Synthesis of the tripeptide domain of sanglifehrins using asymmetric phase-transfer catalysis

Article abstract of DOI:10.1021/jo3027214

The tripeptide (S)-valinyl-(S)-m-hydroxyphenylalanyl-(3S)-piperazate common to immunosuppressant sanglifehrins was synthesized from the constituent amino acid residues in nine steps and 42% overall yield. A key construction was the installation of (S) absolute configuration in m-hydroxyphenylalanine using asymmetric phase-transfer catalysis in the presence of N-(1-naphthyl) cinchonidinium bromide. Cbz-protected (S)-valine was first coupled to the amino group of (S)-m-triisopropylsilyloxyphenylalanine tert-butyl ester, and the resulting dipeptide after ester cleavage was linked to (3S)-methyl piperazate.

Full text of DOI:10.1021/jo3027214

Note
pubs.acs.org/joc
Synthesis of the Tripeptide Domain of Sanglifehrins Using
Asymmetric Phase-Transfer Catalysis
James D. White* and Khomson Suttisintong
Department of Chemistry, Oregon State University, Corvallis, Oregon 97331, United States
S
* Supporting Information
ABSTRACT: The tripeptide (S)-valinyl-(S)-m-hydroxyphe-
nylalanyl-(3S)-piperazate common to immunosuppressant
sanglifehrins was synthesized from the constituent amino
acid residues in nine steps and 42% overall yield. A key
construction was the installation of (S) absolute configuration
in m-hydroxyphenylalanine using asymmetric phase-transfer
catalysis in the presence of N-(1-naphthyl)cinchonidinium
bromide. Cbz-protected (S)-valine was first coupled to the amino group of (S)-m-triisopropylsilyloxyphenylalanine tert-butyl
ester, and the resulting dipeptide after ester cleavage was linked to (3S)-methyl piperazate.
Our initial blueprint for assembling the C1−N12 tripeptide
anglifehrins (e.g., 1 and 2, Figure 1) comprise a family of
Smacrolides produced by Streptomyces sp. A92-308110 with of the sanglifehrins envisioned coupling of a hydroxyl-protected
notewothy immunosuppressive activity.1,2 This property is
version of m-hydroxyphenylalanine (5) with a Boc-protected
valine and subsequent linkage of the resultant dipeptide 4 with
an ester of piperazic acid. Construction of a (S)-m-
hydroxyphenylalanine residue in enantioenriched form was a
primary goal of this plan, and for this operation we chose the
catalytic asymmetric phase-transfer methodology developed by
O’Donnell.9 The key step in this method is alkylation of the
enolate of a N-dibenzylideneglycine ester with a benzylic halide
in the presence of a Cinchona alkaloid derivative.
displayed in the case of 1 by inhibition of mitogen-induced B-
cell proliferation without influencing T-cell receptor-mediated
cytokine production.3 The immunosuppressive activity of
sanglifehrins was assessed in two-way mixed lymphocyte
reaction experiments which found that sanglifehrins A (1)
and B (2) possessed IC50 values of 170 and 120 nM,
respectively. Both compounds showed affinity for cyclophylin
A at a level 20-fold higher than cyclosporine A.1
The starting point for this approach was m-hydroxybenzal-
dehyde (6), which was converted to its triisopropylsilyl (TIPS)
ether 7 before reduction to primary alcohol 8 (Scheme 2). The
derived benzylic iodide 9 was then used to alkylate imino ester
10 in the presence of N-(1-naphthyl)cinchonidinium bromide
11.10 This carefully optimized reaction was carried out in a
mixed solvent system consisting of toluene and dichloro-
methane11 at −10 °C and afforded (S)-imino ester 12 in good
yield.12 A projection depicting attack by 9 at the less sterically
hindered si face of the (Z)-enolate of 10 in the presence of 11 is
shown in Figure 2. Enantiomers of racemic 12 could not be
separated by chiral high-performance liquid chromatography
and therefore it was not possible to determine the enantiomeric
excess of 12 directly. However, selective removal of the silyl
ether from 12 gave phenol derivative 13 which was amenable to
measurement of its enantiomeric excess by chiral HPLC. The
measured value of 88% ee for 13 is likely to be a low estimate
since partial racemization is believed to have occurred during
cleavage of the TIPS ether from 12 with TBAF.
The chemical structures including absolute configuration of
sanglifehrins were determined by NMR techniques in
combination with X-ray crystallographic analysis of the complex
formed by 1 with cyclophilin A.4 These studies revealed that
sanglifehrins are characterized structurally by two principal
domains, a [5.5]-spirolactam portion and a 22-membered
macrolide, connected by a nine-carbon chain. Spanning C13−
C23 of the macrolide of each sanglifehrin is a tripeptide
segment 3 (R1 = H) containing linked (S)-valine, (S)-m-
hydroxyphenylalanine and (3S)-piperazic acid residues. The
impressive biological properties of sanglifehrins have invited
synthetic interest from many sources with the result that total
syntheses of sanglifehrin A have been completed by Nicolaou5
and by Paquette.6 Contributions to this effort have also been
made by the Novartis group7 and others.8 Our initial focus on
the synthesis of sanglifehrins was directed at the C1−N12
tripeptide segment 3 within the macrolide portion, and our
strategy (Scheme 1) envisioned an approach via dipeptide 4
anchored at the central amino acid m-hydroxyphenylalanine
(5). Elaboration outward from amine and carboxylic acid
termini of core unit 5 would add sequentially valine and
piperazic acid residues. We now report a route to the
sanglifehrin tripeptide in which a catalytic phase transfer
reaction provides the key to installing asymmetry in the central
m-hydroxyphenylalanine residue.
