(1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethylammonium benzoate, a versatile building block for chiral 2-aminoalkanols: Concise synthesis and application to nelfinavir, a potent HIV-protease inhibitor

Article abstract of DOI:10.1021/jo991793e

A concise synthesis of a versatile chiral C4 building block for 2- aminoalkanols, (1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]2- hydroxyethylammonium benzoate (1a), was described. 1 (1a and its enantiomener 1b) acted as four stereoisomers of optically active 2-amino-1,3,4- butanetriol. The versatility of 1 was demonstrated by its application to the practical synthesis of nelfinavir (2), a potent HIV-protease inhibitor, as well as by the stereospecific synthesis of three diastereomers of 2.

Full text of DOI:10.1021/jo991793e

J . Org. Chem. 2000, 65, 1623-1628
1623
(1S)-1-[(4R)-2,2-Dim eth yl-1,3-d ioxola n -4-yl]-2-h yd r oxyeth yla m m on iu m
Ben zoa te, A Ver sa tile Bu ild in g Block for Ch ir a l 2-Am in oa lk a n ols:
Con cise Syn th esis a n d Ap p lica tion to Nelfin a vir , a P oten t
HIV-P r otea se In h ibitor
Takashi Inaba,* Yasuki Yamada, Hiroyuki Abe, Shoichi Sagawa, and Hidetsura Cho
Central Pharmaceutical Research Institute, J apan Tobacco, Inc 1-1,
Murasaki-cho Takatsuki Osaka, 569-1125, J apan
Received November 19, 1999
A concise synthesis of a versatile chiral C4 building block for 2-aminoalkanols, (1S)-1-[(4R)-2,2-
dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethylammonium benzoate (1a ), was described. 1 (1a and its
enantiomer 1b) acted as four stereoisomers of optically active 2-amino-1,3,4-butanetriol. The
versatility of 1 was demonstrated by its application to the practical synthesis of nelfinavir (2), a
potent HIV-protease inhibitor, as well as by the stereospecific synthesis of three diastereomers of
2.
In tr od u ction
equivalents, used in the above investigations, were
prepared from isoascorbic acid,1h,4c ascorbic acid,4b,5b
tartaric acid,6 chiral aziridino alcohols obtained by en-
zymatic method,7 chiral R-keto-â-lactam,8 erythrulose,9
and chiral epoxides obtained by Katsuki-Sharpless
asymmetric epoxidation,10 in various protected and un-
protected forms. Recently, Sharpless asymmetric ami-
nohydroxylation has been utilized for the preparation of
ABT equivalents employing 2-butene-1,4-diol derivatives
as substrates.11 To practically utilize ABT as a versatile
building block in various syntheses, ABT should be
available on a large scale and in a favorably protected
form for the selective treatment of its three hydroxyl
groups and an amino group. From this point of view,
there still remained problems in generation of versatile
ABT equivalents. Herein described is a concise and
scalable preparation of favorably protected ABT, i.e.,
(1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethyl-
ammonium benzoate (1a ) and its enantiomer 1b, which
possess three readily differentiated hydroxyls and a free
amino group. Application of 1 (1a and 1b) to the synthesis
of nelfinavir (2, a potent HIV-protease inhibitor)12 and
Chiral 2-aminoalkanol components are often seen in
many biologically active compounds with all sorts of
relative and absolute stereochemical structures. From the
point of view of synthetic chemistry, it is rational to
consider that optically active 2-amino-1,3,4-butanetriol
(ABT) is the smallest suitable retrosynthetic unit for the
chiral 2-aminoalkanol component, because the primary
hydroxyl groups at the both ends of ABT act as handles
for further extension including carbon-carbon bond
formation. In fact, ABT equivalents have been used for
the production of biologically important compounds in-
cluding sphingosines,1 FR900482 (an antitumor antibi-
otic),2 kainic acid,3 liposidomycins (bacterial peptidogly-
can synthesis inhibitors),4 and glycomimetics.5 ABT
(1) (a) Roush, W. R.; Adam, M. A. J . Org. Chem. 1985, 50, 3752. (b)
Shibuya, H.; Kawashima, K.; Ikeda, M.; Kitagawa, I. Tetrahedron Lett.
1989, 30, 7205. (c) Mori, K.; Kinsho, T. Liebigs Ann. Chem. 1991, 1309.
(d) Shibuya, H.; Kawashima, K.; Narita, N.; Ikeda, M.; Kitagawa, I.
Chem. Pharm. Bull. 1992, 40, 1154. (e) Metz, K.; Honda, M.; Komori,
T. Liebigs Ann. Chem. 1993, 55. (f) Shibuya, H.; Kurosu, M.; Minagawa,
K.; Katayama, S.; Kitagawa, I. Chem Pharm. Bull. 1993, 41, 1534. (g)
Miyata, O.; Yamaguchi, S.; Ninomiya, I.; Naito, T.; Okamura, K. Chem.
Pharm. Bull. 1996, 44, 636. (h) Tuch, A.; Sanie`re, M.; Merrer, Y. L.;
Depezay, J . C. Tetrahedron Asymmetry 1996, 7, 897.
(2) (a) Yoshino, T.; Nagata, Y.; Itoh, E.; Hashimoto, M.; Katoh, T.;
Terashima, S. Tetrahedron Lett. 1996, 37, 3475. (b) Katoh, T.; Yoshino,
T.; Nagata, Y.; Nakatani, S.; Terashima, S. Tetrahedron Lett. 1996,
37, 3479. (c) Rollins, S. B.; Williams, R. M. Tetrahedron Lett. 1997,
38, 4033. (d) Yoshino, T.; Nagata, Y.; Itoh, E.; Hashimoto, M.; Katoh,
T.; Terashima, S. Tetrahedron, 1997, 53, 10239.
