Synthesis of (+)-carpamic acid from (+)-alanine

Article abstract of DOI:10.1016/j.tetasy.2006.12.025

(+)-Carpamic acid [(2′R,5′S,6′S)-8-(5′-hydroxy-6′-methylpiperidin-2′-yl)octanoic acid, 1] was synthesized from (S)-alanine, employing intramolecular and reductive amination of acyclic amino ketone 8 as the key step to generate the piperidine ring.

Full text of DOI:10.1016/j.tetasy.2006.12.025

Tetrahedron: Asymmetry 17 (2006) 3380–3385
Synthesis of (+)-carpamic acid from (+)-alanineI
Yui Masuda,a Takuya Tashirob and Kenji Morib,*
aDepartment of Applied Biological Chemistry, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan
bGlycosphingolipid Synthesis Group, Laboratory for Immune Regulation, Research Center for Allergy and Immunology, RIKEN,
Hirosawa 2-1, Wako-shi, Saitama 351-0198, Japan
Received 10 November 2006; accepted 27 December 2006
Abstract—(+)-Carpamic acid [(20R,50S,60S)-8-(50-hydroxy-60-methylpiperidin-20-yl)octanoic acid, 1] was synthesized from (S)-alanine,
employing intramolecular and reductive amination of acyclic amino ketone 8 as the key step to generate the piperidine ring.
ꢀ 2007 Elsevier Ltd. All rights reserved.
H
N
1. Introduction
O
(+)-Carpamic acid [(20R,50S,60S)-8-(50-hydroxy-60-meth-
HO
ylpiperidin-20-yl)octanoic acid, 1]1 is the hydrolysis product
Corey6
(1975)
O
CO2H
( )5
of a piperidine alkaloid (+)-carpaine isolated from the Pa-
paw tree (Carica papaya L.). (+)-Carpaine is the dimeric
macrolactone of 1 as studied by Barger,2 Robinson,3 Rapo-
port,1 Spiteller-Friedmann,4 Coke,5 and others (Fig. 1).
(+)-Carpaine shows various bioactivities as a heart poison
and an antitumor agent, and has been synthesized by
Corey6 through macrolactonization of N-benzyloxy-
carbonyl(Cbz)-protected (+)-carpamic acid 1. A review is
available on the enantioselective synthesis of bio-
active piperidines.7
O
N
H
O
(+)-Carpamic Acid 1
N
H
(+)-Carpaine
OTBS
( )9
TBSO
TsNH OMs
Phytosphingosine derivative
Our experience in sphingolipid chemistry to synthesize
penazetidine A, a marine azetidine alkaloid, by cyclization
of a sphingosine derivative8 made us attempt the synthesis
of (+)-1 through a similar cyclization, especially because
we had synthesized sphingolipids of human epidermis (cer-
amide B and ceramide 7) with a hydroxy group at C-6 of
the sphingosine moiety.9 A literature survey on the synthe-
sis of ( )-110,11 and (+)-112–15 indicated that all the previ-
ous work, except those by Gerlach11 and Kibayashi,14
utilized the cyclization of acyclic d-amino ketone for the
genesis of the piperidine ring by means of a palladium-cat-
alyzed hydrogenation.10,12,13,15 This paper reports a new
OH
Mori8
HO
( )9
N
H
(1996)
Penazetidine A
OH
OH
( )10
( )10
HO
HO
OH
OH
HN
OH
( )21
HN
( )27
OH
O
O
Ceramide B
Ceramide 7
TBS = t-BuSiMe2– Ts = p-MeC6H4SO2–
Ms = MeSO2–
q Synthesis of sphingosine relatives, Part 28. For Part 27, see: Ref. 9.
*
Figure 1. Structures of (+)-carpamic acid 1, (+)-carpaine, and some
Corresponding author. Fax: +81 48 462 1339; e-mail: kjk-mori@
sphingolipids.
arion.ocn.ne.jp
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.12.025

Y. Masuda et al. / Tetrahedron: Asymmetry 17 (2006) 3380–3385
3381
synthesis of (+)-carpamic acid 1 by intramolecular C–N
bond formation of an acyclic d-amino ketone 8.
