A practical stereoselective synthesis of both enantiomers of Threo- and Erythro-β-hydroxy norvaline from (S)-serine derivatives

Article abstract of DOI:10.1016/S0040-4020(00)00038-7

The four enantiopure diastereoisomers of β-hydroxy norvaline have been prepared from L-serine in moderate chemical yield. The method is based on the diastereoselective addition of different organometallics to easily accessible serinal derivatives. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00038-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1523–1531
A Practical Stereoselective Synthesis of both Enantiomers of
Threo- and Erythro-b-Hydroxy Norvaline
from (S)-Serine Derivatives
*
´
´
´
Jose M. Andres, Noemı de Elena and Rafael Pedrosa
´
´
Departamento de Quımica Organica, Facultad de Ciencias, Universidad de Valladolid Doctor Mergelina s/n, 47011 Valladolid, Spain
Received 25 October 1999; revised 20 December 1999; accepted 6 January 2000
Abstract—The four enantiopure diastereoisomers of b-hydroxy norvaline have been prepared from l -serine in moderate chemical yield.
The method is based on the diastereoselective addition of different organometallics to easily accessible serinal derivatives. ᭧ 2000 Elsevier
Science Ltd. All rights reserved.
Introduction
serine derivatives taking threo and erythro-b-hydroxy
norvaline as a model.
The interest in b-hydroxy-a-amino acids, a class of primary
metabolites, is based in their biological activity as enzyme
inhibitors,1 and as starting materials in the synthesis of more
complex molecules.2 In recent years the interest in the
synthesis of both natural and non-proteinogenic amino
acids in enantiopure form has grown and some general
methods have been developed.3 Some stereoselective
approaches are based on aldol condensation of aldehydes
with glycine derivatives,4 Sharpless asymmetric epoxi-
dation/dihydroxylation5 or electrophilic amination of
b-hydroxy esters.6 Stereoselective additions to serine
derivatives7 or stereoselective reductions of a-amino
ketones8 also constitute a good entry to these compounds,
although some of these methods allowed the preparation of
only one stereoisomer.9
The first approach started from 2-amino-1,3-diols syn-2 and
anti-2 prepared by alkylation of (S)-N,N-dibenzyl-O-
TBDMS-serinal in three steps with 73 and 64% overall
yield respectively. The key step of this route was the oxi-
dation of the alcohol into the carboxylic group. Attempts to
convert amino alcohol derivatives 2 into carboxylic acids 4
by oxidation with PDC failed because a very complex
mixture of degradation compounds was formed. Then, the
oxidation was achieved in two steps. First, syn-2 and anti-2
were submitted to Swern oxidation affording syn- and anti-
3-hydroxynorvalinals 3 respectively in excellent yield.
Searching for an oxidant capable to transform the aldehydes
3 into the carboxylic acids 4 and compatible with the
N,N-dibenzylamino and MEM groups some systems have
been tested14 (Scheme 1).
We have previously reported10 that diethylzinc shows a very
high syn selectivity in additions to chiral a-dibenzylamino
aldehydes, and it constitutes an alternative to the use of
some other organometallics.11 In this way (S)-N,N-di-
benzyl-O-TBDMS-serinal 1 has been used by us and
others12 as a starting chiron in the stereodivergent synthesis
of chiral compounds and sphingosine derivatives13 by
tuning the nature of the organometallic used as nucleophile.
Treatment of syn-3 with the system NaIO4-RuO2 at rt15 led
to degradation and the isolation of 7 in 12% yield as only
identified product as a consequence of benzylic oxidation
and oxidation-elimination of the MEM group. When syn-3
and anti-3 were subjected to reaction with KMnO4 in t-
BuOH-5% NaH2PO4 at 0ЊC as described by Masamune16
syn-4 and anti-4 were obtained but in modest yield. The
best results in the protected a-amino-b-hydroxy acids 4
was obtained by oxidation of aldehydes 3 with NaClO2/
KH2PO4/2-methyl-2-butene in tBuOH-CH3CN at 0ЊC by a
modified reported procedure.17 These conditions allowed
reproducible formation of syn- and anti-4 in good
yield, although accompanied by amides 8 and ent-8.
The formation of this by-product, due to C-C bond
cleavage is known to occur for oxidations of enolizable
aldehydes.18
Now we report our efforts on the development of a simple
methodology for the control of the relative and absolute
stereochemistry of the two stereocenters in the stereo-
divergent synthesis of b-hydroxy-a-amino acids from
Keywords: diastereoselective synthesis; aminoalcohols; alkylzincs;
aminoaldehydes.
* Corresponding author. Tel.: ϩ983-423211; fax: ϩ983-423013; e-mail:
pedrosa@qo.uva.es
Deprotection of syn- and anti-4 by treatment with 2N
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00038-7

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J. M. Andres et al. / Tetrahedron 56 (2000) 1523–1531
1524
Scheme 1. Reagents and conditions: (i) (COCl)2, DMSO, Et3N, CH2Cl2, Ϫ78ЊC; (ii) NaIO4-RuO2, CH3CN/CCl4/H2O/(CH3)2CO, rt; (iii) KMnO4, tBuOH-5%
NaH2PO4, 0ЊC; (iv) NaClO2, KH2PO4, 2-methyl-2-butene, CH3CN-tBuOH, 0ЊC; (v) 2N HCl, THF-H2O, 20ЊC for syn-4; NaI, TMSCl, CH3CN, Ϫ20ЊC for anti-
4; (vi) H2, Pd(OH)2-C, MeOH-H2O.
solution of HCl in THF-H2O and NaI/TMSCl in acetonitrile
transformed into the N-Boc derivatives syn- and anti-10
by treatment with Boc2O. The oxidation of N-Boc amino-
alcohols by PDC (5 equiv.) in DMF at 20ЊC yielded the
b-hydroxy-a-amino acid derivatives syn- and anti-11 in
good yields. Finally, removal of the carbamate and MEM
groups under acid conditions delivered the desired syn- and
anti-b-hydroxy norvalines 6.
at Ϫ20ЊC lead to syn- and anti-5, that were efficiently
19
converted by low pressure hydrogenolysis over Pd(OH)2
into the target (2R, 3S)- and (2R, 3R)-b-hydroxy-norvaline
respectively. The physical and spectroscopic data were
coincident with the literature values,9c,20 and their specific
rotations confirmed the stereochemistry and enantiomeric
purity of the final compounds.
Since the utility of the commented synthetic ways was
limited by the oxidation step of the alcohol to the carboxylic
acid an alternative and complementary route was envisaged
to obtain b-hydroxy norvalines more directly avoiding the
oxidation step. The novel approach is based in masking the
carboxylic group of serine as a trioxabicyclo [2.2.2]ortho-
ester (OBO)21 and on the diastereoselective addition of
organometallics to serinal derivative 15.
To overcome the problems in the oxidation step associated to
the presence of the dibenzylamino moiety, an alternative way
to hydroxy norvalines was followed as summarized in
Scheme 2.
In this way, the starting syn- and anti-2 were debenzylated
to syn- and anti-9 by hydrogenolysis over Pd(OH)2 and
Scheme 2. Reagents and conditions: (i) H2, Pd(OH)2-C, MeOH; (ii) Boc2O, CH2Cl2, 20ЊC; (iii) PDC, DMF, 20ЊC; (iv) 1. 2N HCl, 2. Propylene oxide, EtOH,
reflux.

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J. M. Andres et al. / Tetrahedron 56 (2000) 1523–1531
1525
Scheme 3.
Previously the reactions of 15 with different magnesium and
zinc derivatives have been tested. Thus, 15 was converted
into the syn aminoalcohols 16a–d by treatment with an
excess (4 equiv.) of dimethyl-, diethyl-, diisopropyl- and
diphenylzinc respectively (Scheme 3). As expected, the
addition of zinc derivatives proceeded under chelation
control10 leading stereoespecifically to alkyl derivatives
16a–c (entries 2, 4, 6 in Table 1) and with moderate d.e.
to the phenyl derivative 16d (entry 8). In the same way,
methylmagnesium iodide, ethylmagnesium bromide,
isopropylmagnesium bromide and phenylmagnesium
bromide react with 15, in a non chelation mode, giving
anti-16a–d as major diastereoisomers (entries 1, 3, 5 and
7 in Table 1).
