75% yield; 5b 63% yield (cis/
trans & 9/1); 5c 66% yield; 5d 49% yield; 5e 59% yield
Scheme 1 i. NIS, CHCl3, rt, 88%, 80:20 d.r
by means of 1H-NMR spectral data and subsequently
confirmed by NOE experiments (Scheme 1) (Galeazzi
et al. 2004a).
Thus, with the aim to improve stereoselection of the
chirality transfer from C-3 to C-2 of the Baylis–Hillman
adducts 3, we at first devised to use N-acyl carbamates of
Baylis–Hillman adducts (Ciclosi et al. 2002) in order to
increase the stereoselection of the cyclization reaction.
In fact N-trichloroacetyl, N-phenyloxycarbonyl and
N-(4-methoxybenzyloxy)carbonyl carbamates prepared
starting from the Baylis–Hillman adduct 3a were treated
under the reported conditions (Fujita et al. 1997), but we
were unable to find any cyclized product in the reaction
mixture, the starting material being invariably recovered.
Eventually, we devised to use N-tosyl carbamates 4a–e,
obtained in almost quantitative yield by reaction of Baylis–
Hillman adducts with tosyl isocyanate (Scheme 2). The
N-tosyl carbamate moiety was already employed in order
to introduce a nitrogen atom onto a double bond, but the
stereoselection of the cyclofunctionalization was not sat-
isfactory, invariably leading to a diastereomeric mixture
(Hirama et al. 1984), the sole useful cyclization involving
allenic derivatives (Friesen 1990; Friesen and Kolaczewska
1991; Kimura et al. 1991). However, when the compounds
4a–e underwent cyclization in THF on treatment with an
equimolar amount of sodium hydride, followed by NIS/I2,
the cyclization products 5a–e were exclusively obtained in
high yield and with total stereoselection when R2 is Ar. The
cis-relationship between R2 and the iodomethyl group in
these compounds was evidenced by the strong shielding
Fig. 1 Computer-generated ORTEP drawing of 5e at 50% probabil-
ity as determined by single-crystal X-ray diffraction analysis
With compounds 5 in hand, the cleavage of the C–I
bond was performed with N-ethylpiperidinium hypo-
phosphite (Galeazzi et al. 2004a), starting from 5a–c, to
give the corresponding 4-methyl derivatives 6a–c in high
yield (Scheme 3). The subsequent removal of the tosyl
group of 6a–c was carried out using Mg in refluxing
methanol in the presence of NH4Cl and the corresponding
2-oxo-1,3-oxazolidines 7a–c were recovered in good yield.
The hydrolysis of compounds 7a,b carried out with
refluxing 12 M HCl, afforded the 3-hydroxy-2-amino acids
1
effect observed in the H-NMR spectra for the protons of
the iodomethyl group, in analogy with the products arising
from the cyclization of amides of aza-Baylis–Hillman
adducts (Galeazzi et al. 2004b).
Scheme 3 a R1 = CH3, R2 = C6H5; b R1 = CH3, R2 = (CH3)2
CHCH2; c R1 = t-C4H9, R2 = C6H5. i. H3PO2, N-ethylpiperidine,
AIBN, refluxing toluene, 2 h: 6a 67% yield; 6b 87% yield; 6c 64%
yield. ii. Mg, NH4Cl, refluxing methanol, 45 min: 7a quantitative
yield; 7b 75% yield; 7c 98% yield
Eventually, the relative configuration of compounds 5
was confirmed by single-crystal X-ray diffraction analysis
of compound 5e (Fig. 1).
123

Diastereoselective functionalisation of Baylis–Hillman adducts
491
NH2
i
R1
HCl
8a,b
7a,b
COOH
OH
Scheme 4 a R1 = C6H5; b R1 = (CH3)2CHCH2. i. Refluxing 12 M
HCl, a 67% yield; b 95% yield
Scheme 5 R1 = C6H5. i. 10% Pd on charcoal, H2, methanol, 3 h,
86% yield. ii. 6 M HCl at reflux for 24 h, 78% yield
¨
8a,b in moderate yield (Scheme 4) (Schollkopf et al.
¨
1981a,b; Schollkopf 1983; Avenoza et al. 2000).
Fig. 2 Packing of 5e showing the intermolecular H-bond network
On the other hand, when compound 7c was treated with
hydrogen in the presence of 10% Pd on charcoal, the amino
ester 9 was obtained and subsequent hydrolysis carried out
with 6 M HCl afforded the amino acid 10, having the
a-quaternary center, as the corresponding hydrochloride
(Scheme 5) (Wang et al. 2007; Lu and Lin 2008; Tomooka
et al. 2008).
angles of 136ꢀ4ꢁ and 133ꢀ4ꢁ, respectively] and a third one
involving O(3), x, ‘-y, -1/2 ? x [C(9)–H(9)…O(3) with
D..A distance of 3ꢀ191(3) A and D–H..A angle of 162ꢀ5ꢁ].
˚
Conclusions
Finally, we could ascertain that the iodocyclization
reaction occurs without any epimerization at the benzylic
stereogenic center (e.g. compounds 3a,c,d). In fact, we
prepared the Baylis–Hillman adduct (R)-3a in 95% e.e.
according to the literature method (Nakano et al. 2006),
which was converted into the corresponding tosyl carba-
mate (R)-4a. This product underwent the iodocyclization
reaction and the reaction mixture was analyzed by HPLC.
The cyclized product (4S,5R)-5a was obtained in 95% e.e.,
thus confirming the total configuration retention at C-5.
This result was further confirmed by conversion of (4S,5R)-
5a into the hydrochloride (2R,3R)-8a which eventually,
according to the reported method (Avenoza et al. 2000),
gave the free amino acid (2R,3R)-11 in 95% e.e. deter-
mined on the basis of the specific rotation value. It is
noteworthy that, as experimentally verified for 5a, the
crystalline products (5a, 5d and 5e) can be easily obtained
in the enantiopure form by fractional crystallization from
ethyl acetate or dichloromethane.
