Concise and stereocontrolled synthesis of pseudo-C2-symmetric diamino alcohols and triamines for use in HIV protease inhibitors

Article abstract of DOI:10.1021/jo026616j

A new protocol is described for the stereocontrolled synthesis of pseudo-C₂-symmetric core units of interest as candidates for HIV protease inhibition. Addition of unbranched and branched organolithium reagents to cyanohydrins from L-phenylalaninal and L-isoleucinal, followed by in situ reduction of the intermediate imines and CHT deprotection under MW irradiation, led to 1,3-diamino alcohols 6a and 8a as the major products in satisfactory to good yields. The first preparation of a previously unreported pseudo-C₂-symmetric triamino derivative was accomplished expeditiously via high-yielding nitro-Mannich addition of the silylnitronate, from 2-phenyl-1-nitroethane, to the PMP imine derived from L-phenylalaninal. Reduction of the nitro group in the moderately unstable nitro diamine adduct, followed by chromatographic separation of the required diastereoisomer and CHT debenzylation under MW irradiation, led to the 2-PMP-protected triamine 19 isolated as a bis(sulfonamide).

Full text of DOI:10.1021/jo026616j

Con cise a n d Ster eocon tr olled Syn th esis of P seu d o-C2-sym m etr ic
Dia m in o Alcoh ols a n d Tr ia m in es for Use in HIV P r otea se
In h ibitor s
Luca Bernardi,† Bianca F. Bonini,† Gabriella Dessole,† Mariafrancesca Fochi,†
Mauro Comes-Franchini,† Silvia Gavioli,† Alfredo Ricci,*,† and Greta Varchi‡
Dipartimento di Chimica Organica “A. Mangini”, Facolta` di Chimica Industriale, Universita` di Bologna,
Viale Risorgimento 4, 40136 Bologna, Italy, and National Research Council, Research Area of Bologna
(CNR-ISOF), Via Gobetti 101, 40129, Bologna, Italy
ricci@ms.fci.unibo.it
Received October 28, 2002
A new protocol is described for the stereocontrolled synthesis of pseudo-C2-symmetric core units of
interest as candidates for HIV protease inhibition. Addition of unbranched and branched
organolithium reagents to cyanohydrins from L-phenylalaninal and L-isoleucinal, followed by in
situ reduction of the intermediate imines and CHT deprotection under MW irradiation, led to 1,3-
diamino alcohols 6a and 8a as the major products in satisfactory to good yields. The first preparation
of a previously unreported pseudo-C2-symmetric triamino derivative was accomplished expeditiously
via high-yielding nitro-Mannich addition of the silylnitronate, from 2-phenyl-1-nitroethane, to the
PMP imine derived from L-phenylalaninal. Reduction of the nitro group in the moderately unstable
nitro diamine adduct, followed by chromatographic separation of the required diastereoisomer and
CHT debenzylation under MW irradiation, led to the 2-PMP-protected triamine 19 isolated as a
bis(sulfonamide).
In tr od u ction
in the identification of the highly selective and efficient
A-74704 (II),2 has been reported in which the key steps
are the 2C-homologation of phenylalaninal and a double-
bond epoxidation.3
Inhibitors of HIV-protease are effective against the
proliferation of HIV-1 infection in vitro. On the basis of
the inherent symmetry of the protease homodimer, C2-
symmetric and pseudo-C2-symmetric molecules have
been designed, synthesized, and demonstrated to be
potent inhibitors. The hypothesis that the C2-symmetric
inhibitors comprised of a key diamino unit flanked by
acyl groups would be recognized and bound by this
homodimeric retroviral protease led to a great deal of
synthetic efforts aimed at the synthesis of stereochemi-
cally defined molecules possessing the diamino diol and
the diamino alcohol cores. A complementary interest in
the synthesis of these compounds lies moreover on their
ability to act as multidentate chiral ligands able to impart
asymmetry to transition and main group elements.1
Moreover, other efficient syntheses of I based on the
SAMP/RAMP hydrazone method4 and starting from
N-Boc hydroxylactams have been published in which the
absolute stereochemistry was derived from an amino acid
source.5 More recently a stereochemically flexible entry
to the 1,3-diamino propanol units has been devised via
organometallic addition of chiral aldehydes to nitrones
leading to a diamino alcohol stereotriad.6 Furthermore,
a synthetic protocol was proposed on the basis of a
ruthenium-catalyzed asymmetric reduction of a bis-
cinnamic acid derivative.7
We now report an alternative approach to this diamino
alcohol core unit by using a concise synthetic route
starting from easily available nonracemic materials.
(2) Erickson, J .; Neidhart, D. J .; Van Drie, 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.
(3) 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.
The synthesis of a series of pseudo-C2-symmetric
inhibitors derived from the core diamine I, culminating
(4) Enders, D.; J egelka, U.; Du¨cker, B. Angew. Chem., Int. Ed. Engl.
1993, 32, 423-425.
† Universita` di Bologna.
(5) Wittemberger, S. J .; Baker, W. R.; Donner, B. G. Tetrahedron
1993, 49, 1547-1556.
‡ National Research Council.
(1) (a) Whitesell, J . K. Chem. Rev. 1989, 89, 1581-1590. (b) Corey,
E. J .; Kim, S. S. Tetrahedron Lett. 1990, 31, 3715-3718. (c) Zhang,
W.; Loebach, J . L.; Wilson, S. R.; J acobsen, E. N. J . Am. Chem. Soc.
1990, 112, 2801-2803. (d) Tomioka, K.; Makajima, M.; Iitaka, Y.; Koga,
K. Tetrahedron Lett. 1988, 29, 573-576 and references therein.
(6) (a) Dondoni, A.; Perrone, D. Tetrahedron Lett. 1997, 38, 499-
502. (b) Dondoni, A.; Perrone, D.; Rinaldi, M. J . Org. Chem. 1998, 63,
9252-9264.
(7) Doi, T.; Hirabayashi, K.; Kokubo, M.; Komagata, T.; Yamamoto,
K.; Takahashi, T. J . Org. Chem. 1996, 61, 8360-8361.
10.1021/jo026616j CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/22/2003
1418
J . Org. Chem. 2003, 68, 1418-1425

Pseudo-C2-symmetric Diamino Alcohols and Triamines
SCHEME 1
Since desirable features in an HIV protease inhibitor
would include hydrophobic sites to project into the
specific pockets of the enzyme8 and hydrogen-bond donors
to interact with the carbonyl of Gly-27,9 we have also
addressed our efforts toward the synthesis of structural
variants III and IV of the core key unit present in the
inhibitor A-74704.
These results showing a prevalence of the chelation-
controlled adduct, matched well with those previously
obtained by Reetz.12 By virtue of its symmetry charac-
teristic, the central carbon (C3) of I is not stereogenic.
However, even though control of the stereochemistry at
that center would not be a requirement for the stereo-
selective syntheses of type I derivatives, its role in
determining the configuration at C4 must be recognized.
To avoid risk of decomposition on silica gel, the diaster-
eomeric mixture of 3a + 3b was used as such with the
aim of performing the separation at a more advanced
stage of the synthetic sequence. Since trimethylsilyl-
protected cyanohydrins are usually stable under Grig-
nard conditions,13 a benzylmagnesium chloride addition
was first carried out on 3a + 3b as depicted in Scheme
1 followed by the one-pot reduction of the intermediate
imine.
Resu lts a n d Discu ssion
A linear pathway, shown in Scheme 1, was adopted.
The key to the success of this approach was the ability
to produce the protected cyanohydrins 3 and 4 in good
overall yields and to induce their reactivity with the
suitable organometallic reagents. Accordingly, N,N-
dibenzyl-protected phenylalaninal 110 obtained from L-
phenylalanine, by sequential protection, LiAlH4 reduc-
tion, and Swern oxidation, subjected to addition of
Me3SiCN in the presence of MgBr2, led to 3a + 3b in
95% overall yields and with 56% de; in an analogous way,
isoleucinal11 led to 4a + 4b in 92% overall yield and 64%
de.