The synthesis of b-hydroxy norvalines ent-syn-6 and
ent-anti-6 was then envisaged from (S)-serine as summar-
ized in Scheme 4.
Cbz-l -Ser-OBO ester 12 was prepared from commercially
available Cbz-serine in two steps as previously described,7f,g
and transformed into 13 by hydrogenolysis on Pearlman’s
catalyst. Reaction of 13 with benzyl bromide in the presence
of potassium carbonate gave 14, which upon Swern oxida-
tion yielded (S)-N,N-dibenzyl-OBO-serinal 15 in excellent
yield. The stereodivergent preparation of diastereomeric
syn- and anti-16b was achieved, in moderate chemical
yield, by addition of diethylzinc (entry 4 in Table 1) and
ethylmagnesium bromide (entry 3 in Table 1) to 15 respec-
tively. Debenzylation by hydrogenolysis, followed by
elimination of the OBO protective group by sequential treat-
ment with 2N HCl in THF-H2O and Na2CO3 solution lead to
(2S, 3R)-b-hydroxy norvaline (ent-syn-6) and (2S, 3S)-b-
hydroxy norvaline (ent-anti-6).
Table 1. Reaction of serinal derivative 15 with magnesium and zinc deri-
vatives
Entry RM
Solvent
t (H) Yield (%)a 16 (syn:anti)b
1
2
3
4
5
6
7
8
MeMgI
Me2Zn
EtMgBr Et2O
Et2Zn
i-PrMgCl Et2O
i-Pr2Zn
PhMgBr Et2O
Ph2Zn
Et2O
Toluene
1
144
2
48
27c
54e
62
44
79
55
62
16a (17:83)
16a (100:0)d
16b (22:78)
16b (100:0)d
16c (12:88)
16c (100:0)d
16d (17:83)
16d (76:24)
Toluene-hexane
6
4f
Toluene-hexane
2.5
18
6
In summary, the results summarized now show a new
stereodivergent synthesis of all the four diastereoisomers
of b-hydroxy norvaline from serinal derivatives 1 and 15
readily available from l -serine. Further investigation into
the scope and utility of these intermediates for the synthesis
of a variety of enantiopure b-hydroxy-a-amino acids is in
progress.
Toluene
a Yields refer to pure and isolated compounds.
b Measured by integration of the 1H NMR signals in the reaction mixture.
c Aminoaldehyde 15 was recovered (50%).
1
d Stereoisomers anti were not detected in H NMR spectra.
e The reduction alcohol (14) was also isolated (16%).
f The reaction was carried out at Ϫ78ЊC.
Scheme 4. Reagents and conditions: (i) H2, Pd(OH)2-C, MeOH; (ii) BnBr, K2CO3, CH3CN, 20ЊC; (iii) (COCl)2, DMSO, Et3N, Ϫ78ЊC; (iv) Et2Zn, hexane-
toluene, 0ЊC; (v) EtMgBr, Et2O, 0ЊC; (vi) 1. H2, Pd(OH)2-C, MeOH, 2. HCl 2N, THF-H2O, rt. 3. Na2CO3, dioxane-H2O, then HCl 2N. 4. Propylene oxide,
EtOH, reflux.

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J. M. Andres et al. / Tetrahedron 56 (2000) 1523–1531
1526
Experimental
(2R,3R)-2-(N,N-Dibenzylamino)-3-[(2-methoxyethoxy)-
methoxy]-1-pentanoic acid (anti-4). The aminoacid anti-4
was obtained from anti-3 (289 mg, 0.75 mmol) by the
procedure A described for syn-4 and purified by flash chro-
matography (silica gel, hexane/EtOAcˆ1/2): 121 mg
(0.3 mmol, 40%). The same compound was also prepared
from anti-3 (387 mg, 1 mmol) by the procedure B described
for syn-4 and purified by flash chromatography (CH2Cl2/
Et2O: 5/2): 249 mg (0.62 mmol, 62%). Colorless oil.
[a]2D3ˆϩ71.7 (cˆ1, CHCl3). IR (film): 3500–2500, 1700,
General
The reactions were carried out in oven-dried glassware,
under argon atmosphere, and using anhydrous solvents.
Starting aminoaldehydes syn-3 and anti-3 were prepared
as previously described.12a Diethylzinc, as 1 M solution in
hexane and dimethylzinc as 2 M solution in toluene, were
purchased from Aldrich. Diisopropylzinc and diphenylzinc
were prepared from isopropylmagnesium chloride and
1450, 740, 700 cmϪ1 1H NMR (CDCl3): 0.55 (t, 3H,
.
phenyllithium and ZnCl2 by a described method.22 The H
1
Jˆ7.4 Hz, CH3CH2); 1.72 (m, 1H, CHHCH3); 1.84 (m,
1H, CHHCH3); 3.37 (s, 3H, CH3O); 3.42 (d, 1H,
Jˆ9.9 Hz, CHN); 3.47 (d, 2H, Jˆ13.6 Hz, CHHPh); 3.54
(m, 2H, OCH2CH2O); 3.67 (m, 2H, OCH2CH2O); 3.94 (d,
2H, Jˆ13.6 Hz, CHHPh); 4.12 (m, 1H, CHOMEM); 4.70
(d, 1H, Jˆ7.2 Hz, OCHHO); 4.73 (d, 1H, Jˆ7.2 Hz,
OCHHO); 7.20–7.40 (m, 10H, Harom). 13C NMR (CDCl3):
6.7 (CH3CH2); 22.4 (CH2CH3); 55.1 (CH2Ph); 58.9 (CH3O);
62.6 (CHN); 67.2 (OCH2CH2O); 71.7 (OCH2CH2O); 76.1
(CHOMEM); 95.1 (OCH2O); 127.2, 128.2, 129.2 (CHarom);
138.7 (Carom); 175.8 (CO2H). Anal. Calcd for C23H31NO5: C,
68.80; H, 7.78; N, 3.49. Found: C, 68.59; H, 7.82; N, 3.33.
NMR (300 MHz) and 13C NMR (75 MHz) spectra were
registered on a Bruker AC 300 or Bruker AMX 300, using
TMS as internal standard. IR spectra were recorded on a
Philips PU 9706 Spectrometer, as film or KBr dispersion.
Optical rotations were measured on a Perkin–Elmer 241
Polarimeter in a 1 dm. cell.
(2R,3S)-2-(N,N-Dibenzylamino)-3-[(2-methoxyethoxy)-
methoxy]-1-pentanoic acid (syn-4). Procedure A (KMnO4/
NaH2PO4). A solution of syn-3 (289 mg, 0.75 mmol) in
t-BuOH (4 mL) was diluted with an aqueous 5% NaH2PO4
solution (4 mL) and to the resulting mixture was added, with
vigorous stirring, an aqueous 1 M KMnO4 solution
(1.5 mmol, 2 equiv.) at 0ЊC. After 40 min, the reaction
was quenched by addition of a saturated solution of
Na2SO3 and the mixture was adjusted to pHˆ6 by addition
of cold (0ЊC) 10% HCl. The usual extractive workup with
ethyl acetate followed by flash chromatography (silica gel,
hexane/EtOAc: 1/2) provided the carboxylic acid syn-4 as a
colorless oil: 133 mg (0.33 mmol, 44%). [a]2D3ˆϩ47.4
(cˆ0.8, CHCl3). IR (film): 3500–2500, 1700, 1450, 750,
(2R,3S)-2-(N,N-Dibenzylamino)-3-hydroxy-1-pentanoic
acid (syn-5). A mixture of syn-4 (378 mg, 0.94 mmol) and
2N HCl solution in THF-H2O (13 mL) was stirred overnight
at room temperature. The pH of the reaction was adjusted to
6 with saturated NaHCO3 solution and the mixture extracted
with ether (3×15 mL). The combined organic layers were
washed with brine, dried over Na2SO4, concentrated and
chromatographed (CH2Cl2/Et2O: 5/1) to yield syn-5 as a
colorless oil: 215 mg (0.67 mmol, 71%). [a]2D3ˆϩ127.4
(cˆ2.6, CHCl3). IR (film): 3500–2500, 1700, 1600, 750,
700 cmϪ1
.
