Practical Synthesis of Enantiopure Cyclic 1,2-Amino Alcohols via Catalytic Asymmetric Ring Opening of Meso Epoxides

Full text of DOI:10.1021/jo970146p

J . Org. Chem. 1997, 62, 4197-4199
4197
Ta ble 1. Asym m etr ic Rin g Op en in g of 2a -d w ith TMSN3
P r a ctica l Syn th esis of En a n tiop u r e Cyclic
1,2-Am in o Alcoh ols via Ca ta lytic
Asym m etr ic Rin g Op en in g of Meso
Ep oxid es
Ca ta lyzed by (R,R)-1a
% ee (%yield)b
entry
X
method Ac
method Bd
a
b
c
d
CH2
(CH2)2
O
93 (97)
85 (96)
97 (96)
95 (87)
94 (99)
88 (99)
97 (99)
95 (96)
Scott E. Schaus, J ay F. Larrow, and Eric N. J acobsen*
Department of Chemistry and Chemical Biology, Harvard
University, Cambridge, Massachusetts 02138
NCOCF3
a
All reactions were run neat on 25-50 mmol of epoxide at rt
using 1-2 mol % (R,R)-1, and the products were distilled from
Received J anuary 27, 1997
b
the catalyst under reduced pressure. Yield based on mass
In tr od u ction
recovery and corrected for purity, as determined by GC. c Method
d
A refers to reactions with complex 1a . Method B refers to
The importance of cyclic 1,2-amino alcohols is evident
from their presence in a wide variety of biologically
important molecules1 and in their successful application
as stereochemical control elements.2 The asymmetric
ring opening (ARO) of meso epoxides with TMSN3
catalyzed by chiral (salen)Cr(III) complexes (eq 1) pro-
vides efficient access to important representatives of this
class of compounds from inexpensive, commercially avail-
able starting materials.3 This paper provides a detailed
description of the synthesis of a series of valuable cyclic
trans- and cis-1,2-amino alcohols in optically pure form
using the ARO methodology.4
reactions with recycled complex 1b.
no detectable byproducts6 and, in certain cases, with
measurably higher enantioselectivity than does 1a (Table
1).7
Resu lts a n d Discu ssion
The fact that the ARO displays a second-order depen-
dence on catalyst concentration8 has a negative practical
consequence, as it limits to what extent catalyst loadings
can be decreased before the reaction rates become im-
practically slow (e.g., a catalyst loading decrease of a
factor of 10 leads to a 100-fold rate decrease). In this
context, the catalyst recycling procedure is especially
valuable, as it allows the production of multigram
quantities of enantiomerically enriched ring-opened prod-
ucts 3a -d from small amounts of catalyst (see Experi-
mental Section).
The synthesis of the enantiomerically pure trans-amino
alcohols 4a -c was effected through a straightforward
deprotection/reduction/recrystallization sequence (Scheme
1). Removal of the trimethylsilyl group was accomplished
in MeOH using a catalytic amount of TFA (0.1 mol %) at
room temperature. Reduction of the azide by addition
of 2 mol % PtO2 to the resulting methanolic solution and
hydrogenolysis under balloon pressure at room temper-
ature yielded the trans-amino alcohols in essentially
quantitative yields. The crude products obtained by
filtration from the hydrogenation catalyst and solvent
evaporation were recrystallized to chemical and enan-
tiomeric purity (>99% ee) with excellent product recov-
ery. A survey of other hydrogenation catalysts revealed
that 10% Pd/C was also effective at catalyzing the
reduction of azide, but the product obtained required
extensive purification resulting in lower yields. The one-
pot two-step procedure employing PtO2 thus proved to
be the most effective and operationally-simple method
for the production of gram quantities of enantiomerically
enriched trans-amino alcohols.