In line with previous findings14 highlighting the very
high erythro selectivity in the sodium borohydride reduc-
tion of the intramolecularly chelated magnesiated imines,
a mixture of two distinct diastereomeric N,N-dibenzyl-
protected diamino alcohols 5a and 5b was obtained from
this reaction though in modest yields (25% yield, 56%
de). On the other hand, the use of benzyllithium from
(8) Darke, P. L.; Nutt, R. F.; Brady, S. F.; Garsky, V. M.; Ciccarone,
T. M.; Leu, C.-T.; Lumma, P. K.; Freidinger, R. M.; Verber, D. F.; Sigal,
I. S. Biochem. Biophys. Res. Commun. 1988, 156, 297-303.
(9) Fitzgerald, P. M. D.; McKeever, B. M.; Van Middlesworth, J . F.;
Springer, J . P.; Heimbach, J . C.; Leu, C.-T.; Herber, W. K.; Dixon, R.
A. F.; Darke, P. L. J . Biol. Chem. 1990, 265, 14209-14219.
(10) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int.
Ed. Engl. 1987, 26, 1141-1143.
(12) Reetz, M. T.; Drewes, M. W.; Harms, K.; Reif, W. Tetrahedron
Lett. 1988, 29, 3295-3298.
(13) Brussee, J .; Dofferhoff, F.; Kruse, C. G.; Van der Gen, A.
Tetrahedron 1990, 46, 1653-1658.
(11) Reetz, M. T.; Schmitz, A.; Holdgruen, X. Tetrahedron Lett. 1989,
30, 5421-5424.
(14) Krepski, L. R.; Karen, M. J .; Heilmann, S. M.; Rasmussen, J .
K. Synthesis 1986, 301-303.
J . Org. Chem, Vol. 68, No. 4, 2003 1419

Bernardi et al.
SCHEME 2
toluene, n-BuLi, and TMEDA led to a substantial im-
provement, the diamino alcohols 5a and 5b being isolated
in a 78:22 ratio and 72% overall yields from 3a + 3b.
Following this latter procedure, separation of the major
optically active amino alcohol 5a from the precursor of
the meso form 5b by silica gel chromatography, followed
by removal of the protection at nitrogen by catalytic
hydrogen transfer (CHT) methodology under MW ir-
radiation,15 afforded in quantitative yield the diamino
alcohol 6a with the structure and the stereochemistry of
the desired core unit I (43% overall yield from 1).
The synthesis of the isoleucine derivative was carried
out (Scheme 2) by using small variations of the previously
described sequence. For the addition to the cyano group
in 4a ,b, sec-BuLi was the reagent of choice, no reaction
at all being observed with the corresponding Grignard
reagent. After in situ NaBH4 reduction of the intermedi-
ate imine, adducts were obtained in 90% yield. This
reduction is expected to occur giving rise to two couples
of diastereoisomers in a 4:1 ratio whose stereochemistry
should account, as in the previous case, for an anti
relationship between the preexisting hydroxy moiety and
the newly created amino function, in line with a chela-
tion-controlled pathway. Diastereoisomers 7a and 7b
coming from the major OTMS-cyanohydrin could be
separated as a 1:1 mixture from the minor components
in 72% combined yields by column chromatography.
After CHT removal of the protection at nitrogen, 8a
and 8b could be separated by column chromatography
only after derivatization (70% yield) of the free diamino
alcohols into the corresponding sulfonamides: the 1H and
13C NMR spectra of these two isomers (9a and 9b)
present both sets of signals for the two sides of the chain,
thus excluding the presence of a meso form. The product
with a higher Rf (9a , Rf ) 0.60, 1/1 EtOAc/hexane) was
1
then oxidized at the alcoholic function: the H and 13C
NMR spectra of this ketone (10) present only one set of
signals for the two branches of the chain, thus demon-
strating the pseudo-C2-symmetry of its precursor, the
diamino alcohol 9a (24% from 4a + 4b).
With a convenient synthesis of 6a and 9a in hand, we
turned our attention to the assembly of the vicinal
triamine IV. The widely investigated 1,2-diamine struc-
tural motif is important in biologically active products,
in medicinal chemistry, and more recently for use as
chiral auxiliaries and chiral ligands in asymmetric
catalysis.16 Unfortunately, there are very few reports on
the synthesis of stereodefined triamines despite their
importance in a variety of physiological processes17 and
their ability to serve as versatile ligands for catalytic
applications.18 Addition of trimethylsilyl cyanide to the
imine derived from the phenylalaninal in the presence
of a Lewis acid (MgBr2) occurred smoothly to give the
(16) (a) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int.
Ed. 1998, 37, 2580-2627 and references therein. (b) Chhabra, S. R.;
Khan, A. N.; Bycroft, B. W. Tetrahedron Lett. 2000, 41, 1095-1098.
(c) Wei, H.-X.; Kim, S. H.; Li, G. J . Org. Chem. 2002, 67, 4777-4781.
(d) Li, G.; Wei, H.-X.; Kim, S. H.; Carducci, M. D. Angew. Chem., Int.
Ed. 2001, 41, 4277-4281. (e) Wei, H.-X.; Siruta, S.; Li, G. Tetrahedron
Lett. 2002, 43, 3809-3812.
(17) (a) Labarre, J .-P. Top. Curr. Chem. 1985, 129, 173-260. (b)
Geneste, H.; Hesse, M. Chem. Unserer Zeit. 1998, 32, 206-218.
(18) (a) Cernerud, M.; Adolfsson, H.; Moberg C. Tetrahedron:
Asymmetry 1997, 8, 2655-2662. (b) Lake, F.; Moberg, C. Eur. J . Org.
Chem. 2002, 3179-3188.
(15) Banik, B. K.; Barakat, K. J .; Wagle, D. R.; Manhas, M. S.; Bose,
A. K. J . Org. Chem. 1999, 64, 5746-5743.
1420 J . Org. Chem., Vol. 68, No. 4, 2003

Pseudo-C2-symmetric Diamino Alcohols and Triamines
SCHEME 3
SCHEME 4
expected R-aminonitrile 11 in 80% yield.19 However, in
line with the previously observed20 lability of R-amino-
nitriles toward basic reagents, when the Strecker adduct
(11) was subjected to addition of benzylmagnesium
chloride or benzyllithium, the cyano group was predomi-
nantly substituted by the benzyl group (Scheme 3),
leading to compound 12 together with variable amounts
of the diamine 13 from the in situ reduction of the
starting imine formed from the R-aminonitrile via HCN
elimination.
An alternative convergent approach to IV was there-
fore envisaged on the basis of the Henry or nitroaldol
reaction, one of the classical name reactions in organic
synthesis that have seen increasing in utilization.21
Recently, several examples of the nitro-Mannich reaction
have been reported disclosing a suitable entry to the
stereoselective synthesis of 1,2-diamines.22 On these
grounds the reaction of 2-phenylnitroethane, used as a
synthetic equivalent of an R-amino carbanionic synthon
(V), was performed with suitable electrophiles.
procedure, though more straightforward and high yield-
ing, is hampered by the low stereoselectivity of the
coupling. Moreover, attempts at performing the one-step
NO2 reduction-deprotection with thermal or MW-
induced CHT were unsuccessful. For this reason, reduc-
tion of the nitro group was performed at first by using
the NaBH4/NiCl2‚6H2O combination as a reducing sys-
tem,24 leading in 76% yield to a diastereomeric mixture
of the protected diamino alcohols. The subsequent CHT
deprotection occurred smoothly and afforded in quantita-
tive yield the stereotriad of one optically active and two
meso diamino alcohols in a 4:4:1 ratio, respectively. From
this mixture, after derivatization to sulfonamides and
column chromatography, compound 15a could be isolated
in 18% overall yield from 1.
Encouraged by the above results, we turned finally to
the assembly of the backbone IV. To this end, a three-
step sequence was devised on the basis of the use of imine
16 as the 4-methoxyphenyl (PMP) group can be easily
removed using CAN25 and favors the coordination of the
imine nitrogen with a Lewis acid.22a The reaction se-
quence took place as shown in Scheme 5. Addition of the
silylnitronate26 to the imine 16 was screened for different
Lewis acids. After several attempts, the best route
involved the use of catalytic (5%) Sc(OTf)3.27 Although
this Lewis acid turned out to be efficient at catalyzing
the addition of the silyl nitronate to the PMP-imine, the
diastereomeric ratio was poor. The nitroadducts could be
isolated in 68% yield after column chromatography as a
mixture of two diastereoisomers 17a ,b (60:40, 1H NMR).
On a second run, to avoid the already reported retro-
Henry reaction22a that partially occurred on silica gel, the
crude adducts 17a ,b were directly subjected to reduction
using the NaBH4/NiCl2-based protocol.24 After separation
on deactivated silica, the protected triamines 18a and
18b could be isolated as single diastereoisomers in 66%
overall yield starting from the imine 16.
