Stereoselective nucleophilic formylation and cyanation of α-alkoxy- and α-aminoaldehydes

Article abstract of DOI:10.1021/jo015711+

The spontaneous 1,2-addition of formaldehyde N,N-dialkylhydrazones to carbohydrate-derived α-alkoxyaldehydes takes place under neutral conditions and in the absence of catalysts or promoters to afford the corresponding α-hydroxyhydrazones in good to excellent yields and with highly anti diastereoselectivities. Subsequent transformations of the hydrazono group into aldehydes and nitriles following known procedures provide a new entry into the homologation of carbohydrates and the synthesis of cyanohydrins, respectively. Additionally, reaction of methyleneaminopyrrolidine with N-Boc-protected α-aminoaldehydes from natural amino acids efficiently affords the corresponding adducts under the same conditions. From these adducts, a variety of biologically interesting α-hydroxy-β-aminocarbonyl compounds can be accessed upon manipulation of the hydrazone moiety.

Full text of DOI:10.1021/jo015711+

J . Org. Chem. 2001, 66, 5201-5207
5201
Ster eoselective Nu cleop h ilic F or m yla tion a n d Cya n a tion of
r-Alk oxy- a n d r-Am in oa ld eh yd es
Rosario Ferna´ndez,*,† Elo´ısa Mart´ın-Zamora,† Carmen Pareja,† and J ose´ M. Lassaletta*,‡
Departamento de Quı´mica Orga´nica, Facultad de Quı´mica, Universidad de Sevilla,
Apartado de Correos 553, E-41071 Seville, and Instituto de Investigaciones Qu´ımicas (CSIC-USe),
Isla de la Cartuja, Americo Vespucio s/ n, E-41092 Seville, Spain
jmlassa@cica.es
Received April 26, 2001
The spontaneous 1,2-addition of formaldehyde N,N-dialkylhydrazones to carbohydrate-derived
R-alkoxyaldehydes takes place under neutral conditions and in the absence of catalysts or promoters
to afford the corresponding R-hydroxyhydrazones in good to excellent yields and with highly anti
diastereoselectivities. Subsequent transformations of the hydrazono group into aldehydes and
nitriles following known procedures provide a new entry into the homologation of carbohydrates
and the synthesis of cyanohydrins, respectively. Additionally, reaction of methyleneaminopyrrolidine
with N-Boc-protected R-aminoaldehydes from natural amino acids efficiently affords the corre-
sponding adducts under the same conditions. From these adducts, a variety of biologically interesting
R-hydroxy-â-aminocarbonyl compounds can be accessed upon manipulation of the hydrazone moiety.
Sch em e 1. Con ju ga te Ad d ition of F or m a ld eh yd e
N,N-Dia lk ylh yd r a zon es to Mich a el-Typ e
Electr op h iles
In tr od u ction
The aza-enamine character of N,N-dialkylhydrazones
was experimentally established by Brehme and co-
workers from their reactions with strong electrophiles
such as unhindered iminium salts,1 sulfonyl isocyanates,2
and the Vilsmeier reagent,3 and was later confirmed in
trifluoroacetylation reactions.4 On the basis of these
precedents, we found that the enhanced nucleophilicity
of formaldehyde N,N-diakylhydrazones allows it to per-
form addition reactions unto weaker electrophiles such
as conjugated nitroalkenes5 and enones.6 After efficient
deprotections into aldehydes and nitriles, the overall
process appears to be a short approach to the formylation
and cyanation of these substrates (Scheme 1).
In 1993, Katayama et al.7 reported the intramolecular,
Lewis acid-promoted 1,2-addition of the azomethine
carbon of N-aminoindoline-derived hydrazones to a neigh-
boring carbonyl group in carbocyclization reactions.
Unfortunately, it was not possible to develop an inter-
molecular version of this interesting reaction, presumably
due to the poor nucleophilicity of this type of hydrazone.
Trusting again in the higher reactivity exhibited by
formaldehyde N,N-dialkylhydrazones, we started studies
on the intermolecular 1,2-addition of these reagents to
carbonyl compounds.
During our preliminary investigations that were car-
ried out using simple aldehydes, we found that the
desired adducts could be obtained in moderate yields by
using ZnCl2 or Et2AlCl as a promoter.8 However, it was
later discovered that the inductive effect of the R-fluorine
atoms in trifluoromethylketones increases the reactivity
of the carbonyl group up to the level needed for the
spontaneous 1,2-addition of formaldehyde N,N-dialkyl-
hydrazones9 (Scheme 2).
* To whom correspondence should be addressed. Fax: +34 95
4460565. E-mail: jmlassa@cica.es.
† Universidad de Sevilla.
‡ Instituto de Investigaciones Qu´ımicas.
(1) Brehme, R.; Nikolajewski, H. E. Tetrahedron 1976, 32, 731.
(2) Brehme, R.; Nikolajewski, H. E. Tetrahedron Lett. 1982, 23, 1131.
(3) Brehme, R. Chem. Ber. 1990, 123, 2039.
(4) (a) Kamitori, Y.; Hojo, M.; Masuda, R.; Fujitani, T.; Ohara, S.;
Yokohama, T. J . Org. Chem. 1988, 53, 129. (b) Kamitori, Y.; Hojo, M.;
Masuda, R.; Yoshida, T.; Ohara, S.; Yamada, K.; Yoshikawa, N. J . Org.
Chem. 1988, 53, 519.
(5) (a) Lassaletta, J . M.; Ferna´ndez, R. Tetrahedron Lett. 1992, 33,
3691. (b) Lassaletta, J . M.; Ferna´ndez, R.; Gasch, C.; Va´zquez, J .
