Synthesis and immunosuppressive activity of 2-substituted 2- aminopropane-1,3-diols and 2-aminoethanols

Article abstract of DOI:10.1021/jm000173z

A series of 2-substituted 2-aminopropane-1,3-diols was synthesized and evaluated for their lymphocyte-decreasing effect and immunosuppressive effect on rat skin allograft. A phenyl ring was introduced into the alkyl chain of the lead compound 3, which is an immunosuppressive agent structurally simplified from myriocin (1, ISP-I) via compound 2. The potency of the various compounds was dependent upon the position of the phenyl ring within the alkyl side chain. The most suitable length between the quaternary carbon atom and the phenyl ring was two carbon atoms. 2-Substituted 2-aminoethanols were successively synthesized and evaluated for their T-cell-decreasing effect and immunosuppressive effect using a popliteal lymph node gain assay in rats. The absolute configuration at the quaternary carbon affected the activity, and the (pro-S)-hydroxymethyl group of compound 6 was essential for potent immunosuppressive activity. Favorable substituents for the (pro-R)- hydroxymethyl group of 6 were hydroxyalkyl (hydroxyethyl and hydroxypropyl) or lower alkyl (methyl and ethyl) groups. 2-Amino-2-[2-(4- octylphenyl)ethyl]propane-1,3-diol hydrochloride (6, FTY720) was found to possess considerable activity and is expected to be useful as an immunosuppressive drug for organ transplantation.

Full text of DOI:10.1021/jm000173z

2946
J . Med. Chem. 2000, 43, 2946-2961
Syn th esis a n d Im m u n osu p p r essive Activity of 2-Su bstitu ted
2-Am in op r op a n e-1,3-d iols a n d 2-Am in oeth a n ols1,2
Masatoshi Kiuchi,*,† Kunitomo Adachi,† Toshiyuki Kohara,† Masanori Minoguchi,† Tokushi Hanano,†
Yoshiyuki Aoki,† Tadashi Mishina,† Masafumi Arita,† Noriyoshi Nakao,† Makio Ohtsuki,† Yukio Hoshino,†
Koji Teshima,† Kenji Chiba,† Shigeo Sasaki,‡ and Tetsuro Fujita§,|
Drug Discovery Laboratories, Welfide Corporation, 7-25 Koyata 3-chome, Iruma-shi, Saitama 358-0026, J apan,
Research Laboratories, Taito Company, Ltd., 1-26 Higashi Shiriike-shinmachi, Nagata-ku, Kobe 653-0023, J apan,
and Faculty of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8304, J apan
Received April 18, 2000
A series of 2-substituted 2-aminopropane-1,3-diols was synthesized and evaluated for their
lymphocyte-decreasing effect and immunosuppressive effect on rat skin allograft. A phenyl
ring was introduced into the alkyl chain of the lead compound 3, which is an immunosuppressive
agent structurally simplified from myriocin (1, ISP-I) via compound 2. The potency of the various
compounds was dependent upon the position of the phenyl ring within the alkyl side chain.
The most suitable length between the quaternary carbon atom and the phenyl ring was two
carbon atoms. 2-Substituted 2-aminoethanols were successively synthesized and evaluated for
their T-cell-decreasing effect and immunosuppressive effect using a popliteal lymph node gain
assay in rats. The absolute configuration at the quaternary carbon affected the activity, and
the (pro-S)-hydroxymethyl group of compound 6 was essential for potent immunosuppressive
activity. Favorable substituents for the (pro-R)-hydroxymethyl group of 6 were hydroxyalkyl
(hydroxyethyl and hydroxypropyl) or lower alkyl (methyl and ethyl) groups. 2-Amino-2-[2-(4-
octylphenyl)ethyl]propane-1,3-diol hydrochloride (6, FTY720) was found to possess considerable
activity and is expected to be useful as an immunosuppressive drug for organ transplantation.
Ch a r t 1. Structures of Myriocin and Related
Immunosuppressive Compounds
In tr od u ction
Immunosuppressants have important clinical roles in
organ transplantation and the treatment of autoimmune
diseases such as rheumatoid arthritis, systemic lupus
erythematosus, and psoriasis. Both cyclosporin A (CsA)3
and tacrolimus (FK506)4 suppress immune responses
by inhibiting the production of interleukin-2 (IL-2) in
antigen-stimulated helper T-cells5-7 and are standard
medicines for preventing graft rejection after transplant
surgery. Since their clinical use is restricted by severe
side effects, notably renal and liver toxicities,8 they are
used in combination with glucocorticoids or other im-
munosuppressants such as azathioprine9 and mizorib-
ine.10 Novel immunosuppressants should therefore not
only be safer but also possess unique mechanisms of
action.
In the late 1980s Fujita et al.11 of our group isolated
a unique immunosuppressant, ISP-I (1), from the fer-
mentation broth of Isaria sinclairii (ATCC24400), and
the structure was determined as shown in Chart 1.
ISP-I is identical with antifungal antibiotic myriocin12,13
and thermozymocidin,14,15 which are produced by My-
riococcum albomyces and Mycelia sterilia, respectively.
It has been reported that myriocin inhibits serine
palmitoyltransferase of an IL-2-dependent mouse cyto-
toxic T-cell line, CTLL-2, at picomole concentrations16,17
and that sphingofungins,18-20 which are myriocin ana-
logues isolated from Aspergillus fumigatus or Paecilo-
myces variotii, inhibit yeast serine palmitoyltrans-
ferase.20,21 These inhibitory activities appear to be
responsible for their immunosuppressive and antifungal
activity.
Myriocin showed a potent inhibitory effect on mouse
allogeneic mixed lymphocyte reaction (MLR).11 Further-
more, we isolated mycestericins A-G,22-24 which are the
minor components of the myriocin-producing fungus M.
sterilia, and established the structure-activity relation-
* Corresponding author. Phone: +81-42-963-3121. Fax: +81-42-
964-1906. E-mail: kiuchi@welfide.co.jp.
† Welfide Corp.
‡ Taito Co., Ltd.
§ Kyoto University.
| Present address: Faculty of Pharmaceutical Sciences, Setsunan
University, 45-1 Nagaotoge, Hirakata-shi, Osaka 573-0101, J apan.
10.1021/jm000173z CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/11/2000

2-Substituted Aminopropanediols and 2-Aminoethanols
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 15 2947
Ch a r t 2. Structures of Target Compounds
Sch em e 1a
a
(a) Cl2HCOCH3, TiCl4, CH2Cl2; (b) NaBH4, MeOH, 2-propanol;
(c) 48% HBr, toluene; (d) AgNO2, ether; (e) 37% HCHO, 1 N aq
NaOH, EtOH; (f) H2, Raney Ni, EtOH; (g) AcCl, Et3N, EtOH/
CHCl3; (h) 1 N aq NaOH, EtOH.
conformation of the hydrocarbon chain would produce
a favorable result, we substituted a 1,4-phenylene group
for a part of the alkyl chain of 3 because the phenyl
group not only has π bonds but is also considered an
effective template for restricting the conformation of
hydrocarbon chains.28 To do this, we prepared and
evaluated a series of compounds possessing a phenyl
ring at a variety of positions within the side chain of 3,
keeping the chain length constant (m + n ) 10)
(compounds 4-11, Chart 2) in order to identify the
optimum position. Of the resulting compounds, com-
pound 6 displayed excellent activity. The results
prompted us to attempt to improve 6 by the synthesis
of analogues. Compounds 12-18 were synthesized to
confirm the optimal length of the side chain of 6. The
methylene group next to the phenyl ring in the side
chain of 6 was displaced with other groups or atoms
such as a carbonyl and an oxygen (compounds 19-24)
to investigate the most favorable linkage between the
phenyl ring and the alkyl group extending from it. We
also examined regioisomers on the phenyl ring (com-
pounds 25 and 26) and a thiophene analogue, where the
thiophene ring has been considered to be a bioisoster of
the phenyl ring (compound 27).
ships (SAR) of chemically modified derivatives of my-
riocin and mycestericins.22,24,25 Interestingly, most of the
functionalities in the hydrocarbon chain of 1 such as
the 14-ketone, the 6-double bond, and the 4-hydroxy
group, as well as the configuration of the 3-hydroxy
group, are not essential for its activity. However, no
candidates for clinical development were obtained from
either the natural products or the semisynthetic com-
pounds owing to their toxicity and unfavorable physi-
cochemical properties such as insolubility.
As the next step, we simplified the structure of 1 in
order to reduce its toxicity, to improve its physicochem-
ical properties, and to identify the structure essential
for immunosuppressive activity.26,27 Compound 1 has a
hydrophilic zwitterion on one side and a hydrophobic
hydrocarbon long chain on the other side of the mol-
ecule. We reduced the carboxylic acid of 1 to a hy-
droxymethyl group to delete the zwitterion functionality
presumably responsible for its poor solubility and asym-
metric center at position 2 to afford compound 2. The
inhibitory activity of 2 on mouse allogeneic MLR in vitro
was weaker than that of 1. However, it is noteworthy
that the 2-substituted 2-aminopropane-1,3-diols such as
2 prolonged survival time of rat skin allograft in vivo
more effectively than 1 and that they were approxi-
mately 30-fold less toxic.27 This observation suggested
that the conversion of the carboxylic group of 1 to a
hydroxymethyl group was effective in increasing in vivo
activity and reducing toxicity. The SAR of a series of
myriocin and mycestericin derivatives indicated that
simplification of the hydrophobic long chain of 1 was
possible. As a result of simplification of 2, we obtained
the lead compound 3 for the development of new
immunosuppressants. In the present research, we modi-
fied the structure of 3 in order to obtain an immuno-
suppressant with acceptable potency and safety for
clinical use (Chart 2).
Next, we modified the hydrophilic part of 6. We
synthesized 2-substituted 2-aminoethanols (compounds
28-38), with various substituents replacing one of the
hydroxymethyl groups of compounds 6 or 22, and
3-substituted 3-aminopropanol (compounds 39 and 40).
We describe herein the discovery of the novel immuno-
suppressant FTY720 (6) and the synthesis and SAR of
analogues of 6.
Ch em istr y
The synthesis of compound 4 was carried out as
shown in Scheme 1. Decylbenzene was formylated, and
the formyl group was converted to a bromomethyl group.
Nitration of the bromide 41 with silver nitrite29 followed
by hydromethylation gave the 2-nitropropane-1,3-diol
42. The nitro group was reduced with hydrogen and
Raney Ni, and the resulting crude target compound was
purified by acetylation followed by hydrolysis to give 4.
The synthesis of compounds 5-18 is presented in
Scheme 2. Friedel-Crafts acylation of phenylalkyl
acetates followed by reduction with triethylsilane in
trifluoroacetic acid gave 4-alkylated phenylalkyl ace-
tates. The acetates were deprotected to give intermedi-
ates 43. The alcohols 43 were converted into iodides 44
Compound 3 consists of a hydrophilic part (2-amino-
propane-1,3-diol) and a lipophilic part (hydrocarbon
chain). First, we took interest in the lipophilic part
because the double bonds in the hydrophobic long chain
of 1 and 2 were favorable for potent activity.24,26 On the
assumption that introducing a π bond or restricting the

2948 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 15
Kiuchi et al.
Sch em e 2a
Sch em e 5a
a
(a) Heptyl bromide, NaOEt, EtOH; (b) MsCl, Et3N, CH2Cl2;
(c) NaI, 2-butanone.
Sch em e 6a
a
(a) AlCl3, 1,2-dichloroethane; (b) Et3SiH, TFA; (c) NaOMe,
MeOH; (d) MsCl, Et3N, CH2Cl2; (e) NaI, 2-butanone; (f) diethyl
acetamidomalonate, NaOEt, EtOH; (g) LiAlH4, THF; (h) Ac2O,
pyridine; (i) 2 N aq LiOH, MeOH.
Sch em e 3a
a
(a) CH3SCH2SOCH3, Triton B, 1,4-dioxane; (b) HCl, EtOH;
(c) LiAlH4, THF; (d) m-CPBA, CHCl3; (e) MsCl, Et3N; (f) NaI,
2-butanone; (g) diethyl acetamidomalonate, NaOEt, EtOH; (h)
TFA, CH2Cl2; (i) Et3N, EtOH; (j) heptyl bromide, K2CO3, DMF;
(k) LiAlH4, THF; (l) LiOH‚H2O, MeOH/THF/H2O.
a
(a) SOCl2, 1,2-dichloroethane; (b) ethylbenzene, AlCl3, 1,2-
dichloroethane; (c) Et3SiH, TFA; (d) LiAlH4, THF; (e) MsCl, Et3N,
CH2Cl2; (f) NaI, 2-butanone.
Sch em e 7a
Sch em e 4a
a
(a) Octanoyl chloride, AlCl3, 1,2-dichloroethane; (b) aq LiOH,
a
(a) Hexanoyl chloride, Et3N, THF; (b) DHP, p-TsOH‚H2O,
MeOH; (c) NaBH4, MeOH; (d) NH2OH‚HCl, EtOH, CHCl3.
CH2Cl2; (c) MeI, t-BuOK, 1,2-dimethoxyethane; (d) BH3‚THF, THF;
(e) p-TsOH‚H2O, MeOH; (f) MsCl, Et3N, CH2Cl2; (g) NaI, 2-bu-
tanone.
and subsequently condensed with diethyl acetamido-
malonate using a standard method to give 45. Reduction
of 45 with lithium aluminum hydride and successive
acetylation provided triacetylated target compounds,
which were hydrolyzed to give compounds 5-18. For
the preparation of compound 10, the iodide 47 (Scheme
3) was used instead of 44. 10-Phenyldecyl bromide30 was
adopted instead of iodide 44 for the synthesis of com-
pound 11.
Next, target compounds 19-21 were prepared as
outlined in Scheme 4. Phenethyl bromide was converted
to intermediate 48 by the same method as in Scheme
2. Friedel-Crafts acylation of 48 followed by hydrolysis
gave the target compound 19. The ketone 19 was treated
with sodium borohydride or hydroxylamine hydrochlo-
ride to give the target compounds 20 and 21, respec-
tively.
densation with methyl methylsulfinylmethyl sulfide in
the presence of Triton B.31 The acid-catalyzed degrada-
tion of the condensation product gave an ester 51. The
ester group of 51 was reduced, and the sulfide group
was successively oxidized to the sulfoxide. Mesylation
followed by iodination gave iodide 52. Condensation of
52 with diethyl acetamidomalonate followed by Pum-
merer rearrangement using trifluoroacetic anhydride
and triethylamine32 gave intermediate 53, which was
converted into the desired compound 23 in three steps.
The synthesis of amine 24 was carried out according to
the procedure described in Scheme 2, except that the
iodide 55 (Scheme 7) was used instead of 44.
The ortho-substituted analogue 25 was synthesized
using a method similar to that in Scheme 2, except that
the iodide 58 (Scheme 8) was used instead of 44.
2-Bromobenzaldehyde underwent Grignard coupling
with heptyl bromide. Dehydration with P2O5 followed
by formylation gave aldehyde 56. The double bond was
saturated, and the resulting aldehyde was transformed
The ether 22 was synthesized by a method similar to
that in Scheme 2, except that iodide 50 (Scheme 5) was
used instead of 44. The synthesis of the sulfide 23 was
accomplished by the route shown in Scheme 6. 4-Meth-
ylthiobenzaldehyde underwent Knoevenagel-type con-