For the sake of comparison with the procedure outlined
in Scheme 1, we first applied this approach to the
synthesis of 6a . Reaction of the nitronate, generated in
situ by TBAF deprotonation of 2-phenylnitroethane23
with phenylalaninal, led (Scheme 4) after chromatogra-
phy to a mixture of four diastereoisomers of 14 in a 4:3:
1:1 ratio and in 87% combined yields. Compared to the
synthesis previously reported in Scheme 1, this latter
(19) Reetz, M. T.; Hu¨bel, M.; J aeger, R.; Schwickardi, R.; Goddard,
R. Synthesis 1994, 733-738.
(20) (a) Yoshimura, J .; Ohgo, Y.; Sato, T. Bull. Soc. Chem. J pn. 1965,
38, 1809-1813. (b) Vachal, P.; J acobsen, E. N. Org. Lett. 2000, 6, 867-
870.
(21) For a recent review on the Henry reaction, see: Luzzio, F. A.
Tetrahedron 2001, 57, 915-945.
(22) (a) Adams, H.; Anderson, J . C.; Peace, S.; Pennel, A. M. K. J .
Org. Chem. 1998, 63, 9932-9934. (b) Yamada, K.-I.; Harwood, S. J .;
Groger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38, 3504-
3506. (c) Nishiwaki, N.; Rahbek, K.; Gothelf, K. V.; J ørgensen, K. A.
Angew. Chem., Int. Ed. 2001, 40, 2992-2995.
(23) Hanessian, S.; Devasthale, P. V. Tetrahedron Lett. 1996, 37,
987-990.
(24) Corey, E. J .; Zhang, F.-Y. Angew. Chem., Int. Ed. 1999, 38,
1931-1934.
(25) Smith, A. B., III; Leahy, J . W.; Noda, I.; Remiszewski, S. W.;
Liverton, N. J .; Zibuck, R. J . Am. Chem. Soc. 1992, 114, 2995-3007.
(26) Knudsen, K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.;
J ørgensen, K. A. J . Am. Chem. Soc. 2001, 123, 5843-5844.
(27) Anderson, J . C.; Peace, S.; Pih, S. Synlett 2000, 850-852.
J . Org. Chem, Vol. 68, No. 4, 2003 1421

Bernardi et al.
SCHEME 5
(120 °C) glassware under a positive pressure of Ar. Microwave-
induced reactions were performed on a monomode apparatus
(maximum power ) 300 W, frequency ) 2.45 GHz). Transfer
of anhydrous solvents or mixtures was accomplished with
oven-dried syringes/septum techniques. THF was distilled from
sodium/benzophenone just prior to use and stored under Ar.
Et2O was distilled from phosphorus pentoxide. CH2Cl2 was
passed through basic alumina and distilled from CaH2 prior
to use. Light petroleum ether refers to the fraction with a
boiling range of 40-60 °C. Powdered 4 Å molecular sieves were
activated under vacuum at 220 °C for 6 h before use. Protected
phenylalaninal 1,10 PMP-imine 16,29 and isoleucinal 211 were
prepared following literature procedures starting from L-
phenylalanine and L-isoleucine. Benzyllithium was prepared
at room temperature as a toluene solution from n-BuLi (1.6
M in hexanes, 2.95 mL) and dry toluene (9.20 mL) containing
TMEDA (1.10 mL). 2-Phenylnitroethane30 and trimethylsilyl-
2-phenyl-ethylnitronate26 were prepared according to literature
procedures. Thin-layer chromatography (TLC) was performed
SCHEME 6
From X-ray analysis, the configuration of the minor
diastereoisomer 18b28 was established to be (2S,3R,4R),
thus making this compound a precursor of the meso
triamine (2S,3s,4R). CHT debenzylation of the major
component 18a , followed by TsCl derivatization, afforded
the optically active compound 19 in 70% isolated yield,
thus allowing assignment of the (S) configuration at C4
(Scheme 6). Finally, the stereochemistry at C3 of 18a was
tentatively assigned by means of NOE experiments on
its cyclic derivative 20, which suggested a trans relation-
ship between H3 and H4.
on plastic plates coated with (0.20 mm) silica gel 60 F254
.
Column chromatography was carried out on 70-230 mesh
1
silica gel. Melting points were uncorrected. H and 13C NMR
spectra were recorded at 300 and 400 MHz and 75 and 100
MHz, respectively. Chemical shifts were reported in the δ scale
relative to an internal reference of TMS (0 ppm). The coupling
constants (J ) values are given in Hz. 13C NMR spectral
assignments were performed by use of DEPT experiments. The
manufacturer’s software was used for DEPT, gradient-
enhanced COSY, as well as for the inversely detected gradient-
selected heteronuclear correlations gHMBC and gHSQC. Mass
spectra (MS) were obtained at an ionizing voltage of 70 eV
(EIMS) or with an electrospray ionization source (ESIMS). All
ESIMS spectra were performed using MeOH as the solvent.
Optical rotations were obtained at 20 ( 2 °C. In the charac-
terization of new compounds, oily products were characterized
by accurate mass measurements [high-resolution mass spectra
(HRMS)] because of the small scales used for their prepara-
tions. The originality of all compounds was checked by a CAS
online structure search.
(2R,3S)- a n d (2S,3S)-3-N,N-Diben zyla m in o-4-p h en yl-2-
tr im eth ylsila n yloxy Bu tyr on itr ile (3a a n d 3b). To a
solution of freshly prepared aldehyde 1 (2.00 g, 6.10 mmol) in
dry CH2Cl2 (40 mL), cooled to -20 °C and magnetically stirred
under Ar, were subsequently added MgBr2 (1.23 g, 6.67 mmol)
and TMSCN (0.90 mL, 6.67 mmol). After stirring at -20 °C
for 4 h, the mixture was poured into H2O; the layers were
separated, and the aqueous layer was extracted three times
with Et2O. The combined organic extracts were washed with
brine, dried (Na2SO4), and filtered. Evaporation of the solvents
gave 2.49 g (95%) of a pale yellow oil, mainly constituted by
Con clu sion
In summary the results presented here provide a
practical and stereoselective synthesis of the enantiopure
pseudo-C2-symmetric 1,3-diamino-2-propanol units 6a
and 8a . The explored overall process may serve as one
of the most practical synthetic methods of these core key
units because of its directness and operational simplicity.
A stereoselective nitro-Mannich reaction based on an
enantiomerically pure imine gave access to the novel
triamino derivative 19. All of these products can be
diastereomerically enriched with standard chromatog-
raphy and selectively deprotected.
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise noted, all reagents
were obtained from commercial suppliers and used without
further purification. Reactions were conducted in oven-dried
(28) CCDC 195390 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via the
Internet at www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. Fax: +44 1223
336033. E-mail: deposit@ccdc.cam.ac.uk).
(29) Reetz, M. T.; Lee, W. K. Org. Lett. 2001, 20, 3119-3120.
(30) Bachman, G. B.; Maleski, R. J . J . Org. Chem. 1972, 37, 2810-
2814.
1422 J . Org. Chem., Vol. 68, No. 4, 2003

Pseudo-C2-symmetric Diamino Alcohols and Triamines
3a and 3b in a 78:22 ratio (1H NMR). Crude product was used
in the subsequent reaction with no further purification: 1H
NMR (CDCl3, 300 MHz) δ 7.40-7.00 (m, 15Hmin, 15Hmaj), 4.48
(d, J ) 6.3 Hz, 1Hmin), 4.35 (d, J ) 3.9 Hz, 1Hmaj), 4.10 (d, J )
13.8 Hz, 2Hmaj), 3.72 (s, 4Hmin), 3.58 (d, J ) 13.8 Hz, 2Hmaj),
3.39 (m, 1Hmin), 3.19-3.08 (m, 1Hmin, 1Hmaj), 3.07-2.97 (m,
1Hmin, 2Hmaj), 0.18 (s, 9Hmin), 0.15 (s, 9Hmaj); 13C NMR (CDCl3,
75 MHz) δ [minor isomer in brackets] 139.3 (s), [138.9 (s)],
138.7 (s), [129.4 (d)], 129.2 (d), 128.9 (d), [128.8 (d)], 128.5 (d),
[128.4 (d)], 128.3 (d), 127.0 (d), [126.4 (d)], 119.7 (s), 64.2 (d),
[63.2 (d)], [62.8 (d)], 62.0 (d), 55.2 (t), [54.8 (t)], [33.2 (t)], 30.2
(t), -0.4 (q); IR νmax (thin layer, NaCl plate) 2240, 1250, 1090
cm-1; EIMS m/z 428 (M+), 413, 402, 337, 300, 91.
