Grignard addition to aldonitrones. Stereochemical aspects and application to the synthesis of C2-symmetric diamino alcohols and diamino diols

Article abstract of DOI:10.1021/jo980980u

A new example of the stereoselective installation of the amino group at a saturated carbon center via organometallic addition of chiral aldehydes to nitrones is illustrated by the synthesis of 1,3-diamino propanol 1 and 1,4- diamino butandiol 2 units. Three diamino alcohol 1 stereotriads were obtained by stereoselective addition of alkylmagnesium halides (benzyl, cyclohexylmethyl, and metallyl) to the N-benzyl nitrones derived from β- amino-α-hydroxy aldehydes followed by reduction of the resulting N- benzylhydroxylamines. Three 1,4-dibenzyl substituted stereoisomers of type 2 with fixed S configuration at C2 and C3 were prepared by sequential and simultaneous amination in two directions starting from L-threose nitrone and L-tartraldehyde bis-nitrone, respectively. The R,S,S,R isomer obtained by the former route was converted into a seven-membered ring cyclic urea (1,3- diazapin-2-one), i.e., a compound that belongs to a class of nonpeptide HIV- 1 protease inhibitors.

Full text of DOI:10.1021/jo980980u

9252
J . Org. Chem. 1998, 63, 9252-9264
Gr ign a r d Ad d ition to Ald on itr on es. Ster eoch em ica l Asp ects a n d
Ap p lica tion to th e Syn th esis of C2-Sym m etr ic Dia m in o Alcoh ols
a n d Dia m in o Diols
Alessandro Dondoni,* Daniela Perrone, and Marilisa Rinaldi
Dipartimento di Chimica, Laboratorio di Chimica Organica, Universita`, 44100-Ferrara, Italy
Received May 22, 1998
A new example of the stereoselective installation of the amino group at a saturated carbon center
via organometallic addition of chiral aldehydes to nitrones is illustrated by the synthesis of 1,3-
diamino propanol 1 and 1,4-diamino butandiol 2 units. Three diamino alcohol 1 stereotriads were
obtained by stereoselective addition of alkylmagnesium halides (benzyl, cyclohexylmethyl, and
metallyl) to the N-benzyl nitrones derived from â-amino-R-hydroxy aldehydes followed by reduction
of the resulting N-benzylhydroxylamines. Three 1,4-dibenzyl substituted stereoisomers of type 2
with fixed S configuration at C2 and C3 were prepared by sequential and simultaneous amination
in two directions starting from L-threose nitrone and L-tartraldehyde bis-nitrone, respectively. The
R,S,S,R isomer obtained by the former route was converted into a seven-membered ring cyclic
urea (1,3-diazapin-2-one), i.e., a compound that belongs to a class of nonpeptide HIV-1 protease
inhibitors.
In tr od u ction
Our group has been investigating in recent years an
approach in which aldonitrones are used as convenient
iminium derivatives of aldehydes for the synthesis of
amino compounds.1 The method consists of the substrate-
stereocontrolled addition of a carbon nucleophile to the
nitrone functionality and reduction of the resulting hy-
droxylamine (Scheme 1). Tunable syn/anti stereoselec-
tivity of the addition reaction was achieved by precom-
plexation of the nitrone with various metal halides, such
as magnesium, zinc, or aluminum chloride or bromide.
Initially, this synthetic pathway was directed to the
simultaneous introduction of the amino group and an-
other functionality by the use of organometallic reagents
as carbon nucleophiles whose organic moiety was trans-
formable into a functional group. Remarkable examples
of this procedure are provided by the synthesis of R-amino
aldehydes2 and R-amino acids3 by the use of 2-lithiothia-
zole and 2-lithiofuran as masked equivalents of the
formyl and carboxylate carbanions, respectively. Our
total synthesis of the peptidyl nucleoside antibiotic
Polyoxin J stemmed from the application of this meth-
odology.4 More recently, we have considered this ami-
nation method for the synthesis of 1,3-diamino alcohols
1 and 1,4-diamino 2,3-diols 2 (Figure 1) by the use of
alkyl Grignard reagents as carbon nucleophiles.5 Com-
pounds 1 and 2 can exist as different stereoisomers and
therefore are interesting synthetic targets for testing the
Figu r e 1. Structures of the HIV-1 protease inhibitors A-74704,
DMP 323, and DMP 450 and their core units 1 and 2.
Sch em e 1
scope of the nitrone-based stereocontrolled amination of
suitable substrates. Numerous compounds with C2-
symmetry have been reported in recent years mainly for
their potential utility in the area of asymmetric cataly-
sis.6 By contrast, diamino alcohols 1 and diols 2 are
receiving special attention in medicinal chemistry be-
cause they are the key core units of C2-symmetric peptidic
and nonpeptidic HIV-1 protease inhibitors.7,8 Examples
of these types of inhibitors are shown by the modified
peptide7a,b A-74704 incorporating the structural motif of
* E-mail address: adn@dns.unife.it.
(1) (a) Dondoni, A.; Perrone, D. Aldrichimica Acta 1997, 30, 35-
46. (b) Dondoni, A.; Marra, A. In Preparative Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Dekker: New York, 1997; pp 173-205. (c)
Dondoni, A. Synthesis 1998, 1681-1706.
(2) Dondoni, A.; Franco, S.; J unquera, F.; Merchan, F. L.; Merino,
P.; Tejero, T.; Bertolasi, V. Chem. Eur. J . 1995, 1, 505-520.
(3) Dondoni, A.; J unquera, F.; Merchan, F. L.; Merino, P.; Scher-
rmann, M.-C.; Tejero, T. J . Org. Chem. 1997, 62, 5484-5496.
(4) Dondoni, A.; Franco, S.; J unquera, F.; Merchan, F. L.; Merino,
P.; Tejero, T. J . Org. Chem. 1997, 62, 5497-5507.
(5) (a) Dondoni, A.; Perrone, D. Tetrahedron Lett. 1997, 38, 499-
502. (b) Dondoni, A.; Perrone, D.; Rinaldi, M. Tetrahedron Lett. 1998,
39, 2651-2654.
(6) Whitesell, J . K. Chem. Rev. 1989, 89, 1581-1590.
(7) For peptide-type inhibitors, see: (a) Erickson, J .; Neidhart, D.
J .; VanDrie, J .; Kempf, D. J .; Wang, X. C.; Norbeck, D. W.; Plattner,
J . J .; Rittenhouse, J . W.; Turon, M.; Wideburg, N.; Kohlbrenner, W.
E.; Simmer, R.; Helfrich, R.; Paul, D. A.; Knigge, M. Science 1990, 249,
527-533. (b) Kempf, D. J .; Norbeck, D. W.; Codacovi, L. M.; Wang, X.
C.; Kohlbrenner, W. E.; Wideburg, N.; Paul, D. A.; Knigge, M. F.;
Vasavanonda, S.; Craig-Kennard, A.; Saldivar, A.; Rosenbrook, W., J r.;
Clement, J . J .; Plattner, J . J .; Erickson, J . J . Med. Chem. 1990, 33,
2687-2689. (c) Gurjar, M. K.; Pal, S.; Rao, A. V. R. Tetrahedron 1997,
53, 4769-4778. (d) Benedetti, F.; Miertus, S.; Norbedo, S.; Tossi, A.;
Zlatoidzky, P. J . Org. Chem. 1997, 62, 9348-9353.
10.1021/jo980980u CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/20/1998

Amination via Grignard Addition to Aldonitrones
J . Org. Chem., Vol. 63, No. 25, 1998 9253
Sch em e 2
Sch em e 3a,b
a
Key: 3a -7a , R ) Ph; 3b-7b, R ) c-C6H11; 3c-7c, R ) i-C3H7.
b
Reagents and conditions: (a) 2-methoxypropene, PPTS, toluene,
100 °C; (b) 1. MeOTf, MeCN; 2. NaBH4, MeOH; 3. CuO, CuCl2,
H2O, MeCN; (c) BnNHOH, MgSO4, CH2Cl2.
1 and the cyclic ureas8c,e DMP 323 and DMP 450 in-
corporating the motif of 2. It is worth recalling that the
rational design and synthesis of these new potent pro-
tease inhibitors have been stimulated by the recognition
that the aspartic protease encoded by the HIV-1 exists
in its active form as a 2-fold symmetric homodimer.9
Consequently, compounds with C2-symmetry matching
the characteristics of the enzyme structure may act as
potent and selective inhibitors of that enzyme which is
essential for the maturation of fully infectious virion
particles.
R. According to the reaction sequence outlined in Scheme
1, a straightforward entry to these compounds would
require the tunable stereoselective addition of organo-
metallic reagents RM to nitrones of â-amino-R-hydroxy
aldehydes. The easy access to this type of chiral alde-
hydes from R-amino acids by the thiazole-based aldehyde
synthesis has been amply documented.1
Thus, the amino alcohols 3a -c (Scheme 3) were pre-
pared in good yield (ca. 80%) by addition of 2-(trimeth-
ylsilyl)thiazole (2-TST) to the N-Boc-R-amino aldehydes
derived from L-phenylalanine,11 L-cyclohexylalanine,12
and L-leucine,11 as described.13 Acetonation of these
amino alcohols and column chromatography of the mix-
tures of 2-thiazolyl oxazolidine epimers gave pure prod-
ucts 4a -c and 6a -c. Each individual compound was
then subjected to the standard thiazole-to-formyl de-
blocking protocol,14 and the resulting crude aldehyde was
condensed with N-benzylhydroxylamine in the presence
of magnesium sulfate as dehydrating agent. The N-
benzyl nitrones 5a -c and 7a -c were characterized as
being Z isomers by NOE (8-10% enhancement) between
the CHdN and CH2Ph signals.2 These compounds were
white solids which were storable for months without
appreciable decomposition.
After the recent reports5 on the synthesis of some
stereoisomers of type 1 and 2 (R ) Bn), we have since
expanded the scope of our investigation and report here
in extenso the results of the earlier and recent work.
Resu lts a n d Discu ssion
Syn th esis of 1,3-Dia m in o Alcoh ols 1. A sym-
metrically substituted diamino alcohol 1 exists as four
stereoisomers 1A-D (stereotriads),10 i.e., two meso and
two pseudo-C2-symmetric compounds (Scheme 2). There-
fore, the challenge lay in demonstrating the potential of
the nitrone-based amination methodology for the syn-
thesis of various stereotriads carrying different groups
(8) For cyclic ureas, see: (a) Lam, P. Y. S.; J adhav, P. K.; Eyermann,
C. J .; Hodge, C. N.; Ru, Y.; Bacheler, L. T.; Meek, J . L.; Otto, M. J .;
Rayner, M. M.; Wong, Y. N.; Chang, C.-H.; Weber, P. C.; J ackson, D.
A.; Sharpe, T. R.; Erickson-Viitanen, S. Science 1994, 263, 380-384.
(b) Rossano, L. T.; Lo, Y. S.; Anzalone, L.; Lee, Y.-C.; Meloni, D. J .;
Moore, J . R.; Gale, T. M.; Arnett, J . F. Tetrahedron Lett. 1995, 36,
4967-4970. (c) Pierce, M. E.; Harris, G. D.; Islam, Q.; Radesca, L. A.;
Storace, L.; Waltermire, R. E.; Wat, E.; J adhav, P. K.; Emmett, G. C.
J . Org. Chem. 1996, 61, 444-450. (d) Nugiel, D. A.; J acobs, K.; Worley,
T.; Patel, M.; Kaltenbach, R. F., III; Meyer, D. T.; J adhav, P. K.; De
Lucca, G. V.; Smyser, T. E.; Klabe, R. M.; Bacheler, L. T.; Rayner, M.
M.; Seitz, S. P. J . Med. Chem. 1996, 39, 2156-2169. (e) Lam, P. Y. S.;
Ru, Y.; J adhav, P. K.; Aldrich, P. E.; DeLucca, G. V.; Eyermann, C. J .;
Chang, C.-H.; Emmett, G.; Holler, E. R.; Daneker, W. F.; Li, L.;
Confalone, P. N.; McHugh, R. J .; Han, Q.; Li, R.; Markwalder, J . A.;
Seitz, S. P.; Sharpe, T. R.; Bacheler, L. T.; Rayner, M. M.; Klabe, R.
M.; Shum, L.; Winslow, D. L.; Kornhauser, D. M.; J ackson, D. A.;
Erickson-Viitanen, S.; Hodge, C. N. J . Med. Chem. 1996, 39, 3514-
3525. (f) Nugiel, D. A.; J acobs, K.; Cornelius, L.; Chang, C.-H.; J adhav,
P. K.; Holler, E. R.; Klabe, R. M.; Bacheler, L. T.; Cordova, B.; Garber,
S.; Reid, C.; Logue, K. A.; Gorey-Feret, L. J .; Lam, G. N.; Erickson-
Viitanen, S.; Seitz, S. P. J . Med. Chem. 1997, 40, 1465-1474. (g)
Hulte´n, J .; Bonham, N. M.; Nillroth, U.; Hansson, T.; Zuccarello, G.;
Bouzide, A.; A° qvist, J .; Classon, B.; Danielson, U. H.; Karle´n, A.;
Kvarnstro¨m, I.; Samuelsson, B.; Hallberg, A. J . Med. Chem. 1997, 40,
885-897.
Each nitrone of type 5 was reacted with the suitable
Grignard reagent under the same conditions (Et2O/THF,
-78 °C, 3 h), i.e., 5a with benzylmagnesium chloride, 5b
with cyclohexylmethylmagnesium bromide, and 5c with
metallylmagnesium chloride (Scheme 4). Each reaction
produced a mixture of syn and anti hydroxylamines 8
and 9 in good overall yield (Table 1). The reactions of
5a and 5b showed good levels of syn selectivity to give
the corresponding hydroxylamines 8a and 8b as major
products.15 A reversal of the diastereoselectivity to give
the anti adducts 9a and 9b as main products was
achieved by complexation of the nitrones 5a and 5b with
(11) Dondoni, A.; Perrone, D.; Merino, P. J . Org. Chem. 1995, 60,
8074-8080.
(12) Wagner, A.; Mollath, M. Tetrahedron Lett. 1993, 34, 619-622.
(13) Given the syn stereoselective addition of 2-TST to R-amino
aldehydes whose nitrogen is singly protected (see refs 1 and 11), the
amino alcohols 3a -c were obtained as mixtures of syn/anti isomers
in ca. 80:20 ratio. The stereochemical assignment followed the conver-
sion of each pair of these amino alcohols into the corresponding
oxazolidinones and NMR analysis as described (ref 11).
(14) Dondoni, A.; Marra, A.; Perrone, D. J . Org. Chem. 1993, 58,
275-277.
(9) (a) Wlodawer, A.; Miller, M.; J asko´lski, M.; Sathyanarayana, B.
K.; Baldwin, E.; Weber, I. T.; Selk, L. M.; Clawson, L.; Schneider, J .;
Kent, S. B. H. Science 1989, 245, 616-621. (b) Navia, M. A.; Fitzgerald,
P. M. D.; Mckeever, B. M.; Leu, C.-T.; Heimbach, J . C.; Herber, W. K.;
Sigal, I. S.; Darke, P. L.; Springer, J . P. Nature 1989, 337, 615-620.
(10) The central carbon of 1B and its enantiomer 1C, by virtue of
its symmetrical characteristics, is nonstereogenic.
(15) The stereochemistry of the hyroxylamines obtained in this
section was assigned following their conversion into the final
products 1.