NH3Cl
CO2Me
NBn2
a, b
c, d
OH
3
2 (= D)
2. Results and discussion
TMS
BnO
HO
g
2.1. Retrosynthetic analysis
e, f
R
OHC(CH2)7CO2Me
NBn2
NBn2
S
Scheme 1 shows our retrosynthetic analysis of (+)-1. Be-
cause Hiroya et al.16 reported that the addition of lithium
trimethylsilyl(TMS)acetylide to aldehyde i gave (2S,3R)-ii
as the major diastereomer (7:1) as generated under Fel-
kin–Anh control,16 we envisaged C as our intermediate,
whose anion would add to aldehyde B to give A after oxi-
dation. Acetylene C would be prepared from commercially
available hydrochloride D of (S)-alanine methyl ester. It
should be added that t-butoxycarbonyl(Boc)-protected
(S)-alaninal (iii) gave (2S,3S)-iv as the major isomer after
reaction with lithium 1-undecylide.17 The resulting 2:1 mix-
ture of iv and v was hardly separable.
6 (= B)
4
5 (= C)
OH
O
(CH2)7CO2Me
(CH2)7CO2Me
h
BnO
BnO
NBn2
NBn2
7
8 (= A)
–C CTMS
O
H
Me
NBn2
CHO
NBn2
O
vi
HO
vii
CO2Me
( )7
BnO
CO2H
Scheme 2. Synthesis of the key intermediate 8. Reagents and conditions:
(a) NaH, BnBr, THF; (b) LiAlH4, THF, 92% (two steps); (c) (COCl)2,
DMSO, CH2Cl2, 15 min, ꢀ78 ꢁC, then 3, 30 min, then (i-Pr)2NEt; (d)
TMSC„CLi, THF, HMPA, 6 h, ꢀ78 ꢁC to room temperature, 85% (two
steps); (e) NaH, BnBr, THF, 6 h, room temperature; (f) TBAF, THF, 1 h,
room temperature, 94% (two steps); (g) n-BuLi, THF, 1 h, ꢀ78 ꢁC, then 6,
6 h, ꢀ78 ꢁC to room temperature, 61%; (h) (COCl)2, DMSO, CH2Cl2,
15 min, ꢀ78 ꢁC, then 7, then (i-Pr)2NEt, 81%.
( )7
N
H
NBn2
1
A
H
.
HCl
NH2
BnO
+
CO2Me
( )7
O
CO2Me
NBn2
B
D
C
TMS
with lithium TMSacetylide to afford acetylenic alcohol 4.
The depicted (3R,4S)-stereochemistry of 4 was deduced
as shown in vii in analogy with Hiroya’s result.16 This ste-
reochemical assignment was later proved at the stage of
piperidine 9 (vide infra).
CHO
NBn2
HO
TMSC CLi
THF
R
(cf.)
TBSO
CHO
TBSO
NBn2
S
i
ii
R
R
Subsequent benzylation of 4 was followed by removal of
the TMS group to afford 5. At this stage, 1H NMR analysis
of 5 clarified the diastereomeric ratio between (3R,4S)-5
and its (3S,4S)-isomer as 9:1. Reaction between the acetyl-
ide anion derived from 5 and methyl 9-oxononanoate20 in
THF at ꢀ78 ꢁC furnished hydroxy ester 7 in 61% yield.
Swern oxidation of 7 under Dondoni conditions19 gave
keto ester 8, the key substrate for the cyclization reaction.
The overall yield of 8 from (S)-alanine methyl ester hydro-
chloride 2 was 37% over eight steps.
HO
HO
RC CLi
THF
(R = n-C9H19
S
R
+
NHBoc
NHBoc
NHBoc
S
S
)
iii
iv
(2 : 1)
v
Bn = C6H5CH2–
TMS = Me3Si–
Scheme 1. Retrosynthetic analysis of carpamic acid 1.
2.2. Synthesis of acyclic d-amino ketone 8
2.3. Synthesis of (+)-carpamic acid 1
Scheme 2 summarizes the synthesis of the key intermediate
8, the substrate for the ring-forming reaction. Commer-
cially available (S)-alanine methyl ester hydrochloride (2)
was treated with sodium hydride and benzyl bromide,
and the resulting bis-benzylated alanine methyl ester was
reduced with lithium aluminum hydride to give known
(S)-2-N,N-dibenzylamino-1-propanol 3.18 Swern oxidation
of 3 was executed under the Dondoni conditions in the
presence of ethyldiisopropylamine to avoid racemization,19
giving the corresponding aldehyde, which was then treated
Scheme 3 shows the reductive cyclization of 8 to piperidine
derivatives 9 or 10, and the conversion of the latter to (+)-
carpamic acid 1. When 8 was hydrogenated over Pearl-
man’s palladium hydroxide in methanol, reduction of the
triple bond and removal of the two N-benzyl groups fol-
lowed by formation and reduction of a tetrahydropyridine
1
ring took place to give piperidine 9. Its H NMR analysis
revealed the presence of a nuclear Overhauser effect be-
tween the axial protons at C-20 and C-60. The benzyloxy

3382
Y. Masuda et al. / Tetrahedron: Asymmetry 17 (2006) 3380–3385
24
O
222 ꢁC, ½aꢁD ¼ þ6:0 ðc 0:40; MeOHÞ. Its spectral data
were identical to those reported previously.11 Since
Cbz-protected (+)-carpamic acid was converted by
Corey to (+)-carpaine,6 our work constitutes its formal
synthesis.