1H NMR (CDCl3): 0.67 (t, 3H, Jˆ7.4 Hz,
700 cmϪ1
.
1H NMR (CDCl3): 0.95 (t, 3H, Jˆ7.3 Hz,
CH3CH2); 1.82 (m, 2H, CH2CH3); 3.41 (s, 3H, CH3O);
3.53 (d, 1H, Jˆ4.7 Hz, CHN); 3.60 (m, 3H, OCHHCH2O);
3.81 (m, 1H, OCHHCH2O); 3.95 (d, 2H, Jˆ14.0 Hz,
CHHPh); 4.05 (m, 1H, CHOMEM); 4.22 (d, 2H,
Jˆ14.0 Hz, CHHPh); 4.72 (d, 1H, Jˆ7.1 Hz, OCHHO);
4.76 (d, 1H, Jˆ7.1 Hz, OCHHO); 7.20–7.50 (m, 10H,
Harom); 7.75 (br s, 1H, CO2H). 13C NMR (CDCl3): 9.6
(CH3CH2); 24.5 (CH2CH3); 55.8 (CH2Ph); 58.9 (CH3O);
62.8 (CHN); 67.1 (OCH2CH2O); 71.8 (OCH2CH2O); 81.3
(CHOMEM); 95.5 (OCH2O); 127.0, 128.2, 128.9 (CHarom);
139.6 (Carom); 176.3 (CO2H). Anal. Calcd for
C23H31NO5: C, 68.80; H, 7.78; N, 3.49. Found: C,
69.01; H, 7.95; N, 3.68.
CH3CH2); 1.32 (m, 1H, CHHCH3); 1.65 (m, 1H,
CHHCH3); 3.26 (d, 1H, Jˆ9.3 Hz, CHN); 3.68 (d, 2H,
Jˆ13.2 Hz, CHHPh); 3.97 (m, 1H, CHOH); 4.10 (d, 2H,
Jˆ13.2, CHHPh); 4.21 (br s, 1H, OH); 7.20–7.40 (m,
10H, Harom). 13C NMR (CDCl3): 9.8 (CH3); 27.1
(CH2CH3); 54.8 (CH2Ph); 65.8 (CHN); 68.3 (CHOH);
128.1, 128.7, 129.5 (CHarom); 135.6 (Carom); 171.8 (CO2H).
Anal. Calcd for C19H23NO3: C, 72.82; H, 7.40; N, 4.47.
Found: C, 72.72; H, 7.54; N, 4.62.
(2R,3R)-2-(N,N-Dibenzylamino)-3-hydroxy-1-pentanoic
acid (anti-5). To a 0.1 M solution of anti-4 (100 mg,
0.25 mmol) in dry acetonitrile at Ϫ20ЊC was added NaI
(112 mg, 0.75 mmol, 3 equiv.) and TMSCl (0.1 mL,
0.75 mmol, 3 equiv.). The reaction mixture was allowed to
rise rt, stirred overnight and quenched with methanol (3 mL)
and water (3 mL). The pH of the reaction was adjusted to 6
and the mixture extracted with ethyl acetate (3×10 mL). The
combined organic layers were washed with saturated
Na2SO3 solution and with brine, dried over Na2SO4, concen-
trated and chromatographed (silica gel, hexane/EtOAc: 1/1)
to yield anti-5 as a colorless oil: 55 mg (0.17 mmol, 70%).
Procedure B (NaClO2/NaH2PO4/2-methyl-2-butene). To a
solution of aminoaldehyde syn-3 (387 mg, 1 mmol) in
16 mL of t-BuOH–CH3CN (5/3) was added 2-methyl-2-
butene (1.3 mL, 12 mmol, 12 equiv.). To this was added a
solution containing 80% NaClO2 (678 mg, 6 mmol,
6 equiv.) and NaH2PO4·2H2O (936 mg, 6 mmol, 6 equiv.)
in H2O (20 mL) dropwise at 0ЊC. The resulting solution
was stirred at 0ЊC for 30 min and quenched by addition of
a 5% Na2S2O5 solution (5 mL). The solution was adjusted to
pHˆ6 and the mixture was extracted with ethyl acetate
(3×10 mL), the combined organic phases were washed
with brine, dried (Na2SO4) and the solvent was evaporated.
The product was purified by flash chromatography (silica
gel, CH2Cl2/Et2O: 5/2) yielding syn-4 as a colorless oil:
261 mg (0.65 mmol, 65%).
1
[a]2D3ˆϩ45.5 (cˆ0.9, CHCl3). H NMR (CDCl3): 0.83 (t,
3H, Jˆ7.4 Hz, CH3CH2); 1.35 (m, 1H, CHHCH3); 1.86 (m,
1H, CHHCH3); 3.21 (d, 1H Jˆ7.5 Hz, CHN); 3.74 (d, 2H,
Jˆ13.5 Hz, CHHPh); 3.85 (m, 3H, CHHPh and CHOH);
4.02 (s, 1H, OH); 7.20–7.50 (m, 10H, Harom); 7.57 (br s,
1H, CO2H). 13C NMR (CDCl3): 9.7 (CH3); 27.0 (CH2CH3);

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J. M. Andres et al. / Tetrahedron 56 (2000) 1523–1531
1527
55.5 (CH2Ph); 65.9 (CHN); 71.1 (CHOH); 127.3, 128.4,
129.2 (CHarom); 138.5 (Carom); 176.0 (CO2H). Anal. Calcd
for C19H23NO3: C, 72.82; H, 7.40; N, 4.47. Found: C, 72.63;
H, 7.43; N, 4.34.
4.44 (dd, 1H, Jˆ7.8 Hz, Jˆ4.8 Hz, CHOMEM); 4.49 (d,
1H, Jˆ14.6 Hz, CHHPh); 4.52 (s, 2H, CH2Ph); 4.69 (d,
1H, Jˆ14.6 Hz, CHHPh); 7.20–7.40 (m, 10H, Harom). 13C
NMR (CDCl3): 10.1 (CH3CH2); 26.1 (CH2CH3); 48.0
(CH2Ph); 49.1 (CH2Ph); 58.9 (CH3O); 67.2 (OCH2CH2O);
71.5 (OCH2CH2O); 75.4 (CHOMEM); 94.5 (OCH2O);
126.7, 127.4, 127.6, 128.4, 128.5, 128.8 (CHarom); 136.4,
137.0 (Carom); 172.3 (CˆO). Anal. Calcd for C22H29NO4:
C, 71.13; H, 7.87; N, 3.77. Found: C, 70.96; H, 7.96; N,
3.83.
(2R, 3S)-3-Hydroxy norvaline (syn-6). To a solution of
syn-5 (157 mg, 0.5 mmol) in a 1:1 mixture MeOH–H2O
(5 mL) was added 40 mg of 20% Pd(OH)2–C in one portion.
The mixture was stirred under hydrogen atmosphere and the
reaction was monitored by TLC. After 3 h the reaction was
completed, the catalyst was removed by filtration through
celite and washed with water. The solvent was concentrated
under reduced pressure and the residue was purified by flash
chromatography (silica gel, CH2Cl2/CH3OH/NH4OH: 6/4/
1), to give syn-6 as a colorless solid: 56 mg (0.43 mmol,
85%). Mp 229–230ЊC (dec) (H2O/acetone). [a]2D3ˆϩ7.9
(cˆ0.82, H2O). [Lit.20b: mp 232–233ЊC; [a]2D3ˆϩ7.8
(R)-N,N-Dibenzyl-2-[(2-methoxyethoxy)methoxy]-butyr-
amide (ent-8). This compound was obtained as the minor
product in the oxidation of the aminoaldehyde anti-3 by the
procedure B: 104 mg (0.22 mmol, 22%). Colorless oil.