The (salen)Cr(III)Cl complex 1a effectively catalyzes
the ARO of various five- and six-membered ring-fused
meso epoxides (Table 1, method A). The reactions can
be run in the absence of solvent, and the ring-opened
products are conveniently isolated by vacuum distillation
of the reaction mixture. The nonvolatile residue recov-
ered after distillation has been characterized as azide
complex 1b,5 and this catalyst can be reused repeatedly
in ARO reactions (method B) without loss of catalyst
activity or enantioselectivity. In addition, complex 1b
catalyzes the formation of azido silyl ether product with
(1) See, for example: (a) Wang, R.; Wong, C.-H. Tetrahedron Lett.
1996, 37, 5427. (b) Vacca, J . et al. Proc. Natl. Acad. Sci. U.S.A. 1994,
91, 4096. (c) Kikelj, D.; Kidric, J .; Pristovsek, P.; Pecar, S.; Urleb, U.;
Krbavcic, A.; Ho¨nig, H. Tetrahedron 1992, 48, 5915. (d) Shioiri, Y.;
Hamada, Y. Heterocycles 1988, 27, 1035.
The corresponding cis-amino alcohols 5a -c were pre-
pared from the hydroxy acetamides derived from 4a -c
by inversion of the hydroxyl group (Scheme 1). Oxazoline
(2) (a) For a recent review: Ager, D. J .; Prakash, I.; Schaad, D. R.
Chem. Rev. 1996, 96, 8350. (b) Davies, I. W.; Senanayake, C. H.;
Larsen, R. D.; Verhoeven, T. R.; Reider, P. J . Tetrahedron Lett. 1996,
37, 1725.
(3) Mart´ınez, L. E.; Leighton, J . L.; Carsten, D. H.; J acobsen, E. N.
J . Am. Chem. Soc. 1995, 117, 5897.
(4) For alternative synthetic approaches, see: (a) Bo¨rner, A.; Holz,
J .; Kagan, H. B. Tetrahedron Lett. 1993, 34, 5273. (b) Barr, A. A.;
Frencel, I.; Robinson, J . B. Can. J . Chem. 1977, 55, 4180. (c) Tamao,
K.; Nakagawa, Y.; Ito, Y. J . Org. Chem. 1990, 55, 3438. (d) Seebach,
D.; Eberle, M. Chimia 1986, 40. 315. (e) Fu¨lo¨p, F.; Pihlaja, K.;
Neuvonen, K.; Berna´th, G.; Argay, G.; Ka´lma´n, A. J . Org. Chem. 1993,
58, 1967. (f) Didier, E.; Loubinoux, B.; Ramos Tombo, G. M.; Rihs, G.
Tetrahedron 1991, 47, 4941. (g) Fischer J . Org. Chem. 1995, 60, 2026.
(5) Leighton, J . L.; J acobsen, E. N. J . Org. Chem. 1996, 61, 389.
This paper also describes the synthesis of complex 1b directly from
1a by metathesis of the chloride ligand.
(6) As noted previously (ref 3), reactions employing catalyst 1a
produce detectable amounts ring-opened byproducts resulting from
chloride transfer, at levels commensurate with the amount of catalyst
used.
(7) CAUTION! Although these experiments have proceeded without
incident, extreme caution should be excercised in the handling of
organic and metal azides, particularly with manipulations that involve
heating of neat liquids or solid residues.
(8) Hansen, K. B.; Leighton, J . L.; J acobsen, E. N. J . Am. Chem.
Soc. 1996, 118, 10924.
S0022-3263(97)00146-1 CCC: $14.00 © 1997 American Chemical Society

4198 J . Org. Chem., Vol. 62, No. 12, 1997
Notes
Sch em e 1
Sch em e 2
formation with attendant inversion at the oxygen-bearing
stereocenter was accomplished by activation of the hy-
droxy group with SOCl2.9 The oxazolines thus obtained
were effectively pure by 1H NMR analysis, and conversion
to the pure cis-amino alcohols occurred upon heating the
crude oxazoline salt to reflux in 10% HCl for 1 h followed
by recrystallization of the hydrochloride salt.
