Palladium-catalyzed ring opening of isoprene monoxide with nitrogen nucleophiles - Asymmetric synthesis of branched amino sugars

Article abstract of DOI:10.1055/s-2005-918443

The Pd-catalyzed regio- and enantioselective ring opening of isoprene monoxide with primary amines as pronucleophiles is developed with good yield and enantioselectivity, constructing a quaternary stereocenter enantioselectively. This methodology was used

Full text of DOI:10.1055/s-2005-918443

PAPER
3335
Palladium-Catalyzed Ring Opening of Isoprene Monoxide with Nitrogen
Nucleophiles – Asymmetric Synthesis of Branched Amino Sugars
Ring Opening of
a
Isoprene
M
r
onoxide
r
–
A
sym
y
metric Synthesis of
M
Branched Amino
S
ug
.
ars Trost,* Chunhui Jiang, Kristin Hammer
Department of Chemistry, Stanford University, Stanford, CA 94305–5080, USA
Fax +1(650)7250002; E-mail: bmtrost@stanford.edu
Received 24 May 2005
This paper is dedicated to Professor Steven Ley, scholar, educator, and scientific statesman, in honor of his 60th birthday.
H
OH
Abstract: The Pd-catalyzed regio- and enantioselective ring open-
ing of isoprene monoxide with primary amines as pronucleophiles
is developed with good yield and enantioselectivity, constructing a
quaternary stereocenter enantioselectively. This methodology was
used as the chirality inducing key step in the asymmetric synthesis
of vancosamine derivative 19. The synthesis was achieved in 9 total
steps and 28.6% overall yield.
(C3H5PdCl)2, (R,R)-L2
Na2CO3, CH2Cl2
N
O
O
H
N
O
O
+
+
O
H
99%, 98% ee
H
(C3H5PdCl)2, (R,R)-L2
Cs2CO3, CH3CN
OH
O
N
O
O
Me
Key words: palladium catalysis, enantioselectivity, quaternary ste-
reocenter, asymmetric synthesis, amino sugar
N
O
O
Me
62%, 85–90% ee
Scheme 1 Pd-catalyzed ring opening of vinyl epoxides with
phthalimide
Palladium-catalyzed dynamic kinetic asymmetric trans-
formation (DYKAT) on vinyl epoxide type substrates
showcases the efficiency by which the ligands developed
in these laboratories exercise control of the chemo-, regio-,
and enantioselectivities in the asymmetric allylic alkyla-
tion (AAA) reactions. A series of nucleophiles, such as
alcohols,1 carbonates,2 imides,3 carbodiimides,4 and stabi-
lized carbon nucleophiles,5 have been employed in the re-
action. In the previous reported Pd-catalyzed ring opening
of vinyl epoxides with nitrogen nucleophiles,3 while the
reaction between butadiene monoxide and phthalimide af-
fords excellent yield and enantioselectivity, isoprene
monoxide proved to be a more challenging substrate pre-
sumably because a quaternary stereocenter is generated in
the reaction (Scheme 1). Envisioning that sterically less
demanding primary amines might ameliorate some of the
issues in such a case encouraged us to examine the use of
benzylamines and other sterically less demanding nitro-
gen nucleophiles.
Among the nitrogen nucleophiles, benzylamine (BnNH2,
Table 1, entry 5) and p-methoxybenzylamine (PMBNH2,
Table 1, entry 6) gave the best results in terms of both
yield and enantioselectivity. Although the reaction yield
with benzylamine was slightly higher, the PMB group
would be a better protecting group on nitrogen since its
deprotection was easier and more versatile. The further
optimization of PMBNH2 addition is shown in Table 2.