(thin layer, NaCl plate) 3587, 3368 cm-1; EIMS m/z 359, 300,
240, 120, 91. Anal. Calcd for C31H34N2O: C, 82.63; H, 7.61; N,
6.22. Found: C, 82.74; H, 7.53; N, 6.12.
(2S,4S)-2,4-Diam in o-1,5-diph en yl P en tan -3-ol (6a). Pd/C
10% was weighed (44 mg) in a microwave reactor and im-
mediately covered with i-PrOH (1 mL). A solution of 5a (100
mg, 0.22 mmol) in i-PrOH (3 mL) was added, followed by
HCOONH4 (84 mg, 1.33 mmol). After 20 min of irradiation
(30 W with stirring), the mixture was allowed to cool to room
temperature and then filtered through a Celite pad. The pad
was washed with MeOH; then, the solvents were evaporated,
and the crude was purified by chromatography on silica gel
(85/15 CHCl3/MeOH) affording 48 mg (80%) of compound 6a 31
as a white solid: mp ) 136-138 °C; 1H NMR (CDCl3, 300
MHz) δ 7.20-7.05 (m, 10H), 3.40-3.36 (m, 2H), 3.20-3.07 (m,
1H), 3.00 (dd, J ) 3.3, J ) 13.3, 1H), 2.95 (dd, J ) 4.5, J )
13.3, 1H), 2.62 (dd, J ) 9.5, J ) 13.3, 1H), 2.50 (dd, J ) 9.9,
J ) 13.3, 1H), 1.50-1.00 (br s, 5H); EIMS m/z 271 (MH+), 179,
150, 120, 91; ESIMS m/z 271 (M + H+).
(2R,3S,4S)- a n d (2S,3S,4S)-3-N,N-Dib en zyla m in o-4-
m eth yl-2-tr im eth ylsila n yloxy Hexa n en itr ile (4a a n d 4b).
Compounds 4a and 4b were obtained (92%) in a 82:18 ratio
(1H NMR) as a pale yellow oil following the procedure used
for 3, starting from aldehyde 2: 1H NMR (CDCl3, 300 MHz) δ
7.30-7.10 (m, 10Hmin, 10Hmaj), 4.68 (d, J ) 3.3 Hz, 1Hmin
,
1Hmaj), 3.82 (d, J ) 13.8 Hz, 2Hmaj), 3.77 (d, J ) 13.5 Hz, 2Hmin),
3.66 (d, J ) 13.5 Hz, 2Hmaj), 3.55 (d, J ) 13.5 Hz, 2Hmin), 2.70
(dd, J ) 4.8 Hz, J ) 7.8 Hz, 1Hmin), 2.53 (dd, J ) 3.3 Hz, J )
9.3 Hz, 1Hmaj), 2.00-1.70 (m, 2Hmin, 2Hmaj), 1.10-0.90 (m,
1Hmin, 1Hmaj), 0.88 (d, J ) 6.6 Hz, 3Hmin), 0.80 (d, J ) 6.9 Hz,
3Hmaj), 0.70 (t, J ) 7.5 Hz, 3Hmaj), 0.65 (t, J ) 7.5 Hz, 3Hmin),
0.17 (s, 9Hmin), 0.13 (s, 9Hmaj); 13C NMR (CDCl3, 75 MHz) δ
[minor isomer in brackets] 139.4 (s), [139.0 (s)], 129.2 (d), 128.2
(d), 127.0 (d), 120.3 (s), 64.7 (d), [64.0 (d)], 61.7 (d), [61.2 (d)],
54.9 (t), [54.7 (t)], 34.5 (d), [32.8 (d)], [26.9 (t)], 26.1 (t), 16.1
(q), [15.2(q)], 10.9 (q), -0.3 (q); IR νmax (thin layer, NaCl plate)
2234, 1256, 1096 cm-1; EIMS m/z 394 (M+), 379, 337, 266, 91.
(3S,4S,5S,6S,7S)- a n d (3S,4S,5S,6S,7R)-6-Am in o-4-N,N-
d iben zyla m in o-3,7-d im eth yl Non a n -5-ol (7a a n d 7b). Fol-
lowing the procedure used for 5a and 5b, compounds 7a and
7b were obtained as a white solid in 72% yield in a 1:1 mixture
after chromatography on silica gel: 1H NMR (CDCl3, 300 MHz)
δ 7.40-7.15 (m, 20H), 4.05 (d, J ) 13.0 Hz, 4H), 3.85 (dd, J )
3.0 Hz, J ) 6.3 Hz, 1H), 3.78 (dd, J ) 3.8 Hz, J ) 5.3 Hz, 1H),
3.50 (d, J ) 13.0 Hz, 2H), 3.42 (d, J ) 14.0 Hz, 2H), 2.70 (dd,
J ) 2.9 Hz, J ) 6.8 Hz, 2H), 2.60 (dd, 1H), 2.50 (t, J ) 3.5 Hz,
1H), 2.30 (br s, 6H), 2.10-1.90 (m, 2H), 1.50-0.50 (m, 34H);
13C NMR (CDCl3, 75 MHz) δ 139.5 (s), 139.3 (s), 129.3 (d), 129.2
(d), 128.3 (d), 128.0 (d), 127.1 (d), 127.0 (d), 71.9 (d), 71.2 (d),
60.5 (d), 60.4 (d), 58.3 (d), 57.4 (d), 54.9 (t), 54.6 (t), 34.9 (d),
34.4 (d), 33.2 (d), 32.4 (d), 30.0 (t), 29.4 (t), 27.8 (t), 23.3 (t),
17.1 (q), 16.9 (q), 16.9 (q), 13.5 (q), 12.8 (q), 12.6 (q), 11.7 (q),
11.6 (q); EIMS m/z 382 (M+), 354, 308, 297, 267, 240, 91, 86,
65, 41.
(3S,4S,6S,7S)- a n d (3S,4S,5r ,6S,7R)-4,6-Dia m in o-3,7-
d im eth yl Non a n -5-ol (8a a n d 8b). Following the procedure
used for 6a , compounds 8a and 8b were obtained in quantita-
tive yield and in a 1:1 ratio as a white solid; crude 8 was used
in the subsequent step with no further purification: 1H NMR
(CD3OD, 300 MHz) δ 5.00 (br s, 10H), 3.90 (dd, J ) 1.5 Hz, J
) 8.1 Hz, 1H), 3.80 (dd, J ) 1.8 Hz, J ) 8.7 Hz, 1H), 3.08 (dd,
J ) 3.0 Hz, J ) 8.4 Hz, 1H), 3.00 (dd, J ) 3.6 Hz, J ) 8.1 Hz,
1H), 2.95 (m, 2H), 2.23-1.18 (m, 12H), 1.18-1.08 (m, 24H);
13C NMR (CD3OD, 75 MHz) δ 71.9 (d), 71.3 (d), 58.8 (d), 55.8
(d), 55.5 (d), 39.0 (d), 38.9 (d), 36.2 (d), 35.4 (d), 28.1 (t), 26.1
(t), 23.4 (t), 16.6 (q), 15.7 (q), 15.6 (q), 12.4 (q), 12.0 (q), 11.9
(q), 11.2 (q); ESIMS m/z 203 (M + H+).
(2S,3S,4S)- a n d (2S,3R,4R)-4-Am in o-2-N,N-d ib en zyl-
a m in o-1,5-d ip h en yl P en ta n -3-ol (5a a n d 5b). To a cooled
(-78 °C) solution of 3 (1.14 g, 2.66 mmol) in dry Et2O (30 mL),
under Ar, was added a solution of BnLi in toluene (4.72 mmol).
The reaction mixture was stirred at -78 °C for 1 h, and then
MeOH (20 mL) was added, followed by NaBH4 (0.505 g, 13.30
mmol). The resulting suspension was allowed to warm to room
temperature and stirred for 72 h; then, the reaction was
quenched with water, followed by HCl 10% (pH ≈ 2, clear
solution), and the mixture was left under stirring for 30 min.