Synthesis of pyrroline-derived 3,4-amino alcohols 6 and
7 was accomplished using a route similar to the one
outlined above, although circumventing the use of acidic
conditions (Scheme 2). Removal of the trimethylsilyl and
trifluoroacetyl groups with basic methanol, followed by
selective N-protection with di-tert-butyl dicarbonate af-
forded the corresponding Boc-protected azido alcohol.
Reduction under H2 catalyzed by PtO2 yielded the trans-
amino alcohol 6, which was recrystallized to >99% ee in
85% overall yield from 3d . Acylation with TFAA followed
by mesylation and base-induced ring closure generated
the 2-trifluoromethyl oxazoline.10 Hydrolysis with K2CO3
in aqueous methanol yielded the cis-amino alcohol 7 in
92% yield.
pure by GC and 85% ee by chiral GC analysis. Meth od B. The
ARO was carried out using catalyst 1b recovered from method
A and 50 mmol of cyclohexene oxide. Yield from 2b: 10.6 g,
49.8 mmol, 99%; 87% ee.
(3S,4S)-4-Azid o-3-(tr im eth ylsiloxy)tetr a h yd r ofu r a n (3c).
Meth od A. The product was isolated by distillation (<0.5
mmHg, 45 °C) as a clear white oil (9.95 g, 49.5 mmol, 99%), 97%
pure by GC and 97% ee by chiral GC analysis. Meth od B. Yield
from 2c (50 mmol): 10.0 g, 49.7 mmol, 99%; 97% ee.
(3S,4S)-4-Azid o-3-(t r im e t h ylsiloxy)-1-(2,2,2-t r iflu or o-
a cetyl)p yr r olid in e (3d ). Meth od A. The product was isolated
by distillation (<0.5 mmHg, 90 °C) as a clear white oil (13.5 g,
45.6 mmol, 91%) which was shown to be 96% pure by GC and
95% ee by chiral GC analysis. Meth od B. Yield from 2d (50
mmol): 14.2 g, 48.0 mmol, 96%; 95% ee.
Gen er a l P r oced u r e for t h e Syn t h esis of tr a n s-Am in o
Alcoh ols fr om 3: (1S,2S)-2-Am in ocyclop en ta n ol (4a ). A 1
L flask equipped with a stirbar was charged with 3a (20.3 g,
102 mmol), MeOH (340 mL, 0.3 M), and TFA (7 µL, 0.09 mmol),
and the mixture was allowed to stir at rt for 30 min. The
resulting solution was treated with solid PtO2 (432 mg, 1.90
mmol) and placed under a H2 atmosphere (balloon pressure) and
stirred for 40 h at rt. The solution obtained by filtration through
Celite and washing the filter cake with MeOH was concentrated
in vacuo to produce a clear tan-colored solid. This material was
dissolved in 30 mL of hot toluene, and the volume of the solution
was reduced under reduced pressure to 30 mL and then cooled
to 4 °C. The resulting crystals were separated from the mother
liquor and rinsed with cold toluene. The recrystallization
procedure was repeated twice to yield amino alcohol 4a in >99%
ee (determined by chiral GC analysis of the N,O-bis-trifluoro-
acetyl derivative obtained by treatment of the amino alcohol with
TFAA [Chiraldex γ-TA (20 m × 0.25 mm i.d. × 0.125 µm film),
Advanced Separation Technologies, Inc., Whippany, NJ , cat. no.
71020, 100 °C isothermal]. Due to its hygroscopic nature, the
amino alcohol was converted to the HCl salt for the purposes of
characterization. Crystalline 4a was dissolved in 10 mL of EtOH
and diluted to 250 mL with Et2O. Gaseous HCl was bubbled
through until no more precipitate was formed. The mixture was
filtered and the off-white solid collected to yield 12.8 g (93 mmol,
91%). [R]26D +29.7 (c 1.95, EtOH); 1H NMR (CD3OD, 400 MHz)
δ 4.04 (dd, 1H, J ) 6.6 and 13.0 Hz), 3.24 (dd, 1H, J ) 6.2 and
8.0 Hz), 2.13-2.18 (m, 1H), 1.99-2.02 (m, 1H), 1.75-1.83 (m,
2H), 1.55-1.65 (m, 2H); 13C NMR (CD3OD, 100 MHz) δ 76.7,
59.7, 33.3, 28.8, 21.1. HRMS calcd for C5H15N2O (M + NH4)+:
119.1184. Found: 119.1188.
(1S,2S)-2-Am in ocycloh exa n ol (4b). The crude solid prod-
uct obtained from the hydrogenation reaction was dissolved in
60 mL of hot toluene, and the solution was cooled to 4 °C. The
mother liquor was decanted, and the resulting crystals were
rinsed with cold toluene. The recrystallization procedure was
repeated, and the solid was collected by filtration to yield the
amino alcohol in >99% ee (determined by chiral HPLC analysis
of the 2,4-dinitroaniline product obtained by reaction with
Sanger’s reagent, [Chiralcel OD (250 cm × 4.6 mm i.d.), Chiral
Technologies, Inc., 1.0 mL/min, 75:25 hexanes:IPA]. The amino
alcohol was converted to its HCl salt (9.40 g, 81.6 mmol, 83%)
for the purposes of characterization and storage. 4b‚HCl:
Opaque white solid. [R]26D +37.0 (c 1.10, EtOH); 1H NMR (CD3-
OD, 400 MHz) δ 3.36-3.41 (m, 1H), 2.79-2.85 (m, 1H), 2.01-
2.04 (m, 2H), 1.76-1.78 (m, 2H), 1.30-1.40 (m, 4H); 13C NMR
(CD3OD, 100 MHz) δ 72.4, 57.7, 35.2, 30.3, 25.13, 25.08. HRMS
calcd for C6H14NO (M + H)+: 116.1075. Found: 116.1079.
The ARO of meso epoxides with TMSN3 catalyzed by
(R,R)-1 thus provides a most sensible route to an assort-
ment of useful trans- and cis-amino alcohols in optically
pure form. The high volumetric productivity and ease
of product isolation, as well as the possibility of recycling
the catalyst with no loss of catalytic activity, render the
ARO approach extremely attractive for the synthesis of
amino alcohols on either laboratory or industrial scale.
Exp er im en ta l Section
Rep r esen ta tive P r oced u r e for th e Asym m etr ic Rin g
Op en in g of Meso E p oxid es w it h TMSN3: Met h od A.
(1S,2S)-2-Azid o-1-(tr im eth ylsiloxy)cyclop en ta n e (3a ).
A
100 mL flask equipped with a stirbar was charged with 632 mg
of (R,R)-1a (1.00 mmol, 0.02 equiv), flushed with N2, and sealed.
Cyclopentene oxide (4.40 mL, 50.0 mmol) and TMSN3 (6.90 mL,
52.5 mmol, 1.05 equiv) were added sequentially at rt. The
reaction mixture was allowed to stir 12 h, at which time the
excess TMSN3 was removed under reduced pressure, and the
product 3a was isolated by vacuum distillation (<0.5 mmHg,
40 °C) to afford a clear white oil (9.90 g, 49.7 mmol, 99%) which
was shown to be 98% pure by GC and in 93% ee by chiral GC
analysis.
Meth od B. The flask containing catalyst from method A was
flushed with N2 and then charged with cyclopentene oxide (8.80
mL, 100 mmol) and TMSN3 (13.8 mL, 105 mmol). The reaction
was allowed to stir at rt for 24 h at which time the remaining
TMSN3 was removed in vacuo, and the product was isolated by
vacuum distillation to provide 3a (19.8 g, 99.3 mmol, 99%) in
94% ee by chiral GC analysis.
(1S,2S)-2-Azid o-1-(t r im et h ylsiloxy)cycloh exa n e (3b ).
Meth od A. The product was isolated by distillation (<0.5
mmHg, 50 °C) as a clear white oil (10.6 g, 49.5 mmol, 99%), 97%
(9) Bannard, R. A. B.; Gibson, N. C. C.; Parkkari, J . H. Can. J . Chem.
1971, 49, 2064.
