A chiral hydrazone derived from D-glyceraldehyde: A convenient starting material for the stereoselective synthesis of α-hydrazino acids

Article abstract of DOI:10.1016/S0957-4166(97)00128-6

The chiral hydrazone synthesized from 2,3-di-O-benzyl-D-glyceraldehyde and benzoic acid hydrazide undergoes addition with methylmagnesium bromide in the presence of cerium trichloride in a diastereoselective manner. The major addition compound can be easi

Full text of DOI:10.1016/S0957-4166(97)00128-6

Tetrahedron: Asymmetry, Vol 8. No 10, pp. 1605-1610, 1997
(~) 1997 Elsevier Science Ltd. All rights reserved.
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PII: S0957-4166(97)00128-6
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A chiral hydrazone derived from D-glyceraldehyde: a convenient
starting material for the stereoselective synthesis of cc-hydrazino
acids
Carlos Cativiela*,* M a r i a D. Dfaz-de-Villegas* and Jos6 A. Gfilvez
lnstituto de Ciencia de Materiales de Arag6n, Departamento de Qu/mica Org~inica, Universidad de
Zaragoza-C.S.I.C., 50009 Zaragoza, Spain
Abstract: The chiral hydrazone synthesized from 2,3-di-O-benzyl-D-glyceraldehyde and
benzoic acid hydrazide undergoes addition with methylmagnesium bromide in the presence
of cerium trichloride in a diastereoselective manner. The major addition compound can
be easily transformed into cx-hydrazinopropanoic acid in four steps in 57% overall yield.
(~) 1997 Elsevier Science Ltd
There is growing interest in the stereospecific synthesis of ot-hydrazino acids because, as a result of
their strong resemblance to 0~-amino acids, they can act as inhibitors of enzymes which metabolise the
.
.
.
corresponding or-amino acids.1 Moreover, they have been found in natural peptlde antt.blotxcs9- and have
been used for the synthesis of metabolically-stable peptidomimetics with potential for the treatment of
viral infections. 3 In this sense, attempts at introducing hydrazino acids in peptide analogues remains
very limited because of the difficulties in obtaining enantiomerically pure hydrazino acids.
The most efficient procedures described for obtaining non-racemic 0t-hydrazino acids are based on
asymmetric electrophilic "hydrazination" of chiral enolates with azodicarboxylate esters,4 amination
of chiral or-amino acids with N-alkoxycarbonyl-3-phenyloxaziridines,5 displacement of the hydroxyl
group by Boc-hydrazine in chiral 2-nosyloxy and 2-triflyloxy esters,6 and most recently catalytic
asymmetric hydrogenation of N-acylhydrazones derived from ~-keto acids,7 or ring opening of chiral
N-aminoaziridine derivatives by nucleophiles. 8
In our recent work, directed towards the synthesis of amino acid surrogates as modifiers of peptide
backbones, we were interested in developing a new route to c~-hydrazino acids from readily available
and cheap starting materials.
We have recently reported that chiral imines derived from 2,3-di-O-benzyl-D-glyceraldebyde
undergo highly diastereoselective additions of organometallic reagents, a process which constituted
a new route to 0t-hydroxy-13-amino acids9 and n-amino acids. ]° This synthetic methodology can
presumably be applied to the synthesis of the desired hydrazino acids by simply starting from
the appropriate hydrazone. Moreover, there are several examples in the literature reporting the
diastereoselective addition of organometallic reagents to N,N-dimethylhydrazones derived from chiral
ot-alkoxycarbonyl compounds]! in the synthesis of chiral 1,2-aminoaicohols.
Taking into account these precedents we have studied, as a model, the behaviour of acylhydrazones
derived from 2,3-di-O-benzyl-D-glyceraldehyde towards organometallic reagents in order to develop
a new route to ot-hydrazino acids. The N-acyl protecting group is necessary to maintain the hydrazino
moiety in the final deprotection of this functional group.
Chiral acylhydrazone 1 is readily prepared in 94% yield from 2,3-di-O-benzyI-D-glyceraldehyde
and benzoic acid hydrazide. Compound ! was used as the substrate for the addition of methyl
organometallic reagents under a variety of conditions in order to optimise the stereochemical course
of the reaction (Scheme 1).
