Asymmetric aldol route to hydroxyethylamine isostere: Stereoselective synthesis of the core unit of saquinavir

Full text of DOI:10.1021/jo9706943

6080
J . Org. Chem. 1997, 62, 6080-6082
dipeptide isosteres with a variety of designed side chain
substituents.
Asym m etr ic Ald ol Rou te to
Hyd r oxyeth yla m in e Isoster e:
Ster eoselective Syn th esis of th e Cor e Un it
of Sa qu in a vir
Arun K. Ghosh,* Khaja Azhar Hussain, and
Steve Fidanze
Department of Chemistry, University of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607
Received April 17, 1997
Hydroxyethylamine isosteres have been extensively
utilized in the synthesis of potent and selective HIV
protease inhibitors1 including saquinavir,2 a protease
inhibitor recently approved by the U.S. Food and Drug
Administration for the treatment of AIDS.3 These dipep-
tide mimics are typically prepared by opening the cor-
responding protected aminoalkyl epoxides with amines.
In connection with our study aimed at the design and
synthesis of novel protease inhibitors, we required an
enantioselective and efficient synthesis of a number of
protected aminoalkyl epoxides that are not limited to
amino acid derived substituents.4 We describe here a
convenient route to the versatile (1′S,2S)-(1′-((tert-butyl-
oxycarbonyl)amino)-2-phenylethyl)oxirane (2) utilizing an
asymmetric syn-aldol reaction and Curtius rearrange-
ment sequence. The epoxide 2 was converted to the core
unit of saquinavir5 and other protease inhibitors.1,2 The
present synthesis is easily adaptable to a range of other
We planned to insert both of the asymmetric centers
in hydroxyethylamine isostere 1 by Evans’ asymmetric
syn-aldol process.6 The requisite chiral oxazolidinone 5
was prepared from hydrocinnamic acid and commercially
available7 (4S,5R)-indano[1,2-d]oxazolidin-2-one by stan-
dard protocol. Aldol reaction of the boron enolate of 5
with (benzyloxy)acetaldehyde in CH2Cl2 at -78 °C pro-
vided the syn-aldol product 6 as a single diastereomer
in 88% yield after silica gel chromatography. Aldol
reaction of (S)-(-)-benzyl-2-oxazolidinone-derived car-
boximide also provided comparable yield (83%) of syn-
aldol product. The removal of the chiral auxiliary was
effected by exposure to lithium hydroperoxide in aqueous
THF at 0 °C for 1 h.8 To incorporate the amine func-
tionality, the resulting â-hydroxy acid was then subjected
to Curtius rearrangement9 with diphenylphosphoryl
azide and triethylamine in refluxing benzene to provide
the oxazolidinone 7 in 69% yield after chromatography.
The oxazolidinone ring stereochemistry was assigned on
the basis of the precedence that the Curtius rearrange-
ment proceeds with retention of configuration of the
(1) (a) Rich, D. H.; Green, J .; Toth, M. V.; Marshall, G. R.; Kent, S.
B. H. J . Med. Chem. 1990, 33, 1285. (b) Rich, D. H.; Sun, C.-Q.; Vara
Prasad, J . V. N.; Pathiasseril, A.; Toth, M. V.; Marshall, G. R.; Clare,
M.; Mueller, R. A.; Houseman, K. J . Med. Chem. 1991, 34, 1222. (c)
Ghosh, A. K.; Thompson, W. J .; McKee, S. P.; Duong, T. T.; Lyle, T.
A.; Chen, J . C.; Darke, P. L.; Zugay, J . A.; Emini, E. A.; Schleif, W. A.;
Huff, J . R.; Anderson, P. S. J . Med. Chem. 1993, 36, 292. (d) Ghosh,
A. K.; Thompson, W. J .; Lee, H. Y.; McKee, S. P.; Munson, P. M.;
Duong, T. T.; Darke, P. L.; Zugay, J . A.; Emini, E. A.; Schleif, W. A.;
Huff, J . R.; Anderson, P. S. J . Med. Chem. 1993, 36, 924. (e) Ghosh, A.
K.; Thompson, W. J .; Holloway, M. K.; McKee, S. P.; Duong, T. T.;
Lee, H. Y.; Munson, P. M.; Smith, A. M.; Wai, J . M.; Darke, P. L.;
Zugay, J . A.; Emini, E. A.; Schleif, W. A.; Huff, J . R.; Anderson, P. S.