After alkalanization with 3 M aqueous NaOH (pH ≈ 9), the
two layers were separated, and the aqueous layer was ex-
tracted three times with EtOAc. The combined organic extracts
were washed with brine, dried (NaSO4), and filtered. Evapora-
tion of the solvents gave a crude product containing 5a and
5b in a 78:22 ratio (1H NMR). Silica gel chromatography (97/3
CHCl3/MeOH) gave 684 mg of 5a and 178 mg of 5b (72%
overall yield), as white solids.
20
(3S,4S,6S,7S)- a n d (3S,4S,5r ,6S,7R)-3,7-Dim eth yl-4,6-d i-
(p-tolu en su lfon yla m in o) Non a n -5-ol (9a a n d 9b). To a
stirred solution of 8 (100 mg, 0.50 mmol) in H2O/THF (1/2 v/v,
1.5 mL) were sequentially added Na2CO3 (300 mg, 2.80 mmol)
and TsCl (220 mg, 1.15 mmol). After 4 h of stirring at room
temperature, the resulting biphasic mixture was diluted with
Et2O and H2O. The layers were separated, and the aqueous
layer was extracted twice with Et2O. The combined organic
extracts were washed twice with H2O, dried (Na2SO4), filtered,
and evaporated under reduced pressure. The crude product
was then purified, and the two isomers were separated by
chromatography on silica gel (4/1 EtOAc/n-hexane), affording
89 mg of 9a and 91 mg of 9b as white solids (70% overall yield).
(2S,3S,4S)-5a : mp ) 53-55 °C; [R]D +22 (c 1.16, CHCl3);
1H NMR (CDCl3, 300 MHz) δ 7.40-7.00 (m, 18H), 6.60-6.55
(m, 2H), 4.05 (d, J ) 12.9 Hz, 2H), 3.84 (dd, J ) 2.3 Hz, J )
8.2 Hz, 1H), 3.45 (d, J ) 12.9 Hz, 2H), 3.25 (dd, J ) 4.7 Hz, J
) 13.9 Hz, 1H), 3.20-3.10 (m, 1H), 2.85-2.80 (m, 1H), 2.75
(dd, J ) 8.1 Hz, J ) 14.0 Hz, 1H), 2.50-2.30 (bs, 3H), 2.15
(dd, J ) 9.7 Hz, J ) 13.7 Hz, 1H), 2.05 (dd, J ) 4.3 Hz, J )
13.7 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 139.9 (s), 139.1 (s),
138.6 (s), 129.3 (d), 129.2 (d), 128.8 (d), 128.6 (d), 128.3 (d),
127.5 (d), 126.4 (d), 126.0 (d), 74.0 (d), 60.0 (d), 54.4 (d), 53.9
(t), 36.6 (t), 32.3 (t); IR νmax (thin layer, NaCl plate) 3597, 3369
cm-1; EIMS m/z 451 (MH+) 359, 330, 300, 240, 120, 91. Anal.
Calcd for C31H34N2O: C, 82.63; H, 7.61; N, 6.22. Found: C,
82.58; H, 7.49; N, 6.35.
20
(3S,4S,6S,7S)-9a : mp ) 57-58 °C; [R]D -43 (c 0.270,
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.78 (d, J ) 8.1 Hz, 2H),
7.76 (d, J ) 8.1 Hz, 2H), 7.32 (d, J ) 7.3 Hz, 2H), 7.29 (d, J )
7.5 Hz, 2H), 5.52 (d, J ) 9.9 Hz, 1H), 5.07 (d, J ) 8.7 Hz, 1H),
3.68 (dd, J ) 1.8 Hz, J ) 4.2 Hz, 1H), 3.27 (m, 1H), 3.18 (m,
1H), 2.40 (s, 3H), 2.38 (s, 3H), 1.60-1.05 (m, 5H), 1.00-0.60
(m, 14H); 13C NMR (CDCl3, 75 MHz) δ 143.6 (s), 143.4 (s), 138.0
20
(2S,3R,4R)-5b: mp ) 218 °C; [R]D -14 (c 0.997, CHCl3);
1H NMR (CDCl3, 300 MHz) δ 7.40-7.22 (m, 18H), 6.95 (m,
2H), 3.96 (dd, J ) 3.7 Hz, J ) 5.6 Hz, 1H), 3.70 (d, J ) 13.8
Hz, 2H), 3.55 (d, J ) 13.8 Hz, 2H), 3.20 (dt, J t )3.4 Hz, J d
)
11.1 Hz, 1H), 3.11-2.92 (m, 3H) 2.39 (dd, J ) 2.8 Hz, J )
13.6 Hz, 1H), 2.30 (bs, 1H), 2.10 (dd, J ) 11.0 Hz, J ) 13.6
Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 141.8 (s), 139.6 (s), 139.0
(s), 129.6 (d), 129.0 (d), 128.2 (d), 126.9 (d), 126.2 (d), 125.7
(d), 74.5 (d), 60.8 (d), 54.5 (t), 54.2 (d), 35.6 (t), 32.7 (t); IR νmax
(31) Analytic and spectroscopic data are in agreement with the
literature: ref 5a.
J . Org. Chem, Vol. 68, No. 4, 2003 1423

Bernardi et al.
(s), 137.9 (s), 129.7 (d), 129.6 (d), 127.2 (d), 69.4 (d), 61.9 (d),
57.2 (d), 38.6 (d), 35.5 (d), 25.2 (t), 25.1 (t), 21.5 (q), 16.2 (q),
15.2 (q), 11.7 (q), 11.1 (q); IR νmax (thin layer, NaCl plate) 3463,
3293, 1331, 1160 cm-1; EIMS m/z 510 (M+), 270, 240, 155, 91;
ESIMS m/z 533 (M + Na+). Anal. Calcd for C25H38N2O5S2: C,
58.79; H, 7.50; N, 5.49. Found: C, 58.88; H, 7.59; N, 5.41.
and HCl 10% (pH ≈ 2). After alkalanization with NaOH 3M
(pH ≈ 9), the product was extracted three times with EtOAc.
The organic extracts were washed with brine, dried (Na2SO4),
and filtered. Evaporation of the solvents gave 200 mg (76%)
of a mixture of four diastereoisomers of 5 as a white solid: 1H
NMR (CDCl3, 300 MHz) δ 7.50-7.05 (m, 20H) 4.10-1.80 (m,
14H); 13C NMR (CDCl3, 75 MHz) δ 142.2 (s), 141.8 (s), 140.2
(s), 139.9 (s), 139.6 (s), 139.2 (s), 138.6 (s), 129.6 (d), 129.3 (d),
129.0 (d), 128.4 (d), 128.3 (d), 128.1 (d), 127.9 (d), 127.1 (d),
126.9 (d), 126.5 (d), 126.3 (d), 126.0 (d), 125.7 (d), 74.5 (d), 74.0
(d), 73.1 (d), 71.6 (d), 61.0 (d), 60.7 (d), 60.5 (d), 60.2 (d), 59.9
(d), 54.4 (t), 54.3 (t), 54.1 (d), 53.7 (t), 53.3 (d), 53.1 (t), 52.3
(d), 42.0 (t), 40.6 (t), 36.1 (t), 35.5 (t), 32.6 (t), 32.2 (t), 31.8 (t),
31.7 (t); EIMS m/z 451 (MH)+, 359, 300, 240, 210, 120, 91.
(2S,4S)-, (2S,3r ,4R)-, a n d (2S,3s,4R)-2,4-N,N-Dia m in o-
1,5-d ip h en yl P en ta n -3-ol (6). Following the procedure used
for 6a , the three diastereoisomers of 631 were obtained in
quantitative yield as a white solid; the crude product was used
in the subsequent step with no further purification: 1H NMR
(CD3OD, 300 MHz) δ 7.40-7.10 (m, 10H), 3.60-3.10 (m, 3H),
3.00-2.60 (m, 4H); 13C NMR (CD3OD, 75 MHz) δ 139.1 (s),
138.9 (s), 138.7 (s), 131.0 (d), 130.8 (d), 130.7 (d), 130.4 (d),
130.2 (d), 130.1 (d), 128.5 (d), 128.4 (d), 128.3 (d), 128.2 (d),
128.1 (d), 128.0 (d), 75.0 (d), 69.8 (d), 68.5 (d), 58.9 (d), 58.3
(d), 57.5 (d), 54.9 (d), 41.1 (t), 40.0 (t), 39.1 (t), 38.9 (t); ESIMS
m/z 271 (M + H+).