Continuation from 12 toward 3 required selective hydrolysis
of the imine, a transformation achieved in good yield with
aqueous acetic acid in THF (Scheme 3). The resulting amino
Received: December 15, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo3027214 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Figure 1. Structures of sanglifehrins A and B.
ester 14 was coupled to N-Boc (S)-valine (15) in the presence
of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and
1-hydroxybenzotriazole (HOBt) to produce a high yield of
dipeptide 16 as the sole detectable stereoisomer by 13C NMR
after chromatography. We had expected that selective cleavage
of the tert-butyl ester from 16 could be accomplished following
a protocol reported by Yadav,13 but exposure of 16 to the
published conditions using iodine in acetonitrile with a trace of
water gave no indication that carboxylic acid 17 was formed.
Not surprisingly, more vigorous conditions resulted in removal
of both Boc protection and the tert-butyl ester from 16, a
consequence that rendered access to tripeptide 3 via controlled
coupling with valine and piperazic acid moieties untenable.
A solution to the deprotection problem with 16 was sought
by linking 14 with N-carbobenzyloxy-(S)-valine (18). This
reaction, carried out with N,N,N′,N′-tetramethyl-O-7-azabenzo-
triazol-1-yluronium hexafluorophosphate (HATU) and Hunig’s
base in DMF, furnished dipeptide 19 as a single stereoisomer
after chromatographic purification according to 13C NMR. The
tert-butyl ester of 19 was cleaved with complete chemo-
selectivity using thioanisole and trifluoroacetic acid,14 affording
carboxylic acid 20 ready for coupling with a (3S)-piperazic acid
residue.
Scheme 1. Sequence Strategy for Assembly of Sanglifehrin
Tripeptide 3 from m-Hydroxyphenylalanine (5)
Scheme 2. Asymmetric Phase-Transfer Synthesis of m-
Hydroxyphenylalanine Derivative 13
Hale and co-workers have devised a synthesis of (3R)-
piperazic acid using (4R)-benzyloxazolidin-2-one15 as a chiral
adjuvant to generate absolute configuration; our route to the
(3S) piperazate enantiomer was patterned after Hale’s but in
the opposite enantiomeric series (Scheme 4). Thus, (4S)-
benzyloxazolidin-2-one was acylated with 5-bromopentanoyl
chloride, prepared from δ-valerolactone,16 to yield acyloxazo-
lidinone 21. This compound underwent stereoselective
addition to the re face of its (Z)-lithium enolate by di-tert-
butyl azodicarboxylate to produce piperazate derivative 22 as a
9:1 mixture of diastereomers as determined by 13C NMR
spectroscopy. After chromatographic purification, 22 was
hydrolyzed with aqueous lithium hydroxide to remove the
chiral auxiliary and obtain carboxylic acid 23. The acid was
converted to methyl ester 24 with trimethylsilyldiazomethane
in MeOH, and subsequent cleavage of the pair of Boc
protecting groups with TFA furnished (3S)-methyl piperazate
(25) as its trifluoroacetate salt. The latter was identical
spectroscopically with the same substance prepared by Hale.15
Condensation of dipeptide 20 selectively at N(1) of methyl
piperazate 25 using HATU as coupling agent17 gave 26 as a
single diastereomer after chromatographic purification accord-
ing to 13C NMR; final hydrogenolysis of the Cbz-protected
tripeptide then yielded amino ester 27 (Scheme 5).
Figure 2. Stereoview of the attack trajectory by iodide 9 on the ion
pair formed between the (Z)-enolate of imino ester 10 and catalyst 11.
In summary, tripeptide 27 representing C1−N12 of the
macrocyclic domain of the sanglifehrins was synthesized in nine
B
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The Journal of Organic Chemistry
Note
Scheme 3. Synthesis of Boc-Protected Dipeptide 16 and Cbz-Protected Dipeptide 20
Scheme 4. Synthesis of (3S)-Methyl Piperazate (25)
silica plates with fluorescent indicator (254 nm) and visualized with a
UV lamp or phosphomolybdic acid. All commercially available
reagents were purchased and used as received unless stated otherwise.
Melting points were measured on a capillary melting point apparatus.
Optical rotations were measured with a polarimeter at ambient
temperature using a 1 mL capacity cell with 1 dm path length. Infrared
(IR) spectra were recorded using a thin film supported on KBr disks or
Scheme 5. Synthesis of Sanglifehrin Tripeptide 27
1
dispersed in a KBr pellet. H and 13C NMR spectra were recorded in
Fourier transform mode at the field strength specified on a 300, 400,
or 700 MHz spectrometer. Spectra were obtained on CDCl3 solutions
in 5 mm diameter tubes; chemical shifts in ppm (parts per million) are
quoted relative to the residual signals of chloroform (δH 7.26 ppm, or
δC 77.0 ppm). Multiplicities in the 1H NMR spectra are described as:
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =
broad; coupling constants (J) are reported in hertz. Low (MS) and
high (HRMS) resolution mass spectra were measured using a
quadrupole analyzer and are reported with ion mass/charge (m/z)
ratios as values in atomic mass units. High performance liquid
chromatography (HPLC) was carried out using a Daicel Chiralcel OD
column with 9:1 hexane/2-propanol as eluting solvent at a flow rate of
1 mL/min.