J . Med. Chem. 1993, 36, 2300. (f) Ghosh, A. K.; Lee, H. Y.; Thompson,
W. J .; Culberson, J . C.; Holloway, M. K.; McKee, S. P.; Munson, P. M.;
Duong, T. T.; Smith, A. M.; Darke, P. L.; Zugay, J . A.; Emini, E. A.;
Schleif, W. A.; Huff, J . R.; Anderson, P. S. J . Med. Chem. 1994, 37,
1177. (g) Ghosh, A. K.; Thompson, W. J .; Fitzgerald, P. M. D.;
Culberson, J . C.; Axel, M. G.; McKee, S. P.; Huff, J . R.; Anderson, P.
S. J . Med. Chem. 1994, 37, 2506. (h) Vazquez, M. L.; Bryant, M. L.;
Clare, M.; DeCrescenzo, G. A.; Doherty, E. M.; Freskos, J . N.; Getman,
D. P.; Houseman, K. A.; J ulien, J . A.; Kocan, G. P.; Mueller, R. A.;
Shieh, H-S.; Stallings, W. C.; Stegeman, R. A.; Talley, J . J . J . Med.
Chem. 1995, 38, 581. (i) Ghosh, A. K.; Thompson, W. J .; Munson, P.
M.; Liu, W.; Huff, J . R. Bioorg. and Med. Chem. Lett. 1995, 5, 83. (j)
Ghosh, A. K.; Kincaid, J . F.; Walters, D. E.; Chen, Y.; Chaudhuri, N.
C.; Thompson, W. J .; Culberson, C.; Fitzgerald, P. M. D.; Lee, H. Y.;
McKee, S. P.; Munson, P. M.; Duong, T. T.; Darke, P. L.; Zugay, J . A.;
Schleif, W. A.; Axel, M. G.; Lin, J .; Huff, J . R. J . Med. Chem. 1996, 39,
3278 and references cited therein.
1
migrating carbon atom. Indeed, the observed H-NMR
(400 MHz) coupling constant of vicinal protons (J AB ) 8
Hz) is consistent with a syn-stereochemical relationship.10
Basic hydrolysis of oxazolidinone 7 with aqueous KOH
at 70 °C afforded the corresponding syn-amino alcohol
which was treated with di-tert-butyl dicarbonate in
CH2Cl2 at 23 °C to furnish the BOC derivative 8 in 87%
isolated yield (Scheme 1).
For conversion of 8 to the aminoalkyl epoxide 2, the
benzyl group was deprotected by catalytic hydrogenation
of 8 over Pearlman’s catalyst in ethyl acetate for 12 h.
The resulting diol was efficiently converted to epoxide 2
in the following two-step sequence: (1) treatment of the
diol with commercially available 1-(chlorocarbonyl)-1-
methylethyl acetate in dry chloroform at 23 °C; (2)
exposure of the corresponding chloroacetate derivative
to an excess of NaOMe in THF for 4 h to provide the
(2) (a) Roberts, N. A.; Martin, J . A.; Kinchington, D.; Broadhurst,
A. V.; Craig, J . C.; Duncan, I. B.; Galpin, S. A.; Handa, B. K.; Kay, J .;
Krohn, A.; Lambert, R. W.; Merrett, J . H.; Mills, J . S.; Parkes, K. E.
B.; Redshaw, S.; Ritchie, A. J .; Taylor, D. L.; Thomas, G. J .; Machin,
P. J . Science 1990, 248, 358. (b) Skinner, C.; Sedwick, A.; Bragman,
K.; Pinching, A. J .; Weber, J . Abstracts at the 9th Int. Conf. on AIDS,
Berlin, 1993.
(3) (a) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med.
Chem. 1994, 29, 133. (b) Katz, R. A.; Skalka, A. M. Annu. Rev. Biochem.
1994, 63, 133.
(6) (a) Evans, D. A.; Bartroli, J .; Shih, T. L. J . Am. Chem. Soc. 1981,
103, 2127. (b) Evans, D. A. Aldrichimica Acta 1982, 15, 23.
(7) Ghosh, A .K.; Duong, T. T.; McKee, S. P. J . Chem. Soc., Chem.
Commun. 1992, 1673. This chiral auxiliary is now available from
Aldrich Chemical Co.
