Protecting-group-free route to hydroxylated pyrrolidine and piperidine derivatives through Cu(I)-catalyzed intramolecular hydroamination of alkenes

Article abstract of DOI:10.1055/s-0030-1258527

An efficient approach to hydroxylated pyrrolidine and piperidine derivatives through the intramolecular hydroamination catalyzed by a Cu(I)-Xantphos system is described. The transformation allows for the short synthesis of N-alkylated aza-sugars without a

Full text of DOI:10.1055/s-0030-1258527

2136
LETTER
Protecting-Group-Free Route to Hydroxylated Pyrrolidine and Piperidine
Derivatives through Cu(I)-Catalyzed Intramolecular Hydroamination of
Alkenes
P
rotecting-Group-
i
F
ree Ro
r
ute to
H
o
ydroxylated
h
Pyrrolidine
a
i
nd Pip
s
eridine
D
e
a
rivative
s
Ohmiya, Mika Yoshida, Masaya Sawamura*
Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
Fax +81(11)7063749; E-mail: sawamura@sci.hokudai.ac.jp
Received 22 April 2010
N-alkyl substituents through the Cu(I)-catalyzed intramo-
Abstract: An efficient approach to hydroxylated pyrrolidine and
piperidine derivatives through the intramolecular hydroamination
catalyzed by a Cu(I)–Xantphos system is described. The transfor-
mation allows for the short synthesis of N-alkylated aza-sugars
without a protection–deprotection event of the hydroxy groups.
lecular hydroamination of terminal alkenes as a key
step.6,7
The reaction of w-alkenic secondary amine 1aa bearing a
hydroxy group at the allylic position proceeded in the
presence of CuOt-Bu (15 mol%) and Xantphos (15 mol%)
in MeOH–p-xylene (1:1) at 140 °C, affording the mono-
hydroxy pyrrolidine derivative 2aa in 99% NMR yield
(47% isolated yield, dr 86:14) after 72 hours reaction time
Key words: pyrrolidines, piperidines, protecting-group-free syn-
thesis, hydroamination, copper
1
Polyhydroxylated pyrrolidine and piperidine derivatives,
commonly called aza-sugars, have attracted considerable
attention and have been the target of numerous synthetic
efforts due to their potent glycosidase and glycosyltrans-
ferase inhibitory activities.1 Intramolecular cyclization of
highly hydroxylated amino alkenes is one of the simplest
methods for the construction of these nitrogen heterocy-
cles. However, the synthetic sequences via intramolecular
cyclization require intricate protecting-group manipula-
tions of the hydroxy groups, which lead to lengthy synthe-
ses and reduced atom economy.1d We reported earlier that
the Cu(I)–Xantphos system catalyzes the intramolecular
hydroamination of unactivated terminal alkenes bearing
an amino alkyl substituent in alcoholic mixed solvents,
giving pyrrolidine and piperidine derivatives in excellent
yields.2–5 Given that alcoholic solvents are used, we antic-
ipated that amino alkenes with protecting-group-free hy-
droxy groups within the carbon chain tethering the amine
and alkene moieties may be usable as substrates for the
copper-catalyzed hydroamination. This leads directly to
hydroxylated nitrogen heterocycles, whereas removing of
the Thorpe–Ingold effect by the geminal substituents
within the tethering carbon chain was a challenge. Here
we report a protecting-group-free approach to hydroxylat-
ed pyrrolidine and piperidine derivatives with various
(Scheme 1). The H NMR analysis of the crude mixture
indicated that the reaction proceeded cleanly, while the
isolated yield remained 47% because of the material loss
during Kugelrohr distillation. Relative stereochemistry of
the diastereomers is yet to be determined (NOE and cou-
pling constant analyses are ambiguous; procedure A).8
Since CuOt-Bu is not commercially available, we also ex-
amined an in situ prepared copper catalyst system from
commercial sources and found that the reaction could also
be performed well by using CuOAc (15 mol%) and KOt-
Bu (23 mol%) instead of CuOt-Bu (99% NMR yield, dr
76:24; procedure B).8 In all cases we examined different
substrates, and both catalyst systems performed almost
equally well concerning the product yield, while slight de-
viation in diastereoselectivity was observed.