3-(Triisopropylsilyloxy)benzaldehyde (7). To a solution of 3-
hydroxybenzaldehyde (6) (1.12 g, 9.89 mmol) and imidazole (2.02 g,
29.66 mmol) in DMF (33 mL) at −50 °C was added dropwise
TIPSOTf (4.54 g, 14.83 mmol). The stirred mixture was allowed to
warm to room temperature, and after 10 h, it was partitioned between
EtOAc (60 mL) and water (24 mL). The aqueous layer was extracted
with a mixture of EtOAc and hexanes (1:1, 3 × 48 mL), and the
combined extract was washed with brine, dried over anhydrous
Na2SO4, and concentrated under vacuum. The residue was purified by
flash chromatography (10% Et2O in hexanes) to give 7 (3.05 g, 99%)
as a colorless oil: IR (neat) 2945, 2889, 2868, 2723, 1705, 1598, 1583,
steps from m-hydroxybenzaldehyde (6) in an overall yield of
42%. This tripeptide stands ready for connection at its N12
terminus to a carboxylic acid housing C13−C19 of the
sanglifehrin macrolactone, while the carboxylate at C1 will
provide the locus for eventual macrolactonization and
completion of this substructure of the sanglifehrins.
EXPERIMENTAL SECTION
■
General Techniques. All reactions requiring anhydrous conditions
were conducted in flame-dried glass apparatus under an atmosphere of
argon. THF, Et2O, CH2Cl2, DMF, benzene, and acetonitrile were
dried by passage through an activated alumina column under argon.
DMSO was distilled from CaH2 at 15 mmHg and stored over activated
4 Å molecular sieves. Anhydrous MeOH was freshly distilled from
CaH2. Preparative chromatographic separations were performed on
silica gel (35−75 μm); reactions were followed by TLC analysis using
C
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Note
1483, 1446, 1387, 1279, 1167, 1146, 1073, 1003, 968, 920, 882, 829,
789, 733, 683, 644 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm) 1.13
(d, J = 7.2 Hz, 18H), 1.34−1.27 (m, 3H), 7.17 (d, J = 8.0 Hz, 1H),
7.39−7.42 (m, 2H), 7.46−7.48 (d, J = 7.6 Hz, 1H), 9.97 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 12.6, 17.9, 119.6, 123.2, 126.3,
130.0, 138.0, 156.8, 192.0.
quenched with water (0.50 mL), and the aqueous phase was extracted
with Et2O (3 × 0.50 mL). The combined extract was dried over
anhydrous MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash chromatography (10% to 30%
EtOAc in hexanes) gave 13 (34.2 mg, 95%) as a colorless oil: [α]25
D
−137.6 (c 1.00, CHCl3); IR (neat) 3414, 3059, 2977, 2928, 1729,
1602, 1589, 1488, 1454, 1393, 1369, 1275, 1152, 1076, 1029, 1000,
978, 934, 911, 876, 845, 780, 698 cm−1; 1H NMR (400 MHz, CDCl3)
δ (ppm) 1.46 (s, 9H), 3.12 (dd, J = 9.2, 13.2 Hz, 1H), 3.20 (dd, J =
4.4, 13.2 Hz, 1H), 4.15 (dd, J = 4.4, 9.2 Hz, 1H), 5.48 (br s, 1H), 6.55
(s, 1H), 6.62−6.71 (m, 4H), 7.06 (t, J = 8.0 Hz, 1H), 7.28−7.37 (m,
6H), 7.59 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm)
28.1, 39.4, 67.8, 81.4, 113.3, 116.8, 122.1, 127.7, 128.0, 128.1, 128.4,
128.8, 129.3, 130.2, 136.3, 139.5, 140.0, 155.6, 170.8, 170.9; HRMS
(ES) calcd for C26H28NO3 [M + H]+ m/z 402.2069, found m/z
402.2055.
(3-(Triisopropylsilyloxy)phenyl)methanol (8). To a stirred
solution of 7 (2.87 g, 10.31 mmol) in MeOH (50 mL) at room
temperature was added NaBH4 (585 mg, 15.46 mmol), and the
resulting suspension was stirred for 40 min. The reaction mixture was
concentrated under vacuum, the residue was triturated with H2O (30
mL), and the mixture was extracted with EtOAc (3 × 50 mL). The
extract was washed with brine, dried over anhydrous Na2SO4, and
filtered, and the filtrate was concentrated under vacuum to give
virtually pure 8 (2.87 g, 99%) as a colorless oil: IR (neat) 3331 (br),
2945, 2892, 2867, 1604, 1587, 1486, 1464, 1444, 1385, 1367, 1281,
1
1166, 1004, 958, 920, 883, 821, 782, 689 cm−1; H NMR (400 MHz,
(S)-tert-Butyl 2-Amino-3-(3-(triisopropylsilyloxy)phenyl)-
propanoate (14). To a stirred mixture of 12 (302 mg, 0.542
mmol) in THF (1.1 mL) and water (1.1 mL) at room temperature was
added acetic acid (1.1 mL), and the mixture was stirred at room
temperature for 6 h. The mixture was cooled to 0 °C, diluted with
water (3.0 mL), and brought to neutral pH by addition of solid
Na2CO3 (ca. 2 g). The aqueous phase was extracted with EtOAc (3 ×
5.0 mL), and the combined extract was washed with brine (10 mL),
dried over anhydrous MgSO4, filtered, and concentrated. The residue
was purified by flash chromatography (30% EtOAc in hexanes) to
CDCl3) δ (ppm) 1.13 (d, J = 7.6 Hz, 18H), 1.26−1.33 (m, 3H), 2.00
(br s, 1H), 4.66 (s, 2H), 6.83 (d, J = 8.0 Hz, 1H), 6.92−6.95 (m, 2H),
7.22 (t, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 12.7,
17.9, 65.2, 118.4, 119.0, 119.4, 129.5, 142.5, 156.3; HRMS (CI) calcd
for C16H28O2Si [M]+ m/z 280.1859, found m/z 280.1851. This
material was used in the next step without further purification.
