Stereoselective reduction of N-phthaloyl α-amino ketones: An expeditious synthesis of statine

Article abstract of DOI:10.1016/S0957-4166(99)00524-8

A highly diastereoselective synthesis of a protected statine derivative via syn-selective LiAlH(OBu-t)₃ reduction of a leucine derived N-phthaloyl α-amino ketone is described. (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00524-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4633–4637
Stereoselective reduction of N-phthaloyl α-amino ketones:
an expeditious synthesis of statine
Saumitra Sengupta ∗ and Debarati Sen Sarma
Department of Chemistry, Jadavpur University, Calcutta 700 032, India
Received 16 November 1999; accepted 17 November 1999
Abstract
A highly diastereoselective synthesis of a protected statine derivative via syn-selective LiAlH(OBu-t)3 reduction
of a leucine derived N-phthaloyl α-amino ketone is described. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Statine [(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, 1] is the key pharmacophore present in
the naturally occurring renin inhibitor pepstatin.1 Due to its unusual structure and associated biological
importance, especially in the development of the dipeptide isostere theory for inhibition of aspartyl
proteases,1a considerable effort has been directed toward its stereoselective synthesis.2 Since statine
acts as a transition-state mimic of peptide hydrolysis (hydroxyethylene dipeptide isostere), its biological
activities are strongly dependent on the relative (syn) and absolute (3S,4S) configurations of its chiral
centers. Hence, the key challenge in statine synthesis is to establish its syn-aminoalcohol disposition.
Until now, this has been mostly attempted via diastereoselective addition reactions of acetate enolates
to NH-monoprotected leucinal derivatives. These approaches, however, suffer from modest levels of
syn-selectivity and the operational problems that are usually associated with the use of chemically
sensitive and racemization-prone NH-monoprotected α-amino aldehydes. In 1989, Reetz et. al., while
investigating the non-chelation controlled reductions of N,N-Bn2 α-amino ketones, described a com-
plementary strategy in which the syn-aminoalcohol disposition of statine was established in 88% de
via a highly syn-selective borohydride reduction of a leucine derived N,N-Bn2 γ-amino-β-keto ester.3
Similar syn-selective reduction (93% de) of a leucine derived NH-trityl γ-amino-β-keto ester has also
been reported by Hoffman and Tao in their recent statine synthesis.4 This amino ketone reduction strategy
is undoubtedly more attractive than addition reactions to α-amino aldehydes since it provides high levels
∗
Corresponding author. Fax: 91-33-4734266.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00524-8
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of the desired syn-selectivity and at the same time, avoids handling of sensitive educts like the α-amino
aldehydes. The strategy, however, requires special and bulky N-protecting groups like the N,N-Bn2 or
NH-trityl to be present on the α-amino ketone in order to achieve the high levels of syn-selectivity in the
reduction step. It may be noted that borohydride or K-selectride reductions of α-amino ketones having
other common N-protecting groups such as t-Boc, Cbz or Fmoc usually lead to anti-diastereoselectivity.3b
Hence, if applied to statine synthesis, they would lead to the wrong diastereomer (3R,4S) and would
require subsequent inversion of the C-3 stereochemistry.
We have recently reported that N-phthaloyl α-amino ketones, having a conventional N-protecting
group, can be reduced with LiAlH(OBu-t)3 via the Felkin-mode with high syn-selectivity (≥90% des) and
have applied this protocol towards stereoselective syntheses of syn-α-amino epoxides and syn-3-amino-
1,2-diols.5,6As a further application of this protocol, we now present here an expeditious synthesis of
statine via a highly diastereoselective syn-reduction of a leucine derived N-phthaloyl α-amino ketone.