2-Substituted Aminopropanediols and 2-Aminoethanols
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 15 2949
Sch em e 8a
Sch em e 11a
a
(a) Heptyl bromide, Mg, THF; (b) P2O5, benzene; (c) Mg, DMF,
THF; (d) H2, Pd/C, EtOH; (e) CH3SCH2SOCH3, Triton B, 1,4-
dioxane; (f) HCl, EtOH; (g) LiAlH4, THF; (h) MsCl, Et3N; (i) NaI,
2-butanone.
Sch em e 9a
a
(a) RCH(COOEt)2, NaH, DMF; (b) (1) KOH, EtOH, (2) HCl,
H2O; (c) (1) ClCOOEt, Et3N, THF, (2) NaN3; (d) (1) benzene, reflux,
(2) benzene/MeOH; (e) LiBH4, THF; (f) 5 N aq KOH, THF/MeOH.
Sch em e 12a
a
(a) DHP, p-TsOH‚H2O, CH2Cl2; (b) n-BuLi, octyl bromide,
THF; (c) p-TsOH‚H2O; (d) MsCl, Et3N; (e) NaI, 2-butanone.
Sch em e 10a
a
(a) AcNHCH(CN)COOEt, NaH, DMF; (b) LiBH4, THF; (c) HCl,
AcOH, H2O.
into the ester 57 using the same method as for the
synthesis of 51. The desired 58 was obtained from 57
in three steps. The meta-substituted analogue 26 was
synthesized by a similar route to that used for 25.
Thiophene 27 was prepared according to Scheme 2. The
iodide 60 used for the synthesis instead of 44 was
obtained by the procedure shown in Scheme 9.
a
(a) I(CH2)2OTHP, NaH, DMF; (b) 50, NaH, DMF; (c) 1 N aq
HCl, MeOH; (d) 0.25 N aq NaOH, acetone; (e) (1) ClCOOEt, Et3N,
THF, (2) NaN3; (f) (1) benzene, reflux, (2) benzene/MeOH; (g)
LiBH4, THF; (h) Ac2O, pyridine; (i) TMSI, CH2Cl2; (j) 2 N aq LiOH,
THF/MeOH.
ethyl ester 64. Hydrolysis of 64 followed by Curtius
rearrangement afforded an isocyanate, which was
trapped with methanol to give the methylcarbamate 65.
Compound 65 was reduced and successively acetylated
to give 66, which was deprotected into compound 36.
Compound 37 was synthesized using iodide 44 instead
of 50 as in Scheme 12. The synthesis route of compound
38 is shown in Scheme 13. This route is similar to that
for compound 36, except that the tetrahydropyranyl
group (THP) is removed in the last step, since, unlike
in 64, the deprotection of 67 did not yield a δ-lactone
ethyl ester. Compounds 39 and 40 were prepared in a
totally different way (Scheme 14) containing a Ritter
reaction.34,35
The enantiomers of compounds 30, 34, and 36 were
obtained by optical resolution of their N-(3,5-dinitro-
benzoyl) derivatives using chiral column HPLC (Scheme
15). The absolute configuration of the (-)-enantiomer
of compound 34 was determined to be S by X-ray
analysis.2 The absolute configuration of compound 30
was assumed by comparing the optical rotation and
retention time on the chiral HPLC of the optically active
compounds 72a and 72b. (R)-(-)-72a and (R)-(-)-72b,
Compound 28, which has an R-substituted serine
skeleton like myriocin, was synthesized from phenethyl
acetate as a starting material by the route shown in
Scheme 10. The synthesis of compound 29 was reported
in the previous paper.33 Compounds 30-35, having
hydrophobic groups in place of one of the hydroxymethyl
groups of 22, were synthesized from 2-substituted
diethyl malonates as the starting materials (Scheme 11).
Iodide 50 and 2-substituted diethyl malonates were
condensed using NaH to give diesters 62. The diesters
were treated with potassium hydroxide in ethanol to
give half-esters, which were converted to acyl azides.
The acyl azides underwent Curtius rearrangement, and
the resulting isocyanates were trapped with methanol
to afford methylcarbamates 63. Reduction with lithium
borohydride followed by hydrolysis yielded compounds
30-35. Compound 36, having a hydroxyethyl group in
place of one of the hydroxymethyl groups of compound
22, was synthesized by the route shown in Scheme 12.
Diethyl malonate was dialkylated followed by treatment
with aqueous hydrogen chloride to give the γ-lactone

2950 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 15
Kiuchi et al.
Sch em e 13a
Sch em e 16a
a
(a) CH3CH(OC2H5)3, DIPEA, DMF; (b) (1) (COCl)2, DMSO,
CH2Cl2, (2) Et3N; (c) Zn, CH2I2, Me3Al, THF; (d) H2, Pd-C, EtOH;
(e) concd HCl, EtOH; (f) 3,5-dinitrobenzoyl chloride, KHCO3, H2O/
EtOAc.
Resu lts a n d Discu ssion
a
(a) Br(CH2)3OTHP, NaH, DMF; (b) 44, NaH, DMF; (c) (1)
KOH, EtOH, (2) HCl, H2O; (d) (1) ClCOOEt, Et3N, THF, (2) NaN3;
(e) (1) benzene, reflux, (2) benzene/MeOH; (f) LiBH4, THF; (g) 5 N
aq KOH, THF/MeOH; (h) 1 N aq HCl, MeOH.
From the beginning of our search for immunosup-
pressive compounds, we had evaluated the compounds
for their in vitro immunosuppressive activity using
mouse allogeneic MLR. However, 2-alkyl-2-aminopro-
pane-1,3-diols such as 3 prolonged rat skin allograft
survival markedly compared to 1, despite having only
comparable activity on mouse allogeneic MLR.27 This
result prompted us to investigate the mechanism of
action of compounds 1 and 3. We found that 2-alkyl-2-
aminopropane-1,3-diols such as 3 drastically decrease
the number of circulating lymphocytes (T-cells and
B-cells) in peripheral blood and that compound 3, unlike
1, has no inhibitory effect on serine palmitoyltrans-
ferase.27 Myriocin (1), on the other hand, did not
decrease the number of circulating lymphocytes, sug-
gesting that the immunosuppressive mechanism of
2-alkyl-2-aminopropane-1,3-diols such as 3 would be
different from that of 1. We assume that the lymphocyte-
decreasing effect of 3 contributes to its immunosuppres-
sive activity in vivo. In the early stage of this study
(compounds 4-27), all compounds were initially screened
for their lymphocyte-decreasing effect. Most compounds
were also tested for their immunosuppressive activity
in rat skin allograft using LEW donors and F344
recipients (Table 1). In these experiments, the com-
pounds were administered intraperitoneally.
Sch em e 14a
a
(a) HO(CH2)2OH, p-TsOH-H2O, benzene; (b) LiAlH4, THF; (c)
BnBr, NaH, DMF; (d) 1 N aq HCl, acetone/THF; (e) phenethyl
bromide, Mg, THF; (f) H2SO4, CH3CN; (g) H2, Pd-C, AcOH; (h)
Ac2O, pyridine; (i) octanoyl chloride, AlCl3, 1,2-dichloroethane; (j)
Et3SiH, TFA; (k) 2 N aq LiOH, THF/MeOH.
Sch em e 15a
Our attention focused first on the most favorable
position for introducing a phenyl ring into the lipophilic
side chain of 3. We synthesized a series of compounds
having the same length of the side chain containing a
phenyl ring (m + n ) 10, compounds 4-11). This
indicates that the position of the phenyl ring markedly
affected the activities. Compound 6, which has two
carbon atoms between the quaternary carbon atom and
the phenyl ring (m ) 2), decreased the number of
lymphocytes 3 times more effectively than the lead
compound 3 and prolonged allograft survival in a dose-
dependent manner. Moving the phenyl ring of 6 by just
one carbon in either direction resulted in a great loss
of potency, suggesting that the position of the phenyl
ring is of critical importance for the potency of activity.
This finding suggests that the introduction of the phenyl
ring can modify their pharmacological properties pre-
sumably by sterical restriction on the alkyl chain and/
or favorable interaction with target molecules. All
compounds except 6 showed weaker activity than the
lead compound 3.
a
(a) 3,5-Dinitrobenzoyl chloride, KHCO3, EtOAc/H2O; (b) sepa-
ration by HPLC; (c) 2 N aq LiOH, THF/MeOH.
as well as (S)-(+)-72a and (S)-(+)-72b, had the same
retention time on the chiral HPLC and a similar optical
rotation, respectively. The (+)-enantiomer of compound
36 was converted into 75 to determine the absolute
configuration as shown in Scheme 16. The compound
75 derived from (+)-36 had the same optical rotation
and retention time on the chiral HPLC as the R-
enantiomer of 72b. The absolute configuration of (+)-
enantiomer of 36 was thus determined to be S.

2-Substituted Aminopropanediols and 2-Aminoethanols
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 15 2951
Ta ble 1. Lymphocyte-Decreasing Effect (ID50 and ID80, mg/kg) and Immunosuppressive Activity on Rat Skin Allograft (MST ( SE,
days) of 2-Substituted 2-Aminopropane-1,3-diols
MST ( SEb
a
a
compd
ID50
ID80
0.1 mg/kg
0.3 mg/kg
1 mg/kg
3 mg/kg
10 mg/kg
toxicc
control
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
CsA
>3
>3
8.5 ( 0.3
37.3 ( 1.1
NTd
0.3
0.3
0.3
13.8 ( 0.3
26.5 ( 1.8
45.5 ( 2.4
>3
>3
0.1
>3
0.03
>3
>3
0.3
>3
0.3
0.1
0.03
0.1
0.1
0.1
0.03
1
0.03
0.1
0.03
0.03
0.03
1
9.8 ( 0.5
52.0 ( 6.2
9.0 ( 0.6
13.8 ( 1.8
9.8 ( 0.5
8.5 ( 0.3
toxic
11.8 ( 0.5
toxic
10.5 ( 1.0
18.8 ( 1.5
13.5 ( 0.3
8.6 ( 0.3
25.3 ( 0.6
31.3 ( 0.9
39.5 ( 2.8
>3
>3
1
>3
1
11.5 ( 0.9
21.5 ( 3.1
27.0 ( 2.1
NT
0.3
0.1
0.1
0.1
1
23.0 ( 3.9
37.8 ( 2.1
23.3 ( 2.1
22.8 ( 3.7
32.0 ( 1.5
48.0 ( 3.3
39.3 ( 3.5
40.5 ( 3.8
NT
NT
32.5 ( 1.2
NT
toxic
toxic
toxic
53.0 ( 3.5
20.0 ( 1.8
12.0 ( 0.7
toxic
1
>3
0.3
0.3
1
0.1
0.03
1
19.8 ( 1.3
25.5 ( 1.7
toxic
NT
15.0 ( 1.1
22.3 ( 2.2
23.5 ( 1.6
36.0 ( 1.5
33.8 ( 0.5
44.5 ( 2.0
21.3 ( 1.1
NT
39.5 ( 1.6
toxic
29.0 ( 1.1
toxic
toxic
>3
>3
1
>3
>3
>3
NT
13.0 ( 1.1
10.8 ( 0.3
(3 mg/kg)
17.3 ( 0.6
15.0 ( 0.4
(10 mg/kg)
21.0 ( 1.8
19.8 ( 0.5
(30 mg/kg)
>30
>30
8.0 ( 0.4
(1 mg/kg)
toxic
(100 mg/kg)
a
The indicated dose (mg/kg) is the lowest dose required to decrease the number of lymphocytes by 50% or 80% of vehicle-treated
control. MST: mean survival time (days). Each group consisted of four animals. c Animals died. NT, not tested.
b
d
Next we focused on the refinement of the length of
the alkyl chain containing the phenyl ring. When the
length between the quaternary carbon atom and the
phenyl ring was two carbon atoms (m ) 2), most
compounds (12-17) except 18 showed comparable ac-
tivity to 3, suggesting that the activities were not so
sensitive to the length of the alkyl chain attached to
the phenyl ring. This finding contrasts with the case of
alkyl compounds reported previously.27 In the reported
study, we found that the activity of alkyl compounds
containing no phenyl ring was significantly influenced
by the length of the alkyl side chain. When the length
of the alkyl chain was eight (n ) 8, compound 6) or nine
(n ) 9, compound 13) carbon atoms, activity in terms
of lymphocyte-decreasing effect was excellent. On the
other hand, compound 14, of which the alkyl chain had
ten carbon atoms (n ) 10), showed the most potent
immunosuppressive activity on rat skin allograft at a
dose of 1 mg/kg but was toxic at a dose of 3 mg/kg. The
toxicity of the compounds of this series was greatest
when the length of the alkyl chain attached to the
phenyl ring was nine to eleven carbon atoms (n ) 9-11,
compounds 13-15). Although compound 16 with its
longer alkyl chain (n ) 12) effectively prolonged rat skin
allograft survival at high doses (1 and 3 mg/kg), its
activity at low doses (0.1 and 0.3 mg/kg) was weaker
than that of 6. This weak immunosuppressive activity
at low doses is associated with its weak activity on the
lymphocyte-decreasing effect. Since a sufficient separa-
tion of immunosuppressive activity and toxicity has
been achieved with compound 6, we concluded that
compound 6 is superior to 16 as the candidate drug.
Our third focus of attention was the most favorable
linkage between the phenyl ring and the alkyl group
extending from it. Replacement of the methylene group
with a carbonyl or hydroxymethylene (compounds 19
and 20, respectively) resulted in slightly weaker activity
on the lymphocyte-decreasing effect compared with that
of compound 6. Compound 19 was toxic at a dose of 3
mg/kg. Compound 22, which has an oxygen atom, was
equipotent to 6 in terms of lymphocyte-decreasing effect
but did not significantly prolong allograft survival
compared to 6. Introduction of a sulfur atom was
favorable for potent activity on the lymphocyte-decreas-
ing effect and rat skin allograft survival. Unfortunately,
the sulfide 23 combined strong toxicity with its potent
activity. Attempts to replace the methylene group with
nitrogen functional groups (compounds 21 and 24)
resulted in a loss in activity. These findings verify that
hydrophilic groups next to the phenyl ring are unfavor-
able for activity.
The ortho- and meta-substituted derivatives 25 and
26, respectively, showed notably reduced activity. This
finding together with that in the para-substituted
derivative 6 indicates that the phenyl ring affects
activity by restricting the conformation of molecules.
Replacement of the phenyl ring with a thiophene ring
(compound 27) led to a great loss of activity.
On the whole, marked decrease in the number of
peripheral blood lymphocytes was associated with sig-
nificant prolongation of allograft survival. This suggests
that a decrease in peripheral lymphocytes is closely
related to immunosuppressive activity. Among the
compounds described above, we selected 6 (FTY720) as
the candidate drug for clinical trial in view of its marked
lymphocyte-decreasing effect, potent immunosuppres-
sive activity, and low toxicity. FTY720 prolonged rat
skin allograft survival more effectively than CsA and
showed activity in other administration routes (mean
survival time: 24.8 days/0.1 mg/kg, 46.3 days/3 mg/kg,

2952 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 15
Kiuchi et al.
Ta ble 2. T-Cell-Decreasing Activity and Immunosuppressive
Activity of 2-Substituted 2-Amino Alcohols and Related Amino
Alcohols
Ch a r t 3. Comparison of Configuration at Quaternary
Carbon Atoms
ID50 valuesa (mg/kg, po, n ) 4)
compd
T-cells
lymph node
6
22
28
29
0.024 (0.016-0.035)
0.014 (0.012-0.018)
>10
0.0097 (0.032-0.28)
0.049 (0.019-0.15)
>10
>10
>10
30
0.016 (0.013-0.021)
0.0092 (0.0068-0.010)
>1b
0.031 (0.018-0.053)
0.088 (0.032-0.22)
>1b
because of its rapid metabolic change. We also found
that the hydroxy groups of 6 are not always both
necessary for in vivo activity, as compounds 30 and 31,
having a lower alkyl group, showed potent T-cell-
decreasing activity (30: 0.016 mg/kg, 31: 0.044 mg/kg)
and immunosuppressive activity (30: 0.031 mg/kg, 31:
0.059 mg/kg). However, activity weakened with increas-
ing bulkiness of the alkyl group (compounds 32-34).
No activity was observed at larger size (compound 35).
Interestingly, compounds 36-38, which retain two
hydroxy groups such as 6, show a tendency distinct from
that observed in the alkyl derivatives 30-35. Com-
pounds 36-38 showed potent activity despite the in-
creasing volume of the substituent attached to the
quaternary carbon. For example, the bulkiness of the
hydroxyethyl group of compound 36 is similar to that
of the propyl group of compound 34. However, 36
showed potent activity in contrast to the weak activity
of compound 34. These results suggest that, when the
substituent attached to the quaternary carbon is bigger
than an ethyl group, the hydroxyalkyl groups are more
favorable for potent activity than the corresponding
alkyl groups.
(R)-30
(S)-30
31
32
33
0.044 (0.039-0.050)
3.1 (2.1-4.7)
4.5 (3.8-5.6)
7.3 (4.6-12)
4.4 (3.6-4.7)
>10
0.059 (0.029-0.11)
1.9 (0.70-4.9)
2.7 (1.5-4.7)
3.1 (1.6-5.7)
0.63 (0.14-1.9)
>10
34
(R)-34
(S)-34
35
>10
>10
36
0.055 (0.035-0.085)
4.2 (2.8-6.5)
0.018 (0.015-0.021)
0.12 (0.079-0.19)
0.021 (0.015-0.028)
>10
0.038 (0.025-0.058)
4.2 (1.8-10)
0.017 (0.0068-0.035)
0.009 (0.0040-0.021)
0.085 (0.048-0.14)
>10
(R)-36
(S)-36
37
38
39
40
CsA
>10
>30
>10
2.8 (1.2-6.5)
a
b
95% confidence limits are given in parentheses. No activity
at 1 mg/kg, the highest dose tested for this compound.
and 53.5 days/10 mg/kg, iv; 19.3 days/0.1 mg/kg, 41.0
days/3 mg/kg, and 57.8 days/30 mg/kg, po). From our
study on the mechanism of action of FTY720, we
concluded that FTY720 sequesters circulating mature
lymphocytes into peripheral lymph nodes, mesenteric
lymph nodes, and Peyer’s patches by acceleration of
lymphocyte homing and thereby decreases the number
of lymphocytes in peripheral blood.36-39 Meanwhile, we
confirmed that FTY720, like 3, had no inhibitory effect
on serine palmitoyltransferase at a concentration of
1000 nM or less.
During the research to elucidate the mechanism of
action of compound 6, it was proved that the decrease
of T-cells in peripheral blood caused by 6 was more
remarkable than the decrease of B-cells or other cells.37
We presumed that the T-cell-decreasing effect is the
essence of immunosuppressive activity of 6 because
T-cells perform pivotal functions on allograft rejection.
Therefore, we investigated the T-cell-decreasing effect
(Table 2) instead of the lymphocyte-decreasing effect in
the late stage of this study (compounds 28-40) to obtain
an improved compound. Furthermore, we adopted a
popliteal lymph node gain assay40 to evaluate the
immunosuppressive activity. This assay represents one
of the simplest models of graft rejection in transplanta-
tion and is able to express the results as simpler
numerals (e.g. ID50, Table 2) than those of skin allograft.
Compound 6 markedly decreased the number of T-cells
(ID50 ) 0.024 mg/kg) and showed potent immunosup-
pressive activity (ID50 ) 0.0097 mg/kg) on the popliteal
lymph node gain assay.
3-Substituted 3-aminopropanols (compounds 39 and
40) showed no activity, whether the substituent binding
to the quaternary carbon was methyl or hydroxyethyl.
When the results for 39 and 40 were compared with
those for 30 and 36, it became clear that a 2-amino-
ethanol moiety, that is, a hydroxymethyl group attached
to the quaternary carbon, is essential for the immuno-
suppressive activity.
Marked differences in activity were observed between
the enantiomers of three compounds (30, 34, and 36).
For example, (R)-30 showed potent T-cell-decreasing
activity and immunosuppressive activity (ID50 ) 0.0092
and 0.088 mg/kg, respectively), whereas (S)-30 showed
no activity at a dose of 1 mg/kg. (R)-30, (R)-34, and (S)-
36 were more potent than the corresponding enanti-
omers, (S)-30, (S)-34, and (R)-36, respectively. (S)-36
has the same configuration for the quaternary carbon
as (R)-30 and (R)-34, as the priority of the groups
attached to the chiral center is changed. The active
enantiomers have the (pro-S)-hydroxymethyl group of
6 (Chart 3), indicating that the two hydroxymethyl
groups of 6 play different roles for showing immuno-
suppressive activity and that the (pro-S)-hydroxymethyl
group of 6 is essential for immunosuppressive activity.
On the other hand, it is able to replace the (pro-R)-
hydroxymethyl group by other substituents, and the
favorable substituents are lower alkyl (methyl and
ethyl) or hydroxyalkyl (hydroxyethyl and hydroxypro-
pyl) groups shown by compounds 30, 31, and 36-38.
This result suggests that the binding site of the (pro-
R)-hydroxymethyl group in the targeting molecule is
constituted by a lipophilic entrance and a hydrophilic
inner site.
An R-substituted serine 28, the structure of which is
similar to that of myriocin (1), was not active probably
due to its poor solubility. Although we previously
reported that compound 29, which has a hydrogen in
place of one of the hydroxymethyl groups of 6, had a
similar activity to 6 in mouse allogeneic MLR,33 29 was
inactive in vivo at doses of 10 mg/kg or less presumably