BnO
(CH2)7CO2Me
a
BnO
N
(CH2)7CO2Me
H
H
H
NBn2
NOE
8 (=A)
9
3. Conclusion
O
HO
(CH2)7CO2Me
b
In conclusion, (+)-carpamic acid 1 was synthesized from
(S)-alanine methyl ester hydrochloride 2 in 18% overall
yield through 14 steps. The present overall efficiency was
better than those reported by Singh and Ghosh (4%, 21
steps)13 and Hanessian and Frenette (9%, 15 steps),12 but
inferior to that reported by Randl and Blechert (24%, eight
steps).15 The modest overall yield in our synthesis was due
to the undesired and opposite stereoselectivity in the course
of the addition of TMS-protected acetylide anion to the
aldehyde. Nevertheless, the present synthesis is straightfor-
ward, and further illustrates the usefulness of the reductive
cyclization of d-amino ketones in the synthesis of piper-
idine alkaloids.
BnO
N
H
(CH2)7CO2Me
(CH2)7CO2Me
(CH2)7CO2H
NBn2
10
8 (=A)
Hax
O
HO
c
d
N
N
(CH2)7CO2Me
Cbz
Cbz
12
11
Heq
HO
HO
e
f, g
N
(CH2)7CO2Me
N
H
Cbz
4. Experimental
4.1. General
13
1
O
Cbz = C6H5CH2OC–
Melting point (Yanaco MP-S3) is uncorrected. IR spectra
were recorded on a Jasco FT/IR-460 spectrometer. 1H
NMR spectra were recorded at 300 MHz by a Jeol JNM-
AL300 spectrometer or at 500 MHz by a Varian INOVA-
AS500 spectrometer. The peaks for TMS (at d = 0.00),
CDCl3 (at d = 7.26), or CD3OD (at d = 3.30) were used
as the internal standards. 13C NMR spectrum was recorded
at 67.8 MHz by a Jeol JNM-AL270 spectrometer. The
peak for CD3OD (at d 49.0) was used as the internal stan-
dard. Optical rotations were measured on a Jasco P-1010
polarimeter. Mass spectra were measured on a Jeol JMS-
SX102A spectrometer. Column chromatography was car-
ried out on Merck Kieselgel 60 Art 1.07734, and TLC anal-
yses were performed on Merck 60F-254 silica gel plates.
Scheme 3. Synthesis of (+)-carpamic acid 1. Reagents and conditions: (a)
H2, Pd(OH)2–C, MeOH, 1 h, room temperature, 80%; (b) H2, Pd(OH)2,
MeOH, 1 h, room temperature, then AcOH, 12 h, room temperature,
78%; (c) CbzCl, NaHCO3, 1,4-dioxane, H2O, 24 h, room temperature,
82%; (d) Dess–Martin periodinane, CH2Cl2, 2 h, room temperature, 90%;
(e) NaBH4, EtOH, 30 min, 0 ꢁC, quant.; (f) Ba(OH)2Æ8H2O, MeOH,
overnight, 40 ꢁC; (g) H2, Pd(OH)2–C, MeOH, 1 h, room temperature, 86%
(two steps).
group at C-50 of 9 was equatorially oriented, differing from
the axial hydroxy group of target molecule 1. The O-debenz-
ylated product 10 could be secured by adding a small
amount of acetic acid to the hydrogenation mixture to
increase the rate of hydrogenolysis of the O-benzyl group.
4.2. (3R,4S)-1-Trimethylsilyl-4-(N,N-dibenzylamino)pent-1-
yn-3-ol 4
In order to invert the incorrect configuration at C-50 of 10,
there were two options: (i) Mitsunobu inversion or (ii) oxi-
dation to the corresponding ketone and its reduction to the
sterically more congested axial alcohol by the approach of
a reducing agent from the less hindered a-side. Before
attempting these conversions, the amino group of 10 was
protected by treatment with benzyloxycarbonyl chloride
(CbzCl) to give 11. Mitsunobu inversion was attempted
on 11 under the standard conditions,21 but was unsuccess-
ful, yielding only the elimination product with a double
bond at C-40(50). Therefore we turned to the second option.