Interestingly, the amino alkene 1a¢a without the substitu-
ents in the linker chain resisted the reaction (Scheme 2).5
The amino alkene 1a¢¢a bearing a TBDMS-protected hy-
droxy group was also unreactive. These results indicate
that the free hydroxy group plays an important role in ac-
celerating the intramolecular hydroamination. The impact
of the hydroxy group may be comparable to the Thorpe–
Ingold-type steric effects observed in our earlier study
PPh2
PPh2
NH
N
O
CuOt-Bu–Xantphos (15 mol%)
MeOH–p-xylene (1:1)
140 °C, 72 h
Me
Me
OH
2aa
99% NMR, 47% isolated
OH
Xantphos
1aa (0.4 mmol)
Scheme 1
SYNLETT 2010, No. 14, pp 2136–2140
x
x
.x
x
.2
0
1
0
Advanced online publication: 28.07.2010
DOI: 10.1055/s-0030-1258527; Art ID: U03110ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Protecting-Group-Free Route to Hydroxylated Pyrrolidine and Piperidine Derivatives
2137
Table 2 Synthesis of Dihydroxylated Pyrrolidines and Piperidines
NH
CuOt-Bu–Xantphos (15 mol%)
Entry Amino alkene
Product
Yield (%)a drb
no reaction
MeOH–p-xylene (1:1)
140 °C, 72 h
NH
R
N
1c
51e (99)
>20:1
1a'a R = H
1a''a R = OTBDMS
HO
HO
OH
OH
Scheme 2
2ca
1ca
Table 1 Synthesis of Monohydroxylated Pyrrolidines and Piperi-
dines
NH
N
2d
47f (55)
>20:1
>20:1
>20:1
Yield (%)a,b drc
HO
OH
1cb
Entry Amino alkene
Product
HO
OH
2cb
NH
1d
51 (99)
80:20
N
NH
3d
43f (45)
N
OH
OH
1ab
Ph
HO
OH
1cc
2ab
HO
OH
2cc
Ph
NH
OH
N
OH
2e
76 (99)
69:31
NH
N
4c
(56)
OH
OH
1ac
Ph
HO
2ac
HO
OH
OH
2cd
Ph
1cd
Ph
Ph
N
NH
3e
61 (99)
(22)
73:27
82:18
NH
N
5c
trace
–
OH
OH
OH
1ba
2ba
HO
HO
OH
H
OH
NH
NH2
N
2ce
4f
1ce
OH
N
1bb
2bb
6d
41e (99)
62:38
a Isolated yield. The yield in parentheses was determined by 1H NMR.
b The products were isolated by Kugelrohr distillation.
HO
HO
OH
OH
c Diastereomeric ratio. Determined by 1H NMR.
1d
2d
d Conditions: CuOAc (15 mol%), Xantphos (15 mol%), KOt-Bu (23
mol%), 1 (0.4 mmol), MeOH–p-xylene (1:1, 0.8 mL), 140 °C, 72 h.
e Conditions: CuOt-Bu (15 mol%), Xantphos (15 mol%), 1 (0.4
mmol), MeOH–p-xylene (1:1, 0.8 mL), 140 °C, 72 h.
a Isolated yield. The yield in parentheses was determined by 1H NMR.
b Diastereomeric ratio. Determined by 1H NMR.
c Conditions: CuOt-Bu (20 mol%), Xantphos (20 mol%), 1 (0.4
mmol), MeOH–p-xylene (1:1, 0.8 mL), 140 °C, 72 h.
f Conditions: CuOt-Bu (15 mol%), Xantphos (15 mol%), 1 (0.4
mmol), MeOH–p-xylene (1:1, 1.8 mL), 140 °C, 72 h.
d Conditions: CuOAc (20 mol%), Xantphos (20 mol%), KOt-Bu (30
mol%), 1 (0.4 mmol), MeOH–p-xylene (1:1, 0.8 mL), 140 °C, 72 h.
e The product was isolated by Kugelrohr distillation.
