Stereocontrolled synthesis of hydroxyethylamine isosteres via chiral sulfoxide chemistry

Article abstract of DOI:10.1016/j.tetlet.2004.04.160

A novel synthesis of enantiopure hydroxyethylamine isosteres 1 has been developed. Reaction of lithiated β-sulfinylethylamines 3 with N-Cbz-imines generated in situ from α-amino-sulfones 4 afforded in good to excellent yields and moderate stereocontrol the 2-sulfinyl-1,3-diamines 2. The latter were submitted to the nonoxidative Pummerer reaction (NOPR) in CH₂Cl ₂, that produced the target compounds 1 in very good yields with inversion of configuration. In some cases, the use of acetonitrile as solvent resulted in a double-inversion pathway, leading for example to the oxazolidinone 5. The total synthesis of an epimer of Saquinavir has been achieved by this method.

Full text of DOI:10.1016/j.tetlet.2004.04.160

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5125–5129
Stereocontrolled synthesis of hydroxyethylamine isosteres via
chiral sulfoxide chemistry
Cristina Pesenti, Alberto Arnone, Paolo Arosio, Massimo Frigerio, Stefano V. Meille,
Walter Panzeri, Fiorenza Viani and Matteo Zanda*
CNR––Istituto di Chimica del Riconoscimento Molecolare, sezione ‘A. Quilico’, and Dipartimento di Chimica,
Materiali ed Ingegneria Chimica ‘G. Natta’ del Politecnico di Milano, via Mancinelli 7, I-20131 Milano, Italy
Received 8 March2004; revised 27 April 2004; accepted 28 April 2004
Abstract—A novel synthesis of enantiopure hydroxyethylamine isosteres 1 has been developed. Reaction of lithiated b-sulfinyl-
ethylamines 3 with N-Cbz-imines generated in situ from a-amino-sulfones 4 afforded in good to excellent yields and moderate
stereocontrol the 2-sulfinyl-1,3-diamines 2. The latter were submitted to the nonoxidative Pummerer reaction (NOPR) in CH2Cl2,
that produced the target compounds 1 in very good yields withinversion of configuration. In some cases, the use of acetonitrile as
solvent resulted in a double-inversion pathway, leading for example to the oxazolidinone 5. The total synthesis of an epimer of
Saquinavir has been achieved by this method.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Among the most successful approaches to the develop-
ment of potent enzyme inhibitors, modification of a
peptide backbone through the incorporation of hydr-
oxyethylamine dipeptide isosteres 1 (Scheme 1) has
proven to be extremely valuable.1 As an example, of the
six FDA approved drugs that function as inhibitors for
HIV protease, three (Saquinavir, Nelfinavir and Am-
prenavir) feature a hydroxyethylamine module.2 Many
routes to hydroxyethylamine isosteres 1 have been
described,3 but the syntheses on an industrial scale of
Saquinavir,4 Nelfinavir,5 and Amprenavir6 should be
considered as benchmarks from the point of view of
synthetic efficiency. In this communication we describe a
conceptually new, two-step approach to hydroxy-ethyl-
amine isosteres 1, based on: (1) assembly of the
hydroxyethylamine carbon framework through C–C
bond forming reaction of chiral a-lithium b-sulfinyl-
ethylamines 3 (Scheme 1) with the a-amino sulfones 4,
which are N-Cbz imines precursors; (2) stereoselective
displacement of the sulfinyl by hydroxy group from the
intermediate 2-sulfinyl-1,3-diamines
2 through the
nonoxidative Pummerer reaction (NOPR).7
The enantiomerically pure sulfoxide (R)-3a (Scheme 2)
was prepared by conjugate addition of dibenzylamine to
vinyl p-tolylsulfoxide.8 The Mannich-type reaction of a-
lithium 3a (2 equiv) withthe
a-amino-sulfones 4a–d9
occurred withvery good yields and moderate stereo-
control (Table 1),10 affording the 2-sulfinyl-1,3-diamines
2a–d as the major diastereomers.11 The only exception
was the reaction involving 4e (R ¼ CH2SPh), that took
place withlow yields due to partial degradation of 4e
Scheme 1. Retrosynthetic strategy.
Keywords: Peptidomimetics; Sulfoxides; Mannichreaction.
