A stereocontrolled formal asymmetric synthesis of pseudodistomin C

Article abstract of DOI:10.3987/COM-05-10586

An efficient and stereocontrolled formal asymmetric synthesis of pseudodistomin C has been achieved by employing intramolecular transamidation reaction, exo-methylenation, and highly stereoselective hydroboration. The resulting 2-hydroxymethylpiperidine d

Full text of DOI:10.3987/COM-05-10586

HETEROCYCLES, Vol. 68, No. 1, 2006
183
HETEROCYCLES, Vol. 68, No. 1, 2006, pp. 183 – 192. © The Japan Institute of Heterocyclic Chemistry
Received, 6th October, 2005, Accepted, 16th November, 2005, Published online, 18th November, 2005. COM-05-10586
A STEREOCONTROLLED FORMAL ASYMMETRIC SYNTHESIS OF
PSEUDODISTOMIN C
Ken-ichi Tanaka,* Takuya Maesoba, and Hiroyuki Sawanishi
Faculty of Pharmaceutical Science, Hokuriku University, Kanagawa-machi,
Kanazawa 920-1181, Japan. k-tanaka@hokuriku-u.ac.jp
Abstract – An efficient and stereocontrolled formal asymmetric synthesis of
pseudodistomin C has been achieved by employing intramolecular transamidation
reaction, exo-methylenation, and highly stereoselective hydroboration. The
resulting 2-hydroxymethylpiperidine derivative (15) was further converted into
the key intermediate (2) for the synthesis of pseudodistomin C.
Pseudodistomin C (1), isolated in 1995 from the Okinawan tunicate Pseudodistoma kanoko by Kobayashi
et al., is a piperidine alkaloid possessing 2,4,5-trisubstituted structure and shown to have cytotoxicity
against L1210 and human epidermoid carcinoma KB cells in vitro.1 The relative stereochemistry of the
three functional groups on the piperidine ring of 1 was elucidated on the basis of spectral data and the
whole structure of 1 was unambiguously determined in 1996 by Kobayashi co-workers2 via asymmetric
total synthesis. The three functional groups on the piperidine ring of 1 are placed in all cis orientations
(Figure 1).
OH
4S
NH2
5R
2S
N
H
1
Figure 1. The structure of pseudodistomin C
Despite interesting pharmacological activity and unique structural feature, to our knowledge, only two
approaches for the synthesis of pseudodistomin C have been reported to date. Kobayashi and co-workers2
have reported the first total synthesis via intramolecular amidomercuration of homochiral
N-alkenylurethane available from D-serine as a chiral source. On the other hand, Langlois3 have reported
the formal synthesis, in which 6-benzenelsulfonylmethylpyrrolidine derivative, Kobayashi’s synthetic
precursor, was synthesized via intramolecular transamidation (IT)4 of 5-azidomethyl-γ-lactam derivative

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derived from (S)-pyroglutaminol followed by selective ring opening of the resulting δ-lactam derivative
by organometallic reagent and subsequent ring closure. Recently, we have reported the syntheses of
conformationally restricted surrogates of the 2,4-diaminobutanoyl-(Dab)-Gly dipeptide based on IT
reaction.4j,k As an extension of our going program utilizing this reaction on the synthesis of biologically
active compounds, we herein report the stereocontrolled formal asymmetric synthesis of pseudodistomin
C.
O
OR
OR
OR
NBoc
NHBoc
NHBoc
ref. 2
1
HO
N3
O
N
N
O
N
H2C
N
Boc
Boc
Boc
Boc
5
2
3
4
Scheme 1. Retrosynthetic analysis for pseudodistomin C
Our retrosynthetic strategy for the synthesis of pseudodistomin C is outlined in Scheme 1. We envisioned
that Kobayashi’s intermediate (2) could arise from exo-methylene compound (3) via stereoselective
hydroboration. Compound (3) in turn may be prepared by titanium-mediated carbonyl olefination of
δ-lactam derivative (4). Compound (4) could be constructed by IT reaction of 5-azidomethyl
pyrrolidin-2-one derivative (5).