2-Substituted Aminopropanediols and 2-Aminoethanols
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 15 2953
through Celite and evaporated. The residue was dissolved in
pyridine (40 mL) and acetic anhydride (30 mL) and left at room
temperature for 16 h. The reaction mixture was poured into
water and extracted with EtOAc. The extract was washed with
1 N HCl and saturated NaHCO3 and brine, dried, and
evaporated. Silica gel chromatography, eluting with hexanes-
EtOAc (1:2), gave 2-acetamido-2-[2-(4-octylphenyl)ethyl]pro-
pane-1,3-diol diacetate (8.25 g, 88%) as a white solid. To a
solution of this intermediate (8.25 g, 23.6 mmol) in MeOH (100
mL) was added 2 N LiOH (80 mL). The mixture was refluxed
for 2 h, evaporated to remove the organic solvent, and
extracted with EtOAc. The extract was washed with brine,
dried, and evaporated. The residue was converted to hydro-
chloride salt by treatment with EtOH (50 mL) and 1 N HCl
solution in Et2O (50 mL) and recrystallized from EtOH/EtOAc
Con clu sion
A phenyl ring was introduced into the alkyl side chain
of lead compound 3. The position of the phenyl ring was
critical for the lymphocyte-decreasing effect and im-
munosuppressive activity. Activity was especially potent
when the length between the quaternary carbon atom
and the phenyl ring was two carbon atoms. The most
suitable substitution pattern for the phenyl ring was
para. Variation of the length of the alkyl side chain did
not dramatically affect activity but caused the fluctua-
tion of toxicity. Favorable substituents for one of the
hydroxymethyl groups of 6 were hydroxyalkyl (hydroxy-
ethyl and hydroxypropyl) or lower alkyl (methyl and
ethyl) groups. Evaluation of three pairs of enantiomers
revealed that the (pro-S)-hydroxymethyl group of 6 is
indispensable, while the (pro-R)-hydroxymethyl group
plays a supplementary role for the immunosuppressive
activity. FTY720 (6) possesses potent immunosuppres-
sive activity and unique mechanisms of action. It is
therefore expected to be a promising immunosuppres-
sive drug for organ transplantation.
1
to give 6 (4.20 g, 52%) as a white solid: mp 107-108 °C; H
NMR (90 MHz, DMSO-d6) δ 7.94 (brs, 3H), 7.11 (s, 4H), 5.40
(t, 2H, J ) 6 Hz), 3.50 (d, 4H, J ) 6 Hz), 2.63-2.44 (m, 4H),
1.83-1.72 (m, 2H), 1.57-1.45 (m, 2H), 1.29-1.18 (m, 10H),
0.85 (t, 3H, J ) 6 Hz); IR (KBr) 3371, 3265, 2924 cm-1; MS
(EI) m/z 307 (M+). Anal. (C19H33NO2‚HCl) C, H, N.
Compounds 5 and 7-18 were synthesized as described for
6.
2-Am in o-2-(4-n on ylben zyl)p r op a n e-1,3-d iol h yd r och lo-
r id e (5): mp 119-120 °C; 1H NMR (400 MHz, DMSO-d6) δ
7.80 (brs, 3H), 7.17 (d, 2H, J ) 7.9 Hz), 7.12 (d, 2H, J ) 7.9
Hz), 5.42 (t, 2H, J ) 3.9 Hz), 3.37-3.29 (m, 4H), 2.82 (s, 2H),
2.52 (t, 2H, J ) 7.3 Hz), 1.59-1.50 (m, 2H), 1.31-1.18 (m,
12H), 0.84 (t, 3H, J ) 6.9 Hz); IR (KBr) 3362, 3279 cm-1; MS
(EI) m/z 308 (M + H) +. Anal. (C19H33NO2‚HCl) C, H, N.
2-Am in o-2-[3-(4-h ep t ylp h en yl)p r op yl]p r op a n e-1,3-d i-
Exp er im en ta l Section
Ch em istr y. Organic extracts were dried over anhydrous
Na2SO4. Silica gel chromatography was performed on Merck
Kieselgel 60. HPLC was accomplished using a TOSOH SC-
8010 controller, a CCPP-M pump, and a UV-8010 detector.
Melting points were obtained on a Buchi 535 melting point
apparatus and are uncorrected. 1H NMR spectra were recorded
on a J EOL R400 spectrometer (400 MHz) or a HITACHI R-90H
spectrometer (90 MHz) using tetramethylsilane (TMS) as an
internal standard. Mass spectra were measured on a J EOL-
J MS-DX300 instrument. Infrared spectra were recorded on a
J ASCO FT/IR-5300 spectrometer. Optical rotations were
determined on a J ASCO digital polarimeter DIP-360 in a 10-
cm path length cell. Elemental analyses were performed on a
Yanako CHN coder MT-5, and the results indicated by element
symbols are within (0.4% of the calculated values.
2-Am in o-2-(4-decylph en yl)pr opan e-1,3-diol Hydr och lo-
r id e (4). A solution of 42 (337 mg, 1.00 mmol) in EtOH (10
mL) was hydrogenated at room temperature for 16 h using
Raney Ni (500 mg) and 20 atm of hydrogen. The catalyst was
removed by filtration and the filtrate was evaporated. To a
solution of the residue in EtOH (20 mL) and CHCl3 (5 mL)
were added triethylamine (400 µL, 2.89 mmol) and acetyl
chloride (120 µL, 1.69 mmol) at -60 °C. The mixture was
stirred at room temperature for 30 min, evaporated, and
diluted with EtOAc. The solution was washed with 1 N HCl,
saturated NaHCO3 and brine, dried, and evaporated. The
residue was purified by preparative TLC, developing with
CHCl3-CH3CN (4:1), to give 2-acetamido-2-(4-decylphenyl)-
propane-1,3-diol (130 mg, 37%) as a white solid. To a solution
of this intermediate (170 mg, 0.486 mmol) in MeOH (9 mL)
was added 1 N NaOH (3 mL). The mixture was refluxed for 3
h, and the organic solvent was evaporated. The yielded white
solid was the free base of 4 (142 mg, 95%): mp 136-137 °C;
1H NMR (90 MHz, CDCl3/CD3OD) δ 7.33 (d, 2H, J ) 10 Hz),
7.20 (d, 2H, J ) 10 Hz), 4.20-3.50 (m, 4H), 2.70-2.30 (m, 6H),
1.80-1.40 (m, 2H), 1.40-1.10 (m, 14H), 0.88 (t, 3H, J ) 8 Hz).
This product was converted to hydrochloride salt by treat-
ment with HCl/MeOH and recrystallized from 2-propanol to
give 4 (131 mg) as a white solid: mp 117-118 °C; IR (KBr)
3464, 3015, 2919, 2851 cm-1; MS (EI) m/z 307 (M+). Anal.
(C19H33NO2‚HCl) C, H, N.
1
ol h yd r och lor id e (7): mp 124-126 °C; H NMR (400 MHz,
DMSO-d6) δ 7.69 (brs, 3H), 7.08 (s, 4H), 5.29 (t, 2H, J ) 4.4
Hz), 3.46-3.38 (m, 4H), 2.53-2.48 (m, 4H), 1.59-1.48 (m, 6H),
1.29-1.18 (m, 8H), 0.84 (t, 3H, J ) 6.8 Hz); IR (KBr) 3435,
3045 cm-1; MS (EI) m/z 307 (M+). Anal. (C19H33NO2‚HCl) C,
H, N.
2-Am in o-2-[4-(4-h exylph en yl)bu tyl]pr opan e-1,3-diol h y-
d r och lor id e (8): (free base) mp 89-90 °C; 1H NMR (90 MHz,
CDCl3) δ 7.09 (s, 4H), 3.58 (d, 2H, J ) 12 Hz), 3.41 (d, 2H, J
) 12 Hz), 2.61 (t, 4H, J ) 6 Hz), 1.93-1.19 (m, 18H), 0.90 (t,
3H, J ) 6 Hz); IR (KBr) 3347, 3331, 3288, 2927 cm-1; MS (EI)
m/z 307 (M+); (HCl salt) mp 107-108 °C. Anal. (C19H33NO2‚
HCl) C, H, N.
2-Am in o-2-[6-(4-bu tylph en yl)h exyl]pr opan e-1,3-diol h y-
d r och lor id e (9): (free base) mp 70-71 °C; 1H NMR (90 MHz,
CDCl3) δ 7.08 (s, 4H), 3.57 (d, 2H, J ) 12 Hz), 3.40 (d, 2H, J
) 12 Hz), 2.59 (t, 4H, J ) 6 Hz), 1.97 (brs, 4H), 1.83-1.11 (m,
14H), 0.92 (t, 3H, J ) 6 Hz); IR (KBr) 3334, 3289, 3167, 2927
cm-1; MS (EI) m/z 307 (M+); (HCl salt) mp 97-98 °C. Anal.
(C19H33NO2‚HCl) C, H, N.
2-Am in o-2-[8-(4-eth ylph en yl)octyl]pr opa n e-1,3-d iol h y-
d r och lor id e (10): synthesized as described for 6 using 47;
1
(free base) H NMR (90 MHz, CDCl3) δ 7.09 (s, 4H), 3.82 (s,
4H), 2.58 (t, 2H, J ) 7 Hz), 2.54 (t, 2H, J ) 6 Hz), 1.88-1.17
(m, 14H), 1.22 (t, 3H, J ) 7 Hz); IR (KBr) 3491, 3288, 2930
cm-1; MS (EI) m/z 307 (M+); (HCl salt) mp 84-86 °C. Anal.
(C19H33NO2‚HCl‚H2O) C, H, N.
2-Am in o-2-(10-p h en yld ecyl)p r op a n e-1,3-d iol h yd r o-
ch lor id e (11): synthesized as described for 6 using 10-
1
phenyldecyl bromide; (free base) mp 87-89 °C; H NMR (90
MHz, CDCl3) δ 7.35-7.13 (m, 5H), 3.60 (d, 2H, J ) 12 Hz),
3.42 (d, 2H, J ) 12 Hz), 2.62 (t, 2H, J ) 6 Hz), 1.93 (m, 4H),
1.80-1.46 (m, 2H), 1.43-1.19 (m, 14H); IR (KBr) 3347, 3223,
2920, 2852 cm-1; MS (EI) m/z 307 (M+); (HCl salt) mp 97-98
°C. Anal. (C19H33NO2‚HCl) C, H, N.
2-Am in o-2-[2-(4-h eptylph en yl)eth yl]pr opan e-1,3-diol h y-
d r och lor id e (12): mp 109-110 °C; 1H NMR (90 MHz, DMSO-
d6) δ 7.47 (brs, 3H), 7.08 (s, 4H), 3.48 (s, 4H), 3.34 (brs, 2H),
2.62-2.48 (m, 4H), 1.79-1.69 (m, 2H), 1.58-1.45 (m, 2H),
1.33-1.17 (m, 8H), 0.85 (t, 3H, J ) 6 Hz); IR (KBr) 3369, 2926
cm-1; MS (EI) m/z 293 (M+). Anal. (C18H31NO2‚HCl) C, H, N.
2-Am in o-2-[2-(4-n on ylph en yl)eth yl]pr opan e-1,3-diol h y-
d r och lor id e (13): mp 108-110 °C; 1H NMR (400 MHz,
2-Am in o-2-[2-(4-octylph en yl)eth yl]pr opan e-1,3-diol Hy-
d r och lor id e (6). To a suspension of LiAlH4 (3.03 g, 79.8
mmol) in THF (260 mL) at 0 °C was added dropwise a solution
of 45 (11.6 g, 26.8 mmol) in THF (100 mL). After stirring at
room temperature for 2 h, the reaction was quenched with
saturated Na2SO4 (50 mL). The reaction mixture was filtered