[a]2D3ˆϩ41.8 (cˆ0.7, CHCl3). Anal. Calcd for
C22H29NO4: C, 71.13; H, 7.87; N, 3.77. Found: C, 71.01;
H, 7.77; N, 3.80.
1
(cˆ0.85, H2O)]. H NMR (D2O): 0.87 (t, 3H, Jˆ7.4 Hz,
CH3); 1.49 (m, 2H, CH2); 3.58 (d, 1H, Jˆ4.2 Hz, CHN);
3.88 (m, 1H, CHOH). 13C NMR (D2O): 11.8 (CH3); 28.8
(CH2); 61.1 (CHN); 73.7 (CHOH); 175.6 (CO2H).
(2S, 3S)-2-Amino-3-[(2-methoxyethoxy)methoxy]-1-pen-
tanol (syn-9). To a solution of syn-2 (1.72 g, 4.4 mmol) in
methanol (50 mL) was added Pd(OH)2–C (340 mg) in one
portion. The mixture was stirred under hydrogen for 3.5 h
and the catalyst was removed by filtration through celite and
washed with methanol. The solvent was evaporated under
reduced pressure to afford the pure product syn-9 as a color-
less oil: 0.92 g (4.4 mmol, 100%). [a]2D3ˆϩ51.3 (cˆ1.2,
(2R, 3R)-3-Hydroxy norvaline (anti-6). The aminoacid
anti-6 was obtained by debenzylation of anti-5 (47 mg,
0.15 mmol) and purified as described for syn-6: 18 mg
(0.13 mmol, 90%). Colorless solid, mp 223–224ЊC (dec)
(H2O/acetone). [a]D23ˆϪ4.6 (cˆ0.9, H2O). [a]D23ˆϪ25.4
(cˆ1, 1N HCl). [Lit.9c: mp 222–224ЊC; [a]2D3ˆϪ24.3
CHCl3). IR (film): 3340, 1450, 1030 cmϪ1 1H NMR
.
1
(cˆ1, 1N HCl; Lit.20a: [a]2D3ˆϪ0.3 (cˆ1, 1N HCl)]. H
(CDCl3): 0.92 (t, 3H, Jˆ7.4 Hz, CH3CH2); 1.62 (m, 2H,
CH2CH3); 2.96 (m, 1H, CHNH2); 3.25 (br s, 3H, OH and
NH2); 3.40 (s, 3H, CH3O); 3.55 (m, 4H); 3.67 (m, 2H); 3.80
(m, 1H); 4.74 (d, 1H, Jˆ7.0 Hz, OCHHO); 4.79 (d, 1H,
Jˆ7.0 Hz, OCHHO). 13C NMR (CDCl3): 9.4 (CH3CH2);
23.5 (CH2CH3); 54.3 (CHNH2); 59.0 (CH3O); 63.1
(CH2OH); 67.4 (OCH2CH2O); 71.6 (OCH2CH2O); 79.2
(CHOMEM); 95.0 (OCH2O). Anal. Calcd for C9H21NO4:
C, 52.15; H, 10.21; N, 6.76. Found: C, 51.92; H, 10.10;
N, 6.70.
NMR (D2O): 0.80 (t, 3H, Jˆ7.4 Hz, CH3); 1.34 (m, 2H,
CH2); 3.65 (d, 1H, Jˆ3.7 Hz, CHN); 3.82 (m, 1H,
CHOH). 13C NMR (D2O): 12.4 (CH3); 26.7 (CH2); 61.7
(CHN); 73.8 (CHOH); 174.5 (CO2H).
N-Benzyl, N-benzoyl-2-amino-2-penten-1-al (7).
A
solution of aminoaldehyde syn-3 (289 mg, 0.75 mmol) in
a acetonitrile (3 mL)-CCl4 (3 mL)-water (4 mL)-acetone
(1 mL) was stirred with solid NaIO4 (642 mg, 3 mmol) at
room temperature. After 15 min, hydrated RuO2 (3 mg) was
added and the mixture was stirred for a further 1 h. The
mixture was treated with propan-2-ol (1 mL) and filtered
through a Celite pad. The solvent was removed and the
residue was chromatographed over silica gel (hexane/
EtOAc: 8/1) to give 7 as a colorless solid: 26 mg
(0.09 mmol, 12%). Mp 107–108ЊC (from hexane). 1H
NMR (CDCl3): 0.41 (t, 3H, Jˆ7.5 Hz, CH3); 1.60 (m, 2H,
CH2CH3); 4.16 (d, 1H, Jˆ14.1 Hz, CHHPh); 5.55 (d, 1H,
Jˆ14.1 Hz, CHHPh); 6.22 (dd, 1H, Jˆ8.4 Hz, Jˆ6.6 Hz,
CHˆC); 7.20–7.40 (m, 10H, Harom); 9.25 (s, 1H, CHO).
13C NMR (CDCl3): 11.3 (CH3); 22.2 (CH2); 49.8 (CH2Ph);
127.2, 127.8, 128.3, 129.8, 130.2 (CHarom); 135.8, 136.5
(Carom); 141.2 (CˆCH); 157.1 (CHˆC); 170.9 (CON);
190.1 (CHO). Anal. Calcd for C19H19NO2: C, 77.79; H,
6.53; N, 4.77. Found: C, 77.68; H, 6.65; N, 4.82.
(2S, 3R)-2-Amino-3-[(2-methoxyethoxy)methoxy]-1-pen-
tanol (anti-9). The debenzylated aminoalcohol anti-9 was
obtained from anti-2 (2.0 g, 5.2 mmol) by the procedure
described for syn-9: 992 mg (4.79 mmol, 92%). Colorless
oil. [a]2D3ˆϪ56.1 (cˆ1, CHCl3). IR (film): 3300, 1585,
1025 cmϪ1
.
1H NMR (CDCl3): 0.87 (t, 3H, Jˆ7.4 Hz,
CH3CH2); 1.52 (m, 2H, CH2CH3); 2.98 (m, 1H, CHNH2);
3.26 (br s, 3H, OH and NH2); 3.32 (s, 3H, CH3O); 3.51 (m,
3H, OCH2CH2O and CHOMEM); 3.60 (m, 3H,
OCH2CHHO and CH2OH); 3.69 (m, 1H, OCH2CHHO);
4.67 (d, 1H, Jˆ7.1 Hz, OCHHO); 4.71 (d, 1H, Jˆ7.1 Hz,
OCHHO). 13C NMR (CDCl3): 9.5 (CH3CH2); 23.5
(CH2CH3); 54.4 (CHNH2); 58.8 (CH3O); 61.9 (CH2OH);
67.3 (OCH2CH2O); 71.5 (OCH2CH2O); 81.2 (CHOMEM);
95.3 (OCH2O). Anal. Calcd for C9H21NO4: C, 52.15; H,
10.21; N, 6.76. Found: C, 51.99; H, 10.39; N, 6.83.
(S)-N,N-Dibenzyl-2-[(2-methoxyethoxy)methoxy]-butyr-
amide (8). The compound 8 was obtained as the minor
product in the oxidation of the aminoaldehyde syn-3 by
the procedure B: 104 mg (0.28 mmol, 28%). Colorless oil.
[a]2D3ˆϪ44.1 (cˆ1, CHCl3). IR (film): 2910, 1640, 730,
(2S,3S)-2-[tert-Butoxycarbonylamino]-3-[(2-methoxyethoxy)-
methoxy]-1-pentanol (syn-10).
A solution of syn-9
(483 mg, 2.33 mmol) and di-tert-butyl dicarbonate
(537 mg, 2.46 mmol, 1.05 equiv.) in anhydrous CH2Cl2
(15 mL) under argon was kept at 20ЊC for 5 h. At this
time, the reaction was quenched with water (30 mL) and
the aqueous layer was extracted with two 25 mL portions
700 cmϪ1
.