2. Results and discussion
Scheme 1. (i) SOCl2, benzene, reflux; (ii) PhCH2ZnBr, 10% PdCl2(PPh3)2, THF, rt; (iii) LiAlH(OBu-t)3 (2 equiv.), THF, −20°C;
(iv) Ac2O, Et3N, cat. DMAP, CH2Cl2, rt; (v) cat. RuCl3, NaIO4, CH3CN–CCl4–H2O, rt; (vi) CH2N2, ether, 0°C
N-Phthaloyl (NPht) L-leucine 2 was first converted to its acid chloride 3 (SOCl2, benzene, reflux)
7
and the latter coupled with PhCH2ZnBr in the presence of 10% Pd(PPh3)2Cl2 (THF, rt) to give the α-
amino benzyl ketone 4 in 72% yield over two steps (Scheme 1). In earlier studies,6 we have observed
that LiAlH(OBu-t)3 reductions of N-phthaloyl γ-amino β-keto esters lead to complex product mixtures,
perhaps due to the presence of dense functionalities in the latter. Hence, in the present approach, we
decided to use the less functionalized benzyl ketone 4 as a latent γ-amino-β-keto ester. LiAlH(OBu-t)3
reduction of 4 proceeded smoothly in THF at −20°C to give the syn-aminoalcohol 5, virtually as a single
diastereomer (90% de by 1H NMR), in 70% yield. The highest levels of des were obtained only at −20°C;
reductions carried out at 0°C gave, at best, an 85:15 ratio of the syn:anti aminoalcohols. LiAlH(OBu-t)3,
a bulky and chemoselective reducing agent,8 was found to be absolutely essential for this reduction.
NaBH4 or NaB(CN)H3, on the other hand, not only gave lower diastereoselectivities (ca. 40% des) but

S. Sengupta, D. Sen Sarma / Tetrahedron: Asymmetry 10 (1999) 4633–4637
4635
also poor chemical yields due to extensive hydride attacks on the phthaloyl moiety of 4. Moreover, it
was found that two equivalents of LiAlH(OBu-t)3 were necessary for complete reduction of 4. The syn-
1
stereochemistry in 5 was clearly evident from the H NMR spectra, especially after conversion to the
acetate 6 (60%), which showed a relatively large coupling constant between its aminoalcohol protons
H-2 and H-3 (J2,3=7.6 Hz). The synthesis was completed by Sharpless oxidation (cat. RuCl3, NaIO4,
CH3CN–CCl4–H2O)9 of the phenyl ring in 6 to the carboxylic acid and subsequent esterification with
diazomethane to give the protected statine ester 7 in 45% overall yield from 6. The syn-stereochemistry
1
in 7 was again evident from its H NMR spectrum which showed a large J-value for the H-3 and H-4
protons (J3,4=6.8 Hz).
In summary, a facile synthesis of a protected statine ester based on a highly diastereoselective syn-
reduction of NPht leucinyl benzyl ketone with LiAlH(OBu-t)3 has been achieved. Also noteworthy is the
use of a Pd-catalyzed α-amino acylation reaction of an organozinc reagent for the preparation of the key
α-amino benzyl ketone under mild conditions.
3. Experimental
All melting points are uncorrected. IR spectra were taken on a Perkin Elmer R-297 spectrometer. 1H
and 13C NMR spectra were recorded in CDCl3 (TMS as internal standard) on Bruker DPX-200 (200
MHz) and DPX-300 (300 MHz) instruments and reported in ppm scale. Optical rotations were measured
in CHCl3 at 25°C on a JASCO DIP-360 digital polarimeter. Column chromatography was performed on
silica gel (60–120). Pet. ether refers to the fraction boiling at 60–80°C.
3.1. (S)-5-Methyl-1-phenyl-3-phthalimidohexan-2-one 4
A solution of N-Pht L-leucine (2) (0.26 g, 1.0 mmol) and SOCl2 (0.35 g, 3.0 mmol) in benzene (10
ml) was heated under reflux for 3 h. The solution was then evaporated under reduced pressure to afford
the acid chloride 3 which was used as such in the subsequent reaction.
Zinc dust (0.13 g, 2.0 mmol), 1,2-dibromoethane (0.03 g, 0.01 ml, 0.2 mmol) in THF (3 ml) was heated
gently until ebullition of solvent was observed. The suspension was stirred for a few minutes at rt and
heated again. The process was repeated three times. It was then cooled to 0°C and benzyl bromide (0.34
g, 0.23 ml, 2.0 mmol) in THF (2 ml) was added dropwise over 15 min. It was then stirred at rt for 1 h
after which the acid chloride 3 and PdCl2(PPh3)2 (0.07 g, 0.1 mmol) were added in quick succession.