* Corresponding author. Tel.: +39-0223993084; fax: +39-0223993080;
e-mail: matteo.zanda@polimi.it
Scheme 2. Step 1: the condensation.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.160

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C. Pesenti et al. / Tetrahedron Letters 45 (2004) 5125–5129
Table 1. Step 1: addition of lithiated 3a to 4a–e
Product
R
Diastereom. ratioa
Yield (%)b
2a
2b
2c
2d
2e
Isobutyl
C2H5
C6H5
61:24:7.5:7.5
68.5:24:4.5:3c
48:35:12:5
95
86d
78
95
35
CH2C6H5 55:23:15:7
CH2SPh39.5:26.5:21:13
c
a Determined by HPLC analyses.
b Overall isolated yields.
c Stereochemistry not assigned.
d Determined by 1H NMR analysis of the crude.
Scheme 4. Mechanism of the NOPR in dichloromethane.
under the reaction conditions. The stereochemistries of
2c and of one of the minor diastereomers of 2d were
determined by X-ray diffraction, whereas the other ste-
reochemical assignments were made by chemical corre-
lation and NMR spectroscopy.12
Scheme 3). Surprisingly, in this case we observed the
‘normal’ NOPR outcome, with formation of the hydr-
oxyethylamine isostere 1d (79%), that was formed in
CH2Cl2 as well.
The results above can be interpreted as follows. The
NOPR in dichloromethane follows the conventional
mechanism (Scheme 4). One equivalent of TFAA acyl-
ates the sulfinyl oxygen of 2 providing, in the presence
of TMP, the intermediate cyclic four membered sulfo-
nium salt 7, which is possibly in equilibrium with a
r-sulfurane form.
The second step of our strategy, namely the NOPR, has
been studied in detail on the major diastereomers 2a,c
and 2d (Scheme 3). The expected outcome, namely a
formal SN2-type displacement of the sulfinyl auxiliary by
hydroxy group was observed upon treatment with tri-
fluoroacetic anhydride (TFAA) (8 equiv) and sym-colli-
dine (TMP) (3 equiv) in dry dichloromethane, followed
by moderately basic aqueous work-up (typically
NaHCO3 or K2CO3) and finally by NaBH4 reduction.
This protocol afforded the hydroxyethylamine isosteres
1a,c and 1d in very good yields and total stereocontrol.13
Recombination of 7 via SN2-type attack of the triflu-
oroacetoxy anion to the sulfur-substituted stereogenic
carbon, leads to the b-trifluoroacetoxy sulfenamide 8,
which is hydrolyzed to the alcohol 9 at pH > 7, and
transformed into the final hydroxyethylamine isostere 1
However, the presence of the tertiary dibenzylamine
function brought about a remarkable, and unexpected,
modification of the standard NOPR reactivity, when
acetonitrile was used as solvent.14 In fact, 2c afforded the
cis-oxazolidinone 5 in good yield (Scheme 3) and overall
retention of configuration (demonstrated by X-ray dif-
fraction),12 while 2a gave the 2,3-diaminoalcohol 6 with
inversion of configuration.12 We next investigated the
NOPR of 2d in acetonitrile (reaction not shown in
upon reduction withNaBH . As a proof of this mech-
4
anism, compound 8c could be isolated in 84% yield.
In acetonitrile, a highly polar solvent, formation of az-
iridinium ions 10 (Scheme 5) through nucleophilic at-
tack of the dibenzylamino group on the electrophilic
sulfur-substituted carbon of 7 became competitive.15
The aziridinium ion 10c (R ¼ Ph), formed with inversion
of configuration at carbon, can undergo intramolecular
SN2 ring-opening by action of a Cbz oxygen affording
the N-p-tolylsulfanyl oxazolidin-2-one 11 (it could be
isolated in 43% yield), which is easily transformed into
Scheme 3. The stereodivergent ‘nonoxidative’ Pummerer reaction
(NOPR).
Scheme 5. Mechanism of the NOPR of 2a and 2c in acetonitrile.

C. Pesenti et al. / Tetrahedron Letters 45 (2004) 5125–5129
5127
Scheme 6. Total synthesis of a Saquinavir stereoisomer 19.
the final product 5 upon reducing treatment. A different
reaction pathway was observed for the aziridinium ion
10a (R ¼ i-Bu), that underwent intermolecular attack at
the less hindered position by the trifluoroacetoxy
counter-ion, affording the rearranged product 12.
to use 16, obtained in 12% yield by FC, for the com-
pletion of the synthesis.