In summary, starting from Baylis–Hillman adducts 3, by
means of a totally stereocontrolled cyclofunctionalisation,
we obtained rapid access to compounds containing a qua-
ternary carbon bearing nitrogen. In addition, we developed
a short and highly selective method for the synthesis of
a,a-dialkylated amino acids 8 and 10, possessing a chiral
quaternary carbon atom, which are interesting building
blocks for the synthesis of more complex peptides.
Experimental
Melting points were measured on an Electrothermal IA
9000 apparatus and are uncorrected. 1H- and 13C-NMR
spectra were recorded at 200 and 50 MHz respectively, on
a Varian Gemini 200 spectrometer or at 400 and 100 MHz
respectively, on a Varian MR-400 spectrometer. CDCl3
was employed as a solvent unless otherwise stated.
Chemical shifts (d) are reported in ppm relative to TMS
and coupling constants (J) in Hz. Optical rotations were
measured on a Perkin Elmer 341 polarimeter. The samples
were analyzed with a liquid chromatography Agilent
Technologies HP1100, equipped with a Daicel Chiralcel
OD-H column and a diode-array UV detector (210, 230
and 250 nm). n-Hexane and 2-propanol for HPLC were
purchased from Aldrich. The MSD1100 mass detector
was utilized under the following conditions: mass range
100–2,500 uma, positive scanning, energy of fragmentor
Crystal structure of 5e
The crystal packing of 5e (Fig. 2) consists of a 3D network of
molecules joined by intermolecular interactions with par-
ticipation of C–H…O atoms. Two interactions involve the
O(2) atom belonging to the symmetry related x, ‘-y, ‘ ? x
molecule [C(6)–H(6)…O(2) and C(16)–H(16)…O(2) with
˚
D..A distances of 3ꢀ404(6) and 3ꢀ297(3) A and D–H..A
123

492
M. Orena et al.
50 eV, drying gas flow (nitrogen) 10ꢀ0 mL/min, nebulizer
pressure 45 psig, drying gas temperature 350ꢁC and cap-
illary voltage 4,500 V. Elemental analyses were performed
using a Perkin Elmer 2400 CHN Elemental Analyzer.
Column chromatography was performed with silica gel 60
(230–400 mesh).
128ꢀ7, 129ꢀ6, 135ꢀ4, 136ꢀ6, 140ꢀ0, 145ꢀ0, 149ꢀ2, 163ꢀ7;
ESI–MS m/z 431ꢀ1 [M]?, 454ꢀ1 [M ? Na]?. Anal Calcd
for C22H25NO6S (431ꢀ14): C, 61ꢀ24; H, 5ꢀ84; N, 3ꢀ25.
Found: C, 61ꢀ16; H, 5ꢀ90; N, 3ꢀ19.
Ethyl 2-[naphthalen-1-yl(tosylcarbamoyloxy)methyl]
acrylate (4d)
Synthesis of compounds 4a-e. General procedure
1
The title compound was obtained in 98% yield. H-NMR
To a solution of the appropriate Baylis–Hillman adduct 3
(5 mmol) in dry dichloromethane (10 mL), tosyl isocya-
nate (0ꢀ85 mL; 5ꢀ25 mmol) was added at rt and the mixture
was subsequently stirred for 30 min. After removal of the
solvent under reduced pressure, the residue was purified by
silica gel chromatography (cyclohexane:ethyl acetate 9:1)
to give the corresponding N-tosylcarbamates 4 as colorless
oils.
(200 MHz, CDCl3) d 1ꢀ14 (t, J = 7ꢀ4, 3H), 2ꢀ31 (s, 3H),
4ꢀ07 (q, J = 7ꢀ4, 2H), 5ꢀ90 (s, 1H), 6ꢀ45 (s, 1H), 6ꢀ73 (s,
1H), 7ꢀ09–7ꢀ15 (m, 2 ArH), 7ꢀ26–7ꢀ33 (m, 2 ArH), 7ꢀ45–
7ꢀ51 (m, 2 ArH), 7ꢀ70–7ꢀ82 (m, 6 ArH ? NH); 13C-NMR
(50 MHz, CDCl3) d 13ꢀ8, 21ꢀ5, 26ꢀ9, 61ꢀ2, 76ꢀ0, 124ꢀ9,
126ꢀ3, 126ꢀ5, 126ꢀ8, 127ꢀ2, 127ꢀ6, 128ꢀ1, 128ꢀ2, 128ꢀ3,
129ꢀ5, 132ꢀ9, 133ꢀ2, 133ꢀ8, 135ꢀ4, 138ꢀ6, 144ꢀ8, 149ꢀ7,
164ꢀ7; ESI–MS m/z 453ꢀ1 [M]?, 476ꢀ1 [M ? Na]?. Anal
Calcd for C24H23NO6S (453ꢀ12): C, 63ꢀ56; H, 5ꢀ11; N,
3ꢀ09. Found: C, 63ꢀ51; H, 5ꢀ06; N, 3ꢀ15.
Methyl 2-[phenyl(tosylcarbamoyloxy)methyl]acrylate
(4a)
Ethyl 2-[(4-chlorophenyl)(tosylcarbamoyloxy)
1
The title compound was obtained in 94% yield. H-NMR
methyl]acrylate (4e)
(200 MHz, CDCl3) d 2ꢀ42 (s, 3H), 3ꢀ64 (s, 3H), 5ꢀ82 (s,
1H), 6ꢀ40 (s, 1H), 6ꢀ55 (s, 1H), 7ꢀ18–7ꢀ35 (m, 7 ArH), 7ꢀ62
(br s, 1H, NH), 7ꢀ82 (d, J = 8ꢀ5 Hz, 2 ArH); 13C-NMR
(50 MHz, CDCl3) d 21ꢀ1, 51ꢀ6, 75ꢀ3, 126ꢀ4, 127ꢀ2, 127ꢀ7,
128ꢀ1, 128ꢀ3, 129ꢀ2, 135ꢀ3, 136ꢀ1, 138ꢀ2, 144ꢀ5, 149ꢀ4,
164ꢀ8; ESI–MS m/z 389ꢀ1 [M]?, 412ꢀ1 [M ? Na]?. Anal
Calcd for C19H19NO6S (389ꢀ09): C, 58ꢀ60; H, 4ꢀ92; N,
3ꢀ60. Found: C, 58ꢀ55; H, 4ꢀ85; N, 3ꢀ69.