* Corresponding author. Email: cativiela@posta.unizar.es, loladiaz@posta.unizar.es
1605

1606
C. CATIVIELA et al.
BnO
BnO
BnO
B n O x ~ o H2N-NHCOCrH~ B n O ~ N , ,
CH3MgBr BnO s x ~ S CH3
.~
NHCC6H5
OU
H
H
CeC13
NHNHC5CrH"
1
2
O
Scheme l.
Table 1. Selected results for the addition of organometallic reagents to the benzylhydrazone derived from 2.3-di-O-benzyl-
D-glyceraldehyde
d.r. b
Entry
Yield
Organometallic
R e a g e n ta
Solvent
Temperature
[%]
CH3MgBr
CH3MgBr
50/50
50/50
67/33
67/33
100
100
100
100
ether
toluene
ether
r.t.
r.t.
r.t.
r.t.
CH3MgBr-CeCI3
CH3MgBr-CeCI3
4
toluene
CH3MgBr-CeCI3
78•22
50
- 20
6
ether
aFive equivalents of the organometallic reagent were used to ensure complete consumption of the starting material, bThe ratios of
diastereoisomers were determined by IH-NMR ofcrude reaction mixtures.
We initially examined the addition of CH3Li since it has been described l ta that the dimethylhydra-
zone of D-glyceraldehyde acetonide stereoselectively adds CH3Li both in the absence or presence of
a catalytic amount of CuI with excellent yields (95%). However, on using this organometallic reagent
we did not obtain the desired compound, even in the presence of CeC13. No reaction occurred when
THF was used as the solvent and only a complex inseparable mixture of compounds was obtained
when ether was used as the solvent. The same behaviour was observed with the use of the copper-based
organometallic reagent, generated in situ from methylmagnesium bromide and copper(I) bromide
prior to the addition reaction. In some cases improved yields have been reported t2 for the addition
of alkyl copper reagents, complexed with boron trifluoride etherate prior to use, and we also tested
these conditions but, unfortunately, the results were similar. Subsequently we tested the addition of
CH3MgBr to chiral hydrazone I at room temperature and we observed no reaction when THF was used
as the solvent. However, rapid formation (15 rain) of an equimolecular mixture of diastereoisomers
in nearly quantitative yields was observed when ether or toluene were used as the solvent (Table 1).
The same reaction carried out with the cerium-based organometallic reagent prepared from CH3MgBr
and anhydrous CeCI3 afforded a 67/33 mixture of diastereoisomers also in nearly quantitative yields
in 15 min. This result is in contrast to that observed by Baker and Condon I lh who were unable to
successfully obtain significant yields in the addition of cerium-based organometallic reagents to chiral
N,N-dimethylhydrazones.

1607
A chiral hydrazone derived from D-glyceraldehyde
Encouraged by this result we set out to improve the stereoselectivity of the reaction based on
the CH3MgBr-CeCI3 organometallic reagent and assessed the effect of a decrease in the reaction
temperature on the rate and stereoselectivity of the reaction. Three hours were required for complete
conversion to the product at 0°C and the diastereoselectivity improved from 67/33 to 78/22. The same
stereochemical behaviour was observed at - 2 0 ° C but we observed only a 50% conversion in 24 h.
Although diastereoselectivity at 0°C was only moderate, both diastereoisomers can be easily separated
by flash chromatography eluting with hexane/ethyl acetate (1/1) and the pure major diastereoisomer
was isolated in acceptable yields (72%).