Oxidation of 11 with Dess–Martin periodinane22 furnished
ketone 12. Its reduction with sodium borohydride cleanly
gave the axial alcohol, the Cbz-protected derivative 13 of
methyl (+)-carpamate. Finally, alkaline hydrolysis of 13
was followed by hydrogenolytic removal of the Cbz group
to give (+)-carpamic acid (1) as colorless crystals, mp 219–
To a stirred solution of (COCl)2 (2.58 mL, 29.6 mmol) in
CH2Cl2 (100 mL) was added dropwise a solution of dry
DMSO (6.3 mL, 89 mmol) in dry CH2Cl2 (30 mL) at
ꢀ78 ꢁC under Ar. After stirring for 15 min at ꢀ78 ꢁC, a
solution of (S)-N,N-dibenzylalaninol (3, 5.0 g, 20 mmol)
in dry CH2Cl2 (20 mL) was added dropwise to the stirred
mixture at ꢀ78 ꢁC. After stirring for 30 min at ꢀ78 ꢁC,
(i-Pr)2NEt (17.2 mL, 98.7 mmol) was added to the mixture.
The mixture was stirred for 30 min at room temperature,
then poured into water, and extracted with Et2O. The ex-
tract was successively washed with water and brine, dried
with MgSO4, and concentrated in vacuo to give the corre-
sponding aldehyde (5.21 g, crude) as a yellow oil. This was
immediately used in the next step without further
purification.

Y. Masuda et al. / Tetrahedron: Asymmetry 17 (2006) 3380–3385
3383
To a stirred solution of trimethylsilylacetylene (2.94 g,
4.4. Methyl (9RS,12R,13S)-12-benzyloxy-13-(N,N-di-
benzylamino)-9-hydroxy-10-tetradecynoate 7
30 mmol) in dry THF (500 mL) was added dropwise a solu-
tion of n-BuLi (1.60 M in hexane, 19.7 mL, 31.5 mmol) at
ꢀ78 ꢁC under Ar. After stirring for 1 h at ꢀ78 ꢁC, a solu-
tion of crude aldehyde (5.21 g) in dry THF (150 mL) was
added dropwise to the reaction mixture at ꢀ78 ꢁC. The
resulting mixture was stirred for 6 h at room temperature.
The reaction was then quenched by the addition of an
aqueous solution of NH4Cl. The resulting mixture was ex-
tracted with Et2O. The extract was successively washed
with water and brine, dried with MgSO4, and concentrated
in vacuo. The residue was chromatographed on silica gel
To a stirred solution of 5 (3.92 g, 10.6 mmol) in dry THF
(200 mL) was added dropwise a solution of n-BuLi
(1.58 M in hexane, 7.1 mL, 11 mmol) at ꢀ78 ꢁC under
Ar. After stirring for 1.5 h at ꢀ78 ꢁC, a solution of 6
(1.80 g, 9.66 mmol) in dry THF (150 mL) was added drop-
wise to the mixture at ꢀ78 ꢁC. The resulting mixture was
stirred overnight at 0 ꢁC, then poured into an aqueous
solution of NH4Cl, and extracted with Et2O. The extract
was successively washed with water and brine, dried with
MgSO4, and concentrated in vacuo. The residue was
chromatographed on silica gel (80 g, hexane/ethyl ace-
(100 g, hexane/ethyl acetate = 40:1) to give 4 (5.66 g, two
18
steps, 85%) as a yellow solid; mp 58.0–60.5 ꢁC; ½aꢁD
¼
ꢀ24:4 ðc 1:50; CHCl3Þ; mmax (Nujol): 3400 (m, OH), 2165
(w, C„C), 1600 (w, Ar), 1495 (m, Ar), 1250 (s, Si–Me),
845 (s); dH (500 MHz, CDCl3): 0.10 (9H, s, SiCH3 · 3),
1.21 (3H, d, J 7.0, 5-H3), 2.93 (1H, dq, J 6.0, 7.0, 4-H),
3.36 (2H, d, J 13.5, PhCH · 2), 3.86 (1H, br s, OH), 4.11
(1H, d, J 6.0, 3-H), 4.17 (2H, d, J 13.5, PhCH · 2), 7.22–
7.31 (10H, m, Ar); HRMS calcd for C22H30NOSi
[(M+H)+] 352.2097, found 352.2055.