[vide infra (Table 2, entry 6) for similar effect of hydroxy
groups at the homoallylic and bishomoallylic positions].5
f The product was isolated by PTLC (silica gel, MeOH).
tives 2ab and 2ac,14 respectively (Table 1, entries 1 and 2).
Piperidine derivatives were also obtainable by the Cu-
catalyzed hydroamination of the substrate with a longer
tethering chain (1ba, entry 3). However, the reaction of
the primary amine 1bb to yield the N-unsubstituted
2-hydroxy piperidine (2bb) resulted in a lower yield
(22%, trans/cis 82:189) (entry 4).
Various monohydroxy amino alkenes 1ab,ac,ba,bb,
which are different in the N-substituent and in length of
the tethering carbon chain, were transformed into the
corresponding nitrogen heterocycles 2ab,ac,ba,bb in
the presence of the Cu–Xantphos system [CuOt-Bu–
Xantphos or CuOAc–KOt-Bu–Xantphos] (Table 1, pro-
cedures A and B).8 Thus, the amino pentenes 1ab,ac with
N-i-Bu and N-Bn groups underwent hydroamination in
good yields, giving the corresponding pyrrolidine deriva-
Next, we investigated the synthesis of dihydroxylated
N-alkylpyrrolidine derivatives. The chiral 3,4-dihydroxy-
Synlett 2010, No. 14, 2136–2140 © Thieme Stuttgart · New York

2138
H. Ohmiya et al.
LETTER
Ti(Oi-Pr)4 (1.0 equiv)
L-(+)-DET (1.2 equiv)
TBHP (2.0 equiv)
OH
NHR
OH
OH
RNH2
CH2Cl2 (0.13 M)
–27 °C, 130 h
r.t., 24–72 h
O
HO
3
(2R,3S)-4
95% ee
50%, ref. 10
(2R,3S)-1
1ca R = Me 84%
1cb R = Pr 87%
1cc R = i-Bu 88%
1cd R = CH2CH2OH 80%.
1ce R = Bn 77%
Scheme 3
lated 1-amino-5-pentene substrates 1ca–ce with different piperidine derivatives 2d as 62:38 diastereomeric mixture
N-alkyl groups were readily prepared from 1,4-pentadien- (Table 1, entry 6, procedure B).8,16 The successful in-
3-ol (3) without the need for protecting groups tramolecular hydroamination of 1d indicates that the ef-
(Scheme 3). Thus, according to the literature, (2R,3S)- fect of a free hydroxy group to accelerate cyclization can
1,2-epoxy-4-penten-3-ol (4, 95% ee) was prepared operate even at the homoallylic or bishomoallylic posi-
through the enantiotopos-selective Sharpless oxidation of tions, which are virtually not electronically associated
3 with Ti(Oi-Pr)4/L-(+)-DET/TBHP (1 equiv of Ti) in with the alkene moiety. Hence, the effect of the hydroxy
50% yield.10 Subsequent ring opening with various prima- groups is likely to be due to an entropic factor.
ry amines provided the amino alkene substrates 1ca–ce
with good to high yields.