(3) Takano, S.; Sugihara, T.; Satoh, S.; Ogasawara, K. J . Am. Chem.
Soc. 1988, 110, 6467.
(4) (a) Spada, M. R.; Ubukata, M.; Isono, K. Heterocycles 1992, 34,
1147. (b) Kim, K. S.; Cho, I. H.; Ahn, Y. H.; Park, J . I. J . Chem. Soc.,
Perkin Trans. 1 1995, 1783. (c) Pelletier, C. G.; Charvet, I.; Merrer, Y.
L.; Depezay, J . C. J . Carbohyd. Chem. 1997, 16, 129.
(5) (a) Chan, A. W. Y.; Ganem, B. Tetrahedron Lett. 1995, 36, 811.
(b) Banwell, M.; Savi, C. D.; Hockless, D.; Watson, K. Chem. Commun.
1998, 645.
(6) Takano, S.; Kurotaki, A.; Sekiguchi, Y.; Satoh, S.; Hirama, M.;
Ogasawara, K. Synthesis 1986, 811. See refs 1c, 1e, 2a, 2d, and 3, also.
(7) Fuji, K.; Kawabata, T.; Kiryu, Y.; Sugiura, Y. Heterocycles 1996,
42, 701.
(8) Palomo, C.; Aizpurua, J . M.; Ganboa, I.; Carreaux, F.; Cuevas,
C.; Maneiro, E.; Ontoria, J . M. J . Org. Chem. 1994, 59, 3123.
(9) Dequeker, E.; Compernolle, F.; Toppet, S.; Hoornaert, G. Tetra-
hedron 1995, 51, 5877.
(10) (a) Behrens, C. H.; Sharpless, K. B. J . Org. Chem. 1985, 50,
5696. (b) Hatakeyama, S.; Matsumoto, H.; Fukuyama, H.; Mukugi, Y.;
Irie, H. J . Org. Chem. 1997, 62, 2275. See refs 1a, 1b, 1d, 2a, 2c, 2d,
and 4a, also.
(11) Han, H.; Cho, C. W.; J anda, K. D. Chem. Eur. J . 1999, 5, 1565.
(12) (a) Kaldor, S. W.; Kalish, V. J .; Davies, J . F., II; Shetty, B. V.;
Fritz, J . E.; Appelt, K.; Burgess, J . A.; Campanale, K. M.; Chirgadze,
N. Y.; Clawson, D. K.; Dressman, B. A.; Hatch, S. D.; Khalil, D. A.;
Kosa, M. B.; Lubbehusen, P. P.; Muesing, M. A.; Patick, A. K.; Reich,
S. H.; Su, K. S.; Tatlock, J . H. J . Med. Chem. 1997, 40, 3979. (b)
Dressman, B. A.; Fritz, J . E.; Hammond, M.; Hornback, W. J .; Kaldor,
S. W.; Kalish, V. J .; Munroe, J . E.; Reich, S. H.; Tatlock, J . H.;
Shepherd, T. A.; Rodriguez, M. J . U. S. Patent 5,484,926, 1994
(Agouron Pharmaceuticals, Inc.); Chem. Abstr. 1995, 123, 256539v.
10.1021/jo991793e CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/01/2000

1624 J . Org. Chem., Vol. 65, No. 6, 2000
Inaba et al.
Sch em e 1a
its diastereomers (3-5), demonstrates the versatility of
1 as ABT equivalent.
a
Reaction conditions: (a) CbzCl, NaHCO3, toluene, H2O; (b)
PPTS, acetone; (c) MsOH (1.25 equiv), Me2C(OMe)2 (10 mol %),
acetone; (d) Pd(C), H2, PhCO2H, 2-propanol.
selective preparation of 8 and 9, precursors of 6, have
recently become available by means of highly selective
asymmetric aminolysis of meso epoxide 7 using Ti-(S)-
1,1′-bi-2-naphthoxide complex as a chiral catalyst.14
Initially, isomerization of 10 to 11, after protection of the
amino group of 6 with a Cbz group, was examined.
Although isomerization of 10 took place by treatment
with PPTS in acetone, the product was an intractable
oily isomeric mixture containing desired 11 as a major
component (less than 85% selectivity, NMR), which could
not be isolated in pure form even by column chromatog-
raphy (Scheme 1). Direct isomerization of 6 to 1a was
impractical because of the extraction difficulty of the
product due to its water-soluble nature, again. In con-
trast, treatment of 8 with 1.25 equiv of MsOH or dried
TsOH in acetone resulted in smooth migration of ac-
etonide15 and following catalytic hydrogenolysis of the
equilibrium mixture in the presence of benzoic acid
provided pure 1a in 82% from 8 after recrystallization.
The HPLC analysis indicated that the equilibrium mix-
ture, obtained by the acid treatment, was comprised of
desired 12 (91%), 8 (7%), and an unidentified isomer
(2%).16 In addition to the higher selectivity of desired 12
in the isomerization, the advantage of this method is that
enantiomerically and diastereomerically pure 1a can be
efficiently obtained by recrystallization. In this hydro-
Resu lts a n d Discu ssion
We reported that seven-membered ring amino alcohol
6 was a novel and suitable ABT equivalent in the context
of practical synthesis of 2.13 In the study, differentiation
of the left primary hydroxyl group from the right one of
6, in which both hydroxyl groups were protected as an
acetonide, was carried out by oxazoline formation taking
advantage of an amide group introduced on the amino
group of 6. However, 6 seemed to have limitations in its
wide use for the production of other compounds possess-
ing chiral 2-aminoalkanol component(s), since the suc-
cessful differentiation of the two hydroxyl groups was
restricted to the cases that the amino group was protected
by an amide group. Generally, removal of amide-protec-
tion requires strongly acidic conditions, and it could not
be applied to highly functionalized compounds. In con-
trast to 6, the regioisomer 1a is expected to be of wider
application, since the three hydroxyl groups are favorably
differentiated by protection of one of the two primary
hydroxyl groups forming acetonide with the neighboring
secondary one. By protecting the hydroxyl groups in this
fashion, the three hydroxyl groups and the amino group
should be selectively handled.