tate = 10:1) to give 7 (3.60 g, 61%, 9:1 diastereomeric
22
mixture) as
a
yellow oil; n2D8 ¼ 1:5161; ½aꢁD
¼
ꢀ69:1 ðc 1:05; CHCl3Þ; mmax (film): 3450 (m, OH), 1735
(s, CO), 1605 (w, Ar), 1495 (m, Ar), 1065 (s), 745 (s), 700
(s); dH (500 MHz, CDCl3): (12R)-isomer: 1.21 (3H, d, J
6.5, 14-H3), 1.27–1.50 (9H, m, 4-, 5-, 6-, 7-H2, OH), 1.59–
1.65 (2H, m, 3-H2), 1.69–1.76 (2H, m, 8-H2), 2.30 (2H, t,
J 7.5, 2-H2), 3,06 (1H, quint.-like, J 6.5, 13-H), 3.58 (2H,
d, J 14.0, PhCH · 2), 3.67 (3H, s, CO2CH3), 3.75 (2H, d,
J 14.0, PhCH · 2), 4.26 (1H, d, J 6.5, 12-H), 4.42 (1H, q-
like, J 6.5, 9-H), 4.48 (1H, d, J 11.5, PhCH), 4.76 (1H, d,
J 11.5, PhCH), 7.18–7.40 (15H, m, Ar); HRMS calcd for
C36H46NO4 [(M+H)+] 556.3427, found 556.3397.
4.3. (3R,4S)-3-Benzyloxy-4-(N,N-dibenzylamino)pent-1-yne
5
To a stirred solution of 4 (500 mg, 1.4 mmol) in dry THF
(10 mL) were added NaH (60%; 85 mg, 2.1 mmol) and
BnBr (0.33 mL, 2.8 mmol) at 0 ꢁC. After stirring for 6 h
at room temperature, the resulting mixture was poured into
water and extracted with Et2O. The extract was succes-
sively washed with water and brine, dried with MgSO4,
and concentrated in vacuo to give the corresponding benzyl
ether (620 mg, crude) as a yellow oil. This compound was
immediately used in the next reaction without further
purification.
4.5. Methyl (12R,13S)-12-benzyloxy-13-(N,N-dibenzyl-
amino)-9-oxo-10-tetradecynoate 8
To a stirred solution of (COCl)2 (0.57 mL, 7.0 mmol) in
CH2Cl2 (50 mL) was added dropwise a solution of dry
DMSO (1.5 mL, 21 mmol) in dry CH2Cl2 (25 mL) at
ꢀ78 ꢁC under Ar. After stirring for 15 min at ꢀ78 ꢁC, a
solution of 7 (2.6 g, 4.7 mmol) in dry CH2Cl2 (25 mL) was
added dropwise to the mixture at ꢀ78 ꢁC. The resulting
mixture was stirred for 30 min at ꢀ78 ꢁC, then (i-Pr)2NEt
(4.1 mL, 24 mmol) was added to it. The mixture was stirred
for 30 min at room temperature, then poured into water,
and extracted with Et2O. The extract was successively
washed with water and brine, dried with MgSO4, and con-
centrated in vacuo. The residue was chromatographed on
silica gel (50 g, hexane/ethyl acetate = 40:1) to give 8
To a stirred solution of this crude benzyl ether (650 mg) in
dry THF (10 mL) was added a solution of TBAF (1.0 M in
THF, 1.5 mL, 1.5 mmol) at 0 ꢁC. After stirring for 1 h at
room temperature, the mixture was poured into water
and extracted with Et2O. The extract was successively
washed with water and brine, dried with MgSO4, and con-
centrated in vacuo. The residue was chromatographed on
silica gel (40 g, hexane/ethyl acetate = 50:1) to give 5
(493 mg, two steps, 94%, 9:1 diastereomeric mixture) as a
(2.11 g, 81%, 9:1 diastereomeric mixture) as a yellow oil;
23
nD28 ¼ 1:5162; ½aꢁD ¼ ꢀ80:5 ðc 1:05; CHCl3Þ; mmax (film):
yellow oil. Diastereomer ratio was determined by 1H
2205 (m, C„C), 1735 (s, CO), 1675 (s, CO), 1605 (w, Ar),
1495 (m, Ar), 1170 (br s), 745 (s), 700 (s); dH (500 MHz,
CDCl3): 1.22 (3H, d, J 7.0, 14-H3), 1.28–1.35 (6H, m, 4-,
5-, 6-H2), 1.58–1.69 (4H, m, 3-, 7-H2), 2.30 (2H, t, J 7.0,
2-H2), 2.57 (2H, t, J 7.5, 8-H2), 3,14 (1H, quint.-like, J
6.5, 13-H), 3.57 (2H, d, J 14.0, PhCH · 2), 3.66 (3H, s,
CO2CH3), 3.72 (2H, d, J 14.0, PhCH · 2), 4.34 (1H, d, J
6.5, 12-H), 4.48 (1H, d, J 11.5, PhCH), 4.77 (1H, d, J
11.5, PhCH), 7.19–7.37 (15H, m, Ar). HRMS calcd for
C36H44NO4 [(M+H)+] 554.3270, found 554.3318.