Disappointingly, the planned NOPR in CH2Cl2 did not
produce the desired outcome, affording instead complex
mixtures of products.17 However, using acetonitrile as
solvent the reaction occurred in good yields, albeit with
the double-inversion (retention) mechanism, providing
the trans-oxazolidinone 17. Saponification to the b-
amino-alcohol 18 was achieved quantitatively, then
One-pot trifluoroacetate hydrolysis and sulfenamide
reduction afforded the final 2,3-diaminoalcohol 6 in
satisfactory overall yield and total stereocontrol. Ring
openings of aziridinium ions 10a,c to 12 and 11 were
found to be fast-rated processes, and attempts to achieve
intermolecular ring-opening by other amine nucleo-
philes have been hitherto unsuccessful.
coupling with N-(2-quinolyl-carbonyl)-L-asparagine,
according to the conditions described by Hoffmann–La
Roche scientists,18 afforded the epimer 19 of Saquinavir
having opposite configuration at the amine carbon of
the hydroxyethylamine unit.19
Although it is currently not clear why in acetonitrile
three structurally similar substrates 2a,c and 2d react
following three totally different pathways under the
same conditions, it is apparent that the NOPR in ace-
tonitrile is dramatically influenced by the nature of the
R group.16
In conclusion, we have developed a very direct and ste-
reocontrolled approach to hydroxyethylamine dipeptide
isosteres, based on sulfoxide chemistry. The total syn-
thesis of an epimer of Saquinavir has been achieved.
Further synthetic applications of the methodology and
mechanistic studies are in progress.
We next studied the application of this synthetic meth-
odology to the synthesis of a model hydroxyethylamine
target, suchas Saquinavir. The b-decahydroisoquinoline
sulfoxide precursor 15 (Scheme 6) was prepared in good
yields via aza-Michael-reaction of (S)-vinyl-p-tolylsulf-
oxide 13 with the decahydroisoquinoline-3-carboxyl-
amide 14. Condensation of lithiated 15 withthe imine
precursor 4d afforded a mixture of the four possible
diastereomers (32% overall isolated yield, >98% yield of
recovery of unreacted 15) in a 8.0:7.5:3.5:1.0 ratio. The
second most abundant diastereomer 16 was crystallized
and analyzed by X-ray diffraction,12 that allowed us to
assess its absolute stereochemistry. We therefore decided
Acknowledgements
MIUR (Cofin 2002, Project ‘Peptidi Sintetici Bioattivi’),
and CNR are gratefully acknowledged for economic
support.
References and notes
€
1. (a) Olson, G. L.; Bolin, D. R.; Bonner, M. P.; Bos, M.;
Cook, C. M.; Fry, D. C.; Graves, B. J.; Hatada, M.; Hill,

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C. Pesenti et al. / Tetrahedron Letters 45 (2004) 5125–5129
D. E.; Kahn, M.; Madison, V. S.; Rusiecki, V. K.; Sarabu,
THF (20 mL) was added to a solution of LDA (6.6 mmol)
in THF (40 mL) stirred under nitrogen at )75 ꢁC. The
slurry cleared up to a clean solution. Ten minutes later, a
solution of sulfonyl derivative 4 (2.75 mmol) in THF
(20 mL) was added dropwise to the orange solution. The
reaction mixture was left under stirring at the same
temperature for 5 min. The reaction progress was moni-
tored by TLC (n-hexane/ethyl acetate ¼ 7:3). A saturated
NH4Cl solution was added, the organics were extracted
withAcOEt (3 · 30 mL), the combined extracts were dried
over anhydrous sodium sulfate, filtered and the solvent
was evaporated under reduced pressure. The crude was
purified by flash chromatography (FC) affording the
products 2.
R.; Sepinwall, J.; Vincent, G. P.; Voss, M. E. J. Med.
Chem. 1993, 36, 3039–3049; (b) Gante, J. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 1699–1720; (c) Leung, D.;
Abbenante, G.; Fairlie, D. P. J. Med. Chem. 2000, 43,
305–341.
2. Brik, A.; Wong, C.-H. Org. Biomol. Chem. 2003, 1, 5–
14.
3. For some recent examples see: (a) Brewer, M.; Oost, T.;
Sukonpan, C.; Pereckas, M.; Rich, D. H. Org. Lett. 2002,
4, 3469–3472; (b) Tamamura, H.; Koh, Y.; Ueda, S.;
Sasaki, Y.; Yamasaki, T.; Aoki, M.; Maeda, K.; Watai,
Y.; Arikuni, H.; Otaka, A.; Mitsuya, H.; Fujii, N. J. Med.