1H NMR (CDCl3): 0.96 (t, 3H, Jˆ7.4 Hz,
CH3CH2); 1.82 (m, 2H, CH2CH3); 3.33 (s, 3H, CH3O);
3.46 (m, 2H, OCH2CH2O); 3.71 (m, 2H, OCH2CH2O);

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J. M. Andres et al. / Tetrahedron 56 (2000) 1523–1531
1528
of CH2Cl2. The combined organic extracts were washed
with a saturated NaHCO3 solution and worked up as
usual. The crude product was purified by flash chroma-
tography (silica gel, hexane/EtOAc: 2/3) to yield syn-10
(2R,3R)-2-[tert-Butoxycarbonylamino]-3-[(2-methoxy-
ethoxy)methoxy]-1-pentanoic acid (anti-11). The pro-
tected aminoacid anti-11 was prepared from anti-10
(922 mg, 3.0 mmol) as described for syn-11: 713 mg
(2.22 mmol, 74% yield). Colorless oil. [a]2D3ˆϪ25.1
as
a
colorless oil: 702 mg (2.28 mmol, 98%).
1
[a]2D3ˆϩ53.2 (cˆ1, CHCl3). IR (film): 3440, 1700, 1495,
(cˆ0.94, CHCl3). IR (film): 3340, 1710, 1040 cmϪ1. H
1040, 840 cmϪ1. H NMR (CDCl3): 0.87 (t, 3H, Jˆ7.5 Hz,
NMR (CDCl3): 0.98 (t, 3H, Jˆ7.4 Hz, CH3CH2); 1.45 (s,
9H, (CH3)3C); 1.73 (m, 2H, CH2CH3); 3.42 (m, 3H, CH3O);
3.55–3.78 (m, 4H, OCHHCH2O and CHOMEM); 3.86 (m,
1H, OCHHCH2O); 4.45 (d, 1H, Jˆ7.2 Hz, CHN); 4.73 (d,
1H, Jˆ7.4 Hz, OCHHO); 4.81 (d, 1H, Jˆ7.4 Hz, OCHHO);
5.92 (d, 1H, Jˆ8.4 Hz, NH); 8.70 (br s, 1H, CO2H). 13C
NMR (CDCl3): 10.1 (CH3CH2); 24.9 (CH2CH3); 28.2
(C(CH3)3); 56.0 (CHN); 58.8 (CH3O); 67.4 (CH2O); 71.4
(CH2O); 79.7 (C(CH3)3); 82.0 (CHOMEM); 95.6 (OCH2O);
155.5 (NCO2tBu); 173.7 (CO2H). Anal. Calcd for
C14H27NO7: C, 52.32; H, 8.47; N, 4.36. Found: C, 52.12;
H, 8.24; N, 4.28.
1
CH3CH2); 1.38 (s, 9H, (CH3)3C); 1.54 (m, 2H, CH2CH3);
3.34 (s, 3H, CH3O); 3.57 (m, 5H, CH2OH, OCH2CH2O and
CHN); 3.74 (m, 3H, CHOMEM and OCH2CH2O); 4.65 (d,
1H, Jˆ6.9 Hz, OCHHO); 4.72 (d, 1H, Jˆ6.9 Hz, OCHHO);
4.88 (d, 1H, Jˆ9.2 Hz, NH). 13C NMR (CDCl3): 9.7
(CH3CH2); 23.7 (CH2CH3); 28.2 (CH3)3C); 53.0 (CHN);
58.9 (CH3O); 62.4 (CH2OH); 67.2 (OCH2CH2O); 71.5
(OCH2CH2O); 76.9 (CHOMEM); 79.2 (C(CH3)3); 94.3
(OCH2O); 156.1 (CˆO). Anal. Calcd for C14H29NO6: C,
54.70; H, 9.51; N, 4.56. Found: C, 54.56; H, 9.32; N,
4.44.
(2S,3R)-2-[tert-Butoxycarbonylamino]-3-[(2-methoxyethoxy)-
methoxy]-1-pentanol (anti-10). The compound anti-10
was obtained from anti-9 (932 mg, 4.5 mmol) by the
method described for syn-10: 1.25 g (4.05 mmol, 90%).
Experimental procedure for deprotection of amino acids
11
2N HCl solution in THF-H2O (1:1) was added to syn-11
(244 mg, 0.76 mmol) and the solution was stirred at rt over-
night. The THF was eliminated on Rotavapor, the mixture
was extracted with ether (2×10 mL) and the aqueous layer
was evaporated in vacuo. Anhydrous ethanol (10 mL) and a
large excess of propylene oxide (4 mL) was added to the
solid residue and the mixture was refluxed for 30 min. After
removal of the volatiles on Rotavapor, the white residue was
purified by flash chromatography (silica gel, CH2Cl2/
CH3OH/NH4OH: 6/4/1), to give syn-6 as a colorless solid:
61 mg (0.46 mmol, 60%). The compound anti-11 (406 mg,
1.26 mmol) was deprotected by the same procedure to
afford anti-6 as a colorless solid: 105 mg (0.79 mmol, 62%).
Colorless oil. IR (film): 3420, 3320, 1690 cmϪ1
.
[a]2D3ˆϪ40.4 (cˆ1.2, CHCl3). H NMR (CDCl3): 0.95 t,
3H, Jˆ7.4 Hz, CH3CH2); 1.45 (s, 9H, (CH3)3C); 1.62 (m,
2H, CH2CH3); 3.12 (m, 1H, CHN); 3.40 (s, 3H, CH3O); 3.58
(m, 2H, OCH2CH2O); 3.65 (m, 4H, OCHHCH2O and
CH2OH); 3.82 (m, 1H, OCHHCH2O); 4.73 (d, 1H,
Jˆ7.1 Hz, OCHHO); 4.76 (d, 1H, Jˆ7.1 Hz, OCHHO);
5.53 (d, 1H, Jˆ7.1 Hz, NH). C NMR (CDCl3): 9.5
(CH3CH2); 24.5 (CH2CH3); 28.3 (CH3)3C); 53.4 (CHN);
58.9 (CH3O); 61.8 (CH2OH); 67.5 (OCH2CH2O); 71.5
(OCH2CH2O); 79.2 (C(CH3)3); 81.3 (CHOMEM); 95.6
(OCH2O); 156.0 (CˆO). Anal. Calcd for C14H29NO6: C,
54.70; H, 9.51; N, 4.56. Found: C, 54.58; H, 9.42; N,
4.48.
1
1-[(1S)-1-Amino-2-hydroxyethyl]-4-methyl-2,6,7-trioxa-
bicyclo[2.2.2.]octane (13). Compound 12 (4.53 g,
14 mmol) was debenzylated as described for syn-9 to
yield 13 as a colorless solid: 2.62 g (13.8 mmol, 99%).
Mp 101–103ЊC (from hexane). [a]2D3ˆϪ12.8 (cˆ0.5,
(2R,3S)-2-[tert-Butoxycarbonylamino]-3-[(2-methoxyethoxy)-
methoxy]-1-pentanoic acid (syn-11). To a solution of syn-
10 (461 mg, 1.5 mmol) in freshly distilled dimethylform-
amide (6 mL) was slowly added PDC (2.82 g, 7.5 mmol,
5 equiv.). The orange suspension was stirred at room
temperature overnight, and quenched by addition of H2O
(40 mL). The solution was extracted with ether
(6×20 mL), the combined ethereal layers were washed
with H2O and saturated NaCl solution, dried (Na2SO4) and
the volatiles were evaporated. The residue was purified by
flash chromatography (silica gel, EtOAc/EtOH: 2/1) to yield
syn-11 as a colorless oil: 289 mg (0.9 mmol, 60%).