Tetrahedron 1996, 52, 9143. (c) Ferna´ndez, R.; Gasch, C.; Lassaletta,
J . M.; Llera, J . M. Tetrahedron Lett. 1994, 35, 471. (d) Enders, D.;
Syrig, R.; Raabe, G.; Ferna´ndez, R.; Gasch, C.; Lassaletta, J . M.; Llera,
J . M. Synthesis 1996, 48. (e) Ferna´ndez, R.; Gasch, C.; Lassaletta, J .
M.; Llera, J . M. Synthesis 1996, 627.
Taking into account the interest for the expected
products and the availability of the starting materials,
(6) (a) Lassaletta, J . M.; Ferna´ndez, R.; Mart´ın-Zamora, E.; D´ıez,
E. J . Am. Chem. Soc. 1996, 118, 7002. (b) D´ıez, E.; Ferna´ndez, R.;
Gasch, C.; Lassaletta, J . M.; Llera, J . M.; Martı´n-Zamora, E.; Va´zquez,
J . J . Org. Chem. 1997, 62, 5144.
(7) Shen, J .-K.; Katayama, H.; Takatsu, N.; Shiro, I. J . Chem. Soc.,
Perkin Trans. 1 1990, 2087.
(8) Pareja, C. Ph.D. Thesis, University of Seville, Seville, Spain,
1998.
(9) (a) Ferna´ndez, R.; Mart´ın-Zamora, E.; Pareja, C.; Va´zquez, J .;
D´ıez, E.; Monge, A.; Lassaletta, J . M. Angew. Chem., Int. Ed. Engl.
1998, 37, 3428. (b) Pareja, C.; Mart´ın-Zamora, E.; Ferna´ndez, R.;
Lassaletta, J . M. J . Org. Chem. 1999, 64, 8846.
10.1021/jo015711+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/29/2001

5202 J . Org. Chem., Vol. 66, No. 15, 2001
Ferna´ndez et al.
Sch em e 2. 1,2-Ad d ition of F or m a ld eh yd e
N,N-Dia lk ylh yd r a zon es to Tr iflu or om eth ylk eton es
Considering the better performance usually observed
for pyrrolidine-derived enamines,11 we also investigated
the use of readily available 1b9b as the reagent. Fortu-
nately, the higher nucleophilicity of this reagent was
found to furnish faster 1,2-addition reactions, thereby
minimizing or suppressing the formation of the undesired
hydrazones 6 and 7. Consequently, this improvement
enabled the isolation of the corresponding 1,2-adducts 4b
and 5b in acceptable yields (Table 1, entries 2 and 6).
Interestingly, these compounds were obtained as single
Sch em e 3. 1,2-Ad d ition of F or m a ld eh yd e
N,N-Dia lk ylh yd r a zon es to Dia ld oses 2 a n d 3
1
diastereomers (de >98%), as determined by H and 13C
NMR analyses of the reaction crudes. A lower asymmetric
induction was observed for the addition of 1b to 2,3-O-
isopropylidene-D-glyceraldehyde (8). The corresponding
adducts 9 were obtained in 70% yield as a 79:21 mixture
of (2S,3R) and (2R,3R) diastereomers, which could be
easily separated by flash chromatography (Scheme 4,
Table 1, entry 9).
Double-induction experiments using compounds 2 and
3 and chiral formaldehyde (S)-1-amino-2-(methoxymeth-
yl)pyrrolidine (SAMP)-derived hydrazone 1c5d and its (R)
enantiomer 1d 5e were also undertaken. The reactions
between the mismatched pairs 2/1d and 3/1d afforded
products (2R)-4d and (2R)-5d , respectively, in lower
yields and diastereomeric excesses than those observed
for 1b (entries 4 and 8). Therefore, the extent of the
induction effected by these substrates proved to be clearly
higher than that effected by the chiral reagent 1d , and
consequently, the (2S)-4d and (2S)-5d diastereomers are
formed in small percentages only (3 and 11%, respec-
tively). On the other hand, the reactions between the
matched pairs 2/1c and 3/1c afforded adducts (2R)-4c
and (2R)-5c as single diastereomers (entries 3 and 7).
These double-induction experiments appear to lack prac-
tical interest because the “mismatched” reaction is inef-
ficient for the synthesis of syn adducts while the “matched”
reaction does not provide any significant improvement
of the results obtained using the achiral reagent 1b. It
should be pointed out, however, that adducts 4c,d and
5c,d are interesting intermediates in which the chiral
information contained in the original reagent can be used
in further stereoselective C-C bond-forming processes
as in the addition of organometallic reagents12 and
nucleophilic free radicals13 to the CdN bond of chiral
hydrazones.
we also decided to investigate the behavior of other
R-heterosubstituted aldehydes, such as carbohydrate-
derived R-alkoxyaldehydes10 and N-protected R-aminoal-
dehydes from natural amino acids, in this context.
Although the intrinsic enhancement of the carbonyl
reactivity by inductive effect in this case is clearly lower
than that for the three fluorine atoms, it was expected a
priori that these compounds, being more reactive than
simple aldehydes on one side and presenting lower steric
hindrance than trifluoromethylketones on the other,
could also behave as suitable substrates for the uncata-
lyzed addition reaction, which is particularly attractive
for the very mild and experimentally simple conditions
required. In this paper we report the results that were
collected on the basis of this hypothesis.
(11) Ha¨felinger, G.; Mack, H.-G. In The Chemistry of Enamines;
Patai, S., Rappoport, Z., Eds.; Wiley: New York, 1994; pp 1-85.