(10) Golding, B. T.; Nassereddin, I. K. J . Chem. Soc., Perkin Trans.
1 1985, 2017.

Notes
(3S,4S)-4-Am in o-3-h yd r oxytetr a h yd r ofu r a n (4c). The
J . Org. Chem., Vol. 62, No. 12, 1997 4199
570 mL of MeOH (0.1 M) and treated with solid K2CO3 (7.93 g,
57.4 mmol). The mixture was allowed to stir at rt for 5 h solvent
was removed in vacuo, and the residue was dissolved in 60 mL
of 10% Na2CO3 and 60 mL of acetone. The solution was cooled
to 0 °C and treated with 13.2 mL (57.4 mmol) of di-tert-butyl
dicarbonate. The reaction was allowed to warm to rt and stirred
for 12 h. The resulting mixture was diluted with H2O and
extracted with CHCl3 (3×). The combined extracts were dried
over Na2SO4 and concentrated, and the residue was purified by
chromatography over SiO2 using 9:1 to 3:1 hexanes:acetone as
the eluent. The clear white oil obtained was dissolved in 190
mL of MeOH and treated with 255 mg (1.12 mmol) of PtO2. The
reaction was placed under H2 (balloon pressure) and stirred 26
h at rt. The mixture was filtered through Celite, and the filter
cake was rinsed with MeOH. Concentration of the filtrate
provided crude 6 as an opaque white solid. This material was
dissolved in 200 mL of boiling CH2Cl2. The volume was
concentrated to 120 mL, and the solution was allowed to cool to
4 °C. The solid was collected by filtration to yield 6 (9.86 g, 48.7
mmol, 85%) in >99% ee (chiral HPLC analysis of the product
obtained by reaction with Sanger’s reagent, Pirkle Covalent
S-N1N-Naphthylleucine column, 0.60 mL/min, 96:4 hexanes:IPA
for 57 min to 95:5 from 59-80 min). [R]26D -2.3 (c 1.03, EtOH);
1H NMR (CD3OD, 400 MHz) δ 3.94 (s(br), 1H), 3.56-3.60 (m,
2H), 3.12-3.24 (m, 3H), 1.45 (s, 9H); 13C NMR (CD3OD, 100
MHz) δ 156.6, 80.9, 77.0, 76.4, 58.4, 57.8, 52.9, 52.6, 52.4, 52.2,
29.1. HRMS calcd for C9H19N2O3 (M + H)+: 203.1396. Found:
203.1395.
crude solid product obtained from the hydrogenation reaction
was dissolved in 10 mL of hot EtOH, and the solution was
diluted with 15 mL of Et2O and cooled to 4 °C. The mother
liquor was decanted, and the resulting crystals were rinsed with
cold Et2O. Chiral GC analysis of the N,O-bis-trifluoroacetyl
derivative indicated that the amino alcohol was present in >99%
ee (γ-TA, 120 °C isothermal). The HCl salt was generated as
described above: 12.8 g (93 mmol, 91%). [R]26 +16.9 (c 1.79,
D
EtOH); 1H NMR (CD3OD, 400 MHz) δ 4.33 (s, br, 1H), 4.14 (dd,
1H, J ) 5.4 and 10.0 Hz), 4.01 (dd, 1H, J ) 4.9 and 10.5 Hz),
3.80 (d, 1H, J ) 10.5 Hz), 3.59-3.63 (m, 2H); 13C NMR (CD3-
OD, 100 MHz) δ 75.2, 75.0, 70.3, 59.6. HRMS calcd for
C4H13N2O2 (M + NH4)+: 121.0977. Found: 121.0979.
Gen er a l P r oced u r e for th e Syn th esis of cis-Am in o
Alcoh ols fr om 4: (1R,2S)-2-Am in ocyclop en ta n ol Hyd r o-
ch lor id e (5a ). A 250 mL flask equipped with a stir bar was
charged with 4.82 g (35.2 mmol) of the HCl salt of 4a . The
material was suspended in 35 mL of acetone and cooled to 0 °C.