The synthetic utility of this reaction requires the conversion of addition product 2 into the free
hydrazino acid 5 without any degree of racemisation (Scheme 2). As the carboxylic group is generated
through oxidative cleavage of the diol moiety that can also break the NH-NH bond it is necessary to
prevent this undesired process. For this reason we translormed compound 2 into the corresponding
N-Boc derivative 3 in 80% yield by treatment with excess di-tert-butyldicarbonate in the presence
of diisopropylethylamine. Debenzylation of compound 3 was performed by hydrogenolysis in the
presence of palladium hydroxide to afford compound 4 in 92% yield. Finally, the free hydrazino acid 5
was obtained by oxidative cleavage of the diol moiety by treatment with excess sodium periodate in the
presence of ruthenium trichloride and subsequent hydrolysis using 3 N hydrochloric acid. Elution of
the crude hydrazino acid hydrochloride salt through an ion exchange chromatography column yielded
enantiomerically pure (S)-ot-hydrazinopropanoic acid whose specific rotation value { [0t]25o=-28 (c=l
in 6 N HCI), lit7 [0q20D=-28.5 (c=l in 6 N HCI)} allowed us to determine the absolute configuration
of the stereogenic centre created on the addition reaction and confirm the enantiomeric purity of the
final hydrazino acid.
BnO
BnO
BnO S N ~ S CH3
B°c20,, BnO5 x , . ~ C H3
i
H2, Pd(OH)2~,
NHNHCC6H5
BocNNHCC6H5
II
O
II
2
3
O
HO
HOOC@CH3
NHNH2
H O N ~ CH3
i
1) RuCl3, NalO4
BocNNHCC6H 5
2) H3O+
II
4
O
Scheme 2.
In conclusion, this synthetic reaction provides a practical method for the preparation of hydrazino
alanine 5. This method can be extended to include the synthesis of a wide variety of hydrazino acids
from a common precursor, commercially available D-mannitol, by simply changing the organometallic
reagent used.
Experimental
Apparatus
Melting points were determined using a Btichi 510 capillary melting point apparatus and are
uncorrected. Specific rotations were recorded using a Perkin-Elmer 241-C polarimeter with a
thermally-jacketed 10 cm cell at 25°C. IR spectra were obtained on a Perkin-Elmer 1600 FTIR infrared
spectrophotometer. 1H NMR and 13C NMR spectra were recorded in deuterochloroform or deuterated
water and referenced with respect to the residual solvent signal on a Varian Unity 300 or a Bruker
AMX300 spectrometer. All chemical shifts are quoted in parts per million relative to tetramethylsilane
(8 0.00 ppm), and coupling constants (J) are measured in Hertz. The 1H NMR and 13C NMR spectra
of N-Boc protected compounds were not conclusive at room temperature due to the presence of a

1608
C. CATIVIELA et al.
dynamic equilibrium between rotamers caused by the restricted rotation of the nitrogen-carbon bond
of the amide group. In order to overcome this problem NMR spectra of these compounds were run at
55°C. Elemental analyses were performed on a Perkin-EImer 200 C,H,N,S elemental analyser. Mass
spectra under electron impact conditions (EI) were determined on a high resolution VG-Autospec
spectrometer. The spectra are presented as m/z (% relative intensity).
Chemicals
All reactions were carried out under argon with magnetic stirring. Solvents were dried prior to use.
All reagents were obtained from commercial sources and were of analytical grade. TLC was performed
on precoated silica-gel plates which were visualised using UV light and anisaldehyde/sulphuric
acid/ethanol (2/1/100). Flash column chromatography was undertaken on silica gel (Kiesegel 60).
( 2S )-2,3-Di-O-benzylglyceraldehyde N-benzoylhydrazone13 1
A solution of (2R)-2,3-di-O-benzyI-D-glyceraidehyde (!.35 g, 5 mmol) in dry THF (20 ml) was
added to a stirred solution of benzoic acid hydrazide (816 mg, 6 mmol) in dry THF (20 ml) and the
mixture was stirred at 80°C for 6 h. The solvent was evaporated in vacuo to afford the crude hydrazone
which was purified by flash chromatography (ether) yielding 1.8 g (94% yield) of pure (2S)-2,3-di-
O-benzylglyceraldehyde N-benzoylhydrazone 1 as a white solid. M.p.=105°C; [t~]25D=+28.8 (c, 1
in chloroform); IR (Nujol) 3205, 1665, 1650 c m - I ; IH NMR (CDCI3, 300 MHz) 6 3.65-3.80 (m,
2H), 4.32--4.40 (m, 1H), 4.52 (s, 2H), 4.53 (d, 1H, J=12), 4.61 (d, 1H, J=12), 7.20-7.60 (m, 14H),
7.76-7.82 (m, 2H), 9.44 (s, IH); 13C NMR (CDC13, 75 MHz) ~i 71.3, 71.5, 73.5, 77.7, 127.3, 127.7,
127.8,128.3,128.5, 128.6, 132.1,132.7, 137.8, 149.6, 164.2. Anal. Calcd. for C24H24N203: C, 74.21;
H, 6.23; N, 7.21. Found: C, 74.08; H, 6.47; N, 7.05.