The results indicate that decreasing the catalyst loading
and increasing the reaction concentration at the same time
improved the reaction yield, while the enantioselectivity
slightly dropped. The rationalization of this dependency is
illustrated in Scheme 2. The full equilibration between the
diastereomeric intermediates I-1 and I-2 is the prerequi-
site for the high enantioselectivity of the DYKAT reac-
tion. At higher concentration and lower catalyst loading,
the relatively high concentration of the amine nucleophile
Optimization of the Palladium-Catalyzed Ring
Opening of Isoprene Monoxide with Nitrogen
Nucleophiles
O
O
O
O
Ph2P
NH HN
PPh2
Ph2P
NH HN
PPh2
Table 1 summarizes the series of nitrogen nucleophiles
that were screened for the Pd-catalyzed asymmetric ring
opening of isoprene monoxide and the results. The chiral
ligands used in the reaction are shown in Figure 1.
(S,S)-L1
(S,S)-L2
Ph
Ph
O
O
NH
N
H
PPh2 Ph2P
(S,S)-L3
SYNTHESIS 2005, No. 19, pp 3335–3345
x
x.
x
x
.
2
0
0
5
Advanced online publication: 25.10.2005
DOI: 10.1055/s-2005-918443; Art ID: C04605SS
Figure 1 Chiral ligands used in the Pd-catalyzed DYKAT reaction
© Georg Thieme Verlag Stuttgart · New York

3336
B. M. Trost et al.
PAPER
Table 1 Pd-Catalyzed Ring Opening of Isoprene Monoxide with Nitrogen Nucleophiles
[Pd], L*, NuH
OH
Nuc
O
Nucleophile
phthalamide
HN(CHO)2
HN(Boc)2
H2NCbz
Conditionsa
Yield (%)
ee (%)
1
2
Pd(II), L2, MeCN, 10% Cs2CO3
Pd(0), L1, CH2Cl2, 10% Cs2CO3
Pd(II), L1, CH2Cl2, 10% Cs2CO3
Pd(0), L1, CH2Cl2
62
4
85–90%
–
3
5
–
4
0
–
5
BnNH2
Pd(II), L3, CH2Cl2, 5% Et3N
Pd(0), L1, CH2Cl2, 40 °C
Pd(0), L1, CH2Cl2
83
74
67
0
94b
94b
74.5b
–
6
PMBNH2
7
2,4-(MeO)2C6H3CH2NH2
Bn2NH
8
Pd(II), L3, CH2Cl2, 5% Et3N
Pd(0), L1, CH2Cl2
9
(PMB)2NH
BnONH2·HCl
NaNO2
0
–
10
11
12
Pd(0), L1, CH2Cl2, Et3N
Pd(0), L1, CH2Cl2–H2O, Et3N·HCl
Pd(0), L1, CH2Cl2
0
–
30
70
0
TMSN3
NDc
a Pd source: Pd(0): Pd2(dba)3·CHCl3; Pd(II): [(h3-C3H5)PdCl]2. 2 mol% Pd and 3 mol% ligand were used in all cases. Reactions were carried
out using concentrations of 0.1–0.2 M at r.t. unless otherwise indicated.
b Determined by chiral HPLC after protecting the initial product with a N-Cbz group.
c Not determined. The 1,2-adduct slowly transforms to the 1,4-adduct at r.t.
compared to the active species I-1 and I-2 results in a fast- 3 and 5). The conditions in entry 5 were used for the large-
er nucleophilic addition and possibly incomplete equili- scale preparation of compound 1.
bration between I-1 and I-2, which is responsible for the
lower enantioselectivity. On the other hand, at low con-
centration and high catalyst loading, since the nucleo-
The absolute configuration of the 1,2-adduct 1 was deter-
mined by transforming it to known derivatives 3, 4, and 6,
as shown in Scheme 3. Table 3 lists their measured and
philic addition is not fast enough, other side reactions of
literature reported optical rotation values. All three optical
the active species become competitive, such as the 1,2-hy-
rotations clearly indicated that compound 1, prepared us-
ing the (R,R)-L1 ligand, has an S configuration in accor-
dride migration to form the aldehyde byproduct 2.