Regarding the preparation of 1, seven-membered ring
compounds 6, 8, and 9 were expected to be good precur-
sors of 1a , because these compounds should effectively
migrate to the thermodynamically more favorable five-
membered dioxolanes by acid treatment. Moreover, the
advantage of using these compounds is that the stereo-
(14) Sagawa, S.; Abe, H.; Hase, Y.; Inaba, T. J . Org. Chem. 1999,
64, 4962.
(15) The isomerization was carried out in the presence of 2,2-
dimethoxypropane (10 mol %) preventing hydrolysis of acetonide, see
Experimental Section.
(16) HPLC conditions: column YMC AM-302, 150 × 1.6 mm i.d.,
S-5 µm, 120A.; mobile phase acetonitrile/10 mM phosphate buffer (pH
7) ) 40/60; detection UV 214 nm; flow rate 1.0 mL/min; column temp.
40 °C, tR ) 5.6 min (8, 6.6%), 6.8 min (12, 91.4%), 7.5 min (unidentifi-
able isomer, 2.0%).
(13) Inaba, T.; Birchler, A. G.; Yamada, Y.; Sagawa, S.; Yokota, K.;
Ando, K.; Uchida, I. J . Org. Chem. 1998, 63, 7582.

Building Block for Chiral 2-Aminoalkanols
J . Org. Chem., Vol. 65, No. 6, 2000 1625
Sch em e 2a
Sch em e 3a
a
Reaction conditions: (a) TsCl, pyridine; (b) KOH, 2-propanol,
H2O; (c) 19, MeOH, reflux, then KOH; (d) (i) 3-acetoxy-2-methyl-
benzoyl chloride, NaHCO3, AcOEt, H2O, (ii) NH3, MeOH.
successively treated with MsCl and PhSH providing
sulfide 14 in a one-pot fashion. The acetonide protection
was removed by the action of HCl in aqueous MeOH to
give 15. Transformation of 1a into 15 involved no
purification procedure, and crude 15 was used for the
next reaction. The quantitative HPLC analysis suggested
that the yield of 15 was more than 95% from 1a . Since
transformation of 15 into 18 required stereochemical
inversion of the secondary hydroxyl group of 15, this
group was converted to a leaving group by treatment with
MsCl after protection of the primary hydroxyl group with
4-nitrobenzoyl chloride (PNBCl) in the presence of 2-pi-
coline. These sequential processes were carried out in a
one-pot fashion without isolation of the intermediate 16.
The yield of mesylate 17 was 80-84% from 1a after
purification by recrystallization. HPLC indicated that the
regioselectivity of the protection of the primary hydroxyl
group was 93-95%. The selectivity was lower than 80%
when NEt3 or pyridine was used as a base in place of
2-picoline. The advantages of using a PNB group as a
protective group were the efficient isolation of 17 by
recrystallization and the facile saponification of the ester
in the next step. Alkaline treatment of 17 promoted
hydrolysis of the PNB group and the spontaneous ring
closure giving epoxide 18 in 98%, which was reported to
be efficiently converted to nelfinavir 2 through interme-
diate 2018 in three steps.12 Alternatively, it was also
successful to obtain 20 from 17 without isolation of 18.
When 17 was treated with K2CO3 in the presence of
amine 1919 in aqueous MeOH, 20 was precipitated out
from the reaction mixture as fine crystals in 86% yield.
Epoxide 22 was obtained by selective sulfonylation of
the primary hydroxyl group of 15 followed by alkaline
treatment (Scheme 3). Thus, treatment of 15 with TsCl
gave 21 in 75% and subsequent alkaline treatment gave
22 in 92%. Ring-opening of 22 with 19 followed by
removal of the Cbz group afforded 23 in 74%. Coupling
of 23 with 3-acetoxy-2-methylbenzoyl chloride13 and
successive removal of the acetyl group gave 3 in 74%
yield. The stereochemistry of 23 was confirmed by X-ray
crystallographic analysis to verify the stereochemistry of
a
Reaction conditions: (a) Cbz-Cl, K2CO3, toluene, H2O; (b)
MsCl, NEt3, toluene; (c) PhSH, NaOH, Bu4NBr, toluene, H2O; (d)
HCl, MeOH, H2O; (e) PNB-Cl, 2-picoline, AcOEt; (f) MsCl, NEt3,
AcOEt; (g) KOH, 1,4-dioxane, H2O; (h) K2CO3, H2O, MeOH.
genolysis condition, benzoic acid acts not only as an
accelerator of hydrogenolysis but also as an acid that
makes the product into a salt of fine crystals, so that
removal of other undesired minor isomers is effectively
carried out. The production procedure of 1a does not
involve any hazardous reagents, low temperature reac-
tion conditions, strictly dry conditions, or purification by
column chromatography. Hence, 1a has been produced
on 1 kg-scale in 74% yield from 7, which is readily
accessible from commercially available cis-2-butene-1,4-
diol,17 through a process involving three steps. 1a was
similarly obtained in 73% yield from 7, through 9 and
13. The asymmetric centers of 9 were induced from
catalytic amount of (S)-1,1′-bi-2-naphthol as a sole chiral
source.14 The antipode 1b was also similarly obtained
from the enantiomer of 9 which was obtained using Ti-
(R)-1,1′-bi-2-naphthoxide complex as a chiral catalyst.