(4) For previous synthesis of nonamino acid derived synthesis, see:
Ghosh, A. K.; McKee, S. P.; Lee, H. Y.; Thompson, W. J . J . Chem. Soc.,
Chem. Commun. 1992, 273 and see ref 1e.
(5) Parkes, K. E. B.; Bushnell, D. J .; Crackett, P. H.; Dunsdon, S.
J .; Freeman, A. C.; Gunn, M. P.; Hopkins, R. A.; Lambert, R. W.;
Martin, J . A.; Merrett, J . H.; Redshaw, S.; Spurden, W. C.; Thomas,
G. J . J . Org. Chem. 1994, 59, 3656.
(8) Evans, D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron Lett. 1987,
28, 6141.
(9) (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J . Am. Chem. Soc. 1972,
94, 6203. (b) Grunewald, G. L.; Ye, Q. J . Org. Chem. 1988, 53, 4021.
(c) Ghosh, A. K.; Liu, W. J . Org. Chem. 1996, 61, 6175.
(10) Ghosh, A. K.; McKee, S. P.; Thompson, W. J . Tetrahedron Lett.
1991, 32, 5729 and references cited therein.
S0022-3263(97)00694-4 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 17, 1997 6081
Sch em e 1a
Exp er im en ta l Section
All melting points are uncorrected. Analytical HPLC analyses
were performed on a µBondapak C-18 column, 4.6 mm × 25 cm,
40% CH3CN/H2O as solvent, flow rate 2.0 mL/min. Anhydrous
solvents were obtained as follows: methylene chloride, distilla-
tion from P4O10; tetrahydrofuran, distillation from sodium/
benzophenone; pyridine, distillation from CaH2. All other
solvents were HPLC grade. Column chromatography was
performed with Whatman 240-400 mesh silica gel under a low
pressure of 5-10 psi. Thin-layer chromatography (TLC) was
carried out with E. Merck silica gel 60 F-254 plates.
N-(3-P h en ylp r op ion yl)-(4S,5R)-in d a n o[ 1,2-d ]oxa zolid in -
2-on e (5). To a stirred solution of hydrocinnamic acid (4) (1 g,
6.65 mmol) in THF (15 mL) at -20 °C was added Me3CCOCl
(0.9 mL, 7.73 mmol) dropwise over a period of 5 min. After 10
min, Et3N (1.2 mL, 8.64 mmol) was added and the resulting
mixture was allowed to warm to -10 °C for 1 h. In a separate
flask, commercial (4S,5R)-indano[1,2-d]oxazolidin-2-one (1.28 g,
7.31 mmol, Aldrich) was dissolved in dry THF (15 mL), the
resulting solution was cooled to -78 °C, and to this solution was
added n-BuLi in hexanes (2.5 M solution, 2.9 mL) over a period
of 10 min. The cold solution was taken up in a syringe and
added to the mixed anhydride prepared above. After the mixture
was stirred for 30 min at -78 °C, the reaction was quenched
with aqueous sodium bisulfate (1 N, 10 mL). The mixture was
then concentrated under reduced pressure, and the residue was
extracted with EtOAc (3 × 10 mL). The combined extracts were
washed with aqueous NaHCO3 solution and then dried over
anhydrous Na2SO4 and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(25% EtOAc/hexanes) to afford 5 (1.62 g, 79%) as a white solid
(mp 168-170 °C). 1H NMR (200 MHz, CDCl3) δ, 7.57 (d, 1H, J
) 7.2 Hz), 7.28 (m, 8H), 5.93 (d, 1H, J ) 7 Hz), 5.27 (m, 1H),
3.37 (d, 2H, J ) 3.5 Hz), 3.26 (m, 2H), 3.02 (m, 2H); IR (neat)
3050, 2926, 1778, 1698, 1377, 1175, 1120, 1048, 755 cm-1; mass
(CI) m/ z 308 (M+ + H). Anal. Calcd for C19H17NO3: C, 74.25;
H, 5.57; N, 4.55. Found: C, 73.84; H, 5.53; N, 4.70.