This ring-opening reaction was easy to scale up without dance with the prediction of the working model of the
affecting the yield and enantioselectivity (Table 2, entries chiral ligand.6
Table 2 Optimization of the Palladium-Catalyzed Ring Opening of Isoprene Monoxide with p-Methoxybenzylaminea
Pd2dba3⋅CHCl3, (R,R)-L1
OH
+
PMBNH2
O
NHPMB
1
CH2Cl2, 40 °C
Entry
Catalyst loading
(mol%)
Concentration
(M)
Scale (mmol)
Reaction time (h) Yield (%)
eeb (%)
1
2
3
4
5
6
1.0
0.2
0.4
0.4
0.8
0.8
1.33
0.5
1.0
4
74
76
80
86
85
87
94
0.5
5
93
0.5
10
2.0
20
2.0
6.5
93
0.25
0.25
0.125
22
90
24
45
89.5
81.5
a The molar ratio of (Pd/L1) is 1:1.5. The molar ratio of the two starting materials is 1:1.
b Determined by chiral HPLC after N-Cbz protection.
Synthesis 2005, No. 19, 3335–3345 © Thieme Stuttgart · New York

PAPER
Ring Opening of Isoprene Monoxide – Asymmetric Synthesis of Branched Amino Sugars
3337
or noncarbohydrate starting materials. Three racemic
syntheses12 and more than 13 asymmetric syntheses13 of
vancosamine and its derivatives have been reported. In al-
most all the asymmetric syntheses, enantiopure chiral
compounds were employed as the starting materials and
the quaternary stereocenter was introduced at a later stage
by a diastereoselective process. The only exception is the
synthesis of Fronza,13h in which an enzyme-catalyzed re-
action was used to synthesize the enantiopure intermedi-
ate in low yield. Using the Pd-catalyzed ring opening of
isoprene monoxide with PMBNH2, we could synthesize
the vancosamine derivative starting from racemic iso-
prene monoxide via DYKAT.
O
O
PdL*n
PdL*n
PMBNH2
PMBNH2
PMBNH2
H
O
H
O
H
PdL*n
PdL*n
O
NH
NH
PdL*n
I-2
I-1
I-3
PMB
PMB
HO
HO
O
NHPMB
NHPMB
(R)-1
2
(S)-1
Scheme 2 Rationalization of the dependency of the reaction yield
and enantioselectivity on the concentration and catalyst loading
O
OH
HO
H2N
H2 (80 psi),
Pd(OH)2/C
triphosgene, Et3N
DMAP, CH2Cl2
L-vancosamine (7)
OH
NHPMB
OH
NH2
O
HN
MeOH, 93%
Figure 2 Structure of L-vancosamine
70%
1
3
4
O
90% ee, from (R,R)-L1
The retrosynthetic analysis for the asymmetric synthesis
of L-vancosamine is shown in Scheme 4. Since the direct
Moffatt–Swern oxidation of the initial 1,2-adduct 1 was
problematic, the secondary amine in 1 was further protect-
ed by a Cbz group. While the Cbz protection in tetrahy-
drofuran solvent resulted in a slow reaction and
significant amount of doubly protected product, in aque-
ous conditions the reaction proceeded smoothly and gave
the N-protected product 8 in excellent yield (see
Scheme 5). The alcohol 8 was transformed smoothly into
the aldehyde 9 by a Moffatt–Swern oxidation, and this
compound was olefinated by a modified Julia olefination
to afford the diene 10 with complete geometric selectivity
for the E isomer. The diene 10 was chemoselectively hy-
droborated and oxidized to the primary alcohol 11 effi-
ciently.
(Boc)2O, Et3N
DMAP, CH2Cl2
Cs2CO3, MeOH
67%
OH
NHBoc
O
N
Boc
91%
6
O
5
Scheme 3 Determination of the absolute configuration of the 1,2-
adduct 1
Asymmetric Synthesis of the L-Vancosamine Deriva-
tive
Partially deoxygenated branched amino sugars are impor-
tant components of several classes of natural products
with significant antibiotic and anticancer activities. In par-
ticular, L-vancosamine (7) (Figure 2) is a carbohydrate
component of the glycopeptide antibiotic vancomycin9
and glycosidic antibiotic sopraviridin.10 Vancomycin has
been demonstrated to be an important drug for use against
antibiotic-resistant infections caused by Gram-positive
bacteria,11 while sopraviridin is active against Gram-pos-
itive bacteria, acid-fast bacteria, and trichophyton, but
highly toxic with hemolytic activity. Synthetically, the
structure of vancosamine is a challenge to synthetic chem-
ists because of the Me–C–NH2 branch at the 3-position.