9254 J . Org. Chem., Vol. 63, No. 25, 1998
Dondoni et al.
Sch em e 4a
of metallylmagnesium chloride to 7c was carried out in
the absence of any complexing agent. These reactions
afforded the expected anti adducts 10a -c with high
levels of selectivity, and the yields ranged from modest
to good values (Table 1). The reduction of these com-
pounds and removal of the protective groups as described
above gave the meso 2,3-diamino alcohols 1Da -c in
comparable overall yields. These products showed NMR
spectra consistent with their configuration.
a
Key: 8a and 9a , R ) R′ ) Ph; 8b and 9b, R ) R′ ) c-C6H11
8c and 9c, R ) i-C3H7, R′ ) C(CH3)dCH2.
;
In conclusion, the 1,3-diamino propanol stereotriads
1A, 1B, and 1D with R ) benzyl, methylcyclohexyl, and
isobutyl have been prepared, and a route to 1C has been
delineated. Some of these compounds have been previ-
ously prepared by different methods employing either
R-amino acid derivatives20 or suitable chiral precursors
as starting materials.21 Instead, we have carried out the
synthesis of various compounds of type 1 by a single
synthetic scheme.
Syn th esis of 1,4-Dia m in o 2,3-Diols 2 (R ) Bn ). Be-
cause compounds 2 can exist as a large number of
stereoisomers, we decided to focus only on the synthe-
sis of stereotetrads 2a -c with the fixed S,S configura-
tion of the diol moiety and a benzyl group at both sides
of the chain (Scheme 7). These structural features are
those embodied in the above-mentioned HIV-1 protease
inhibitors.7,8
A simultaneous double amination via Grignard addi-
tion to a bis-nitrone 11 incorporating the diol moiety was
envisaged as a first approach to compounds 2a -c. This
appealing route would allow the symmetrical extension
of the diol chain in two directions by a single operation.22
The double elaboration of symmetrically substituted
diols, such as bis-epoxides,23 bis-hydrazones,8b,24 bis-
aziridines,25 and bis-enones26 has been employed to
introduce either the amino or the alkyl groups by suitable
reactions. The O-isopropylidene (S,S)-tartraldehyde dini-
trone 11a (Scheme 8) was designed to allow the planned
two-dimensional synthetic approach. This compound was
prepared in a multigram scale starting from dimethyl
L-tartrate, by protection of the hydroxy groups by aceto-
nation and reduction of the ester to formyl groups with
DIBAL as described.27 The dialdehyde was not isolated.
Instead, the resulting bis-aluminum acetal intermediate
was treated with excess N-benzylhydroxylamine to give
the pure bis-nitrone 11a as a white solid in 51% isolated
yield by chromatography. This compound was character-
ized as a Z,Z isomer by NOE (8% enhancement) between
the CHdN and CH2Ph signals.2
diethylaluminum chloride (Et2AlCl) prior to the Grignard
addition. These stereochemical outcomes match those of
other organometal additions to nitrones2,3 and therefore
are consistent with the same nonchelate Houk-type and
metal chelate transition-state models A and B, respec-
tively (Figure 2). Tunable selectivity as above could not
be achieved in the addition of metallylmagnesium chlo-
ride to the nitrone 5c because this reaction afforded the
anti hydroxylamine 9c as the major diastereomer even
in the absence of Et2AlCl.16 The activating agent tri-
methylsilyl chloride (Me3SiCl)2,17 or the complex-destroy-
ing agent dimethylpropylene urea (DMPU)18 had no
substantial effect on the stereochemical outcome of this
reaction. The same exceptional behavior had been
registered2 in the addition of 2-lithiothiazole to the
nitrone derived from D-arabinose. Hence, a similar
transition-state model C may be adopted in the metal-
lylmagnesium chloride addition to 5c. This type of model
was earlier proposed by Kita and co-workers for the
addition of O-silylated ketene acetals to nitrones.19 Its
recourse is justified when the increased size of R makes
model A improbable because of the severe steric interac-
tion of R with the incoming nucleophile.
Having isolated the individual N-benzylhydroxyl-
amines 8a -c (syn adducts) and 9a -c (anti adducts), each
compound was converted into the corresponding unpro-
tected 2,3-diamino alcohol 1 (Scheme 5). The general
procedure that was adopted involved the reduction of the
N-benzylhydroxylamino group to the amino group by
hydrogenolysis over Pd(OH)2 and the removal of the
isopropylidene and tert-butoxycarbonyl (Boc) protective
groups by acid treatment. Thus, compounds 8a -c gave
the meso isomers 1Aa -c and compounds 9a -c gave the
S,S isomers 1Ba -c in satisfactory yields up to 84%.
These stereoisomers were easily characterized through
their NMR spectra.
Although the R,R stereoisomers 1Ca -c (not shown)
can be prepared using the enantiomers of nitrones 5a -
c, the synthesis of the meso compounds 1Da -c had to
be demonstrated. The anti addition of the Grignard
reagents to nitrones 7a -c was considered as a possible
approach for the synthesis of the latter class of stereo-
isomers. Guided by the above results, benzylmagnesium
chloride and cyclohexylmethylmagnesium bromide were
added to the Et2AlCl-precomplexed nitrones 7a and 7b,
respectively (Scheme 6). On the other hand, the addition
The addition of excess benzylmagnesium chloride (4
equiv) to 11a under the above standard conditions (Et2O/
(20) (a) Kempf, D. J .; Sowin, T. J .; Doherty, E. M.; Hannick, S. M.;
Codavoci, L. M.; Henry, R. F.; Green, B. E.; Spanton, S. G.; Norbeck,
D. W. J . Org. Chem. 1992, 57, 5692-5700. (b) Wittenberger, S. J .;
Baker, W. R.; Donner, B. G. Tetrahedron 1993, 49, 1547-1556.
(21) Enders, D.; J egelka, U.; Du¨cker, B. Angew. Chem., Int. Ed. Engl.
1993, 32, 423-425.
(22) For reviews on simultaneous synthesis in two directions, see:
(a) Maier, M. In Organic Synthesis Highlights II; Waldmann, H., Ed.;
VCH: Weinheim, 1995; pp 203-222. (b) Magnuson, S. R. Tetrahedron
1995, 51, 2167-2213.
(16) The same diastereoselectivity was obtained by addition of
2-methylvinylmagnesium chloride to 5c, whereas i-butylmagnesium
bromide proved to be unreactive.
(17) (a) Wuts, P. G. M.; J ung, Y.-W. J . Org. Chem. 1988, 53, 1957-
1965. (b) Dhavale, D. D.; Trombini, C. Heterocyles 1992, 34, 2253-
2258.
(18) Mulzer, J .; Pietschmann, C.; Buschmann, J .; Luger, P. J . Org.
Chem. 1997, 62, 3938-3943.
(19) (a) Kita, Y.; Itoh, F.; Tamura, O.; Ke, Y. Y. Tetrahedron Lett.
1987, 28, 1431-1434. (b) Kita, Y.; Tamura, O.; Itoh, F.; Kishino, H.;
Miki, T.; Kohno, M. Tamura, Y. J . Chem. Soc., Chem. Commun. 1988,
761-763.
(23) Ghosh, A. K., McKee, S. P., Thompson, W. J . Tetrahedron Lett.
1991, 32, 5729-5732.
(24) Baker, W. R.; Condon, S. L. J . Org. Chem. 1993, 58, 3277-
3284.
(25) Kang, S. H.; Ryu, D. H. Chem. Commun. 1996, 355-356.
(26) Schreiner, E. P.; Pruckner, A. J . Org. Chem. 1997, 62, 5380-
5384.
(27) Krief, A.; Dumont, W.; Pasau, P.; Lecomte, Ph. Tetrahedron
1989, 45, 3039-3052.

Amination via Grignard Addition to Aldonitrones
J . Org. Chem., Vol. 63, No. 25, 1998 9255
Ta ble 1. Ad d ition of Gr ign a r d Rea gen ts to Nitr on es 5 a n d 7a
Grignard
R′CH2MgX
nitrone
additive
product
yieldb
ratio or dr%c
5a , R ) Ph
R′ ) Ph
8a + 9a
8a + 9a
8b + 9b
8b + 9b
8c + 9c
8c + 9c
9c
10a
10b
10c
90%
89%
75%
75%
86%
85%
96%
96%
65%
62%
95:5
6:94
5a , R ) Ph
R′ ) Ph
Et2AlCl
Et2AlCl
5b, R ) c-C6H11
5b, R ) c-C6H11
5c, R ) i-C3H7
5c, R ) i-C3H7
5c, R ) i-C3H7
7a , R ) Ph
R′ ) c-C6H11
R′ ) c-C6H11
R′ ) C(Me)dCH2
R′ ) C(Me)dCH2
R′ ) C(Me)dCH2
R′ ) Ph
80:20
15:85
20:80
15:85
g95
g95
g95
g95
Me3SiCl
DMPUd
Et2AlCl
Et2AlCl
7b, R ) c-C6H11
7c, R ) i-C3H7
R′ ) c-C6H11
R′ ) C(Me)dCH2
a
b
All reactions were carried out in Et2O/THF or Et2O at -78 °C; additivies were added to the nitrone at room temperature. Isolated
chemical yields of mixtures of 8 and 9 or 10 only. c Diastereomeric ratios (dr) were determined by H NMR analysis of the crude mixture.
DMPU ) dimethylpropylene urea.
1
d
Sch em e 6a
a
Reagents and conditions: (a) H2, Pd(OH)2; (b) HCl.
Sch em e 7
F igu r e 2. Proposed transition-state models for the Grignard
addition to nitrones 5a -c.
Sch em e 5
Sch em e 8a
a
Reagents and conditions: (a) BnNHOH, CH2Cl2.
Sch em e 9
THF, -78 °C, 3 h) afforded a complex mixture of products
from which the bis-hydroxylamines 13 and 14 were
isolated in 60:40 ratio and 40% overall yield (Scheme 9).
Similar ratios and yields were obtained in reactions
performed in the presence of dimethylpropylene urea
(DMPU) or by precomplexation of 11a with MgBr2 and
ZnBr2. The use of Et2AlCl and CeCl3 increased substan-
tially the diastereomeric ratio of 13 to 14 (80:20 and 86:
14) and to some extent the overall yield (43% and 68%).
Overall, these results show that the BnMgCl addition to
the bis-nitrone 11a occurs with a double facial anti
selectivity either in the absence of any additive or in the
presence of chelate complex-destroying (DMPU) or com-
plex-inducing (MgBr2 and ZnBr2) agents. This prefer-
ential stereochemical outcome contrasts with the syn
addition of the same Grignard reagent to the nitrone 5a
in the absence of complexing agents (see Scheme 4 and
Table 1). By analogy with the models that have been
employed to rationalize the stereochemical outcomes in
double Michael addition reactions to bis-enones26 and bis-
enoates,28 the four ground-state conformations D-G of
the nitrone 11a can be considered (Figure 3). The double

9256 J . Org. Chem., Vol. 63, No. 25, 1998
Dondoni et al.
Sch em e 10
F igu r e 3. Newman projections of some ground-state confor-
mations of 11a .
anti selectivity is consistent with either D and E and
Grignard double attack from the outside faces of the
nitrone groups. Semiempirical calculations29 indicate
that D is a lower energy conformation than E. However,
the equilibrium between these forms can easily occur by
inversion of the twist conformation of the 1,3-dioxolane
ring. The double interaction of Lewis acids with both
nitrone groups might concur to further stabilize these
forms, thus explaining the anti selectivity under these
conditions as well. The formation of the minor syn,anti
adduct 14 may be due to the attack from outside to the
nitrone diastereofaces of conformation F . On the other
hand, since the bis-hydroxylamine arising from a double
syn addition was not observed, the conformation G can
be reasonably ruled out in this context. The above
explanations are merely tentative.30 Other approaches
based on accurate calculations of transition-state models
should be considered in future studies.
Sch em e 11a
The elaboration of bis-hydroxylamines 13 and 14 to
diamino diol (S,S,S,S)-2a (74%) and (R,S,S,S)-2b (73%)
was carried out by the standard two-step protocol, i.e.,
reduction of the N-benzylhydroxylamino to amino groups
by low-pressure hydrogenolysis over Pd(OH)2 and deac-
etonation by aqueous hydrochloric acid (Scheme 10). In
addition to consistent NMR spectra, the structures of
these compounds were demonstrated from selected cou-
pling constants in the NMR spectra of the corresponding
bis-oxazolidinones 15 and 16. Consistent with its sym-
metrical structure, compound 15 showed a single cou-
pling constant value (J ) 8.0 Hz) for the two pairs of H4
and H5 protons, whereas 16 showed different values for
each pair (J ) 8.0 and 5.7 Hz).
The inherent anti selectivity of the double Grignard
addition to the bis-nitrone 11a restricted the use of this
reagent to the convenient synthesis of the diamino diol
2a . Therefore, we envisaged a different approach to
stereoisomers 2b and 2c featuring syn/syn/anti and syn/
syn/syn motifs, via sequential double amination starting
from a mono-nitrone of type 12 (Scheme 7). The known2
L-threose nitrone 12a , readily available in enantiomeri-
cally pure form from dimethyl L-tartrate, appeared to be
a
Reagents and conditions: (a) BnMgCl, -78 °C, Et2O, THF;
(b) (AcO)2Cu, Zn, AcOH, H2O; (c) (CF3CO)2O, Et3N, CH2Cl2; (d)
Pd(OH)2, H2; (e) (Boc)2O, dioxane; (f) (COCl)2, DMSO, i-Pr2NEt,
-78 °C, CH2Cl2; (g) BnNHOH, MgSO4, CH2Cl2.
a suitable starting material in this approach. The
Grignard addition to this nitrone proceeded smoothly in
THF at -78 °C to give the hydroxylamine 17 as a mixture
of diastereoisomers in 87:13 ratio and 90% overall yield
(Scheme 11). Because the separation of these isomers
turned out to be quite difficult by normal column chro-
matography, the mixture was first converted into the
N,N-diprotected amine 18. This transformation of the
nitrogen functionality involved the removal of the hy-
droxy group by reduction with Zn/Cu(OAc)2 and then
(28) Saito, S.; Narahara, O.; Ishikawa, T.; Asahara, M.; Morikawe,
T. J . Org. Chem. 1993, 58, 6292-6302.
(29) We thank Dr. H. Banks (U.S. Army ERDEC) for the AM1
results obtained using Spartan 5.0.
(30) The ground-state conformation control on a Grignard addition
reaction has been recently discussed (see ref 18).