Chem. 2003, 46, 1764–1768; (c) Datta, A.; Veeresa, G. J.
Org. Chem. 2000, 65, 7609–7611; (d) Kim, B. M.; Bae, S.
J.; So, S. M.; Yoo, H. T.; Chang, S. K.; Lee, J. H.; Kang,
J. S. Org. Lett. 2001, 3, 2349–2351; (e) Rocheblave, L.;
Bihel, F.; De Michelis, C.; Priem, G.; Courcambeck, J.;
Bonnet, B.; Chermann, J.-C.; Kraus, J.-L. J. Med. Chem.
2002, 45, 3321–3324; (f) Edmonds, M. K.; Abell, A. D. J.
Org. Chem. 2001, 66, 3747–3752; (g) Chino, M.; Wakao,
M.; Ellman, J. A. Tetrahedron 2002, 58, 6305–6310; (h)
Ghosh, A. K.; Swanson, L. M.; Liu, C.; Hussain, K. A.;
Cho, H.; Walters, D. E.; Holland, L.; Buthod, J. Bioorg.
Med. Chem. Lett. 2002, 12, 1993–1996; (i) Chen, X.;
Kempf, D. J.; Sham, H. L.; Green, B. E.; Molla, A.;
Korneyeva, M.; Vasavanonda, S.; Wideburg, N. E.;
Saldivar, A.; Marsh, K. C.; McDonald, E.; Norbeck, D.
W. Bioorg. Med. Chem. Lett. 1998, 8, 3531–3536; (j) Abell,
A. D.; Foulds, G. J. J. Chem. Soc., Perkin Trans. 1 1997,
2475–2482; (k) Tamamura, H.; Hori, T.; Otaka, A.; Fujii,
N. J. Chem. Soc., Perkin Trans. 1 2002, 577–580.
11. (a) Pure compounds 2a,c,d were isolated by standard flash
chromatography on silica gel. (b) The following additional
stereochemical assignments have been made based on X-
ray diffraction, NMR studies and chemical correlations: in
the reaction with 4a the major diastereomer is (1S,10R,RS)-
{1-[20-dibenzylamino-10-(toluene-4-sulfinyl)-ethyl]-3-methyl-
butyl}-carbamic acid benzyl ester (2a), whereas the second
(in abundance) diastereomer has (1R,10S,RS)-stereochemis-
try; in the reaction with 4c the major diastereomer is
(1S,2R,RS)-[3-dibenzylamino-1-phenyl-2-(toluene-4-sulfin-
yl)-propyl]-carbamic acid benzyl ester (2c), whereas the
second (in abundance) diastereomer has (1R,2S,RS)-ste-
reochemistry; in the reaction with 4d the major diastereo-
mer is (1S,2R,RS)-[1-benzyl-3-dibenzylamino-2-(toluene-4-
sulfinyl)-propyl]-carbamic acid benzyl ester (2d), whereas
the second (in abundance) diastereomer has (1R,2S,RS)-
stereochemistry.
12. Experimental details of X-ray diffraction and 1H NMR
stereochemical assignments will be published in a full
paper.
€
4. Gohring, W.; Gokhale, S.; Hilpert, H.; Roessler, F.;
Schlageter, M.; Vogt, P. Chimia 1996, 50, 532–537.
5. (a) Ikunaka, M.; Matsumoto, J.; Fujima, Y.; Hirayama,
Y. J. Org. Process Res. Dev. 2002, 6, 49–53; see also: (b)
Kaldor, S. W.; Kalish, V. J.; Davies, J. F., II; Shetty, B.
V.; Fritz, J. E.; Appelt, K.; Burgess, J. A.; Campanale, K.
M.; Chirgadze, N. Y.; Clawson, D. K.; Dressman, B. A.;
Hatch, S. D.; Khalil, D. A.; Kosa, M. B.; Lubbehusen, P.
P.; Muesing, M. A.; Patick, A. K.; Reich, S. H.; Su, K. S.;
Tatlock, J. H. J. Med. Chem. 1997, 40, 3979–3985; (c)
Proctor, L. D.; Warr, A. J. Org. Process Res. Dev. 2002, 6,
884–892.
6. Corey, E. J.; Zhang, F.-Y. Angew. Chem., Int. Ed. 1999,
38, 1931–1934, and references cited therein.