Tremendous efforts have been devoted to the synthesis of
vancosamine and its derivatives from either carbohydrate
OH
P
O
OH
HO
OH
HO
N
P
HO
P
N
P
NH2
vancosamine (7)
OH
NHPMB
1
Scheme 4 Retrosynthetic analysis
Table 3 Comparison of the Measured and Literature-Reported Optical Rotation Values
3
4
6
[a]D (measured)
[a]D (lit.)
–2.58 (c 6.1, EtOH)
–1.44 (c 7.3, EtOH)
–3.87 (c 2.2, MeOH)
+1.2 (c 7.21, EtOH)
(46% ee, R-isomer)
+1.0 (c 5.92, EtOH)
(46% ee, R-isomer)
+4.1 (c 1.00, MeOH)
(R-isomer)
7
7
8
Ref.
Synthesis 2005, No. 19, 3335–3345 © Thieme Stuttgart · New York

3338
B. M. Trost et al.
PAPER
OH
OH
OH
Cbz-Cl, NaHCO3
(COCl)2, DMSO
Et3N
OH
HO
OH
NHPMB
OH
N
HO
+
HO
[O]
H2O
91%
PMB
N
Cbz
PMB
N
N
1
Cbz
PMB
8
PMB
Cbz
12a
Cbz
12b
11
N
N
N
SO2Et
O
PMB
N
Ph
1) 9-BBNH
2) NaOAc, H2O2
N
O
O
MeO OMe
PTSA, CH2Cl2
N
Cbz
10
O
Cbz
HO
O
HO
PMB
KHMDS, DME, –60 °C
81%
9
+
75% from 8
N
N
PMB
PMB
Cbz
Cbz
13b
13a
HO
N
Cbz
11
Scheme 6 Dihydroxylation of 11
PMB
The pure acetonides 13a and 13b were oxidized to the cor-
responding aldehydes 14a and 14b, respectively, by
Dess–Martin periodinane in nearly quantitative yield
(Scheme 7). Acidic deprotection of the acetonide with 10
mol% p-toluenesulfonic acid in methanol gave the cy-
clized products 15 as a 1:1 mixture of the two anomers,
easily separable by column chromatography on silica gel.
Instead of the thermodynamically more stable pyran sug-
ars, the furan sugars were actually obtained. The rationale
was as follows: the deprotection of the acetonide from the
1,2-diol proceeded in a stepwise fashion, with the sterical-
ly more hindered hydroxy group preferentially deprotect-
ed. This hydroxy group attacked the aldehyde to form the
furan sugar products without further isomerization. Under
hydrogenolysis conditions, the Cbz and PMB groups were
removed successively in one pot, to afford the furanoid
amino sugar 16 in good yields.
Scheme 5 Synthesis of intermediate 11
The diastereoselective dihydroxylation of 11 was a chal-
lenging problem (see Scheme 6 and Table 4). Because of
the steric hindrance of the adjacent quaternary center and
the sensitivity of the molecule toward oxidation, many di-
hydroxylation conditions failed to provide the desired
product. Among the conditions screened, osmium(VIII)
oxide/N-methylmorpholine N-oxide (OsO4/NMO) in a
mixed solvent of acetone and water was the best oxidation
system. Careful control of the reaction conditions gave the
desired triol 12 as the only product. After the protection of
the 1,2-diol in 12 as an acetonide, the diastereomers 13a
and 13b were easily separable by column chromatography
on silica gel, giving a diastereomeric ratio of 1.2:1 and
isolated yield of 93% over the two steps (Table 4, entry 1).
When DABCO (1.5 equiv) was used as an additive, the dia-
stereoselectivity was improved to 2:1 (Table 4, entry 2).