(3-(Iodomethyl)phenoxy)triisopropylsilane (9). To a stirred
solution of PPh3 (561 mg, 2.14 mmol) and imidazole (146 mg, 2.14
mmol) in CH2Cl2 (10 mL) at room temperature was added I2 (543
mg, 2.14 mmol). After 15 min, a solution of 8 (500 mg, 1.78 mmol) in
CH2Cl2 (5 mL) was added dropwise to the reaction mixture, and
stirring was continued for 30 min. The resulting suspension was passed
through a short column of silica and eluted with CH2Cl2. The eluate
was shaken with saturated aqueous Na2S2O3 (15 mL), dried over
anhydrous MgSO4, filtered, and concentrated to give virtually pure 9
(669 mg, 96%) as a pale yellow oil: IR (neat) 2944, 2891, 2866, 1602,
1584, 1484, 1464, 1440, 1385, 1282, 1173, 1156, 1072, 1003, 978, 920,
882, 817, 782, 690 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm) 1.13
(d, J = 7.2 Hz, 18H), 1.23−1.32 (m, 3H), 4.42 (s, 2H), 6.77 (d, J = 8.0
Hz, 1H), 6.92 (s, 1H), 6.96 (d, J = 7.6 Hz, 1H), 7.15 (t, J = 7.6 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 5.5, 12.7, 17.9, 119.5,
120.4, 121.3, 129.6, 140.6, 156.2; HRMS (EI) calcd for C16H27IOSi
[M]+ m/z 390.0876, found m/z 390.0873. This material was used in
the next step without further purification.
afford 14 (197 mg, 93%) as a pale yellow oil: [α]20 +4.5 (c 1.00,
D
CHCl3); IR (neat) 2944, 2867, 1732, 1603, 1584, 1486, 1464, 1445,
1391, 1367, 1277, 1156, 1005, 883, 837, 782, 688 cm−1; 1H NMR (400
MHz, CDCl3) δ (ppm) 1.12 (d, J = 7.6 Hz, 18H), 1.24−1.32 (m, 3H),
1.47 (s, 9H), 1.55 (br s, 2H), 2.80 (dd, J = 7.6, 13.6 Hz, 1H), 3.02 (dd,
J = 5.2, 13.6 Hz, 1H), 3.62 (br s, 1H), 6.77−6.82 (m, 3H), 7.14−7.18
(m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 12.7, 17.9, 28.0, 41.2,
56.3, 81.2, 118.0, 121.1, 122.1, 129.3, 139.1, 156.1, 174.2; HRMS (ES)
calcd for C22H40NO3Si [M + H]+ m/z 394.2777, found m/z 394.2748.
(S)-tert-Butyl 2-((S)-2-(tert-Butoxycarbonyl)-3-methylbutana-
mido)-3-(3-(triisopropylsilyloxy)phenyl)propanoate (16). To a
stirred solution of 14 (170.9 mg, 0.434 mmol), 15 (141.5 mg, 0.651
mmol), and HOBt (167.2 mg, 1.237 mmol) in CH2Cl2 (3.0 mL) at 0
°C was added EDCI (249.7 mg, 1.303 mmol). The mixture was
allowed to warm to room temperature and was stirred at that
temperature for 3 h. The mixture was diluted with water (3.0 mL), and
the layers were separated. The aqueous phase was extracted with
EtOAc (3 × 5 mL), and the combined extract was dried over
anhydrous MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash chromatography (20% EtOAc in
(S)-tert-Butyl 2-(Diphenylmethyleneamino)-3-(3-(triiso-
propylsilyloxy)phenyl)propanoate (12). To a stirred solution of
9 (2.50 g, 6.40 mmol) in a mixture of CH2Cl2 (25 mL) and toluene
(50 mL) at −10 °C were added 10 (1.89 g, 6.40 mmol) and 11 (556
mg, 1.02 mmol). To this solution was added a 50% aqueous KOH
solution (50 mL), and the resulting mixture was stirred vigorously at
−5 °C for 33 h. Heptane (65 mL) and water (65 mL) were added to
the mixture, and the separated aqueous layer was extracted with
heptane (2 × 100 mL). The combined organic extract was washed
with water (200 mL), dried over anhydrous MgSO4, filtered, and
concentrated. The residue was purified by flash chromatography (10%
EtOAc in hexanes with 1% Et3N) to give 12 (2.92 g, 82%) as a viscous
hexanes) afforded 16 (221.9 mg, 86%) as a colorless foam: [α]21
D
+19.5 (c 1.00, CHCl3); IR (neat) 3316 (br), 2965, 2929, 2868, 1737,
1656, 1604, 1585, 1530, 1487, 1447, 1392, 1367, 1278, 1160, 1005,
1
920, 883, 844, 784, 737, 688 cm−1; H NMR (400 MHz, CDCl3) δ
(ppm) 0.90 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 1.12 (d, J =
7.2 Hz, 18H), 1.24−1.31 (m, 3H), 1.41 (s, 9H), 1.47 (s, 9H), 2.11−
2.19 (m, 1H), 2.98−3.10 (m, 2H), 3.95 (br s, 1H), 4.70−4.75 (m,
1H), 5.04 (br s, 1H), 6.29 (br s, 1H), 6.74−6.77 (m, 3H), 7.12−7.15
(m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 12.7, 17.9, 19.2, 27.9,
28.3, 31.0, 38.1, 53.5, 59.8, 82.3, 118.2, 121.1, 122.2, 129.2, 137.5,
156.1, 170.3, 170.9; HRMS (ES) calcd for C32H56N2O6NaSi [M +
Na]+ m/z 615.3805, found m/z 615.3809.