20
(3S,4S,5r ,6S,7R)-9b: mp ) 53-54 °C; [R]D -40 (c 0.385,
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.75 (d, J ) 8.1 Hz, 2H),
7.73 (d, J ) 8.1 Hz, 2H), 7.27 (d, J ) 7.8 Hz, 2H), 7.25 (d, J )
7.5 Hz, 2H), 5.55 (d, J ) 9.9 Hz, 1H), 5.07 (d, J ) 8.7 Hz, 1H),
3.58 (t, J ) 4.4 Hz, 1H), 3.27 (quint, J ) 4.2 Hz, 1H), 3.18
(quint, J ) 4.8 Hz, 1H), 2.41 (s, 3H), 2.39 (s, 3H), 1.60-1.50
(m, 1H), 1.38-0.80 (m, 4H), 0.80-0.60 (m, 14H); 13C NMR
(CDCl3, 75 MHz) δ 143.5 (s), 143.4 (s), 138.0 (s), 137.9 (s), 129.6
(d), 127.1 (d), 127.1 (d), 70.7 (d), 59.1 (d), 58.4 (d), 37.5 (d),
34.6 (d), 27.0 (t), 24.2 (t), 21.5 (q), 15.4 (q), 11.8 (q), 11.1 (q);
IR νmax (thin layer, NaCl plate) 3450, 3320, 1333, 1159 cm-1
;
-
EIMS m/z 510 (M+), 270, 240, 91. Anal. Calcd for C25H38
N2O5S2: C, 58.79; H, 7.50; N, 5.49. Found: C, 58.83; H, 7.42;
N, 5.38.
(3S,4S,6S,7S)-3,7-Dim eth yl-4,6-di-(p-tolu en su lfon ylam i-
n o) Non a n -5-on e (10). To a stirred solution of 9a (35 mg,
0.069 mmol) in DMF (2 mL) was added PDC (132 mg, 0.35
mmol). The reaction mixture was left standing at room
temperature for 72 h, with stirring, and then H2O and EtOAc
were added. The layers were separated, and the organic layer
was washed with H2O and brine and then dried (Na2SO4).
After filtration and evaporation of the solvents, the crude
product was purified by preparative TLC (7/3 n-hexane/
EtOAc), affording 21 mg (60%) of compound 10 as a white
(2S,4S)-, (2S,3r ,4R)-, a n d (2S,3s,4R)-1,5-Dip h en yl-2,4-
[d i-(p-tolu en su lfon yla m in o)] P en ta n -3-ol (15a , 15b a n d
15c). Following the procedure used for compounds 9, the three
diastereoisomers of 6 were reacted with TsCl affording, after
separation by preparative TLC (9/1 CHCl3/EtOAc), 15a , 15b,
and 15c as white solids in 60% overall yield and 4:4:1 ratio
(1H NMR of the crude).
20
1
solid: mp ) 164-165 °C; [R]D +126 (c ) 0.980, CHCl3); H
NMR (CDCl3, 300 MHz) δ 7.62 (d, J ) 8.4 Hz, 4H), 7.20 (d, J
) 9.9 Hz, 4H), 5.27 (d, J ) 8.7 Hz, 2H), 3.93 (dd, J ) 2.7 Hz,
J ) 8.7 Hz, 2H), 2.28 (s, 6H), 1.60 (m, 2H), 0.87 (d, J ) 6.9
Hz, 6H), 0.78-0.60 (m, 2H), 0.60 (t, J ) 6.5 Hz, 6H), 0.30-
0.20 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 223.2 (s), 143.7 (s),
129.6 (d), 127.3 (d), 64.2 (d), 37.5 (d), 22.5 (t), 21.5 (d), 16.1
(q), 11.7 (q); IR νmax (thin layer, NaCl plate) 3331, 1716, 1343,
1161 cm-1; ESIMS m/z 531 (M + Na+). Anal. Calcd for
20
(2S,4S)-15a : mp ) 94-96 °C; [R]D -44 (c 0.460, CHCl3);
1H NMR (CDCl3, 300 MHz) δ 7.76 (d, J ) 8.4 Hz, 2H), 7.46 (d,
J ) 8.4 Hz, 2H), 7.31 (br d, J ) 8.4 Hz, 2H), 7.10-6.89 (m,
10H), 6.69 (d, J ) 7.2 Hz, 2H), 5.40 (d, J ) 9.2 Hz, 1H), 5.05
(d, J ) 9.2 Hz, 1H), 3.76 (m, 1H), 3.62 (m, 1H), 3.49 (m, 1H),
2.78 (dd, J ) 13.4 Hz, J ) 9.7 Hz, 1H), 2.60 (dd, J ) 14.2 Hz,
J ) 7.8 Hz, 1H), 2.50-2.44 (m, 2H), 2.43 (s, 3H), 2.39 (s, 3H),
1.80 (br s, 1H); 13C NMR (CDCl3, 75 MHz) δ 143.8 (s), 143.2
(s), 136.8 (s), 136.3 (s), 129.9 (d), 129.6 (d), 129.2 (d), 128.9
(d), 128.6 (d), 128.5 (d), 127.1 (d), 126.9 (d), 126.7 (d), 126.4
(d), 70.0 (d), 58.3 (d), 55.1 (d), 37.0 (t), 36.4 (t), 21.6 (q), 21.5
C
25H36N2O5S2: C, 59.03; H, 7.13; N, 5.51. Found: C, 59.11; H,
7.26; N, 5.39.
(2S,3S,4S)-, (2S,3R,4S)-, (2R,3S,4S)-, a n d (2R,3R,4S)-4-
N,N-Diben zylam in o-1,5-diph en yl-2-n itr o P en tan -3-ol (14).
To a stirred solution of TBAF‚xH2O (730 mg, 2.80 mmol) in
THF (60 mL), cooled to 0 °C, was added 2-phenylnitroethane
(450 mg, 2.98 mmol) in THF (8 mL) and, after 5 min, a solution
of aldehyde 1 (670 mg, 2.09 mmol) in THF (15 mL). After 20
min of stirring at the same temperature, the mixture was
poured onto saturated NaHCO3 and extracted three times with
Et2O. The organic extracts were then washed with brine, dried
(Na2SO4), filtered, and evaporated. Chromatography on silica
gel (95/5 n-hexane/EtOAc) gave 872 mg (87%) of a colorless
oil constituted by the four stereoisomers of 14 in a 4:3:1:1 ratio
(1H NMR analysis of the R-nitro protons): 1H NMR (CDCl3) δ
7.50-6.80 (m, 20H), 5.30-2.40 (m, 12H); 13C NMR (CDCl3, 75
MHz) δ 140.8 (s), 140.1 (s), 139.2 (s), 138.8 (s), 138.6 (s), 135.5
(s), 135.1 (s), 129.3 (d), 129.2 (d), 129.1 (d), 128.9 (d), 128.8
(d), 128.8 (d), 128.6 (d), 128.6 (d), 128.5 (d), 128.4 (d), 128.3
(d), 127.8 (d), 127.5 (d), 127.1 (d), 126.9 (d), 126.7 (d), 126.6
(d), 126.2 (d), 90.9 (d), 90.8 (d), 90.4 (d), 90.2 (d), 73.1 (d), 73.0
(d), 70.8 (d), 61.1 (d), 60.8 (d), 60.2 (d), 59.4 (d), 54.8 (t), 54.5
(t), 53.6 (t), 36.9 (t), 35.7 (t), 32.9 (t), 32.4 (t), 32.0 (t), 31.8 (t),
31.4 (t), 30.8 (t); IR νmax (thin layer, NaCl plate) 3350, 1551,
1372 cm-1; EIMS m/z 481 (MH+), 389, 371, 342, 300, 238, 181,
104, 91.
(q); IR νmax (thin layer, NaCl plate) 3370, 1338, 1158 cm-1
;
ESIMS m/z 601 (M + Na+). Anal. Calcd for C31H34N2O5S2: C,
64.33; H, 5.92; N, 4.84. Found: C, 64.41; H, 5.82; N, 4.95.