The versatility of 1a and 1b was demonstrated by their
stereospecific transformation into epoxide 18 and 22, and
into their enantiomers, respectively. 18 was reported to
be a key intermediate of nelfinavir 2.12 Biologically less
active isomers 3, 4 and 5 were obtained from 22,
enantiomer of 18, and that of 22, respectively.
Transformation of 1a into 18 was performed as shown
in Scheme 2. Protection of the amino group of 1a with
CbzCl in a bilayer system gave 11, which was then
(18) Rieger, D. L. J . Org. Chem. 1997, 62, 8546.
(19) (a) Houpis, I. N.; Molina, A.; Reamer, R. A.; Lynch, J . E.;
Volante, R. P.; Reider, P. J . Tetrahedron Lett. 1993, 34, 2593. (b)
Gohring, W.; Gokhale, S.; Hilpert, H.; Roessler, F.; Schlageter, M.; Vogt,
P. Chimia 1996, 50, 532.
(17) Elliott, W. J .; Fried, J . J . Org. Chem. 1976, 41, 2469. See
Supporting Information in ref 13, also.

1626 J . Org. Chem., Vol. 65, No. 6, 2000
Inaba et al.
22.20 The other stereoisomers, i.e., 4 and 5, were similarly
and specifically prepared from the enantiomer of 18 and
that of 22 in 69% and 80%, respectively.21
4.05 (t, 1H, J ) 7.5 Hz), 3.84-3.70 (m, 4H), 2.54 (br s, 1H),
1.42 (s, 3H), 1.35 (s, 3H); IR (neat) 3440, 1703, 1530, 1216,
1069 cm-1; [R]25 -23.5 (c 1.02, MeOH); HRMS (FAB) calcd
D
for C15H23NO5 296.1498, found 296.1491.
(1R)-1-Ben zyloxyca r bon yla m in o-1-[(4R)-2,2-d im eth yl-
1,3-d ioxola n -4-yl]-2-p h en ylth ioeth a n e (14). To a mixture
of crude 11 (prepared from 1a (770 g, 2.72 mol)), toluene (7.00
L), and triethylamine (330 g, 3.26 mol) was added MsCl (342
g, 2.99 mol) at a temperature below 10 °C over 30 min, and
the mixture was stirred at this temperature for 1.5 h. Then,
thiophenol (335 mL, 3.26 mol), NaOH (250 g, 3.25 mol), Bu4-
NBr (17.5 g, 54.4 mmol), and water (3.08 L) were successively
added under a nitrogen atmosphere. The mixture was stirred
at 55 °C for 2.5 h and cooled to room temperature, and the
aqueous layer was split off. The organic layer was successively
washed with 1 M NaOH and 1 M HCl, and concentrated to
give 14 as colorless oil (1.93 kg), which was used for the next
reaction without purification. An analytically pure sample was
prepared by recrystallization from hexane/diethyl ether: mp
64-65 °C; 1H NMR (CDCl3) δ 7.43-7.15 (m, 10H), 5.16 (d, 1H,
J ) 12.5 Hz), 5.12 (br s, 1 H), 5.98 (d, 1H, J ) 12.5 Hz), 4.50
(td, 1H, J ) 6.9, 1.8 Hz), 3.99 (m, 1H), 3.86 (m, 1H), 3.66 (dd,
1H, J ) 8.1, 7.0 Hz), 3.24 (dd, 1H, J ) 13.8, 5.9 Hz), 3.04 (dd,
1H, J ) 13.8, 8.6 Hz), 1.42 (s, 3H), 1.30 (s, 3H); IR (KBr) 3308,
2986, 1688, 1540, 1262 cm-1; [R]25D -78.6 (c 0.99, EtOH). Anal.
Calcd for C21H25NO4S: C, 65.09; H, 6.50; N, 3.61. Found: C,
65.12; H, 6.56; N, 3.56.
Con clu sion
Isomerically pure 1a was produced on a 1 kg-scale via
five steps from commercially available cis-2-butene-1,4-
diol in more than 60% yield without chromatography
purification. 1 was demonstrated to be a versatile chiral
C4 building block for 2-amino-1,3,4-butanetriol of a
variety of absolute and relative stereochemical structures
by selective treatments of its three hydroxyl groups and
an amino group. Especially, 1a was shown to be suitable
building block for the construction of 2-aminoalkanol
moiety of aspartic protease inhibitors such as an HIV
protease inhibitor 2. It is also expected that 1a and 1b
will be used for the synthesis of other biologically active
compounds containing chiral 2-aminoalkanol compon-
ent(s).1-5
Exp er im en ta l Section
1
Gen er a l. All melting points are uncorrected. The H NMR
spectra were recorded at 300 MHz unless otherwise noted.
Solvents, starting materials and reagents were used as
purchased without further purification. Silica gel 60 (230-
400 mesh, Merck) was used for column chromatography.
(1S)-1-[(4R)-2,2-Dim eth yl-1,3-d ioxola n -4-yl]-2-h yd r oxy-
eth yla m m on iu m Ben zoa te (1a ). To a mixture of 813,14 (1.00
kg, 3.77 mol), 2,2-dimethoxypropane (39.3 g, 377 mmol), and
acetone (2.00 L) was added MsOH (435 g, 4.52 mol) over 25
min with stirring (<25 °C). After stirring for 4 h, the reaction
mixture was poured into a solution of K2CO3 (625 g, 4.52 mol)
in water (3.00 L), and the product was extracted with toluene
(3.00 L). The organic layer was concentrated to give a crude
oily residue, which was mainly comprised of 12. This crude
material was diluted with 2-propanol (6.00 L) and hydrogen-
ated (5% Pd-C (100 g, 50% wet type) with H2 (5 kg/cm2), 60
°C, 9 h) in the presence of benzoic acid (460 g, 3.77 mol). Then
the catalyst was removed, and then the filtrate was concen-
trated so that the crude residue contained 1.1 L of 2-propanol.