2954 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 15
Kiuchi et al.
DMSO-d6) δ 7.79 (brs, 3H), 7.09 (s, 4H), 5.36 (t, 2H, J ) 5.3
Hz), 3.51 (d, 4H, J ) 5.3 Hz), 2.57-2.49 (m, 4H), 1.79-1.74
(m, 2H), 1.55-1.51 (m, 2H), 1.28-1.21 (m, 12H), 0.84 (t, 3H,
J ) 6.9 Hz); IR (KBr) 3348, 2921 cm-1; MS (EI) m/z 321 (M+).
Anal. (C20H35NO2‚HCl) C, H, N.
2-Am in o-2-[2-(4-decylph en yl)eth yl]pr opan e-1,3-diol h y-
d r och lor id e (14): mp 107-109 °C; 1H NMR (400 MHz,
DMSO-d6) δ 7.83 (brs, 3H), 7.09 (s, 4H), 5.32 (t, 2H, J ) 5.2
Hz), 3.50 (d, 4H, J ) 5.2 Hz), 2.56-2.49 (m, 4H), 1.79-1.74
(m, 2H), 1.55-1.50 (m, 2H), 1.29-1.21 (m, 14H), 0.84 (t, 3H,
J ) 6.8 Hz); IR (KBr) 3255, 2920 cm-1; MS (EI) m/z 335 (M+).
Anal. (C21H37NO2‚HCl) C, H, N.
2-Am in o-2-[2-(4-u n d ecylp h en yl)eth yl]p r op a n e-1,3-d i-
ol h yd r och lor id e (15): mp 108-110 °C; 1H NMR (400 MHz,
DMSO-d6) δ 7.83 (brs, 3H), 7.09 (s, 4H), 5.37 (t, 2H, J ) 5.2
Hz), 3.51 (d, 4H, J ) 5.2 Hz), 2.57-2.49 (m, 4H), 1.78-1.74
(m, 2H), 1.55-1.50 (m, 2H), 1.29-1.20 (m, 16H), 0.84 (t, 3H,
J ) 6.9 Hz); IR (KBr) 3345, 3249, 2916 cm-1; MS (EI) m/z 349
(M+). Anal. (C22H39NO2‚HCl) C, H, N.
2.56 (t, 2H, J ) 8.0 Hz), 1.78-1.73 (m, 2H), 1.65-1.60 (m, 2H),
1.39-1.22 (m, 10H), 0.86 (t, 3H, J ) 6.9 Hz); IR (KBr) 3338
cm-1; MS (EI) m/z 323 (M+). Anal. (C19H33NO3‚H2O) C, H, N.
2-Am in o-2-[2-[4-(1-h yd r oxyim in ooct yl)p h en yl]et h yl]-
p r op a n e-1,3-d iol (21). A mixture of 19 (1.20 g, 3.73 mmol)
and hydroxylamine hydrochloride (310 mg, 4.46 mmol) in
EtOH (16 mL) and CHCl3 (3 mL) was refluxed for 1.5 h. The
mixture was evaporated, diluted with 1 N NaOH, and ex-
tracted with EtOAc. The extract was washed with brine, dried,
and evaporated. Silica gel chromatography, eluting with
CHCl3-MeOH (9:1), followed by recrystallization from EtOAc-
isopropyl ether, gave 21 (320 mg, 25%) as a yellowish solid:
mp 90-93 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H),
7.50 (d, 2H, J ) 8.3 Hz), 7.18 (d, 2H, J ) 8.3 Hz), 4.49 (brs,
2H), 3.26 (d, 2H, J ) 10.5 Hz), 3.22 (d, 2H, J ) 10.5 Hz), 2.67
(t, 2H, J ) 7.6 Hz), 2.60-2.56 (m, 2H), 1.78 (brs, 2H), 1.52-
1.48 (m, 2H), 1.43-1.39 (m, 2H), 1.24-1.21 (m, 10H), 0.83 (t,
3H, J ) 7.1 Hz); IR (KBr) 3341, 3180 cm-1; MS (EI) m/z 336
(M+). Anal. (C19H32N2O3‚0.25H2O) C, H, N.
2-Am in o-2-[2-(4-h ep t yloxyp h en yl)et h yl]p r op a n e-1,3-
d iol h yd r och lor id e (22): synthesized as described for 6 using
50; mp 111-112 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.80 (brs,
3H), 7.08 (d, 2H, J ) 8.3 Hz), 6.83 (d, 2H, J ) 8.3 Hz), 5.36 (t,
2H, J ) 4.9 Hz), 3.89 (t, 2H, J ) 6.6 Hz), 3.50 (d, 4H, J ) 4.9
Hz), 2.53-2.49 (m, 2H), 1.76-1.63 (m, 4H), 1.38-1.25 (m, 8H),
0.85 (t, 3H, J ) 6.4 Hz); IR (KBr) 3355, 3274, 3033, 2924, 2855
cm-1; MS (EI) m/z 309 (M+). Anal. (C18H31NO3‚HCl) C, H, N.
2-Am in o-2-[2-(4-d od ecylp h en yl)et h yl]p r op a n e-1,3-d i-
ol h yd r och lor id e (16): mp 108-110 °C; H NMR (90 MHz,
1
DMSO-d6) δ 8.07 (brs, 3H), 7.12 (d, 2H, J ) 8 Hz), 7.06 (d,
2H, J ) 6 Hz), 4.79 (brs, 2H), 3.65 (d, 2H, J ) 11 Hz), 3.56 (d,
2H, J ) 11 Hz), 2.68-2.56 (m, 4H), 2.02-1.94 (m, 2H), 1.58-
1.52 (m, 2H), 1.30-1.20 (m, 18H), 0.87 (t, 3H, J ) 6 Hz); IR
(KBr) 3375, 3270, 2922 cm-1; MS (EI) m/z 363 (M+). Anal.
(C23H41NO2‚HCl) C, H, N.
2-Am in o-2-[2-(4-h ep t ylt h iop h en yl)et h yl]p r op a n e-1,3-
d iol (23). To a solution of 53 (1.80 g, 5.09 mmol) in DMF (20
mL) were added K2CO3 (829 mg, 6.00 mmol) and heptyl
bromide (1.07 g, 6.00 mmol). After stirring at room tempera-
ture for 1 h, the mixture was diluted with EtOAc. The organic
solution was washed with brine, dried, and evaporated. Silica
gel chromatography, eluting with hexanes-EtOAc (4:1), gave
diethyl 2-acetamido-2-[2-(4-heptylthiophenyl)ethyl]malonate
(1.86 g, 81%) as a white solid. To a suspension of LiAlH4 (380
mg, 10.0 mmol) in THF (15 mL) at 0 °C was added dropwise
a solution of the malonate (1.13 g, 2.50 mmol) obtained above
in THF (10 mL). After stirring at room temperature for 1 h,
the reaction was quenched with saturated Na2SO4 (20 mL).
The reaction mixture was filtered through Celite and evapo-
rated. Silica gel chromatography, eluting with CHCl3-MeOH
(20:1), gave 2-acetamido-2-[2-(4-heptylthiophenyl)ethyl]pro-
pane-1,3-diol (560 mg, 61%) as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 7.24 (d, 2H, J ) 7.6 Hz), 7.11 (d, 2H, J ) 7.6
Hz), 5.88 (s, 1H), 3.85 (dd, 2H, J ) 11.2, 5.4 Hz), 3.71 (t, 2H,
J ) 5.4 Hz), 3.62 (dd, 2H, J ) 11.2, 5.4 Hz), 2.87 (t, 2H, J )
7.4 Hz), 2.63-2.60 (m, 2H), 1.98 (s, 3H), 1.98-1.93 (m, 2H),
1.63-1.59 (m, 2H), 1.42-1.38 (m, 2H), 1.32-1.20 (m, 6H), 0.87
(t, 3H, J ) 7.1 Hz).
2-Am in o-2-[2-(4-t r id ecylp h en yl)et h yl]p r op a n e-1,3-d i-
ol h yd r och lor id e (17): mp 109-110 °C; H NMR (90 MHz,
DMSO-d6) δ 7.91 (brs, 3H), 7.08 (s, 4H), 5.38 (brs, 2H), 3.51
(s, 4H), 2.60-2.44 (m, 4H), 1.80-1.73 (m, 2H), 1.53-1.45 (m,
2H), 1.30-1.15 (m, 20H), 0.84 (t, 3H, J ) 6 Hz); IR (KBr) 3265,
2922 cm-1; MS (EI) m/z 377 (M+). Anal. (C24H43NO2‚HCl) C,
H, N.
2-Am in o-2-[2-(4-t et r a d ecylp h en yl)et h yl]p r op a n e-1,3-
d iol h yd r och lor id e (18): mp 109-111 °C; 1H NMR (90 MHz,
DMSO-d6) δ 7.99 (brs, 3H), 7.07 (s, 4H), 4.90 (brs, 2H), 3.51
(s, 4H), 2.62-2.56 (m, 2H), 2.46 (t, 2H, J ) 6 Hz), 1.80-1.72
(m, 2H), 1.53-1.45 (m, 2H), 1.30-1.12 (m, 22H), 0.83 (t, 3H,
J ) 6 Hz); IR (KBr) 3267, 2922 cm-1; MS (EI) m/z 391 (M+).
Anal. (C25H45NO2‚HCl) C, H, N.
2-Am in o-2-[2-(4-octa n oylp h en yl)eth yl]p r op a n e-1,3-d i-
ol (19). To a suspension of AlCl3 (31.0 g, 232 mmol) in 1,2-
dichloroethane (460 mL) was added dropwise octanoyl chloride
(19.8 mL, 116 mmol). After stirring at room temperature for
1 h, a solution of 48 (9.34 g, 29.0 mmol) in 1,2-dichloroethane
was added. The mixture was stirred for 12 h, poured into 1 N
NaOH, and extracted with Et2O. The extract was washed with
brine, dried, and evaporated. Silica gel chromatography,
eluting with hexanes-EtOAc (1:1), gave 2-acetamido-2-[2-(4-
octanoylphenyl)ethyl]propane-1,3-diol diacetate (8.30 g, 64%)
as a yellowish solid. To a solution of this intermediate (8.30 g,
19.0 mmol) in MeOH (200 mL) and THF (100 mL) was added
2 N LiOH (80 mL). The solution was refluxed for 3 h,
evaporated to remove the organic solvent, and extracted with
EtOAc. The extract was washed with brine, dried, and
evaporated. Recrystallization from hexanes-EtOAc gave 19
(3.02 g, 51%) as a white solid: mp 116-117 °C; 1H NMR (400
MHz, CDCl3) δ 7.87 (d, 2H, J ) 8.3 Hz), 7.27 (d, 2H, J ) 8.3
Hz), 3.60 (d, 2H, J ) 10.7 Hz), 3.52 (d, 2H, J ) 10.7 Hz), 2.93
(t, 2H, J ) 7.3 Hz), 2.73-2.69 (m, 2H), 1.72-1.68 (m, 4H),
1.32-1.26 (m, 8H), 0.88 (t, 3H, J ) 6.9 Hz); IR (KBr) 3350,
2926, 1678 cm-1; MS (EI) m/z 321 (M+). Anal. (C19H31NO3) C,
H, N.
2-Am in o-2-[2-[4-(1-h ydr oxyoctyl)ph en yl]eth yl]pr opan e-
1,3-d iol (20). To a solution of 19 (643 mg, 2.00 mmol) in EtOH
(50 mL) was added NaBH4 (151 mg, 4.0 mmol). After stirring
at room temperature for 3 h, the mixture was evaporated, and
diluted with EtOAc. The organic solution was washed with
brine, dried, and evaporated. Silica gel chromatography,
eluting with CHCl3-MeOH (4:1), gave 20 (429 mg, 66%) as a
yellowish oil: 1H NMR (400 MHz, CDCl3) δ 7.21 (d, 2H, J )
7.8 Hz), 7.12 (d, 2H, J ) 7.8 Hz), 4.59 (t, 1H, J ) 6.1 Hz), 3.50
(d, 2H, J ) 10.7 Hz), 3.40 (d, 2H, J ) 10.7 Hz), 2.74 (brs, 5H),
1
A solution of this intermediate (500 mg, 1.36 mmol) and
LiOH‚H2O (420 mg, 10.0 mmol) in MeOH (5 mL), THF (2 mL),
and water (5 mL) was stirred at 50 °C for 4 h and diluted with
EtOAc. The solution was washed with brine, dried, and
evaporated. Recrystallization from EtOAc-hexane gave 23
1
(120 mg, 27%) as a white solid: mp 70-72 °C; H NMR (400
MHz, CDCl3) δ 7.25 (d, 2H, J ) 8.3 Hz), 7.10 (d, 2H, J ) 8.3
Hz), 3.60 (d, 2H, J ) 10.8 Hz), 3.50 (d, 2H, J ) 10.8 Hz), 2.87
(t, 2H, J ) 7.4 Hz), 2.63-2.59 (m, 2H), 2.20-1.80 (m, 4H),
1.70-1.66 (m, 2H), 1.62 (quint, 2H, J ) 7.4 Hz), 1.43-1.34
(m, 2H), 1.34-1.20 (m, 6H), 0.87 (t, 3H, J ) 6.8 Hz); IR (KBr)
3352, 3289, 2923 cm-1; MS (EI) m/z 325 (M+). Anal. (C18H31
-
NO2S) C, H, N.
2-Am in o-2-[2-[4-(N-m eth ylh ep tyla m in o)p h en yl]eth yl]-
p r op a n e-1,3-d iol h yd r och lor id e (24): synthesized as de-
1
scribed for 6 using 55; mp 128-129 °C; H NMR (400 MHz,
DMSO-d6) δ 6.97 (d, 2H, J ) 8.3 Hz), 6.59 (d, 2H, J ) 8.3 Hz),
5.35 (t, 2H, J ) 5.0 Hz), 3.49 (d, 4H, J ) 5.0 Hz), 3.23 (t, 2H,
J ) 7.4 Hz), 2.81 (s, 3H), 2.46-2.42 (m, 2H), 1.74-1.70 (m,
2H), 1.46-1.21 (m, 10H), 0.84 (t, 3H, J ) 6.8 Hz); IR (KBr)
3277 cm-1; MS (EI) m/z 322 (M+). Anal. (C19H34N2O2‚HCl‚
1.5H2O) C, N; H: calcd, 9.92; found, 9.39.
2-Am in o-2-[2-(2-octylp h en yl)eth yl]p r opa n e-1,3-d iol h y-
d r och lor id e (25): synthesized as described for 6 using 58;