Amination via Grignard Addition to Aldonitrones
J . Org. Chem., Vol. 63, No. 25, 1998 9257
Sch em e 13a
F igu r e 4. Proposed transition-state models for the addition
of BnMgCl to nitrones 20 and 21.
Sch em e 12a
a
Reagents and conditions: (a) NaBH4, EtOH, 60 °C; (b) H2,
Pd(OH)2; (c) HCl; (d) (Boc)2O, dioxane; (e) NaH, THF, 50 °C.
afforded a mixture of N-benzylhydroxylamines 26 and
27 in 78% overall yield with the anti adduct 27 as major
diastereomer (dr 70%). Nevertheless, these opposite
stereochemical outcomes paved the way to a more ef-
ficient synthesis of 2b and, even more important, to the
so far elusive stereotetrad 2c. The isolated hydroxy-
lamine 24 was converted into the diamino diol 2c by
sequential NaBH4 reduction, hydrogenolysis, and acid
hydrolysis (Scheme 13). A conclusive proof of the struc-
ture of 2c came from the NMR spectra of the correspond-
ing bis-oxazolidinone 28. The N-benzylhydroxylamine 27
was elaborated in a similar way to give the diamino diol
2b that was identical in all respects to the product
obtained as described in Scheme 10. Also the minor
isomers 25 and 26 were adequately characterized by
conversion into the corresponding free diamino diols 2b
and 2c, respectively. From these results, we can safely
conclude that the main stereochemical outcome of the
Grignard addition to the nitrone 12a corresponds to a
syn addition, and therefore compounds 17, 18, and 19
are mixtures of syn and anti diastereisomers in the
observed 87:13 ratio. For the same reasons, the structure
of nitrones 20 and 21 is as depicted.
The reversal of diastereoselectivity of the Grignard
addition to nitrones 20 and 21 was intriguing since the
only difference between these compounds was repre-
sented by the differentially protected amino group, which
however was three carbon atoms remote from the reac-
tion site. Nevertheless, the syn addition to 20 can be
explained by the Houk-type transition-state32 model H
previously applied to other reactions of R-alkoxy ni-
trones,2 whereas the anti addition to 21 is consistent with
model I where the antiperiplanar position is occupied by
the alkyl chain and the attack of the organometal occurs
from the opposite site (Figure 4). The increased conges-
tion around the nitrone group in H by the bulky N-Boc
that is present in 21 justifies switching to I. Evidently,
models H and I are essentially identical to models A and
C, respectively, depicted in Figure 2.
a
Key: 24 and 25, R ) Bn, R′ ) COCF3 (overall yield 89%). 26
and 27, R ) H, R′ ) Boc (overall yield 78%).
reaction with trifluoroacetic anhydride to introduce the
COCF3 protective group.4 On the other hand, attempted
double protection with the bulkier Boc was very difficult
and therefore was abandoned. Alternatively, the mixture
of hydroxylamines 17 was converted into a mixture of
N-monoprotected (N-Boc) amines 19. This transforma-
tion was carried out in the usual way, i.e., hydrogenolysis
over Pd(OH)2 followed by reaction with the pyrocarbonate
(Boc)2O. Obviously, the reductive step induced also the
removal of the O-benzyl group. Both compounds 18 and
1
19 were proven by H NMR analysis as being mixtures
of diastereoisomers in the same 87:13 ratio as 17. Thus,
the first amino group appeared to have been inserted in
the carbon chain with a satisfactory stereoselectivity. It
will become evident soon that the major stereoisomer of
each pair of epimers 18 and 19 possessed the antici-
pated31 syn relationship between the amino and the
adjacent alkoxy group. Compounds 18 and 19 were
ready to face the conversion to nitrones that served for
the installation of the second amino group. Accordingly,
the removal of the O-benzyl group from 18 by hydro-
genolysis over Pd(OH)2, followed by the Swern oxidation
and condensation of the resulting aldehyde with N-
benzylhydroxylamine, afforded the pure N-benzyl nitrone
20 as the main product in 76% isolated yield by column
chromatography. The same oxidation-condensation se-
quence was applied to the alcohol 19 to give the pure
nitrone 21 in 74% yield. The all-syn relationship at the
three contiguous stereocenters of nitrones 20 and 21 was
demonstrated at a later point. Also isolated were the
minor products 22 (not shown), epimer of 20, and 23,
epimer of 21. All these compounds were proved to be Z
isomers by NOE (8-10% enhancement) between the
CHdN and CH2Ph signals.2
The Grignard addition to nitrones 20 and 21 was the
second crucial step. In the event, the N,N-diprotected
nitrone 20 was treated with excess benzylmagnesium
chloride in THF at -78 °C (Scheme 12) as described for
12a . The resulting mixture of products consisted of syn
and anti N-benzylhydroxylamines 24 and 25 in 84:16
ratio and 89% overall yield. The syn selectivity parallels
that observed in the same Grignard addition to the
nitrone 12a . Rather surprisingly, the benzylmagnesium
chloride addition to the N-monoprotected nitrone 21
Collectively, these examples show that it is possible
to construct the 1,4-diamino 2,3-butandiol stereotetrads
2a -c by double and sequential addition of BnMgCl to a
(31) The syn addition of BnMgCl to 12a was expected to be the main
stereochemical outcome on the basis of earlier organometallic additions
to the same nitrone (see ref 2).
(32) Houk, K. N.; Paddon-Row, N. M.; Rondan, N. G.; Wu, Y.-D.;
Brown, F. K.; Spellmeyer, D. C.; Metz, J . T.; Li, Y.; Loncharich, R. J .
Science 1986, 231, 1108-1117.

9258 J . Org. Chem., Vol. 63, No. 25, 1998
Dondoni et al.
Sch em e 14a
sequential removal of the hydroxy group and for deacety-
lation. The cyclic urea 30 (77%) was obtained by adding
via syringe pumping toluene solutions of 29 and phosgene
to N-methylmorpholine at 100 °C. Deacetonation of 30
to 31 was carried out by treatment with hydrochloric acid
in dioxane without any apparent cleavage of the seven-
membered ring cyclic urea. The overall yield of 31 from
24 was 52%.
Con clu sion s
The above results demonstrate that the nitrone-based
amination method can be effectively employed for the
synthesis of diamino alcohols and diols in different con-
figurational arrays. The flexibility of the method relies
on the Lewis acid mediated tunable stereoselectivity of
the Grignard addition to the nitrone. However, in some
cases, the stereochemical outcome of this key reaction
could not be controlled. Current research is devoted to
examining the possibilities of better stereochemical con-
trol on the 2-fold amination with bis-nitrones.
a
Reagents and conditions: (a) (AcO)2Cu, Zn, AcOH, H2O; (b)
NaBH4, 60 °C, EtOH; (c) COCl2, N-methylmorpoline, toluene, 100
°C; (d) HCl, dioxane.
bis- and mono-nitrone, respectively. The sequential
method appears to be wider in scope because it allows
the differentiation of the stereochemical outcome of the
first and second addition reaction. It is worth noting that
compound 2a has been previously reported7d,20a and
considered to be the nonscissile core unit of a peptide
HIVp inhibitor.33 The isomer 2c featuring the syn/syn/
syn motif is also a very interesting product because it
represents the scaffold for the construction of cyclic ureas
endowed with similar HIVp inhibitory activity.
Exp er im en ta l Section
All moisture-sensitive reactions were performed under a
nitrogen atmosphere using oven-dried glassware. Solvents
were dried over standard drying agents35 and freshly distilled
prior to use. Flash column chromatography36 was performed
on silica gel 60 (230-400 mesh), under positive pressure from
a compressed air line. Reactions were monitored by TLC on
silica gel 60 F254 with detection by charring with alcoholic
solutions of ninhydrin or sulfuric acid. After extractive
workup, organic solutions were dried over Na2SO4, filtered
through a cotton plug, and evaporated under reduced pressure.
Melting points were determined with a capillary apparatus
and are uncorrected. Optical rotations were measured at 20
( 2 °C. 1H (300 MHz) and 13C (75 MHz) NMR spectra were
recorded at room temperature for CDCl3 solutions, unless
otherwise specified. Benzylmagnesium chloride and cyclo-
hexylmethylmagnesium bromide were prepared according to
the typical literature procedure. Metallylmagnesium chloride
was prepared as reported.37
2-[(4S,5R)- a n d (4S,5S)-4-Ben zyl-3-ter t-bu toxyca r bo-
n yl-2,2-d im eth yl-1,3-oxa zolid in -5-yl]-1,3-th ia zole (4a a n d
6a ). To a solution of 3a 11 (1.0 g, 3.0 mmol) in toluene (15.0
mL) were added 2-methoxypropene (3.0 mL, 30.0 mmol) and
PPTS (catalytic). The solution was refluxed for 18 h and then
concentrated to dryness. The crude residue was chromato-
graphed on silica gel with cyclohexane/EtOAc (10:1) to give
as first eluted the (4S,5R)-1,3-oxazolidine derivative 4a (0.75
g, 67%) and then the S,S epimer 6a (0.22 g, 20%). 4a : mp
84-85 °C; [R]D -53.3 (c 1.4, CHCl3); 1H NMR (DMSO-d6, 120
°C) δ 1.37 (s, 3 H), 1.45 (s, 3 H), 1.56 (s, 9 H), 3.13 (dd, 1 H, J
) 7.5, 13.5 Hz), 3.18 (dd, 1 H, J ) 4.5, 13.5 Hz), 4.62 (ddd, 1
H, J ) 4.0, 4.5, 7.5 Hz), 5.21 (d, 1 H, J ) 4.0 Hz), 7.17-7.34
(m, 5 H), 7.63 (d, 1 H, J ) 3.2 Hz), 7.72 (d, 1 H, J ) 3.2 Hz).
Anal. Calcd for C20H26N2O3S: C, 64.14; H, 7.00; N, 7.48; S,
8.56. Found: C, 64.36; H, 6.89; N, 7.54; S, 8.63. 6a : mp 103-
106 °C; [R]D +34.1 (c 0.7, CHCl3); 1H NMR (DMSO-d6, 120 °C)
δ 1.35 (s, 9 H), 1.64 (s, 3 H), 1.70 (s, 3 H), 2.65 (dd, 1 H, J )
7.0, 14.0 Hz), 2.72 (dd, 1 H, J ) 6.0, 14.0 Hz), 4.59 (ddd, 1 H,
J ) 5.5, 6.0, 7.0 Hz), 5.57 (d, 1 H, J ) 5.5 Hz), 6.80-6.86 (m,
2 H), 7.02-7.15 (m, 3 H), 7.61 (d, 1 H, J ) 3.2 Hz), 7.67 (d, 1
H, J ) 3.2 Hz). Anal. Calcd for C20H26N2O3S: C, 64.14; H,
7.00; N, 7.48; S, 8.56. Found: C, 64.42; H, 7.25; N, 7.38; S,
8.58.
Syn th esis of a Cyclic Ur ea . Seven-membered ring
cyclic urea derivatives (1,3-diazapin-2-ones) incorporating
a chiral S,S-butandiol moiety have been designed as
small, rigid, C2-symmetrical HIVp inhibitors by a DuPont
Merck group.8a,b Compound DMP 323 (Figure 1) was
chosen as a clinical candidate, but unfortunately that
clinical trial was terminated due to highly variable
human oral bioavailability. Compound DMP 450 is
presently in human clinical trials.34 The efficient syn-
thesis of these cyclic ureas is far from being a trivial
problem because it involves the cyclization of suitably
protected diamino diols with carbonyldiimidazole or
similar reagents.8c The protection of the diol functional-
ity is required in order to avoid the formation of bis-
oxazolidinones of type 28. Among the numerous protec-
tive groups that were screened for this purpose, the
acetonide proved to be of little utility because the five-
membered dioxolane ring imposes such a strain on the
intermediate that cyclization to 1,3-diazapin-2-one be-
comes very difficult.8b,c Nevertheless, cyclic ureas with
the acetonide-protected diol were convenient intermedi-
ates, for example, for the synthesis of DMP 323. There-
fore, we investigated the conversion of 24 into a cyclic
urea. The best route involved the dibenzylamine 29 as
an intermediate (Scheme 14). This compound was ob-
tained from 24 by methods that were applied above, i.e.,
reduction with Zn/Cu(OAc)2 and then with NaBH4 for the
(33) (a) Kempf, D. J .; Codacovi, L.; Wang, X. C.; Kohlbrenner, W.
E.; Wideburg, N. E.; Saldivar, A.; Vasavanonda, S.; Marsh, K. C.;
Bryant, P.; Sham, H. L.; Green, B. E.; Betebenner, D. A.; Erickson, J .;
Norbeck, D. W. J . Med. Chem. 1993, 36, 320-330. (b) Hosur, M. V.;
Bhat, T. N.; Kempf, D. J .; Baldwin, E. T.; Liu, B.; Gulnik, S.; Wideburg,
N. E.; Norbeck, D. W.; Appelt, K.; Erickson, J . W. J . Am. Chem. Soc.
1994, 116, 847-855.
(34) Hodge, C. N.; Aldrich, P. E.; Bacheler, L. T.; Ghang, C.-H.;
Eyerman, C. J .; Gribb, M. F.; J ackson, D. A.; J adhav, P. K.; Korant,
B.; Lam, P. Y. S.; Maurin, M. B.; Meek, J . L.; Otto, M. J .; Rayner, M.
M.; Sharpe, T. R.; Shum, L.; Winslow, D. L.; Erickson-Viitanen, S.
Chem. Biol. 1996, 3, 301-314.
(35) Perrin, D. D.; Armarego, W. L. Purification of Laboratory
Chemicals; Pergamon: New York, 1988.
(36) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.
(37) Tius, M. A.; Kannangara, G. S. K. Org. Synth. 1992, 71, 158-
166.

