An Improved Synthesis of (4S,5S)-2-Phenyl-4-(methoxycarbonyl)-5-isopropyloxazoline from (S)-Phenylglycinol

Full text of DOI:10.1021/jo972013+

2382
J . Org. Chem. 1998, 63, 2382-2384
Sch em e 1
An Im p r oved Syn th esis of
(4S,5S)-2-P h en yl-4-(m eth oxyca r bon yl)-5-
isop r op yloxa zolin e fr om (S)-P h en ylglycin ol
J ames S. Panek* and Craig E. Masse†
Department of Chemistry Metcalf Center for Science
and Engineering, Boston University,
Boston, Massachusetts 02215
Received November 3, 1997
In tr od u ction
(4S,5S)-2-Phenyl-4-(methoxycarbonyl)-5-isopropylox-
azoline (6) is a useful chiral auxiliary for the stoichio-
metric, asymmetric aldol reaction. This auxiliary has
been utilized in asymmetric alkylation reactions1 and
more recently in asymmetric aldol reactions aimed at the
synthesis of the neurotrophic agent, (+)-lactacystin (eq
1).2 Currently, the most efficient approach to oxazoline
6 requires 10 steps with an overall yield of 60% from (E)-
4-methyl-2-penten-1-ol.2a The central issue in the prepa-
ration of 6 relies on the asymmetric synthesis of the
3-hydroxyleucine derivative 5. 3-Hydroxyleucine has
attracted considerable attention as an amino acid com-
ponent of numerous peptide antibiotics such as azino-
thricin,3 telomycin,4 and lysobacin.5 More recently, it has
been sought after as a key synthon in the synthesis of
(+)-lactacystin and its analogues.
thesis of (+)-lactacystin, as well as its analogues, we
required an efficient method for the preparation of
multiple grams of the (2S,3S)-isomer of 3-hydroxyleucine
methyl ester. Herein we describe an efficient and concise
approach to the synthesis of (2S,3S)-hydroxyleucine
methyl ester (5) employing commercially available ma-
terials utilizing an underdeveloped anti-selective aldol
reaction between a oxazolidine-based chiral glycine eno-
late and isobutyraldehyde.
To develop an efficient synthesis of oxazoline 6, we first
needed to devise a concise and stereoselective synthesis
of hydroxyleucine 5. Numerous approaches to the 3-hy-
droxyleucine synthon 5 have been reported. However,
they either lack the flexibility to prepare the various
isomers, require the preparation of a chiral catalyst
system, or are prohibitively lengthy for large scale
preparations.6 As part of a program aimed at the syn-
Resu lts a n d Discu ssion
Our preparation of 3-hydroxyleucine methyl ester 5 is
outlined in Scheme 1 and makes use of an anti-selective
aldol reaction of chiral oxazolidine 2 derived from (S)-
phenylglycinol.7 Preparation of the oxazolidine auxiliary
began with the N-alkylation of (S)-phenylglycinol8 with
methyl bromoacetate to afford 1. Condensation of 1 with
diphenylacetaldehyde and anhydrous magnesium sulfate
at ambient temperature afforded the 2,4-disubstituted
oxazolidine 2 as a single diastereomer9 which serves as
the chiral glycine equivalent for the subsequent aldol.
The anti-selective aldol reaction between the lithium
enolate of the phenylglycinol derived oxazolidine 2 with
† Recipient of a Graduate Fellowship from the Organic Chemistry
Division of American Chemical Society 1996-1997, sponsored by
Organic Syntheses Inc.
(1) Seebach, D.; J uaristi, E.; Miller, D. D.; Schaicbli, C.; Weber, T.
Helv. Chim. Acta 1987, 70, 1194-1215.
(2) (a) Nagamitsu, T.; Sunazuka, T.; Tanaka, H.; Omura, S.;
Sprengeler, P. A.; Smith, A. B. III. J . Am. Chem. Soc. 1996, 118, 3584-
3590. (b) Corey, E. J .; Choi, S. Tetrahedron Lett. 1993, 34, 6969-6972.