(2S,3S)-N-[(2-Ben zyl-4-(ben zyloxy)-3-h yd r oxybu ta n oyl)-
(4S,5R)-in d a n o[1,2-d ]oxa zolid in -2-on e (6). To a stirred solu-
tion of 5 (800 mg, 2.6 mmol) in CH2Cl2 (3 mL) at 0 °C was added
dibutylboron triflate (3.4 mL, 3.38 mmol, Aldrich) followed by
ethyldiisopropylamine (0.68 mL, 3.9 mmol). The resulting
mixture was stirred at 23 °C for 1 h. The mixture was cooled to
-78 °C, and a CH2Cl2 solution of (benzyloxy)acetaldehyde (780
mg, 5.2 mmol) was added. The mixture was stirred at -78 °C
for 30 min and then warmed to 23 °C for 2 h. After this period,
the reaction was quenched with pH 7.4 buffer solution (2.5 mL).
The mixture was cooled to 0 °C, MeOH (7 mL) followed by a 2:1
mixture of MeOH and 30% H2O2 (6 mL) was added, and the
resulting mixture was stirred for an additional 1 h. After this
period, the reaction mixture was concentrated under reduced
pressure and the residue was extracted with EtOAc (2 × 15 mL).
The combined organic layers were washed with a saturated
NaHCO3 solution and brine and then dried over anhydrous
Na2SO4. Evaporation of the solvent gave a residue which was
chromatographed over silica gel (35% EtOAc/hexanes) to provide
6 (1.07 g, 88%) as a white solid (mp 82-83 °C). 1H NMR (200
MHz, CDCl3) δ 7.02-7.17 (m, 14 H), 5.72 (d, 1H, J ) 7 Hz),
4.96 (m, 1H), 4.52 (m, 1H), 4.5 (s, 2H), 4.2 (m, 1H), 3.52 (d, 2H,
J ) 6.1 Hz), 3.25 (d, 2H, J ) 5.2 Hz), 3.1 (d, 2H, J ) 8 Hz), 2.63
(d, 1H, J ) 4.4 Hz); IR (neat) 3510, 3055, 2921, 2857, 1693, 1361,
1119, 1027, 722 cm-1; mass (CI) m/ z 458 (M+ + H), 440, 350,
176. Anal. Calcd for C28H27NO5: C, 73.50; H, 5.94; N, 3.06.
Found: C, 73.82; H, 6.35; N, 3.0.
(4S,5S)-4-Ben zyl-5-((ben zyloxy)m eth yl)oxazolidin on e (7).
To a stirred mixture of 6 (950 mg, 2.07 mmol) in 50% aqueous
THF (4 mL) at 0 °C was added H2O2 (30%, 1 mL) followed by
LiOH‚H2O (173 mg, 4.14 mmol). The resulting reaction mixture
was stirred for 1 h at 0 °C, and the reaction was quenched with
an aqueous Na2SO3 solution (1.5 M, 5 mL). The mixture was
concentrated under reduced pressure, and the residue was
diluted with brine and extracted with CH2Cl2 (2 × 15 mL). The
combined extracts were dried over anhydrous Na2SO4 and
evaporated to obtain 297 mg (82%) of chiral oxazolidinone. The
aqueous layer was acidified to pH 1 with aqueous HCl (2 N) and
extracted with EtOAc (2 × 10 mL). The combined extracts were
dried over anhydrous Na2SO4 and concentrated under reduced
a
Key: (a) Me3CCOCl, Et3N, THF, -15 to 0 °C, then N-lithio-
(4S,5R)-indano[1,2-d]oxazolidin-2-one, -78 °C; (b) Bu2BOTf,
(iPr)2NEt, CH2Cl2, 0 °C, then BnOCH2CHO, -78 to 23 °C; (c)
LiOOH, THF:H2O (1:1), 0 °C; (d) (PhO)2P(O)N3, Et3N, PhH, 80
°C; (e) aqueous KOH, EtOH, 70 °C; (f) BOC2O, CH2Cl2, 23 °C; (g)
H2, Pd(OH)2, EtOAc; (h) AcOC(Me)2COCl, CHCl3, 23 °C, then
i
NaOMe, THF, 0 to 23 °C; (i) amine 9, PrOH, 70 °C.
epoxide 2 in 56% yield (from 8) after silica gel chroma-
tography.11 The epoxide 2 is the key intermediate for
the synthesis of hydroxyethylene12 and hydroxyethyl-
amine isosteres.1,2 For example, reaction of epoxide 2
with decahydroisoquinoline derivative 9 in 2-propanol at
reflux furnished the hydroxyethylamine isostere 10 in
75% yield after chromatography. The peptide isostere
10 has been previously converted to saquinavir5 and
other potent inhibitors.1,2
In summary, we have developed a stereocontrolled
route to aminoalkyl epoxide, an important intermediate
for the synthesis of HIV protease inhibitors. The ster-
eochemistry of both stereogenic centers was assembled
unequivocally by asymmetric syn-aldol reaction. The
present method should provide an enantioselective entry
to other useful dipeptide isosteres that are not limited
to amino acid derived side chain substituents. Applica-
tion of this method in the synthesis of novel protease
inhibitors is in progress.