Amination via Grignard Addition to Aldonitrones
J . Org. Chem., Vol. 63, No. 25, 1998 9259
2-[(4S,5R)- a n d (4S,5S)-3-ter t-Bu toxyca r bon yl-4-cyclo-
h exylm eth yl-2,2-d im eth yl-1,3-oxa zolid in -5-yl]-1,3-th ia z-
ole (4b a n d 6b). The reaction was carried out as described
above for 4a , starting from the mixture of the thiazole
derivative 3b12 (1.90 g, 5.61 mmol). Chromatography on silica
gel of the crude residue with cyclohexane/EtOAc (10:1) gave
as first eluted the (4S,5R)-1,3-oxazolidine derivative 4b (1.53
g, 72%) and then the S,S epimer 6b (0.38 g, 18%). 4b: mp
80-83 °C; [R]D -65.3 (c 0.4, CHCl3); 1H NMR δ 0.90-1.46 (m,
7 H), 1.48 (s, 9 H), 1.55 (s, 3 H), 1.61 (s, 3 H), 1.62-1.90 (m, 6
H), 4.54 (dt, 1 H, J ) 2.8, 10.5 Hz), 5.14 (d, 1 H, J ) 2.8 Hz),
7.36 (d, 1 H, J ) 3.2 Hz), 7.76 (d, 1 H, J ) 3.2 Hz); 13C
NMR δ 26.0, 26.2, 26.4, 27.8, 28.5, 32.3, 34.4, 34.9, 41.8,
60.7, 80.0, 95.7, 119.8, 142.6, 151.5, 172.0. Anal. Calcd for
d6, 120 °C) δ 1.25 (s, 3 H), 1.47 (s, 9 H), 1.50 (s, 3 H), 2.97-
3.08 (m, 2 H), 4.11 (ddd, 1 H, J ) 4.0, 5.0, 6.5 Hz), 4.87 (d, 1
H, J ) 13.0 Hz), 4.92 (d, 1 H, J ) 13.0 Hz), 4.99 (dd, 1 H, J )
4.0, 6.5 Hz), 7.14-7.31 (m, 6 H), 7.32-7.40 (m, 5 H). Anal.
Calcd for C25H32N2O4: C, 70.74; H, 7.60; N, 6.59. Found: C,
70.58; H, 7.71; N, 6.73.
(Z)-N -[(4S ,5R )-3-t er t -Bu t oxyca r b on yl-4-cycloh e xyl-
m et h yl-2,2-d im et h yl-5-m et h ylen yl-1,3-oxa zolid in e]b en -
zyla m in e N-oxid e (5b). The same procedure as described
for the synthesis of 5a was applied to 4b (1.0 g, 2.63 mmol).
Chromatography on silica gel of the crude product with
cyclohexane/EtOAc (2:1) gave the nitrone 5b as a white solid
1
(0.85 g, 75%): mp 109-111 °C; [R]D +26.7 (c 1.1, CHCl3); H
NMR (DMSO-d6, 120 °C) δ 0.84-1.42 (m, 8 H), 1.44 (s, 9 H),
1.49 (s, 3 H), 1.53 (s, 3 H), 1.55-1.82 (m, 5 H), 3.96 (ddd, 1 H,
J ) 2.5, 4.0, 9.0 Hz), 4.84 (dd, 1 H, J ) 2.5, 6.0 Hz), 4.96 (s, 2
H), 7.30 (d, 1 H, J ) 6.0 Hz), 7.35-7.45 (m, 5 H). Anal. Calcd
for C25H38N2O4: C, 69.74; H, 8.90; N, 6.50. Found: C, 69.98;
H, 9.17; N, 6.51.
C
20H32N2O3S: C, 63.13; H, 8.48 N, 7.36; S, 8.43. Found: C,
63.34; H, 8.69; N, 7.57; S, 8.25. 6b: mp 55-65 °C; [R]D -5.1
1
(c 0.7, CHCl3); H NMR (DMSO-d6, 120 °C) δ 0.55-1.40 (m,
11 H), 1.48 (s, 9 H), 1.46-1.60 (m, 2 H), 1.61 (s, 3 H), 1.64 (s,
3 H), 4.29 (ddd, 1 H, J ) 4.5, 5.5, 8.0 Hz), 5.52 (d, 1 H, J ) 5.5
Hz), 7.67 (d, 1 H, J ) 3.2 Hz), 7.83 (d, 1 H, J ) 3.2 Hz); 13C
NMR δ 24.2, 26.1, 26.3, 26.4, 27.3, 28.5, 32.8, 33.9, 34.0, 38.7,
57.8, 77.1, 93.7, 119.1, 142.6, 151.6, 167.0. Anal. Calcd for
(Z)-N-[(4S,5R)-3-ter t-Bu t oxyca r b on yl-2,2-d im et h yl-4-
isobu tyl-5-m eth ylen yl-1,3-oxa zolid in e]ben zyla m in e N-
oxid e (5c). The same procedure as described for the synthesis
of 5a was applied to 4c (1.70 g, 5.0 mmol). Chromatography
on silica gel of the crude product with cyclohexane/CH2Cl2/
EtOAc (6.5:1:2.5) gave the nitrone 5c as a white solid (1.43 g,
73%): mp 91-92 °C; [R]D +45.2 (c 0.7, CHCl3); 1H NMR
(DMSO-d6, 120 °C) δ 0.89 (d, 3 H, J ) 6.5 Hz), 0.91 (d, 3 H, J
) 6.5 Hz), 1.45 (s, 9 H), 1.49 (s, 3 H), 1.54 (s, 3 H), 1.51-1.59
(m, 2 H), 1.65-1.80 (m, 1 H), 3.93 (ddd, 1 H, J ) 2.5, 4.5, 8.5
Hz), 4.86 (dd, 1 H, J ) 2.5, 6.5 Hz), 4.96 (s, 2 H), 7.30-7.45
(m, 6 H). Anal. Calcd for C22H34N2O4: C, 67.67; H, 8.77; N,
7.17. Found: C, 67.99; H, 8.64; N, 7.28.
C
20H32N2O3S: C, 63.13; H, 8.48; N, 7.36; S, 8.43. Found: C,
63.21; H, 8.45; N, 7.43; S, 8.37.
2-[(4S,5R)- a n d (4S,5S)-3-ter t-Bu t oxyca r b on yl-2,2-d i-
m eth yl-4-isobu tyl-1,3-oxazolidin -5-yl]-1,3-th iazole (4c an d
6c). The reaction was carried out as described above for 4a ,
starting from the mixture of the thiazole derivative 3c11 (1.50
g, 5.0 mmol). Chromatography on silica gel of the crude
residue with cyclohexane/Et2O (6:1) gave as first eluted the
(4S,5R)-1,3-oxazolidine derivative 4c (1.28 g, 72%) and then
the S,S epimer 6c (0.22 g, 13%). 4c: mp 44.5-46.0 °C; [R]D
-66.1 (c 0.8, CHCl3); 1H NMR δ 0.95 (d, 6 H, J ) 6.5 Hz), 1.47
(s, 9 H), 1.56 (s, 3 H), 1.60 (s, 3 H), 1.60-1.84 (m, 3 H), 4.45-
4.53 (m, 1 H), 5.14 (d, 1 H, J ) 2.8 Hz), 7.33 (d, 1 H, J ) 3.2
Hz), 7.75 (d, 1 H, J ) 3.2 Hz); 13C NMR δ 21.4, 23.9, 25.6,
27.7, 28.1, 28.5, 43.5, 61.2, 79.7, 80.0, 95.7, 119.7, 142.7, 151.4,
166.5. Anal. Calcd for C17H28N2O3S: C, 59.97; H, 8.29; N,
8.22; S, 9.40. Found: C, 60.17; H, 8.56; N, 8.28; S, 9.08. 6c:
(Z)-N-[(4S,5S)-4-Ben zyl-3-ter t-b u t oxyca r b on yl-2,2-d i-
m eth yl-5-m eth ylen yl-1,3-oxa zolid in e]ben zyla m in e N-ox-
id e (7a ). The same procedure as described for the synthesis
of 5a was applied to 6a (0.56 g, 1.50 mmol). Chromatography
on silica gel of the crude product with cyclohexane/Et2O (4:
1.5) gave the nitrone 7a as a white solid (0.44 g, 70%): mp
1
153-154 °C; [R]D -108.9 (c 0.3, CHCl3); H NMR (DMSO-d6,
1
mp 101-103 °C; [R]D +17.9 (c 0.6, CH3OH); H NMR δ 0.60
120 °C) δ 1.35 (s, 9 H), 1.50 (s, 6 H), 2.66 (dd, 1 H, J ) 5.5,
14.0 Hz), 2.74 (dd, 1 H, J ) 7.0, 14.0 Hz), 4.51 (dt, 1 H, J )
5.5, 7.0 Hz), 4.68 (d, 1 H, J ) 13.5 Hz), 4.84 (d, 1 H, J ) 13.5
Hz), 5.02 (t, 1 H, J ) 5.5 Hz), 7.10-7.45 (m, 11 H). Anal. Calcd
for C25H32N2O4: C, 70.74; H, 7.60; N, 6.59. Found: C, 70.87;
H, 7.52; N, 6.68.
(s, 3 H), 0.80 (s, 3 H), 1.05-1.60 (m, 3 H), 1.50 (s, 9 H), 1.65
(s, 3 H), 1.70 (s, 3 H), 4.20-4.45 (m, 1 H), 5.50 (d, 1 H, J )
5.2 Hz), 7.35 (d, 1 H, J ) 3.2 Hz), 7.80 (d, 1 H, J ) 3.2 Hz);
13C NMR δ 21.9, 23.5, 24.3, 25.4, 27.3, 28.5, 40.3, 58.3, 76.8,
80.1, 93.7, 119.2, 142.6, 151.6, 166.9. Anal. Calcd for
C
17H28N2O3S: C, 59.97; H, 8.29; N, 8.22; S, 9.40. Found: C,
(Z)-N -[(4S ,5S )-3-t er t -Bu t oxyca r b on yl-4-cycloh e xyl-
m et h yl-2,2-d im et h yl-5-m et h ylen yl-1,3-oxa zolid in e]b en -
zyla m in e N-oxid e (7b). The same procedure as described
for the synthesis of 5a was applied to 6b (0.50 g, 1.31 mmol).
Chromatography on silica gel of the crude product with
cyclohexane/EtOAc (2:1) gave the nitrone 7b (0.43 g, 76%) as
a white solid: mp 98-101 °C; [R]D -62.2 (c 0.5, CHCl3); 1H
NMR (DMSO-d6, 120 °C) δ 0.65-1.20 (m, 9 H), 1.45 (s, 9 H),
1.50 (s, 3 H), 1.52 (s, 3 H), 1.52-1.70 (m, 4 H), 4.21 (ddd, 1 H,
J ) 5.0, 6.5, 10.5 Hz), 4.92 (d, 1 H, J ) 14.0 Hz), 4.93-4.98
(m, 1 H), 4.99 (d, 1 H, J ) 14.0 Hz), 7.25 (d, 1 H, J ) 5.0 Hz),
7.32-7.42 (m, 3 H), 7.43-7.52 (m, 2 H). Anal. Calcd for
59.84; H, 8.40; N, 8.01; S, 9.62.
(Z)-N-[(4S,5R)-4-Ben zyl-3-ter t-b u t oxyca r b on yl-2,2-d i-
m eth yl-5-m eth ylen yl-1,3-oxa zolid in e]ben zyla m in e N-ox-
id e (5a ). A mixture of 4a (1.0 g, 2.67 mmol), activated 4 Å
powdered molecular sieves (5.30 g), and anhydrous MeCN
(26.0 mL) was stirred at room temperature for 10 min, and
then methyl triflate (0.39 mL, 3.47 mmol) was added. The
suspension was stirred for 15 min and then concentrated to
dryness. The residue was suspended in MeOH (26.0 mL),
cooled to 0 °C, and then treated with NaBH4 (0.22 g, 5.90
mmol). The mixture was stirred at room temperature for 10
min, diluted with acetone (0.50 mL), filtered through Celite,
and concentrated. To a solution of the residue in MeCN/H2O
(10:1, 26.0 mL) were added CuO (1.70 g, 21.40 mmol) and then
CuCl2‚H2O (0.45 g, 2.67 mmol) portionwise and under vigorous
stirring. The mixture was stirred for 15 min and then filtered
through Celite. After the removal of the solvent (bath tem-
perature not exceeding 40 °C), the crude brown residue was
taken up in Et2O (5 × 26.0 mL) and sonicated by an ultrasonic
cleaning bath. The liquid layer was pipetted and filtered
through a pad of Florisil (100-200 mesh). The almost colorless
filtrate was concentrated to give the crude aldehyde, which
was dissolved in CH2Cl2 (15.0 mL) and treated with anhydrous
MgSO4 (0.50 g) and N-benzylhydroxylamine (0.27 g, 2.17
mmol). The resulting mixture was stirred at room tempera-
ture for 30 min, filtered through Celite, and concentrated.
Chromatography on silica gel of the residue with cyclohexane/
EtOAc (7:3) gave the nitrone 5a as a white solid (0.61 g, 78%):
C
25H38N2O4: C, 69.74; H, 8.90; N, 6.50. Found: C, 69.83; H,
8.89; N, 6.34.
(Z)-N-[(4S,5S)-3-ter t-Bu t oxyca r b on yl-2,2-d im et h yl-4-
isobu tyl-5-m eth ylen yl-1,3-oxa zolid in e]ben zyla m in e N-
oxid e (7c). The same procedure as described for the synthesis
of 5a was applied to 6c (0.50 g, 1.48 mmol). Chromatography
on silica gel of the crude product with cyclohexane/CH2Cl2/
EtOAc (6.5:1:2.5) gave the nitrone 7c (0.49 g, 85%) as a white
solid: mp 78-81 °C; [R]D -52.8 (c 0.5, CHCl3); 1H NMR
(DMSO-d6, 120 °C) δ 0.74 (d, 3 H, J ) 6.5 Hz), 0.79 (d, 3 H, J
) 6.5 Hz), 1.10-1.40 (m, 3 H), 1.44 (s, 9 H), 1.49 (s, 3 H), 1.53
(s, 3 H), 4.13-4.20 (m, 1 H), 4.91 (d, 1 H, J ) 13.0 Hz), 4.94-
4.97 (m, 1 H), 5.00 (d, 1 H, J ) 13.0 Hz), 7.23-7.30 (m, 1 H),
7.34-7.50 (m, 5 H). Anal. Calcd for C22H34N2O4: C, 67.67;
H, 8.77; N, 7.17. Found: C, 67.41; H, 8.90; N, 6.93.
(2R,3R,4S)-2-N-Ben zylh yd r oxyla m in e-4-ter t-b u t oxy-
car bon ylam in o-1,5-diph en yl-4N,3O-isopr opyliden e-3-pen -
ta n ol (8a ). To a cold (-78 °C) solution of nitrone 5a (0.50 g,
1
mp 125-126 °C; [R]D +17.7 (c 0.6, CHCl3); H NMR (DMSO-