(12) (a) Takahashi, H.; Tomita, K.; Otomasu, H. J . Chem. Soc.,
Chem. Commun. 1979, 668. (b) Claremon, D. A.; Lumma, P. K.;
Phillips, B. T. J . Am. Chem. Soc. 1986, 108, 8265. (c) Thiam, M.;
Chastrette, F. Tetrahedron Lett. 1990, 31, 1429. (d) Alexakis, A.;
Lensen, N.; Tranchier, J .-P.; Manganey, P.; Feneau-Dupont, J .; De-
clercq, J . P. Synthesis 1995, 1038. (e) Kim, Y. H.; Choi, J . Y.
Tetrahedron Lett. 1996, 37, 5543. (f) Bataille, P.; Paterne, M.; Brown,
E. Tetrahedron: Asymmetry 1998, 9, 2181. (g) Hsieh, Y.-T.; Lee, G.-
H.; Wang, Y.; Luh, T.-Y. J . Org. Chem. 1998, 63, 1484. (h) Enders, D.;
Nu¨bling, C.; Schubert, H. Angew. Chem., Int. Ed. Engl. 1986, 25, 1109.
(i) Enders, D.; Nu¨bling, C.; Schubert, H. Liebigs Ann. 1997, 1089 and
references therein. (j) Denmark, S. E.; Weber, T.; Piotrowski, D. W. J .
Am. Chem. Soc. 1987, 109, 2224. (k) Enders, D.; D´ıez, E.; Ferna´ndez,
R.; Mart´ın-Zamora, E.; Mun˜oz, J . M.; Pappalardo, R. R.; Lassaletta,
J . M. J . Org. Chem. 1999, 64, 6329. (l) Cere`, V.; Peri, F.; Pollicino, S.;
Ricci, A. Synlett 2000, 1585.
(13) (a) Sturino, C. F.; Fallis, A. G. J . Am. Chem. Soc. 1994, 116,
7447. (b) Friestad, G. K. Org. Lett. 1999, 1, 1499. (c) El Kaim, L.; Gacon,
A.; Perroux, A. Tetrahedron Lett. 1998, 39, 371. (d) Kim, S.; Kee, I. S.;
Lee, S. J . Am. Chem. Soc. 1991, 113, 9882. (e) Marco-Contelles, J .;
Balme, G.; Bouyssi, D.; Destabel, C.; Henriet-Bernard, C. D.; Grimaldi,
J .; Hatem, J . M. J . Org. Chem. 1997, 62, 1202. (f) Miyata, O.; Muroya,
K.; Koide, J .; Naito, T. Synlett 1998, 271. (g) Friestad, G. K.; Qin, J . J .
Am. Chem. Soc. 2000, 122, 8329.
Resu lts a n d Discu ssion
We started by studying the addition of the simplest
formaldehyde N,N-dimethylhydrazone 1a to readily avail-
able R-D-xylodialdofuranose and R-D-galactodialdopyra-
nose derivatives 2 and 3. Although the expected adducts
4a and 5a were obtained under uncatalyzed conditions,
the results using this reagent were disappointing due to
the competition of a hydrazono transfer reaction, which
afforded substantial amounts of hydrazones 6a and 7a
as undesired byproducts (Scheme 3, Table 1, entries 1
and 5).
(10) Preliminary communication: Lassaletta, J . M.; Ferna´ndez, R.;
Mart´ın-Zamora, E.; Pareja, C. Tetrahedron Lett. 1996, 37, 5787.

Formylation/Cyanation of R-Alkoxy(amino)aldehydes
J . Org. Chem., Vol. 66, No. 15, 2001 5203
Ta ble 1. Syn th esis of r-Hyd r oxyh yd r a zon es 4, 5, 9, 12, a n d 13
a
b
Spontaneously formed in dry CH2Cl2 at room temperature. Isolated yield. c Determined in the reaction crude by 1H NMR and/or 13C
d
NMR. Inseparable mixture of diastereomers.

5204 J . Org. Chem., Vol. 66, No. 15, 2001
Ferna´ndez et al.
Sch em e 4. 1,2-Ad d ition of F or m a ld eh yd e
N,N-Dia lk ylh yd r a zon es to Isop r op ylid en e
Glycer a ld eh yd e 8
Sch em e 6. Tr a n sfor m a tion s fr om Hyd r a zon es 4b,
5b, (2S,3S)-12, a n d (2S,3S)-13
Sch em e 5. 1,2-Ad d ition of F or m a ld eh yd e
N,N-Dia lk ylh yd r a zon es to r-Am in oa ld eh yd es
Sch em e 7. Tr a n sfor m a tion s fr om Hyd r a zon e
(2S,3R)-9
To explore the desirable extension of this methodology
to R-aminoaldehydes, the addition of 1b to N-Boc-L-
phenylalaninal 10 and N-Boc-L-leucinal 11 was also
investigated. Considering the lower electronegativity of
nitrogen, we chose the N-Boc protecting group as the first
option in order to procure a reasonable inductive effect
by the nitrogenated moiety (higher aldehyde reactivity)
while maintaining a relatively low steric hindrance with
respect to other common derivatives such as R-dibenzy-
laminoaldehydes. The 1,2-addition of 1b to 10 and 11
proceeded smoothly to afford the expected adducts 12 and
13 in good yields and moderate-to-good anti selectivities,
along with small amounts (8 and 6%, respectively) of
hydrazono transfer byproducts 14 and 15 (Scheme 5,
Table 1, entries 10 and 11). Both the major (2S,3S) and
minor (2R,3S) diastereomers of 12 and 13 could be easily
separated by flash chromatography to get optically pure
compounds. It should be stressed here that erythro-â-
amino-R-hydroxyacids are important components of sev-
eral biologically active compounds. For instance, (2S,3S)-
3-amino-2-hydroxy-4-phenylbutanoic acid (allophenylnor-
statine, AHPA, see transformations from 12 below) is a
key component of HIV-protease inhibitors KNI-227 and
KNI-272,14 and several of its derivatives are potent and
specific inhibitors of leukotriene A4 hydrolase.15
4, 5, 9, 12, and 13 upon manipulation of their hydrazono
terminus. According to the procedure we previously
reported,16 magnesium monoperoxyphthalate (MMPP)
was successfully used as the reagent for the racemization-
free oxidative cleavage of the hydrazone moiety of the
new R-hydroxyhydrazones to give the corresponding
cyanohydrins in high yields (Schemes 6 and 7, Table 2)
and in optically pure form. Thus, the â-alkoxy-R-hydroxy-
hydrazones 4b, 5b, and (2S,3R)-9 were directly trans-
formed into the â-alkoxycyanohydrins 16-18, while
â-amino-R-hydroxyhydrazones (2S,3S)-12 and (2S,3S)-13
afforded the corresponding â-aminocyanohydrins 19 and
20 in a similar way (Schemes 6 and 7, Table 2). In
addition to the advantages mentioned above for the
choice of N-Boc protecting groups in the original ami-
noaldehydes 10 and 11, a supplementary benefit for this
kind of protection now comes into view: the low-nucleo-
philic carbamate nitrogen in derivatives 12 and 13 easily
survives the oxidative conditions needed for the synthesis
of these cyanohydrins.