26
NMR analysis (500 MHz); n2D4 ¼ 1:5158; ½aꢁD
¼
ꢀ85:9 ðc 1:05; CHCl3Þ; mmax (film): 3290 (s, C„C–H),
2110 (w, C„C), 1600 (w, Ar), 1495 (m, Ar), 1070 (s), 745
(s), 700 (s); dH (500 MHz, CDCl3): 3R-isomer: 1.22 (3H,
d, J 7.0, 5-H3), 2.50 (1H, dd, J 0.5, 2.0, 1-H), 3.09 (1H,
br quint.-like, J 7.0, 4-H), 3.60 (2H, d, J 14.0, PhCH · 2),
3.76 (2H, d, J 14.0, PhCH · 2), 4.25 (1H, dd, J 2.0, 7.0,
3-H), 4.50 (1H, d, J 12.0, PhCH), 4.81 (1H, d, J 12.0,
PhCH), 7.18–7.38 (10H, m, Ar); 3S-isomer: 1.23 (3H, d,
J 7.0, 5-H3), 2.52 (1H, dd, J 0.5, 2.0, 1-H), 3.12 (1H, br
quint.-like, J 6.5, 4-H), 3.57 (2H, d, J 14.0, PhCH · 2),
3.83 (2H, d, J 14.0, PhCH · 2), 4.24 (1H, dd, J 2.0, 5.5,
3-H), 4.47 (1H, d, J 12.0, PhCH), 4.78 (1H, d, J 12.0,
PhCH), 7.18–7.38 (10H, m, Ar); HRMS calcd for
C26H28NO [(M+H)+] 370.2171, found 370.2168.
4.6. Methyl (20R,50R,60S)-8-(50-benzyloxy-60-methylpiper-
idin-20-yl)octanoate 9
Pearlman’s Pd(OH)2–C (20%, 12 mg) was added to a solu-
tion of 8 (200 mg, 0.361 mmol) in MeOH (2 mL). The

3384
Y. Masuda et al. / Tetrahedron: Asymmetry 17 (2006) 3380–3385
25
mixture was stirred under H2 (balloon) for 1 h at room
temperature. An additional amount of Pd(OH)2–C (20%,
120 mg) was then added to the mixture, and the resulting
mixture was stirred under H2 (balloon) for 6 h at room
temperature. The mixture was then diluted with MeOH
and filtered through a bed of Celite. The filtrate was con-
centrated in vacuo, and the residue was chromatographed
on silica gel (4 g, CHCl3/MeOH = 50:1) to give 104 mg
orless oil; nD28 ¼ 1:5008; ½aꢁD ¼ ꢀ2:6 ðc 0:60; CHCl3Þ; mmax
(film): 3455 (m, OH), 1740 (s, CO), 1690 (s, CO), 1585 (w,
Ar), 755 (s), 700 (s); dH (500 MHz, CDCl3): 1.19 (3H, d, J
7.0, 60-CH3), 1.21–1.38 (10H, m, 4-, 5-, 6-, 7-, 8-H2), 1.40–
1.71 (5H, m, 30-Ha, 40-Ha, 3-H2, OH), 1.88 (1H, ddt, J 2.5,
3.5, 13.5, 40-Hb), 2.03 (1H, ddt, J 3.5, 6.0, 13.5, 30-Hb), 2.29
(2H, t, J 7.0, 2-H2), 3.67 (3H, s, CO2CH3), 3.77 (1H, br s,
50-H), 4.15–4.21 (1H, m, 20-H), 4.30 (1H, br q, J 7.0,
60-H), 5.09–5.17 (2H, m, PhCH2), 7.28–7.38 (5H, m, Ar);
HRMS calcd for C23H35NO5 [(M+H)+] 406.2593, found
406.2568.