1
15b: mp ) 172-174 °C; H NMR (CDCl3, 300 MHz) δ 7.54
(d, J ) 8.4 Hz, 4H), 7.18 (d, J ) 8.2 Hz, 4H), 7.10-7.00 (m,
6H), 6.88 (dd, J ) 7.8 Hz, J ) 1.5 Hz, 4H), 4.80 (d, J ) 8.4 Hz,
2H), 3.80 (m, 2H), 3.70 (m, 1H), 3.23 (br d, J ) 5.1 Hz, 1H),
2.90 (dd, J ) 13.8 Hz, J ) 7.8 Hz, 2H), 2.65 (dd, J ) 13.8 Hz,
J ) 4.5 Hz, 2H), 2.42 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ
140.5 (s), 137.3 (s), 135.9 (s), 129.8 (d), 129.6 (d), 128.7 (d),
127.0 (d), 126.7 (d), 76.5 (d), 56.6 (d), 35.8 (t), 21.6 (q); IR νmax
(thin layer, NaCl plate) 3360, 1340, 1160 cm-1; ESIMS m/z
601 (M + Na+). Anal. Calcd for C31H34N2O5S2: C, 64.33; H,
5.92; N, 4.84. Found: C, 64.29; H, 5.85; N, 4.91.
1
15c: mp ) 137-139 °C; H NMR (CDCl3, 300 MHz) δ 7.65
(d, J ) 8.6 Hz, 4H), 7.25 (d, J ) 8.1 Hz, 4H), 7.19-7.03 (m,
6H), 6.80 (d, J ) 6.8 Hz, 4H), 4.90 (d, J ) 9.6 Hz, 2H), 3.60
(m, 2H), 3.30 (br t, J ) 5.3 Hz, 1H), 2.75 (dd, J ) 13.4 Hz, J
) 7.7 Hz, 2H), 2.43 (s, 6H), 2.43 (dd, J ) 13.4 Hz, J ) 6.0 Hz,
2H); 13C NMR (CDCl3, 75 MHz) δ 143.5 (s), 136.1 (s), 129.4
(d), 128.6 (d), 127.0 (d), 126.6 (d), 70.6 (d), 56.2 (d), 37.3 (t),
21.5 (q); IR νmax (thin layer, NaCl plate) 3375, 1339, 1160 cm-1
;
(2S,3S,4S)-, (2S,3R,4R)-, (2S,3S,4R)-, a n d (2S,3R,4S)-4-
Am in o-2-N,N-diben zylam in o-1,5-diph en yl P en tan -3-ol (5).
To a stirred solution of compound 14 (280 mg, 0.58 mmol) in
MeOH (13 mL), cooled to 0 °C, was added NiCl2‚6H2O (344
mg, 1.45 mmol), followed by NaBH4 (365 mg, 9.61 mmol). The
resulting dark suspension was stirred at the same temperature
for 20 min, and then the reaction was quenched with water
ESIMS m/z 601 (M + Na+). Anal. Calcd for C31H34N2O5S2: C,
64.33; H, 5.92; N, 4.84. Found: C, 64.48; H, 6.03; N, 4.75.
(2S,3S,4S)- an d (2S,3S,4R)-N2,N2-(Diben zyl)-N3-(4-m eth -
oxyph en yl)-4-n itr o-1,5-diph en yl-2,3-pen tan ediam in e (17a
a n d 17b). Sc(OTf)3 (0.074 g, 0.15 mmol) and trimethylsilyl
2-phenylnitronate (0.80 g, 3.64 mmol) were added to a stirred
1424 J . Org. Chem., Vol. 68, No. 4, 2003

Pseudo-C2-symmetric Diamino Alcohols and Triamines
solution of 16 (1.30 g, 3.00 mmol) in dry CH3CN (15 mL) at 0
°C. The resulting mixture was stirred for 2 h at 0 °C; then,
the reaction was quenched with H2O, and the mixture was
extracted three times with CH2Cl2. The combined organic
extracts were dried (MgSO4) and concentrated in vacuo,
affording a yellow solid in quantitative yield, mainly consti-
tuted by the two diastereoisomers 17a and 17b in a 60:40 ratio
(1H NMR), which were used in the subsequent step with no
further purification. An analytical sample for the distereomeric
mixture 17a ,b was obtained in 68% yield by chromatography
NMR (CDCl3, 300 MHz) δ 7.50-7.30 (m, 10H), 6.75 (d, J )
8.7 Hz, 2H), 6.55 (d, J ) 8.7 Hz, 2H), 3.80 (s, 3H), 3.83-3.78
(m, 1H), 3.70-3.60 (m, 1H), 3.40-3.20 (m, 1H), 3.0-2.4 (m,
4H); 13C NMR (CDCl3, 75 MHz) δ 151.5 (s), 142.5 (s), 139.1
(s), 138.9 (s), 129.4 (d), 129.0 (d), 128.5 (d), 128.5 (d), 128.2
(d), 126.3 (d), 115.0 (d), 114.0 (d), 58.7 (d), 55.8 (q), 55.4 (d),
52.4 (d), 42.2 (t), 41.4 (t); ESIMS m/z 398 (M + Na+).
(2S,4R)-N3-(4-Meth oxyp h en yl)-1,5-d ip h en yl-N2,N4-(d i-
p-t olu en su lfon yl)-2,3,4-p en t a n et r ia m in e (19). Following
the procedure used for compounds 9, use of crude (2S,4R)-N3-
(4-methoxyphenyl)-1,5-diphenyl-2,3,4-pentanetriamine as a
starting material afforded compound 19 in 70% yield after
chromatography on silica gel (97/3 CH2Cl2/Et2O) as a white
solid: mp ) 92-94 °C; [R]D20 -66 (c ) 1.048, CHCl3); 1H NMR
(CDCl3, 300 MHz) δ 7.79 (d, J ) 6.0 Hz, 2H), 7.57 (d, J ) 8.4
Hz, 2H), 7.40-6.90 (m, 10H), 6.71 (d, J ) 6.3 Hz, 2H), 6.58 (d,
J ) 9.0 Hz, 2H), 6.50 (d, J ) 6.9 Hz, 2H), 6.10 (d, J ) 8.7 Hz,
2H), 5.95 (d, J ) 10.2 Hz, 1H), 4.95-4.80 (br s, 1H), 4.98-
3.80 (m, 2H), 3.70 (s, 3H), 3.72-3.65 (m, 1H), 3.18 (br s, 1H),
2.67-2.60 (m, 2H), 2.50 (dd, J ) 9.3 Hz, J ) 13.8 Hz, 1H),
2.42 (s, 3H), 2.36 (s, 3H), 2.27 (dd, J ) 13.5 Hz, J ) 5.1 Hz,
1H); 13C NMR (CDCl3, 75 MHz) δ 152.5 (s), 144.1 (s), 142.9
(s), 140.5 (s), 138.1 (s), 136.8 (s), 136.7 (s), 130.1 (d), 129.6 (d),
129.3 (d), 128.7 (d), 128.6 (d), 128.5 (d), 127.3 (d), 126.9 (d),
126.8 (d), 126.2 (d), 115.4 (d), 114.6 (d), 57.3 (d), 55.6 (q), 54.7
(d), 53.7 (d), 40.1 (t), 38.5 (t), 21.6 (q), 21.5 (q); IR νmax (thin
film, NaCl plate) 3352, 3250, 1333, 1158 cm-1; ESIMS m/z 706
(M + Na+). Anal. Calcd for C38H41N3O5S2: C, 66.74; H, 6.04;
N, 6.14. Found: C, 66.69; H, 6.13; N, 6.18.
on silica gel: 1H NMR (C6D6, 400 MHz) δ 7.66-7.12 (m, 20Hmaj
,
20Hmin), 7.02 (d, J ) 8.7 Hz, 2Hmaj, 2Hmin), 6.68 (d, J ) 9.3 Hz,
2Hmin), 6.52 (d, J ) 8.7 Hz, 2Hmaj), 5.7 (m, 1Hmaj, 1Hmin), 4.85
(m, 1Hmin), 4.05 (m, 1Hmaj), 4.00 (d, J ) 10.2 Hz, 2Hmin), 3.85
(d, J ) 10.2 Hz, 2Hmaj), 3.78 (m, 1Hmaj, 1Hmin), 3.66 (s, 3Hmaj),
3.65 (d, J ) 10.2 Hz, 2Hmaj), 3.64 (s, 3Hmin), 3.63 (d, J ) 10.2
Hz, 2Hmin), 3.43 (m, 1Hmaj, 1Hmin), 3.5-2.7 (m, 4Hmaj, 4Hmin);13C
NMR (C6D6, 100 MHz) δ 152.9 (s), 152.6 (s), 141.3 (s), 140.7
(s), 140.5 (s), 140.4 (s), 139.5 (s), 139.2 (s), 136.4 (s), 136.2 (s),
129.3 (d), 129.2 (d), 129.1 (d), 129.0 (d), 128.7 (d), 128.6 (d),
128.5 (d), 127.4 (d), 127.2 (d), 126.9 (d), 126.3 (d), 126.1 (d),
115.4 (d), 115.3 (d), 114.3 (d), 90.3 (d), 90.0 (d), 64.0 (d), 62.1
(d), 60.0 (d), 57.7 (d), 55.3 (q), 55.3 (t), 55.3 (q), 54.4 (t), 37.6-
(t), 33.9 (t), 33.1 (t), 33.0 (t); IR νmax (thin layer, NaCl plate)
3030, 1513, 1246 cm-1; ESIMS m/z 586 (M + H+).