[a]2D3ˆϪ26.7 (cˆ1, MeOH). IR (film): 3300, 1710,
1
CHCl3). IR (KBr): 3400 cmϪ1. H NMR (CDCl3): 0.82 (s,
3H, CH3); 3.17 (dd, 1H, Jˆ7.6 Hz, Jˆ4.1 Hz, CHN); 3.69
(dd, 1H, Jˆ11.7 Hz, Jˆ7.6 Hz, CHHOH); 3.83 (dd, 1H,
Jˆ11.7 Hz, Jˆ4.1 Hz, CHHOH); 3.94 (m, 6H, CH2); 4.88
(br s, 3H, NH2 and OH). 13C NMR (CDCl3): 14.1 (CH3);
30.4 (C(CH3)); 56.1 (CHN); 60.0 (CH2OH); 72.5 (CH2O);
107.3 (CO3). Anal. Calcd for C8H15NO4: C, 50.78; H, 7.99;
N, 7.40. Found: C, 50.93; H, 7.78; N, 7.21.
1-[N,N-Dibenzyl-(1S)-1-amino-2-hydroxyethyl]-4-methyl-
2,6,7-trioxabicyclo [2.2.2.]octane (14). A mixture of 13
(2.62 g, 13.8 mmol), benzyl bromide (3.61 mL, 30.4
mmol, 2.2 equiv.) and K2CO3 (4.57 g, 33.1 mmol, 2.4
equiv.) in acetonitrile (85 mL) was stirred at room tempera-
ture overnight. The solid was separated by filtration, the
filtrate was concentrated under reduced pressure and the
residue was purified by flash chromatography (silica gel,
hexane/EtOAc: 6/1) to yield 14 as a colorless solid: 4.13 g
(11.2 mmol, 81%). Mp 82–83ЊC (from hexane).
[a]2D3ˆϪ113 (cˆ1.1, CHCl3). IR (KBr): 3420, 1610,
1035 cmϪ1
.
1H NMR (CDCl3): 0.95 (t, 3H, Jˆ7.4 Hz,
CH3CH2); 1.44 (s, 9H, (CH3)3C); 1.62 (m, 2H, CH2CH3);
3.38 (s, 3H, CH3O); 3.54 (m, 3H, OCHHCH2O); 3.72 (m,
1H, OCHHCH2O); 4.09 (m, 1H, CHOMEM); 4.44 (d, 1H,
Jˆ9.7 Hz, CHN); 4.68 (d, 1H, Jˆ7.1 Hz, OCHHO); 4.74 (d,
1H, Jˆ7.1 Hz, OCHHO); 5.33 (d, 1H, NH); 9.20 (br s, 1H,
OH). 13C NMR (CDCl3): 10.1 (CH3CH2); 24.6 (CH2CH3);
28.3 ((CH3)3C); 56.9 (CHN); 58.9 (CH3O); 67.2
(OCH2CH2O); 71.6 (OCH2CH2O); 79.4 (CHOMEM); 80.3
(C(CH3)3); 95.2 (OCH2O); 156.2 (NCO2tBu); 177.4
(CO2H). Anal. Calcd for C14H27NO7: C, 52.32; H, 8.47;
N, 4.36. Found: C, 52.27; H, 8.32; N, 4.40.
1450, 745, 700 cmϪ1 1H NMR (CDCl3): 0.78 (s, 3H,
.
CH3); 2.70 (br s, 1H, OH); 2.98 (dd, 1H, Jˆ9.1 Hz,

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J. M. Andres et al. / Tetrahedron 56 (2000) 1523–1531
1529
Jˆ5.5 Hz, CHN); 3.57 (dd, 1H, Jˆ10.5 Hz, Jˆ5.5 Hz,
CHHOH); 3.62 (dd, 1H, Jˆ10.5 Hz, Jˆ9.1 Hz, CHHOH);
3.83 (d, 2H, Jˆ13.5 Hz, CHHPh); 3.88 (m, 6H, CH2); 3.98
(d, 2H, Jˆ13.5 Hz, CHHPh); 7.15–7.35 (m, 10H, Harom).13C
NMR (CDCl3): 14.5 (CH3); 30.2 (C(CH3)); 54.3 (CH2Ph);
58.1 (CH2OH); 61.7 (CHN); 71.9 (CH2O); 109.7 (CO3);
126.8, 128.2; 129.2 (CHarom); 140.2 (Carom). Anal. Calcd
for C22H27NO4: C, 71.52; H, 7.37; N, 3.79. Found: C,
71.32; H, 7.20; N, 3.68.
(m, 2H, CHOH and OH); 3.92 (s, 6H, CH2O); 4.03 (d, 2H,
Jˆ13.4 Hz, CHHPh); 7.15–7.35 (m, 10H, Harom). 13C NMR
(CDCl3): 14.6 (CH3); 19.7 (CH3CH); 30.4 (CCH3); 55.1
(CH2Ph); 63.8 (CHN); 66.8 (CHOH); 71.8 (CH2O); 110.0
(CO3); 126.9, 128.3, 129.5 (CHarom); 140.0 (Carom). Anal.
Calcd for C23H29NO4: C, 72.04; H, 7.62; N, 3.65. Found:
C, 71.88; H, 7.73; N, 3.77.
1-[N,N-Dibenzyl-(1S,2R)-1-amino-2-hydroxybutyl]-4-
methyl-2,6,7-trioxabicyclo [2.2.2.]octane (syn-16b).
Compound syn-16b was obtained from 15 (368 mg,
1 mmol) by reaction with Et2Zn. The product was purified
by flash chromatography (silica gel, hexane/EtOAc: 8/1):
246 mg (0.62 mmol, 62%). [a]2D3ˆϪ71.5 (cˆ1, CHCl3).
Colorless solid, mp 78–80ЊC (from hexane). IR (KBr):
1-[N,N-Dibenzyl-(1S)-1-amino-2-oxoethyl]-4-methyl-2,6,
7-trioxabicyclo [2.2.2.]octane (15). To a stirred solution of
oxalyl chloride (0.65 mL, 7.45 mmol) in dichloromethane
(15 mL) at Ϫ78ЊC under argon was added dimethyl sulf-
oxide (1.1 mL, 15.5 mmol). After 15 min, a solution of
aminoalcohol 14 (2.03 g, 5.5 mmol) in dichloromethane
(15 mL) was added, and the mixture was stirred for
30 min at Ϫ78ЊC before addition of triethylamine
(2.2 mL, 15.8 mmol). Then, the reaction was allowed to
reach the room temperature under stirring for 45 min and
the mixture quenched with water (15 mL). The aqueous
phase was extracted with dichloromethane (15 mL) and
the combined organic layers were washed with saturated
aqueous NaHCO3 and brine. The organic phase was dried
(MgSO4) and concentrated to yield an oil that was used
without further purification in the next step: 2.00 g
(5.4 mmol, 99%). Colorless solid, mp 106–108ЊC (from
hexane). [a]2D3ˆϪ106.8 (cˆ0.9, CHCl3). IR (KBr): 1715,
1585, 740, 690 cmϪ1. 1H NMR (CDCl3): 0.83 (s, 3H, CH3);
3.46 (s, 1H, CHN); 3.95 (m, 10H, CH2O and CH2Ph); 7.18–
7.45 (m, 10H, Harom); 9.75 (s, 1H, CHO). 13C NMR
(CDCl3): 14.5 (CH3); 30.7 (CCH3); 55.1 (CH2Ph); 69.5
(CHN); 72.3 (CH2O); 109.2 (CO3); 126.7, 128.1, 128.9
(CHarom); 140.3 (Carom); 200.2 (CHO). Anal. Calcd for
C22H25NO4: C, 71.91; H, 6.86; N, 3.81. Found: C,
71.76; H, 6.70; N, 3.58.