orange oil: [α]22 −110.6 (c 1.00, CHCl3); IR (neat) 3059, 3020,
D
2944, 2892, 2867, 1735, 1624, 1601, 1585, 1485, 1463, 1445, 1391,
1368, 1272, 1152, 1073, 1030, 1004, 980, 910, 883, 850, 805, 780, 694
1
cm−1; H NMR (400 MHz, CDCl3) δ (ppm) 1.05 (d, J = 7.2 Hz,
18H), 1.13−1.19 (m, 3H), 1.47 (s, 9H), 3.12 (dd, J = 9.2, 13.2 Hz,
1H), 3.23 (dd, J = 4.4, 13.2 Hz, 1H), 4.14 (dd, J = 4.4, 9.2 Hz, 1H),
6.64−6.75 (m, 5H), 7.07 (t, J = 8.0 Hz, 1H), 7.29−7.41 (m, 6H), 7.63
(d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 12.6, 17.9,
28.1, 39.6, 67.9, 81.0, 117.6, 121.4, 122.5, 127.8, 127.9, 128.1, 128.2,
128.8, 128.9, 130.0, 136.5, 139.6, 139.9, 155.8, 170.2, 170.8; HRMS
(ES) calcd for C35H48NO3Si [M + H]+ m/z 558.3403, found m/z
558.3384.
(S)-tert-Butyl 2-(Diphenylmethyleneamino)-3-(3-hydroxy-
phenyl)propanoate (13). To a stirred solution of 12 (50.0 mg,
0.0896 mmol) in THF (0.45 mL) at room temperature was added
TBAF (1 M solution in THF, 0.11 mL, 0.110 mmol), and the resulting
solution was stirred at room temperature for 4 h. The reaction was
(S)-tert-Butyl 2-((S)-2-(Benzyloxycarbonyl)-3-methylbutana-
mido)-3-(3-(triisopropylsilyloxy)phenyl)propanoate (19). To a
stirred solution of 18 (597 mg, 2.375 mmol) and HATU (903 mg,
2.375 mmol) in DMF (14 mL) at room temperature was added
DIPEA (1.24 mL, 7.126 mmol). The mixture was stirred for 5 min, at
which point a solution of 14 (850 mg, 2.159 mmol) in DMF (14 mL)
was added. The mixture was stirred for 45 min and then was diluted
with EtOAc (30 mL). The resulting solution was washed with water
(30 mL) and brine (30 mL), dried over anhydrous MgSO4, filtered,
and concentrated under vacuum. The residue was purified by flash
chromatography (10% EtOAc in hexanes) to give 19 (1.258 g, 93%) as
a colorless foam: [α]20 +20.1 (c 1.00, CHCl3); IR (neat) 3309 (br),
D
D
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The Journal of Organic Chemistry
Note
2965, 2944, 2868, 1732, 1657, 1604, 1585, 1537, 1486, 1455, 1392,
1368, 1279, 1246, 1159, 1105, 1028, 1005, 919, 883, 833, 784, 735,
695, 661 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm) 0.91 (d, J = 6.8
Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 1.11 (d, J = 7.2 Hz, 18H), 1.22−
1.28 (m, 3H), 1.41 (s, 9H), 2.11−2.16 (m, 1H), 3.00−3.05 (m, 2H),
4.02−4.04 (m, 1H), 4.70−4.75 (m, 1H), 5.12 (s, 2H), 5.39 (d, J = 8.4
Hz, 1H), 6.29 (d, J = 8.0 Hz, 1H), 6.72−6.76 (m, 3H), 7.11 (t, J = 8.4
Hz, 1H), 7.32−7.38 (m, 5H); 13C NMR (100 MHz, CDCl3) δ (ppm)
12.7, 17.6, 17.9, 19.1, 27.9, 29.7, 31.2, 38.0, 53.6, 60.2, 67.0, 82.4,
118.2, 121.1, 122.2, 128.0, 128.1, 128.5, 129.3, 136.4, 137.4, 156.1,
156.2, 170.3, 170.5; HRMS (CI) calcd for C35H55O6N2Si [M + H]+
m/z 627.3829, found m/z 627.3852.