(3) Maehr, H.; Liu, C.-M.; Palleroni, N. J .; Smallheer, J .; Todan, L.;
Williams, T. H.; Blount, J . F. J . Antibiot. 1986, 39, 17-21.
(4) Sheehan, J . C.; Maeda, K.; Sen, A. K.; Stock, J . A.; J . Am. Chem.
Soc. 1962, 84, 1303-1305.
(7) For the preparation of a similar auxiliary see: Iwanowicz, E. J .;
Smith, K. Synth. Commun. 1998, in press. For the use of the above
auxiliary in an anti-selective aldol reaction with various aldehydes
see: Iwanowicz, E. J .; Blomgren, P.; Cheng, P. T. W.; Smith, K.; Lau,
W. F.; Pan, Y. Y.; Gu, H. H.; Malley, M. F.; Gougoutas, J . Z. Synlett
1998, in press.
(5) Tymiak, A. A.; McCormick, T. J .; Unger, S. E.; J . Org. Chem.
1989, 54, 1149-1157.
(6) (a) Sunazuka, T.; Nagamitsu, T.; Tanaka, H.; Omura, S.;
Sprengler, P. A.; Smith, A. B. III. Tetrahedron Lett. 1993, 28, 4447-
4448. (b) Corey, E. J .; Lee, D.-H.; Choi, S. Tetrahedron Lett. 1992, 33,
6735-6738. (c) Caldwell, C. G.; Bundy, S. S. Synthesis 1990, 34-36.
(d) J ung, M. E.; J ung, Y. H. Tetrahedron Lett. 1989, 30, 6636-6640.
(e) Evans, D. A.; Sjogren, E. B.; Weber, A. E.; Conn, R. E. Tetrahedron
Lett. 1987, 28, 39-43.
(8) Prepared by reduction of (S)-phenylglycine with NaBH4/H2SO4
see: Abiko, A.; Masamune, S. Tetrahedron Lett. 1992, 33, 5517-5518.
(9) The relative stereochemical assignment of the C2 center of the
phenylglycinol derived oxazolidines has been established to be a cis-
relationship based on recent 1H NMR studies: see Arseniyadis, S.;
Huang, P. Q.; Morellet, N.; Beloeil, J .-C.; Husson, H.-P. Heterocycles
1990, 31, 1789-1799 and references therein.
S0022-3263(97)02013-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/17/1998

Notes
J . Org. Chem., Vol. 63, No. 7, 1998 2383
isobutyraldehyde afforded the aldol product 3 as a single
diastereomer (de > 30:1 anti/ syn). The aldol bond
construction of such R-amino esters have been shown to
exhibit high levels of anti stereoselection (simple dias-
tereoselectivity).10 Such literature precedent warranted
an investigation into the use of phenylglycinol derived
oxazolidine 2 for the preparation of the chiral isopropyl-
oxazoline 6. The stereochemical outcome of this aldol
condensation is critically dependent on the geometry of
the glycine enolate. However, there are conflicting
literature precedents regarding the conformational pref-
erence of such glycine enolates.11 The high levels of anti-
stereoselection observed in this aldol reaction would
require either a chairlike transition state via the E(O)-
enolate or a twist-boat transition structure via the Z(O)-
enolate. While the steric bulk of the auxiliary favors the
(E) geometry, the potential for internal coordination of
the amine moiety to the lithium counterion may predis-
pose the glycine enolate to the (Z) geometry. Studies are
ongoing to determine the operative enolate configuration
with oxazolidine 2. Amino alcohol 3 was then treated
with formic acid to hydrolyze the oxazolidine. Subse-
quent heterogeneous hydrogenation to remove the phen-
ylglycinol derived amino protecting group afforded the
(2S,3S)-3-hydroxyleucine methyl ester 5.12 Finally, treat-
ment of 5 with trimethyl orthobenzoate in the presence
of p-toluenesulfonic acid affords the cis-oxazoline 6.13 The
virtues of this approach are apparent from the follow-
ing: (i) the concise nature of the synthetic sequence, (ii)
the auxiliary is prepared from readily available and
inexpensive chiral pool materials with high optical purity,
(iii) preparation of the auxiliary and deprotection steps,
which include acid-promoted hydrolysis of oxazolidine
and hydrogenation of the benzylic N-protecting group,
are conducted under mild reaction conditions which in
principle makes the synthesis readily scaled to gram
quantities of oxazoline, (iv) the (2R,3R)-antipode can be
accessed by using the (R)-phenylglycinol derived auxil-
iary.