9260 J . Org. Chem., Vol. 63, No. 25, 1998
Dondoni et al.
1.18 mmol) in Et2O/THF (3:1, 6.0 mL) was added dropwise a
freshly prepared solution of BnMgCl (0.5 M in Et2O, 12.0 mL).
The reaction solution was stirred for 3 h at -78 °C, treated
with aqueous phosphate buffer (pH 7, 6.0 mL), and allowed to
warm to room temperature. The white suspension was filtered
through Celite, and the phases were separated. The aqueous
phase was extracted with EtOAc (3 × 5.0 mL), and the
combined organic phases were dried and concentrated. Chro-
matography on silica gel of the residue with cyclohexane/
EtOAc (9:1) afforded 8a (0.55 g, 90%) as a syrup: [R]D +15.1
(c 0.6, CHCl3); 1H NMR (C2D2Cl4, 120 °C) δ 1.28 (s, 3 H), 1.63
(s, 9 H), 1.72 (s, 3 H), 2.72 (ddd, 1 H, J ) 5.0, 7.0, 9.0 Hz),
2.83 (dd, 1 H, J ) 8.0, 13.0 Hz), 2.93 (dd, 1 H, J ) 9.0, 14.0
Hz), 3.07 (dd, 1 H, J ) 3.0, 13.0 Hz), 3.20 (dd, 1 H, J ) 5.0,
14.0 Hz), 3.76 (d, 1 H, J ) 14.0 Hz), 4.02 (dd, 1 H, J ) 3.0, 7.0
Hz), 4.16 (d, 1 H, J ) 14.0 Hz), 4.36 (dt, 1 H, J ) 3.0, 8.0 Hz),
4.90 (s, 1 H), 6.83 (d, 2 H, J ) 6.1 Hz), 7.10-7.20 (m, 5 H),
7.25-7.48 (m, 8 H). Anal. Calcd for C32H40N2O4: C, 74.39;
H, 7.80; N, 5.42. Found: C, 74.11; H, 7.65; N, 5.48.
reaction mixture was stirred for 3 h at -78 °C, quenched, and
processed as described above for 8a . Chromatography on silica
gel of the crude residue with cyclohexane/Et2O (9:1) gave as
first eluted 9c (0.79 g, 69%) as a white solid and then 8c (0.21
g, 17%) as a syrup. 8c: [R]D +9.2 (c 0.4, CHCl3); 1H NMR
(DMSO-d6, 120 °C) δ 0.92 (d, 3 H, J ) 6.0 Hz), 1.43 (s, 3 H),
1.45 (s, 3 H), 1.40-1.65 (m, 3 H), 1.78 (s, 3 H), 2.13 (dd, 1 H,
J ) 7.5, 15.0 Hz), 3.08 (ddd, 1 H, J ) 4.5, 5.7, 7.5 Hz), 3.83 (d,
1 H, J ) 14.0 Hz), 4.04 (dd, 1 H, J ) 4.0, 5.7 Hz), 4.05 (d, 1 H,
J ) 14.0 Hz), 4.13 (ddd, 1 H, J ) 3.5, 4.0, 8.5 Hz), 4.81 (s, 1
H), 4.84 (s, 1 H), 7.10 (s, 1 H), 7.15-7.45 (m, 5 H). Anal. Calcd
for C26H42N2O4: C, 69.93; H, 9.48; N, 6.27. Found: C, 70.14;
H, 9.61; N, 6.05. 9c: mp 75-77 °C; [R]D +13.9 (c 0.6, CHCl3);
1H NMR (DMSO-d6, 120 °C) δ 0.93 (d, 3 H, J ) 6.5 Hz), 0.95
(d, 3 H, J ) 6.5 Hz), 1.45 (s, 12 H), 1.51 (s, 3 H), 1.53-1.60
(m, 2 H), 1.67-1.79 (m, 1 H), 1.80 (s, 3 H), 2.29 (dd, 1 H, J )
4.0, 15.0 Hz), 2.60 (dd, 1 H, J ) 7.5, 15.0 Hz), 3.05 (ddd, 1 H,
J ) 4.0, 6.5, 7.5 Hz), 3.95 (s, 2 H), 4.04 (dd, 1 H, J ) 3.5, 6.5
Hz), 4.06-4.12 (m, 1 H), 4.80 (s, 1 H), 4.85 (s, 1 H), 7.03 (s, 1
H), 7.15-7.35 (m, 5 H). Anal. Calcd for C26H42N2O4: C, 69.93;
H, 9.48; N, 6.27. Found: C, 70.06; H, 9.77; N, 5.93.
(2R,3S,4S)-2-N-Ben zylh yd r oxyla m in e-4-ter t-b u t oxy-
car bon ylam in o-1,5-diph en yl-4N,3O-isopr opyliden e-3-pen -
ta n ol (10a ). The reaction was carried out as described above
for the synthesis of the compound 9a , starting from the nitrone
7a (0.10 g, 0.24 mmol). Chromatography on silica gel of the
crude residue with cyclohexane/Et2O (5:1) gave 10a (0.12 g,
96%) as a white solid: mp 88-90 °C; [R]D +10.1 (c 0.3, CHCl3);
1H NMR (DMSO-d6, 120 °C) δ 1.20 (s, 9 H), 1.51 (s, 6 H), 2.58
(dd, 1 H, J ) 8.4, 13.5 Hz), 2.96 (dd, 1 H, J ) 4.1, 14.5 Hz),
3.01 (dd, 1 H, J ) 4.9, 13.5 Hz), 3.31 (dd, 1 H, J ) 6.0, 14.5
Hz), 3.39 (ddd, 1 H, J ) 4.1, 6.0, 9.3 Hz), 3.63 (d, 1 H, J )
14.0 Hz), 3.83 (d, 1 H, J ) 14.0 Hz), 4.25 (dd, 1 H, J ) 4.5, 9.3
Hz), 4.41 (ddd, 1 H, J ) 4.5, 4.9, 8.4 Hz), 7.05-7.49 (m, 16 H).
Anal. Calcd for C32H40N2O4: C, 74.39; H, 7.80; N, 5.42.
Found: C, 74.56; H, 7.63; N, 5.55.
(2S,3R,4S)-2-N-Ben zylh yd r oxyla m in e-4-ter t-b u t oxy-
car bon ylam in o-1,5-diph en yl-4N,3O-isopr opyliden e-3-pen -
ta n ol (9a ). To a solution of nitrone 5a (0.50 g, 1.18 mmol) in
Et2O/THF (3:1, 6.0 mL) was added a solution of Et2AlCl (1 M
in hexane, 1.18 mL). The resulting mixture was stirred at
room temperature for 15 min, cooled (-78 °C), and treated as
described above for 8a . Chromatography on silica gel of the
crude residue with cyclohexane/Et2O (9:1) gave as first eluted
8a (30.5 mg, 5%) and then 9a (0.51 g, 84%) as a white solid:
1
mp 114-116 °C; [R]D -107.4 (c 0.9, CHCl3); H NMR (C2D2-
Cl4, 120 °C) δ 1.55 (s, 6 H), 1.60 (s, 9 H), 2.78 (dd, 1 H, J )
10.1, 12.8 Hz), 2.94-3.06 (m, 2 H), 3.18 (dd, 1 H, J ) 8.3, 15.6
Hz), 3.39 (dd, 1 H, J ) 3.2, 12.8 Hz), 3.59 (d, 1 H, J ) 13.8
Hz), 3.71 (d, 1 H, J ) 13.8 Hz), 4.17 (dd, 1 H, J ) 3.2, 7.3 Hz),
4.39 (dt, 1 H, J ) 3.2, 10.1 Hz), 7.05-7.45 (m, 15 H). Anal.
Calcd for C32H40N2O4: C, 74.39; H, 7.80; N, 5.42. Found: C,
74.40; H, 7.76; N, 5.35.
(2R,3R,4S)-2-N-Ben zylh yd r oxyla m in e-4-ter t-b u t oxy-
ca r bon yla m in o-1,5-d icycloh exyl-4N,3O-isop r op ylid en e-
3-p en ta n ol (8b). To a cold (-78 °C) solution of nitrone 5b
(0.40 g, 0.93 mmol) in Et2O/THF (10:1, 5.0 mL) was added
dropwise a freshly prepared solution of cyclohexylmethylmag-
nesium bromide (1 M in Et2O, 4.65 mL). The reaction solution
was stirred for 3 h at -78 °C, quenched, and processed as
described above for 8a . Chromatography on silica gel of the
residue with cyclohexane/Et2O (9:1) gave as first eluted 9b
(0.07 g, 14%; see below) and then 8b (0.30 g, 61%) as a white
solid: mp 54-56 °C; [R]D -9.7 (c 0.5, CH3OH); 1H NMR
(DMSO-d6, 120 °C) δ 0.90-1.40 (m, 14 H), 1.45 (s, 12 H), 1.53
(s, 3 H), 1.54-1.84 (m, 12 H), 2.87-2.94 (m, 1 H), 3.91 (d, 1
H, J ) 14.0 Hz), 3.98 (d, 1 H, J ) 14.0 Hz), 4.04-4.11 (m, 2
H), 6.95 (s, 1 H), 7.20-7.40 (m, 5 H). Anal. Calcd for
(2R,3S,4S)-2-N-Ben zylh yd r oxyla m in e-4-ter t-b u t oxy-
ca r bon yla m in o-1,5-d icycloh exyl-4N,3O-isop r op ylid en e-
3-p en ta n ol (10b). The reaction was carried out as described
above for the synthesis of the compound 9b, starting from the
nitrone 7b (0.32 g, 0.74 mmol). Chromatography on silica gel
of the crude residue with cyclohexane/Et2O (9:1) gave 10b (0.25
g, 65%) as a syrup: [R]D -4.8 (c 0.6, CHCl3); 1H NMR (DMSO-
d6, 120 °C) δ 0.80-1.45 (m, 12 H), 1.46 (s, 9 H), 1.48 (s, 3 H),
1.50 (s, 3 H), 1.51-1.98 (m, 14 H), 2.93 (ddd, 1 H, J ) 5.0, 5.0,
9.0 Hz), 3.74 (d, 1 H, J ) 14.0 Hz), 3.89 (d, 1 H, J ) 14.0 Hz),
4.07 (dd, 1 H, J ) 4.5, 9.0 Hz), 4.17 (ddd, 1 H, J ) 4.5, 5.5, 8.0
Hz), 7.18-7.38 (m, 5 H). Anal. Calcd for C32H52N2O4: C,
72.68; H, 9.91; N, 5.29. Found: C, 72.44; H, 9.71; N, 4.94.
(4R,5S,6S)-4-N-Ben zylh yd r oxyla m in e-6-ter t-b u t oxy-
ca r bon yla m in o-6N,5O-isop r op ylid en e-8-m eth yl-2-vin yl-
5-n on a n ol (10c). The reaction was carried out as described
above for the synthesis of the compounds 8c and 9c, starting
from the nitrone 7c (0.20 g, 0.51 mmol). Chromatography on
silica gel of the crude residue with cyclohexane/Et2O (9:1) gave
10c (0.14 g, 62%) as syrup: [R]D +10.7 (c 0.3, CHCl3); 1H NMR
(DMSO-d6, 120 °C) δ 0.87 (d, 3 H, J ) 6.5 Hz), 0.92 (d, 3 H, J
) 6.5 Hz), 1.20-1.32 (m, 1 H), 1.45 (s, 9 H), 1.48 (s, 3 H), 1.50
(s, 3 H), 1.50-1.58 (m, 1 H), 1.64-1.82 (m, 1 H), 1.82 (s, 3 H),
2.25 (dd, 1 H, J ) 4.5, 15.0 Hz), 2.76 (dd, 1 H, J ) 5.5, 15.0
Hz), 3.09 (ddd, 1 H, J ) 4.5, 5.5, 9.5 Hz), 3.79 (d, 1 H, J )
13.5 Hz), 3.97 (d, 1 H, J ) 13.5 Hz), 4.07 (dd, 1 H, J ) 4.5, 9.5
Hz), 4.13-4.21 (m, 1 H), 4.79 (s, 1 H), 4.86 (s, 1 H), 7.20-7.35
(m, 5 H), 8.19 (s, 1 H). Anal. Calcd for C26H42N2O4: C, 69.93;
H, 9.48; N, 6.27. Found: C, 70.15; H, 9.39; N, 6.54.
C
32H52N2O4: C, 72.68; H, 9.91; N, 5.29. Found: C, 72.45; H,
9.63; N, 5.32.
(2S,3R,4S)-2-N-Ben zylh yd r oxyla m in e-4-ter t-b u t oxy-
ca r bon yla m in o-1,5-d icycloh exyl-4N,3O-isop r op ylid en e-
3-p en ta n ol (9b). To a solution of nitrone 5b (0.10 g, 0.23
mmol) in Et2O/THF (10:1, 2.0 mL) was added a solution of
Et2AlCl (1 M in hexane, 0.23 mL). The resulting mixture was
stirred at room temperature for 15 min, cooled (-78 °C), and
treated as described above for 8b. Chromatography on silica
gel of the crude residue with cyclohexane/Et2O (9:1) gave as
first eluted 9b (0.08 g, 64%) as a white solid and then 8b (0.01
g, 11%). 9b: mp 136-138 °C; [R]D -7.2 (c 0.5, CHCl3); 1H
NMR (DMSO-d6, 120 °C) δ 0.90-1.30 (m, 11 H), 1.46 (s, 12
H), 1.51 (s, 3 H), 1.58-1.90 (m, 15 H), 2.90-2.97 (m, 1 H),
3.85 (d, 1 H, J ) 14.0 Hz), 3.92 (d, 1 H, J ) 14.0 Hz), 4.03-
4.12 (m, 2 H), 7.12 (s, 1 H), 7.18-7.37 (m, 5 H). Anal. Calcd
for C32H52N2O4: C, 72.68; H, 9.91; N, 5.29. Found: C, 72.89;
H, 9.74; N, 5.50.
(2R,3r ,4S)-2,4-Dia m in o-1,5-d ip h en yl-3-p en ta n ol (1Aa ).
To a solution of 8a (0.20 g, 0.39 mmol) in AcOH/EtOH (9:1,
4.0 mL) was added Pd(OH)2 (20% on C, 0.10 g). The resulting
mixture was stirred at room temperature under 3 atm of H2
for 18 h, filtered through Celite, and concentrated. To the
residue was added an aqueous solution of HCl (6.0 M, 3.0 mL),
and the resulting suspension was heated to 90 °C for 3 h and
then concentrated. The crude residue was neutralized with
an aqueous solution of NaOH (3.0 M) and extracted with
CHCl3 (3 × 5.0 mL). The combined organic layers were dried
(4R,5R,6S)- a n d (4S,5R,6S)-4-N-Ben zylh yd r oxyla m in e-
6-ter t-b u t oxyca r b on yla m in o-6N,5O-isop r op ylid en e-8-
m eth yl-2-vin yl-5-n on a n ol (8c a n d 9c). To a cold (-78 °C)
slurry of freshly prepared metallylmagnesium chloride (1 M
in Et2O, 25.6 mmol) was added dropwise a solution of the
nitrone 5c (1.0 g, 2.56 mmol) in Et2O/THF (3:1, 13.0 mL). The