1
The title compound was obtained in 93% yield. H-NMR
(200 MHz, CDCl3) d 1ꢀ16 (t, J = 7ꢀ4, 3H), 2ꢀ43 (s, 3H),
4ꢀ08 (q, J = 7ꢀ4, 2H), 5ꢀ82 (s, 1H), 6ꢀ40 (s, 1H), 6ꢀ50 (s,
1H), 6,95–7ꢀ41 (m, 7H, 6 ArH ? NH), 7ꢀ78 (d, J = 8ꢀ3, 2
ArH); 13C-NMR (50 MHz, CDCl3) d 13ꢀ9, 21ꢀ7, 61ꢀ3,
75ꢀ2, 126ꢀ7, 128ꢀ2, 128ꢀ7, 129ꢀ1, 129ꢀ6, 134ꢀ6, 135ꢀ1,
138ꢀ3, 145ꢀ2, 149ꢀ5, 164ꢀ5; ESI–MS m/z 437ꢀ1 [M]?,
460ꢀ1 [M ? Na]?. Anal Calcd for C20H20ClNO6S
(437ꢀ07): C, 54ꢀ86; H, 4ꢀ60; N, 3ꢀ20. Found: C, 54ꢀ80; H,
4ꢀ56; N, 3ꢀ15.
Methyl 5-methyl-2-methylene-3-(tosylcarbamoyloxy)
hexanoate (4b)
1
The title compound was obtained in 95% yield. H-NMR
Synthesis of compounds 5a-e. General procedure
(200 MHz, CDCl3) d 0ꢀ76 (d, J = 6ꢀ0, 3H), 0ꢀ83 (d,
J = 6ꢀ0. 3H), 1ꢀ08–1ꢀ50 (m, 3H), 2ꢀ44 (s, 3H), 3ꢀ72 (s, 3H),
5ꢀ56 (dd, J = 6ꢀ0, J = 6ꢀ6, 1H), 5ꢀ69 (s, 1H), 6ꢀ23 (s, 1H),
7ꢀ34 (d, J = 7ꢀ3, 2 ArH), 7ꢀ90 (d, J = 7ꢀ3, 2 ArH), 7ꢀ94 (br
s, 1H, NH); 13C-NMR (50 MHz, CDCl3) d 21ꢀ3, 21ꢀ5, 22ꢀ9,
24ꢀ4, 43ꢀ4, 52ꢀ0, 73ꢀ1, 126ꢀ0, 128ꢀ0, 129ꢀ4, 136ꢀ5, 139ꢀ5,
144ꢀ2, 151ꢀ5, 165ꢀ7; ESI–MS m/z 369ꢀ1 [M]?, 392ꢀ1
[M ? Na]?. Anal Calcd for C17H23NO6S (369ꢀ12): C,
55ꢀ27; H, 6ꢀ28; N, 3ꢀ79. Found: C, 55ꢀ21; H, 6ꢀ34; N, 3ꢀ74.
To a solution of compound 4a–e (2ꢀ0 mmol) in dry THF
(5 mL) under inert atmosphere, NaH (84 mg of 60% dis-
persion in mineral oil, 2ꢀ1 mmol) was slowly added. After
the evolution of hydrogen had ceased, iodine (1ꢀ53 g,
6ꢀ0 mmol) and NIS (450 mg, 2ꢀ0 mmol) were added.
When the conversion was almost complete (3–7 days), the
reaction mixture was directly poured into a saturated
solution of Na2S2O3 (10 mL) and ethyl acetate (20 mL).
After separation, the aqueous phase was further extracted
with ethyl acetate (10 mL). The organic phases were dried
(Na2SO4) and the solvent was removed under reduced
pressure. The crude material was purified by chromatog-
raphy over silica gel (cyclohexane/ethyl acetate 90:10 as
eluent) obtaining pure compounds 5a–e. Crystallization
from ethyl acetate furnished crystalline samples of 5a, 5d
and 5e, although only 5e was suitable for diffractometric
analysis.
t-Butyl 2-[phenyl(tosylcarbamoyloxy)methyl]acrylate
(4c)
1
The title compound was obtained in 96% yield. H-NMR
(200 MHz, CDCl3) d 1ꢀ30 (s, 9H), 2ꢀ42 (s, 3H), 5ꢀ68 (s,
1H), 6ꢀ32 (s, 1H), 6ꢀ51 (s, 1H), 7ꢀ18–7ꢀ35 (m, 7 ArH), 7ꢀ68
(br s, 1H, NH), 7ꢀ83 (d, J = 8ꢀ5, 2 ArH); 13C-NMR
(50 MHz, CDCl3) d 21ꢀ6, 27ꢀ8, 81ꢀ7, 127ꢀ8, 128ꢀ3, 128ꢀ4,
123

Diastereoselective functionalisation of Baylis–Hillman adducts
493
Methyl (4S*,5R*)-4-(iodomethyl)-2-oxo-5-phenyl-3-
tosyloxazolidine-4-carboxylate (5a)
Ethyl (4S*,5R*)-4-(iodomethyl)-5-(naphthalen-1-yl)-2-
oxo-3-tosyloxazolidine-4-carboxylate (5d)
The title compound was obtained in 75% yield. White
1
The title compound was obtained in 49% yield. White
crystals; mp 108ꢁC; 1H-NMR (200 MHz, CDCl3) d 1ꢀ49 (t,
J = 7ꢀ1, 3H), 2ꢀ47 (s, 3H), 3ꢀ12 (d, J = 11ꢀ6, 1H), 3ꢀ97 (d,
J = 11ꢀ6, 1H), 4ꢀ55 (q, J = 7ꢀ1, 2H), 5ꢀ95 (s, 1H), 7ꢀ25–
7ꢀ60 (m, 5 ArH), 7ꢀ80–8ꢀ15 (m, 6 ArH); 13C-NMR
(50 MHz, CDCl3) d 3ꢀ7, 14ꢀ1, 21ꢀ9, 64ꢀ2, 71ꢀ1, 82ꢀ9, 123ꢀ0,
126ꢀ9, 127ꢀ0, 127ꢀ1, 127ꢀ2, 127ꢀ9, 128ꢀ3, 128ꢀ5, 129ꢀ5,
129ꢀ9, 132ꢀ5, 133ꢀ4, 134ꢀ2, 146ꢀ2, 150ꢀ8, 167ꢀ4; ESI–MS
m/z 579ꢀ0 [M]?, 602ꢀ0 [M ? Na]?. Anal Calcd for
C24H22INO6S (579ꢀ02): C, 49ꢀ75; H, 3ꢀ83; N, 2ꢀ42. Found:
C, 49ꢀ70; H, 3ꢀ87; N, 2ꢀ38.