O
OR
OTBDPS
OH
OTBDPS
N3
a
c
d
O
O
O
N
N
O
N
H
N
R
O
O
Ph
Ph
10: R=H
11: R=Boc
9
6
7: R=H
8: R=TBDPS
e
b
OTBDPS
NHBoc
OTBDPS
NHBoc
OTBDPS
NH2
g
f
O
N
N
O
N
H2C
Boc
R
Boc
12: R=H
13: R=Boc
14
e
Scheme 2. Reagents and conditions: (a) ( PhSe)2, NaBH4, AcOH, EtOH, rt, 86%; (b)
TBDPS-Cl, Im, DMF, 0°C to rt; (c) H2NNH2-H2O, 10% Pd-C, MeOH, reflux, 86% (2 steps);
(d) (i) MsCl, Et3N, CH2Cl2, 0°C; (ii) NaN3, DMF, 80°C; (e) Boc2O, 4-DMAP, CH2Cl2, rt, 88%
(3 steps); (f) H2, 10% Pd-C, MeOH-H2O (12:1), 3 atm, rt, 92%; (g) Cp2TiMe2, toluene, 105°C,
78%.
Thus, we started from known α,β-epoxylactam (6),5 which was prepared from (S)-pyroglutaminol as a
homochiral source (Scheme 2). For the conversion of 6 into the known hydroxyl lactam (7),5a,c a few
methods for the regioselective reductive ring-opening of α,β-epoxylactams have been reported.5a,c,6 In
view of mild reaction conditions at room temperature, we decided to explore the (PhSe)2/NaBH4/AcOH
system developed by Miyashita6 to prepare the compound (7). Thus, 6 was treated with borane complex
Na[PhSeB(OEt)3] generated in situ with (PhSe)2 and NaBH4 in EtOH at room temperature to afford the

HETEROCYCLES, Vol. 68, No. 1, 2006
185
desired hydroxyl lactam (7) as a sole product in 86% yield. Protection of hydroxy group in 7 with
tert-butylchlorodiphenylsilane (TBDPS-Cl) and then removal of benzylidene acetal group in 8 employing
the transfer hydrogenation7 by the use of hydrazine hydrate as a hydrogen source and 10% Pd-C in MeOH
gave N-unsubstituted γ-lactam (9) in 86% overall yield from 7. Sequential mesylation of the resulting
alcohol (9) with methanesulfonyl chloride (MsCl) and triethylamine (Et3N) in CH2Cl2, azidation with
NaN3, and N-protection with Boc2O and 4-dimethylaminopyridine (4-DMAP) afforded azido-γ-lactam
(11) in 88% overall yield from 9. Next, intramolecular transamidation of the azido γ-lactam (11) was
performed using our previous reported reaction conditions.4j,k Thus, a catalytic hydrogenation of the azido
group in 11 in the presence of 10% Pd-C in MeOH-H2O (12:1) at room temperature under 3 atm
hydrogen atmosphere for 48 h afforded the expected N-unsubstituted δ-lactam (12) in 92% yield. After
protection of the lactam ring nitrogen of 12 with Boc2O and 4-DMAP, we turn out our attention on the
titanium-mediated carbonyl olefination of the resulting N-Boc-δ-lactam (13). Compound (13) was reacted
with 1.4 equiv. of dimethyltitanocene (Cp2TiMe2)8 in toluene at 105°C, affording the desired
exo-methylene compound (14) in 78% yield without isomerization to the endocyclic unsaturated
compound.9 Compound (14) was stable during a few days.
OR
O
NHBoc
NBoc
a
c
ref. 2
14
Pseudodistomin C
HO
HO
N
N
Boc
Boc
15: R=TBDPS
16: R=H
2
b
Scheme 3. Reagents and conditions: (a) (i) 9-BBM, THF, rt; (ii) H2O2, NaOH, 75%; (b) n-Bu4NF,
THF, rt; (c) Me2C(OMe)2, p-TsOH,acetone, rt, 79% (2 steps).
Next, hydroboration of the olefin moiety in 14 using the sterically demanding 9-borabicyclo[3,3,1]-
nonane (9-BBN) described by Herdeis et al.10 followed by treatment with hydrogen peroxide afforded the
corresponding primary alcohol (15) as a single diastereoisomer in 75% yield, in which the three
substituents at C2-, C4-, and C5-positions are all cis to each other (Scheme 3). This structure was
assigned by its NOESY spectrum, in which marked NOEs between C2-H and C4-H, and C4-H and C5-H
were observed. Thus, the absolute configuration of 15 was unambiguously determined as (2S,4S,5R)-15.