Amination via Grignard Addition to Aldonitrones
J . Org. Chem., Vol. 63, No. 25, 1998 9261
and concentrated. Chromatography on silica gel with
CH2Cl2/MeOH/NH4OH (89:10:1) gave pure 1Aa (90.0 mg, 84%)
as a white solid: mp 105-107 °C; 1H NMR δ 2.59 (dd, 2 H, J
) 9.0, 13.5 Hz), 2.92 (dd, 2 H, J ) 5.0, 13.5 Hz), 3.09 (ddd, 2
H, J ) 3.5, 5.0, 9.0 Hz), 3.31 (t, 1 H, J ) 3.5 Hz), 7.15-7.40
(m, 10 H); 13C NMR δ 42.1, 55.3, 74.0, 126.3, 128.5, 129.3,
138.9. Anal. Calcd for C17H22N2O: C, 75.52; H, 8.20; N, 10.36.
Found: C, 75.34; H, 8.32; N, 10.28.
(2R ,3r ,4S)-2,4-Dia m in o-1,5-d icycloh e xyl-3-p e n t a n ol
(1Ab). The same procedure as described above for 1Aa was
applied to 8b (0.15 g, 0.29 mmol). Chromatography on silica
gel of the crude product with CH2Cl2/MeOH/NH4OH (86:13:1)
gave pure 1Ab (56.0 mg, 69%) as a syrup: 1H NMR δ 0.80-
1.95 (m, 26 H), 2.84 (ddd, 2 H, J ) 4.0, 4.3, 8.3 Hz), 2.99 (t, 1
H, J ) 4.0 Hz); 13C NMR δ 26.1, 26.3, 26.5, 32.7, 34.2, 34.3,
43.3, 50.0, 76.2. Anal. Calcd for C17H34N2O: C, 72.29; H,
12.13; N, 9.91. Found: C, 72.34; H, 11.95; N, 9.65.
13:1) gave pure 1Db (73.0 mg, 68%) as a white solid: mp 136-
1
140 °C from CHCl3/AcOEt; H NMR δ 0.75-2.00 (m, 26 H),
3.02 (ddd, 2 H, J ) 2.5, 5.5, 10.0 Hz), 3.19 (t, 1 H, J ) 5.5 Hz);
13C NMR (CDCl3) δ 26.1, 26.4, 26.5, 32.2, 34.1, 34.9, 39.8, 49.2,
78.8. Anal. Calcd for C17H34N2O: C, 72.29; H, 12.13; N, 9.91.
Found: C, 72.54; H, 12.55; N, 9.95.
(4R,5s,6S)-4,6-Dia m in o-2,8-d im eth yl-5-n on a n ol (1Dc).
The same procedure as described above for 1Aa was applied
to 10c (0.10 g, 0.22 mmol). Chromatography on silica gel of
the crude compound with CH2Cl2/MeOH/NH4OH (89:10:1) gave
pure 1Dc (29.0 mg, 65%) as a white solid: mp 121-124 °C
1
from EtOAc; H NMR δ 0.92 (d, 6 H, J ) 6.5 Hz), 0.97 (d, 6
H, J ) 6.5 Hz), 1.27 (ddd, 2 H, J ) 4.0, 10.0, 14.0 Hz), 1.40
(ddd, 2 H, J ) 3.0, 10.0, 14.0 Hz), 1.66-1.82 (m, 2 H), 2.99
(ddd, 2 H, J ) 3.0, 5.5, 10.0 Hz), 3.17 (t, 1 H, J ) 5.5 Hz); 13
C
NMR δ 21.3, 24.2, 24.6, 41.3, 50.0, 78.9. Anal. Calcd for
C
11H26N2O: C, 65.30; H, 12.95; N, 13.84. Found: C, 65.23;
(4R,5r ,6S)-4,6-Dia m in o-2,8-d im eth yl-5-n on a n ol (1Ac).
The same procedure as described above for 1Aa was applied
to 8c (0.21 g, 0.47 mmol). Chromatography on silica gel of
the crude product with CH2Cl2/MeOH/NH4OH (89:10:1) gave
pure 1Ac (65.0 mg, 68%) as a syrup: 1H NMR δ 0.90 (d, 6 H,
J ) 6.5 Hz), 0.94 (d, 6 H, J ) 6.5 Hz), 1.20-1.38 (m, 4 H),
1.68-1.82 (m, 2 H), 2.76-2.86 (m, 2 H), 3.03 (t, 1 H, J ) 4.0
Hz); 13C NMR δ 21.85, 23.5, 24.6, 44.7, 51.0, 75.9. Anal. Calcd
for C11H26N2O: C, 65.30; H, 12.95; N, 13.84. Found: C, 65.35;
H, 13.16; N, 14.07.
H, 12.71; N, 13.79.
(Z,Z)-N,N-[(4S,5S)-2,2-d im et h yl-4,5-d im et h ylen yl-1,3-
d ioxola n e]-bis(ben zyla m in e N-oxid e) (11a ). To a cold
(-40 °C) solution of dimethyl isopropylidene L-tartrate27 (3.50
g, 16.0 mmol) in CH2Cl2 (50.0 mL) was added dropwise a
solution of DIBAL (1.5 M, 21.30 mL). The solution was stirred
at this temperature for 2 h and then treated with MeOH (1.25
mL). When the H2 evolution was completed, the reaction
mixture was allowed to warm to -5 °C and then a solution of
N-benzylhydroxylamine (4.13 g, 33.60 mmol) in CH2Cl2 (5.0
mL) was added. The resulting mixture was stirred at this
temperature for 30 min and at room temperature for 2 h and
then treated with an aqueous solution of NaOH (1 M, 50.0
mL). The two phases were separated, and the aqueous layer
was extracted with CH2Cl2 (3 × 15.0 mL). The combined
(2S,4S)-2,4-Diam in o-1,5-diph en yl-3-pen tan ol (1Ba). The
same procedure as described above for 1Aa was applied to 9a
(0.18 g, 0.35 mmol). Chromatography on silica gel of the crude
compound with CH2Cl2/MeOH/NH4OH (89:10:1) gave pure
1Ba (78.0 mg, 82%) as a white solid: mp 138-139 °C from
cyclohexane/EtOAc (lit.20a 135-137 °C); [R]D -11.1 (c 0.4,
organic layers were washed with
a solution of aqueous
1
CHCl3); H NMR δ 2.50 (dd, 1 H, J ) 9.7, 13.4 Hz), 2.65 (dd,
phosphate buffer (pH 7, 50.0 mL), dried, and concentrated.
Chromatography of the residue on silica gel with EtOAc/MeOH
(9:1) gave the bis-nitrone 11a (3.0 g, 51%) as a white solid:
mp 105-106 °C from Et2O; [R]D +78.9 (c 0.4, CHCl3); 1H NMR
δ 1.40 (s, 6 H), 4.90 (s, 4 H), 5.02-5.10 (m, 2 H), 6.86-6.94
(m, 2 H), 7.36-7.46 (m, 10 H); 13C NMR δ 26.3, 69.3, 73.4,
110.6, 128.9, 129.0, 129.4, 132.0, 135.4. Anal. Calcd for
1 H, J ) 9.4, 13.4 Hz), 2.91 (dd, 1 H, J ) 4.6, 13.4 Hz), 3.01
(dd, 1 H, J ) 3.2, 13.4 Hz), 3.14 (ddd, 1 H, J ) 3.2, 4.8, 9.7
Hz), 3.31-3.43 (m, 2 H), 7.15-7.45 (m, 10 H); 13C NMR δ 40.0,
41.5, 52.5, 55.8, 75.2, 126.3, 126.4, 128.5, 128.6, 129.2, 138.9,
139.2. Anal. Calcd for C17H22N2O: C, 75.52; H, 8.20; N, 10.36.
Found: C, 75.47; H, 8.29; N, 10.43.
(2S,4S)-2,4-Dia m in o-1,5-d icycloh exyl-3-p en ta n ol (1Bb).
The same procedure as described above for 1Aa was applied
to 9b (0.07 g, 0.14 mmol). Chromatography on silica gel of
the crude compound with CH2Cl2/MeOH/NH4OH (86:13:1) gave
pure 1Bb (26.0 mg, 67%) as a white solid: mp 63-65 °C; [R]D
-25.5 (c 0.3, CHCl3); 1H NMR δ 0.75-1.90 (m, 26 H), 2.99 (ddd,
2 H, J ) 4.1, 4.5, 8.8 Hz), 3.14 (t, 1 H, J ) 4.1 Hz); 13C NMR
δ 26.1, 26.3, 26.4, 26.5, 32.4, 32.7, 34.1, 34.2, 34.6, 40.2, 42.8,
48.1, 50.8, 76.7. Anal. Calcd for C17H34N2O: C, 72.29; H,
12.13; N, 9.91. Found: C, 72.47; H, 12.38; N, 9.69.
(4S,6S)-4,6-Dia m in o-2,8-d im eth yl-5-n on a n ol (1Bc). The
same procedure as described above for 1Aa was applied to 9c
(0.50 g, 1.12 mmol). Chromatography on silica gel of the crude
compound with CH2Cl2/MeOH/NH4OH (89:10:1) gave pure 1Bc
(0.18 g, 79%) as a white solid: mp 60-61 °C; [R]D -27.3 (c
0.5, CHCl3); 1H NMR δ 0.88 (d, 3 H, J ) 6.5 Hz), 0.94 (d, 3 H,
J ) 6.5 Hz), 0.96 (d, 3 H, J ) 6.5 Hz), 1.16-1.40 (m, 4 H),
1.62-1.78 (m, 2 H), 2.94-3.60 (m, 2 H), 3.18 (t, 1 H, J ) 4
Hz); 13C NMR δ 21.5, 21.8, 23.4, 23.9, 24.5, 24.6, 41.4, 43.9,
49.1, 51.7, 76.0. Anal. Calcd for C11H26N2O: C, 65.30; H,
12.95; N, 13.84. Found: C, 65.20; H, 12.84; N, 13.95.
(2R,3s,4S)-2,4-Dia m in o-1,5-d ip h en yl-3-p en ta n ol (1Da ).
The same procedure as described above for 1Aa was applied
to 10a (0.11 g, 0.21 mmol). Chromatography on silica gel of
the crude compound with CH2Cl2/MeOH/NH4OH (89:10:1) gave
pure 1Da (47.0 mg, 83%) as a white solid: mp 131-133 °C;
1H NMR δ 2.52 (dd, 2 H, J ) 10.1, 13.5 Hz), 3.17 (dd, 2 H, J
) 3.0, 13.5 Hz), 3.29 (ddd, 2 H, J ) 3.0, 5.7, 10.1 Hz), 3.39 (t,
1 H, J ) 5.7 Hz), 7.17-7.40 (m, 10 H); 13C NMR δ 38.5, 53.5,
76.0, 126.3, 128.5, 129.4, 139.1. Anal. Calcd for C17H22N2O:
C, 75.52; H, 8.20; N, 10.36. Found: C, 75.69; H, 8.11; N, 10.22.
(2R ,3s,4S )-2,4-Dia m in o-1,5-d icycloh e xyl-3-p e n t a n ol
(1Db). The same procedure as described above for 1Aa was
applied to 10b (0.20 g, 0.38 mmol). Chromatography on silica
gel of the crude compound with CH2Cl2/MeOH/NH4OH (86:
C21H24N2O4: C, 68.46; H, 6.57; N, 7.60. Found: C, 68.20; H,
6.26; N, 7.67.
(2S,3S,4S,5S)- a n d (2R,3S,4S,5S)-2,5-Bis(N-ben zylh y-
d r oxyla m in e)-3,4-O-isop r op ylid en e-1,6-d ip h en yl-3,4-h ex-
a n d iol (13 a n d 14). To a cold (-78 °C) solution of nitrone
11a (0.50 g, 1.36 mmol) in THF/Et2O (1:1, 7.0 mL) was added
dropwise a freshly prepared solution of BnMgCl (0.5 M in Et2O,
10.9 mL). The reaction was stirred for 3 h at -78 °C, treated
with a solution of aqueous phosphate buffer (pH 7, 15.0 mL),
and allowed to warm to room temperature. The white suspen-
sion was filtered through Celite, and the phases were sepa-
rated. The aqueous phase was extracted with EtOAc (3 × 5.0
mL), and the combined organic phases were dried and con-
centrated. Chromatography on silica gel of the residue with
cyclohexane/Et2O (9:1) gave as first eluted the compound 13
(0.18 g, 24%) as a white solid and then 14 (0.12 g, 16%) as a
1
white solid. 13: mp 91-92 °C; [R]D -80.7 (c 0.5, CHCl3); H
NMR δ 1.35 (s, 6 H), 3.09 (dd, 2 H, J ) 2.6, 15.0 Hz), 3.14
(ddd, 2 H, J ) 2.6, 6.1, 9.3 Hz), 3.46 (dd, 2 H, J ) 6.1, 15.0
Hz), 3.46 (d, 2 H, J ) 12.8 Hz), 3.85 (d, 2 H, J ) 12.8 Hz), 4.10
(d, 2 H, J ) 9.3 Hz), 6.83-6.89 (m, 4 H), 7.09 (s, 2 H), 7.15-
7.35 (m, 16 H); 13C NMR δ 26.9, 31.5, 61.3, 72.5, 81.7, 108.6,
125.7, 127.5, 128.4, 129.3, 129.4, 136.4, 142.3. Anal. Calcd
for C35H40N2O4: C, 76.06; H, 7.29; N, 5.07. Found: C, 75.96;
H, 7.27; N, 5.46. 14: mp 136-138 °C from cyclohexane/EtOAc;
1
[R]D -62.2 (c 0.5, CHCl3); H NMR δ 1.35 (s, 3 H), 1.50 (s, 3
H), 2.63 (dd, 1 H, J ) 6.0, 15.0 Hz), 3.08-3.23 (m, 3 H), 3.33-
3.54 (m, 3 H), 3.40 (d, 1 H, J ) 13.0 Hz), 3.80 (d, 1 H, J ) 13.0
Hz), 4.01 (d, 1 H, J ) 13.5 Hz), 4.25 (dd, 1 H, J ) 7.0, 10.0
Hz), 4.62-4.70 (m, 1 H), 6.78-6.90 (m, 2 H), 7.00-7.50 (m,
20 H); 13C NMR δ 26.6, 27.3, 31.9, 33.0 61.0, 61.6, 70.5, 72.0,
78.7, 79.1, 108.6, 125.8, 126.2, 127.2, 127.3, 128.2, 128.4, 128.6,
128.8, 128.9, 129.1, 129.2, 136.4, 137.3, 140.8, 142.0. Anal.
Calcd for C35H40N2O4: C, 76.06; H, 7.29; N, 5.07. Found: C,
75.99; H, 7.36; N, 5.19

9262 J . Org. Chem., Vol. 63, No. 25, 1998
Dondoni et al.
Ad d it ion of Bn MgCl t o t h e Bis-n it r on e 11a w it h
DMP U. A cold (-78 °C) solution of nitrone 11a (0.10 g, 0.27
mmol) in THF/DMPU (1:1, 2.0 mL) was treated as described
above for the synthesis of 13 and 14. Chromatography on
silica gel of the crude residue afforded 13 (54.0 mg, 36%) and
14 (36.0 mg, 24%).
Ad d ition of CeCl3/Bn MgCl to th e Bis-n itr on e 11a . To
a cold (-78 °C) suspension of anhydrous CeCl3 (0.67 g, 2.71
mmol) in THF (6.0 mL) was added a solution of freshly
prepared BnMgCl in Et2O (0.5 M, 10.8 mL). The resulting
yellow slurry was stirred at this temperature for 1 h, and then
a solution of the bis-nitrone 11a (0.10 g, 0.27 mmol) in THF
(1.35 mL) was added. The reaction was stirred at -78 °C for
1 h and then slowly allowed to warm to 0 °C. A solution of
aqueous phosphate buffer (pH 7, 17.0 mL) was added, and the
mixture was processed as described above for 13 and 14.
Chromatography on silica gel of the crude residue afforded 13
(88.0 mg, 59%) and 14 (13.0 mg, 9%).
Ad d ition of Bn MgCl to th e Bis-n itr on e 11a P r ecom -
p lexed w ith Et2AlCl. To a solution of nitrone 11a (0.10 g,
0.27 mmol) in THF (1.50 mL) was added a solution of Et2AlCl
(1 M in hexane, 0.27 mL). The resulting mixture was stirred
at room temperature for 15 min, cooled (-78 °C), and treated
as described above for 13 and 14. Chromatography on silica
gel of the crude residue afforded 13 (54.0 mg, 36%) and 14
(13.0 mg, 9%).
Ad d ition of Bn MgCl to th e Bis-n itr on e 11a P r ecom -
p lexed w ith MgBr 2. To a solution of nitrone 11a (0.10 g,
0.27 mmol) in THF (1.50 mL) was added anhydrous MgBr2
(0.05 g, 0.27 mmol). The resulting mixture was stirred at room
temperature for 15 min, cooled (-78 °C), and treated as
described above for 13 and 14. Chromatography on silica gel
of the crude residue afforded 13 (40.0 mg, 27%) and 14 (27.0
mg, 18%).
and concentrated. Chromatography on silica gel of the residue
with CHCl3/EtOAc (3:2) afforded 15 (17.0 mg 69%) as a white
solid: mp 270 °C (dec) from CHCl3; [R]D +168.0 (c 0.5, DMSO);
1H NMR δ 3.03 (dd, 2 H, J ) 4.4, 14.0 Hz), 3.11 (dd, 2 H, J )
10.5, 14.0 Hz), 4.29 (ddd, 2 H, J ) 4.4, 8.0, 10.5 Hz), 4.94 (d,
2 H, J ) 8.0 Hz), 5.00 (s, 2 H), 7.00-7.50 (m, 10 H); 13C NMR
δ 36.9, 56.3, 75.2, 127.5, 128.8, 129.3, 136.4, 156.9. Anal. Calcd
for C20H20N2O4: C, 68.17; H, 5.72; N, 7.95. Found: C, 68.45;
H, 5.57; N, 7.94.
(4R,5S,4′S,5′S)-5,5′-Bis(4-ben zyloxa zolid in -2-on e) (16).
The reaction was carried out as described above for the
synthesis of the bis-oxazolidinone 15, starting from 2b (20.0
mg, 0.07 mmol). Chromatography on silica gel of the residue
with CHCl3/EtOAc (3:2) afforded 16 (16.0 mg, 65%) as a white
solid: mp 167-170 °C from CHCl3; [R]D +66.0 (c 0.5, DMSO);
1H NMR δ 2.73 (dd, 1 H, J ) 7.5, 13.5 Hz), 2.95 (dd, 1 H, J )
6.0, 14.0 Hz), 2.97 (dd, 1 H, J ) 6.5, 13.5 Hz), 3.08 (dd, 1 H, J
) 9.0, 14.0 Hz), 4.05 (d, 1 H, J ) 8.0 Hz), 4.10 (ddd, 1 H, J )
5.7, 6.5, 7.5 Hz), 4.20 (ddd, 1 H, J ) 6.0, 8.0, 9.0 Hz), 4.41 (d,
1 H, J ) 5.7 Hz), 5.40 (s, 1 H), 6.00 (s, 1 H), 6.95-7.10 (m, 2
H), 7.12-7.20 (m, 2 H), 7.20-7.40 (m, 6 H); 13C NMR δ 36.4,
41.5, 55.7, 77.2, 78.5, 127.4, 127.6, 128.7, 128.9, 129.2, 134.9,
136.5, 156.8, 157.1. Anal. Calcd for C20H20N2O4: C, 68.17;
H, 5.72; N, 7.95. Found: C, 67.83; H, 5.84; N, 8.18.
(2S,3S,4R)- a n d (2S,3S,4S)-4-N-Ben zylh yd r oxyla m in e-
1-O-ben zyl-2,3-O-isopr opyliden e-5-ph en yl-1,2,3-pen tan tr i-
ol (17). To a cold (-78 °C) solution of the nitrone 12a 2 (3.0 g,
8.50 mmol) in Et2O/THF (1:2, 35.0 mL) was added a solution
of freshly prepared BnMgCl in Et2O (0.5 M, 34.0 mL). The
resulting mixture was stirred at this temperature for 2 h,
quenched with a solution of aqueous phosphate buffer (pH 7,
30.0 mL), and allowed to warm to room temperature. The
white suspension was filtered through Celite, and the phases
were separated. The aqueous phase was extracted with Et2O
(3 × 10.0 mL), and the combined organic phases were dried
and concentrated. Chromatography on silica gel of the residue
with cyclohexane/EtOAc (9:1) gave 17 (3.41 g, 90%) as a
mixture of (2S,3S,4R)- and (2S,3S,4S)-N-benzylhydroxy-
Ad d ition of Bn MgCl to th e Bis-n itr on e 11a P r ecom -
p lexed w ith Zn Br 2. To a solution of nitrone 11a (0.10 g, 0.27
mmol) in THF (1.50 mL) was added anhydrous ZnBr2 (60.8
mg, 0.27 mmol). The resulting mixture was stirred at room
temperature for 15 min, cooled (-78 °C), and treated as
described above for 13 and 14. Chromatography on silica gel
of the crude residue afforded 13 (49.0 mg, 33%) and 14 (25.0
mg, 17%).
1
lamines in a 87:13 ratio (by H NMR analysis). Attempts to
separate these compounds by flash chromatography failed.
NMR for the major 2S,3S,4R isomer: 1H NMR δ 1.38 (s, 3 H),
1.50 (s, 3 H), 2.95-3.14 (m, 2 H), 3.24-3.31 (m, 1 H), 3.32
(dd, 1 H, J ) 4.7, 10.3 Hz), 3.41 (dd, 1 H, J ) 4.7, 10.3 Hz),
3.84 (d, 1 H, J ) 13.2 Hz), 3.98 (dd, 1 H, J ) 1.5, 8.5 Hz), 4.17
(d, 1 H, J ) 13.2 Hz), 4.38 (s, 2 H), 4.38-4.45 (m, 1 H), 5.35
(s, 1 H), 7.05-7.15 (m, 2 H), 7.15-7.35 (m, 13 H); 13C NMR δ
26.7, 27.2, 30.6, 61.0, 65.0, 70.5, 73.4, 76.0, 79.2, 108.8, 137.8,
138.1, 140.1. Anal. Calcd for C28H33NO4: C, 75.14; H, 7.43;
N, 3.13. Found: C, 74.84; H, 7.07; N, 3.08.
(2S,3S,4S,5S)-2,5-Dia m in o-1,6-d ip h en yl-3,4-h exa n d i-
ol (2a ). The same procedure as described above for the
synthesis of 1Aa was applied to 13 (0.15 g, 0.27 mmol).
Chromatography on silica gel of the crude compound with
CHCl3/MeOH/NH4OH (89:10:1) afforded 2a (60.0 mg 74%) as
a white solid: mp 183-185 °C (dec) [lit.7d 150 °C (dec)]; [R]D
1
-31.7 (c 0.3, CHCl3) [lit.7d -33.0 (c 0.18, CHCl3)]; H NMR δ
2.64 (dd, 2 H, J ) 10.6, 13.4 Hz), 2.85 (dd, 2 H, J ) 3.5, 13.4
Hz), 3.60 (ddd, 2 H, J ) 2.8, 3.5, 10.6 Hz), 3.92 (d, 2 H, J )
2.8 Hz), 7.15-7.42 (m, 10 H); 13C NMR δ 38.5, 56.8, 72.8, 126.7,
128.8, 129.0, 138.5. Anal. Calcd for C18H24N2O2: C, 71.97;
H, 8.05; N, 9.32. Found: C, 71.69; H, 8.18; N, 9.52.
(2S,3S,4R)- a n d (2S,3S,4S)-1-O-Ben zyl-2,3-O-isop r o-
pyliden e-5-ph en yl-4-(N-tr iflu or oacetyl)ben zylam in e-1,2,3-
p en ta n tr iol (18). To a solution of (AcO)2Cu‚H2O (0.18 g, 0.90
mmol) in AcOH (20.0 mL) was added Zn dust (3.0 g, 45.9
mmol). The resulting suspension was vigorously stirred at
room temperature for 15 min, and then a solution of benzyl-
hydroxylamines 17 (4.0 g, 9.0 mmol) in AcOH/H2O (3:1, 32.0
mL) was added. The stirring was continued for 1 h; the
suspension was filtered through Celite; and the collected
solution was neutralized with an aqueous solution of NaOH
(3 M), extracted with EtOAc (3 × 20.0 mL), and washed with
a saturated aqueous solution of EDTA. The organic phase was
dried and concentrated to give 3.90 g of the corresponding
crude benzylamines. To a suspension of these and activated
4 Å powdered molecular sieves (3.0 g) in CH2Cl2 (35.0 mL) were
added Et3N (7.50 mL, 54.0 mmol) and (CF3CO)2O (3.80 mL,
27.0 mmol). The resulting mixture was stirred at room
temperature for 1.5 h, treated with MeOH (3.0 mL), filtered
through Celite, and concentrated. The crude residue was
chromatographed with cyclohexane/EtOAc (4:1) to give a
mixture of the expected trifluoroacetylbenzylamines 18 (4.15
g, 88%) as a syrup. Attempts to separate these compounds
by flash chromatography failed. 1H NMR for the major
2S,3S,4R isomer: (DMSO-d6, 160 °C) δ 1.25 (s, 3 H), 1.32 (s,
3 H), 2.95 (dd, 1 H, J ) 5.5, 14.0 Hz), 3.06 (dd, 1H, J ) 8.5,
14.0 Hz), 3.60 (dd, 1 H, J ) 5.0, 11.5 Hz), 3.66 (dd, 1 H, J )
(2R,3S,4S,5S)-2,5-Dia m in o-1,6-d ip h en yl-3,4-h exa n d i-
ol (2b). The same procedure as described above for the
synthesis of 1Aa was applied to 14 (0.15 g, 0.27 mmol).
Chromatography on silica gel of the crude compound with
CHCl3/MeOH/NH4OH (89:10:1) afforded 2b (59.0 mg 73%) as
a white solid: mp 114-115 °C; [R]D -45.6 (c 0.75, CHCl3); 1H
NMR δ 2.60 (dd, 1 H, J ) 10.3, 13.3 Hz), 2.72 (dd, 1 H, J )
3.3, 11.5 Hz), 2.80 (dd, 1 H, J ) 4.2, 13.3 Hz), 2.94 (dd, 1 H, J
) 5.4, 11.5 Hz), 2.95-3.01 (m, 1 H), 3.52 (ddd, 1 H, J ) 3.6,
4.2, 10.3 Hz), 3.60 (dd, 1 H, J ) 1.2, 3.6 Hz), 3.96 (bs, 1 H),
7.10-7.36 (m, 10 H); 13C NMR δ 38.6, 43.3, 56.7, 57.5, 71.0,
76.2, 126.4, 126.6, 128.6, 128.7, 129.0, 129.3, 138.6, 138.8.
Anal. Calcd for C18H24N2O2: C, 71.97; H, 8.05; N, 9.32.
Found: C, 72.04; H, 7.85; N, 9.32.
(4S,5S,4′S,5′S)-5,5′-Bis(4-ben zyloxa zolid in -2-on e) (15).
To a solution of 2a (20.0 mg, 0.07 mmol) in dioxane (2.0 mL)
was added (Boc)2O (34.0 mg, 0.15 mmol). The solution was
stirred at room temperature for 18 h and then concentrated.
The residue was dissolved in THF (2.0 mL) and treated with
NaH (60% oil dispersion, 6.0 mg, 0.15 mmol). The resulting
suspension was refluxed for 3 h, treated with MeOH (2 drops),