The rapidly-stirred mixture was treated with 35 mL of aqueous
10% Na2CO3 followed by slow addition of Ac2O (3.33 mL, 35.2
mmoL). The reaction was allowed to warm to rt over 1 h and
stirred for an additional 2 h, during which time the solution
became homogeneous. The reaction was diluted with 10 mL
each of NaHCO3 (saturated) and NaCl (saturated). The solution
was then extracted 5 × 9:1 CHCl3:IPA. The combined organic
extracts were dried over Na2SO4, filtered, and concentrated to
yield 4.75 g (33.3 mmol, 95%) of the crude hydroxy acetamide
as a viscous oil. This material was dissolved in 17 mL of CHCl3
and slowly added to neat SOCl2 with stirring (10.2 mL, 141
mmol) at 0 °C. The reaction was allowed to warm to rt over 1
hour and stirred for an additional 2 h. The crude mixture was
concentrated in vacuo to yield the cis-fused bicyclic oxazoline‚-
HCl salt. Analysis of the 1H NMR spectrum of the crude product
indicated clean conversion to the oxazoline salt (see Supporting
Information), so this material was used without further purifica-
tion. The material was dissolved in 117 mL of aqueous 10% HCl
and heated to reflux for 1 h. The cooled solution was concen-
trated in vacuo, and the resulting residue was dissolved in 1:1
MeOH:CH2Cl2. The mixture was filtered through Celite, and
the filtrate was concentrated to yield off-white crystals which
were recrystallized from EtOH/Et2O to afford 4.30 g (31.2 mmol,
(3R,4S)-4-Am in o-3-h yd r oxy-1-(ter t-bu toxyca r bon yl)p yr -
r olid in e (7). A 250 mL oven-dried flask was charged with 6
(4.34 g, 21.5 mmol) and a stir bar, sealed with a rubber septum,
and placed under N2. The material was suspended in 70 mL of
THF (0.3 M) and cooled to 0 °C, and TFAA (3.03 mL, 21.5 mmol)
and TEA (3.60 mL, 25.8 mmol) were added sequentially. The
reaction was allowed to warm to rt and stirred 12 h at which
time the solution was diluted with H2O and extracted 3 × 9:1
CHCl3:IPA. The combined organic extracts were dried over Na2-
SO4, filtered, and concentrated in vacuo. The crude trifluoro-
acetamide thus obtained was dissolved in 110 mL of CH2Cl2 (0.2
M) and cooled to 0 °C under N2, followed by addition of TEA
(3.6 mL, 25.8 mmol) and MsCl (1.48 mL, 23.6 mmol). The
reaction was allowed to stir 15 min at 0 °C and then at rt for 1
h. Oxazoline formation was affected by treatment of the reaction
mixture with DBU (9.64 mL, 64.5 mmol). Stirring was contin-
ued for 30 min at which time the reaction mixture was
concentrated under reduced pressure, filtered through SiO2, and
rinsed with 300 mL of 3:2 hexanes:acetone. The filtrate was
concentrated, and the crude oil was dissolved in 80 mL of MeOH
and 40 mL of H2O. Hydrolysis was effected by addition of solid
K2CO3 (18.0 g, 129 mmol). The reaction was allowed to stir for
10 h at which time the volume was reduced in vacuo. The
aqueous layer was extracted 5 × 9:1 CHCl3:IPA, and the
combined extracts were dried over K2CO3. The extracts were
filtered and concentrated to yield a crude solid which was
recrystallized from CH2Cl2 to yield 7 (3.98 g, 19.7 mmol, 92%)
89%) of opaque white crystals of 5a ‚HCl. [R]26 -18.6 (c 1.14,
D
EtOH); 1H NMR (CD3OD, 400 MHz) δ 4.21 (dd, 1H, J ) 4.1 and
8.2 Hz), 3.40 (dd, 1H, J ) 7.9 and 13.0 Hz), 2.01-2.05 (m, 1H),
1.88-1.94 (m, 2H), 1.64-1.75 (m, 3H); 13C NMR (CD3OD, 100
MHz) δ 71.8, 55.6, 33.7, 28.5, 21.3. HRMS calcd for C5H15N2O
(M + NH4)+: 119.1184. Found: 119.1185.