Hydroboration of 14 occurred exclusively from less hinder β-side. The stereoselectivity could be
explained by the fact that the α-side of both conformers of 14A and 14B is shielded by the sterically
bulky tert-butyldiphenylsilyloxy and tert-butyloxycarbonylamino groups respectively. In both
half-chair-like conformers of 14A and 14B 1,3-diaxial interactions are operating, so a roughly 1:1
equibrium mixture of these conformers is present. Therefore, the sterically bulky borane reagent, 9-BBN,
attacked the olefin moiety of 14 from less hinder β-side (Figure 2).

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HETEROCYCLES, Vol. 68, No. 1, 2006
hydroboration
hydroboration
H
H
5
Boc
N
H
OTBDPS
3
Boc
N
H
BocN
H
H
NBoc
1,3-interaction
OTBDPS
1,3-interaction
14A
14B
Figure 2.
For the synthesis of Kobayashi’s intermediate (2), removal of the O-TBDPS group in 15 with n-Bu4NF
followed by simultaneous protection of the hydroxy and N-tert-butoxycarbonylamino groups with
2,2-dimethoxypropane and p-TsOH gave the known oxazolidine (2) [mp 104-105°C, [α]24 -10.8°
D
(c=1.30, CHCl3); lit.,2 mp 104°C, [α]24 -7.3° (c=1.0, CHCl3)] in 79% overall yield from 15, which was
D
already converted into pseudodistomin C triacetate by Kobayashi et al.2 The spectral data were good
agreement with those reported.2
In summary, an efficient and stereocontrolled formal synthesis of pseudodistomin C (1) has been
developed. This route featured intramolecular transamidation reaction of azido-γ-lactam (11),
exo-methylenation of the resulting δ-lactam (13), and highly stereoselective hydroboration of 14.
EXPERIMENTAL
Melting points were measured on a Yanako MP-S3 micromelting point apparatus and are uncorrected.
Optical rotations were measured with a JASCO DIP-370 automatic digital polarimeter. IR spectra were
1
13
recorded with a HORIBA FT-720 spectrophotometer. H- and C-NMR spectra were measured with a
JNM-ECP-500 spectrometer. Chemical shifts are expressed in ppm (δ) downfield from tetramethylsilane
as internal standard in CDCl3 solutions. EIMS, FABMS, and high resolution fast atom bombardment MS
spectra were obtained with JMS-SX-102A spectrometer. Routine monitoring of reaction was carried out
using Merck TLC aluminum sheet silica gel 60 F254. Flash column chromatography was performed with
indicated solvents on Merck silica gel, 230-400 mesh. All solvents were dried and purified before use.
(2R,5R,6R,7R)-6,7-Epoxy-2-phenyl-3-oxa-1-azabicyclo[3,3,0]octane-8-one (6) was prepared according to
a literature procedure.5
(2R,5R,6S)-6-Hydroxy-2-phenyl-3-oxa-1-azabicyclo[3,3,0]octan-8-one (7)
To a mixture of (PhSe)2 (8.8 g, 27.6 mmol) in EtOH (50 mL) at rt under nitrogen atmosphere, NaBH4
(2.09 g, 55.2 mmol) was added and the mixture was vigorously stirred for 20 min. The reaction mixture
was cooled to 0°C, to which AcOH (4.2 mL, 73.6 mmol) was added. The resulting mixture was stirred for
5 min at 0°C, and then added to a solution of an α,β-epoxylactam (6) (4.0 g, 18.4 mmol) in EtOH (30
mL) under nitrogen atmosphere. The mixture was stirred for 30 min and then diluted with AcOEt (40 mL),
in which oxygen was passed for 5 min. The mixture was washed with brine and the extract was dried over

HETEROCYCLES, Vol. 68, No. 1, 2006
187
Na2SO4. Concentration of the solvent in vacuo gave a residue, which was purified by column
chromatography [CHCl3-MeOH (20:1, v/v)] to give 7 (3.47 g, 86%) as a colorless solid. Recrystallization
from AcOEt-isopropyl ether gave an analytical sample of 7 as a colorless needles; mp132-133°C; [α]25
D
+231° (c=1.02, CHCl3). [lit.,5 mp 132-133°C; [α]20D +228° (c=0.204, CHCl3)].