(11) (a) Verheyden, J . P. H.; Moffatt, J . G. J . Org. Chem. 1972, 37,
2289. (b) Greenberg, S.; Moffatt, J . G. J . Am. Chem. Soc. 1973, 95,
4016.
(12) Evans, B. E.; Rittle, K. E.; Homnick, C. F.; Springer, J . P.;
Hirshfield, J .; Veber, D. F. J . Org. Chem. 1985, 50, 4615.

6082 J . Org. Chem., Vol. 62, No. 17, 1997
Notes
pressure to obtain a residue which was chromatographed over
silica gel (65% EtOAc/hexanes) to afford the corresponding acid
(465 mg).
chromatography over silica gel (80% EtOAc/hexanes) to provide
the diol (180 mg, 96%) as an oil.
To a stirred solution of the above diol (175 mg, 0.64 mmol) in
dry chloroform (1 mL) at 0 °C was added 1-(chlorocarbonyl)-1-
methylethyl acetate (137 mg, 0.83 mmol). The resulting mixture
was stirred at 23 °C for 3 h. After this period, the reaction was
quenched with saturated aqueous NaHCO3 solution and the
mixture was extracted with EtOAc (2 × 3 mL). The combined
extracts were washed with brine, dried over anhydrous Na2SO4,
and evaporated under reduced pressure. The resulting residue
was dissolved in dry THF (2 mL), and the solution was cooled
to 0 °C. To this solution was added solid NaOMe (51 mg, 0.64
mmol), and the reaction mixture was stirred for 4 h at 23 °C.
The above acid (410 mg, 1.37 mmol) was dissolved in dry
benzene (3 mL), and diphenylphosphoryl azide (450 mg, 1.64
mmol) followed by Et3N (0.25 mL, 1.77 mmol) was added. The
resulting mixture was heated at reflux for 4 h. After this period,
the reaction was cooled to 23 °C and diluted with EtOAc (6 mL).
The mixture was washed with a saturated aqueous NaHCO3
solution and dried over anhydrous Na2SO4. The solvents were
evaporated under reduced pressure, and the residue was chro-
matographed over silica gel (25% EtOAc/hexanes) to afford 7
(374 mg, 69% from 6) as an oil: 1H NMR (200 MHz, CDCl3) δ,
7.02-7.33 (m, 10 H), 5.1 (br s, 1H), 4.84 (q, 1H, J ) 6.5), 4.61
(s, 2H), 4.07 (m, 1H), 3.8 (d, 2H, J ) 5.9 Hz), 2.95 (dd, 1H, J )
13.3, 3.5 Hz), 2.7 (dd, 1H, J ) 13.3, 11.1 Hz); 13C NMR (50 MHz,
CDCl3) 157.89, 137.28, 136.65, 129.02, 128.84, 128.47, 127.9,
127.8, 127.1, 76.3, 73.74, 67.15, 55.89, 35.9; IR (neat) 3278, 3065,
The reaction was then quenched with
a saturated NH4Cl
solution (3 mL), and the layers were separated. The aqueous
layer was extracted with EtOAc (3 × 2 mL), and the combined
extracts were washed with brine, dried over anhydrous Na2SO4,
and evaporated under reduced pressure. The residue was
chromatographed over silica gel (25% EtOAc/hexanes) to afford
the title epoxide 2 (94 mg, 56%) as an amorphous solid (mp 123-
2922, 1671, 1385, 1234, 1071 cm-1; mass (CI) m/ z 298 (M+
H). Anal. Calcd for C18H19NO3: C, 72.70; H, 6.44; N, 4.71.
Found: C, 72.83; H, 6.31; N, 5.12.