2-Substituted Aminopropanediols and 2-Aminoethanols
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 15 2955
mp 157-159 °C; 1H NMR (90 MHz, DMSO-d6) δ 7.89 (brs, 3H),
7.17-7.05 (m, 4H), 5.40 (t, 2H, J ) 4 Hz), 3.59-3.49 (m, 4H),
2.63-2.52 (m, 4H), 1.78-1.68 (m, 2H), 1.54-1.43 (m, 2H),
1.37-1.22 (m, 10H), 0.85 (t, 3H, J ) 6 Hz); IR (KBr) 3385,
3272, 2925 cm-1; MS (EI) m/z 307 (M+). Anal. (C19H33NO2‚
HCl) C, H, N.
6.9 Hz); IR (KBr) 3359, 3183, 2928, 2871 cm-1; MS (EI) m/z
307 (M+). Anal. (C19H33NO2‚HCl) C, H, N.
2-Am in o-2-[2-(4-h e p t yloxyp h e n yl)e t h yl]-4-p e n t e n ol
(32): not converted to hydrochloride salt; a brownish noncrys-
talline powder; 1H NMR (400 MHz, CDCl3) δ 7.08 (d, 2H, J )
8.6 Hz), 6.81 (d, 2H, J ) 8.6 Hz), 5.88-5.81 (m, 1H), 5.18-
5.14 (m, 2H), 3.92 (t, 2H, J ) 6.6 Hz), 3.39 (s, 2H), 2.60-2.55
(m, 2H), 2.26 (dd, 1H, J ) 14.1 and 7.8 Hz), 2.19 (dd, 1H, J )
13.7 and 7.8 Hz), 1.80-1.72 (m, 2H), 1.72-1.27 (m, 10H), 0.89
(t, 3H, J ) 6.9 Hz); IR (KBr) 3349, 3314, 3282, 3067, 2923,
2856, 2751 cm-1; MS (EI) m/z 319 (M+). Anal. (C20H33NO2) C,
H, N.
2-Am in o-2-[2-(3-octylp h en yl)eth yl]p r opa n e-1,3-diol h y-
d r och lor id e (26): synthesized as described for 25; mp 97-
98 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.70 (brs, 3H), 7.18 (t,
1H, J ) 7.3 Hz), 7.01-6.97 (m, 3H), 5.33 (brs, 2H), 3.45 (s,
4H), 2.60-2.40 (m, 4H), 1.76-1.72 (m, 2H), 1.55-1.50 (m, 2H),
1.38-1.20 (m, 10H), 0.84 (t, 3H, J ) 6.8 Hz); IR (KBr) 3366,
3178, 2924, 2853 cm-1; MS (EI) m/z 307 (M+). Anal. (C19H33
NO2‚HCl) C, H, N.
-
2-Am in o-4-(4-h eptyloxyp h en yl)-2-isopr op ylbu ta n ol h y-
1
d r och lor id e (33): a yellow noncrystalline powder; H NMR
(400 MHz, DMSO-d6) δ 7.89 (brs, 3H), 7.11 (d, 2H, J ) 8.6
Hz), 6.83 (d, 2H, J ) 8.6 Hz), 5.39 (t, 1H, J ) 4.9 Hz), 3.89 (t,
2H, J ) 6.6 Hz), 3.57-3.52 (m, 2H), 2.53-2.49 (m, 2H), 2.11-
2.08 (m, 1H), 1.75-1.70 (m, 2H), 1.70-1.63 (m, 2H), 1.38-
1.26 (m, 8H), 0.92 (d, 6H, J ) 6.8 Hz), 0.85 (t, 3H, J ) 6.8
Hz); IR (KBr) 3349, 3185, 2923, 2852, 2616 cm-1; MS (EI) m/z
321 (M+). Anal. (C20H35NO2‚HCl‚1/2H2O) C, H, N.
2-Am in o-2-[2-(4-h ep tyloxyp h en yl)eth yl]p en ta n ol (34):
not converted to hydrochloride salt; a white solid; mp 48-50
°C; 1H NMR (400 MHz, CDCl3) δ 7.09 (d, 2H, J ) 8.3 Hz),
6.81 (d, 2H, J ) 8.3 Hz), 3.92 (t, 2H, J ) 6.6 Hz), 3.36 (s, 2H),
2.55-2.51 (m, 2H), 1.79-1.73 (m, 2H), 1.73-1.30 (m, 14H),
0.95 (t, 3H, J ) 6.8 Hz), 0.89 (t, 3H, J ) 6.8 Hz); IR (KBr)
3337, 3277, 3132, 2956, 2936, 2859 cm-1; MS (EI) m/z 321 (M+).
Anal. (C20H35NO2) C, H, N.
2-Am in o-2-[2-(4-h ep t yloxyp h en yl)et h yl]h exa n ol (35):
not converted to hydrochloride salt; a white solid; mp 47-49
°C; 1H NMR (400 MHz, DMSO-d6) δ 7.09 (d, 2H, J ) 8.5 Hz),
6.79 (d, 2H, J ) 8.5 Hz), 3.88 (t, 2H, J ) 6.4 Hz), 3.29 (s, 2H),
2.48-2.42 (m, 2H), 1.67 (quint, 2H, J ) 7.4 Hz), 1.45-1.25
(m, 16H), 0.87 (t, 3H, J ) 5.4 Hz), 0.85 (t, 3H, J ) 6.8 Hz); IR
(KBr) 3328, 3280, 3124, 3031, 2956, 2933, 2858 cm-1; MS (EI)
m/z 335 (M+). Anal. (C21H37NO2‚1/10H2O) C, H, N.
2-Am in o-2-[2-(5-oct ylt h ien -2-yl)et h yl]p r op a n e-1,3-d i-
ol h yd r och lor id e (27): synthesized as described for 6 using
1
60; mp 63-65 °C; H NMR (400 MHz, CD3OD) δ 6.54 (d, 1H,
J ) 3.4 Hz), 6.47 (d, 1H, J ) 3.4 Hz), 3.67 (d, 2H, J ) 12.2
Hz), 3.61 (d, 2H, J ) 12.2 Hz), 2.76-2.72 (m, 2H), 2.63 (t, 2H,
J ) 7.5 Hz), 1.97-1.94 (m, 2H), 1.55-1.51 (m, 2H), 1.29-1.15
(m, 10H), 0.79 (t, 3H, J ) 6.9 Hz); IR (KBr) 3366, 3178, 2924,
2853 cm-1; MS (EI) m/z 307 (M+). Anal. (C17H31NO2S‚HCl) C,
H, N.
2-Am in o-2-h yd r oxym eth yl-4-(4-octylp h en yl)bu ta n oic
Acid (28). To a solution of 61 (17.9 g, 46.3 mmol) in THF (270
mL) was slowly added LiBH4 (910 mg, 41.8 mmol). The
mixture was refluxed for 6 h and cooled to 0 °C. The reaction
mixture was acidified with 2 N HCl (20 mL), diluted with
water, and extracted with EtOAc. The extract was washed
with brine, dried, and evaporated. Silica gel chromatography,
eluting with EtOAc, followed by recrystallization from EtOAc-
diisopropyl ether gave N-[1-cyano-1-hydroxymethyl-3-(4-octyl-
phenyl)propyl]acetamide (8.67 g, 54%) as a white solid. A
solution of this intermediate (7.71 g, 22.4 mmol) in concen-
trated HCl (110 mL), AcOH (40 mL), and water (40 mL) was
refluxed for 7 h and cooled to room temperature. The separated
oil was collected, dispersed in water (100 mL), and neutralized
with 2 N NaOH. The yielded white crystalline solid was
collected and washed with MeOH to give 28 (4.76 g, 66%): mp
246-250 °C; 1H NMR (400 MHz, CD3OD) δ 7.08 (s, 4H), 3.91-
3.87 (m, 2H), 3.30 (brs, 4H), 2.56 (t, 4H, J ) 7.8 Hz), 2.08 (t,
2H, J ) 7.8 Hz), 1.60-1.55 (m, 2H), 1.29-1.26 (m, 10H), 0.89
(t, 3H, J ) 7.0 Hz); IR (KBr) 3047, 1639 cm-1; MS (EI) m/z
321 (M+). Anal. (C19H31NO3) C, H, N.
2-Am in o-2-[2-(4-h ep tyloxyp h en yl)eth yl]bu ta n e-1,4-d i-
ol (36). To a solution of 66 (14.9 g, 31.9 mmol) in CH2Cl2 (250
mL) was added trimethylsilyl iodide (7.16 mL, 50.3 mmol). The
solution was stirred for 7 h, diluted with MeOH (20 mL), and
evaporated. The resultant residue was dissolved in pyridine
(25 mL) and acetic anhydride (20 mL) and left for 13 h. The
reaction mixture was poured into water and extracted with
EtOAc. The extract was washed with 1 N HCl, saturated
NaHCO3 and brine, dried, and evaporated. Silica gel chroma-
tography, eluting with hexanes-EtOAc (1:1), gave 2-acet-
amido-2-[2-(4-heptyloxyphenyl)ethyl]butane-1,4-diol diacetate
(10.1 g, 70%) as a colorless oil. To a solution of this intermedi-
ate (10.0 g, 22.2 mmol) in THF (50 mL) and MeOH (100 mL)
was added 2 M LiOH (100 mL). The solution was refluxed for
2 h and concentrated. The mixture was diluted with water and
extracted with EtOAc. The extract was washed with brine,
dried, and evaporated. Recrystallization from EtOAc-hexane
gave 36 (6.71 g, 93%) as a white solid: mp 64-65 °C; 1H NMR
(400 MHz, DMSO-d6) δ 7.05 (d, 2H, J ) 8.6 Hz), 6.79 (d, 2H,
J ) 8.6 Hz), 4.59 (brs, 1H), 3.88 (t, 2H, J ) 6.8 Hz), 3.54 (t,
2H, J ) 6.8 Hz), 3.19 (brs, 2H), 2.47-2.44 (m, 2H), 1.67 (quint,
2H, J ) 6.8 Hz), 1.51-1.47 (m, 4H), 1.38-1.26 (m, 8H), 0.86
(t, 3H, J ) 6.8 Hz); IR (KBr) 3360, 3268, 3068, 2927, 2858,
2673 cm-1; MS (EI) m/z 323 (M+). Anal. (C19H33NO3) C, H, N.
2-Am in o-2-[2-(4-octylp h en yl)eth yl]bu ta n e-1,4-d iol (37):
2-Am in o-4-(4-h ep tyloxyp h en yl)-2-m eth ylbu ta n ol Hy-
d r och lor id e (30). To a solution of 63 (18.2 g, 46.3 mmol) in
THF (300 mL) was slowly added LiBH4 (2.01 g, 92.3 mmol).
The mixture was refluxed for 3 h and cooled to 0 °C. The
reaction mixture was acidified with 2 N HCl (45 mL), diluted
with water, and extracted with EtOAc. The extract was
washed with brine, dried, and evaporated. The residue was
dissolved in THF (100 mL), MeOH (150 mL), and 5 N KOH
(100 mL), and the solution was refluxed for 13 h. The reaction
mixture was concentrated, diluted with water, and extracted
with EtOAc. The extract was washed with brine, dried, and
evaporated. The residue was converted to hydrochloride salt
by treatment with EtOH (200 mL) and 1 N HCl solution in
Et2O (50 mL) and recrystallized from EtOH-EtOAc to give
1
30 (10.0 g, 66%) as a white solid: mp 162-163 °C; H NMR
(400 MHz, DMSO-d6) δ 7.77 (brs, 3H), 7.09 (d, 2H, J ) 8.5
Hz), 6.83 (d, 2H, J ) 8.5 Hz), 5.51 (t, 1H, J ) 4.9 Hz), 3.90 (t,
2H, J ) 6.6 Hz), 3.47-3.36 (m, 2H), 2.52-2.49 (m, 2H), 1.78-
1.64 (m, 4H), 1.38-1.26 (m, 8H), 1.18 (s, 3H), 0.86 (t, 3H, J )
1
mp 75-76 °C; H NMR (400 MHz, DMSO-d6) δ 7.05 (s, 4H),
4.59 (brs, 1H), 3.54 (t, 2H, J ) 6.9 Hz), 3.18 (brs, 2H), 2.55-
2.49 (m, 4H), 1.53-1.45 (m, 6H), 1.25-1.23 (m, 10H), 0.84 (t,
3H, J ) 6.9 Hz); IR (KBr) 3367, 3296, 2927, 2854 cm-1; MS
(EI) m/z 321 (M+). Anal. (C20H35NO2‚1/10H2O) C, H, N.
2-Am in o-2-[2-(4-octylph en yl)eth yl]pen tan e-1,5-diol Hy-
d r och lor id e (38). 68 (1.30 g, 2.50 mmol) was converted to
2-amino-2-[2-(4-octylphenyl)ethyl]-5-(tetrahydro-2H-pyran-2-
yloxy)pentanol (820 mg, 78%) as described for 30. This was
purified by silica gel chromatography eluting with CHCl3-
MeOH (95:5): 1H NMR (400 MHz, CDCl3) δ 7.10 (d, 2H, J )
8.5 Hz), 7.08 (d, 2H, J ) 8.5 Hz), 4.58 (m, 1H), 3.87 (m, 1H),
6.8 Hz); IR (KBr) 3374, 3025, 2933, 1518, 1242, 1060 cm-1
;
MS (EI) m/z 293 (M+). Anal. (C18H31NO2‚HCl) C, H, N.
Similarly, compounds 31-35 were prepared from 50 and
2-substituted diethyl malonates.
2-Am in o-2-eth yl-4-(4-h ep tyloxyp h en yl)bu ta n ol h yd r o-
1
ch lor id e (31): a white solid; mp 108-110 °C; H NMR (400
MHz, CD3OD) δ 7.11 (d, 2H, J ) 8.8 Hz), 6.83 (d, 2H, J ) 8.8
Hz), 3.92 (t, 2H, J ) 6.3 Hz), 3.60 (s, 2H), 2.59-2.53 (m, 2H),
1.88-1.83 (m, 2H), 1.81-1.72 (m, 4H), 1.48-1.44 (m, 2H),
1.40-1.31 (m, 6H), 1.00 (t, 3H, J ) 7.3 Hz), 0.90 (t, 3H, J )

2956 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 15
Kiuchi et al.
3.76 (m, 1H), 3.52-3.46 (m, 4H), 2.62-2.53 (m, 4H), 1.80-
1.54 (m, 14H), 1.30-1.26 (m, 10H), 0.88 (t, 3H, J ) 7.1 Hz);
IR (neat) 3348, 2924, 2856 cm-1; MS (EI) m/z 419 (M+).
solid. A mixture of this intermediate (2.60 g, 9.37 mmol) in
EtOH (15 mL) and 1,4-dioxane (6 mL), 1 N NaOH (0.05 mL),
and 37% aqueous formaldehyde (1.70 mL) was stirred at room
temperature for 15 h. After addition of 37% aqueous formal-
dehyde (0.50 mL), the mixture was stirred at 50 °C for 6 h.
The reaction mixture was evaporated and diluted with EtOAc.
The organic solution was washed with brine, dried, and
evaporated. Crystallization from hexane gave 42 (1.75 g, 55%)
To a solution of this intermediate (800 mg, 1.91 mmol) in
MeOH (30 mL) was added a 1 N HCl solution in ether (3 mL).
The mixture was stirred for 30 min, diluted with water, and
washed with ether. The aqueous solution was alkalified with
1 N KOH and extracted with EtOAc. The extract was washed
with brine, dried, and evaporated. The residue was converted
to hydrochloride salt by treatment with EtOH (30 mL) and 1
N HCl solution in ether (5 mL). This residue was suspended
in ether (10 mL), and the sediment was collected to give 38
(230 mg, 32%) as a thick purple oil: 1H NMR (400 MHz,
DMSO-d6) δ 7.85 (brs, 3H), 7.09 (s, 4H), 5.48 (t, 1H, J ) 4.9
Hz), 4.59 (t, 1H, J ) 5.1 Hz), 3.47-3.45 (m, 2H), 3.42-3.39
(m, 2H), 2.55-2.51 (m, 4H), 1.75-1.71 (m, 2H), 1.63-1.58 (m,
2H), 1.52-1.46 (m, 4H), 1.25-1.23 (m, 10H), 0.84 (t, 3H, J )
6.9 Hz); IR (neat) 3346, 3009, 2924, 2854 cm-1; MS (EI) m/z
335 (M+). Anal. (C21H37NO2‚HCl‚1/4H2O) C, H, N.
1
as a white solid: mp 80-81 °C; H NMR (90 MHz, CDCl3) δ
7.21 (d, 2H, J ) 10 Hz), 7.17 (d, 2H, J ) 10 Hz), 4.60 (m, 2H),
4.35 (m, 2H), 2.77 (m, 2H), 2.59 (t, 2H, J ) 8 Hz), 1.60-1.50
(m, 2H), 1.30-1.20 (m, 14H), 0.88 (t, 3H, J ) 6 Hz).
4-Octylp h en eth yl Alcoh ol (43, m ) 2 a n d n ) 8). To a
suspension of AlCl3 (14.7 g, 110 mmol) in 1,2-dichloroethane
(200 mL) at 0 °C was added dropwise a solution of phenethyl
acetate (12.1 g, 73.7 mmol) and octanoyl chloride (12.0 g, 73.8
mmol) in 1,2-dichloroethane (50 mL). After stirring at room
temperature for 3 h, the mixture was poured into water, and
extracted with Et2O. The extract was washed with brine, dried,
and evaporated. Silica gel chromatography, eluting with
hexanes-EtOAc (8:1), gave 4-octanoylphenethyl acetate (9.20
g, 43%) as a colorless oil. To a solution of this acetate (4.20 g,
14.5 mmol) in trifluoroacetic acid (50 mL) was added tri-
ethylsilane (5.06 g, 28.9 mmol). After stirring at room tem-
perature for 3 h, the mixture was concentrated and diluted
with EtOAc. The solution was washed with 1 N NaOH and
brine, dried, and evaporated. Silica gel chromatography,
eluting with hexanes-EtOAc (8:1), gave 4-octylphenethyl
acetate (4.94 g, crude) as a colorless oil. To a solution of this
acetate (4.94 g) in MeOH (100 mL) was added sodium
methoxide (2.05 g, 28.9 mmol). The mixture was refluxed for
2 h, evaporated, and partitioned between EtOAc and water.
The organic layer was separated and washed with brine. The
solution was dried over Na2SO4 and evaporated to provide 43
(3.40 g, 100%) as a brown oil: 1H NMR (90 MHz, CDCl3) δ
7.13 (brs, 4H), 3.84 (q, 2H, J ) 6 Hz), 2.83 (t, 2H, J ) 6 Hz),
2.58 (t, 2H, J ) 6 Hz), 2.34 (t, 1H, J ) 6 Hz), 1.81-1.45 (m,
2H), 1.45-1.10 (m, 10H), 0.86 (t, 3H, J ) 6 Hz).
4-Octylp h en eth yl Iod id e (44, m ) 2 a n d n ) 8). To a
solution of 43 (15.9 g, 67.8 mmol) and triethylamine (12.2 mL,
88.1 mmol) in CH2Cl2 (200 mL) at 0 °C was added methane-
sulfonyl chloride (9.32 g, 81.4 mmol). After stirring at room
temperature for 1 h, the mixture was washed with brine, dried,
and evaporated. A mixture of the residue and NaI (10.2 g, 67.8
mmol) in 2-butanone (400 mL) was refluxed for 2 h. The
reaction mixture was concentrated and partitioned between
EtOAc and water. The organic layer was separated and
washed with 10% Na2S2O3 and brine. The solution was dried
and evaporated. Silica gel chromatography, eluting with
hexanes-EtOAc (95:5), gave 44 (16.0 g, 69%) as a colorless
oil: 1H NMR (90 MHz, CDCl3) δ 7.11 (s, 4H), 3.47-3.01 (m,
4H), 2.58 (t, 2H, J ) 8 Hz), 1.79-1.46 (m, 2H), 1.43-1.08 (m,
10H), 0.87 (t, 3H, J ) 6 Hz); MS (EI) m/z 344 (M+).
3-Am in o-3-m eth yl-5-(4-octylp h en yl)p en ta n ol Hyd r o-
ch lor id e (39). Compound 71 (5.00 g, 18.0 mmol) was alkylated
in two steps as described for 43 to give 3-acetamido-3-methyl-
5-(4-octylphenyl)pentyl acetate (4.96 g, 87%) as a white solid.
To a solution of this intermediate (4.95 g, 12.7 mmol) in THF
(50 mL) and MeOH (50 mL) was added 2 N LiOH (50 mL).
The solution was refluxed for 4 h, concentrated, diluted with
water, and extracted with EtOAc. The extract was washed
with brine, dried, and evaporated. The residue was converted
to hydrochloride salt by treatment with EtOH (50 mL) and 1
N HCl solution in ether (20 mL) and recrystallized from
EtOH-EtOAc to give 39 (4.12 g, 96%) as a white solid: mp
1
137-141 °C; H NMR (400 MHz, DMSO-d6) δ 8.00 (brs, 3H),
7.09 (s, 4H), 4.92 (brs, 1H), 3.59 (t, 2H, J ) 6.1 Hz), 2.59-
2.52 (m, 4H), 1.87-1.73 (m, 4H), 1.53-1.50 (m, 2H), 1.28 (s,
3H), 1.25-1.23 (m, 10H), 0.84 (t, 3H, J ) 6.9 Hz); IR (KBr)
3120, 2956, 2854 cm-1; MS (EI) m/z 305 (M+). Anal. (C20H35
NO‚HCl) C, H, N.
-
Similarly, compound 40 was prepared from dimethyl 1,3-
acetonedicarboxylate. Compound 40 was not converted to
hydrochloride salt.
3-Am in o-3-[2-(4-octylph en yl)eth yl]pen tan e-1,5-diol (40):
a white solid; mp 57-59 °C; 1H NMR (400 MHz, CDCl3) δ 7.10
(s, 4H), 3.88 (t, 4H, J ) 5.9 Hz), 2.59-2.53 (m, 4H), 1.82-1.70
(m, 6H), 1.59-1.57 (m, 2H), 1.30-1.27 (m, 10H), 0.88 (t, 3H,
J ) 6.8 Hz); IR (KBr) 3375, 3326, 3267, 3061, 2922, 2849 cm-1
MS (EI) m/z 335 (M+). Anal. (C21H37NO2‚1/10H2O) C, H, N.
;
4-Decylben zyl Br om id e (41). To a solution of decylben-
zene (13.1 g, 60.0 mmol) in CH2Cl2 (40 mL) at 0 °C were added
dropwise TiCl4 (19.0 g, 100 mmol) and dichloromethyl methyl
ether (5.75 g, 50.0 mmol). After stirring at room temperature
for 1 h, the reaction mixture was poured into water and
extracted with CH2Cl2. The extract was washed with brine,
dried, and evaporated. To a solution of the residue in MeOH
(30 mL) and 2-propanol (30 mL) was added NaBH4 (1.13 g,
30.2 mmol). After stirring at room temperature for 10 min,
the reaction mixture was evaporated, diluted with water, and
extracted with isopropyl ether. The extract was washed with
brine, dried, and evaporated. Silica gel chromatography,
eluting with hexanes-EtOAc (9:1), gave 4-decylbenzyl alcohol
(6.98 g, 56%) as a white solid. A mixture of this intermediate
(4.48 g, 18.0 mmol), 48% HBr (50 mL), and toluene (40 mL)
was stirred at 90 °C for 24 h. The organic layer was separated
and washed with saturated NaHCO3 and brine. The solution
was dried and evaporated to provide 41 (5.50 g, 98%) as an
oil: 1H NMR (400 MHz, CDCl3) δ 7.28 (d, 2H, J ) 8.1 Hz),
7.13 (d, 2H, J ) 8.1 Hz), 4.47 (s, 2H), 2.57 (t, 2H, J ) 7.6 Hz),
1.60-1.50 (m, 2H), 1.30-1.20 (m, 14H), 0.86 (t, 3H, J ) 6.6
Hz); MS (EI) m/z 312 (M + 1)+, 310 (M - 1)+.
Dieth yl 2-Acetam ido-2-[2-(4-octylph en yl)eth yl]m alon ate
(45, m ) 2 a n d n ) 8). To a solution of diethyl acetamido-
malonate (26.0 g, 120 mmol) in EtOH (300 mL) was added a
solution of sodium ethoxide (8.20 g, 120 mmol) in EtOH (80
mL). After stirring at room temperature for 30 min, 44 (6.89
g, 20 mmol) was added. The mixture was stirred at 65 °C for
3 h, concentrated, and partitioned between EtOAc and water.
The organic layer was separated and washed with brine. The
solution was dried and evaporated. Silica gel chromatography,
eluting with hexanes-EtOAc (3:1), gave 45 (10.6 g, 61%) as a
1
white solid: mp 51-53 °C; H NMR (90 MHz, CDCl3) δ 7.06
(s, 4H), 6.73 (brs, 1H), 4.20 (q, 4H, J ) 6 Hz), 2.82-2.30 (m,
6H), 1.96 (s, 3H), 1.70-1.44 (m, 2H), 1.44-1.10 (m, 10H), 1.23
(t, 6H, J ) 6 Hz), 0.86 (t, 3H, J ) 6 Hz); IR (KBr) 3253, 2923,
1747, 1644 cm-1; MS (EI) m/z 433 (M+).
2-(4-Decylp h en yl)-2-n itr op r op a n e-1,3-d iol (42). To a
suspension of AgNO2 (4.15 g, 27.0 mmol) in Et2O (20 mL) at 0
°C was added dropwise a solution of 41 (5.50 g, 17.7 mmol) in
Et2O (10 mL). After stirring at 0 °C for 4 h, the reaction
mixture was filtered and evaporated. Crystallization in pen-
tane gave 4-decylphenylnitromethane (2.32 g, 47%) as a yellow
Meth yl 8-(4-Eth ylp h en yl)octa n oa te (46). To a suspen-
sion of AlCl3 (8.06 g, 60.5 mmol) in 1,2-dichloroethane (100
mL) at 0 °C was added dropwise a solution of ethylbenzene
(6.16 g, 58.1 mmol) and methyl 8-chloro-8-oxooctanoate (10.0
g, 48.4 mmol) in 1,2-dichloroethane (50 mL). The mixture was
stirred at room temperature for 3 h, poured into water, and