filtered, and concentrated in vacuo to afford pure carboxylic acid 23
(1.31 g, 87%) as colorless prisms: mp 103−106 °C; [α]26 −18.2 (c
D
1.00, MeOH); IR (neat) 3200−2500 (br), 2979, 2934, 1732, 1479,
1457, 1417, 1367, 1317, 1254, 1156, 1086, 1064, 1050, 1033, 967, 919,
1
881, 852, 735, 704, 647, 614 cm−1; H NMR (400 MHz, CDCl3) δ
(ppm) 1.45 (s), 1.48 (s), 1.36−2.30 (br m), 2.85 (br m), 3.10 (br m),
3.90 (m), 4.03 (m), 4.60−5.08 (br m); 13C NMR (100 MHz, CDCl3)
δ (ppm) 20.2, 20.5, 23.4, 23.7, 28.0, 28.1, 42.2, 44.2, 56.9, 82.7, 83.3,
83.6, 152.7, 170.9, 171.5; HRMS (EI) calcd for C15H27O6N2 [M + H]+
m/z 331.1869, found m/z 331.1861.
(S)-1,2-Di-tert-butyl 3-Methyl Piperazine-1,2,3-tricarboxy-
late (24). To a cooled (0 °C) solution of 23 (1.22 g, 3.70 mmol)
in MeOH (20 mL) was added dropwise a solution of TMSCHN2 (2M
solution in Et2O, 2.8 mL, 5.56 mmol) at 0 °C. The mixture was
allowed to warm to room temperature with stirring, and after 12.5 h
the reaction was quenched with 10% aqueous AcOH (10 mL). The
mixture was extracted with Et2O (3 × 30 mL), and the combined
extract was washed with saturated NaHCO3 (30 mL), dried over
anhydrous MgSO4, filtered, and concentrated. The residue was
purified by flash chromatography (1:7 Et2O/hexanes 10−40% then
(S)-2-((S)-2-(Benzyloxycarbonyl)-3-methylbutanamido)-3-(3-
(triisopropylsilyloxy)phenyl)propanoic Acid (20). To a solution
of 19 (10.0 mg, 0.0160 mmol) and thioanisole (0.04 mL, 0.340 mmol)
in CH2Cl2 (0.40 mL) at 0 °C was added TFA (0.04 mL, 0.522 mmol).
The stirred mixture was allowed to warm to room temperature, and
after 5 h a second portion of TFA (0.30 mL) was added. The mixture
was stirred for a further 4 h and then was concentrated under reduced
pressure. The residue was purified by flash chromatography (30%
EtOAc in hexanes) to furnish 20 (7.0 mg, 77%) as a colorless solid:
mp 120−122 °C; [α]20D +73.6 (c 3.71, CHCl3); IR (film) 3310, 3066,
3035, 2961, 2945, 2867, 1717, 1653, 1603, 1585, 1540, 1487, 1446,
EtOAc/hexanes) to afford 24 (0.80 g, 63%) as a colorless oil: [α]30
D
−36.4 (c 1.00, CHCl3); IR (neat) 2977, 2931, 2856, 1740, 1703, 1478,
1456, 1393, 1367, 1326, 1297, 1252, 1168, 1127, 1086, 1051, 1033,
1
1279, 1248, 1162, 1004, 883, 831, 694 cm−1; H NMR (400 MHz,
1
1007, 952, 910, 880, 857, 755 cm−1; H NMR (400 MHz, CDCl3) δ
CDCl3) δ (ppm) 0.86 (d, J = 6.1 Hz, 3H), 0.91 (d, J = 6.5 Hz, 3H),
1.10 (d, J = 7.2 Hz, 18H), 1.21−1.30 (m, 3H), 2.04−2.10 (m, 1H)
3.05−3.06 (m, 1H), 3.12−3.15 (m, 1H), 4.02−4.09 (m, 1H), 4.80−
4.83 (m, 1H), 5.07−5.15 (AB quartet, 2H), 5.56 (br s, 1H), 6.54 (br s,
1H), 6.74−6.76 (m, 3H), 7.10 (t, J = 7.9 Hz, 1H), 7.30−7.38 (m, 5H);
13C NMR (100 MHz, CDCl3) δ (ppm) 12.7, 17.7, 17.9, 19.0, 30.3,
31.0, 37.3, 53.2, 60.4, 60.5, 67.2, 118.7, 120.8, 122.0, 128.0, 128.2,
128.5, 129.5, 137.2, 156.3, 156.5, 171.5, 174.5; HRMS (CI) calcd for
C31H47N2O6Si [M + H]+ m/z 571.3203, found m/z 571.3220.
(ppm) 1.48 (s), 1.49 (s), 1.75 (br m), 1.90 (br m), 2.20 (m), 2.85 (br
m), 3.74 (s), 3.95 (br), 4.12 (m), 4.81 (br), 5.01 (br); 13C NMR (100
MHz, CDCl3) δ (ppm) 20.0, 24.3, 28.2, 42.7, 51.9, 54.5, 80.2, 81.7,
154.0, 154.6, 170.4; HRMS (CI) calcd for C16H29N2O6 [M + H]+ m/z
345.2026, found m/z 345.2014.