+
124 °C); [R]23 -6.6 (c 0.67, CHCl3); 1H NMR (400 MHz, CDCl3)
D
(1S,2S)-1-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-1-ben zyl-3-
(ben zyloxy)p r op a n -2-ol (8). To a stirred solution of 7 (252
mg, 0.84 mmol) in 50% aqueous EtOH (1 mL) at 23 °C was added
solid KOH (190 mg, 3.5 mmol), and the mixture was heated at
70 °C for 3 h. After this period, the mixture was cooled to 23 °C
and neutralized to pH 7 with dilute HCl. The mixture was
concentrated under reduced pressure, and to the residue were
added CH2Cl2 (1 mL) and di-tert-butyl dicarbonate (368 mg, 1.7
mmol). The resulting mixture was stirred at 23 °C for 2 h. After
this period, saturated NH4Cl solution was added and the mixture
was extracted with ethyl acetate (2 × 5 mL). The combined
extracts were washed with brine, dried over anhydrous Na2SO4,
and then evaporated under reduced pressure. The residue was
purified by silica gel chromatography (35% EtOAc/hexanes) to
afford 8 (266 mg, 87%) as a white soild (mp 107-109 °C). 1H
NMR (200 MHz, CDCl3) δ, 7.02-7.28 (m, 10H), 4.73 (d, 1H, J )
7.8 Hz), 4.55 (s, 2H), 3.94 (m, 1H), 3.86 (m, 1H), 3.56 (d, 2H, J
) 5.7 Hz), 2.95 (br d, 1H, J ) 4.2 Hz), 2.87 (d, 2H, J ) 6.3 Hz),
1.35 (s, 9H); IR (neat) 3356, 3045, 2989, 2830, 2790, 1689, 1527,
1366, 1018 cm-1; mass (CI) m/ z 372 (M+ + H), 316, 272. Anal.
Calcd for C22H29NO4: C, 71.14; H, 7.86; N, 3.77. Found: C,
70.83; H, 8.10; N, 4.03.
δ 7.2-7.4 (m, 5H), 4.45 (br s, 1H), 3.68 (m, 1H), 2.9 (dd, 1H, J
) 13.7, 3.8 Hz), 2.9 (m, 2H), 2.81 (t, 1H, J ) 4.2 Hz), 2.75 (br s,
1H), 1.37 (s, 9H).
N-ter t-Bu tyl-2-[2(R)-h yd r oxy-4-p h en yl-3(S)-((ter t-bu tyl-
oxyca r bon yl)a m in o)bu tyl]d eca h yd r o-(4a S,8a S)-isoqu in o-
lin e-3(S)-ca r boxa m id e (10). A mixture of epoxide 2 (85 mg,
0.32 mmol) and decahydroisoquinoline 9 (92 mg, 0.38 mmol) in
2-propanol (2 mL) was heated at reflux for 2 h. The reaction
mixture was cooled to 23 °C and then concentrated under
reduced pressure. The residue was flash chromatographed over
silica gel (35% EtOAc/hexanes) to provide the title hydroxyeth-
ylamine isostere 10 (121 mg, 75%) as a semisolid: [R]23 -58 (c
D
0.67, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 5H), 5.83
(s, 1H), 4.88 (d, 1H, J ) 7 Hz), 3.9-3.58 (m, 3H), 3.08 (t, 1H, J
) 11 Hz), 2.9 (m, 2H), 2.65 (dd, 1H, J ) 14.7, 6.2 Hz), 2.62 (d,
1H, J ) 11.7 Hz), 2.26 (m, 2H), 1.94 (q, 1H, J ) 11.7 Hz), 1.85-
1.2 (m, 11H), 1.3 (s, 18H); mass (CI) m/ z 502 (M+ + H).
Ack n ow led gm en t. Financial support of this work
by the National Institute of Health (GM 53386) is
gratefully acknowledged. We thank Dr. Scott Laneman
of NSC Technologies for a generous gift of optically pure
decahydroisoquinoline derivative 9 for our studies. We
also thank Merck Research Laboratories and BASF,
Germany, for (1S,2R)-aminoindan-2-ol used for the
chiral auxiliary preparation.
2(S)-[1′-(S)-N-((ter t-Bu tyloxyca r bon yl)a m in o)-2-p h en yl-
et h yl]oxir a n e (2). To a stirred solution of 8 (250 mg, 0.69
mmol) in EtOAc (1.5 mL) was suspended Pd(OH)2 (15 mg), and
the mixture was hydrogenated under a balloon filled with
hydrogen for 12 h. The reaction mixture was then filtered
through a pad of Celite, and the Celite pad was washed with
MeOH (2 mL). The filtrate was concentrated under reduced
pressure to obtain
a
residue which was purified by flash
J O9706943