tional aspects of this approach for large scale synthesis.
Application of the synthesis of oxazoline 6 to the syn-
thesis of (+)-lactacystin and its analogues will be reported
at a later time.
Exp er im en ta l Section
1H NMR spectra were recorded on a 400 MHz spectrometer
at ambient temperature. 13C NMR spectra were recorded on a
75.5 Hz spectrometer at ambient temperature. Chemical shifts
are reported in parts per million relative to chloroform (1H, δ
7.24; 13C, δ 77.0), acetone (1H, δ 2.05; 13C, δ 29.92), or methanol
(1H, δ 3.31; 13C, δ 49.15). All 13C NMR spectra were recorded
with complete proton decoupling. Infrared spectra were recorded
on a FT-spectrophotometer. Optical rotations were recorded on
a digital polarimeter at 589 nm. High resolution mass spectra
were obtained in the Boston University Mass Spectrometry
Laboratory. Analytical thin-layer chromatography was per-
formed on 0.25 mm silica gel 60-F plates. Flash chromatography
was performed as previously described.14 Melting points were
determined on a Thomas-Hoover apparatus. When specified as
“anhydrous”, solvents were distilled and/or stored over 4 Å sieves
prior to use. All reactions were carried out in oven-dried
glassware under a dry argon atmosphere. Tetrahydrofuran was
freshly distilled under argon from sodium/benzophenone ketyl.
Dichloromethane (CH2Cl2) and diisopropylamine were distilled
from calcium hydride. Isobutyraldehyde was distilled from
calcium sulfate and stored over 4 Å sieves. The (S)-phenylgly-
cine, methyl bromoacetate, diphenylacetaldehyde, trimethyl
orthobenzoate, and dimethoxyethane were purchased from Al-
drich and used as received. The anhydrous magnesium sulfate
was purchased from J . T. Baker and used as received.
N-(Meth yla cetyl)-(S)-p h en ylglycin ol (1). To a solution of
(S)-phenylglycinol (10.0 g, 72.9 mmol) in 300 mL of dry THF
(0.25 M) at 0 °C was added triethylamine (12.3 mL, 87.6 mmol,
1.2 equiv) followed by dropwise addition of a solution of methyl
bromoacetate (7.6 mL, 80.2 mmol, 1.1 equiv) in THF (80 mL, 1
M). The reaction mixture was warmed to room temperature over
a 10 h period and subsequently diluted with saturated NH4Cl
solution (60 mL). The reaction mixture was extracted with Et2O
(3 × 25 mL), dried (MgSO4), and concentrated in vacuo to afford
a white solid. Purification is accomplished either by recrystal-
lization from 1:1 EtOAc/PE or on SiO2 (50% EtOAc/PE) to afford
1 as a white solid (14.0 g, 92%): 1H NMR (400 MHz, CDCl3) δ
7.32-7.25 (m, 5H), 3.78-3.75 (m, 1H), 3.70 (dd, 1H, J 1 ) 4.4
Hz, J 2 ) 4.0 Hz), 3.65 (s, 3H), 3.60-3.55 (m, 1H), 3.35 and 3.25
(ABq, 2H, J AB ) 17.6 Hz), 2.49 (s, br, 2H); 13C NMR (75.5 MHz,
CDCl3) δ 173.0, 140.0, 127.8, 127.3, 66.9, 64.2, 51.8, 48.3; IR
(neat) νmax 3384, 2954, 1718, 1646; CIMS (NH3 gas) 210.1, 178.1,
118.1, 91.0; CIHRMS M + H+ (calculated for C11H16NO3):
Con clu sion
In summary, multigram quantities of (2S,3S)-3-hy-
droxyleucine methyl ester and resulting oxazoline 6 can
be readily prepared in 63% overall yield with high
enantiomeric purity using the concise sequence described
above. Additionally, only intermediates 3 and the final
product 6 require chromatographic purification; all other
intermediates can be recrystallized or carried through
the sequence without purification, enhancing the opera-
210.1130, found: 210.1117; [R]23 ) -80.7° (c ) 1.23, CHCl3);
D
mp ) 69-70 °C.