To the residue was added heptane (10.0 L) at 55-60 °C, and
the resulting solution was stirred at 0-5 °C for 1 h. Deposited
crystals were collected by filtration to give 1a (879 g, 82% from
(2R,3R)-3-Ben zyloxyca r bon yla m in o-4-p h en ylth io-1,2-
bu ta n ed iol (15). To a solution of crude 14, prepared from 1a
(770 g, 2.72 mol), in MeOH (4.20 L) were successively added
water (1.05 L) and concd HCl (11.3 mL, 136 mmol). The
resultant bilayer system was heated to reflux for 3.5 h,
affording a clear solution. Then the reaction mixture was
concentrated and mixed with water (3.16 L) containing
NaHCO3 (9.13 g, 109 mmol) and NaCl (790 g). The deposited
oily product was extracted with AcOEt (5.27 L). Then the
organic phase was concentrated to give a residue, which was
diluted with AcOEt (3.00 L) and concentrated again to remove
MeOH and moisture, affording 15 as colorless oil. This crude
material was used for the next reaction without purification.
An analytically pure sample was obtained by recrystallization
from toluene: mp 73-74 °C; 1H NMR (CDCl3) δ 7.51-7.22 (m,
10H), 5.27 (br d, 1H, J ) 8.8 Hz), 5.09 (s, 2H), 4.01 (m, 1H),
3.86 (m, 1H), 3.54-3.53 (m, 2H), 3.21 (dd, 1H, J ) 13.7, 6.7
Hz), 3.12 (dd, 1H, J ) 13.7, 7.5 Hz), 2.58 (br s, 1H), 2.47 (br s,
1H); IR (KBr) 3306, 2934, 1693, 1428, 1049 cm-1; [R]25D -46.9
(c 1.00, EtOH). Anal. Calcd for C18H21NO4S: C, 62.23; H, 6.09;
N, 4.03. Found: C, 62.39; H, 6.09; N, 3.99.
1
8) as colorless crystals: mp 112-113 °C; H NMR (CDCl3) δ
7.99 (m, 2H), 7.44 (m, 1H), 7.34 (m, 2H), 6.33 (br s, 3H), 4.18
(td, 1H, J ) 6.2, 7.7 Hz), 4.01 (dd, 1H, J ) 6.6, 8.4 Hz), 3.78
(dd, 1H, J ) 3.7, 12.5 Hz), 3.70 (dd, 1H, J ) 5.9, 8.8 Hz), 3.63
(dd, 1H, J ) 6.2, 12.5 Hz), 3.12 (m, 1H), 1.32 (s, 3H), 1.24 (s,
(2R,3R)-3-Ben zyloxyca r b on yla m in o-4-p h en ylt h io-2-
m eth a n esu lfon yloxy-1-(4-n itr oben zoyloxy)bu ta n e (17).
To a solution of crude 15, prepared from 1a (770 g, 2.72 mol),
in AcOEt (6.61 L) were successively added 2-picoline (329 g,
3.53 mol) and 4-nitrobenzoyl chloride (605 g, 3.26 mol) at a
temperature below 10 °C. The mixture was stirred at 5-10
°C for 8.5 h under a nitrogen atmosphere, and methanesulfonyl
chloride (374 g, 3.26 mol) was added. Then, triethylamine (660
g, 6.52 mol) was added dropwise to the mixture at a temper-
ature below 15 °C, and the mixture was stirred for 30 min.
The reaction was stopped by the addition of MeOH (87.1 g,
2.27 mol), followed by stirring at ambient temperature for 1.5
h. The mixture was successively washed with 1 M HCl (5.67
L), 8% aqueous NaHCO3 (5.67 L), and water (2.83 L) and was
refluxed for 1 h in the presence of activated carbon (46.9 g).
Insoluble material was removed, and the filtrate was concen-
trated to give a yellow solid. Recrystallization of this material
from AcOEt (3.0 L)/heptane (12.0 L) followed by rinsing with
MeOH (4.72 L) gave 17 (1.31 kg, 84.0% yield from 1a ) as pale
3H); IR (KBr) 2983, 1610, 1517, 1393, 1048 cm-1; [R]25 +2.8
D
(c 1.00, CHCl3). Anal. Calcd for C14H21NO5: C, 59.35; H, 7.47;
N, 4.94. Found: C, 59.11; H, 7.65; N, 4.98. 1a was similarly
obtained in 73% form 7 via 9.14
(2S)-2-Ben zyloxyca r bon yla m in o-2-[(4R)-2,2-d im eth yl-
1,3-d ioxola n e-4-yl]eth a n ol (11). To a mixture of toluene
(3.85 L), water (3.85 L), and K2CO3 (470 g, 3.40 mol) were
successively added 1a (770 g, 2.72 mol) and CbzCl (488 g, 2.72
mol) with vigorous stirring at a temperature below 25 °C. After
stirring at room temperature for 3 h, triethylamine (27.5 g,
270 mmol) and NaCl (578 g) were successively added, and the
mixture was stirred for a further 30 min. The organic layer
was separated and concentrated to give 11 as oil, which was
used for the next reaction without purification. The analytical
sample was prepared by column chromatography; 1H NMR
(CDCl3) δ 7.40-7.29 (m, 5H), 5.32 (br d, 1H, J ) 5.5 Hz), 5.15
(d, 1H, J ) 12.2 Hz), 5.09 (d, 1H, J ) 12.2 Hz), 4.34 (m, 1H),
1
yellow crystals: mp 117-118 °C; H NMR (CDCl3) δ 8.24 (d,
2H, J ) 8.7 Hz), 8.12 (d, 2H, J ) 8.7 Hz), 7.44-7.21 (m, 10H),
5.44 (ddd, 1H, J ) 6.9, 5.1, 2.3 Hz), 5.11 (s, 2H), 5.09 (br d,
1H, J ) 9.5 Hz), 4.57 (dd, 1H, J ) 12.0, 6.9 Hz), 4.50 (dd, 1H,
J ) 12.0, 5.1 Hz), 4.21 (m, 1H), 3.25 (dd, 1H, J ) 14.0, 6.2
Hz), 3.05 (s, 3H), 3.05 (dd, 1H, J ) 14.0, 8.2 Hz); IR (KBr)
1725, 1699, 1531, 1349, 1283 cm-1; [R]25D -13.4 (c 1.00, CHCl3).