(2S, 3S)- 1,2-Di-benzyloxy-3-(2-benzoylhydrazino)butane 2
A flask fitted with septum and gas inlet was charged with anhydrous CeCI3 (4.93 g, 20 mmol),
vented to dry argon, and ether was added via syringe. This slurry was stirred for 1 h at room
temperature. To this white suspension was added methylmagnesium bromide (3 M solution in dibutyl
ether, 6.66 ml, 20 mmol) slowly via syringe, and the reaction mixture was stirred for 1 h and cooled
to 0°C. A solution of (2S)-2,3-di-O-benzylglyceraldehyde N-benzoylhydrazone 1 (1.55 g, 4 mmol)
in ether/dichloromethane 1/1 (30 ml) was added slowly via syringe. After being stirred for 3 h at
room temperature, the reaction mixture was poured into water (100 ml), and extracted with ether.
The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to afford
a 78/22 mixture of diastereoisomers in nearly quantitative yield. Purification of the residue by flash
chromatography (hexane/ethyl acetate 1:1) afforded 1.16 g (72% yield) of diastereomericaily pure
(2S,3S)-l,2-di-benzyloxy-3-(2-benzoylhydrazino)butane 2 as a colourless oil. [ot]25D=-33.2 (c, 1 in
chloroform); IR (Nujol) 3285, 1636 c m - l ; IH NMR (CDCI3, 300 MHz): ~ 1.14 (d, 3H, J=6.9), 2.93
(dq, 1H, J=6.9, J=6.3), 3.66-3.80 (m, 3H), 4.53 (d, IH, J=12.0), 4.57 (d, IH, J=12.0), 4.66 (d, IH,
J= 11,7), 4.75 (d, 1H, J=1 ! .7), 7.20-7.45 (m, 14H), 7.45-7.60 (m, 2H), 7.95 (s, 1H); 13C NMR (CDCI3,
75 MHz): ~ 14.5, 58.0, 70.4, 72.4, 73.5, 82.5, 126.7, 127.7, 128.0, 128.4, 128.5, 131.4, 132.8, 138.0,
138.4, 165.9. Anal. Calcd. for C25H28N203: C, 74.23; H, 6.98; N, 6.93. Found: C, 74.51; H, 6.87;
N, 6.81.
(2S,3S)- 1,2-Di-benzyloxy-3-(2-benzoyl- l-tert-butox3,carbonylhydrazino)butane 3
Di-tert-butyl dicarbonate (1.25 g, 5.75 mmol) was added to a stirred solution of (2S,3S)-l,2-di-
benzyloxy-3-(2-benzoylhydrazino)butane 2 (1 g, 2.5 mmol) and diisopropylethylamine (33 mg, 0.25
mmol) in dioxane (10 ml). After being stirred for 15 h at 50°C, the reaction mixture was treated with
ether, washed with ! M aqueous KHSO4 solution, dried over MgSO4 and concentrated in vacuo.
Purification of the residue by flash chromatography (hexane/ethyl acetate I/3) afforded 1.0 g (80%) of
(2S,3S)- 1,2-di-benzyloxy-3-(2-benzoyl- I-tert-butoxycarbonylhydrazino)butane 3 as a colourless oil.