(2S ,4S )-2-(D i p h e n y lm e t h y l)-3-N -(m e t h y la c e t y l)-4-
p h en yloxa zolid in e (2). To a solution of N-(methylacetyl)-(S)-
phenylglycinol (1) (14.0 g, 67.0 mmol) in CH2Cl2 (260 mL, 0.25
M) was added diphenylacetaldehyde (13.0 mL, 73.8 mmol, 1.1
equiv) followed by the addition of anhydrous magnesium sulfate
(8.0 g, 67.0 mmol, 1.0 equiv). The reaction mixture was stirred
at ambient temperature for 12 h and subsequently diluted with
H2O (200 mL). The reaction mixture was extracted with Et2O
(3 × 25 mL), dried (MgSO4), and concentrated in vacuo.
Purification is accomplished either by recrystallization from 1:3
EtOAc/PE or on SiO2 (10% EtOAc/PE) to afford 2 as a light
yellow solid (25.8 g, 100%): 1H NMR (400 MHz, CDCl3) δ 7.52-
7.25 (m, 13H), 7.16-7.13 (m, 2H), 5.55 (d, 1H, J ) 4.0 Hz), 4.37
(dd, 1H, J 1 ) 6.8 Hz, J 2 ) 7.2 Hz), 4.26 (d, 1H, J ) 4.0 Hz),
4.19-4.15 (m, 1H), 3.62 (s, 3H), 3.35-3.28 (m, 2H), 3.19 (d, 1H,
J ) 17.6 Hz); 13C NMR (75.5 MHz, CDCl3) δ 171.0, 141.7, 140.6,
138.8, 132.4, 130.0, 129.2, 129.0, 128.5, 128.4, 127.8, 127.6, 126.5,
126.4, 73.7, 65.3, 55.4, 51.3, 48.7; IR (neat) νmax 3027, 1740, 1600,
1451; CIMS (NH3 gas) 388.3, 220.1, 192.1, 132.1; CIHRMS M +
(10) Shanzer, A.; Somekh, L.; Butina, D. J . Org. Chem. 1979, 44,
3967-3969.
(11) (a) J astrzebski, J . T. B. H.; van Koten, G.; van de Mieroop, W.
F. Inorg. Chim. Acta 1988, 142, 169-171. (b) van der Steen, F. H.;
Kleijn, H.; J astrzebski, J . T. B. H.; van Koten, G. J . Org. Chem. 1991,
56, 5147-5158.
(12) The absolute stereochemistry of 5 was determined by conversion
to (2S,3S)-3-hydroxyleucine (7) via the following sequence:
H+ (calculated for C25H26NO3): 388.1913, found: 388.1939; [R]23
) +2.8° (c ) 1.14, CHCl3); mp ) 58-60 °C.
D
Optical rotation and mp for compound 7: [R]23 ) +37.2° (c ) 0.40, 1
D
N aq HCl) {lit. [R]20D ) +35.0° (c ) 0.41, 1 N aq HCl)}, mp ) 219-221
°C (lit. mp ) 218-222 °C); see ref 4.
(13) Moss, R. A.; Lee, T. B. K. J . Chem Soc., Perkin Trans. 1 1973,
2778-2781.
(14) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.