A route to a trihydroxy-N-methylpiperidine derivative 2e
is outlined in Scheme 5. The Sharpless asymmetric oxida-
The dihydroxylated alkene 1ca–cd underwent hydroami- tion of meso-1,2-divinylethylene glycol (7) with the
nation using an increased catalyst loading (20 mol% Cu), Ti(Oi-Pr)4/L-(+)-DIPT/TBHP (1 equiv of Ti) system af-
providing dihydroxylated pyrrolidine derivatives 2ca–cd forded a diastereomeric mixture (dr = 81:19) of optically
with a high diastereoselectivity (>20:1; Table 2, proce- active epoxides (2S,3R,4R)-8 (90% ee) and (2R,3R,4R)-8
dures A and B).8,15 Thus, substituents such as Me, Pr, (90% ee).12 Temporary diacetylation of the diol epoxides
i-Bu, and hydroxylethyl groups were tolerated at the nitro- allowed for the isolation of the major isomer by silica gel
gen atom (entries 1–4). On the other hand, the reaction of chromatography. The treatment of the diacetoxy epoxide
the amino pentene 1ce with an N-Bn group resulted in a with MeNH2 caused epoxide ring opening and simulta-
low conversion (entry 5).
Ti(Oi-Pr)4 (0.10 equiv)
D-(–)-DIPT (0.15 equiv)
TBHP (0.60 equiv)
OH
OH
Extension of the protecting-group-free protocol to the
synthesis of a piperidine derivative, 3,4-dihydroxy-1,6-
dimethylpiperidine (2d) was feasible by replacing the ep-
oxidation substrate 3 with its one-carbon homologue
( )-5 (Scheme 4 and Table 1, entry 6). Thus, the Sharpless
kinetic resolution11 of dienyl alcohol ( )-5 with Ti(Oi-
Pr)4/D-(–)-DIPT/TBHP (0.1 equiv of Ti) system afforded
(2S,3R)-1,2-epoxy-5-hexen-3-ol (6) with 99% ee in 35%
yield [based on ( )-5]. Subsequent ring opening with me-
thylamine provided the hydroamination precursor
(2S,3R)-1d in 65% yield (Scheme 4). The Cu-catalyzed
hydroamination of (2S,3R)-1d afforded the corresponding
CH2Cl2 (0.10 M)
–20 °C, 23 h
O
+
( )-5
–
(2S,3R)-6
99% ee
35%, ref. 11
NH
MeNH2
r.t., 24 h
HO
OH
(2S,3R)-1d 65%
Scheme 4
Ti(Oi-Pr)4 (1.0 equiv)
L-(+)-DIPT (2.0 equiv)
TBHP (30 equiv)
OH
OH
OH
OH
+
CH2Cl2 (0.15 M)
–20 °C, 90 h
O
O
OH
OH
(2S,3R,4R)-8
(2R,3R,4R)-8
(90% ee, respectively)12
29%
7
(2S,3R,4R)-8/(2R,3R,4R)-8 = 81:19
N
NH
1) Ac2O, pyridine
2) MeNH2
CuOAc–Xantphos (20 mol%)
KOt-Bu (30 mol%)
MeOH–p-xylene (1:1)
140 °C, 72 h
43%
HO
OH
HO
OH
OH
OH
(2S,3R,4R)-1e
[from (2S,3R,4R)-8]
2e 53%
dr 61:39
Scheme 5
Synlett 2010, No. 14, 2136–2140 © Thieme Stuttgart · New York

LETTER
Protecting-Group-Free Route to Hydroxylated Pyrrolidine and Piperidine Derivatives
2139
(8) General Procedure for the Cu(I)-Catalyzed
neous deacetylation to provide the chiral amino triol
(2S,3R,4R)-1e with a terminal alkene moiety. The copper-
catalyzed hydroamination of 1e under the conditions iden-
tical to those for Table 2, entries 2–4 and 6 furnished the
corresponding trihydroxylated piperidine derivative 2e in
53% yield (dr = 61:39) after extraction with H2O followed
by concentration to dryness (procedure C).13,17,18
Hydroamination of Amino Alkene [Procedure A with
CuOt-Bu–Xantphos (Scheme 1, Tables 1 and 2)]
In a glove box, CuOt-Bu (0.06 mmol, 8.2 mg or 0.08 mmol,
10.9 mg) and Xantphos (0.06 mmol, 34.7 mg or 0.08 mmol,
46.3 mg) were placed in a screw vial. Anhydrous, degassed
mixed solvent, MeOH–p-xylene (1:1, 0.4 mL) was added
and stirred at r.t. for 10 min to give a pale yellow solution.