(20) See Supporting Information. The atomic coordinates have been
deposited with Cambridge Crystallographic Data Center, 12 Union
Road, Cambridge, CB2 1EZ, UK.
(21) The enantiomer of 18 and that of 22 were obtained from 1b by
the identical methods to those used in the preparation of 18 and 22
from 1a , respectively.

Building Block for Chiral 2-Aminoalkanols
J . Org. Chem., Vol. 65, No. 6, 2000 1627
Anal. Calcd for C26H26N2O9S2: C, 54.35; H, 4.56; N, 4.88.
Found: C, 54.47; H, 4.42; N, 4.90.
2.6, 4.3 Hz); IR (KBr) 3306, 2954, 1694, 1537, 1245 cm-1; [R]25
D
+54.3 (c 1.00, EtOH). Anal. Calcd for C18H19NO3S: C, 65.63;
H, 5.81; N, 4.25. Found: C, 65.73; H, 5.75; N, 4.20.
(2S,3R)-3-Ben zyloxyca r b on yla m in o-4-p h en ylt h io-1-
bu ten eoxid e (18).12 To a solution of 17 (3.78 g, 6.58 mmol)
in 1,4-dioxane (30 mL) was added 2 M aqueous KOH (7.30
mL), and the reaction mixture was stirred at room tempera-
ture for 1 h. Then the mixture was diluted with water (50 mL)
and extracted with toluene (50 mL). The organic layer was
separated, successively washed with aqueous NaHCO3 and
brine (50 mL), dried over MgSO4, and concentrated under
reduced pressure to give a colorless solid. Column chromatog-
raphy purification afforded 18 (2.12 g, 98%) as colorless
crystals: mp 61-62 °C (ether/hexane); 1H NMR (CDCl3-D2O)
δ 7.40-7.17 (m, 10H), 5.11 (d, 1H, J ) 12.1 Hz), 5.06 (d, 1H,
J ) 12.1 Hz), 3.70 (m, 1H), 3.22 (d, 2H, J ) 5.6 Hz), 2.99 (m,
1H), 2.80-2.71 (m, 2H); IR (KBr) 3302, 1694, 1538, 1256, 1028
(3S,4aS,8aS)-N-ter t-Bu tyl-2-[(2S,3R)-3-am in o-2-h ydr oxy-
4-(p h en ylth io)bu tyl]d eca h yd r oisoqu in olin e-3-ca r boxa -
m id e (23). A mixture of 22 (6.84 g, 20.8 mmol) and 19 (4.95
g, 20.8 mmol) in 2-propanol (100 mL) was stirred at 80 °C for
4 h. Then 2 M aqueous KOH (48 mL) was added, and the
mixture was again stirred at 80 °C for 18 h. The reaction
mixture was concentrated to 1/3 volume and diluted with
water (100 mL). The deposited product was extracted with
AcOEt (100 mL × 2). The combined organic layers were dried
over MgSO4 and evaporated to dryness. Purification of the
residue by column chromatography (CHCl3:MeOH ) 10:1) gave
23 (6.68 g, 74%) as colorless crystals. Recrystallization from a
mixed solvent (hexane and toluene) gave fine crystals that
were used for X-ray crystallographic analysis:20 mp 150-152
°C; 1H NMR (CDCl3) δ 7.37-7.33 (m, 2H), 7.30-7.24 (m, 2H),
7.19 (m, 1H), 6.21 (br s, 1H), 3.70 (ddd, 1H, J ) 3.0, 3.3, 10.5
Hz), 3.41 (br s, 1H), 3.16 (dd, 1H, J ) 4.6, 13.4 Hz), 2.88 (dd,
1H, J ) 8.5, 13.3 Hz), 2.84 (dd, 1H, J ) 2.0, 11.5 Hz), 2.71-
2.59 (m, 3H), 2.13 (dd, 1H, J ) 3.3, 11.5 Hz), 1.98 (dd, 1H, J
) 2.6, 12.7 Hz), 1.94-1.70 (m, 4H), 1.68-1.15 (m, 7H), 1.34
cm-1; [R]25 -26.2 (c 1.01, CHCl3). Anal. Calcd for C18H19
-
D
NO3S: C, 65.63; H, 5.81; N, 4.25. Found: C, 65.36; H, 5.85;
N, 4.33.