(2R,5R,6S)-6-(tert-Butyldiphenylsilyloxy)-3-oxa-2-phenyl-1-azabicyclo[3,3,0]octan-8-one (8)
To a stirred solution of 7 (2.0 g, 6.25 mmol) in dry DMF (40 mL) at 0°C were successively added
imidazole (1.88 g, 1.87 mmol) and TBDPS-Cl (2.06g, 7.50 mmol) and the mixture was stirred at rt for 8 h.
The reaction mixture was diluted with H2O and extracted with AcOEt (40 mL). The extract was washed
with brine, dried over Na2SO4. Concentration of the solvent in vacuo gave a residue, which was purified
by column chromatography [hexane-AcOEt (4:1, v/v)] to give 8 (3.97 g, 95%) as a colorless oil. [α]26
D
+103.6° (c=1.00, CHCl3); IR (neat) 3070, 2890, 1712; 1H-NMR (CDCl3) δ 1.06 (9H, s, (CH3)3CSi), 2.68
(1H, dd, J=16.5, 7.80 Hz, C7-H), 2.96 (1H, dd, J=16.5, 8.20 Hz, C7-H), 3.04 (1H, dd, J=8.70, 6.80 Hz,
C4-H), 3.62 (1H, dd, J=8.70, 6.70 Hz, C4-H), 4.01 (1H, m, C5-H), 4.31 (1H, m, C6-H), 6.21 (1H, s,
C2-H), 7.34-7.62 (15H, m, Ph-H); 13C-NMR (CDCl3) δ 18.96 (s, (CH3)3CSi), 26.77 (q, (CH3)3CSi), 43.93
(t, C7), 67.13 (d, C5), 69.47 (t, C4), 72.88 (d, C6), 87.00 (d, C2), 125.96, 128.01, 128.42, 130.27, 130.34,
135.56, 135.59 (Ph), 174.90 (s, lactam C=O); HRFABMS Calcd for C28H32NO3Si: 458.2152. Found:
458.2153.
(4S,5R)-5-Hydroxymethyl-4-(tert-butyldiphenylsilyloxy)pyrrolidin-2-one (9)
To a stirred solution of 8 (1.5 g, 3.3 mmol) in EtOH (40 mL) was added 10% Pd-C (1.65 g) and 100%
H2NNH2-H2O (3.3 mL) at rt under nitrogen atmosphere. The suspension was refluxed with vigorously
stirring for 10 h. The catalyst was filtered and washed with EtOH. The combined filtrates were
evaporated in vacuo and then the residue was purified by column chromatography [CHCl3-MeOH (15:1,
v/v)] to give 9 (1.1 g, 90%) as a colorless viscous oil. [α]24 +8.91° (c=1.28, CHCl3); IR (neat) 3072,
D
2931, 2885, 1693; 1H-NMR (CDCl3) δ 1.05 (9H, s, (CH3)3CSi), 2.27 (1H, dd, J=17.4, 3.2 Hz, C3-H), 2.41
(1H, dd, J=17.4, 7.3 Hz, C3-H), 2.96 (1H, dd, J=11.9, 5.5 Hz, CH2OH), 3.28 (1H, dd, J=11.4, 3.3 Hz,
CH2OH), 3.51-3.53 (1H, m, C5-H), 4.20-4.21 (1H, m, C4-H), 7.59-7.63 (10H, m, Ph-H); 13C-NMR
(CDCl3) δ 19.00 (s, (CH3)3CSi), 26.85 (q, (CH3)3CSi), 40.93 (t, C3), 53.42 (t, CH2OH), 62.91 (d, C5),
70.66 (d, C4), 127.88, 130.04, 133.05, 135.69 (Ph), 177.30 (s, lactam C=O); FABMS m/z 370 (M+1)+;
HRFABMS Calcd for C21H28NO3Si (M+1)+: 370.1839. Found: 370.1840.