2-Substituted Aminopropanediols and 2-Aminoethanols
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 15 2957
extracted with EtOAc. The extract was washed with 1 N NaOH
and brine, dried, and evaporated. Silica gel chromatography,
eluting with hexanes-EtOAc (5:1), gave methyl 8-(4-ethyl-
phenyl)-8-oxooctanoate (8.80 g, 66%) as a colorless oil. This
intermediate (8.80 g, 31.8 mmol) was reduced as described for
43 to give 46 (2.60 g, 31%) as a colorless oil: 1H NMR (90 MHz,
CDCl3) δ 7.10 (s, 4H), 3.66 (s, 3H), 2.62 (q, 2H, J ) 6 Hz), 2.56
(t, 2H, J ) 6 Hz), 2.28 (t, 2H, J ) 6 Hz), 1.81-1.18 (m, 10H),
1.21 (t, 3H, J ) 6 Hz); IR (KBr) 2931, 2856, 1737 cm-1; MS
(EI) m/z 262 (M+).
8-(4-Eth ylp h en yl)octyl Iod id e (47). To a suspension of
LiAlH4 (560 mg, 14.8 mmol) in THF (100 mL) at 0 °C was
added dropwise a solution of 46 (2.60 g, 9.91 mmol) in THF
(25 mL). After stirring at room temperature for 1 h, the
reaction was quenched with saturated Na2SO4 (20 mL). The
reaction mixture was filtered through Celite and evaporated
to provide 8-(4-ethylphenyl)octanol (2.32 g, 100%) as a colorless
oil. This intermediate was converted to 47 as described for 44.
47: 1H NMR (90 MHz, CDCl3) δ 7.11 (s, 4H), 3.18 (t, 2H, J )
7 Hz), 2.63 (q, 2H, J ) 6 Hz), 2.58 (t, 2H, J ) 7 Hz), 1.95-
1.17 (m, 12H), 1.22 (t, 3H, J ) 7 Hz); MS (EI) m/z 344 (M+).
2-Acet a m id o-2-p h en et h ylp r op a n e-1,3-d iol d ia cet a t e
(48): synthesized as illustrated in Scheme 2 using phenethyl
bromide; mp 116-117 °C; 1H NMR (400 MHz, CDCl3) δ 7.28-
7.15 (m, 5H), 5.64 (brs, 1H), 4.33 (s, 4H), 2.59 (m, 2H), 2.20
(m, 2H), 2.07 (s, 6H), 1.94 (s, 3H); IR (KBr) 3293, 3090, 1744,
1651 cm-1; MS (EI) m/z 321 (M+).
4-Hep tyloxyp h en eth yl Alcoh ol (49). To a solution of
4-hydroxyphenethyl alcohol (30.9 g, 223 mmol) and sodium
ethoxide (17.0 g, 250 mmol) in EtOH (1 L) was added heptyl
bromide (40.0 g, 223 mmol). The reaction mixture was refluxed
for 7 h and concentrated. The residue was diluted with water
and extracted with EtOAc. The extract was washed with 1 N
NaOH and brine, dried, and evaporated to give 49 (49.3 g, 94%)
as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.13 (d, 2H, J )
8.5 Hz), 6.85 (d, 2H, J ) 8.5 Hz), 3.93 (t, 2H, J ) 6.6 Hz), 3.82
(q, 2H, J ) 6.3 Hz), 2.81 (t, 2H, J ) 6.6 Hz), 1.77 (quint, 2H,
J ) 6.6 Hz), 1.46-1.43 (m, 2H), 1.39-1.24 (m, 7H), 0.89 (t,
3H, J ) 6.9 Hz); IR (neat) 3355, 2931, 2859 cm-1; MS (EI) m/z
236 (M+).
to 52 (10.7 g, 63%) as described for 44: 1H NMR (400 MHz,
CDCl3) δ 7.52 (d, 2H, J ) 8.3 Hz), 7.15 (d, 2H, J ) 8.3 Hz),
3.30 (t, 2H, J ) 7.8 Hz), 3.12 (t, 2H, J ) 7.8 Hz), 2.70 (s, 3H);
MS (EI) m/z 294 (M+).
Dieth yl 2-Aceta m id o-2-[2-(4-m er ca p top h en yl)eth yl]-
m a lon a te (53). Compound 52 (7.66 g, 26.0 mmol) was
condensed with diethyl acetamidomalonate as described for
45 to give diethyl 2-acetamido-2-[2-(4-methylsulfinylphenyl)-
ethyl]malonate (5.16 g, 62%) as a colorless oil. To a solution
of this intermediate (4.00 g, 10.4 mmol) in CH2Cl2 (100 mL)
at 0 °C was added trifluoroacetic anhydride (3.00 mL, 21.2
mmol). After stirring at room temperature for 1 h, the mixture
was evaporated. The residue was dissolved in EtOH (50 mL)
and triethylamine (50 mL), and the mixture was stirred at
room temperature for 1 h. The reaction mixture was concen-
trated and partitioned between CHCl3 and aqueous NH4Cl.
The organic layer was separated, dried, and evaporated. Silica
gel chromatography, eluting with CHCl3-MeOH (24:1), gave
53 (3.37 g, 92%) as an oil: 1H NMR (400 MHz, CDCl3) δ 7.16
(d, 2H, J ) 8.3 Hz), 7.00 (d, 2H, J ) 8.3 Hz), 6.74 (s, 1H), 4.18
(m, 4H), 3.37 (s, 1H), 2.64 (t, 2H, J ) 7.8 Hz), 2.43 (t, 2H, J )
7.8 Hz), 1.96 (s, 3H), 1.22 (t, 6H, J ) 7.3 Hz); MS (EI) m/z 353
(M+).
N-Meth yl-N-[4-[2-(tetr a h yd r o-2H-p yr a n -2-yloxy)eth yl]-
p h en yl]h ep ta n a m id e (54). To a solution of 4-aminophen-
ethyl alcohol (13.8 g, 101 mmol) and triethylamine (10.8 g, 107
mmol) in THF (300 mL) at 0 °C was added dropwise heptanoyl
chloride (15.0 g, 101 mmol). The mixture was stirred at room
temperature for 3 h, poured into water, and extracted with
EtOAc. The extract was washed with brine, dried, and
evaporated. Recrystallization from EtOAc/isopropyl ether gave
N-[4-(2-hydroxyethyl)phenyl]heptanamide (13.2 g, 52%) as a
white solid. To a solution of this intermediate (4.45 g, 17.8
mmol) and p-toluenesulfonic acid monohydrate (95.0 mg, 0.499
mmol) in THF (50 mL) and CH2Cl2 (50 mL) was added 3,4-
dihydro-2H-pyran (1.96 g, 23.3 mmol). After stirring at room
temperature for 7 h, the mixture was evaporated and purified
by silica gel chromatography, eluting with hexanes-EtOAc (1:
1), to give N-[4-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]phenyl]-
heptanamide. To a solution of this material in 1,2-dimethoxy-
ethane (120 mL) were added potassium tert-butoxide (5.18 g,
46.2 mmol) and MeI (16.4 g, 116 mmol). The mixture was
stirred at 60 °C for 1 h, concentrated and purified by silica
gel chromatography, eluting with hexanes-EtOAc (7:1), to
provide 54 (5.95 g, 96%) as an oil: 1H NMR (400 MHz, CDCl3)
δ 7.42 (d, 2H, J ) 8.3 Hz), 7.19 (d, 2H, J ) 8.3 Hz), 4.58 (t,
1H, J ) 3.9 Hz), 3.92 (dt, 1H, J ) 7.3 and 9.8 Hz), 3.79-3.76
(m, 1H), 3.47 (dt, 2H, J ) 7.3 and 9.7 Hz), 3.47 (t, 2H, J ) 6.4
Hz), 3.26 (s, 3H), 2.04 (t, 2H, J ) 6.4 Hz), 1.90-1.63 (m, 4H),
1.60-1.42 (m, 4H), 1.26-1.17 (m, 6H), 0.83 (t, 3H, J ) 6.8
Hz); IR (neat) 1655 cm-1; MS (EI) m/z 347 (M+).
4-Hep tyloxyp h en eth yl iod id e (50): compound 49 was
converted to 50 as described for 44; 1H NMR (400 MHz, CDCl3)
δ 7.09 (d, 2H, J ) 8.3 Hz), 6.84 (d, 2H, J ) 8.3 Hz), 3.93 (t,
2H, J ) 6.5 Hz), 3.31 (t, 2H, J ) 7.8 Hz), 3.11 (t, 2H, J ) 7.8
Hz), 1.77 (quint, 2H, J ) 6.8 Hz), 1.46-1.41 (m, 2H), 1.39-
1.24 (m, 6H), 0.89 (t, 3H, J ) 6.9 Hz); IR (neat) 2928, 2854
cm-1; MS (EI) m/z 346 (M+).
Eth yl 4-Meth ylth iop h en yla ceta te (51). To a solution of
4-methylthiobenzaldehyde (7.61 g, 50.0 mmol) and methyl
methylsulfinylmethyl sulfide (6.22 g, 50.0 mmol) in 1,4-dioxane
(50 mL) was added Triton B (40% solution in MeOH, 4.18 g,
10.0 mmol). The mixture was stirred at 80 °C for 2 h,
concentrated, and partitioned between EtOAc and water. The
organic layer was separated, dried, and evaporated. Silica gel
chromatography, eluting with hexanes-EtOAc (5:1), gave
methyl 1-methylsulfinyl-2-(4-methylthiophenyl)vinyl sulfide
(10.9 g, 84%) as a yellow oil. A solution of this intermediate
(1.62 g, 6.27 mmol) in 26% HCl/EtOH was stirred at room
temperature for 30 min and evaporated. Silica gel chroma-
tography, eluting with hexanes-EtOAc (20:1), gave 51 (1.22
4-(N-Meth ylh ep tyla m in o)p h en eth yl Iod id e (55). To a
solution of 54 (5.95 g, 17.1 mmol) in THF (90 mL) at 0 °C was
added 1 M solution of BH3‚THF in THF (32.2 mL). After
stirring at 0 °C for 3 h, MeOH (60 mL) was added. The reaction
mixture was concentrated and purified by silica gel chroma-
tography, eluting with hexanes-EtOAc (7:1). To a solution of
this material in MeOH (60 mL) was added p-toluenesulfonic
acid monohydrate (3.10 g, 16.3 mmol). After stirring at room
temperature for 3 h, the mixture was concentrated and
purified by silica gel chromatography, eluting with CHCl3-
MeOH (12:1), to provide 4-(N-methylheptylamino)phenethyl
alcohol (3.22 g, 76%) as an oil. This intermediate alcohol (3.65
g, 14.6 mmol) was converted into the iodide as described for
44 to yield 55 (2.58 g, 49%) as an oil: 1H NMR (400 MHz,
CDCl3) δ 7.04 (d, 2H, J ) 8.3 Hz), 6.62 (d, 2H, J ) 8.3 Hz),
3.65 (t, 2H, J ) 7.8 Hz), 3.63 (t, 2H, J ) 5.9 Hz), 3.07 (t, 2H,
J ) 7.8 Hz), 2.90 (s, 3H), 1.40-1.22 (m, 10H), 0.88 (t, 3H, J )
7.3 Hz); MS (EI) m/z 359 (M+).
1
g, 93%) as a white solid: mp 30-32 °C; H NMR (400 MHz,
CDCl3) δ 7.28 (d, 2H, J ) 8.3 Hz), 7.20 (d, 2H, J ) 8.3 Hz),
4.15 (q, 2H, J ) 7.3 Hz), 3.65 (s, 2H), 2.45 (s, 3H), 1.24 (t, 3H,
J ) 7.3 Hz); MS (EI) m/z 210 (M+).
4-(2-Iod oeth yl)p h en yl Meth yl Su lfoxid e (52). To a sus-
pension of LiAlH4 (2.30 g, 60.6 mmol) in THF (100 mL) at 0
°C was added dropwise a solution of 51 (12.2 g, 58.0 mmol) in
THF (50 mL). After stirring at room temperature for 30 min,
the reaction was quenched with saturated Na2SO4 (50 mL).
The reaction mixture was filtered through Celite and evapo-
rated. To a solution of the residue in CHCl3 (100 mL) at 0 °C
was added m-CPBA (10.0 g, 58.0 mmol). The mixture was
stirred at room temperature for 2 h, washed with 1 N NaOH
and brine, dried, and evaporated. The residue was converted
(E)-2-(1-Octen yl)ben za ld eh yd e (56). To a mixture of
magnesium (6.56 g, 270 mmol) and I2 (20 mg) in THF (10 mL)
was added dropwise a solution of heptyl bromide (48.4 g, 270
mmol) in THF (200 mL). After the mixture had been stirred
at 40 °C for 1 h, a solution of 2-bromobenzaldehyde (25.0 g,