2384 J . Org. Chem., Vol. 63, No. 7, 1998
Notes
An ti-Ald ol P r od u ct (3). To a cooled solution of (2S,4S)-2-
(diphenylmethyl)-3-N-(methylacetyl)-4-phenyloxazolidine (2) (10.0
g, 25.8 mmol) at -78 °C in 260 mL THF (0.1 M) was added
dropwise lithium diisopropylamide (28.4 mmol, 1.1 equiv). The
bright orange solution was stirred at -78 °C for 1 h, after which
time a solution of isobutyraldehyde (2.8 mL, 31.0 mmol, 1.2
equiv) in THF (31 mL, 1.0 M) was added. The light yellow
solution was stirred at -78 °C for an additional 1 h and
subsequently diluted with NaHCO3 solution and warmed to
room temperature. The reaction mixture was extracted with
EtOAc (3 × 25 mL), dried (MgSO4), and concentrated in vacuo.
Purification on SiO2 (5% f 20% EtOAc/PE) afforded 3 as a light
yellow oil, single diastereomer (de > 30:1) (10.7 g, 90%): 1H NMR
(400 MHz, acetone-d6) δ 7.61-7.18 (m, 13H), 7.08-7.00 (m, 2H),
5.30 (d, 1H, J ) 5.2 Hz), 4.85 (t, 1H, J ) 6.0 Hz), 4.40 (d, 1H, J
) 4.8 Hz), 4.15 (t, 1H, J ) 6.2 Hz), 3.70 (s, 3H), 3.64-3.58 (m,
2H), 3.42-3.38 (m, 2H), 1.63-1.58 (m, 1H), 0.60 (d, 3H, J ) 6.4
Hz), 0.28 (d, 3H, J ) 6.8 Hz); 13C NMR (75.5 MHz, acetone-d6)
δ 173.1, 144.6, 143.2, 142.1, 130.8, 129.8, 129.3, 128.8, 128.5,
128.3, 127.6, 127.2, 127.1, 98.1, 74.7, 74.5, 66.2, 61.5, 56.0, 51.3,
28.6, 19.9, 15.0; IR (neat) νmax 3461, 3028, 1727, 1601, 1452;
CIMS (NH3 gas) 460.3, 293.2, 264.2, 220.1, 167.1; CIHRMS M
+ H+ (calculated for C29H34NO4): 460.2488, found: 460.2452;
suspension was stirred under 1 atm of hydrogen for 24 h. The
resulting suspension was filtered through Celite, washed with
MeOH, and concentrated in vacuo. Purification is accomplished
either by recrystallization from 1:1 EtOAc/PE or on SiO2 (50%
f 100% EtOAc/PE) to afford 5 as a white solid (2.8 g, 100%):
1H NMR (400 MHz, CD3OD) δ 4.12-4.06 (m, 1H), 3.85 (s, 3H),
3.70-3.67 (m, 1H), 2.85 (s, br, 3H), 1.78-1.74 (m, 1H), 1.02 (d,
3H, J ) 4.0 Hz), 1.01 (d, 3H, J ) 4.4 Hz); 13C NMR (75.5 MHz,
CD3OD) δ 129.6, 80.4, 57.9, 52.5, 31.7, 20.3, 18.7; IR (neat) νmax
3433, 1646, 1457; CIMS (NH3 gas) 162.1, 154.1, 112.1, 104.0;
CIHRMS M + H+ (calculated for C7H15NO3): 162.1130, found:
162.1117; [R]23 ) +10.5° (c ) 0.39, MeOH); mp ) 100-103 °C
D
(MeOH).