(3S,4a S,8a S)-N-ter t-Bu t yl-2-[(2R,3R)-3-b en zyloxyca r -
bon ylam in o-2-h ydr oxy-4-(ph en ylth io)bu tyl]decah ydr oiso-
qu in olin e-3-ca r boxa m id e (20).12,18 To a suspension of 17
(1.30 kg, 2.26 mol) in 67% MeOH (11.7 L) were successively
added 1919 (539 g, 2.26 mol) and K2CO3 (641 g, 4.64 mol) at
room temperature. The mixture was stirred at 60 °C for 7 h,
water (3.90 L) was added to the suspension at 60-55 °C. After
cooling to room temperature, deposited crystals were collected
by centrifugation, washed successively with 33% MeOH (3.90
L) and water (3.90 L), and dried to give 20 (1.102 kg, 86% yield
from 17) as colorless crystals: mp 138-140 °C; 1H NMR
(CDCl3) δ 7.39-7.13 (m, 10H), 5.91 (br d, 1H, J ) 8.1 Hz),
5.68 (s, 1H), 5.08 (d, 1H, J ) 12.5 Hz), 5.03 (d, 1H, J ) 12.5
Hz), 4.05-3.94 (m 2H), 3.42 (br s, 1H), 3.39 (br s, 1H), 3.13
(br s, 1H), 2.91 (br d, 1H, J ) 11.4 Hz), 2.60 (dd, 1H, J ) 7.7,
13.2 Hz), 2.50 (dd, 1H, J ) 2.9, 11.0 Hz), 2.22 (dd, 1H, J )
5.5, 13.2 Hz), 2.19 (dd, 1H, J ) 2.6, 11.6 Hz), 1.96 (q, 1H, J )
12.5 Hz), 1.80-1.18 (m, 11H), 1.30 (s, 9H); IR (KBr) 3333, 2927,
1711, 1638, 1543 cm-1; [R]25D -82.3 (c 1.00, CHCl3). Anal. Calcd
for C32H45N3O4S: C, 67.69; H, 7.99; N, 7.40. Found: C, 67.84;
H, 8.18; N, 7.48.
(s, 9H); IR (KBr) 3277, 2928, 1640, 1479, 1454 cm-1; [R]25
D
-119.3 (c 0.98, CHCl3). Anal. Calcd for C24H39N3O2S: C, 66.47;
H, 9.06; N, 9.69. Found: C, 66.87; H, 9.29; N, 9.57.
(3S,4a S,8a S)-N-ter t-Bu tyl-2-[(2S,3R)-2-h yd r oxy-3-(3-h y-
d r oxy-2-m e t h ylb e n zoyla m in o)-4-(p h e n ylt h io)b u t yl]-
d eca h yd r oisoqu in olin e-3-ca r boxa m id e (3). To a solution
of 23 (3.04 g, 7.02 mmol) in AcOEt (30 mL) were added water
(30 mL) and NaHCO3 (3.40 g, 40.5 mmol). A solution of
3-acetoxy-2-methylbenzoyl chloride (freshly prepared from
3-acetoxy-2-methylbenzoic acid (1.56 g, 8.04 mmol))13 in AcOEt
(20 mL) was added to the bilayer system with stirring at 0
°C. After the reaction was stirred at room temperature for 1.5
h, the organic phase was diluted with AcOEt (20 mL) and
separated. The organic phase was washed with aqueous NaCl
(30 mL), dried over MgSO4, and then evaporated to dryness.
The colorless amorphous material was dissolved in MeOH (50
mL), and 28% aqueous NH3 (6.2 mL) solution was added at
room temperature. After stirring for 3 h, the mixture was
evaporated. The residue was suspended in water (50 mL) and
extracted with CHCl3 (50 mL × 2). The combined organic
layers were dried over MgSO4 and evaporated to give a viscous
residue that was then purified by column chromatography
(CHCl3:MeOH ) 50:1) to give a colorless amorphous material.
This material was suspended in AcOEt (50 mL), refluxed for
1 h, and cooled to room temperature. Deposited crystals were
collected by filtration to give 3 (2.84 g, 74%) as colorless
crystals: mp 193-195 °C; 1H NMR (CD3OD) δ 7.46-7.41 (m,
2H), 7.33-7.26 (m, 2H), 7.23-7.17 (m, 1H), 7.00 (t, 1H, J )
7.8 Hz), 6.82-6.78 (m, 2H), 4.12-4.02 (m, 2H), 3.26 (dd, 1H,
J ) 6.0, 13.8 Hz), 3.18 (dd, 1H, J ) 8.1, 13.8 Hz), 2.88 (dd,
1H, J ) 2.1, 11.4 Hz), 2.62 (dd, 1H, J ) 3.3, 11.1 Hz), 2.51
(dd, 1H, J ) 10.2, 12.9 Hz), 2.22 (s, 3H), 2.19 (dd, 1H, J ) 3.0,
11.4 Hz), 2.07 (dd, 1H, J ) 2.4, 13.2 Hz), 2.00-1.20 (m, 12H),
(2R,3R)-1-(4-Meth ylben zen esu lfon yloxy)-3-ben zyloxy-
ca r bon yla m in o-2-h yd r oxy-4-(p h en ylth io)bu ta n e (21). To
a solution of 15 (21.8 g, 62.7 mmol) in pyridine (140 mL) was
added p-toluenesulfonyl chloride (12.0 g, 62.7 mmol) at 0 °C.
The mixture was stirred at the same temperature for 15 min
and at room temperature for 4 h. Then the mixture was
concentrated to give a viscous residue that was diluted with
AcOEt (300 mL). The mixture was successively washed with
2 M aqueous HCl (300 mL), water (200 mL), aqueous NaHCO3
(200 mL), and brine (200 mL), dried over MgSO4, and
evaporated to dryness. Recrystallization of the residue from
hexane/AcOEt gave 21 (21.1 g, 67%) as colorless crystals: mp
113-114 °C; 1H NMR (CDCl3) δ 7.75 (d, 2H, J ) 8.2 Hz), 7.42-
7.19 (m, 12H), 5.19 (br d, 1H, J ) 8.7 Hz), 5.07 (d, 1H, J )
10.3 Hz), 5.05 (d, 1H, J ) 10.3 Hz), 4.27 (br s, 1H), 4.06-3.93
(m, 2H), 3.72 (br q, 1H, J ) 7.9 Hz), 3.19 (dd, 1H, J ) 5.9,
13.9 Hz), 3.09 (dd, 1H, J ) 8.2, 13.5 Hz), 2.93 (br s, 1H), 2.44
1.25 (s, 9H); IR (KBr) 3422, 2928, 1643, 1538, 1361 cm-1; [R]25
D
(s, 3H); IR (KBr) 3529, 3313, 1692, 1347, 1265, 1172 cm-1
;
-149.9 (c 0.99, MeOH). Anal. Calcd for C32H45N3O4S: C, 67.62;
[R]25 -16.0 (c 1.07, CHCl3). Anal. Calcd for C25H27NO6S2: C,
H, 7.99; N, 7.40. Found: C, 67.51; H, 8.11; N, 7.28.