(80%) of 9 as a yellow oil. Its 50-epimer could be removed
23
at this stage; n2D8 ¼ 1:4981; ½aꢁD ¼ ꢀ41:8 ðc 1:05; CHCl3Þ;
mmax (film): 3610 (w, NH), 1735 (s, CO), 1495 (w, Ar),
1095 (br s), 735 (s), 700 (s); dH (300 MHz, CDCl3): 1.07–
1.39 (13H, m, 30-, 40-Ha, 4-, 5-, 6-, 7-, 8-H2, NH), 1.20
(3H, d, J 6.0, 60-CH3), 1.55–1.80 (3H, m, 30-Hb, 3-H2),
2.20 (1H, dq, J 3.6, 12.3, 40-Hb), 2.30 (2H, t, J 7.5, 2-H2),
2.46–2.55 (1H, m, 20-H), 2.63 (1H, dq, J 6.0, 8.7, 60-H),
2.95 (1H, ddd, J 4.5, 8.7, 10.5, 50-H), 3.67 (3H, s, CO2CH3),
4.47 (1H, d, J 11.7, PhCH), 4.64 (1H, d, J 11.7, PhCH),
7.27–7.35 (5H, m, Ar); NOE was observed between the
protons at C-20 and C-60. HRMS calcd for C22H36NO3
[(M+H)+] 362.2695, found 362.2675.
4.9. Methyl (20R,60S)-8-(N-benzyloxycarbonyl-60-methyl-50-
oxopiperidin-20-yl)octanoate 12
To a stirred solution of 11 (20 mg, 0.049 mmol) in CH2Cl2
(1 mL) was added Dess–Martin periodinane (24 mg,
0.058 mmol) at 0 ꢁC. After stirring for 2 h at room temper-
ature, the reaction was quenched by the addition of sodium
thiosulfate (27 mg, 0.174 mmol). The resulting mixture was
poured into saturated aqueous NaHCO3 solution and ex-
tracted with CH2Cl2. The extract was successively washed
with water, saturated aqueous NaHCO3 solution and
brine, dried with MgSO4, and concentrated in vacuo. The
residue was chromatographed on silica gel (2.5 g, hexane/
4.7. Methyl (20R,50R,60S)-8-(50-hydroxy-60-methylpiperidin-
20-yl)octanoate 10
Pearlman’s Pd(OH)2–C (20%, 30 mg) was added to a solu-
tion of 8 (500 mg, 0.904 mmol) in MeOH (5 mL). The mix-
ture was stirred under H2 (balloon) for 1 h at room
temperature. An additional amount of Pd(OH)2–C (20%,
300 mg) was then added to the reaction mixture, and the
resulting mixture was stirred under H2 (balloon) for 6 h
at room temperature. To the mixture was added a catalytic
amount of AcOH (three drops), the resulting mixture was
stirred under H2 (balloon) for 12 h. The mixture was then
diluted with MeOH and filtered through a bed of Celite.
The filtrate was concentrated in vacuo, and the residue
was chromatographed on silica gel (10 g, CHCl3/
MeOH = 20:1) to give 190 mg (78%) of 10 as a colorless
waxy semi-solid. Its 50-epimer could be removed at this
ethyl acetate = 20:1) to give 12 (18 mg, 90%) as a color-
24
less oil; n2D8 ¼ 1:5029; ½aꢁD ¼ þ53:7 ðc 0:25; CHCl3Þ;
mmax (film): 1730 (s, CO), 1695 (s, CO), 1495 (w, Ar),
1410 (s, Ar), 1310 (s), 750 (s), 700 (s); dH (500 MHz,
CDCl3): 1.18–1.46 (8H, m, 4-, 5-, 6-, 7-H2), 1.39 (3H, d,
J 7.5, 60-CH3), 1.56–1.85 (5H, m, 30-Ha, 3-, 8-H2), 2.26–
2.32 (1H, m, 30-Hb), 2.29 (2H, t, J 7.5, 2-H2), 2.43 (1H,
dd, J 5.5, 10.0, 40-Ha), 2.45 (1H, br t, J 5.5, 40-Hb), 3.66
(3H, s, CO2CH3), 4.10–4.27 (1H, m, 20-H), 4.54–4.80
(1H, m, 60-H), 5.10–5.20 (2H, m, PhCH2), 7.31–7.38
(5H, m, Ar); HRMS calcd for C23H34NO5 [(M+H)+]
404.2437, found 404.2481.
stage. This was immediately used in the next step without
4.10. Methyl (20R,50S,60S)-8-(N-benzyloxycarbonyl-50-
23
further purification; ½aꢁD ¼ ꢀ11:3 ðc 0:90; CHCl3Þ; mmax
hydroxy-60-methylpiperidin-20-yl)octanoate 13
(Nujol): 3380 (m, OH), 3255 (m, NH), 1740 (s, CO), 1575
(s), 1170 (s), 1060 (m); dH (300 MHz, CDCl3): 1.17–1.65
(17H, m, 60-CH3, 30-, 40-Ha, 3-, 4-, 5-, 6-, 7-, 8-H2), 1.78–
1.85 (1H, m, 30-Hb), 1.95 (1H, s, NH), 2.02–2.10 (1H, m,
40-Hb), 2.29 (2H, t, J 7.5, 2-H2), 2.59–2.66 (2H, m, 20-,
60-H), 3.28–3.49 (1H, m, 50-H), 3.66 (3H, s, CO2CH3),
4.03 (1H, br s, OH); HRMS calcd for C15H29NO3 (M+)
271.2147, found 271.2145.