1
3400, 1460, 745, 690 cmϪ1. H NMR (CDCl3): 0.80 (t,
3H, Jˆ7.4 Hz, CH3CH2); 0.84 (s, 3H, CH3); 1.24 (m, 1H,
CHHCH3); 1.65 (m, 1H, CHHCH3); 2.63 (d, 1H, Jˆ8.0 Hz,
CHN); 3.71 (dt, 1H, Jˆ8.0 Hz, Jˆ3.1 Hz, CHOH); 3.83 (d,
2H, Jˆ13.4 Hz, CHHPh); 3.92 (m, 6H, CH2O); 4.03 (d,
2H, Jˆ13.4 Hz, CHHPh); 7.15–7.30 (m, 10H, Harom).
13C NMR (CDCl3): 10.1 (CH3CH2); 14.6 (CH3); 26.4
(CH2CH3); 30.4 (CCH3); 55.1 (CH2Ph); 64.5 (CHN);
68.7 (CHOH); 71.8 (CH2O); 110.2 (CO3); 126.8,
128.2, 129.5 (CHarom); 140.0 (Carom). Anal. Calcd for
C24H31NO4: C, 72.52; H, 7.86; N, 3.52. Found: C,
72.29; H, 7.82; N, 3.73.
1-[N,N-Dibenzyl-(1S,2R)-1-amino-2-hydroxy-3-methyl-
butyl]-4-methyl-2,6,7-trioxabicyclo [2.2.2.]octane (syn-
16c). Compound syn-16c was obtained from 15 (368 mg,
1 mmol) by reaction with i-Pr2Zn. The product was purified
by flash chromatography (silica gel, hexane/EtOAc: 8/1):
324 mg (0.79 mmol, 79%). Colorless solid, mp 92–93ЊC
(from hexane). [a]2D3ˆϪ77.8 (cˆ1.2, CHCl3). IR (KBr):
1
3400, 1435, 740, 690 cmϪ1. H NMR (CDCl3): 0.46 (d,
3H, Jˆ6.6 Hz, CH3CH); 0.81 (s, 3H, CH3); 0.89 (d, 3H,
Jˆ7.0 Hz, CH3CH); 1.91 (m, 1H, CH(CH3)2); 2.81 (d, 1H,
Jˆ8.8 Hz, CHN); 3.68 (dd, 1H, Jˆ8.8 Hz, Jˆ2.5 Hz,
CHOH); 3.83 (d, 2H, Jˆ13.2 Hz, CHHPh); 3.89 (s, 6H,
CH2O); 4.02 (d, 2H, Jˆ13.2 Hz, CHHPh); 7.15–7.30 (m,
10H, Harom). 13C NMR (CDCl3): 14.0 (CH3CH); 14.6 (CH3);
21.3 (CH3CH); 28.8 (CH(CH3)2); 30.3 (CCH3); 54.9
(CH2Ph); 61.8 (CHN); 70.4 (CHOH); 71.7 (CH2O); 110.3
(CO3); 126.8, 128.2, 129.6 (CHarom); 139.9 (Carom). Anal.
Calcd for C25H33NO4: C, 72.96; H, 8.08; N, 3.40. Found:
C, 72.84; H, 8.21; N, 3.54.
Alkylation of aminoaldehyde 15 with R2Zn
General method. To a solution of aminoaldehyde 15.
(368 mg, 1 mmol) in anhydrous toluene (10 mL) at 0ЊC
(ice bath) under argon was added dropwise a 1 M solution
of dialkylzinc in hexane or toluene (4 mmol, 4 equiv.).
The mixture was stirred at that temperature until the
reaction was finished (TLC), and then quenched with
aqueous saturated solution of ammonium chloride
(30 mL). The organic layer was separated and the
aqueous phase was extracted with diethyl ether
(2×20 mL). The combined organic layers were washed
with brine, and dried over anhydrous Na2SO4. The
solvents were eliminated under vacuum and the residue
was purified by flash chromatography.
1-[N,N-Dibenzyl-(1S,2R)-1-amino-2-hydroxy-2-phenyl-
ethyl]-4-methyl-2,6,7-trioxabicyclo [2.2.2.]octane (syn-
16d). Compound syn-16d was obtained as the major dia-
stereomer in the reaction of 15 (300 mg, 0.82 mmol) with
Ph2Zn and purified by flash chromatography (silica gel,
hexane/EtOAc: 6/1): 171 mg (0.38 mmol, 47%). Colorless
oil. [a]2D3ˆϪ71.8 (cˆ0.4, CHCl3). IR (film): 3360, 1600,
1-[N,N-Dibenzyl-(1S,2R)-1-amino-2-hydroxypropyl]-4-
methyl-2,6,7-trioxabicyclo [2.2.2.]octane (syn-16a).
Compound syn-16a was obtained from 15 (276 mg,
0.75 mmol) by reaction with Me2Zn. The product was puri-
fied by flash chromatography (silica gel, hexane/Et2O: 4/1):
78 mg (0.20 mmol, 27%). Colorless solid, mp 82–83ЊC
(from hexane). [a]2D3ˆϪ88.6 (cˆ0.4, CHCl3). IR (KBr):
3300, 1430, 730, 690 cmϪ1 1H NMR (CDCl3): 0.83 (s,
3H, CH3); 1.10 (d, 3H, Jˆ6.0 Hz, CH3CH); 2.54 (d, 1H,
Jˆ8.4 Hz, CHN); 3.83 (d, 2H, Jˆ13.4 Hz, CHHPh); 3.89
1
745, 700 cmϪ1. H NMR (CDCl3): 0.75 (s, 3H, CH3); 2.93
(d, 1H, Jˆ8.7 Hz, CHN); 3.73 (m, 6H, CH2O); 3.88 (d, 2H,
Jˆ13.3 Hz, CHHPh); 4.12 (d, 2H, Jˆ13.3 Hz, CHHPh);
4.68 (br s, 1H, OH); 4.82 (d, 1H, Jˆ8.7 Hz, CHOH);
7.05–7.40 (m, 15H, Harom). 13C NMR (CDCl3): 14.5
(CH3); 30.4 (CCH3); 54.8 (CH2Ph); 66.8 (CHN); 69.6
(CHOH); 71.5 (CH2O); 109.8 (CO3); 126.7, 127.0, 127.3,
127.4, 128.4, 129.5 (CHarom); 139.6, 143.1 (Carom). Anal.

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J. M. Andres et al. / Tetrahedron 56 (2000) 1523–1531
1530
Calcd for C28H31NO4: C, 75.48; H, 7.01; N, 3.14. Found: C,
75.29; H, 7.09; N, 3.26.
CH(CH3)2); 2.81 (d, 1H, Jˆ9.6 Hz, CHN); 3.16 (br s, 1H,
OH); 3.70 (dd, 1H, Jˆ9.6 Hz, Jˆ2.0 Hz, CHOH); 3.81 (d,
2H, Jˆ13.5 Hz, CHHPh); 3.92 (d, 2H, Jˆ13.5 Hz,
CHHPh); 3.97 (s, 6H, CH2O); 7.15–7.35 (m, 10H, Harom).
13C NMR (CDCl3): 13.4 (CH3); 14.5 (CH3CH); 20.8
(CH3CH); 28.4 (CH(CH3)2); 30.4 (CCH3); 55.4 (CH2Ph);
60.8 (CHN); 71.8 (CH2O); 73.8 (CHOH); 111.2 (CO3);
126.6, 128.0, 129.6 (CHarom); 140.5 (Carom). Anal. Calcd
for C25H33NO4: C, 72.96; H, 8.08; N, 3.40. Found: C,
72.71; H, 8.04; N, 3.35.
Alkylation of aminoaldehyde 15 with RMgX.
General method. To a solution of aminoaldehyde 15
(368 mg, 1 mmol) in ether (10 mL) at 0ЊC was added 1 M
solution of RMgX in ether (2 mL, 2 mmol, 2 equiv.). After
stirring at this temperature until the reaction was finished
(TLC), saturated NH4Cl solution (10 mL) was added and the
mixture was extracted with ether (3×10 mL). The combined
organic layers were washed with brine, dried over Na2SO4
and the solvent evaporated under vacuum. The residue was
purified by flash chromatography.