After stirring overnight at rt, the reaction mixture was diluted with water (10 ml), extracted with ether
(3×10 ml), dried and evaporated under reduced pressure. The crude product was then purified by silica-
25
gel chromatography (5% EtOAc in pet. ether) to give 4 as an oil (0.23 g, 72%); [α]D −3.5 (c 1.5,
1
CHCl3); IR (neat): 1700–1740 (br), 1770, 2860, 2950 cm−1; H NMR (CDCl3, 200 MHz): δ 0.88 (d,
3H, J=6 Hz), 0.91 (d, 3H, J=6 Hz), 1.42–1.47 (m, 1H), 1.84–1.99 (m, 1H), 2.19–2.34 (m, 1H), 3.75 (s,
2H), 4.87 (dd, 1H, J=4.3, 11.4 Hz), 7.07–7.12 (m, 2H), 7.18–7.26 (m, 3H), 7.69–7.74 (m, 2H), 7.80–7.86
(m, 2H). Found: C, 75.06; H, 6.25; N, 4.20; C21H21NO3 requires C, 75.22; H, 6.26 and N, 4.17%.
3.2. (2S,3S)-2-Acetoxy-5-methyl-1-phenyl-3-phthalimidohexane 6
LiAlH(OBu-t)3 (1.53 g, 6.0 mmol) was added to a solution of 4 (1.0 g, 3.0 mmol) in THF (15 ml)
at −20°C. After 30 min, the reaction mixture was diluted with water (10 ml) and extracted with ether
(3×10 ml). The organic layer was dried, evaporated under reduced pressure and the residue purified by

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S. Sengupta, D. Sen Sarma / Tetrahedron: Asymmetry 10 (1999) 4633–4637
silica-gel chromatography (10% EtOAc in pet. ether) to give 5 (0.70 g, 70%); mp 95–96°C (EtOAc–pet.
ether). To a solution of 5 (0.67 g, 2.0 mmol) in CH2Cl2 (10 ml) was added acetic anhydride (0.4 g, 4.0
mmol), Et3N (0.24, 2.4 mmol) and DMAP (0.002 g) and the mixture was stirred at rt for 12 h. It was then
washed with water, dried and evaporated under reduced pressure. The residue was purified by silica-gel
25
chromatography (7–8% EtOAc in pet. ether) to give 6 (0.45 g, 60%); mp 84–85°C; [α]D –5.1 (c 1,
1
CHCl3); IR (CHCl3): 1700–1740 (br), 1765, 2950 cm−1; H NMR (CDCl3, 300 MHz): δ 0.86 (d, 3H,
J=5.8 Hz), 0.90 (d, 3H, J=6 Hz), 1.35–1.44 (m, 2H), 1.73 (s, 3H), 2.40–2.48 (m, 1H), 2.76 (dd, 1H, J=9.4,
14.1 Hz), 3.10 (dd, 1H, J=3.6, 14.1 Hz), 4.46 (ddd, 1H, J=3.8, 7.6, 11.7 Hz), 5.62 (ddd, 1H, J=3.6, 7.6,
9.4 Hz), 7.17–7.29 (m, 5H), 7.70–7.72 (m, 2H), 7.81–7.84 (m, 2H). Found: C, 72.65; H, 6.70; N, 3.71;
C23H25NO4 requires C, 72.82; H, 6.59 and N, 3.69%.
3.3. (3S,4S)-Methyl (3-acetoxy-6-methyl-4-phthalimido)heptanoate 7
To a biphasic mixture of 6 (0.38 g, 1.0 mmol) in CH3CN (4 ml), CCl4 (4 ml) and H2O (8 ml) was added
NaIO4 (3.85 g, 18.0 mmol) and RuCl3·H2O (0.004 g, 0.022 mmol) and the mixture stirred vigorously
at rt for 48 h. It was then filtered, CH2Cl2 (15 ml) added to the filtrate and the organic layer separated.