Catalyst-controlled stereoselectivity using the Sharpless
AD reaction failed. It should be noted that this diastereo-
selectivity is among the best obtained to date in the dihy-
droxylations of similar intermediates in other
vancosamine syntheses.13a,c
It was suggested that a stronger acid in the deprotection–
cyclization step is required to force the equilibration be-
tween the furan and pyran sugars. As shown in Scheme 8,
under prolonged treatment with 0.7 M hydrogen chloride
in methanol, the furan sugars 15b1 and 15b2 as well as
their precursor 14b, derived from the minor diastereomer
Table 4 Dihydroxylation of 11
Entry
Conditions
Outcome
1
2
OsO4, NMO, acetone–H2O, 0 °C to r.t.
OsO4, NMO, DABCO, acetone–H2O, 0 °C to r.t.
OsO4, NMO, CH2Cl2–H2O, r.t.
OsO4, Me3NO, acetone–H2O, r.t.
OsO4, Me3NO, CH2Cl2–H2O, r.t.
AD-mix-a or AD-mix-b
12 [93%;a ratio (13a/13b) 1.2:1]
12 [90%;a ratio (13a/13b) 2:1]
starting material + Cbz-NH-PMB
complex mixture
3
4
5
complex mixture and starting material
<5% conversion
6
7
K2OsO4, K3Fe(CN)6, K2CO3
12 (1:1 dr) with byproducts
complex mixture
8
OsO4, K3Fe(CN)6, K2CO3, DABCO
RuCl3, NaIO4, EtOAc–MeCN, 0 °C
KMnO4, 18-crown-6, acetone–benzene
9
decomposition
10
starting material + Cbz-NH-PMB
Yield of 13 after the protection of the 1,2-diol with acetonide.
Synthesis 2005, No. 19, 3335–3345 © Thieme Stuttgart · New York

PAPER
Ring Opening of Isoprene Monoxide – Asymmetric Synthesis of Branched Amino Sugars
3339
The furan sugars 15a1 and 15a2 or their precursor 14a,
derived from the major diastereomer in the dihydroxyla-
tion step, were also transformed to the corresponding py-
ran sugar completely when stirred with 0.7 M hydrogen
chloride in methanol at room temperature. The cyclic car-
bamate was formed from the partial deprotection of Cbz
group during the reaction (Scheme 9). Both anomers of 19
were initially observed, while longer reaction time al-
lowed further equilibration to give the more stable a-ano-
mer as the sole product, which was a derivative of L-
vancosamine. Compound 19 was further transformed to a
O
O
PTSA, MeOH
Dess-Martin
quant.
O
HO
O
O
78–96%
2 anomers
separable
N
Cbz
N
Cbz
PMB
PMB
13a: 3S,4S,5S
13b: 3S,4R,5R
14a: 3S,4S,5S
14b: 3S,4R,5R
OMe
O
OH
Pd(OH)2/C (10 mol%)
H2 (35 psi), MeOH
O
OMe
O
OMe
24 h, 74–84%
NPMB
Cbz
NPMB
Cbz
24
known derivative of vancosamine 21 {[a]D –105.12 (c
0.1, MeOH), lit. [a]D –132 (c 1.4, MeOH)13g or [a]D –118
(c 0.09, MeOH)9b} by oxidative cleavage of the PMB
group and hydrolysis of the carbamate. The 1H NMR data
of 21 also matched with those reported in the literature.13g
15a1,a2: 3S,4S,5S
15b1,b2: 3S,4R,5R
OH
O
OMe
NH2
OH
16a1,a2: 3S,4S,5S
16b1,b2: 3S,4R,5R
O
O
OMe
0.7 M HCl, MeOH
5 d
O
O
or
Scheme 7 Lactol cyclization under kinetic conditions
100%
NPMB
Cbz
N
Cbz
PMB
14a
15a1,a2
in the dihydroxylation step, were transformed to the pyran
sugar 17, a 4,5-di-epi-vancosamine derivative, as a single
diastereomer. The Cbz group was removed in situ during
the reaction. The relative configuration of 17 was con-
firmed by single crystal X-ray analysis (Figure 3). Com-
pound 17 was finally transformed to the amino sugar 18 in
quantitative yield by hydrogenolysis.