1-[N,N-Dibenzyl-(1S,2S)-1-amino-2-hydroxy-2-phenylethyl]-
4-methyl-2,6,7-trioxabicyclo [2.2.2.]octane (anti-16d).
Anti-16d was obtained as the major diastereomer in the
reaction of 15 (240 mg, 0.65 mmol) with PhMgBr and
purified by flash chromatography (silica gel, hexane/
EtOAc: 6/1): 133 mg (0.30 mmol, 46%). Colorless solid,
mp 144–146ЊC (from hexane). [a]2D3ˆϪ55.5 (cˆ1,
1-[N,N-Dibenzyl-(1S,2S)-1-amino-2-hydroxypropyl]-4-
methyl-2,6,7-trioxabicyclo [2.2.2.]octane (anti-16a).
Compound anti-16a was obtained as the major diastereomer
in the reaction of 15 (276 mg, 0.75 mmol) with MeMgI and
purified by flash chromatography (silica gel, hexane/Et2O:
4/1): 115 mg (0.3 mmol, 40%). Colorless solid, mp 107–
109ЊC (from hexane). [a]2D3ˆϪ106.9 (cˆ1.6, CHCl3). IR
1
CHCl3). IR (KBr): 3460, 1450, 750, 690 cmϪ1. H NMR
(CDCl3): 0.89 (s, 3H, CH3); 3.16 (d, 1H, Jˆ9.2 Hz,
CHN); 3.78 (br s, 1H, OH); 3.83 (d, 2H, Jˆ13.8 Hz,
CHHPh); 4.04 (s, 6H, CH2O); 4.06 (d, 2H, Jˆ13.8 Hz,
CHHPh); 5.00 (d, 1H, Jˆ9.2 Hz, CHOH); 6.90–7.35 (m,
15H, Harom). 13C NMR (CDCl3): 14.4 (CH3); 30.3 (CCH3);
54.8 (CH2Ph); 63.9 (CHN); 71.9 (CH2O); 73.5 (CHOH);
111.2 (CO3); 126.3, 127.2, 127.7, 128.4, 129.2 (CHarom);
139.7, 142.3 (Carom). Anal. Calcd for C28H31NO4: C,
75.48; H, 7.01; N, 3.14. Found: C, 75.62; H, 7.13; N,
3.23.
(KBr): 3480, 1445, 745, 690 cmϪ1 1H NMR (CDCl3):
.
0.85 (s, 3H, CH3); 1.14 (d, 3H, Jˆ6.2 Hz, CH3CH); 2.66
(d, 1H, Jˆ8.7 Hz, CHN); 3.37 (br s, 1H, OH); 3.83 (d, 2H,
Jˆ13.7 Hz, CHHPh); 3.92 (d, 2H, Jˆ13.7 Hz, CHHPh);
3.97 (s, 6H, CH2O); 4.08 (m, 1H, CHOH); 7.15–7.35 (m,
10H, Harom). 13C NMR (CDCl3): 14.4 (CH3); 21.1 (CH3CH);
30.2 (CCH3); 55.4 (CH2Ph); 64.8 (CHN); 66.4 (CHOH);
71.7 (CH2O); 110.9 (CO3); 126.5, 127.9, 129.2 (CHarom);
140.4 (Carom). Anal. Calcd for C23H29NO4: C, 72.04; H,
7.62; N, 3.65. Found: C, 71.84; H, 7.69; N, 3.55.
(2S, 3R)-3-Hydroxy norvaline (ent-syn-6). Compound
syn-16b (80 mg, 0.2 mmol) was debenzylated over
Pd(OH)2 in MeOH as described for syn-9 and stirred with
3 mL of 2N HCl solution in THF/H2O (1/1) overnight at
room temperature. The solvent was removed under reduced
pressure and the residue was dissolved in dioxane/H2O
(2 mL) and treated with Na2CO3 (106 mg, 1 mmol) for
18 h at room temperature. The dioxane was removed, the
mixture was extracted with ether, the aqueous layer was
acidified with 2N HCl and then evaporated to dryness
under vacuum to give (2S, 3R)-3-hydroxy norvaline hydro-
chloride. From this compound, the free b-hydroxy-a-amino
acid was obtained by refluxing the salt in ethanol with
excess propylene oxide followed by purification by flash
chromatography (silica gel, CH2Cl2/CH3OH/NH4OH: 6/4/
1-[N,N-Dibenzyl-(1S,2S)-1-amino-2-hydroxybutyl]-4-
methyl-2,6,7-trioxabicyclo [2.2.2.]octane (anti-16b).
Compound anti-16b was obtained as the major diastereomer
in the reaction of 15 (368 mg, 1 mmol) with EtMgBr and
purified by flash chromatography (silica gel, hexane/EtOAc:
8/1): 166 mg (0.42 mmol, 42%). [a]2D3ˆϪ93.3 (cˆ1.3,
CHCl3). Colorless solid, mp 96–98ЊC (from hexane). IR
(KBr): 3480, 1450, 750, 700 cmϪ1 1H NMR (CDCl3):
.
0.75 (t, 3H, Jˆ7.4 Hz, CH3CH2); 0.85 (s, 3H, CH3); 1.18
(m, 1H, CHHCH3); 1.88 (m, 1H, CHHCH3); 2.74 (d, 1H,
Jˆ8.8 Hz, CHN); 3.33 (br s, 1H, OH); 3.80 (m, 1H,
CHOH); 3.83 (d, 2H, Jˆ13.7 Hz, CHHPh); 3.92 (d, 2H,
Jˆ13.7 Hz, CHHPh); 3.97 (m, 6H, CH2O); 7.15–7.35 (m,
10H, Harom). 13C NMR (CDCl3): 9.6 (CH3CH2); 14.6 (CH3);
26.9 (CH2CH3); 30.4 (CCH3); 55.5 (CH2Ph); 63.1 (CHN);
71.3 (CHOH); 71.8 (CH2O); 111.1 (CO3); 126.6, 128.0,
129.4 (CHarom); 140.5 (Carom). Anal. Calcd for C24H31NO4:
C, 72.52; H, 7.86; N, 3.52. Found: C, 72.65; H, 7.83; N,
3.45.
1), to give ent-syn-6 as
a colorless solid: 19 mg
(0.14 mmol, 70%). Mp 230–232ЊC (dec). [a]2D3ˆϪ7.6
(cˆ0.9, H2O).
(2S, 3S)-3-Hydroxy norvaline (ent-anti-6). Compound
anti-16b (119 mg, 0.3 mmol) was deprotected as described
for syn-16b to afford ent-anti-6 as a colorless solid: 27 mg
(0.2 mmol, 66%). Mp 222–223ЊC (dec). [a]2D3ˆϩ4.4
(cˆ0.8, H2O).
1-[N,N-Dibenzyl-(1S,2S)-1-amino-2-hydroxy-3-methyl-
butyl]-4-methyl-2,6,7-trioxabicyclo [2.2.2.]octane (anti-
16c). The compound was obtained as the major diastereo-
mer in the reaction of 15 (294 mg, 0.8 mmol) with i-PrMgCl
and purified by flash chromatography (silica gel, hexane/
EtOAc: 6/1): 127 mg (0.31 mmol, 39%). Colorless solid,
mp 149–150ЊC (from hexane). [a]2D3ˆϪ89.5 (cˆ0.9,
Acknowledgements
We thank the Spanish DGICYT (Project PB95-707) and
1
CHCl3). IR (KBr): 3470, 1440, 740, 690 cmϪ1. H NMR
Junta de Castilla y Leon (Project VA67/99) for financial
´
(CDCl3): 0.16 (d, 3H, Jˆ6.7 Hz, CH3CH); 0.84 (s, 3H,
support of this work. One of us (N.E.) thanks the Spanish
MEC for a predoctoral fellowship (FPU).
CH3); 0.92 (d, 3H, Jˆ7.1 Hz, CH3CH); 2.15 (m, 1H,

´
J. M. Andres et al. / Tetrahedron 56 (2000) 1523–1531
1531
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