Amination via Grignard Addition to Aldonitrones
J . Org. Chem., Vol. 63, No. 25, 1998 9263
4.0, 11.5 Hz), 4.04-4.12 (m, 1 H), 4.21-4.36 (m, 2 H), 4.53 (s,
2 H), 4.50-4.60 (m, 1 H), 4.68 (d, 1 H, J ) 16.0 Hz), 7.02-
7.10 (m, 2 H), 7.12-7.35 (m, 13 H). Anal. Calcd for C30H32F3-
NO4: C, 68.30; H, 6.11; N, 2.65. Found: C, 67.98; H, 6.48; N,
2.89.
(DMSO-d6, 180 °C) δ -66.1. Anal. Calcd for C30H31F3N2O4:
C, 66.66; H, 5.78; N, 5.18. Found: C, 66.32; H, 5.46; N, 5.13.
(Z)-N-[(2S,3S,4R)- a n d (2S,3S,4S)-4-N-ter t-Bu toxyca r -
b on yla m in e-2,3-isop r op ylid en ed ioxy-5-p h en ylp en t yl-
id en e]ben zyla m in e N-oxid e (21 a n d 23). A mixture of the
alcohols 19 (1.0 g, 2.84 mmol) was oxidized as described above
for 20 and 22. The crude aldehydes were dissolved in CH2Cl2
(15.0 mL) and treated with MgSO4 (0.50 g) and N-benzylhy-
droxylamine (0.39 g, 3.17 mmol). The resulting mixture was
stirred at room temperature for 4 h, filtered through Celite,
and concentrated. Chromatography on silica gel of the residue
with cyclohexane/EtOAc (3.5:2) gave as first eluted the nitrone
21 (0.95 g, 74%) as a colorless syrup and then the nitrone 23
(0.19 g, 15%) as a colorless syrup. 21: [R]D +23.0 (c 0.9,
CHCl3); 1H NMR (DMSO-d6, 120 °C) δ 1.28 (s, 9 H), 1.37 (s, 3
H), 1.42 (s, 3 H), 2.69 (dd, 1 H, J ) 9.5, 14.0 Hz), 2.88 (dd, 1
H, J ) 4.5, 14.0 Hz), 3.99 (dd, 1 H, J ) 4.5, 7.0 Hz), 4.07 (ddd,
1 H, J ) 4.5, 9.0, 9.5 Hz), 4.90-5.00 (m, 1 H), 4.94 (d, 1 H, J
) 13.0 Hz), 5.00 (d, 1 H, J ) 13.0 Hz), 6.07 (d, 1 H, J ) 9.0
Hz), 7.12-7.28 (m, 6 H), 7.30-7.48 (m, 5 H). Anal. Calcd for
(2S,3S,4R)- an d (2S,3S,4S)-4-ter t-Bu toxycar bon ylam in o-
2,3-O-isop r op ylid en e-5-p h en yl-1,2,3-p en ta n tr iol (19). To
a solution of the benzylhydroxylamines 17 (2.0 g, 4.47 mmol)
in MeOH (15.0 mL) was added Pd(OH)2 (20% on C, 0.60 g).
The resulting mixture was stirred at room temperature under
1 atm of H2 for 8 h, filtered through Celite, and concentrated.
To the residue dissolved in dioxane (15.0 mL) was added
(Boc)2O (1.17 g, 5.36 mmol), and the resulting solution was
stirred at room temperature for 18 h and then concentrated.
Chromatography on silica gel of the crude residue with
cyclohexane/EtOAc (3:2) gave a mixture of the expected tert-
butoxycarbonylamines 19 (1.11 g, 70%). Careful chromatog-
raphy of a portion of the mixture 19 with cyclohexane/Et2O
(3:2) provided a pure sample of the major 2S,3S,4R isomer as
a colorless syrup: [R]D +19.1 (c 1.1, CHCl3); 1H NMR (DMSO-
d6, 160 °C) δ 1.34 (s, 9 H), 1.36 (s, 3 H), 1.40 (s, 3 H), 2.79 (dd,
1 H, J ) 8.5, 13.8 Hz), 2.89 (dd, 1 H, J ) 5.5, 13.8 Hz), 3.56
(d, 2 H, J ) 4.0 Hz), 3.80-3.97 (m, 3 H), 3.98-4.12 (m, 1 H),
5.58 (d, 1 H, J ) 8.0 Hz), 7.12-7.30 (m, 5 H). Anal. Calcd for
C
26H34N2O5: C, 68.70; H, 7.54; N, 6.16. Found: C, 68.91; H,
1
7.29; N, 6.41. 23: [R]D +12.3 (c 0.5, CHCl3); H NMR δ 1.35
(s, 3 H), 1.37 (s, 9 H), 1.43 (s, 3 H), 2.78 (dd, 1 H, J ) 7.0, 13.5
Hz), 2.98 (dd, 1 H, J ) 5.4, 13.5 Hz), 3.94 (t, 1 H, J ) 6.0 Hz),
4.06-4.20 (m, 1 H), 4.90 (s, 2 H), 5.08 (t, 1 H, J ) 6.0 Hz),
5.40 (d, 1 H, J ) 7.5 Hz), 6.81 (d, 1 H, J ) 5.5 Hz), 7.10-7.35
(m, 5 H), 7.42 (s, 5 H); 13C NMR δ 27.0, 27.2, 28.3, 36.2,
52.7, 69.6, 73.4, 79.0, 80.7, 110.4, 126.2, 128.2, 129.1, 129.3,
129.5, 129.6, 131.9, 137.4, 137.7, 155.6. Anal. Calcd for
C
19H29NO5: C, 64.94; H, 8.32; N, 3.99. Found: C, 64.74; H,
7.96; N, 3.72.
(Z)-N-[(2S,3S,4R)- a n d (2S,3S,4S)-2,3-Isop r op ylid en e-
d ioxy-5-p h en yl-4-(N-t r iflu or oa cet ylb en zyla m in e)p en -
tylid en e]ben zyla m in e N-oxid e (20 a n d 22). To a solution
of 18 (4.0 g, 7.58 mmol) in EtOAc (25.0 mL) was added
Pd(OH)2 (20% on C, 0.80 g). The resulting mixture was stirred
at room temperature under 1 atm of H2 for 24 h, filtered
through Celite, and concentrated to give 3.25 g of crude
alcohols which were employed for the Swern oxidation without
purification. To a cold (-78 °C) solution of (COCl)2 (0.70 mL,
8.10 mmol) in CH2Cl2 (35.0 mL) was added DMSO (1.10 mL,
15.30 mmol) in CH2Cl2 (1.50 mL). The solution was stirred
at -78 °C for 20 min, and then the above crude alcohols (3.25
g) in CH2Cl2 (8.0 mL) were added. After the reaction solution
had been stirred at this temperature for 1 h, i-Pr2NEt (6.30
mL, 37.0 mmol) was added. The cooling bath was removed,
and the reaction flask was allowed to warm to 0 °C over 10
min. The reaction solution was neutralized with ice-cold 1 M
HCl solution. The two phases were separated; the aqueous
phase was extracted with CH2Cl2 (3 × 20.0 mL); and the
combined organic phases were washed with aqueous phos-
phate buffer (pH 7, 4 × 20.0 mL), dried, and concentrated.
The crude aldehydes were dissolved in CH2Cl2 (35.0 mL) and
treated with anhydrous MgSO4 (1.0 g) and N-benzylhydroxy-
lamine (1.02 g, 8.30 mmol). The resulting mixture was stirred
at room temperature for 4 h, filtered through Celite, and
concentrated. Chromatography on silica gel of the residue
with cyclohexane/EtOAc (3:1) gave as first eluted the nitrone
22 (0.60 g 16%) as a white solid and then the nitrone 20 (3.14
g, 76%) as a syrup which solidified on standing. 20: mp 59-
C
26H34N2O5: C, 68.70; H, 7.54; N, 6.16. Found: C, 68.99; H,
7.48; N, 6.21.
(2R,3S,4S,5R)- a n d (2S,3S,4S,5R)-2-N-Ben zylh yd r oxy-
la m in e-1,6-d ip h en yl-3,4-O-isop r op ylid en e-5-(N-tr iflu or o-
a cetyl)ben zyla m in e-3,4-h exa n d iol (24 a n d 25). To a cold
(-78 °C) solution of nitrone 20 (0.80 g, 1.48 mmol) in THF
(15.0 mL) was added a solution of freshly prepared BnMgCl
in Et2O (0.5 M, 7.40 mL). The resulting solution was stirred
at this temperature for 3 h, treated with a solution of aqueous
phosphate buffer (pH 7, 15.0 mL), and allowed to warm to room
temperature. The white suspension was filtered through
Celite, and the phases were separated. The aqueous phase
was extracted with EtOAc (3 × 10.0 mL), and the combined
organic phases were dried and concentrated. Chromatography
on silica gel of the residue with cyclohexane/Et2O (9:1) gave
as first eluted the hexandiol 25 (0.14 g, 15%) as a white solid
and then the epimer 24 (0.69 g, 74%) as a white solid. 24:
1
mp 65-68 °C; [R]D +10.2 (c 0.5, CHCl3); H NMR (DMSO-d6,
180 °C) δ 1.28 (s, 3 H), 1.34 (s, 3 H), 2.68 (dd, 1 H, J ) 5.5, 9.5
Hz), 2.90 (dd, 1 H, J ) 9.0, 14.5 Hz), 2.95 (dd, 1 H, J ) 10.0,
14.5 Hz), 3.25-3.34 (m, 2 H), 3.91 (d, 1 H, J ) 13.5 Hz), 3.93
(dd, 1 H, J ) 2.5, 8.0 Hz), 4.12 (d, 1 H, J ) 13.5 Hz), 4.23-
4.33 (m, 1 H), 4.57-4.64 (m, 1 H), 4.61 (s, 2 H), 6.85-6.98 (m,
2 H), 7.10-7.34 (m, 19 H); 19F NMR (DMSO-d6, 180 °C) δ
-65.9. Anal. Calcd for C37H39F3N2O4: C, 70.24; H, 6.21; N,
4.43. Found: C, 70.11; H, 6.27; N, 4.44. 25: mp 94-97 °C;
1
[R]D +4.4 (c 0.9, CHCl3); H NMR (DMSO-d6, 180 °C) δ 1.25
1
62 °C; [R]D -19.7 (c 1.0, CHCl3); H NMR (DMSO-d6, 180 °C)
(s, 3 H), 1.34 (s, 3 H), 2.91 (dd, 1 H, J ) 5.0, 15.0 Hz), 2.97
(dd, 1 H, J ) 9.5, 15.0 Hz), 3.09 (dd, 1 H, J ) 5.0, 14.5 Hz),
3.17 (dd, 1 H, J ) 7.0, 14.5 Hz), 3.34-3.41 (m, 1 H), 4.17 (t, 1
H, J ) 7.0 Hz), 4.43 (dd, 1 H, J ) 4.5, 7.5 Hz), 4.46-4.54 (m,
1 H), 4.58 (d, 1 H, J ) 15.0 Hz), 4.67 (d, 1 H, J ) 15.0 Hz),
7.04-7.10 (m, 2 H), 7.11-7.30 (m, 19 H); 19F NMR (DMSO-
d6, 180 °C) δ -65.9. Anal. Calcd for C37H39F3N2O4: C, 70.24;
H, 6.21; N, 4.43. Found: C, 70.62; H, 6.52; N, 4.80.
δ 1.29 (s, 3 H), 1.33 (s, 3 H), 2.86 (dd, 1 H, J ) 4.5, 14.0 Hz),
2.97 (dd, 1 H, J ) 9.5, 14.0 Hz), 4.18-4.29 (m, 1 H), 4.34 (t, 1
H, J ) 7.5 Hz), 4.42 (d, 1 H, J ) 15.0 Hz), 4.62 (d, 1 H, J )
15.0 Hz), 4.93 (d, 1 H, J ) 13.0 Hz), 4.98 (d, 1 H, J ) 13.0 Hz),
4.94-5.02 (m, 1 H), 7.00-7.10 (m, 2 H), 7.15-7.45 (m, 14 H);
13C NMR δ 26.4 (CH3), 26.5 (CH3), 32.0 (CH2Ph), 53.6 (PhCH2N),
64.5 (CHNCOCF3), 70.3 (N+CH2Ph), 73.8 (OCH), 78.1 (OCH),
109.9 (C(CH3)2), 116.2 (q, J ) 288.0 Hz), 126.6, 127.8, 128.3,
128.5, 128.9, 129.2, 131.9, 133.8, 134.7 (CHdN+), 137.1, 157.2
(q, J ) 36.0 Hz); 19F NMR (DMSO-d6, 180 °C) δ -66.1. Anal.
Calcd for C30H31F3N2O4: C, 66.66; H, 5.78; N, 5.18. Found:
C, 66.82; H, 5.90; N, 5.04. 22: mp 113-115 °C; [R]D -46.9 (c
(2R,3S,4S,5R)- a n d (2S,3S,4S,5R)-2-N-Ben zylh yd r oxy-
la m in e-5-ter t-bu toxyca r bon yla m in e-1,6-d ip h en yl-3,4-O-
isop r op ylid en e-3,4-h exa n d iol (26 a n d 27). To a cold (-78
°C) solution of nitrone 21 (0.50 g, 1.10 mmol) in THF (11.0
mL) was added a solution of freshly prepared BnMgCl in Et2O
(0.5 M, 17.7 mL). The resulting solution was stirred at this
temperature for 5 h, treated with a solution of aqueous
phosphate buffer (pH 7, 15.0 mL), and allowed to warm to room
temperature. The white suspension was filtered through
Celite, and the phases were separated. The aqueous phase
was extracted with EtOAc (3 × 10.0 mL), and the combined
1
0.5, CHCl3); H NMR (DMSO-d6, 180 °C) δ 1.20 (s, 3 H), 1.35
(s, 3 H), 3.12 (dd, 1 H, J ) 8.5, 15.0 Hz), 3.18 (dd, 1 H, J )
5.0, 15.0 Hz), 4.28 (dd, 1 H, J ) 3.5, 7.5 Hz), 4.54 (d, 1 H, J )
16.0 Hz), 4.63 (ddd, 1 H, J ) 3.5, 5.0, 8.5 Hz), 4.71 (d, 1 H, J
) 16.0 Hz), 4.94 (d, 1 H, J ) 14.0 Hz), 4.99 (d, 1 H, J ) 14.0
Hz), 5.01 (t, 1 H, J ) 7.0 Hz), 7.08-7.50 (m, 16 H); 19F NMR