7. (a) Pesenti, C.; Bravo, P.; Corradi, E.; Frigerio, M.;
Meille, S. V.; Panzeri, W.; Viani, F.; Zanda, M. J. Org.
Chem. 2001, 66, 5637–5640, and references cited therein;
13. The stereochemistry of 1c was unambiguously assigned by
X-ray diffraction of a N-Bn oxazolidinone derivative (see
Note 12), whereas the configurations of 1a,d were deter-
mined on the basis of spectroscopic analogies with 1c. (b)
Pummerer reaction. General procedure in CH2Cl2. To a
solution of (RS)-sulfinyl substrate 2 (2.00 mmol) in anhy-
drous CH2Cl2 (70 mL) stirred at 0 ꢁC, neat TMP
(6.0 mmol, 900 lL) and TFAA (10.0 mmol, 1.4 mL) were
added dropwise and temperature was allowed to reachrt.
The reaction progress was monitored by TLC (n-hexane/
ethyl acetate, 7:3) until completion. A 5% aqueous
NaHCO3 solution was then added up to pH 7. The
organics were extracted withAcOEt (3 · 30 mL), dried
over anhydrous sodium sulfate, filtered and evaporated to
dryness. The residue was dissolved in a THF/H2O 4:1
mixture (12 mL) and treated portionwise withsolid
NaBH4. Gas evolution occurred and the reaction mixture
was left under stirring overnight. The reaction progress
was monitored by TLC (n-hexane/ethyl acetate, 7:3) until
completion. A saturated NH4Cl solution was then added,
the resulting mixture was diluted with water and the
organics were extracted withetyhl acetate (3 · 50 mL),
dried over anhydrous sodium sulfate, filtered and the
solvent evaporated at reduced pressure to give a residue,
that was purified by FC.
ꢀ
see also: (b) Garcıa Ruano, J. L.; Alcudia, A.; del Prado,
M.; Barros, D.; Maestro, M. C.; Fernandez, I. J. Org.
ꢀ
Chem. 2000, 65, 2856–2862.
8. (a) Maignan, C.; Guessous, A.; Rouessac, F. Tetrahedron
Lett. 1986, 27, 2603–2606; (b) Hiroi, K.; Suzuki, Y.; Abe,
I.; Hasegawa, Y.; Suzuki, K. Tetrahedron: Asymmetry
1998, 9, 3797–3817.
9. (a) Mecozzi, T.; Petrini, M. J. Org. Chem. 1999, 64, 8970–
8972; see also: (b) Palomo, C.; Oiarbide, M.; Landa, A.;
ꢀ
Gonzalez-Rego, M. C.; Garcıa, J. M.; Gonzalez, A.;
Odriozola, J. M.; Martın-Pastor, M.; Linden, A. J. Am.
ꢀ
ꢀ
ꢀ
14. Acetonitrile has been so far used as the solvent of choice
for the NOPR.
Chem. Soc. 2002, 124, 8637–8643, and references cited
therein.
10. (a) Attempts to improve the stereocontrol by modification
of base, solvent or reaction conditions have been so far
unsuccessful. (b) Condensation reactions. General proce-
dure. A solution of (RS)-b-sulfinyl amine 3a (5.5 mmol) in
15. For some key studies on the application of aziridinium
ions in synthesis see: (a) Chuang, T.-H.; Sharpless, K. B.
Org. Lett. 2000, 2, 3555–3557; (b) Weber, K.; Kuklinski,
S.; Gmeiner, P. Org. Lett. 2000, 2, 647–649; (c) O’Brxien,
P.; Towers, T. D. J. Org. Chem. 2002, 67, 304–307.

C. Pesenti et al. / Tetrahedron Letters 45 (2004) 5125–5129
5129
16. The influence of stereochemistry on the NOPR of
substrates 2 is currently under investigation.
17. The main side-process, according to H NMR analysis of
the mixtures, was the cleavage of the N-tert-butyl group
on the decahydroisoquinoline-3-carboxylamide residue.
18. Hohler, M.; Vogt, P. U.S. Patent 5 536 816, 1996.
19. Indeed, 1H NMR analysis showed that 19 is a dia-
stereomer of Saquinavir, according to the spectra
accurately described in: Gilbert, J. C.; Redshaw, S.;
Simmonite, H. S.; Thomas, W. A.; Whitcombe, I.
W. A. J. Chem. Soc., Perkin Trans. 2 1993, 475–
479.
1