2958 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 15
Kiuchi et al.
135 mmol) was added dropwise at 0 °C. The solution was
stirred at room temperature for 1 h, poured into saturated
NH4Cl, and extracted with EtOAc. The extract was washed
with brine, dried, and evaporated. Silica gel chromatography,
eluting with hexanes-EtOAc (8:1), gave 1-(2-bromophenyl)-
octanol (18.9 g, 49%) as a colorless oil. To a solution of this
intermediate (15.6 g, 54.7 mmol) in benzene (300 mL) was
added P2O5 (23.3 g, 164 mmol). The mixture was refluxed for
2 h, filtered, and diluted with EtOAc. The solution was washed
with brine, dried, and evaporated. Silica gel chromatography,
eluting with hexanes-EtOAc (20:1), gave (E)-1-(2-bromo-
phenyl)-1-octene (12.0 g, 82%) as a yellowish oil. To a mixture
of magnesium (3.74 g, 154 mmol) and I2 (20 mg) in THF (10
mL) was added dropwise a solution of the intermediate (37.4
g, 140 mmol) in THF (100 mL). After the mixture had been
stirred at 50 °C for 30 min, a solution of DMF (10.9 g, 149
mmol) in THF (100 mL) was added dropwise at room temper-
ature. The solution was stirred at room temperature for 15 h,
poured into saturated NH4Cl, and extracted with EtOAc. The
extract was washed with brine, dried, and evaporated. Silica
gel chromatography, eluting with hexanes-EtOAc (15:1), gave
56 (26.7 g, 88%) as a colorless oil: 1H NMR (90 MHz, CDCl3)
δ 10.31 (s, 1H), 7.58 (d, 1H, J ) 8 Hz), 7.53-7.48 (m, 2H),
7.37-7.33 (m, 1H), 7.15 (d, 1H, J ) 16 Hz), 6.18-6.11 (m, 1H),
2.36-2.24 (m, 2H), 1.52-1.45 (m, 2H), 1.38-1.22 (m, 6H), 0.88
(t, 3H, J ) 6 Hz); IR (neat) 2927, 2855, 1699 cm-1; MS (EI)
m/z 216 (M+).
Eth yl 2-Aceta m id o-2-cya n o-4-(4-octylp h en yl)bu tyr a te
(61). 44 (21.3 g, 61.9 mmol) was condensed with ethyl
acetamidocyanoacetate as described for 45 to give 61 (18.0 g,
75%) as a white solid: mp 83-84 °C; 1H NMR (400 MHz,
CDCl3) δ 7.13 (d, 2H, J ) 8.0 Hz), 7.10 (d, 2H, J ) 8.0 Hz),
5.99 (brs, 1H), 4.30 (q, 2H, J ) 8.0 Hz), 2.81 (t, 2H, J ) 4.0
Hz), 2.57 (m, 4H), 1.94 (s, 3H), 1.58-1.55 (m, 2H), 1.37 (t, 3H,
J ) 8.0 Hz), 1.29-1.26 (m, 10H), 0.88 (t, 3H, J ) 6.3 Hz); IR
(KBr) 3281, 1755, 1660 cm-1; MS (EI) m/z 387 (M+).
Dieth yl 2-[2-(4-Heptyloxyph en yl)eth yl]-2-m eth ylm alon -
a te (62, R ) CH3). To a suspension of NaH (60% dispersion
in mineral oil, 5.12 g, 128 mmol) in DMF (110 mL) was added
a solution of diethyl methylmalonate (20.6 g, 118 mmol) in
DMF (50 mL). After the mixture had been stirred for 30 min,
50 (37.2 g, 107 mmol) was added. The suspension was stirred
for 3 h, poured into water, and extracted with EtOAc. The
extract was washed with brine, dried, and evaporated. Silica
gel chromatography, eluting with hexanes-EtOAc (9:1), gave
62 (33.3 g, 79%) as a colorless oil: 1H NMR (400 MHz, CDCl3)
δ 7.08 (d, 2H, J ) 8.6 Hz), 6.81 (d, 2H, J ) 8.6 Hz), 4.19 (q,
4H, J ) 7.3 Hz), 3.92 (t, 2H, J ) 6.6 Hz), 2.51-2.46 (m, 2H),
2.15-2.10 (m, 2H), 1.78-1.70 (m, 2H), 1.48 (s, 3H), 1.48-1.27
(m, 8H), 1.26 (t, 6H, J ) 7.3 Hz), 0.89 (t, 3H, J ) 7.3 Hz); IR
(neat) 2933, 2860, 1732 cm-1; MS (EI) m/z 392 (M+).
Eth yl 4-(4-Heptyloxyph en yl)-2-m eth oxycar bon ylam in o-
2-m eth ylbu tyr a te (63, R ) CH3). To a solution of 62 (33.3
g, 84.8 mmol) in EtOH (100 mL) was added KOH (85% pellets,
5.59 g, 84.8 mmol). The mixture was stirred for 6 h at 50 °C,
evaporated, and diluted with water (600 mL). The aqueous
solution was washed with hexane, acidified with 2 N HCl, and
extracted with EtOAc. The extract was washed with brine,
dried, and evaporated to give 2-ethoxycarbonyl-4-(4-heptyloxy-
phenyl)-2-methylbutyric acid (22.7 g, 73%) as a yellow oil. To
Eth yl 2-Octylp h en yla ceta te (57). A solution of 56 (26.7
g, 123 mmol) in EtOH (200 mL) was stirred under a hydrogen
atmosphere in the presence of 5% Pd/C (1.0 g) for 4 h. The
catalyst was removed by filtration and the filtrate was
evaporated and purified by silica gel chromatography, eluting
with hexanes-EtOAc (20:1), to provide 2-octylbenzaldehyde
(22.0 g, 82%) as a colorless oil. This intermediate was converted
into 57 as described for 51. 57 was obtained as a yellowish oil
(20.2 g, 72%): 1H NMR (90 MHz, CDCl3) δ 7.35-7.10 (m, 4H),
4.13 (q, 2H, J ) 6 Hz), 3.85 (s, 2H), 2.59 (t, 2H, J ) 6 Hz),
1.62-1.49 (m, 2H), 1.38-1.19 (m, 10H), 1.24 (t, 3H, J ) 6 Hz),
0.86 (t, 3H, J ) 6 Hz); MS (EI) m/z 276 (M+).
a
solution of this intermediate (22.7 g, 62.0 mmol) and
triethylamine (7.53 g, 74.4 mmol) in THF (300 mL) was added
ethyl chloroformate (8.07 g, 74.4 mmol) at -5 °C. After the
mixture had been stirred for 15 min, a solution of NaN3 (8.06
g, 124 mmol) in water (20 mL) was added. The mixture was
stirred for 1 h at 0 °C, poured into water, and extracted with
EtOAc. The extract was washed with brine, dried, and
evaporated. The residue was dissolved in benzene (250 mL),
and the solution was refluxed for 1 h. After addition of MeOH
(250 mL), the mixture was refluxed for 7 h and evaporated.
Silica gel chromatography, eluting with hexanes-EtOAc (85:
15), gave 63 (18.3 g, 75%) as a yellow oil: 1H NMR (400 MHz,
CDCl3) δ 7.04 (d, 2H, J ) 8.3 Hz), 6.80 (d, 2H, J ) 8.3 Hz),
5.68 (brs, 1H), 4.17 (dq, 2H, J ) 2.0 and 7.3 Hz), 3.91 (t, 2H,
J ) 6.6 Hz), 3.66 (s, 3H), 2.57-2.50 (m, 2H), 2.35-2.30 (m,
1H), 2.11-2.05 (m, 1H), 1.76 (quint, 2H, J ) 6.9 Hz), 1.60 (s,
3H), 1.46-1.40 (m, 2H), 1.34-1.28 (m, 6H), 1.28 (t, 3H, J )
7.3 Hz), 0.89 (t, 3H, J ) 6.8 Hz); IR (neat) 3421, 3363, 2933,
2859, 1725 cm-1; MS (EI) m/z 393 (M+).
2-E t h oxyca r b on yl-2-[2-(4-h ep t yloxyp h en yl)et h yl]-4-
bu ta n olid e (64). Diethyl malonate (33.5 g, 209 mmol) was
alkylated with 2-(tetrahydro-2H-pyran-2-yloxy)ethyl iodide
(56.1 g, 219 mmol) as described for 62 to give diethyl 2-[2-
(tetrahydro-2H-pyran-2-yloxy)ethyl]malonate (45.1 g, 75%) as
a colorless oil. This intermediate (44.9 g, 156 mmol) was
alkylated with 50 (64.7 g, 187 mmol) as described for 62 to
give diethyl 2-[2-(4-heptyloxyphenyl)ethyl]-2-[2-(tetrahydro-
2H-pyran-2-yloxy)ethyl]malonate (67.9 g, 86%) as a yellow oil.
To a solution of this intermediate (66.9 g, 132 mmol) in MeOH
(400 mL) was added 1 N HCl solution in ether (5 mL). The
solution was stirred for 5 h, concentrated, and diluted with
EtOAc. The solution was washed with brine, dried, and
evaporated. Silica gel chromatography, eluting with hexanes-
EtOAc (9:1), gave 64 (43.0 g, 86%) as a yellowish oil: 1H NMR
(CDCl3) δ 7.07 (d, 2H, J ) 8.8 Hz), 6.80 (d, 2H, J ) 8.8 Hz),
4.33 (dd, 2H, J ) 8.8 and 5.3 Hz), 4.22 (dq, 2H, J ) 2.2 and
7.1 Hz), 3.90 (t, 2H, J ) 6.8 Hz), 2.76 (dt, 1H, J ) 12.9 and
5.3 Hz), 2.65 (ddd, 1H, J ) 13.7, 11.7 and 4.9 Hz), 2.51 (ddd,
1H, J ) 13.7, 11.7 and 4.9 Hz), 2.37 (ddd, 1H, J ) 13.7, 11.7
and 4.9 Hz), 2.24 (dt, 1H, J ) 12.9 and 8.8 Hz), 2.02 (ddd, 1H,
J ) 13.7, 11.7 and 4.9 Hz), 1.74 (quint, 2H, J ) 6.8 Hz), 1.44-
2-Octylp h en eth yl iod id e (58): synthesized from 57 as
1
described for 47; H NMR (90 MHz, CDCl3) δ 7.25-7.10 (m,
4H), 3.28 (t, 2H, J ) 6 Hz), 3.18 (t, 2H, J ) 6 Hz), 2.57 (t, 2H,
J ) 6 Hz), 1.59-1.50 (m, 2H), 1.41-1.18 (m, 10H), 0.87 (t,
3H, J ) 6 Hz); MS (EI) m/z 344 (M+).
5-Octyl-2-[2-(tetr a h yd r o-2H-p yr a n -2-yloxy)eth yl]th io-
p h en e (59). To a solution of 2-thiopheneethanol (12.8 g, 100
mmol) in CH2Cl2 (100 mL) were added 3,4-dihydro-2H-pyran
(9.25 g, 110 mmol) and p-toluenesulfonic acid monohydrate
(2.00 g, 10.5 mmol). The mixture was stirred at room temper-
ature for 4 h and evaporated. Distillation (107-108 °C/1
mmHg) gave 2-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]thiophene
(13.5 g, 64%) as an oil. To a solution of this intermediate (8.50
g, 40.0 mmol) in THF (100 mL) at -78 °C was added dropwise
1.6 M n-BuLi in hexanes (30 mL, 48.0 mmol). The mixture
was stirred at 0 °C for 1 h; 1-bromooctane (10.0 g, 51.8 mmol)
in THF (15 mL) was added. The mixture was stirred at room
temperature for 7 h, poured into water, and extracted with
EtOAc. The extract was washed with saturated NH4Cl, dried,
and evaporated. Silica gel chromatography, eluting with
hexanes-EtOAc (20:1), gave 59 (6.59 g, 51%) as a yellowish
oil: 1H NMR (400 MHz, CDCl3) δ 6.61 (d, 1H, J ) 3.4 Hz),
6.54 (d, 1H, J ) 3.4 Hz), 4.61 (t, 1H, J ) 3.5 Hz), 3.92 (dt, 1H,
J ) 10.2 and 7.3 Hz), 3.82-3.78 (m, 1H), 3.60 (dt, 1H, J )
10.2 and 7.3 Hz), 3.45-3.43 (m, 1H), 3.02 (t, 2H, J ) 7.3 Hz),
2.71 (t, 2H, J ) 7.2 Hz), 1.84-1.80 (m, 1H), 1.73-1.69 (m, 1H),
1.64-1.60 (m, 2H), 1.57-1.51 (m, 4H), 1.42-1.21 (m, 10H),
0.85 (t, 3H, J ) 6.9 Hz).
2-(2-Iod oeth yl)-5-octylth iop h en e (60): compound 59 was
converted to 60 as described for 44; 1H NMR (400 MHz, CDCl3)
δ 6.63 (d, 1H, J ) 3.4 Hz), 6.57 (d, 1H, J ) 3.4 Hz), 3.34-3.27
(m, 4H), 2.72 (t, 2H, J ) 7.4 Hz), 1.62 (quint, 2H, J ) 7.4 Hz),
1.39-1.22 (m, 10H), 0.87 (t, 3H, J ) 6.9 Hz); MS (EI) m/z 350
(M+).

2-Substituted Aminopropanediols and 2-Aminoethanols
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 15 2959
1.38 (m, 2H), 1.34-1.26 (m, 6H), 1.28 (t, 3H, J ) 7.1 Hz), 0.87
refluxed for 17 h using a Dean-Stark apparatus. The reaction
mixture was diluted with EtOAc, washed with brine, dried,
and evaporated. Silica gel chromatography, eluting with
hexanes-EtOAc (9:1), gave ethyl acetoacetate ethylene acetal
(63.8 g, 95%) as a colorless oil. To a suspension of LiAlH4 (13.9
g, 365 mmol) in THF (400 mL) was slowly added a solution of
this intermediate (63.5 g, 365 mmol) in THF (200 mL) at 0
°C. After the mixture had been stirred for 30 min at 0 °C, the
reaction was quenched with saturated Na2SO4 (250 mL). The
reaction mixture was filtered through Celite and evaporated.
A solution of the residue in DMF (50 mL) was added to a
suspension of NaH (60% dispersion in mineral oil, 16.1 g, 402
mmol) in DMF (250 mL). After the mixture had been stirred
for 15 min, a solution of benzyl bromide (65.5 g, 383 mmol) in
DMF (50 mL) was added at 0 °C. The mixture was stirred for
30 min at room temperature, evaporated, diluted with water,
and extracted with EtOAc. The extract was washed with brine,
dried, and evaporated. Silica gel chromatography, eluting with
hexanes-EtOAc (9:1), gave 69 (34.5 g, 43%) as a yellowish
oil: 1H NMR (400 MHz, CDCl3) δ 7.34-7.26 (m, 5H), 4.51 (s,
2H), 3.97-3.88 (m, 4H), 3.60 (t, 2H, J ) 7.1 Hz), 2.02 (t, 2H,
J ) 7.1 Hz), 1.35 (s, 3H); IR (neat) 3030, 2983, 2957, 2878
(t, 3H, J ) 6.9 Hz); IR (neat) 2929, 2859, 1774, 1735 cm-1
MS (EI) m/z 376 (M+).
;
2-[2-(4-Heptyloxyph en yl)eth yl]-2-m eth oxycar bon ylam i-
n o-4-bu ta n olid e (65). To a solution of 64 (42.6 g, 113 mmol)
in acetone (350 mL) was added 0.25 N NaOH (500 mL) at 0
°C. After the solution had been stirred for 1.5 h at room
temperature, the acetone was removed. The aqueous solution
was acidified with 2 N HCl (100 mL) and extracted with
EtOAc. The extract was washed with brine, dried, and
evaporated to give the intermediate, 2-[2-(4-heptyloxyphenyl)-
ethyl]-4-butanolide-2-carboxylic acid (39.9 g, 100%), as a white
solid. This intermediate (39.9 g, 115 mmol) underwent Curtius
rearrangement to give 65 as described for 63. 65 (26.9 g, 62%)
1
was obtained as a white solid: mp 86-88 °C; H NMR (400
MHz, CDCl3) δ 7.05 (d, 2H, J ) 8.8 Hz), 6.80 (d, 2H, J ) 8.8
Hz), 5.22 (brs, 1H), 4.47 (t, 1H, J ) 9.3 Hz), 4.25 (dt, 1H, J )
9.3 and 7.1 Hz), 3.90 (t, 2H, J ) 6.9 Hz), 3.65 (s, 3H), 2.75-
2.67 (m, 1H), 2.64 (t, 2H, J ) 8.6 Hz), 2.54-2.50 (m, 1H), 2.22-
2.14 (m, 1H), 2.02-1.94 (m, 1H), 1.74 (quint, 2H, J ) 6.9 Hz),
1.44-1.38 (m, 2H), 1.34-1.28 (m, 6H), 0.87 (t, 3H, J ) 6.8
Hz); IR (neat) 3531, 3346, 2932, 2859, 1771, 1733 cm-1; MS
(FAB, NBA) m/z 378 (M + H)+.
cm-1
.
1-Ben zyloxy-3-m et h yl-5-p h en yl-3-p en t a n ol (70, R )
CH3). A solution of 69 (34.4 g, 155 mmol) in THF (200 mL),
acetone (200 mL), and 2 N HCl (200 mL) was stirred for 2 h.
The reaction mixture was concentrated, diluted with water,
and extracted with EtOAc. The extract was washed with brine,
dried, and evaporated. Silica gel chromatography, eluting with
hexanes-EtOAc (9:1), gave 4-benzyloxy-2-butanone (23.7 g,
86%) as a colorless oil. To a mixture of magnesium (3.45 g,
142 mmol) and I2 (10 mg) in THF (20 mL) was added dropwise
over 15 min a solution of phenethyl bromide (26.3 g, 142 mmol)
in THF (70 mL). After the mixture had been stirred for 30
min, a solution of 4-benzyloxy-2-butanone (23.0 g, 129 mmol)
in THF (150 mL) was added at 0 °C dropwise to the reaction
mixture. The solution was stirred for 1 h at 0 °C, poured into
saturated NH4Cl, and extracted with EtOAc. The extract was
washed with brine, dried, and evaporated. Silica gel chroma-
tography, eluting with hexanes-EtOAc (9:1), gave 70 (25.1 g,
68%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.37-
7.16 (m, 10H), 4.52 (s, 2H), 3.76-3.69 (m, 2H), 3.27 (s, 1H),
2.76-2.62 (m, 2H), 1.94-1.71 (m, 4H), 1.26 (s, 3H); IR (neat)
2-[2-(4-Heptyloxyph en yl)eth yl]-2-m eth oxycar bon ylam i-
n obu ta n e-1,4-d iol Dia ceta te (66). To a solution of 65 (17.3
g, 45.7 mmol) in THF (400 mL) was added LiBH4 (1.99 g, 91.4
mmol). The mixture was refluxed for 30 min, acidified with 2
N HCl (20 mL) at 0 °C, diluted with water, and extracted with
EtOAc. The extract was washed with brine, dried, and
evaporated. The resultant oil was dissolved in pyridine (40 mL)
and acetic anhydride (35 mL) and left for 13 h at room
temperature. The reaction mixture was poured into water and
extracted with EtOAc. The extract was washed with 1 N HCl,
saturated NaHCO3 and brine, dried, and evaporated. Silica
gel chromatography, eluting with hexanes-EtOAc (7:3), gave
66 (14.9 g, 70%) as a white solid: mp 75-76 °C; 1H NMR (400
MHz, CDCl3) δ 7.04 (d, 2H, J ) 8.3 Hz), 6.79 (d, 2H, J ) 8.3
Hz), 4.83 (brs, 1H), 4.25 (s, 2H), 4.16 (t, 2H, J ) 6.8 Hz), 3.90
(t, 2H, J ) 6.8 Hz), 3.62 (s, 3H), 2.52 (dd, 2H, J ) 10.7 and 6.4
Hz), 2.13 (t, 2H, J ) 6.8 Hz), 2.08 (s, 3H), 2.02 (s, 3H), 2.00-
1.96 (m, 2H), 1.74 (quint, 2H, J ) 6.8 Hz), 1.44-1.38 (m, 2H),
1.34-1.28 (m, 6H), 0.87 (t, 3H, J ) 6.8 Hz); IR (neat) 3359,
2933, 2859, 1733, 1717, 1699 cm-1; MS (EI) m/z 465 (M+).
3434, 3028, 2937, 2866 cm-1
.
Diet h yl 2-[2-(4-Oct ylp h en yl)et h yl]-2-[3-(t et r a h yd r o-
2H-p yr a n -2-yloxy)p r op yl]m a lon a te (67). Diethyl malonate
(28.7 g, 179 mmol) was condensed with 3-(tetrahydro-2H-
pyran-2-yloxy)propyl bromide (40.0 g, 179 mmol) as described
for 62 to give diethyl 2-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-
malonate (30.3 g, 56%) as a colorless oil. This intermediate
(10.0 g, 33.1 mmol) was condensed with 44 (13.7 g, 39.7 mmol)
as described for 62 to give 67 (13.1 g, 76%) as a yellow oil: 1H
NMR (400 MHz, CDCl3) δ 7.08 (s, 4H), 4.59-4.57 (m, 1H), 4.19
(q, 4H, J ) 7.3 Hz), 3.88-3.83 (m, 1H), 3.77-3.72 (m, 1H),
3.52-3.47 (m, 1H), 3.42-3.36 (m, 1H), 2.58-2.54 (m, 2H),
2.50-2.46 (m, 2H), 2.21-2.16 (m, 2H), 2.06-2.02 (m, 2H),
1.84-1.81 (m, 1H), 1.73-1.68 (m, 1H), 1.58-1.50 (m, 8H),
1.29-1.27 (m, 10H), 1.26 (t, 6H, J ) 7.1 Hz), 0.88 (t, 3H, J )
3-Aceta m id o-3-m eth yl-5-p h en ylp en tyl Aceta te (71, R
) CH3). To a solution of 70 (24.8 g, 87.2 mmol) in CH3CN (150
mL) was added dropwise concentrated H2SO4 (9.27 mL, 174
mmol) at 0 °C. After being stirred for 5 h at room temperature,
the reaction mixture was diluted with water (500 mL),
concentrated, and extracted with EtOAc. The extract was
washed with saturated NaHCO3 and brine, dried, and evapo-
rated. Silica gel chromatography, eluting with hexanes-EtOAc
(85:15), gave N-[3-benzyloxy-1-methyl-1-(2-phenethyl)propyl]-
acetamide (17.0 g, 60%) as a white solid. A solution of this
intermediate (16.8 g, 51.6 mmol) in AcOH (150 mL) was stirred
under a hydrogen atmosphere in the presence of 10% Pd-
(OH)2/C (1.7 g) until the starting material was converted to a
single more polar compound. The catalyst was removed by
filtration and the filtrate was evaporated. The resultant oil
was dissolved in pyridine (25 mL) and acetic anhydride (25
mL), and left for 15 h at room temperature. The reaction
mixture was poured into water and extracted with EtOAc. The
extract was washed with 1 N HCl, saturated NaHCO3 and
brine, dried, and evaporated. Silica gel chromatography,
eluting with hexanes-EtOAc (2:3), gave 71 (13.1 g, 92%) as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.29-7.25 (m, 2H),
7.19-7.16 (m, 3H), 5.37 (s, 1H), 4.18-4.09 (m, 2H), 2.63-2.53
(m, 2H), 2.34-2.17 (m, 2H), 2.04 (s, 3H), 2.03-1.92 (m, 2H),
1.90 (s, 3H), 1.36 (s, 3H); IR (neat) 3308, 3064, 3028, 2974,
2935, 1733, 1652 cm-1; MS (EI) m/z 277 (M+).
6.8 Hz); IR (neat) 2927, 2856, 1732 cm-1
.
Eth yl 2-m eth oxyca r bon yla m in o-2-[2-(4-octylp h en yl)-
eth yl]-5-(tetr a h yd r o-2H-p yr a n -2-yloxy)va ler a te (68): syn-
thesized according to the procedure described for 63; a yellow
1
oil (11%); H NMR (400 MHz, CDCl3) δ 7.07 (d, 2H, J ) 8.3
Hz), 7.03 (d, 2H, J ) 8.3 Hz), 5.87 (brs, 1H), 4.54 (m, 1H),
4.21-4.10 (m, 2H), 3.85-3.81 (m, 1H), 3.72-3.67 (m, 1H), 3.64
(s, 3H), 3.49-3.47 (m, 1H), 3.39-3.31 (m, 1H), 2.70-2.56 (m,
2H), 2.56-2.52 (m, 2H), 2.36-2.25 (m, 2H), 2.12-2.05 (m, 1H),
1.88-1.78 (m, 2H), 1.72-1.67 (m, 1H), 1.64-1.50 (m, 6H),
1.30-1.24 (m, 12H), 1.28 (t, 3H, J ) 7.3 Hz), 0.88 (t, 3H, J )
6.8 Hz); IR (neat) 3423, 3381, 2928, 2856, 1721 cm-1; MS (EI)
m/z 519 (M+).
4-Ben zyloxy-2-b u t a n on e E t h ylen e Acet a l (69, R
)
3,5-Din itr o-N-[3-(4-h eptyloxyph en yl)-1-h ydr oxym eth yl-
1-m eth ylp r op yl]ben za m id e (72a ). To a mixture of 30 (562
mg, 1.70 mmol) and KHCO3 (512 mg, 5.11 mmol) in EtOAc
(40 mL) and water (40 mL) was added 3,5-dinitrobenzoyl
CH3). A solution of ethyl acetoacetate (50.0 g, 384 mmol),
ethylene glycol (64.1 mL, 1.15 mol), and p-toluenesulfonic acid
monohydrate (570 mg, 3.00 mmol) in benzene (500 mL) was