A solution of a hydroxylated amino alkene (0.4 mmol) in
MeOH–p-xylene (1:1, 0.4 mL) was added. The vial was
sealed with a screw cap and was removed from the glove
box. The mixture was stirred and heated at 140 °C for 72 h.
The reaction mixture was cooled to r.t. and concentrated. An
internal standard (1,1,2,2-tetrachloroethane) was added to
the residue. The yield of the product was determined by 1H
NMR. Purification by Kugelrohr distillation or preparative
TLC (silica gel, MeOH) gave the desired product in a
practically pure form.
In summary, we have developed protecting-group-free
routes to a variety of hydroxylated pyrrolidine and piperi-
dine derivatives by way of the Cu(I)-catalyzed intramo-
lecular hydroamination of amino alcohols with a terminal
alkene moiety. The presence of one or more free hydroxy
groups in the tethering chain connecting the amine and
alkene moieties was beneficial for the cyclization to pro-
ceed efficiently. Having flexibility in introducing differ-
ent N-alkyl groups in the substrate preparation and a broad
tolerance of the copper catalysis toward various N-alkyl
groups, the present approach would possibly be a useful
alternative to the existing methods for the preparation of
N-alkyl aza-sugars.
General Procedure for the Cu(I)-Catalyzed
Hydroamination of Amino Alkene [Procedure B with
CuOAc–KOt-Bu–Xantphos (Tables 1 and 2)]
In a glove box, CuOAc (0.06 mmol, 7.4 mg or 0.08 mmol,
9.8 mg), Xantphos (0.06 mmol, 34.7 mg or 0.08 mmol, 46.3
mg), and KOt-Bu (0.09 mmol, 12.3 mg or 0.12 mmol, 16.4
mg) were placed in a screw vial. Anhydrous, degassed mixed
solvent, MeOH–p-xylene (1:1, 0.4 mL) was added and
stirred at r.t. for 10 min to give a pale yellow solution. The
following procedure is identical to that described above.
(9) The relative stereochemistry of 2bb was assigned according
to the literature. See: Andrés, J. M.; Pedrosa, R.; Pérez-
Encabo, A. Eur. J. Org. Chem. 2007, 1803.
Acknowledgment
This work was supported by Grants-in-Aid for Scientific Research
(B) from the Ministry of Education, Culture, Sports, Science and
Technology, Government of Japan.
(10) The ee of (2R,3S)-4 (95% ee) was determined by chiral
HPLC analysis of the p-nitrobenzoate derivative. See: Jäger,
V.; Hümmer, W.; Stahl, U.; Gracza, T. Synthesis 1991, 769.
(11) The ee value of (2S,3R)-6 (99% ee) was determined by the
Mosher’s NMR spectroscopic method. See: Crimmins,
M. T.; Powell, M. T. J. Am. Chem. Soc. 2003, 125, 7592.
(12) The epoxides 8 were prepared according to the reported
procedure. The ee of 8 has not been determined in our hand.
See: Takano, S.; Iwabuchi, Y.; Ogasawara, K. J. Am. Chem.
Soc. 1991, 113, 2786.
References and Notes
(1) For reviews: (a) Iminosugars as Glycosidase Inhibitors –
Nojirimycin and Beyond; Stütz, A. E., Ed.; Wiley-VCH:
Weinheim, 1999. (b) Asano, N.; Nash, R. J.; Molyneux,
R. J.; Fleet, G. W. Tetrahedron: Asymmetry 2000, 11, 1645.
(c) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M.
Chem. Rev. 2002, 102, 515. (d) Pearson, M. S. M.; Mathe-
Allainmat, M.; Fargeas, V.; Lebreton, J. Eur. J. Org. Chem.
2005, 2159.
(2) For reviews on the hydroamination of alkenes and alkynes,
see: (a) Müller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675.
(b) Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.;
Tada, M. Chem. Rev. 2008, 108, 3795.