(4S,5S)-2-P h en yl-4-(m et h oxyca r b on yl)-5-isop r op ylox-
a zolin e (6). To a solution of (2S,3S)-3-hydroxyleucine methyl
ester (5) (1.00 g, 6.2 mmol) in dimethoxyethane (120 mL, 0.5
M) was added p-toluenesulfonic acid (0.56 g, 6.2 mmol, 1.0 equiv)
followed by trimethyl orthobenzoate (3.20 mL, 18.6 mmol, 3.0
equiv). The reaction mixture was refluxed 4 h and subsequently
diluted with H2O (20 mL). The reaction mixture was extracted
with CHCl3 (3 × 25 mL), dried (MgSO4), and concentrated in
vacuo to afford the crude oxazoline. Purification on SiO2 (10%
EtOAc/PE) afforded 6 as a light yellow oil (1.35 g, 85%): 1H NMR
(400 MHz, CDCl3) δ 7.99-7.96 (m, 2H), 7.48-7.46 (m, 1H), 7.41-
7.38 (m, 2H), 4.65 (t, 1H, J ) 7.2 Hz), 4.55 (d, 1H, J ) 7.2 Hz),
3.79 (s, 3H), 1.95-1.93 (m, 1H), 1.01 (d, 3H, J ) 6.8 Hz), 0.98
(d, 3H, J ) 6.8 Hz); 13C NMR (75.5 MHz, CDCl3) δ 172.0, 165.7,
131.7, 128.5, 128.3, 127.1, 87.2, 71.2, 52.6, 32.4, 17.4, 17.2; IR
(neat) νmax 2963, 2877, 1740, 1646, 1581, 1451; CIMS (NH3 gas)
247.1, 188.1, 105.0, 49.0, 30.0; CIHRMS M+ (calculated for
[R]23 ) +17.8° (c ) 2.42, CHCl3).
D
(2S,3S)-2-N-((S)-P h en ylglycin yl)-3-h ydr oxyleu cin e Meth -
yl Ester (4). A dilute solution of aldol product 3 (10.7 g, 23.3
mmol) in a 3:1:1 mixture of THF/H2O/formic acid (230 mL, 0.1
M) was stirred at ambient temperature for 24 h and subse-
quently diluted portionwise with NaHCO3 solution to pH 7 (100
mL). The reaction mixture was extracted with EtOAc (3 × 25
mL), dried (MgSO4), and concentrated in vacuo. Purification is
accomplished either by recrystallization from 1:1 EtOAc/PE or
on SiO2 (50% f 100% EtOAc/PE) to afford 4 as a white solid
(5.2 g, 80%): 1H NMR (400 MHz, CDCl3) δ 7.39-7.26 (m, 5H),
3.83-3.77 (m, 2H), 3.69-3.66 (m, 1H), 3.62-3.59 (m, 1H), 3.57-
3.41 (m, 2H), 3.42 (s, 3H), 2.48 (s, br, 2H), 1.77-1.72 (m, 1H),
0.99 (d, 3H, J ) 6.8 Hz), 0.90 (d, 3H, J ) 6.4 Hz); 13C NMR
(75.5 MHz, CDCl3) δ 174.1, 140.0, 128.5, 127.8, 127.2, 77.8, 66.3,
63.7, 61.4, 51.6, 30.8, 19.2, 18.2; IR (neat) νmax 3400, 1710, 1640,
1400; CIMS (NH3 gas) 282.2, 250.2, 191.0, 183.0, 104.0; CIHRMS
M + H+ (calculated for C15H24NO4): 282.1705, found: 282.1703;
C
14H17NO3): 247.1208, found: 247.1220; [R]23 ) -105.7° (c )
D
1.32, CHCl3).
Ack n ow led gm en t. This work has been financially
supported by the National Institutes of Health
(RO1CA56304 and GM55740). We are grateful to Dr.
Edwin Iwanowicz for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectral
data for all reaction products (12 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
[R]23 ) +43.9° (c ) 1.63, CHCl3); mp ) 70-72 °C.
D
(2S,3S)-3-Hyd r oxyleu cin e Meth yl Ester (5). A dilute
solution of (2S,3S)-2-N-((S)-phenylglycinyl)-3-hydroxyleucine
methyl ester (4) (5.0 g, 17.8 mmol) in anhydrous MeOH (350
mL, 0.050 M) was treated with 10% Pd-C (1.0 g, 20 wt %). The
J O972013+