crystals; mp 170ꢁC; H-NMR (200 MHz, CDCl3) d 2ꢀ46
(s, 3H), 3ꢀ14 (d, J = 12ꢀ2 Hz, 1H), 3ꢀ95 (d, J = 12ꢀ2 Hz,
1H), 4ꢀ03 (s, 3H), 5ꢀ78 (s, 1H), 7ꢀ30–7ꢀ45 (m, 7 ArH),
8ꢀ07 (d, J = 8ꢀ5 Hz, 2 ArH); 13C-NMR (50 MHz, CDCl3)
d 3ꢀ3, 21ꢀ6, 54ꢀ3, 70ꢀ8, 82ꢀ4, 126ꢀ4, 128ꢀ3, 129ꢀ3, 129ꢀ6,
134ꢀ0, 146ꢀ0, 150ꢀ4, 167ꢀ5; ESI–MS m/z 515ꢀ0 [M]?,
538ꢀ0 [M ? Na]?. Anal Calcd for C19H18INO6S (514ꢀ99):
C, 44ꢀ28; H, 3ꢀ52; N, 2ꢀ72. Found: C, 44ꢀ23; H, 3ꢀ47; N,
2ꢀ77.
Methyl (4S*,5R*)-4-(iodomethyl)-5-isobutyl-2-oxo-3-
tosyloxazolidine-4-carboxylate (5b)
Ethyl (4S*,5R*)-5-(4-chlorophenyl)-4-(iodomethyl)-2-
oxo-3-tosyloxazolidine-4-carboxylate (5e)
The title compound was obtained in 63% yield as a sepa-
rable diastereomeric mixture (9:1 d.r.). Major diastereomer
The title compound was obtained in 59% yield. White
1
crystals; mp 170ꢁC; H-NMR (200 MHz, CDCl3) d 1ꢀ44
1
(4S*,5R*): colorless oil; H-NMR (200 MHz, CDCl3) d
0ꢀ89 (d, J = 6ꢀ6, 3H), 0ꢀ94 (d, J = 6ꢀ6, 3H), 1ꢀ30–1,55 (m,
1H), 1ꢀ65–1ꢀ83 (m, 1H), 2ꢀ08–2ꢀ27 (m, 1H), 2ꢀ45 (s, 3H),
3ꢀ65 (d, J = 12ꢀ6, 1H), 3ꢀ92 (s, 3H), 4ꢀ08 (d, J = 12ꢀ6,
1H), 4ꢀ68 (dd, J = 3ꢀ0, J = 10ꢀ4, 1H), 7ꢀ30 (d, J = 8ꢀ0, 2
ArH), 8ꢀ03 (d, J = 8ꢀ0, 2 ArH); 13C-NMR (50 MHz,
CDCl3) d 2ꢀ1, 21ꢀ7, 21ꢀ8, 22ꢀ8, 24ꢀ9, 35ꢀ0, 54ꢀ2, 70ꢀ7, 80ꢀ5,
129ꢀ4, 129ꢀ6, 134ꢀ3, 146ꢀ0, 150ꢀ9, 167ꢀ2. Minor diaste-
reomer (4S*,5S*): colorless oil; 1H-NMR (400 MHz,
CDCl3) d 0ꢀ92 (d, J = 6ꢀ8, 3H), 0ꢀ93 (s, J = 6ꢀ8, 3H), 1ꢀ21
(ddd, J = 2ꢀ4, J = 8ꢀ8, J = 14ꢀ0, 1H), 1ꢀ55 (ddd, J = 4ꢀ4,
J = 10ꢀ8, J = 14ꢀ0, 1H), 1ꢀ77–1ꢀ87 (m, 1H), 2ꢀ45 (s, 3H),
3ꢀ75 (d, J = 12ꢀ0, 1H), 3ꢀ86 (s, 3H), 4ꢀ26 (d, J = 12ꢀ0,
1H), 4ꢀ54 (dd, J = 2ꢀ4, J = 11ꢀ2, 1H), 7ꢀ35 (d, J = 8ꢀ4, 2
ArH), 8ꢀ03 (d, J = 8ꢀ4, 2 ArH); 13C-NMR (100 MHz,
CDCl3) 10ꢀ2, 21ꢀ5, 21ꢀ9, 23ꢀ3, 25ꢀ0, 39ꢀ0, 53ꢀ7, 71ꢀ5, 80ꢀ8,
129ꢀ4, 130ꢀ0, 134ꢀ5, 146ꢀ1, 151ꢀ4, 165ꢀ9; ESI–MS m/z
495ꢀ0 [M]?, 518ꢀ0 [M ? Na]?. Anal Calcd for
C17H22INO6S (495ꢀ02): C, 41ꢀ22; H, 4ꢀ48; N, 2ꢀ83. Found:
C, 41ꢀ17; H, 4ꢀ41; N, 2ꢀ78.