(1R,2S)-2-Am in oh exa n ol Hyd r och lor id e (5b). The solid
obtained from hydrolysis of the oxazoline was recrystallized from
EtOH/Et2O to yield 4.24 g (28.0 mmol, 93%) of opaque white
crystals. [R]26 -27.9 (c 1.10, EtOH); 1H NMR (CD3OD, 400
D
MHz) δ 3.95-3.96 (m, 1H), 3.29-3.31 (m, 1H), 1.57-1.79 (m,
6H), 1.39-1.42 (m, 2H); 13C NMR (CD3OD, 100 MHz) δ 66.5,
54.0, 32.3, 26.1, 24.2, 20.1. HRMS calcd for C6H13NO (M)+:
115.0997. Found: 115.0997.
as opaque white platelets. [R]26 +5.0 (c 1.08, EtOH); 1H NMR
D
(CD3OD, 400 MHz) δ 4.04-4.06 (m, 1H), 3.51-3.56 (m, 1H), 3.44
(td, 1H, J ) 4.4 and 12.1 Hz), 3.33 (m, 1H), 3.01 (t, 1H, J ) 10.1
Hz), 1.45 (s, 9H); 13C NMR (CD3OD, 100 MHz) δ 156.4, 80.92,
80.86, 72.3, 71.6, 55.0, 54.5, 54.0, 53.7, 51.3, 50.9, 28.7. HRMS
calcd for C9H19N2O3 (M + H)+: 203.1396. Found: 203.1391.
(3R,4S)-4-Am in o-3-h yd r oxytetr a h yd r ofu r a n Hyd r och lo-
r id e (5c). A 250 mL flask was charged with 4c (3.03 g, 29.5
mmol), capped with a rubber septum, placed under N2 atmo-
sphere, and cooled to 0 °C. The material was suspended in 30
mL of CH2Cl2, and then Ac2O (8.40 mL, 88.5 mmol) was added
by syringe. The reaction was allowed to warm to rt over 1 hour
at which time the reaction became homogenous. The reaction
was allowed to stir at room temperature for 1 h, and then solvent
was removed in vacuo to yield the crude acetamide as an off-
white solid. This material was converted to the crude cis-amino
alcohol 5c‚HCl according to the general procedure. The crude
material was dissolved in 10 mL of hot EtOH and diluted with
20 mL of THF. The mixture was heated until dissolution was
complete and then cooled to 4 °C. After 18 h, the resulting
opaque white platelets were collected by vacuum filtration to
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (GM-43214). We thank
Charles J . Boudreau, Matthew B. Francis, and Sandra
A. Filla for preliminary work and the Ford Foundation
and Eli Lilly for Predoctoral fellowships to S.E.S. and
J .F.L., respectively.
Su p p or t in g In for m a t ion Ava ila b le: Chromatographic
analyses of racemic and enantiomerically pure trans-amino
alcohol derivatives, and copies of 1H NMR spectra of all
relevant synthetic intermediates and products (25 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.
yield 5c‚HCl (3.95 g, 28.3 mmol, 96%). [R]26 -2.6 (c 1.03,
D
EtOH); 1H NMR (CD3OD, 400 MHz) δ 4.50 (dd, 1H, J ) 5.2 and
8.4 Hz), 3.91-3.99 (m, 2H), 3.72-3.82 (m, 3H); 13C NMR (CD3-
OD, 100 MHz) δ 75.3, 70.2, 70.1, 54.0. HRMS calcd for C4H10
NO2 (M + H)+: 104.0712. Found: 104.0713.
-
(3S,4S)-4-Am in o-3-h yd r oxy-1-(ter t-bu toxyca r bon yl)p yr -
r olid in e (6). A 1 L flask equipped with a stirbar was charged
with 3d (17.01 g, 57.4 mmol). The material was dissolved in
J O970146P