The aqueous layer was extracted with CH2Cl2 (2×10 ml) and the combined organic layer dried and
concentrated under reduced pressure to a volume of 5 ml. It was then added dropwise to a freshly
prepared solution of CH2N2 [prepared from nitrosomethyl urea (0.41 g, 4.0 mmol) and KOH (0.5 g)]
in ether (10 ml) at 0°C. After reaching rt, the solution was washed with satd. NaHCO3 soln., dried and
evaporated under reduced pressure. The residue was purified by silica-gel chromatography (15% EtOAc
25
in pet. ether) to give 7 as an oil (0.16 g, 45%); [α]D −4.2 (c 0.09, CHCl3); IR (neat): 1700–1740
(br), 1770, 2950 cm−1; 1H NMR (CDCl3, 300 MHz): δ 0.88 (d, 3H, J=5.8 Hz), 0.90 (d, 3H, J=5.8 Hz),
1.33–1.47 (m, 2H), 1.93 (s, 3H), 2.35–2.42 (m, 1H), 2.59 (dd, 1H, J=8.0, 15.8 Hz), 2.75 (dd, 1H, J=4.4,
15.8 Hz), 3.69 (s, 3H), 4.52 (ddd, 1H, J=4.1, 6.8, 11.5 Hz), 5.70 (ddd, 1H, J=4.4, 6.8, 8.0 Hz), 7.71–7.75
(m, 2H), 7.81–7.85 (m, 2H); 13C NMR (CDCl3, 75 MHz): δ 20.7, 21.1, 23.3, 25.0, 36.4, 36.9, 51.9, 52.3,
70.5, 123.3, 131.5, 134.0, 168.4, 170.0, 170.1. Found: C, 63.30; H, 6.12; N, 3.90; C19H23NO6 requires
C, 63.15; H, 6.37 and N, 3.87%.
Acknowledgements
Financial support from DST (SP/S1/G-14/97) and UGC (a senior research fellowship to DSS) is
gratefully acknowledged.
References
1. (a) Dutta, A. S. Small Peptides: Chemistry, Biology and Clinical Studies; Elsevier: Amsterdam, 1993; p. 416; (b) Rich, D.
H. J. Med. Chem. 1985, 28, 264; (c) Umezawa, U.; Aoyagi, T.; Morishima, H.; Matsuzaki, M.; Hamada, H.; Takeuchi, T. J.
Antibiot. 1970, 23, 259.
2. For reviews, see: (a) Castejon, P.; Moyano, A.; Pericas, M. A.; Riera, A. Tetrahedron 1996, 52, 7063; (b) Williams, R. M.
In Biologically Active Peptides: Design, Synthesis and Utilization; Williams, W. V.; Weiner, D. B., Eds.; Technomic Pub.:
Lancaster, 1993; Vol. 1, Chapter 8; (c) Wuts, P. G. M.; Putt, S. R. Synthesis 1989, 951; for some recent syntheses, see: (d)
Aoyagi, Y.; Williams, R. M. Tetrahedron 1998, 54, 10419; (e) Veeresa, G.; Datta, A. Tetrahedron Lett. 1997, 38, 5223; (f)
Ma, D.; Ma, J.; Ding, W.; Dai, L. Tetrahedron: Asymmetry 1996, 7, 2365; (g) Nebois, P.; Greene, A. G. J. Org. Chem. 1996,
52, 5210.

S. Sengupta, D. Sen Sarma / Tetrahedron: Asymmetry 10 (1999) 4633–4637
4637
3. (a) Reetz, M. T.; Drewes, M. W.; Matthews, B. R.; Lennick, K. J. Chem. Soc., Chem. Commun. 1989, 1474; (b) Hoffman, R.
V.; Tao, J.-H. J. Org. Chem. 1997, 62, 2292; for reviews on diastereoselective reactions of N,N-Bn2 α-amino aldehydes and
ketones, see: (c) Reetz, M. T. Chem. Rev. 1999, 99, 1121; (d) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531.
4. Hoffman, R. V.; Tao, J.-H. J. Org. Chem. 1998, 63, 3979.
5. Sengupta, S.; Sen Sarma, D.; Das, D. Tetrahedron: Asymmetry 1999, 10, 1653.
6. Sen Sarma, D. Ph.D. Thesis, Jadavpur University.
7. (a) Jackson, R. F. W.; Wishart, N.; Wood, A.; James, K.; Wythes, M. J. J. Org. Chem. 1992, 57, 3397; (b) Sakurai, M.; Hata,
T.; Yabe, Y. Tetrahedron Lett. 1993, 34, 5939; (c) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T. Tetrahedron
Lett. 1998, 39, 3189.
8. Málek, J. Org. React. 1985, 34, 1.
9. Shiori, T.; Matsuura, F.; Hamada, Y. Pure Appl. Chem. 1994, 66, 2151.