2960 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 15
Kiuchi et al.
chloride (412 mg, 1.79 mmol). The mixture was stirred for 15
min at room temperature and diluted with EtOAc (100 mL).
The organic layer was washed with brine, dried, and evapo-
rated. Recrystallization from EtOAc-hexane gave 72a (670
mg, 81%) as a white solid: mp 132-133 °C; 1H NMR (400
MHz, CDCl3) δ 9.12 (t, 1H, J ) 1.9 Hz), 8.64 (d, 2H, J ) 1.9
Hz), 7.11 (d, 2H, J ) 8.7 Hz), 6.70 (d, 2H, J ) 8.7 Hz), 6.11
(brs, 1H), 3.88 (dd, 1H, J ) 11.2 and 6.3 Hz), 3.79-3.71 (m,
2H), 3.76 (dd, 1H, J ) 11.2 and 6.3 Hz), 3.49 (t, 1H, J ) 6.3
Hz), 2.80-2.75 (m, 1H), 2.72-2.65 (m, 1H), 2.37-2.29 (m, 1H),
2.09-2.02 (m, 1H), 1.69 (quint, 2H, J ) 7.3 Hz), 1.50 (s, 3H),
1.37-1.31 (m, 8H), 0.90 (t, 3H, J ) 6.8 Hz); IR (KBr) 3250,
3102, 2928, 2857, 1642 cm-1; MS (EI) m/z 487 (M+).
washed with brine, dried, and evaporated. Silica gel chroma-
tography, eluting with CHCl3-MeOH (97:3), gave 73 (215 mg,
69%) as an oil: [R]27 +60.8° (c 0.60, CHCl3); MS (EI) m/z 347
D
(M+).
4-[2-(4-H ep t yloxyp h en yl)et h yl]-2-m et h yl-4-p r op yl-2-
oxa zolin e (74). To a solution of oxalyl chloride (157 mL, 1.79
mmol) in CH2Cl2 (10 mL) was added DMSO (191 mL, 2.69
mmol) at -70 °C. After the solution had been stirred for 30
min at -70 °C, a solution of 73 (210 mg, 0.604 mmol) in CH2Cl2
(5 mL) was added dropwise to the solution. The mixture was
stirred for 2 h at -55 °C, and triethylamine (933 mL, 6.73
mmol) was added. The reaction mixture was poured into
saturated NH4Cl and extracted with CH2Cl2. The extract was
washed with brine, dried, and evaporated to give an aldehyde
as a yellow oil. To a mixture of zinc powder (528 mg, 8.07
mmol) and CH2I2 (217 mL, 2.69 mmol) in THF (7 mL) was
added a 2 M trimethylalminium solution in hexane (269 mL,
0.538 mmol). After the solution was stirred for 20 min at room
temperature, a solution of the aldehyde described above in
THF (5 mL) was added at -15 °C. The mixture was stirred
for 16 h at 0 °C and diluted with EtOAc. The solution was
washed with saturated NaHCO3 and brine, dried, and evapo-
rated. Silica gel chromatography, eluting with hexanes-EtOAc
(8:2), gave 4-[2-(4-heptyloxyphenyl)ethyl]-2-methyl-4-(2-pro-
penyl)-2-oxazoline (19.1 mg, 8.7%). A solution of this interme-
diate (19 mg, 0.055 mmol) in EtOH (10 mL) was stirred under
a hydrogen atmosphere in the presence of 10% Pd/C (20 mg)
for 4 h. The catalyst was removed by filtration and the filtrate
was evaporated to give 74 (19 mg, 99%) as an oil: MS (EI)
m/z 345 (M+).
(R)- a n d (S)-3,5-Din it r o-N-[3-(4-h ep t yloxyp h en yl)-1-
h yd r oxym eth yl-1-m eth ylp r op yl]ben za m id e [(R)-72a a n d
(S)-72a ]. The racemic 72a was separated by HPLC using a
CHIRALCEL OD column [20 mm × 500 mm, hexanes-EtOH
(55:45), 4.6 mL/min] into the enantiomers. The optical purity
for both enantiomers was estimated to be >99% ee by HPLC
analyses. (R)-72a : retention time 56 min; mp 150-151 °C;
[R]24 -18.0° (c 0.83, CHCl3). (S)-72a : retention time 68 min;
D
mp 150-151 °C; [R]24 +17.2° (c 1.15, CHCl3).
D
Similarly, racemic 72b and 72c were separated into the
enantiomers.
(R)- a n d (S)-3,5-Din itr o-N-[1-[2-(4-h ep tyloxyp h en yl)-
et h yl]-1-h yd r oxym et h ylb u t yl]b en za m id e [(R)-72b a n d
(S)-72b]. (R)-72b: retention time 56 min (hexanes-EtOH
6:4); mp 115-116 °C; [R]24 -20.7° (c 0.98, CHCl3). (S)-72b:
D
retention time 68 min (hexanes-EtOH 6:4); mp 114-115 °C;
[R]24 +18.2° (c 0.71, CHCl3).
D
(R)- a n d (S)-3,5-Din itr o-N-[1-[2-(4-h ep tyloxyp h en yl)-
eth yl]-3-h ydr oxy-1-h ydr oxym eth ylpr opyl]ben zam ide [(R)-
72c a n d (S)-72c]. (R)-72c: retention time 61 min (hexanes-
EtOH 4:6); mp 115-116 °C; [R]26D -13.8° (c 0.46, CHCl3). (S)-
72c: retention time 47 min (hexanes-EtOH 4:6); mp 115-
3,5-Din it r o-N -[1-[2-(4-h e p t yloxyp h e n yl)e t h yl]-1-h y-
d r oxym eth ylbu tyl]ben za m id e (75). A solution of 74 (19 mg,
0.055 mmol) in EtOH (6 mL) and concentrated HCl (2 mL)
was refluxed for 1 h and evaporated. The residue was acylated
as described for 72a to give 75 (22.1 mg, 77%) as a yellow oil.
Its optical rotation and retention time on HPLC were identical
to those of (R)-72b: retention time 56 min (hexanes-EtOH
116 °C; [R]23 +15.2° (c 0.46, CHCl3).
D
(R)-2-Am in o-4-(4-h ep t yloxyp h en yl)-2-m et h ylb u t a n ol
Hyd r och lor id e [(R)-30]. To a solution of (R)-72a (400 mg,
0.820 mmol) in MeOH (20 mL) and THF (15 mL) was added 2
N LiOH (3 mL). The mixture was stirred for 30 min at room
temperature, concentrated, diluted with water, and extracted
with EtOAc. The extract was washed with brine, dried, and
evaporated. The residue was converted to hydrochloride salt
by treatment with MeOH (10 mL) and 1 N HCl solution in
ether (2 mL) and solidified from EtOH/ether to give (R)-30
6:4); [R]24 -17.3° (c 0.30, CHCl3).
D
Biologica l P r oced u r es. 1. Lym p h ocyte-Decr ea sin g Ef-
fect. F344 rats were purchased from J apan Charles River and
used at 5 weeks of age. Compounds were dissolved in 20%
hydroxypropyl-â-cyclodextrin and administered intraperito-
neally. Peripheral blood was collected 24 h later, and the
number of total lymphocytes was determined by lymphocyte-
gating method. Flow cytometry analysis was performed by
using EPICS XL-MCL (Coulter). The numbers of T-cells and
B-cells were determined by two-color flow cytometry using
fluorescein isothiocyanate-conjugated mouse anti-rat CD3
monoclonal antibody (MAb) (clone: 1F4) and phycoerythrin-
conjugated mouse anti-rat CD45RA or A/B MAb (clone: OX-
33).
(70 mg, 26%) as a yellowish noncrystalline powder: [R]25
D
+3.30° (c 0.42, CHCl3). Anal. (C18H31NO2‚HCl‚1/2H2O) C, H,
N.
Similarly, compounds (S)-30, (R)-34, (S)-34, (R)-36 and (S)-
36 were prepared from (S)-72a , (R)-72b, (S)-72b, (R)-72c and
(S)-72c, respectively.
(S)-2-Am in o-4-(4-h eptyloxyph en yl)-2-m eth ylbu tan ol h y-
2. Ra t Sk in Allogr a ft. Major histocompatibility complex-
compatible rat skin allograft was performed using LEW rats
(RT1l) as donors and F344 rats (RT1lv1) as recipients. F344
rats and LEW rats were purchased from J apan Charles River.
All rats were used at 4-6 weeks of age. Full-thickness skin
grafts (square pieces 2.0 × 2.0 cm) from donor rats were
transplanted to the lateral thorax of the recipient rats and
covered with sterile bactericidal gauze. The entire chest was
then wrapped with an elastic bandage. The dressings were
removed on day 5, and the grafts were inspected daily until
rejection, which was defined as more than 90% necrosis of the
graft epithelium. Compounds were dissolved in 20% hydroxy-
propyl-â-cyclodextrin and administered intraperitoneally to the
allografted recipients daily for 10 days from the day of
transplantation.
3. P op litea l Lym p h Nod e Ga in Assa y a n d T-Cell-
Decr ea sin g Effect. Spleen cells (5 × 106 cells) of WKAH rats
(RT1k) were injected into the footpad of LEW rats (RT1l) to
induce an enlargement of the draining popliteal lymph node.
Compounds were administered orally for 4 days from the day
of the injection of spleen cells, and the weight of the popliteal
lymph node was then measured. The number of T-cells in
peripheral blood was determined by flow cytometry using
d r och lor id e [(S)-30]: [R]25 -3.61° (c 0.31, CHCl3). Anal.
D
(C18H31NO2‚HCl‚1/2H2O) C, H, N.
(R)-2-Am in o-2-[2-(4-h eptyloxyph en yl)eth yl]pen tan ol h y-
d r och lor id e [(R)-34]: mp 89-90 °C; [R]24 +1.68° (c 0.51,
D
EtOH). Anal. (C20H35NO2‚HCl) C, H, N.
(S)-2-Am in o-2-[2-(4-h eptyloxyph en yl)eth yl]pen tan ol h y-
d r och lor id e [(S)-34]: mp 90-91 °C; [R]26 -0.45° (c 0.51,
D
EtOH). Anal. (C20H35NO2‚HCl) C, H, N.
(R)-2-Am in o-2-[2-(4-h ep tyloxyp h en yl)eth yl]bu ta n e-1,4-
d iol [(R)-36]: not converted to hydrochloride salt; mp 77-79
°C; [R]27 -4.08° (c 0.40, CHCl3). Anal. (C19H33NO3‚1/5H2O)
D
C, H, N.
(S)-2-Am in o-2-[2-(4-h ep tyloxyp h en yl)eth yl]bu ta n e-1,4-
d iol [(S)-36]: not converted to hydrochloride salt; mp 78-79
°C; [R]27 +4.01° (c 0.49, CHCl3). Anal. (C19H33NO3‚1/5H2O)
D
C, H, N.
4-[2-(4-H ep t yloxyp h en yl)et h yl]-4-(2-h yd r oxyet h yl)-2-
m eth yl-2-oxa zolin e (73). To a solution of (+)-36 (290 mg,
0.897 mmol) and N,N-diisopropylethylamine (0.173 mL, 0.987
mmol) in DMF (10 mL) was added triethyl orthoacetate (0.181
mL, 0.987 mmol). The solution was stirred for 2.5 h at 115 °C,
diluted with H2O, and extracted with EtOAc. The extract was

2-Substituted Aminopropanediols and 2-Aminoethanols
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 15 2961
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