(4S,5R)-5-Azidomethyl-4-(tert-butyldiphenylsilyloxy)pyrrolidin-2-one (10)
To a stirred solution of 9 (3.21 g, 8.68 mmol) and Et3N (1.32 g, 13.0 mmol) in CH2Cl2 (40 mL) was
added MsCl (1.2 g, 10.4 mmol) under nitrogen atmosphere and stirred for 12 h. Saturated aqueous citric

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acid (30 mL) and CH2Cl2 (30 mL) were added and the layers were separated. The organic layer was
washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo to
afford colorless oil. To a solution of this oil in DMF (30 mL), NaN3 (1.7 g, 26.1 mmol) was added and the
mixture was heated at 80°C for 6 h. H2O (20 mL) and AcOEt (40 mL) were added and the layers were
separated. The organic layer was washed with brine, dried over Na2SO4. Concentration of the solvent in
vacuo gave a residue, which was purified by column chromatography [hexane-AcOEt 1:1 (v/v)] to give
10 (3.02 g, 88%) as a colorless viscous oil. [α]24D +30.19° (c=1.10, CHCl3); IR (neat) 3250, 2104, 1705;
1H-NMR (CDCl3) δ 1.07 (9H, s, (CH3)3CSi), 2.37 (1H, dd, J=17.9, 3.7 Hz, C3-H), 2.51 (1H, dd, J=17.9,
5.9 Hz, C3-H), 2.76 (1H, dd, J=12.6, 6.0 Hz, CH2N3), 3.02 (1H, dd, J=12.4, 4.1 Hz, CH2N3), 3.42-3.58
(1H, m, C5-H), 4.02-4.32 (1H, m, C4-H), 7.40-7.66 (10H, Ph-H); 13C-NMR (CDCl3) δ 18.98 (s,
(CH3)3CSi), 26.81 (q, (CH3)3CSi), 40.26 (t, C3), 53.02 (t, CH2N3), 62.99 (d, C5), 70.95 (d, C4), 127.94,
127.96, 130.14, 130.21, 135.66, 135.68 (Ph), 176.30 (s, lactam C=O); FABMS m/z 395 (M+1)+;
HRFABMS Calcd for C21H29N4O2Si (M+1)+: 395.1903. Found : 395.1905.
(4S,5R)-5-Azidomethyl-1-tert-butoxycarbonyl-4-(tert-butyldiphenylsilyloxy)pyrrolidin-2-one (11)
To a solution of 10 (2.86 g, 7.25 mmol) and 4-DMAP (0.18 g, 1.45 mmol) in CH2Cl2 (40 mL) was added
Boc2O (3.16 g, 14.5 mmol) at rt. After being stirred for 8 h, the mixture was quenched by saturated
aqueous citric acid and extracted with CH2Cl2. The organic layer was washed with brine, dried over
Na2SO4. Concentration of the solvent in vacuo gave a residue, which was purified by column
chromatography [hexane-AcOEt 2:1 (v/v)] to give 11 (3.45 g, 96%) as a colorless viscous oil. [α]24
D
1
-27.6° (c=1.08, CHCl3); IR (neat) 3072, 2933, 2108, 1789, 1758, 1716; H-NMR (CDCl3) δ 1.06 (9H, s,
(CH3)3CSi), 1.59 (9H, s, (CH3)3CO), 2.48 (1H, br d, J=17.9 Hz, C3-H), 2.78 (1H, dd, 17.9, 6.0 Hz, C3-H),
2.92 (1H, dd, J=12.8, 2.8 Hz, CH2N3), 3.36 (1H, dd, J=12.8, 5.5 Hz, CH2N3), 3.99 (1H, dd, J=5.1, 2.8 Hz,
13
C5-H), 4.13-4.15 (1H, m, C4-H), 7.40-7.65 (10H, m, Ph-H); C-NMR (CDCl3) δ 18.96 (s, (CH3)3CSi),
26.74 (q, (CH3)3CSi), 28.00 (q, (CH3)3CO), 41.93 (t, C3), 51.10 (t, CH2N3), 66.04 (d, C5), 68.24 (d, C4),
127.98, 130.22, 132.57, 132.95, 135.61 (Ph), 149.75 (s, urethane C=O), 172.28 (s, lactam C=O); FABMS
m/z 495 (M+1)+; HRFABMS Calcd for C26H34N4O4Si (M+1)+: 495.2427. Found: 495.2424.