To a stirred solution of 12 (18 mg, 0.045 mmol) in EtOH
(1 mL) was added NaBH4 (1.7 mg, 0.045 mmol) at
0 ꢁC. After stirring for 30 min, the reaction was quenched
with aqueous 1 M HCl solution. The resulting mixture
was then extracted with diethyl ether. The extract was suc-
cessively washed with water, saturated aqueous NaHCO3
solution, and brine, dried with MgSO4, and concentrated
in vacuo. The residue was chromatographed on silica
4.8. Methyl (20R,50R,60S)-8-(N-benzyloxycarbonyl-50-
gel (400 mg, hexane/ethyl acetate = 10:1) to give 13
25
hydroxy-60-methylpiperidin-2-yl)octanoate 11
(18 mg, quant.) as a colorless oil; n2D8 ¼ 1:5050; ½aꢁD
¼
ꢀ6:9 ðc 0:35; CHCl3Þ; mmax (film): 3455 (m, OH), 1740 (s,
CO), 1695 (s, CO), 1500 (w, Ar), 1415 (s), 1300 (s), 700
(s); dH (500 MHz, CDCl3): 1.09 (3H, d, J 7.0, 60-CH3),
1.10–1.30 (8H, m, 4-, 5-, 6-, 7-H2), 1.37–1.66 (8H, m,
30-Ha, 3-, 40-, 8-H2, OH), 1.86–2.01 (1H, m, 30-Hb), 2.20
(2H, t, J 7.5, 2-H2), 3.58 (3H, s, CO2CH3), 3.66–3.71
(1H, m, 50-H), 3.98–4.05 (1H, m, 20-H), 4.38–4.44 (1H,
m, 60-H), 5.02 (1H, d, J 12.5, PhCH), 5.06 (1H, d, J 12.5,
PhCH), 7.17–7.28 (5H, m, Ar); HRMS calcd for
C23H36NO5 [(M+H)+] 406.2593, found 406.2553.
To a stirred solution of 10 (390 mg, 1.44 mmol) in H2O
(8 mL) and 1,4-dioxane (8 mL) were added NaHCO3
(360 mg, 4.32 mmol) and CbzCl (2.73 g, 14.4 mmol) at
0 ꢁC. After stirring for 24 h at room temperature, the
resulting mixture was diluted with water and extracted with
CH2Cl2. The extract was successively washed with water
and brine, dried with MgSO4, and concentrated in vacuo.
The residue was chromatographed on silica gel (8 g, hex-
ane/ethyl acetate = 10:1) to give 11 (479 mg, 82%) as a col-

Y. Masuda et al. / Tetrahedron: Asymmetry 17 (2006) 3380–3385
3385
4.11. (+)-Carpamic acid 1
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21
227 ꢁC); ½aꢁD ¼ þ6:0 ðc 0:40; MeOHÞ {Ref. 13: ½aꢁD
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þ5:1 ðc 1:38; MeOHÞ}; mmax (Nujol): 3330 (m, OH,
CO2H), 3205 (m, NH), 2925 (s, CH), 2850 (s, CH), 1730
(w, CO), 1650 (m), 1555 (s), 1465 (s), 1375 (s), 1100 (w),
840 (m), 665 (m); dH (300 MHz, CD3OD): 1.27–1.50 (8H,
m, 4-, 5-, 6-, 7-H2), 1.30 (3H, d, J 6.6, 60-CH3), 1.50–1.83
(7H, m, 3-, 8-, 30-H2, 40-Heq), 1.89–1.97 (1H, m, 40-Hax),
2.14 (2H, t, J 7.0, 2-H2), 2.98–3.10 (1H, m, 20-H), 3.18–
3.27 (1H, m, 60-H), 3.81 (1H, br s, 50-H); dC (67.8 MHz,
CD3OD): 16.0, 23.7, 26.1, 27.4, 30.0, 30.1, 30.4, 31.1,
34.6, 38.8, 57.4, 58.6, 65.9, 182.3; HRMS calcd for
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Acknowledgements
We thank Professor Hidenori Watanabe and Dr. Ken Ishi-
gami (The University of Tokyo) for their cooperation and
support.