Taking into account the limited stability of R-hydroxy-
aldehydes, we recognized that the free 2-hydroxy groups
had to be protected before the regeneration of the
carbonyl group from the parent of R-hydroxyhydrazones.
Hence, compounds 4b, 5b, (2S,3R)-9, 12, and 13 were
transformed into their corresponding benzyl ethers 21-
25 under standard conditions (NaH, BnBr, and TBAI).
Subsequent cleavage of these materials by ozonolysis
Syn th esis of r,â-Dih yd r oxy- a n d â-Am in o-r-h y-
d r oxyca r bon yl Der iva tives. A variety of densely func-
tionalized compounds can be synthesized from adducts
(14) (a) Mimoto, T.; Imai, J .; Kisanuki, S.; Enomoto, H.; Hattori,
N.; Akaji, K.; Kiso, Y. Chem. Pharm. Bull. 1992, 40, 2251. (b)
Kageyama, S.; Mimoto, T.; Murakawa, Y.; Nomizu, M.; Ford, H., J r.;
Shirasaka, T.; Gulnik, S.; Erickson, J .; Takada, K.; Hayashi, H.; Broder,
S.; Kiso, Y.; Mitsuya, H. Antimicrob. Agents Chemother. 1993, 37, 810.
(15) Yuam, W.; Munoz, B.; Wong, C.-H.; Haeggstro¨m, J . Z.; Wet-
terholm, A.; Samuelsson, B. J . Med. Chem. 1993, 36, 211.
(16) Ferna´ndez, R.; Gasch, C.; Lassaletta, J . M.; Llera, J . M.;
Va´zquez, J . Tetrahedron Lett. 1993, 34, 141.

Formylation/Cyanation of R-Alkoxy(amino)aldehydes
J . Org. Chem., Vol. 66, No. 15, 2001 5205
Ta ble 2. Syn th esis of F r ee Cya n oh yd r in s 16-20, Ben zyloxyh yd r a zon es 21-25, Ben zyloxya ld eh yd es 26-30, a n d
Ben zylcya n oh yd r in s 31-35
starting
material
cyanohydrins
yield
(%)
hydrazones
21-25
yield
(%)
aldehydes
26-30
yield
(%)
cyanohydrins
yield
(%)
16-20
31-35
4b
5b
16
17
18
19
20
86
73
71
82
85
21
22
23
24
25
85
84
83
72
73
26
27
28
29
30
74
61
64
51
62
31
32
33
34
35
89
93
88
93
87
(2S,3R)-9
(2S,3S)-12
(2S,3S)-13
4c, and 4d after transformation of these adducts into the
same known compound 38 (Scheme 8).
Con clu sion s
The moderate enhancement of aldehyde carbonyl re-
activity that is effected by an oxygen or nitrogen atom
at the R-position suffices for the spontaneous 1,2-addition
of formaldehyde N,N-dialkylhydrazones, behaving as soft
and neutral carbon nucleophiles. Using this reaction as
the key step, adequate substrates available from natural
sources can be transformed into useful compounds in a
very simple way. Thus, after regeneration of the carbonyl
group, the process starting from carbohydrate-derived
R-alkoxyaldehydes represents an alternative to the few
existing methods for their stereoselective homologation.20
Starting from aminoaldehydes, the â-amino-R-hydroxy-
carbonyl compounds that are synthesized constitute
valuable, densely functionalized intermediates.
F igu r e 1. Model for nucleophilic addition to compounds 2, 3,
8, 10, and 11.
Sch em e 8
Finally, the high-yielding, racemization-free hydra-
zone-to-nitrile transformation proved to be useful for the
synthesis of diverse, optically pure carbohydrate-derived
cyanohydrins and R-hydroxy-â-aminonitriles, which
complement the synthetic potential of the methodology.
afforded R-benzyloxyaldehydes 26-30 in moderate-to-
good yields. Alternatively, compounds 21-25 could also
be transformed into the corresponding benzyl-protected
cyanohydrins 31-35 using again MMPP for the oxidative
cleavage of the hydrazone moiety. Finally, dialdose
derivatives 21 and 22 were hydrolyzed (5 M HCl/Et2O)
and reduced in situ to afford aldoses 36 and 37 in 71 and
65% yields, respectively (Scheme 6).