O
OMe
O
OMe
CAN, MeCN/H2O
50%
O
O
NH
N
O
PMB
O
20
19
O
OMe
KOH (aq), reflux
80%
OH
O
HO
H2N
21
O
OMe
0.7 M HCl, MeOH
3 days
O
O
or
Scheme 9 Lactol equilibration of L-vancosamine derivative
57%
NPMB
N
Cbz
PMB
Cbz
14b
15b1,b2
Palladium-catalyzed asymmetric ring opening of isoprene
monoxide with nitrogen nucleophiles was further investi-
gated. The scope of nitrogen nucleophiles used was ex-
tended to primary amines, such as benzylamine and p-
methoxybenzylamine, with high yields and enantioselec-
tivities obtained in the reaction. A quaternary stereocenter
is generated in a highly enantioselective fashion. The ring
opening of isoprene monoxide by p-methoxybenzylamine
was used as a key step in the asymmetric synthesis of L-
vancosamine derivative 19. Compound 19 was synthe-
sized in 9 total steps and 28.6% overall yield from racemic
isoprene monoxide. It is the first asymmetric synthesis of
the vancosamine derivative using a nonenzyme-catalyzed
enantioselective reaction as the source of chirality. How-
ever, the modest diastereoselectivity in the dihydroxyla-
tion of 11 calls for the development of new methodologies
for more efficient dihydroxylation of olefins.
O
OMe
O
OMe
H2 (50 psi), Pd(OH)2
MeOH
HO
HO
NHPMB
NH2
100%
17
18
Scheme 8 Lactol equilibration of a 4,5-di-epi-vancosamine deriva-
tive
All reactions were performed in oven-dried glassware, under an at-
mosphere of dry argon. Solvents were dried and distilled using stan-
dard
procedures.
Dichloromethane,
1,2-dichloroethane,
acetonitrile, pyridine, and triethylamine were distilled from calcium
hydride; tetrahydrofuran, diethyl ether, and toluene were distilled
from sodium/benzophenone, while benzene was distilled from
Figure 3 X-ray analysis of the relative configuration of 17
Synthesis 2005, No. 19, 3335–3345 © Thieme Stuttgart · New York

3340
B. M. Trost et al.
PAPER
sodium metal. Petroleum ether (PE) used had the boiling range
36–60 °C.
IR (film): 3301, 3081, 2933, 2883, 1612, 1513, 1464, 1301, 1248,
1177, 1036, 921 cm–1.
NMR spectra were recorded using a Varian Gemini 300 (300 MHz
for 1H NMR, 75 MHz for 13C NMR) or Unity Inova 500 (500 MHz
1H NMR (500 MHz, CDCl3): d = 7.24 (d, J = 8.7 Hz, 2 H), 6.86 (d,
J = 8.7 Hz, 2 H), 5.85 (dd, J = 10.9, 17.7 Hz, 1 H), 5.24 (d, J = 11.0
Hz, 1 H), 5.17 (d, J = 17.7 Hz, 1 H), 3.80 (s, 3 H), 3.59 (d, J = 12.1
Hz, 1 H), 3.56 (d, J = 12.0 Hz, 1 H), 3.44 (d, J = 10.5 Hz, 1 H), 3.40
(d, J = 10.5 Hz, 1 H), 1.24 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 158.58, 141.98, 132.62, 129.36,
114.75, 113.78, 68.07, 58.38, 55.21, 46.10, 20.86.
1
for H NMR, 125 MHz for 13C NMR) spectrometer using TMS
(0.00 ppm), residue CHCl3 (7.26 ppm) and CDCl3 (77.0 ppm) as the
internal standard. IR spectra were recorded on liquid films (NaCl
plates) employing a Perkin-Elmer Paragon 500 FTIR spectropho-
tometer. Optical rotations were measured in a Jasco DIP-360 digital
polarimeter in 5-cm cells at r.t. Elemental analyses were obtained
from M-H-W Laboratories, Phoenix, Arizona. Mass spectra were
obtained from the Mass Spectrometry Facility at the School of Phar-
macy, UCSF, California, 94143-0446.