(t, J = 7ꢀ4, 3H), 2ꢀ46 (s, 3H), 3ꢀ10 (d, J = 12ꢀ4, 1H), 3ꢀ96
(d, J = 12ꢀ4, 1H), 4ꢀ49 (q, J = 7ꢀ4, 2H, 50%), 4ꢀ50
(q, J = 7ꢀ4, 2H, 50%), 5ꢀ73 (s, 1H), 7ꢀ18–7ꢀ43 (m, 6 ArH),
7ꢀ98 (d, J = 8ꢀ3, 2 ArH); 13C-NMR (50 MHz, CDCl3) d
3ꢀ5, 14ꢀ0, 21ꢀ8, 64ꢀ2, 70ꢀ8, 81ꢀ9, 128ꢀ0, 128ꢀ3, 128ꢀ6, 129ꢀ4,
129ꢀ7, 133ꢀ9, 135ꢀ3, 146ꢀ2, 150ꢀ4, 167ꢀ0; ESI–MS m/z
563ꢀ0 [M]?, 586ꢀ0 [M ? Na]?. Anal Calcd for
C20H19ClINO6S (562ꢀ97): C, 42ꢀ61; H, 3ꢀ40; N, 2ꢀ48.
Found: C, 42ꢀ56; H, 3ꢀ44; N, 2ꢀ52.
Preparation of compounds 6a–c. General Procedure
To a solution containing products 5a–c (4ꢀ21 mmol) in
toluene (12ꢀ6 mL), H3PO2 (4ꢀ4 mL, 42ꢀ1 mmol) and eth-
ylpiperidine (5ꢀ9 mL, 42ꢀ1 mmol) were added and the
mixture was heated at reflux. Then, AIBN (235 mg,
1ꢀ4 mmol) was added, followed by a further portion after
1 h (235 mg). After 1 h the reaction mixture was poured in
H2O (15 mL) and extracted with ethyl acetate
(2 9 30 mL). After drying (Na2SO4), the solvent was
removed under reduced pressure and the residue was
purified by silica gel chromatography (cyclohexane:ethyl
acetate 7:3), to give compounds 6a–c.
t-Butyl (4S*,5R*)-4-(iodomethyl)-2-oxo-5-phenyl-3-
tosyloxazolidine-4-carboxylate (5c)
The title compound was obtained in 66% yield. Colorless
oil; 1H-NMR (200 MHz, CDCl3) d 1ꢀ65 (s, 9H), 2ꢀ44
(s, 3H), 3ꢀ06 (d, J = 12ꢀ2 Hz, 1H), 3ꢀ94 (d, J = 12ꢀ2 Hz,
1H), 5ꢀ78 (s, 1H), 7ꢀ30–7ꢀ40 (m, 7 ArH), 8ꢀ07 (d,
J = 8ꢀ5 Hz, 2 ArH); 13C-NMR (50 MHz, CDCl3) d 3ꢀ9,
21ꢀ7, 27ꢀ7, 71ꢀ5, 82ꢀ8, 85ꢀ8, 126ꢀ4, 128ꢀ3, 129ꢀ2, 129ꢀ8,
129ꢀ9, 134ꢀ1, 145ꢀ8, 150ꢀ7, 165ꢀ8; ESI–MS m/z 557ꢀ0
[M]?, 580ꢀ0 [M ? Na]?. Anal Calcd for C22H24INO6S
(557ꢀ04): C, 47ꢀ41; H, 4ꢀ34; N, 2ꢀ51. Found: C, 47ꢀ38; H,
4ꢀ38; N, 2ꢀ46.
Methyl (4S*,5R*)-4-methyl-2-oxo-5-phenyl-3-
tosyloxazolidine-4-carboxylate (6a)
The title compound was obtained in 67% yield. White
1
crystals; mp 122ꢁC; H-NMR (200 MHz, CDCl3) d 1ꢀ36
(s, 3H), 2ꢀ46 (s, 3H), 3ꢀ98 (s, 3H), 5ꢀ61 (s, 1H), 7ꢀ12–7ꢀ20
(m, 2 ArH), 7ꢀ30–7ꢀ43 (m, 5 ArH), 8ꢀ01 (d, J = 8ꢀ5, 2
ArH); 13C-NMR (50 MHz, CDCl3) d 18ꢀ7, 21ꢀ5, 53ꢀ6,
70ꢀ2, 82ꢀ4, 128ꢀ6, 129ꢀ1, 129ꢀ3, 129ꢀ4, 131ꢀ6, 134ꢀ4, 145ꢀ7,
123

494
M. Orena et al.
150ꢀ8, 170ꢀ2; ESI–MS m/z 389ꢀ1 [M]?, 412ꢀ1 [M ? Na]?.
Anal Calcd for C19H19NO6S (389ꢀ09): C, 58ꢀ60; H, 4ꢀ92;
N, 3ꢀ60. Found: C, 58ꢀ55; H, 4ꢀ87; N, 3ꢀ64.
C12H13NO4 (235ꢀ08): C, 61ꢀ27; H, 5ꢀ57; N, 5ꢀ95. Found: C,
61ꢀ21; H, 5ꢀ52; N, 6ꢀ01.
Methyl (4S*,5R*)-5-isobutyl-4-methyl-2-oxo-
oxazolidine-4-carboxylate (7b)
Methyl (4S*,5R*)-4-methyl-2-oxo-5-isobutyl-3-
tosyloxazolidine-4-carboxylate (6b)
The title compound was obtained in 75% yield. Colorless
gum; 1H-NMR (400 MHz, CDCl3) d 0ꢀ96 (d, J = 6ꢀ8, 3H),
0ꢀ98 (s, J = 6ꢀ8, 3H), 1ꢀ40 (ddd, J = 2ꢀ0, J = 9ꢀ2,
J = 14ꢀ0, 1H), 1ꢀ42 (s, 3H), 1ꢀ71 (ddd, J = 4ꢀ4, J = 11ꢀ2,
J = 14ꢀ0, 1H), 1ꢀ83 – 1ꢀ93 (m, 1H), 3ꢀ79 (s, 3H), 4ꢀ71 (dd,
J = 2ꢀ0, J = 11ꢀ2, 1H), 6ꢀ01 (br s, 1H, NH); 13C-NMR
(100 MHz, CDCl3) d 19ꢀ9, 21ꢀ4, 23ꢀ6, 24ꢀ9, 38ꢀ4, 53ꢀ2,
63ꢀ4, 79ꢀ8, 157ꢀ7, 172ꢀ8; ESI–MS m/z 215ꢀ1 [M]?, 238ꢀ1
[M ? Na]?. Anal Calcd for C10H17NO4 (215ꢀ12): C,
55ꢀ80; H, 7ꢀ96; N, 6ꢀ51. Found: C, 55ꢀ69; H, 7ꢀ90; N, 6ꢀ42.