Exp er im en ta l Section
Melting points were determined using a metal block and
are uncorrected. Optical rotations were measured at room
temperature. 1H and 13C NMR spectra were obtained in CDCl3
with either TMS (1H, 0.00 ppm; 13C, 0.00 ppm) or CDCl3 (1H,
7.26 ppm; 13C, 77.00 ppm) as an internal reference. FT-IR
spectra were recorded for KBr pellets or films. EI-mass spectra
were recorded at 70 eV using an ionizing current of 100 µA,
an accelerating voltage of 4 kV, and a resolution of 1000 or
10 000 (10% valley definition). The reactions were monitored
by TLC. Purification of the products was carried out by flash
chromatography (silica gel, 0.063-0.200 nm). The light petro-
leum ether (PE) used had a boiling range of 40-65 °C.
Tetrahydrofuran (THF) was distilled from sodium benzophe-
noneketyl immediately prior to use.
Syn th esis of Ad d u cts 4, 5, 9, 12, a n d 13: Gen er a l
P r oced u r e. To a solution of aldehyde 2, 3, 8, 10, or 11 (1
mmol) in dry CH2Cl2 (4 mL) was added the hydrazone 1a -d
(2 mmol) under an argon atmosphere. The mixture was stirred
at room temperature until TLC or 1H NMR indicated total
consumption of the starting material had occurred. The crude
was evaporated, and the residue was purified by flash chro-
matography. Representative spectral and analytical data for
compounds 4b and 12 follow.
Ster eoch em ica l Asp ects. The absolute configura-
tions of the newly created stereogenic centers of 4b, 5b,
and (2S,3R)-9 and their derivatives were inferred from
those of their corresponding R-benzyloxyaldehydes 26-
28, respectively. The latter were determined after com-
parison of their physical and spectroscopical data with
those reported in the literature.17 The (2S) configuration
of â-aminocyanohydrin 19 was deduced after comparison
of its physical and spectroscopic characteristics with
those of the known (2R,3S) isomer;18 those of parent
(2S,3S)-12 and its derivatives were deduced thereafter,
and those of (2S,3S)-13 and its derivatives were assigned
by analogy. In all cases, erythro-configured compounds
were isolated as major or sole products; the anti selectivi-
ties observed for the 1,2-addition to the aldehyde are in
agreement with the nonchelated Felkin-Ahn model for
nucleophilic addition to chiral carbonyl compounds19
(Figure 1, structures A-D). The (2R) configuration
established for 4b was also assigned to compounds 4a ,
3-O-Ben zyl-1,2-O-isop r op ylid en e-r-D-glu coh exod ia ld o-
1,4-fu r a n ose N,N-Bu tylen eh yd r a zon e (4b). Flash chroma-
tography (1:1 Et2O/PE) gave 275 mg (73%) of crystalline 4b:
mp 70-72 °C; [R]25D -27.6 (c 1, CH2Cl2); 1H NMR (CDCl3, 300
MHz) δ 1.33 (s, 3H), 1.49 (s, 3H), 1.90 (m, 4H), 3.18 (m, 4H),
3.75 (d, 1H, J ) 2.9 Hz), 4.05 (dd, 1H, J ) 2.9, 8.2 Hz), 4.19
(17) (a) 26: Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.
Tetrahedron 1987, 43, 3533 and references therein. (b) 27: Danishef-
sky, S. J .; Pearson, W. H.; Harvey, D. F.; Maring, C. J .; Springer, J . P.
J . Am. Chem. Soc. 1985, 107, 1256. (c) 28: Dondoni, A.; Ordun˜a, J .;
Merino, P. Synthesis 1992, 201 and references therein.
(18) Parris, K. D.; Hoover, D. J .; Damon, D. B.; Davies, D. R.
Biochemistry 1992, 31, 8125.
(19) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199. (b) Anh, N. T.; Eisenstein, O. Nouv. J . Chim. 1977, 1, 61.
(20) Dondoni, A.; Marra, A. In Preparative Carbohydrate Chemistry;
Hanessian, H., Ed.; Marcel Dekker: New York, 1997; pp 173-205 and
references therein.

5206 J . Org. Chem., Vol. 66, No. 15, 2001
Ferna´ndez et al.
(d, 1H, J ) 2.9 Hz), 4.59-4.61 (m, 1H), 4.62 (d, 1H, J ) 3.7
Hz), 4.70 (m, 2H), 5.98 (d, 1H, J ) 3.7 Hz), 6.73 (d, 1H, J )
2.9 Hz), 7.28-7.41 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 23.1,
26.1, 26.7, 51.2, 67.9, 72.4, 82.0, 82.2, 105.2, 111.6, 127.7, 128.3,
133.9, 137.5; IR (film, cm-1) 3647-3088, 1597, 1495; MS (EI)
376 (M+, 21), 361 (19), 358 (100). Anal. Calcd for C20H28N2O5:
C, 63.80; H, 7.50; N, 7.44. Found: C, 64.02; H, 7.44; N, 7.46.
(2S,3S)- a n d (2R,3S)-3-(ter t-Bu toxyca r bon yla m in o)-2-
h yd r oxy-4-p h en ylb u t yr a ld eh yd e N,N-Bu t ylen eh yd r a -
zon e [(2S,3S)- a n d (2R,3S)-12]. Flash chromatography (1:2
Et2O/hexane) gave 240 mg (69%) of (2S,3S)-12 and 41 mg
organic layer was washed with saturated NH4Cl (3 × 10 mL)
and H2O (20 mL), dried (Na2SO4), and concentrated. The
residue was purified by flash chromatography. Representative
spectral and analytical data for compounds 21 and 24 are as
follows.