9264 J . Org. Chem., Vol. 63, No. 25, 1998
Dondoni et al.
organic phases were dried and concentrated. Chromatography
on silica gel of the residue with cyclohexane/Et2O (3:2) gave
as first eluted the hexandiol 26 (0.33 g, 55%) as a white solid
and then the epimer 27 (0.14 g, 23%) as a colorless syrup. 26:
(2R,3S,4S,5R)-2,5-Bis(p h en ylm et h yla m in o)-3,4-O-iso-
p r op ylid en e-1,6-d ip h en yl-3,4-h exa n d iol (29). To a solu-
tion of (AcO)2Cu‚H2O (0.03 g, 0.13 mmol) in AcOH (5.0 mL)
was added Zn dust (0.45 g, 6.85 mmol). The resulting
suspension was vigorously stirred at room temperature for 15
min, and then a solution of benzylhydroxylamine 24 (0.85 g,
1.34 mmol) in AcOH/H2O (3:1, 8.0 mL) was added. The
stirring was continued for 4 h, the suspension was filtered
through Celite, and the collected solution was neutralized with
an aqueous solution of NaOH (3 M) and extracted with EtOAc
(3 × 10.0 mL). The combined organic phases were washed
1
mp 53-55 °C; [R]D +10.8 (c 0.7, CHCl3); H NMR (DMSO-d6,
120 °C) δ 1.24 (s, 9 H), 1.55 (s, 3 H), 1.57 (s, 3 H), 2.76 (d, 2 H,
J ) 7.8 Hz), 2.84 (dd, 1 H, J ) 7.0, 13.5 Hz), 3.14 (dd, 1 H, J
) 6.5, 13.5 Hz), 3.26 (ddd, 1 H, J ) 4.5, 6.5, 7.0 Hz), 3.88 (d,
1 H, J ) 14.0 Hz), 3.91-3.98 (m, 1 H), 4.01 (dd, 1 H, J ) 4.5,
8.5 Hz), 4.05 (d, 1 H, J ) 14.0 Hz), 4.21 (dd, 1 H, J ) 2.1, 8.5
Hz), 5.64 (d, 1 H, J ) 7.5 Hz), 7.10-7.30 (m, 21 H). Anal.
Calcd for C33H42N2O5: C, 72.50; H, 7.74; N, 5.12. Found: C,
72.27; H, 7.78; N, 5.12. 27: [R]D -7.8 (c 0.6, CHCl3); 1H NMR
(DMSO-d6, 120 °C) δ 1.26 (s, 3 H), 1.31 (s, 9 H), 1.39 (s, 3 H),
2.81-2.93 (m, 3 H), 3.08 (ddd, 1 H, J ) 4.0, 6.5, 7.5 Hz), 3.24
(dd, 1 H, J ) 6.5, 14.5 Hz), 3.70 (d, 1 H, J ) 14.0 Hz), 3.82 (d,
1 H, J ) 14.0 Hz), 3.86 (dd, 1 H, J ) 2.0, 7.5 Hz), 3.98 (t, 1 H,
J ) 7.5 Hz), 4.18-4.28 (m, 1 H), 6.11 (d, 1 H, J ) 8.0 Hz),
7.02 (s, 1 H), 7.05-7.30 (m, 15 H); 13C NMR δ 26.9, 28.3, 31.7,
40.1, 52.1, 62.0, 70.1, 77.4, 80.4, 82.3, 107.8, 125.5, 126.5, 126.8,
128.0, 128.2, 128.4, 128.8, 129.3, 129.6, 138.0, 142.4, 157.2.
Anal. Calcd for C33H42N2O5: C, 72.50; H, 7.74; N, 5.12.
Found: C, 72.63; H, 7.58; N, 5.52.
with
a saturated aqueous solution of EDTA, dried, and
concentrated to give 0.83 g of the corresponding crude ben-
zylamine which was suspended in EtOH (15.0 mL) and treated
with NaBH4 (0.20 g, 5.36 mmol). The resulting mixture was
stirred at 60 °C for 18 h, quenched with acetone (3-4 drops),
and concentrated. The crude residue was partitioned with
CH2Cl2 (3 × 5.0 mL) and saturated aqueous NaHCO3 (15.0
mL). The combined organic layers were dried and concen-
trated. Chromatography on silica gel of the residue with
cyclohexane/EtOAc (4:1) afforded the bisbenzylamine 29 (0.59
g, 85%) as a white solid: mp 106-108 °C; [R]D -9.3 (c 0.5,
CHCl3); 1H NMR δ 1.43 (s, 6 H), 2.58-2.72 (m, 4 H), 2.86 (dd,
2 H, J ) 9.5, 16.0 Hz), 3.52 (d, 2 H, J ) 13.0 Hz), 3.68 (d, 2 H,
J ) 13.0 Hz), 4.15 (s, 2 H), 7.00-7.30 (m, 20 H); 13C NMR δ
27.3, 38.3, 51.6, 57.9, 77.6, 107.9, 126.0, 126.7, 128.1, 128.3,
129.3, 139.5, 140.6. Anal. Calcd for C35H40N2O2: C, 80.73;
H, 7.74; N, 5.38. Found: C, 80.85; H, 7.47; N, 5.05.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-isop r op ylid en ed ioxy-4,7-
bis(ph en ylm eth yl)-1,3-bis(ph en ylm eth yl)-2H-1,3-diazapin -
2-on e (30). To a solution of N-methylmorpholine (0.09 mL,
0.81 mmol) in toluene (10.0 mL) were added under vigorous
stirring the amine 29 (0.10 g, 0.19 mmol) in toluene (0.83 mL)
and phosgene (1.28 M in toluene, 0.30 mL) simultaneously by
two syringe pumps within 4 h at 100 °C. After an additional
1 h at 100 °C, N-methylmorpholine (0.09 mL, 0.81 mmol) and
H2O (0.30 mL) were added. The resulting mixture was filtered
through Celite and then concentrated. Chromatography on
silica gel of the residue with cyclohexane/EtOAc (8:1) gave the
pure cyclic urea 30 (0.08 g, 77%) as a white solid: mp 126-
129 °C; [R]D +77.5 (c 0.4, CHCl3); 1H NMR δ 1.34 (s, 6 H),
2.86-3.00 (m, 4 H), 3.08 (d, 2 H, J ) 14.6 Hz), 3.74-3.83 (m,
2 H), 3.84 (s, 2 H), 5.00 (d, 2 H, J ) 14.6 Hz), 7.10-7.20 (m,
8 H), 7.20-7.40 (m, 12 H); 13C NMR δ 26.7, 33.5, 56.3, 60.8,
75.5, 110.1, 126.6, 127.5, 128.5, 128.6, 129.1, 129.4, 138.3,
138.9, 161.6. Anal. Calcd for C36H38N2O3: C, 79.09; H, 7.01;
N, 5.12. Found: C, 78.99; H, 6.95; N, 4.80.
(4R ,5S ,6S ,7R )-H e x a h y d r o -5,6-d i h y d r o x y -4,7-b i s -
(p h en ylm eth yl)-1,3-bis(p h en ylm eth yl)-2H-1,3-d ia za p in -
2-on e (31). To a solution of cyclic urea 30 (0.08 g, 0.15 mmol)
in MeOH (1.0 mL) was added a solution of HCl in dioxane (4.8
M, 0.50 mL). The solution was stirred at room temperature
for 3 h, neutralized with an aqueous solution of NaOH (1 M),
and extracted with CH2Cl2 (3 × 5.0 mL). The combined organic
phases were dried and concentrated. Chromatography on
silica gel with CHCl3/MeOH (94:6) afforded pure urea 31 (0.06
g, 79%) as a white crystal: mp 164-165 °C from cyclohexane/
EtOAc; [R]D +134.1 (c 0.6, MeOH);1H NMR (CD3OD) δ 2.92
(dd, 2 H, J ) 10.0, 13.5 Hz), 2.94 (d, 2 H, J ) 14.2 Hz), 3.04
(dd, 2 H, J ) 2.2, 13.5 Hz), 3.53-3.65 (m, 4 H), 4.74 (d, 2 H,
J ) 14.2 Hz), 7.03-7.40 (m, 20 H); 13C NMR (CD3OD) δ 33.5,
57.1, 67.2, 72.0, 127.5, 128.8, 129.6, 129.7, 130.5, 130.6, 139.3,
141.1, 163.9. Anal. Calcd for C33H34N2O3: C, 78.23; H, 6.76;
N, 5.53. Found: C, 78.32; H, 6.42; N, 5.64.
(2R,3S,4S,5R)-2,5-Dia m in o-1,6-d ip h en yl-3,4-h exa n d i-
ol (2c). To a solution of 24 (0.90 g, 1.42 mmol) in EtOH (9.0
mL) was added NaBH4 (0.22 g, 5.70 mmol). The resulting
mixture was stirred at 60 °C for 1 h, treated with acetone (3-4
drops), and concentrated. To the residue dissolved in AcOH/
EtOH (9:1, 5.0 mL) was added Pd(OH)2 (20% on C, 0.30 g).
The mixture was stirred at room temperature under 3 atm of
H2 for 18 h, filtered through Celite, and concentrated. To the
crude residue was added an aqueous solution of HCl (6 M, 5.0
mL), and the resulting suspension was heated to 90 °C for 1
h and then concentrated. The crude salts were neutralized
with an aqueous solution of NaOH (3.0 M) and extracted with
CHCl3 (3 × 5.0 mL). The combined organic layers were dried
and concentrated. Chromatography on silica gel with CHCl3/
MeOH/NH4OH (89:10:1) afforded 2c (0.30 g, 70%) as a white
solid: mp 96-100 °C; [R]D -48.5 (c 1.0, CHCl3); 1H NMR δ
2.73 (dd, 2 H, J ) 9.0, 13.2 Hz), 2.93 (dd, 2 H, J ) 5.7, 13.2
Hz), 3.04 (dd, 2 H, J ) 5.7, 9.0 Hz), 3.10-3.65 (m, 6 H), 3.70
(s, 2 H), 7.15-7.37 (m, 10 H); 13C NMR δ 43.0, 57.5, 74.3, 126.3,
128.6, 129.3, 138.7. Anal. Calcd for C18H24N2O2: C, 71.97;
H, 8.05; N, 9.32. Found: C, 71.86; H, 7.84; N, 8.98.
Syn th esis of 2b fr om 25. The same procedure as described
above for the synthesis of 2c was applied to 25 (0.3 g, 0.47
mmol). Chromatography on silica gel of the crude compound
with CHCl3/MeOH/NH4OH (89:10:1) afforded 2b (92.0 mg,
65%).
Syn th esis of 2c fr om 26. The same procedure as described
above for the synthesis of 1Aa was applied to 26 (0.25 g, 0.46
mmol). Chromatography on silica gel of the crude compound
with CHCl3/MeOH/NH4OH (89:10:1) gave pure 2c (0.11 g,
79%).
Syn th esis of 2b fr om 27. The same procedure as described
above for the synthesis of 1Aa was applied to 27 (0.25 g, 0.46
mmol). Chromatography on silica gel of the crude compound
with CHCl3/MeOH/NH4OH (89:10:1) gave pure 2b (0.10 g,
75%).
(4R,5S,4′R,5′S)-5,5′-Bis(4-ben zyloxa zolid in -2-on e) (28).
The reaction was carried out as described above for the
synthesis of the bis-oxazolidinone 15 starting from 2c (20.0
mg, 0.07 mmol). Chromatography on silica gel of the crude
compound with CHCl3/EtOAc (3:2) afforded 28 (15.0 mg, 61%)
as a white solid: mp 171-172 °C from EtOAc; [R]D +106.0 (c
1
0.5, CHCl3); H NMR δ 2.76 (dd, 2 H, J ) 6.3, 14.0 Hz), 2.86
(dd, 2 H, J ) 7.6, 14.0 Hz), 3.99 (d, 2 H, J ) 5.8 Hz), 4.04-
4.15 (m, 2 H), 4.98 (s, 2 H), 7.05-7.15 (m, 4 H), 7.30-7.40 (m,
6 H); 13C NMR δ 41.3, 54.5, 79.6, 127.5, 129.1, 134.9, 157.4.
Anal. Calcd for C20H20N2O4: C, 68.17; H, 5.72; N, 7.95.
Found: C, 67.85; H, 5.40; N, 7.81.
Ack n ow led gm en t. Financial support from CNR
(Rome) is gratefully acknowledged. We thank Mr. Paolo
Formaglio for the assistance in NMR analysis.
J O980980U