The title compound was obtained in 87% yield. Colorless
1
oil; H-NMR (400 MHz, CDCl3) d 0ꢀ89 (d, J = 6ꢀ8, 3H),
0ꢀ92 (s, J = 6ꢀ8, 3H), 1ꢀ31 (ddd, J = 3ꢀ2, J = 4ꢀ0,
J = 14ꢀ0, 1H), 1ꢀ64 (ddd, J = 5ꢀ6, J = 10ꢀ0, J = 14ꢀ0,
1H), 1ꢀ70–1ꢀ81 (m, 1H), 1ꢀ74 (s, 3H), 2ꢀ45 (s, 3H), 3ꢀ90
(s, 3H), 4ꢀ53 (dd, J = 3ꢀ2, J = 10ꢀ0, 1H), 7ꢀ35 (d, J = 8ꢀ4,
2 ArH), 7ꢀ99 (d, J = 8ꢀ4, 2 ArH); 13C-NMR (100 MHz,
CDCl3) d 17ꢀ3, 21ꢀ8, 21ꢀ9, 23ꢀ0, 23ꢀ5, 24ꢀ8, 37ꢀ4, 53ꢀ8,
69ꢀ9, 80ꢀ4, 129ꢀ4, 129ꢀ6, 134ꢀ8, 145ꢀ8, 151ꢀ2, 170ꢀ3; ESI–
MS m/z 369ꢀ1 [M]?, 392ꢀ1 [M ? Na]?. Anal Calcd for
C17H23NO6S (369ꢀ12): C, 55ꢀ27; H, 6ꢀ28; N, 3ꢀ79. Found:
C, 55ꢀ16; H, 6ꢀ19; N, 3ꢀ85.
t-Butyl (4S*,5R*)-4-methyl-2-oxo-5-
phenyloxazolidine-4-carboxylate (7c)
t-Butyl (4S*,5R*)-4-methyl-2-oxo-5-phenyl-3-
tosyloxazolidine-4-carboxylate (6c)
The title compound was obtained in 98% yield. Colorless
1
oil; H-NMR (200 MHz, CDCl3) d 1ꢀ01 (s, 3H), 1ꢀ55 (s,
9H), 5ꢀ63 (br s, 1H, NH), 5ꢀ84 (s, 1H), 7ꢀ39 (m, 5 ArH);
13C-NMR (50 MHz, CDCl3) d 22ꢀ2, 27ꢀ9, 64ꢀ4, 82ꢀ2, 83ꢀ7,
126ꢀ5, 128ꢀ5, 128ꢀ9, 134ꢀ5, 157ꢀ1, 171ꢀ6; ESI–MS m/z
277ꢀ1 [M]?, 300ꢀ1 [M ? Na]?. Anal Calcd for C15H19NO4
(277ꢀ13): C, 64ꢀ97; H, 6ꢀ91; N, 5ꢀ05. Found: C, 64ꢀ92; H,
6ꢀ86; N, 5ꢀ01.
The title compound was obtained in 64% yield. Colorless
oil; 1H-NMR (200 MHz, CDCl3) d 1ꢀ29 (s, 3H), 1ꢀ62
(s, 9H), 2ꢀ45 (s, 3H), 5ꢀ60 (s, 1H), 7ꢀ12–7ꢀ44 (m, 7 ArH),
8ꢀ02 (d, J = 8ꢀ5 Hz, 2 ArH); 13C-NMR (50 MHz, CDCl3)
d 18ꢀ6, 23ꢀ3, 27ꢀ7, 70ꢀ8, 82ꢀ8, 84ꢀ2, 125ꢀ8, 128ꢀ6, 129ꢀ2,
129ꢀ4, 132ꢀ1, 134ꢀ9, 145ꢀ5, 151ꢀ1, 168ꢀ6; ESI–MS
m/z 431ꢀ1 [M]?, 454ꢀ1 [M ? Na]?. Anal Calcd for
C22H25NO6S (431ꢀ14): C, 61ꢀ24; H, 5ꢀ84; N, 3ꢀ25. Found:
C, 61ꢀ29; H, 5ꢀ81; N, 3ꢀ29.
Cleavage of products 7a,b. General procedure
To a solution containing compounds 7a,b (1ꢀ0 mmol) in
methanol (1 mL), 12 M HCl (5 mL) was added and the
mixture was heated at reflux for 10 h. The solvents were
removed under reduced pressure and another 12 M HCl
(5 mL) was added. The mixture was heated at reflux for
10 h for 7a and 20 h for 7b. After partial removal of HCl
under reduced pressure, the aqueous phase was diluted with
water (10 mL), washed with ethyl acetate (3 9 5 mL) and
finally evaporated under reduced pressure to give pure
8a,b.
Preparation of compounds 7a-c. General procedure
To a solution containing products 6a–c (0ꢀ194 mmol) in
dry methanol (6ꢀ0 mL), Mg turnings (47 mg, 1ꢀ94 mmol)
and NH4Cl (52 mg, 0ꢀ97 mmol) were added and suspen-
sion was refluxed for 2 h. After removal of the solvent
under reduced pressure, the residue was purified by silica
gel chromatography (cyclohexane:ethyl acetate 70:30), to
give compounds 7a–c.