(13) The isolated 2e was contaminated with unidentified
materials. See experimental procedure in note 17.
(14) 1-Benzyl-3-hydroxy-2-methylpyrrolidine (2ac, 69:31
mixture of diastereomers)
Viscous oil. 1H NMR (300 MHz, CDCl3): d (major isomer)
= 1.22 (d, J = 6.3 Hz, 3 H), 1.66 (m, 1 H), 1.97–2.16 (m, 2
H), 2.30 (m, 1 H), 2.93 (ddd, J = 11.1, 8.4, 2.1 Hz, 1 H), 3.10
(d, J = 12.9 Hz, 1 H), 4.02 (d, J = 12.9 Hz, 1 H), 4.03 (m, 1
H), 7.23–7.35 (m, 5 H); d (minor isomer) = 1.18 (d, J = 6.3
Hz, 3 H), 1.53 (m, 1 H), 1.97–2.16 (m, 2 H), 2.41 (m, 1 H),
2.79 (ddd, J = 11.4, 8.7, 2.4 Hz, 1 H), 3.29 (d, J = 12.9 Hz, 1
H), 3.89 (m, 1 H), 3.94 (d, J = 12.9 Hz, 1 H), 7.23–7.35 (m,
5 H). 13C NMR (75 MHz, CDCl3): d = 12.84 16.25, 32.22,
32.84, 50.89, 51.24, 57.51, 57.77, 63.85, 67.26, 74.31,
78.22, 126.98, 127.01, 128.27 (2×), 128.98, 129.03, 138.99,
139.04. ESI-HRMS: m/z [M + H]+ calcd for C12H18ON:
192.1382; found: 192.1381.
(3) For late transition-metal-catalyzed intramolecular
hydroaminations of amino alkenes bearing a protecting-
group-free hydroxy group, see: Rh: (a) Liu, Z.; Hartwig,
J. F. J. Am. Chem. Soc. 2008, 130, 1570. Pt: (b) Han, X.;
Widenhoefer, R. A. Angew. Chem Int. Ed. 2006, 45, 1747.
Pd: (c) Michael, F. E.; Cochran, B. M. J. Am. Chem. Soc.
2006, 128, 4246.
(4) For intramolecular amidomercurations of amidoalkenes
bearing a protecting-group-free free hydroxy group, see:
(a) Singh, S.; Chikkanna, D.; Singh, O. V.; Han, H. Synlett
2003, 1279. (b) Chikkanna, D.; Han, H. Synlett 2004, 2311;
see also ref. 2.
(5) Ohmiya, H.; Moriya, T.; Sawamura, M. Org. Lett. 2009, 11,
2145.
(6) For reviews on the protecting-group-free synthesis, see:
(a) Hoffmann, R. W. Synthesis 2006, 3531. (b)Young, I. S.;
Baran, P. S. Nature Chem. 2009, 1, 193.
(15) (3S,4R)-3,4-Dihydroxy-1,2-dimethylpyrrolidine (2ca,
>20:1 mixture of diastereomers)
Viscous oil. 1H NMR (300 MHz, CDCl3): d = 1.15 (d, J = 6.6
Hz, 3 H), 2.26 (s, 3 H), 2.31 (m, 1 H), 2.42 (dd, J = 11.0, 6.9
Hz, 1 H), 2.97 (dd, J = 11.0, 2.7 Hz, 1 H), 4.00 (dd, J = 6.3,
5.2 Hz, 1 H), 4.22 (ddd, J = 6.9, 6.3, 2.7 Hz, 1 H). 13C NMR
(75 MHz, CDCl3): d = 12.27, 39.84, 63.42, 65.02, 69.53,
(7) For a synthesis of hydroxypyrrolidines without protecting
groups, see: Dangerfield, E. M.; Timmer, M. S. M.; Stocker,
B. L. Org. Lett. 2009, 11, 535.
Synlett 2010, No. 14, 2136–2140 © Thieme Stuttgart · New York

2140
H. Ohmiya et al.
LETTER
(0.2 mmol) in MeOH–p-xylene (1:1, 0.2 mL) was added.