(S)-Methyl Piperazine-3-carboxylate (25). To a stirred solution
of 24 (776 mg, 2.25 mmol) in CH2Cl2 (7.5 mL) at 0 °C was added
TFA (7.5 mL) over 1 min. The mixture was allowed to warm to room
temperature and was stirred for 1 h, then was concentrated in vacuo.
The oily residue was azeotroped with toluene to remove residual traces
of acid. This furnished crude 25 (743 mg, 89%) as a pale yellow oil:
[α]23D +2.5 (c 1.00, CHCl3); IR (neat) 3420, 3259, 2960, 2922, 2851,
(S)-Di-tert-butyl 3-((S)-4-Benzyl-2-oxooxazolidine-3-
carbonyl)piperazine-1,2-dicarboxylate (22). To a stirred solution
of 21 (2.57 g, 7.56 mmol) in THF (9.3 mL) at −78 °C was added
dropwise a freshly prepared LDA solution (1 M solution in THF, 8.32
mL, 8.32 mmol). The mixture was stirred at −78 °C for 55 min, at
which point a precooled (−78 °C) solution of di-tert-butyl
azodicarboxylate (2.09 g, 9.07 mmol) in CH2Cl2 (13.6 mL) was
added in one portion via cannula. The solution was stirred at −78 °C
for 1 h during which DMPU (23.7 mL, 197 mmol) was added
dropwise (by the end of the addition, the reaction mixture had frozen).
The mixture was slowly warmed to room temperature, stirred for 6 h,
and then added to Et2O (190 mL) layered above a saturated aqueous
solution of KH2PO4 (70 mL). The two layers were shaken briefly but
vigorously and the aqueous phase was extracted with Et2O (3 × 70
mL). The combined extract was washed with saturated aqueous
NaHCO3 (70 mL) and H2O (120 mL) and was dried over anhydrous
MgSO4 and filtered. The filtrate was concentrated in vacuo to afford a
yellow oily residue which was purified by flash chromatography (1:1
1
2747, 1734, 1682, 1444, 1204, 1139, 840, 801, 723 cm−1; H NMR
(400 MHz, CDCl3) δ (ppm) 1.94−2.01 (m, 3H), 2.18−2.21 (m, 1H),
3.30−3.40 (m, 2H), 3.82 (s, 3H), 3.99−4.02 (m, 1H), 6.20 (br s, 2H);
13C NMR (100 MHz, CDCl3) δ (ppm) 19.7, 24.7, 45.1, 52.8, 55.8,
171.4; HRMS (CI) calcd for C6H11N2O2 [M-H]+ m/z 143.0821,
found m/z 143.0813. This material was used in the next step without
further purification.
(S)-Methyl 1-((S)-2-((S)-2-(Benzyloxycarbonyl)-3-methylbu-
tanamido)-3-(3-(triisopropylsilyloxy)phenyl)propanoyl)-
piperazine-3-carboxylate (26). To a solution of 20 (4.5 mg, 7.9
μmol) in DMF (0.10 mL) at room temperature were added HATU
(3.6 mg, 9.5 μmol) and DIPEA (4.9 μL, 28.4 μmol). The mixture was
stirred for 5 min, at which point a solution of 25 (2.9 mg, 7.9 μmol) in
DMF (0.10 mL) was added. The mixture was stirred for 2 h and
diluted with EtOAc (2 mL), and the resulting solution was washed
with brine (2 mL), dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (20−40% EtOAc in hexanes) to give 26 (4.5
Et2O/hexanes) to afford 22 (2.80 g, 76%) as a colorless foam: [α]30
D
+29.0 (c 1.00, MeOH); IR (neat) 3055, 3022, 2978, 2932, 2853, 1783,
1698, 1478, 1455, 1393, 1367, 1296, 1253, 1220, 1166, 1111, 1071,
1
1049, 1031, 988, 911, 881, 854, 823, 753, 737, 704 cm−1; H NMR
mg, 82%) as a colorless oil: [α]20 −25.4 (c 1.00, CHCl3); IR (neat)
D
(400 MHz, CDCl3) δ (ppm) 1.50 (m), 1.70−2.20 (m), 2.60−2.71
(m), 2.90 (br s), 3.95 (br s), 4.10−4.25 (m), 4.70 (br s), 5.80 (br s),
6.05 (br s), 7.20−7.49 (m); 13C NMR (100 MHz, CDCl3) δ (ppm)
28.1, 28.2, 37.6, 55.6, 66.5, 80.3, 81.3, 127.4, 129.0, 129.4, 135.2, 152.6,
170.4; HRMS (CI) calcd for C25H35N3O7 [M]+ m/z 489.2475, found
m/z 489.2481.