HRMS (EI): m/z calcd for C12H16NO (M+ – OCH3): 190.1232;
found 190.1236.
Anal. Calcd for C13H19NO2: C, 70.55; H, 8.65. Found: C, 70.78; H,
8.40.
Chiral HPLC was performed on a Thermo Separation Products
Spectra Series P100 HPLC using Chiralpak OD columns with de-
tection at 254 nm. Chiral gas–liquid chromatography was per-
formed on a HP 6890 capillary gas chromatograph using a 30 m ×
0.252 mm J&W Cyclosil B column, with a split ratio of ~80:1 and
1.0 mL·min–1 He as the carrier gas.
(R)-2-Benzylamino-2-methylbut-3-en-1-ol
Following the above procedure, 2-(R)-benzylamino-2-methylbut-3-
en-1-ol was synthesized with the following quantities of reagents
and solvent: [(h3-C3H5)PdCl]2 (0.91 mg, 2.5 mmol), (S,S)-L3 (5.2
mg, 7.5 mmol), CH2Cl2 (2 mL), BnNH2 (21.4 mg, 22 mL, 0.2 mmol),
Et3N (1.0 mg, 1.3 mL, 0.01 mmol), and isoprene monoxide (17 mg,
19 mL, 0.2 mmol). The reaction was complete in 2 h at r.t. and the
crude product was purified by flash chromatography (silica gel, PE–
EtOAc 2:1, with 5% Et3N) to afford the desired compound as a col-
orless oil in 94% ee (determined after N-Cbz protection); yield: 32
mg (83%).
[a]D22 +12.54 (c 1.01, CH2Cl2).
IR (film): 3330, 1456, 1048, 921 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.31–7.23 (m, 5 H), 5.84 (dd, J =
10.9, 17.4 Hz, 1 H), 5.23 (dd, J = 1.0, 11.0 Hz, 1 H), 5.17 (dd, J =
0.9, 17.4 Hz, 1 H), 3.62 (dd, J = 2.9, 12.3 Hz, 2 H), 3.41 (dd, J = 4.8,
15.3 Hz, 2 H), 2.20 (br s, NH, OH), 1.23 (s, 3 H).
Tris(dibenzylideneacetone)dipalladium–chloroform
complex
(Pd2dba3·CHCl3) was prepared according to the method described
by Ukai et. al.14
(S)-2-(4-Methoxybenzyl)amino-2-methylbut-3-en-1-ol (1)
Specific reaction details are given in Table 5. To an oven-dried,
round-bottom flask were added Pd2dba3·CHCl3, (R,R)-L1, and a
stirbar. The flask was then placed under reduced pressure (vacuum
pump) for 10 s and refilled with Ar; this purging procedure was re-
peated five times to ensure no oxygen remained in the reaction ves-
sel. After being placed under an Ar atmosphere, freshly distilled
CH2Cl2 was added and the resulting dark purple solution was stirred
at r.t. for 10 min until it turned a deep orange color. During this time,
neat PMBNH2 was added. Finally, 2-methyl-2-vinyloxirane was
added to the mixture and the solution turned bright yellow. The so-
lution was heated to 40 °C and stirring was continued for the time
indicated in Table 2, at which point the orange color returned. The
solvent was removed in vacuo. The crude product was purified by
flash chromatography (PE–EtOAc 2:1, with 5 vol% Et3N) on silica
gel to afford the desired product 1 as a colorless oil. The enantiose-
lectivity was determined in the form of 8 after the N-Cbz protection
of 1.
13C NMR (75 MHz, CDCl3): d = 142.1, 140.7, 128.4, 127.0, 114.8,
68.1, 58.5, 46.8, 21.1.
HRMS (EI): m/z calcd for C11H14N (M+ – OCH3): 160.1126; found:
160.1127.
(S)-2-Amino-2-methylbutan-1-ol (3)
A mixture of (S)-1 (90% ee) (200 mg, 0.904 mmol) and Pd(OH)2/C
(20 wt% with 50 wt% H2O, 127 mg, 0.090 mmol) in MeOH (10 mL)
was stirred under 80 psi H2 at r.t. for 20 h. After filtration and re-
moval of the solvent in vacuo, the residue was redissolved in Et2O
[a]D22 –17.84 (c 0.98, CHCl3) (93% ee).