(2S*,3R*)-2-Amino-3-hydroxy-2-methyl-3-
phenylpropanoic acid hydrochloride (8a)
Methyl (4S*,5R*)-4-methyl-2-oxo-5-
phenyloxazolidine-4-carboxylate (7a)
The title compound was obtained in 67% yield as amor-
phous solid. 1H-NMR (200 MHz, DMSO-d6) d 1ꢀ38
(s, 3H), 5ꢀ13 (s, 1H), 7ꢀ35–7ꢀ51 (m, 5 ArH); 13C-NMR
(50 MHz, DMSO-d6) d 18ꢀ9, 65ꢀ1, 75ꢀ8, 128ꢀ7, 129ꢀ6,
129ꢀ9, 138ꢀ9, 172ꢀ9; ESI–MS m/z 196ꢀ2 [MH]?, 219ꢀ2
[M ? Na]?. Anal Calcd for C10H14ClNO3 (231ꢀ17): C,
51ꢀ84; H, 6ꢀ09; N, 6ꢀ05. Found: C, 51ꢀ79; H, 6ꢀ03; N, 6ꢀ11.
The title compound was obtained in quantitative yield.
1
Colorless oil; H-NMR (200 MHz, CDCl3) d 1ꢀ05 (s, 3H),
3ꢀ87 (s, 3H), 5ꢀ86 (s, 1H), 6ꢀ48 (br s, 1H, NH), 7ꢀ39 (m, 5
ArH); 13C-NMR (50 MHz, CDCl3) d 21ꢀ8, 53ꢀ3, 64ꢀ3,
82ꢀ3, 126ꢀ4, 128ꢀ5, 128ꢀ9, 134ꢀ3, 157ꢀ7, 173ꢀ1; ESI–MS
m/z 235ꢀ1 [M]?, 258ꢀ1 [M ? Na]?. Anal Calcd for
123

Diastereoselective functionalisation of Baylis–Hillman adducts
495
(2S*,3R*)-2-Amino-3-hydroxy-2,5-dimethylhexanoic
acid hydrochloride (8b)
39ꢀ1 min (S). [a]D-124ꢀ0 (c 1ꢀ30, CH3OH) [lit. (Nakano
et al. 2006) [a]D-124ꢀ6 (c 1ꢀ30, CH3OH)].
The title compound was obtained in 95% yield as amor-
phous solid. 1H-NMR (400 MHz, DMSO-d6) d 0ꢀ84
(d, J = 6ꢀ4, 3H), 0ꢀ90 (d, J = 6ꢀ4, 3H), 1ꢀ10–1ꢀ18 (m, 1H),
1ꢀ29 (s, 3H), 1ꢀ32–1ꢀ39 (m, 1H), 1ꢀ72–1ꢀ85 (m, 1H), 3ꢀ36
(br s, 4H, OH ? NH), 3ꢀ77 (dd, J = 11ꢀ2, J = 1ꢀ6, 1H),
8ꢀ18 (br s, 1H, COOH); 13C-NMR (100 MHz, DMSO-d6) d
17ꢀ3, 21ꢀ0, 23ꢀ8, 23ꢀ9, 39ꢀ2, 63ꢀ5, 70ꢀ4, 172ꢀ2; ESI–MS
m/z 175ꢀ1 [MH]?, 198ꢀ1 [M ? Na]?. Anal Calcd for
C8H18ClNO3 (211ꢀ10): C, 43ꢀ59; H, 8ꢀ57; N, 6ꢀ62. Found:
C, 43ꢀ48; H, 8ꢀ46; N, 6ꢀ54.
Methyl (4S,5R)-4-(iodomethyl)-2-oxo-5-phenyl-3-
tosyloxazolidine-4-carboxylate (4S,5R)-(5a)
Starting from (R)-3a, methyl (R)-2-[phenyl(tosylcarba-
moyloxy)methyl]acrylate (R)-4a was prepared as reported
for compound 4a, and the product was cyclized without
purification to give the title compound as white crystals in
65% yield and 95% e.e. HPLC conditions: Daicel Chiralcel
OD-H, hexane:2-propanol 80:20 (0ꢀ7 mL/min), tR 17ꢀ2 min
(4S,5R) and 19ꢀ3 min (4R,5S). [a]D 14ꢀ1 (c 0ꢀ9, CHCl3).
Enantiopure (R)-3a was obtained by fractional crystalliza-
tion from dichloromethane (86% yield of recovered prod-
uct). [a]D 14ꢀ9 (c 0ꢀ77, CHCl3). It is worth mentioning that
careful preparation of the samples was needed, owing to the
very low solubility of the product in the elution mixture.
In fact, the product was dissolved in dichloromethane
(2 mL/mmol) and 4 lL of this solution was evaporated
under reduced pressure. The residue (about 0ꢀ1 mg) was
dissolved in 2-propanol (3 mL) and this solution was used
for HPLC analysis.
t-Butyl (2S*,3R*)-2-amino-2-methyl-3-
phenylpropanoate (9)
To a solution of compound 7c (52ꢀ6 mg, 0ꢀ19 mmol) in dry
methanol (0ꢀ19 mL) Pd–C 10% (19 mg) was added and the
suspension was stirred under a hydrogen atmosphere. After
3 h the catalyst was filtered off and removal of the solvent
gave the product 9 (39 mg, 86%) as a colorless oil.
1H-NMR (200 MHz, CDCl3) d 1ꢀ34 (s, 3H), 1ꢀ45 (s, 9H),
1ꢀ63 (s, 2H, NH2), 2ꢀ77 (d, J = 13ꢀ2 Hz, 1H), 3ꢀ11 (d,
J = 13ꢀ2 Hz, 1H), 7ꢀ18–7ꢀ28 (m, 5 ArH); 13C-NMR
(50 MHz, CDCl3) d 27ꢀ0, 28ꢀ0, 46ꢀ4, 58ꢀ8, 81ꢀ1, 126ꢀ8,
128ꢀ2, 130ꢀ2, 136ꢀ8, 176ꢀ3; ESI–MS m/z 251ꢀ2 [MH]?,
274ꢀ2 [M ? Na]?. Anal Calcd for C14H21NO3 (251ꢀ15): C,
66ꢀ91; H, 8ꢀ42; N, 5ꢀ57. Found: C, 66ꢀ86; H, 8ꢀ46; N, 5ꢀ53.