D
59.86; H, 5.43; N, 2.79. Found: C, 60.32; H, 5.40; N, 2.79. The
additional amount of 21 (2.52 g, 8%) was isolated from the
filtrate by column chromatography.
(3S,4a S,8a S)-N-ter t-Bu tyl-2-[(2S,3S)-2-h yd r oxy-3-(3-h y-
d r oxy-2-m e t h ylb e n zoyla m in o)-4-(p h e n ylt h io)b u t yl]-
d eca h yd r oisoqu in olin e-3-ca r boxa m id e (4). The similar
procedure, used in the preparation of 3, gave 4 (69% from the
enantiomer of 18) as a colorless amorphous material: 1H NMR
(CDCl3) δ 7.40-7.36 (m, 2H), 7.30-7.14 (m, 3H), 7.18 (br s,
1H), 6.95 (t, 1H, J ) 7.7 Hz), 6.84 (dd, 1H, J ) 1.1, 8.1 Hz),
6.81 (dd, 1H, J ) 1.1, 7.3 Hz), 6.38 (br d, 1H, J ) 8.8 Hz), 6.16
(br s, 1H), 4.20 (br s, 1H), 4.15 (m, 1H), 3.91 (m, 1H), 3.28-
3.18 (m, 2H), 2.80 (br d, 1H, J ) 11.4 Hz), 2.63 (br d, 1H, J )
11.0 Hz), 2.54 (br t, 1H, J ) 11.0 Hz), 2.16 (s, 3H), 2.18-2.12
(m, 2H), 1.99-1.14 (m, 12H), 1.35 (s, 9H); IR (KBr) 3304, 2926,
(2R,3R)-3-Ben zyloxyca r b on yla m in o-4-p h en ylt h io-1-
bu ten eoxid e (22). To a solution of 21 (20.6 g, 41.1 mmol) in
2-propanol (210 mL) was added 2 M aqueous KOH (41 mL) at
room temperature. After the reaction was stirred for 1 h, water
(200 mL) was added and the product was extracted with
toluene (250 mL × 2). The combined organic layers were
washed with brine (200 mL), dried over MgSO4, and concen-
trated to a give a viscous residue. This material was purified
by column chromatography (hexane:AcOEt ) 4:1-3:1) to give
22 (12.4 g, 92%) as a colorless solid: mp 58-59 °C (ether/
hexane); 1H NMR (CDCl3) δ 7.43-7.16 (m, 10H), 5.09 (s, 2H),
4.88 (br s, 1H), 4.11 (m, 1H), 3.30-3.23 (m, 2H), 3.11 (dd, 1H,
J ) 7.6, 13.6 Hz), 2.75 (t, 1H, J ) 4.2 Hz), 2.62 (dd, 1H, J )
1648, 1528, 1285 cm-1; [R]25 -2.29 (c 1.09, MeOH). HRMS
D
(FAB) calcd for C32H46N3O4S 568.3209, found 568.3217.
(3S,4a S,8a S)-N-ter t-Bu tyl-2-[(2R,3S)-2-h yd r oxy-3-(3-h y-
d r oxy-2-m e t h ylb e n zoyla m in o)-4-(p h e n ylt h io)b u t yl]-

1628 J . Org. Chem., Vol. 65, No. 6, 2000
Inaba et al.
d eca h yd r oisoqu in olin e-3-ca r boxa m id e (5). The similar
procedure, used in the preparation of 3, gave 5 (80% from the
enantiomer of 22) as a colorless amorphous material: 1H NMR
(CDCl3) δ 7.46-7.41 (m, 2H), 7.32-7.25 (m, 2H), 7.16 (m, 1H),
7.02 (br d, 1H, J ) 8.3 Hz), 6.96 (t, 1H, J ) 7.6 Hz), 6.92 (dd,
1H, J ) 1.5, 7.6 Hz), 6.79 (dd, 1H, J ) 1.4, 7.7 Hz), 5.81 (br s,
1H), 4.13 (br t, 1H, J ) 7.0 Hz), 4.02 (br q, 1H, J ) 7.5 Hz),
3.53 (dd, 1H, J ) 6.9, 13.9 Hz), 3.34 (dd, 1H, J ) 7.5, 13.9
Hz), 2.72 (dd, 1H, J ) 2.5, 11.7 Hz), 2.53 (dd, 1H, J ) 3.0,
10.8 Hz), 2.49 (dd, 1H, J ) 6.6, 13.2 Hz), 2.33-2.21 (m, 2H),
2.24 (s, 3H), 1.92 (m, 1H), 1.76-1.05 (m, 11H), 1.27 (s, 9H);
Ack n ow led gm en t. The authors thank Drs. I. Uchi-
da, K. Ando, G. Marzoni, and A. G. Birchler for their
useful advice, and Mr. E. Inagaki for the X-ray crystal-
lographic analysis of 23. The authors also express their
appreciation to Mr. Masami Tsuboshima for his encour-
agement throughout this work.
Su p p or tin g In for m a tion Ava ila ble: Crystal structure
data for 23 and 300 MHz 1H NMR spectra of 4, 5, and 11.
This material is available free of charge via the Internet at
http://pubs.acs.org.
IR (KBr) 3339, 2925, 1647, 1585, 1519 cm-1; [R]25 +10.9 (c
D
1.09, MeOH). HRMS (FAB) calcd for C32H46N3O4S 568.3209,
found 568.3197.
J O991793E