3,5-Di-O-ben zyl-1,2-O-isop r op ylid en e-r-D-glu co-h exo-
d ia ld o-1,4-fu r a n ose N,N-Bu tylen eh yd r a zon e (21). Flash
chromatography (1:2 Et2O/hexane) gave 238 mg (85%) of 21
as an oil: [R]25D -36.5 (c 1, CHCl3); 1H NMR (CDCl3, 500 MHz)
δ 1.30 (s, 3H), 1.49 (s, 3H), 1.87-1.89 (m, 4H), 3.18-3.27 (m,
4H), 4.12 (d, 1H, J ) 2.9 Hz), 4.33 (dd, 1H, J ) 2.9, 9.2 Hz),
4.37 (dd, 1H, J ) 7.2, 9.2 Hz), 4.40 (d, 1H, J ) 11.5 Hz), 4.52
(d, 1H, J ) 11.8 Hz), 4.60 (d, 1H, J ) 3.8 Hz), 4.63 (d, 1H, J
) 11.8 Hz), 4.64 (d, 1H, J ) 11.5 Hz), 5.93 (d, 1H, J ) 3.8 Hz),
6.38 (d, 1H, J ) 3.8 Hz), 7.26-7.28 (m, 10H); 13C NMR (CDCl3,
75 MHz) δ 23.3, 26.1, 26.6, 50.6, 70.0, 72.0, 76.7, 80.6, 81.5,
82.1, 105.0, 111.4, 127.3, 127.3, 127.5, 127.6, 128.1, 128.2,
131.8; IR (film, cm-1) 2874, 1497; MS (EI) 466 (M+, 2), 108
(100). Anal. Calcd for C27H34N2O5: C, 69.50; H, 7.34; N, 6.00.
Found: C, 69.91; H, 7.84; N, 5.57.
(12%) of (2R,3S)-12 as oils. (2S,3S)-12: [R]29 -20.3 (c 1, CH2-
D
Cl2); 1H NMR (DMSO-d6, 70 °C, 300 MHz) δ 1.30 (s, 9H), 1.75-
1.84 (m, 4H), 2.66 (dd, 1H, J ) 8.6, 13.7 Hz), 2.86 (dd, 1H, J
) 5.8, 13.7 Hz), 3.02-3.06 (m, 4H), 3.71-3.80 (m, 1H), 3.96-
4.00 (m, 1H), 4.69 (bs, 1H), 6.08 (bs, 1H), 6.40 (d, 1H, J ) 5.6
Hz), 7.13-7.25 (m, 5H); 13C NMR (CDCl3, 70 °C, 75 MHz) δ
23.1, 28.2, 38.3, 51.2, 54.4, 70.2, 79.0, 126.2, 128.3, 129.4, 134.0,
138.3, 155.7; IR (film, cm-1) br 3360, 1707, 1499; MS (EI) 347
(M+, 1), 127 (85), 71 (100); HRMS m/z calcd for C19H29N3O3
347.2209, found 347.2215. (2R,3S)-12: [R]29 +1.0 (c 1, CH2-
(2S,3S)-2-Ben zyloxy-3-(ter t-bu toxyca r bon yla m in o)-4-
ph en ylbu tyr aldeh yde N,N-Bu tylen eh ydr azon e (24). Flash
chromatography (1:2 Et2O/hexane) gave 189 mg (72%) of 24
D
Cl2); 1H NMR (DMSO-d6, 70 °C, 500 MHz) δ 1.26 (s, 9H), 1.75-
1.84 (m, 4H), 2.58 (dd, 1H, J ) 10.0, 14.0 Hz), 2.99 (dd, 1H, J
) 3.9, 13.9 Hz), 3.02-3.06 (m, 4H), 3.67-3.77 (m, 1H), 3.89-
3.94 (m, 1H), 4.83 (bs, 1H), 6.25 (bs, 1H), 6.40 (d, 1H, J ) 6.1
Hz), 7.13-7.25 (m, 5H); 13C NMR (CDCl3, 70 °C, 75 MHz) δ
22.5, 27.9, 38.7, 50.2, 54.7, 69.2, 77.3, 80.3, 126.5, 128.8, 129.9,
130.3, 137.2, 140.5, 154.9; IR (film, cm-1) br 3370, 1705, 1498;
MS (EI) 347 (M+, 3), 127 (95), 71 (100). Anal. Calcd for
as an oil: [R]25 -3.8 (c 1.42, CH2Cl2); 1H NMR (DMSO-d6, 75
D
°C, 300 MHz) δ 1.30 (s, 9H), 1.78-1.85 (m, 4H), 2.69 (dd, 1H,
J ) 8.7, 13.7 Hz), 2.86 (dd, 1H, J ) 5.2, 13.7 Hz), 3.5-3.09
(m, 4H), 3.80-3.91 (m, 2H), 4.37 (d, 1H, J ) 12.2 Hz), 4.54 (d,
1H, J ) 12.2 Hz), 6.31 (d, 1H, J ) 6.9 Hz), 6.32 (bs, 1H), 7.14-
7.34 (m, 10H); 13C NMR (DMSO-d6, 75 MHz) δ 22.8, 28.2, 36.5,
50.4, 54.9, 69.3, 77.5, 80.2, 125.8, 127.2, 127.4, 128.0, 130.0,
132.3, 138.8, 139.1, 155.3; IR (film, cm-1) 1696, 1593; MS (EI)
437 (M+, 1), 217 (65), 91 (100); HRMS m/z calcd for C26H35N3O3
437.2678, found 437.2678.