(4S,5R)-5-(tert-Butoxycarbonylamino)-4-(tert-butyldiphenylsilyloxy)piperidin-2-one (12)
A mixture of 11 (1.2 g, 2.4 mmol) and 10% Pd-C (0.3 g) in MeOH-H2O (65 mL, 12/1 (v/v)) was stirred
for 48 h at rt under hydrogen atmosphere (3 atm). The catalyst was filtered off and the filtrate was
concentrated in vacuo to give a residue, which was partitioned between CHCl3 and H2O. The aqueous
layer was backwashed with CHCl3. The combined organic layer was dried over Na2SO4. Concentration of
the solvent in vacuo gave a residue, which was purified by column chromatography [CHCl3-MeOH 10:1
(v/v)] to give 12 (1.05 g, 92%) as a colorless viscous oil. [α]24D +32.5° (c=0.90, MeOH); IR (neat) 3450,

HETEROCYCLES, Vol. 68, No. 1, 2006
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3072, 2964, 1716, 1662; 1H-NMR (CDCl3) δ 1.01 (9H, s, (CH3)3CSi), 1.41 (9H, s, (CH3)3CO), 2.31-2.45
(2H, m, C3-H), 3.25-3.32 (1H, m, C6-H),3.45-3.55 (1H, m, C6-H), 3.86-3.97 (1H, m, C5-H), 4.11-4.21
(1H, m, C4-H), 4.76 (1H, d, J=7.40 Hz, NHBoc), 7.04 (1H, m, NHCO), 7.37-7.67 (10H, m, Ph-H);
13C-NMR (CDCl3) δ 19.31 (s, (CH3)3CSi), 26.97 (q, (CH3)3CSi), 28.29 (q, (CH3)3CO), 38.34 (t, C3),
41.79 (t, C6), 48.52 (d, C5), 68.27 (d, C4), 79.74 (s, (CH3)3CO), 127.94, 127.99, 130.15, 132.89, 135.67,
135.70 (Ph), 155.75 (s, urethane C=O), 170.14 (s, lactam C=O); FABMS m/z 469 (M+1)+; HRFABMS
Calcd for C26H37N2O4Si (M+1)+: 469.2522. Found: 469.2521.
(4S,5R)-1-tert-Butoxycarbonyl-5-(tert-butoxycarbonylamino)-4-(tert-butyldiphenylsilyloxy)piperidin-2-
one (13)
Treatment of 12 (1.20 g, 2.56 mmol) in a similar manner to that described for the preparation of 11 from
10 gave 13 (1.31 g, 90%) as a pale yellow oil, after purification by column chromatography
[hexane-AcOEt 3:1 (v/v)]. [α]24D +18.2° (c=0.95, MeOH); IR (neat) 3363, 1774, 1712; 1H-NMR (CDCl3)
δ 1.09 (9H, s, (CH3)3CSi), 1.41 and 1.53 (18H, each s, (CH3)3CO), 2.50-2.55 (2H, m, C3-H), 3.70-3.75
(2H, m, C6-H), 3.90-4.00 (1H, m, C5-H), 4.10-4.20 (1H, m, C4-H), 4.72 (1H, d, J=7.40Hz, NHBoc),
13
7.39-7.63 (10H, m, Ph-H); C-NMR (CDCl3) δ 19.32 (s, (CH3)3CSi), 27.00 (q, (CH3)3CSi), 27.99 and
28.29 (each q, (CH3)3CO x 2), 41.93 (t, C3), 45.34 (t, C6), 48.89 (d, C5), 68.41 (d, C4), 79.93 and 83.32
(each s, (CH3)3CO x 2), 128.01, 128.07, 130.29, 135.69, 135.77 (Ph), 152.18 and 155.00 (each s, urethane
C=O x 2), 168.31 (s, lactam C=O); FABMS m/z 569 (M+1)+; HRFABMS Calcd for C31H45N2O6Si:
569.3047. Found: 569.3046.
(4S,5R)-1-tert-Butoxycarbonyl-5-(tert-butoxycarbonylamino)-4-(tert-butydiphenylsilyloxy)-2-methylene-
piperidine (14)
To a solution of 13 (0.84 g, 1.47 mmol) in toluene (10 mL) was added Cp2TiMe2 (0.37 g, 1.8 mmol) and
the mixture was heated at 105°C for 3 h. After evaporation of the solvent, the brown oil was diluted with
pentane (20 mL) and the solution was filtered, and the filtrate was concentrated in vacuo. The orange
colored oil residue was purified by column chromatography [hexane-AcOEt 5:1 (v/v)] to give 14 (0.65 g,
1
78%) as a yellow oil. [α]25 +24.5° (c=0.66, CHCl3); IR (neat) 3450, 2875, 1716, 1655; H-NMR
D
(CDCl3) δ 1.08 (9H, s, (CH3)3CSi), 1.42 and 1.45 (18H, each s, (CH3)3CO x 2), 2.12-2.18 (2H, m, C3-H),
3.40-3.50 (1H, m, C6-H), 3.70-3.72 (1H, m, C6-H), 3.79 (1H, m, C5-H), 4.02-4.06 (1H, m, C4-H), 4.71
(1H, s, =CHE), 4.76 (1H, d, J=7.40 Hz, NHBoc), 4.97 (1H, s, =CHZ), 7.37-7.69 (10H, m, Ph-H);
13C-NMR (CDCl3) δ 19.42 (s, (CH3)3CSi), 27.07 (q, (CH3)3CSi), 28.26 and 28.37 (q, (CH3)3CO x 2),
38.62 (t, C3), 44.81 (t, C6), 50.05 (d, C5), 69.95 (d, C4), 77.29 and 80.36 (each s, (CH3)3CO x 2), 109.42
(t, =CH2), 127.69, 127.85, 129.99, 133.56, 135.77, 135.86, 135.93 (Ph), 138.91 (s, C2), 153.77 and

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155.09 (each s, urethane C=O); FABMS m/z 567 (M+1)+; HRFABMS Calcd for C32H47N2O5Si:
567.3254. Found: 567.3256.
(2S,4S,5R)-1-tert-Butoxycarbonyl-5-(tert-butoxycarbonylamino)-2-hydroxymethyl-4-(tert-butyldiphenyl-
silyloxy)piperidine (15)
To a solution of 14 (0.45 g, 0.79 mmol) in THF (40 mL) was added 0.5 M solution of 9-BBN (2.7 mL,
1.34 mmol) and the mixture was stirred at rt for 20 h. After addition of 30% hydrogen peroxide (4.0 mL,
39.5 mmol) and 3.0 M NaOH (4.0 mL, 12.0 mmol), the mixture was stirred at rt for 2 h. Potassium
carbonate was added and the layers were separated. The aqueous layer was extracted with AcOEt and the
combined organic layers were washed with brine, dried over Na2SO4. Concentration of the solvent in
vacuo gave a residue, which was purified by column chromatography [hexane-AcOEt 4:1 (v/v)] to give
15 (0.34 g, 75%) as a colorless solid. Recrystallization from AcOEt-isopropyl ether gave an analytical
sample of 15 as a colorless needless; mp 103-104°C; [α]25D -3.27° (c=1.10, CHCl3); IR (KBr) 3423, 1718,
1695; 1H-NMR (CDCl3) δ 1.10 (9H, s, (CH3)3CSi), 1.37 and 1.45 (18H, each s, (CH3)3CO x 2), 1.66-1.70
(2H, m, C3-H), 2.60 (1H, br s, OH), 3.08-3.30 (1H, m, C6-H), 3.50-3.68 (2H, m, CH2OH), 3.72-3.87 (1H,
m, C6-H), 3.92-4.18 (3H, m, C2-, C4-, and C5-H), 4.67 (1H, br d, J=7.42 Hz, NHBoc), 7.37-7.70 (10H,
m, Ph); 13C-NMR (CDCl3) δ 19.36 (s, (CH3)3CSi), 27.19 (q, (CH3)3CSi), 28.34 and 28.36(each q,
(CH3)3CO x 2), 32.10 (t, C3), 38.81 (t, C6), 49.93 (d, C5), 51.40 (d, C2), 64.31 (t, CH2OH), 69.02 (d, C4),
79.34 and 80.50 (each s, (CH3)3CO x 2), 127.97, 130.09, 130.24, 132.68, 133.08, 135.85, 136.00 (Ph),
154.81 and 154.88 (each s, urethane C=O x 2); FABMS m/z 585 (M+1)+; Anal. Calcd for C32H49N2O6Si:
C, 65.72; H, 8.27; N, 4.79. Found: C, 65.58; H, 8.10; N, 4.62.