(2S,3R)-2-Amino-3-hydroxy-2-methyl-3-
phenylpropanoic acid (11)
In a way similar to that described for compound (2S*,3R*)-
8a, starting from (4S,5R)-5a (2S,3R)-(8a) (154 mg) was
obtained, directly dissolved in H2O (1 mL) and subjected
to ion exchange column (Dowex 50WX2, elution with 1 M
NH4OH) to give, after evaporation of water under reduced
pressure, the corresponding amino acid 11 (68%) as a white
solid. mp 228ꢁC; 1H-NMR (400 MHz, D2O) d 0ꢀ72 (s, 3H),
5ꢀ11 (s, 1H), 7ꢀ40–7ꢀ53 (m, 5 ArH); 13C-NMR (100 MHz,
D2O) d 18ꢀ5, 65ꢀ2, 74ꢀ9, 127ꢀ3, 128ꢀ6, 130ꢀ0, 137ꢀ3, 175ꢀ5;
[a]D-34ꢀ7 [c 0ꢀ3, H2O) [lit. (Avenoza et al., 2000) [a]D-35ꢀ6
(c 0ꢀ35, H2O) for 96% e.e.)]. ESI–MS m/z 196ꢀ2 [MH]?,
218ꢀ2 [M ? Na]?. Anal Calcd for C10H13NO3 (195ꢀ22): C,
61ꢀ53; H, 6ꢀ71; N, 7ꢀ17. Found: C, 61ꢀ45; H, 6ꢀ61; N, 7ꢀ23.
(R,S)-2-Amino-2-methyl-3-phenylpropanoic acid
hydrochloride (10)
The compound 9 (251 mg; 1ꢀ0 mmol) was dissolved in
6 M HCl (3 mL) and the solution was refluxed for 24 h.
After washing of the aqueous layer with ethyl acetate
(3 9 5 mL), water was removed under reduced pressure
to give the product 10 (195 mg, 78%) as a colorless
1
viscous oil. H-NMR (200 MHz, CD3OD) d 1ꢀ48 (s, 3H),
3ꢀ12 (s, 2H), 7ꢀ21–7ꢀ36 (m, 5ArH), 8ꢀ49 (s, 3H);
13C-NMR (50 MHz, CD3OD) d 21ꢀ9, 42ꢀ3, 59ꢀ9, 127ꢀ6,
128ꢀ7, 130ꢀ5, 134ꢀ1, 172ꢀ3. ESI–MS m/z 180ꢀ1 [MH]?,
202ꢀ1 [M ? Na]?. Anal Calcd for C10H14ClNO2
(215ꢀ07): C, 55ꢀ69; H, 6ꢀ54; N, 6ꢀ49. Found: C, 55ꢀ64; H,
6ꢀ50; N, 6ꢀ44.
X-ray data
Crystal data for 5e were collected on a Oxford Xcalibur S
˚
with Mo–Ka radiation, k = 0ꢀ71073 A, monochromator
graphite and equipped with a liquid nitrogen Oxford-
Cryostream device, hmax = 25ꢁ. A monoclinic P21/c space
group is obtained for the compound studied. The structure
was solved by direct methods (Altomare et al. 1993) and
refined against F2 (Sheldrick 2008). A geometric check
was performed with Platon (Spek 2008). The hydrogen
atoms were constrained to calculated positions and refined
using a riding model in all cases. An ORTEP plot in Fig. 1
Methyl (R)-3-hydroxy-2-methylene-3-
phenylpropanoate (R)-(3a)
According to the reported literature (Nakano et al. 2006)
the title compound was obtained as a colorless oil in 95%
e.e. HPLC conditions: Daicel Chiralcel OD-H, hexane:
2-propanol 98:2 (0ꢀ25 mL/min), tR 32ꢀ9 min (R) and
123

496
M. Orena et al.
a-allenic alcohols. Highly diastereoselective synthesis of syn-1,
2-amino alcohols and trans-5-alkyl-1-oxo-2-oxazolidine-4-car-
boxylic acids. J Org Chem 56:4888–4895
illustrates the structure at 50% probability level and the
crystallographic numbering (Farrugia 1997).
Mercury (MacRae et al. 2008) was used for the graph-
ical representation of the crystal packing. CCDC 747429
contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from
the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: (?44)1223-336-033;
or e-mail: deposit@ccdc.cam.ac.uk).
Fujita M, Kitagawa O, Suzuki T, Taguchi T (1997) Regiocontrolled
iodoaminocyclization reaction of an ambident nucleophile
mediated by basic metallic reagent. J Org Chem 62:7330–7335
Galeazzi R, Martelli G, Orena M, Rinaldi S (2004a) a-Methylene-b-
trichloroacetylamino alkanoates from trichloroacetimidates of
the Baylis–Hillman adducts. Synthesis 2560–2566
Galeazzi R, Martelli G, Mobbili G, Orena M, Rinaldi S (2004b)
Stereoselective iodocyclization of 3-acylamino-2-methylene
alkanoates: synthesis of analogues of N-benzoyl-syn-phenyliso-
serine. Org Lett 6:2571–2574
Hirama M, Iwashita M, Yamazaki Y, Ito S (1984) Carbamate
mediated functionalization of unsaturated alcohols II. Regio- and
stereo-selective synthesis of 1, 3-syn and 1, 2-anti amino alcohol
derivatives via iodocarbamation. Tetrahedron Lett 25:4963–
4964
Acknowledgments We thank Nanodream s.r.l. (Iesi, Ancona, Italy)
for financial support and Dr. Samuele Agostinelli for valuable tech-
nical support.
Imai M, Goto T, Furuta T, Wakimoto T, Kan T (2008) Stereocon-
trolled total synthesis of (-)-myriocin. Tetrahedron Asymmetr
19:2771–2773
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