73.37. HRMS–FAB: m/z [M + H]+ calcd for C6H13O2N:
131.0946; found: 132.1032. [a]D27 +37.0 (c 0.6, MeOH).
The vial was sealed with a screw cap, and was removed from
the glove box. The mixture was stirred and heated at 140 °C
for 72 h. The reaction mixture was cooled to r.t. and
concentrated. The residue was dissolved in EtOAc (5 mL)
and H2O (5 mL). The mixture was extracted with H2O (3 × 5
mL). The combined aqueous layers were evaporated under
reduced pressure to give a pale yellow oil (25.5 mg). 1H
NMR analysis of the material using t-BuOH as an internal
standard indicated that the yield and purity of 2e were 53%
(17.7 mg) and 67%, respectively.
(16) (4R,5S)-4,5-Dihydroxy-1,2-dimethylpiperidine (2d,
62:38 mixture of diastereomers)
Viscous oil. 1H NMR (300 MHz, CD3OD): d (major isomer)
= 1.10 (d, J = 6.3 Hz, 3 H), 1.54–1.67 (m, 2 H), 2.18–2.41
(m, 2 H), 2.19 (s, 3 H), 2.91 (dd, J = 12.6, 3.3 Hz, 1 H), 3.55
(m, 1 H), 3.77 (m, 1 H); d (minor isomer) = 1.04 (d, J = 6.3
Hz, 3 H), 1.44 (ddd, J = 14.7, 11.8, 2.7 Hz, 1 H), 1.77 (dt,
J = 14.7, 3.6 Hz, 1 H), 2.18–2.41 (m, 2 H), 2.27 (s, 3 H), 2.62
(dd, J = 10.8, 4.8 Hz, 1 H), 3.65 (m, 1 H), 3.90 (m, 1 H).
13C NMR (75 MHz, CD3OD): d = 19.38, 20.25, 37.71, 40.50,
42.57, 43.15, 53.45, 57.39, 58.89, 61.80, 68.61, 69.61,
69.70, 70.95. ESI-HRMS: m/z [M + H]+ calcd for C7H15O2N:
145.1103; found: 146.1179. [a]D27 +19.8 (c 1.0, MeOH).
(17) Procedure for the Synthesis of Trihydroxylated
Piperidine 2e (Procedure C, Scheme 5)
(18) (3R,4S,5S)-3,4,5-Trihydroxy-1,2-dimethylpiperidine(2e,
61:39 mixture of diastereomers)
Oil. 1H NMR (600 MHz, D2O): d (major isomer) = 1.14 (d,
J = 6.6 Hz, 3 H), 2.25 (m, 1 H), 2.28 (s, 3 H), 2.41 (m, 1 H),
2.66 (dd, J = 11.4, 4.8 Hz, 1 H), 3.26 (m, 1 H), 3.72 (m, 1 H),
4.02 (m, 1 H); d (minor isomer) = 1.17 (d, J = 6.6 Hz, 3 H),
2.19 (s, 3 H), 2.25 (m, 1 H), 2.35 (d, J = 12.6 Hz, 1 H), 2.41
(m, 1 H), 2.96 (m, 1 H), 3.72 (m, 1 H), 3.97 (m, 1 H). ESI-
HRMS: m/z [M + H]+ calcd for C7H16O3N: 162.11247;
found: 162.11242.
In a glove box, CuOAc (0.04 mmol, 4.9 mg), Xantphos (0.04
mmol, 23.1 mg), and KOt-Bu (0.06 mmol, 8.2 mg) were
placed in a screw vial. Anhydrous, degassed mixed solvent,
MeOH–p-xylene (1:1, 0.2 mL) was added and stirred at r.t.
for 10 min to give a pale yellow solution. A solution of 1e
Synlett 2010, No. 14, 2136–2140 © Thieme Stuttgart · New York