(2S,4S,5R)-1-tert-Butoxycarbonyl-5-(tert-butoxycarbonylamino)-2-hydroxymethyl-4-hydroxypiperidine
(16)
Tetra-n-butylammonium fluoride (TBAF) in THF (1.0 M solution, 2.46 mL) was added dropwise to a
stirred solution of 15 (0.48 g, 0.82 mmol) in THF (30 mL) at rt and the mixture was stirred for 6 h. The
reaction mixture was concentrated in vacuo and the residue was purified by column chromatography
(AcOEt) to give 16 (0.25 g, 88%) as a colorless viscous oil. [α]25D -14.3° (c=0.88, CHCl3); IR (neat) 3444,
1
3336, 1722; H-NMR (CDCl3) δ 1.44 and 1.46 (18H, each s, (CH3)3CO), 1.93-2.08 (2H, m, C3-H), 2.59
and 2.78 (2H, each br s, OH x 2), 2.94-3.08 (1H, m, C6-H), 3.48-3.59 (1H, m, C6-H), 3.60-3.70 and
3.80-3.92 (2H, each m, CH2OH), 3.92-4.08 (2H, m, C2- and C5-H), 4.12-4.28 (1H, m, C4-H), 5.29 (1H,
13
br d, J=7.45 Hz, NHBoc); C-NMR (CDCl3) δ 28.22 and 28.38 (each q, (CH3)3CO x 2), 33.16 (t, C3),
40.20 (t, C6), 49.67 (d, C5), 50.47 (d, C2), 64.85 (d, C4), 65.06 (t, CH2OH), 77.37 and 80.46 (s,
(CH3)3CO x 2), 155.18 and 155.49 (each s, urethane C=O x 2); FABMS m/z 347 (M+1)+; HRFABMS
Calcd for C16H31N2O6: 347.2182. Found: 347.2187.

HETEROCYCLES, Vol. 68, No. 1, 2006
191
tert-Butyl (3aR,6S,7aS)-3-tert-Butoxycarbonyl-2,2-dimethyl-6-hydroxymethylperhydrooxazolo [4,5-c]
pyridine-5-carboxylate (2)
To a solution of 16 (0.15 g, 0.43 mmol) in acetone (10 mL) was added 2,2-dimethoxypropane (0.14 g, 1.3
mmol) and p-TsOH (15.0 mg, 0.08 mmol) at 0°C. After stirring at rt for 12 h, the same amount of
2,2-dimethoxypropane and p-TsOH were added and the mixture was stirred for 12 h. After addition of
saturated solution of NaHCO3, the mixture was extracted with CH2Cl2. The organic layer was washed
with brine and dried over Na2SO4. Concentration of the solvent in vacuo gave a residue, which was
purified by column chromatography [hexane-AcOEt 1:1 (v/v)] to give 2 (0.15 g, 90%) as a colorless solid.
Recrystallization from AcOEt-isopropyl ether gave an analytical sample of 2 as a colorless needless; mp
104-105°C (lit.,2 mp 104°C) ; [α]24D -10.8° (c=1.30, CHCl3) (lit.,2 [α]24D -7.3° (c=1.0, CHCl3)); IR (KBr)
1
3457, 1710, 1674; H-NMR (CDCl3) δ 1.46 and 1.48 (18H, each s, (CH3)3CO x 2), 1.51 and 1.64 (6H,
each s, CH3 x 2), 1.93-2.04 (2H, m, C7-H), 2.66 (1H, m, C4-H), 2.80-2.93 and 3.62-3.70 (2H, m,
CH2OH), 3.77-3.84 (1H, m, C7a-H ), 3.86-3.95 (1H, m, C3a-H ), 4.18-4.35 (2H, m, C4- and C6-H);
13C-NMR (CDCl3) δ 23.95 and 27.09 (each q, CH3 x 2), 28.50 and 28.40 (each q, (CH3)3CO x 2), 40.15 (t,
C7), 49.63 (d, C6), 50.20 (t, C4), 53.50 (d, C3a), 62.97 (t, CH2OH), 69.86 (d, C7a), 79.93 and 80.30 (each
s, (CH3)3CO), 93.82 (s, C2), 151.60 and 155.70 (each s, urethane C=O x 2); FABMS m/z 387 (M+1)+;
Anal. Calcd for C19H34N2O6: C, 59.03; H, 8.87; N, 7.25. Found: C, 58.98; H, 8.64; N, 7.02.
REFERENCES AND NOTES
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oxycarbonyl)-2,2-dimethyl-6-oxoperhydro[4,5-c]pyridine-5-carboxylate, with Cp2TiMe2 afforded
only endocyclic unsaturated compound via isomerization of the created double bond. See ref. 3.
O
O
NBoc
NBoc
ref. 3
N
O
N
Boc
Boc
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