C
19H29N3O3: C, 65.68; H, 5.51; N, 12.10. Found: C, 66.01; H,
5.82; N, 12.37.
Syn th esis of Cya n oh yd r in s 16-20: Gen er a l P r oce-
d u r e. To a stirred, cooled (-45 °C) solution of R-hydroxyhy-
drazone 4b, 5b, (2S,3R)-9, (2S,3S)-12, or (2S,3S)-13 (1 mmol)
in MeOH (3 mL) was added dropwise a precooled (-45 °C)
solution of magnesium monoperoxyphthalate hexahydrate (2.5
mmol) in MeOH (10 mL). After completion (10-15 min), CH2-
Cl2 and H2O were added, and the organic layer was washed
with brine (2 × 10 mL), dried (Na2SO4), and concentrated. The
residue was purified by flash chromatography. Representative
spectral and analytical data for compounds 16 and 19 are as
follows.
Syn th esis of r-Ben zyloxya ld eh yd es 26-30: General
Procedure. Dry ozone was bubbled through a cooled (-78 °C)
solution of R-benzyloxyhydrazone 21-25 (0.5 mmol) in CH2-
Cl2 (5 mL) until the appearance of a permanent blue color
arose. After addition of Me2S (0.5 mL), the mixture was
allowed to reach room temperature and concentrated, and the
residue was purified by flash chromatography. Compounds
26-28 were identified by a comparison of their spectral and
analytical data with those previously reported.14 Representa-
tive spectral and analytical data for compound 30 are as
follows.
3-O-Ben zyl-1,2-O-isop r op ylid en e-r-D-glu co-h exofu r a -
n u r on on itr ile (16). Flash chromatography (1:2 Et2O/PE) gave
275 mg (90%) of crystalline 16: mp 78-80 °C; [R]25 -63.9 (c
(2S,3S)-2-Ben zyloxy-3-(ter t-bu toxyca r bon yla m in o)-5-
m eth ylh exa n a l (30). Flash chromatography (1:2 Et2O/hex-
D
1
1, CHCl3); H NMR (CDCl3, 500 MHz) δ 1.34 (s, 3H), 1.48 (s,
3H), 3.86 (bs, 1H), 4.32 (d, 1H, J ) 3.7 Hz), 4.39 (dd, 1H, J )
3.7, 5.3 Hz), 4.62 (d, 1H, J ) 11.3 Hz), 4.65 (d, 1H, J ) 3.6
Hz), 4.74 (d, 1H, J ) 11.3 Hz), 4.74-4.76 (m, 1H), 6.03 (d, 1H,
J ) 3.6 Hz), 7.26-7.40 (m, 5H); 13C NMR (CDCl3, 125 MHz) δ
26.1, 26.8, 60.3, 72.9, 79.0, 81.7, 82.9, 105.5, 112.5, 118.0, 128.1,
128.5, 128.7, 135.9; IR (film, cm-1) br 3423, 1454; MS (EI) 263
(2), 91 (100). Anal. Calcd for C16H19NO5: C, 62.94; H, 6.27; N,
4.59. Found: C, 62.89; H, 6.50; N, 4.51.
ane) gave 104 mg (62%) of 30 as an oil: [R]25 -38.6 (c 0.6,
D
1
CH2Cl2); H NMR (DMSO-d6, 75 °C, 300 MHz) δ 0.86 (d, 3H,
J ) 6.7 Hz), 0.89 (d, 3H, J ) 6.7 Hz), 1.29-1.35 (m, 2H), 1.39
(s, 9H), 1.56-1.62 (m, 1H), 3.87-3.91 (m, 1H), 4.45 (d, 1H, J
) 12.0 Hz), 4.58-4.63 (m, 1H), 4.69 (d, 1H, J ) 12.0 Hz), 6.61
(bs, 1H), 7.25-7.35 (m, 5H), 9.58 (s, 1H); 13C NMR (DMSO-
d6, 75 °C, 75 MHz) δ 21.4, 22.6, 23.9, 27.9, 48.7, 71.7, 85.3,
126.2, 127.3, 127.9, 128.4, 137.8, 155.1, 201.6; IR (film, cm-1
)
(2S,3S)-3-(ter t-Bu toxycar bon ylam in o)-2-h ydr oxy-4-ph e-
n ylbu tyr on itr ile (19). Flash chromatography (1:2 Et2O/PE)
1713; MS (CI) 336 (M+ + 1, 40), 306 (35), 294 (35), 280 (70);
HRMS m/z calcd for C19H29NO4 335.2089, found 335.2083.
Syn th esis of O-Ben zylcya n oh yd r in s 31-35: Gen er a l
P r oced u r e. A solution of MMPP‚6H2O (1.25 mmol) in MeOH
(4 mL) was added dropwise to a cooled (0 °C) solution of
R-benzyloxyhydrazone 21-25 (0.5 mmol) in MeOH (1 mL).
After completion (5 min), CH2Cl2 (10 mL) and H2O (10 mL)
were added, and the organic layer was washed with brine (2
× 5 mL) and H2O (5 mL), dried (Na2SO4), and concentrated.
The resulting residue was purified by flash chromatography.