(S)-1,2-Bis(tert-butoxycarbonyl)piperazine-3-carboxylic Acid
(23). To a stirred solution of 22 (2.22 g, 4.53 mmol) in THF (17.8
mL) at −5 °C was added a solution of LiOH·H2O (438 mg, 10.43
mmol) in H2O (8.9 mL). The mixture was stirred vigorously for 2 h at
0 °C and then was diluted with water (22 mL) and extracted with
Et2O (3 × 55 mL). The combined extract was washed with saturated
aqueous NaHCO3 (55 mL), and the aqueous layers were combined,
acidified to pH 2 with solid NaHSO4, and extracted with EtOAc (3 ×
110 mL). The combined extract was dried over anhydrous MgSO4,
3302, 3066, 3032, 2945, 2867, 1745, 1642, 1537, 1486, 1442, 1271,
1236, 1164, 1004, 983, 883, 834, 757, 695 cm−1; 1H NMR (400 MHz,
CDCl3) δ (ppm) 0.81 and 0.96 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8
Hz, 3H), 1.11 (d, J = 7.2 Hz, 18H), 1.22−1.28 (m, 3H), 1.42−1.51
(m, 2H), 1.61−1.86 (m, 3H), 2.02−2.18 (m, 1H), 2.50−2.61 (m, 1H),
2.83−2.96 (m, 2H), 3.23 and 3.47 (d, J = 11.0 Hz, 1H), 3.72 and 3.76
(s, 3H), 4.03−4.08 (m, 1H), 4.03−4.08 and 4.48−4.52 (m, 1H),
5.10−5.17 (m, 2H), 5.38 (br s, 1H), 5.61−5.66 and 5.73−5.78 (m,
1H), 6.51 (m, 1H), 6.67−6.79 (m, 3H), 7.09−7.14 (m, 1H), 7.32−
7.39 (m, 5H); 13C NMR (100 MHz, CDCl3) δ (ppm) 12.7, 17.3 and
17.5, 17.9, 19.2, 22.4 and 22.9, 28.2 and 28.7, 31.4 and 31.7, 39.1 and
39.5, 41.9 and 42.0, 49.7 and 50.0, 52.1, 57.7 and 58.4, 60.0 and 60.2,
67.0, 118.1, 121.0 and 121.4, 122.2 and 122.4, 128.1, 128.5, 129.1 and
129.2, 136.4, 138.0, 156.0, 156.1, 156.3, 170.2 and 170.4, 171.5 and
E
dx.doi.org/10.1021/jo3027214 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
171.7, 172.3; HRMS (ES) calcd for C37H57N4O7Si [M + H]+ m/z
697.3997, found m/z 697.3976.
(8) (a) Gurjar, M. K.; Chaudhuri, A. R. Tetrahedron Lett. 2002, 43,
2435−2438. (b) Dias, L.; Salles, A. G. Tetrahedron Lett. 2006, 47,
2213−2216.
(S)-Methyl 1-((S)-2-((S)-2-Amino-3-methylbutanamido)-3-(3-
(triisopropylsilyloxy)phenyl)propanoyl)piperazine-3-carboxy-
late (27). A suspension of 26 (164 mg, 0.236 mmol) and 10% Pd/C
in EtOH (12.0 mL) was stirred under H2 (1 atm) for 19 h. The
catalyst was removed by filtration, and the filtrate was concentrated
under vacuum. The residue was purified by flash chromatography
(10% MeOH in CH2Cl2 + 1% Et3N) to afford 27 (131 mg, 99%) as a
(9) O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506−517.
(10) The benzylic bromide analogous to 9 was unreactive in this
alkylation.
(11) The use of this mixed solvent system with dielectric constants of
9 (CH2Cl2) and 2.4 (toluene) is important for promoting phase-
transfer catalysis.
(12) Absolute configuration is inferred from Corey’s stereochemical
analysis of analogous asymmetric catalytic phase-transfer reactions:
Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414−
12415.
pale yellow oil: [α]20 −21.5 (c 1.00, CHCl3); IR (neat) 3336, 3245,
D
2925, 2867, 1746, 1652, 1603, 1585, 1486, 1443, 1273, 1164, 1004,
982, 883, 834, 688, 662 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm)
0.84−1.00 (m, 6H), 1.10 (d, J = 7.2 Hz, 18H), 1.21−1.29 (m, 3H),
1.40−1.80 (m, 4H), 2.01−2.30 (m, 3H), 2.70−2.95 (m, 3H), 3.50 (br
s, 1H), 3.60−3.70 (m, 6H), 4.20−4.30 (m, 1H), 5.65−5.72 (m, 1H),
6.69−6.90 (m, 3H), 7.05−7.12 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 12.7, 14.1, 17.1, 17.5, 17.9, 19.2, 22.7, 28.2, 29.7,
29.7, 30.6, 30.8, 38.0, 39.0, 41.7, 49.7, 52.1, 57.9, 59.9, 70.6, 118.0,
120.9, 121.4, 122.4, 129.1, 129.2, 138.3, 138.6, 156.0, 156.1, 171.8,
172.1, 172.5; HRMS (ES) calcd for C29H51N4O5Si [M + H]+ m/z
563.3629, found m/z 563.3615.
(13) Yadav, J. S.; Balanarsaiah, E.; Raghavendra, S.; Satyanarayana, M.
Tetrahedron Lett. 2006, 47, 4921−4924.
(14) Evans, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1989, 111, 1063−
1072.
(15) Hale, K. J.; Cai, J. Q.; Delisser, V.; Manaviazar, S.; Peak, S. A.;
Bhatia, G. S.; Collins, T. C.; Jogiya, N. Tetrahedron 1996, 52, 1047−
1068.
(16) Sashida, H.; Nakayama, A.; Kaname, M. Synthesis 2008, 3229−
3236.
(17) Highly selective peptide coupling at the more basic N(1) of 25
occurs under these conditions (see refs 5c and 6d).
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: james.white@oregonstate.edu.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
■
K.S. thanks the Ministry of Science and Technology of the
Royal Thai Government for financial support.
REFERENCES
■
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F
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