[ot125D=21.1 (c, 1 in chloroform); IR (Nujol) 3306, 1706 c m - l ; IH NMR (CDCi3, 300 MHz): ~i 1.25

A chiral hydrazone derived from D-glyceraldehyde
1609
(d, 3H, J=6.8), 1.44 (s, 9H), 3.65-3.74 (m, 3H), 4.50 (d, 1H, J=l 1.7), 4.51 (d, IH, J=l 1.4), 4.55 (d,
IH, J=l 1.7), 4.72 (d, 1H, J=l 1.4), 7.25-7.50 (m, 15H), 7.75 (s, IH); 13C NMR (CDCI3, 75 MHz):
13.4, 28.2, 55.1, 71.4, 73.0, 73.9, 81.0, 81.1, 127.0, 127.7, 127.8, 127.9, 128.4, 131.4, 133.0, 137.8,
138.4, 154.3, 166.5. Anal. Calcd. for C30H36N2Os: C, 71.41; H, 7.19; N, 5.55. Found: C, 71.68; H,
7.08; N, 5.42.
(2S,3S)-3-(2-Benzoyl- l-tert-butox),carbonylhydrazino)_ 1,2-butanediol 4
A solution of (2S,3S)- 1,2-di-benzyloxy-3-(2-benzoyl- 1 -tert-butoxycarbonylhydrazino)butane 3 (756
mg, 1.5 mmol) in methanol (10 ml) was hydrogenated with Pd(OH)2 (200 mg) as catalyst at
room temperature for 12 h. When the reaction was complete the catalyst was removed by filtration
and the filtrate evaporated to dryness to aflbrd 447 mg (92% yield) of (2S,3S)-3-(2-benzoyl-l-tert-
butoxycarbonylhydrazino)-l,2-butanediol 4 as a white solid. M.p.=117°C; [¢X]25D=-34.0 (c, 0.8 in
chloroform), IR (Nujol) 3205, 1711 c m - I ; IH NMR (CDCI3, 300 MHz): 5 1.20 (d, 3H, J=6.9), 1.39
(s, 9H), 3.52-4.00 (m, 3H), 4.10-4.35 (m, 1H), 7.63-7.54 (m, 3H), 7.66-7.90 (m, 2H), 8.42 (brs, 1H);
13C NMR (CDC13, 75 MHz): 8 12.4, 28.2, 56.0, 63.3, 74.0, 82.2, 127.4, 128.7, 132.2, 132.5, 155.1,
168.5. Anal. Calcd. for C16H24N205: C, 59.25; H, 7.46; N, 8.64. Found: C, 59.09; H, 7.61; N, 8.72.
(S)-o~-Hydrazinopropanoic acid 5
Small portions of NalO4 (850 ms, 4 mmol) were added to a stirred solution of (2S,3S)-3-(2-benzoyl-
1-tert-butoxycarbonylhydrazino)-l,2-butanediol 4 (324 mg, 1 mmol) in 2:2:3 acetonitrile-carbon
tetrachloride-water (20 ml). After being vigorously stirred for 5 min following completion of the
addition the mixture was treated with RuCI3. H20 (8 ms, 0.04 mmol) and stirring was continued for
2 h. Dichloromethane (40 ml) was added and the mixture was extracted with 1 M aqueous NaHCO3.
The aqueous solution was washed with ethyl acetate, carefully acidified with 1 M aqueous KHSO4
solution and extracted with dichloromethane (3×30 ml). The organic layer was dried over MgSO4 and
concentrated in vacuo. The residue was hydrolysed by refluxing for 5 h with 3 N hydrochloric acid (15
ml). After filtration the aqueous solution was washed with ether and evaporated in vacuo to give the
crude product, which was purified by ion exchange chromatography (Dowex 50x8) to afford 81 mg
(78% yield) of (S)-~x-hydrazinopropanoic acid. [0(]259=-28.0 (c, 1 in 6 N HC1), lit.7 [~X]20D=--28.5
(c, 1 in 6 N HC1); IH NMR (D20, 300 MHz): ~ 1.30 (d, 3H, J=7.2), 3.59 (q, IH, J=7.2); 13C NMR
(D20, 75 MHz): 6 12.4, 58.8, 173.8. Anal. Calcd. for C3H8N202: C, 34.61; H, 7.75; N, 26.91. Found:
C, 34.49; H, 7.92; N, 27.03; MS (El) 105 (10, MH+), 77 (7), 59 (100).
Acknowledgements
This work was supported by the Direcci6n General de Investigaci6n Cientffica y T6cnica, project
number PB94-0578.
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(Received in UK 7 March 1997)