Representative spectral and analytical data for compounds 31
and 34 are as follows.
gave 226 mg (82%) of crystalline 19: mp 93-94 °C; [R]25
D
1
-30.3 (c 1, CH2Cl2); H NMR (DMSO-d6, 70 °C, 300 MHz) δ
1.30 (s, 9H), 2.72 (dd, 1H, J ) 10.4, 14.0 Hz), 2.94 (dd, 1H, J
) 4.0, 14.0 Hz), 3.82-3.91 (m, 1H), 4.54 (dd, 1H, J ) 4.3, 6.2
Hz), 6.50 (d, 1H, J ) 6.2 Hz), 6.76 (bs, 1H), 7.14-7.34 (m, 5H);
13C NMR (DMSO-d6, 75 MHz) δ 28.1, 35.5, 55.8, 63.8, 81.2,
118.5, 127.0, 128.8, 129.1, 136.4, 156.6; IR (film, cm-1) br 3385,
1696, 1516; MS (CI) 277 (M+ + 1, 5), 194 (100). Anal. Calcd
for C15H20N2O3: C, 65.20; H, 7.30; N, 10.14. Found: C, 65.04;
H, 7.53; N, 9.82.
Syn th esis of r-Ben zyloxyh yd r a zon es 21-25: General
Procedure. To a stirred solution of R-hydroxyhydrazone 4, 5,
(S)-9, (S)-12, or (S)-13 (0.6 mmol) in dry THF (3 mL) were
added Bu4NI (0.06 mmol), BnBr (0.9 mmol), and NaH (0.9
mmol) under an argon atmosphere. The reaction mixture was
stirred at room temperature until completion (TLC monitoring)
and treated with NaOMe (1 M in MeOH, 0.5 mL) for 15 min.
Et2O (10 mL) and H2O (10 mL) were added, the aqueous phase
was extracted with more Et2O (5 mL), and the combined
3,5-Di-O-ben zyl-1,2-O-isop r op ylid en e-r-D-glu co-h exo-
fu r a n u r on on itr ile (31). Flash chromatography (1:5 Et2O/
hexane) gave 176 mg (89%) of crystalline 31: mp 93-95 °C;
1
[R]25 -61.8 (c 1, CHCl3); H NMR (CDCl3, 300 MHz) δ 1.38
D
(s, 3H), 1.56 (s, 3H), 4.12 (d, 1H, J ) 1.7 Hz), 4.51 (d, 1H, J )
11.1 Hz), 4.51 (dd, 1H, J ) 3.3, 8.3 Hz), 4.57 (d, 1H, J ) 11.8
Hz), 4.60 (d, 1H, J ) 8.3 Hz), 4.66 (d, 1H, J ) 4.8 Hz), 4.71 (d,
1H, J ) 11.1 Hz), 4.91 (d, 1H, J ) 11.8 Hz), 6.02 (d, 1H, J )
3.7 Hz), 7.33-7.40 (m, 10H); 13C NMR (CDCl3, 75 MHz) δ 26.2,

Formylation/Cyanation of R-Alkoxy(amino)aldehydes
J . Org. Chem., Vol. 66, No. 15, 2001 5207
26.8, 65.9, 72.2, 72.5, 79.1, 80.6, 81.7, 105.3, 112.4, 116.8, 127.4,
Anal. Calcd for C22H26N2O3: C, 72.11; H, 7.15; N, 7.64.
Found: C, 71.77; H, 7.27; N, 7.32.
128.0, 128.2, 128.5, 128.5, 128.6, 134.5, 136.8; IR (film, cm-1
)
2221, 1442; MS (EI) 395 (M+, 1), 91 (100). Anal. Calcd for
23H25NO5: C, 69.86; H, 6.37; N, 3.54. Found: C, 69.75; H,
Ack n ow led gm en t. We thank the Direccio´n General
de Investigacio´n Cient´ıfica y Te´cnica (Grants PB 97/
0747 and PPQ2000-1341) and the J unta de Andaluc´ıa
for financial support.
C
6.58; N, 3.47.
(2S,3S)-2-Ben zyloxy-3-(ter t-bu toxyca r bon yla m in o)-4-
p h en ylbu tyr on itr ile (34). Flash chromatography (1:2 Et2O/
hexane) gave 170 mg (93%) of crystalline 34: mp 112-114 °C;
[R]23D +4.1 (c 1, CH2Cl2); 1H NMR (DMSO-d6, 70 °C, 300 MHz)
δ 1,29 (s, 9H), 2.80 (dd, 1H, J ) 10.1, 14.1 Hz), 2.92 (dd, 1H,
J ) 4.3, 14.1 Hz), 4.01-4.10 (m, 1H), 4.54 (d, 1H, J ) 4.6 Hz),
4.62 (d, 1H, J ) 11.7 Hz), 4.78 (d, 1H, J ) 11.7 Hz), 6.88 (bs,
1H), 7.13-7.39 (m, 10H); 13C NMR (DMSO-d6, 75 MHz) δ 27.8,
33.6, 52.6, 70.5, 71.6, 74.7, 117.1, 126.0, 127.3, 127.6, 127.8,
128.1, 128.8, 137.0, 137.6, 155.1; IR (film, cm-1) 3379, 2143,
1690; MS (EI) 375 (M+, 1), 360 (3), 269 (18), 211 (11), 91 (100).
Su p p or tin g In for m a tion Ava ila ble: Spectral and ana-
lytical data for compounds 4a ,c,d , 5a -d , 6a , 7a -c, (2S,3R)-
9, (2R,3R)-9, (2S,3S)-13, (2R,3S)-13, 14, 15, 17, 18, 20, 29,
32, 33, 35, 36, and 37, and the 13C NMR spectra for compounds
4a ,c,d , 5a -d , 7a -c, (2S,3R)-9, (2R,3R)-9, (2S,3S)-12, (2R,3S)-
13, 17, 22, 24, 25, 29, 30, and 35. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O015711+