(2S,3R,4S)- a n d (2S,3R,4R)-N2,N2-Diben zyl-N3-(4-m eth -
oxyp h en yl)-1,5-d ip h en yl-2,3,4-p en ta n etr ia m in e (18a a n d
18b). NiCl2‚6H2O (99 mg, 0.42 mmol) and NaBH4 (16 mg, 4.2
mmol) were added to a cooled solution (-20 °C) of the crude
diastereomeric mixture 17a ,b (102 mg, 0.17 mmol) in MeOH
(6 mL). The resulting mixture was left at 0 °C for 30 min with
stirring, and then the reaction was quenched with H2O
followed by HCl 10% (pH ≈ 2). After alkalanization with NaOH
3M (pH ≈ 9), the product was extracted three times with
CHCl3. The organic extracts were washed with brine, dried
(4S,5S)-5-[(1S)-1-N,N-Diben zyla m in o-2-p h en yleth yl]-4-
ben zyl-1-(4-m eth oxyp h en yl)-tetr a h yd r o-2H-im id a zol-2-
on e (20). To a stirred solution of 18a (44 mg, 0.07 mmol) in
CH2Cl2 (3 mL), cooled to 0 °C, was added a 20% solution of
phosgene in toluene (0.055 mL, 0.10 mmol), followed by Et3N
(0.030 mL, 0.21 mmol). The reaction mixture was left standing
at room-temperature overnight, with stirring, and then CH2-
Cl2 was added, followed by H2O and NaOH 6M (1 mL). The
two layers were separated, and the aqueous layer was ex-
tracted twice with CH2Cl2. The combined organic extracts were
dried (MgSO4), filtered, and evaporated. Purification by pre-
parative TLC (light petroleum/EtOAc) afforded 14 mg of 20
as a thick colorless oil: [R]D20 -25 (c ) 0.645, CHCl3); 1H NMR
(CDCl3, 400 MHz) δ 7.40-7.10 (m, 22H), 6.75 (d, J ) 9.0 Hz,
2H), 4.50 (s, 1H), 4.00-3.90 (br d, J ) 6.3 Hz, 1H), 3.80 (s,
3H), 3.80-3.70 (m, 1H), 3.68 (d, J ) 13.8 Hz, 2H), 3.50-3.40
(m, 1H), 3.47 (d, J ) 13.8 Hz, 2H), 2.90-2.60 (m, 4H); 13C NMR
(CDCl3, 100 MHz) δ 158.9 (s), 156.0 (s), 139.9 (s), 139.3 (s),
136.7 (s), 132.6 (s), 129.3 (d), 129.2 (d), 128.9 (d), 128.9 (d),
128.5 (d), 128.3 (d), 127.1 (d), 127.0 (d), 126.3 (d), 123.1 (d),
114.2 (d), 63.4 (d), 62.2 (d), 55.5 (q), 54.9 (t), 54.7 (d), 42.7 (t),
33.4 (t); IR νmax (thin film, NaCl plate) 1706 cm-1; ESIMS m/z
582 (M + H+). The trans configuration was elucidated by NOE
experiments. Saturation of the resonance at 3.9-4.0 ppm (H3)
produced a significant increase in the intensity of the aromatic
proton signal at 7.2 ppm (25%), whereas it was not possible
to detect any positive NOE effect on the H4 signal at 3.80-
3.70 ppm.
1
(Na2SO4), and filtered. H NMR spectra of the crude reaction
mixture showed the presence of two diastereoisomers of 18 in
a 60:40 ratio. Chromatography on deactivated (1% Et3N) silica
gel (9/1 CH2Cl2/EtOAc) afforded the major diastereoisomer 18a
as a yellow brown oil and the minor diastereoisomer 18b as a
pale yellow solid in 66% overall yield.
20
(2S,3R,4S)-18a : [R]D +11 (c ) 1.215, CHCl3); 1H NMR
(C6D6, 400 MHz) δ 7.3-6.9 (m, 20H), 6.79 (d, J ) 8.9 Hz, 2H),
6.44 (d, J ) 8.9 Hz, 2H), 4.42 (bd, J ) 9.0 Hz, 1H), 3.88 (bt, J
) 7.5 Hz, 1H), 3.65 (d, J ) 13.6 Hz, 2H), 3.40 (s, 3H), 3.30
(bd, J ) 13.5 Hz, 3H), 3.05 (dd, J ) 14.1 Hz, J ) 4.5 Hz, 1H),
2.90 (dd, J ) 14.1 Hz, J ) 7.2 Hz, 1H), 2.60 (dd, J ) 13.3 Hz,
J ) 6.6 Hz, 1H), 2.42 (dd, J ) 13.3 Hz, J ) 8.1 Hz, 1H); 13C
NMR (C6D6, 100 MHz) δ 151.8 (s), 143.9 (s), 142.9 (s), 140.2
(s), 139.7 (s), 129.5 (d), 129.4 (d), 128.5 (d), 128.4 (d), 128.3
(d), 127.1 (d), 126.3 (d), 125.7 (d), 115.3 (d), 113.9(d), 58.6 (d),
55.4 (q), 54.7 (t), 52.7 (d), 41.8 (t), 33.6 (t); ESIMS m/z 556 (M
+ H+).
(2S,3R,4R)-18b: mp ) 135-145 °C (EtOH); [R]D20 -13 (c )
1.03, CHCl3); 1H NMR (C6D6, 400 MHz) δ 7.25 (d, J ) 7.5 Hz,
2H), 7.23-6.98 (m, 16H), 6.86 (d, J ) 7.5 Hz, 2H), 6.81 (d, J
) 8.9 Hz, 2H), 5.89 (d, J ) 8.9 Hz, 2H), 3.82 (m, 1H), 3.74 (d,
J ) 14.0 Hz, 2H), 3.55 (d, J ) 14.0 Hz, 2H), 3.40 (s, 3H), 3.35
(m, 1H), 3.26 (m, 1H), 3.11 (d, J ) 10.3 Hz, 1H), 2.96 (dd, J )
14.0 Hz, J ) 6.6 Hz, 1H), 2.73 (dd, J ) 14.0 Hz, J ) 6.4 Hz,
1H), 2.67 (dd, J ) 13.3 Hz, J ) 13.3 Hz, 1H), 1.96 (dd, J )
13.3 Hz, J ) 10.6 Hz, 1H); 13C NMR (C6D6, 100 MHz) δ 152.3
(s), 142.5 (s), 141.5 (s), 140.1 (s), 140.0 (s), 129.5 (d), 129.2 (d),
128.4 (d), 128.4 (d), 128.3 (d), 127.0 (d), 115.2 (d), 114.4 (d),
61.2 (d), 60.5 (d), 55.7 (d), 55.4 (q), 54.7 (t), 40.7 (t), 33.4 (t);
ESIMS m/z 556 (M + H+). Anal. Calcd for C38H41N3O: C, 82.12;
H, 7.44; N, 7.56. Found: C, 82.21; H, 7.38; N, 7.49.
Ack n ow led gm en t. We acknowledge financial sup-
port from the University of Bologna (Funds for Selected
Research Topics, A.A. 1999-2001), the National Project
“Stereoselezione in Sintesi Organica. Metodologie ed
Applicazioni” 2002-2003, and the TRM Project “Design,
Analysis and Computation for Catalytic Organic Reac-
tions” (Contract HPRN-CT-2001-00172). Thanks are due
to Dr. Cristina Femoni (University of Bologna) for
providing the X-ray diffraction structure.
(2S,4R)-N3-(4-Meth oxyp h en yl)-1,5-d ip h en yl-2,3,4-p en -
ta n etr ia m in e. Following the procedure used for 6a , the title
compound was obtained in quantitative yield as a thick yellow
oil and used in the next step with no further purification: 1H
J O026616J
J . Org. Chem, Vol. 68, No. 4, 2003 1425