Rf = 0.43 (hexanes–EtOAc–Et2NH, 1:1:0.1).
Table 5 Reaction Details for the Pd-Catalyzed Ring Opening of Isoprene Monoxide with PMBNH2
Entry
2-Methyl-2-
vinyloxirane
PMBNH2
Pd2dba3·CHCl3
(R,R)-L1
CH2Cl2
2.5 mL
2.5 mL
25 mL
2.5 mL
25 mL
1.5 mL
Yield
ee (%)
94
1
2
3
4
5
6
42 mg,
0.50 mmol
69 mg,
0.50 mmol
5.2 mg,
5.0 mmol
10.4 mg,
15.0 mmol
82 mg
(74%)
84 mg,
1.0 mmol
137 mg,
1.0 mmol
5.2 mg,
5.0 mmol
10.4 mg,
15.0 mmol
168 mg
(76%)
93
840 mg,
10.0 mmol
1.38 g,
10.0 mmol
52 mg,
0.050 mmol
104 mg,
0.150 mmol
1.775 g
(80%)
93
168 mg,
2.0 mmol
274 mg,
2.0 mmol
5.2 mg,
5.0 mmol
10.4 mg,
15.0 mmol
379 mg
(86%)
90
1.68 g,
20.0 mmol
2.74 g,
20.0 mmol
52 mg,
0.050 mmol
104 mg,
0.150 mmol
3.760 g
(85%)
89.5
81.5
168 mg,
2.0 mmol
274 mg,
2.0 mmol
2.6 mg,
2.5 mmol
5.2 mg,
7.5 mmol
387 mg
(87%)
Synthesis 2005, No. 19, 3335–3345 © Thieme Stuttgart · New York

PAPER
Ring Opening of Isoprene Monoxide – Asymmetric Synthesis of Branched Amino Sugars
3341
and dried (Na2SO4), and the solvent was removed in vacuo to afford
87 mg of 3 (93%) along with some 4-methylanisole. The mixture
can be carried on for the next step directly. To remove 4-methylani-
sole, the mixture was dissolved in 5% aq NaHSO4 and extracted
with Et2O. The aqueous layer was basified with 1 M NaOH, saturat-
ed with K2CO3, and then extracted with EtOAc. The organic layers
were dried (Na2SO4) and the solvent was removed in vacuo to af-
ford pure 3.
removal of the solvent in vacuo, the crude product was purified by
flash chromatography (silica gel, PE–EtOAc 5:1 → 2:1) to afford
the desired product 8 as a colorless oil; yield: 5.48 g (91%).
HPLC (Chiralcel OD, heptane–i-PrOH 90:10, 1.0 mL·min–1, 254
nm): 9.62 min (R-isomer), 12.16 min (S-isomer).
[a]D26 –20.97 (c 1.30, CHCl3) (93% ee).
Rf = 0.15 (hexanes–EtOAc, 4:1).
[a]D24 –2.58 (c 6.1, EtOH) {lit.7 [a]D15 +1.2 (c 7.21, EtOH) (46% ee,
R-isomer)}.
IR (film): 3447, 3032, 2953, 2835, 2360, 1684, 1613, 1586, 1513,
1458, 1398, 1352 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.33 (d, J = 10.4 Hz, 1 H), 3.28 (d,
J = 10.4 Hz, 1 H), 1.45 (dq, J = 7.6, 13.7 Hz, 1 H), 1.37 (dq, J = 7.6,
13.8 Hz, 1 H), 1.03 (s, 3 H), 0.90 (t, J = 7.6 Hz, 3 H).
1H NMR (500 MHz, CDCl3): d = 7.22–7.32 (m, 3 H), 7.08–7.20 (m,
2 H), 7.08 (d, J = 8.4 Hz, 2 H), 6.81 (d, J = 8.5 Hz, 2 H), 5.96 (dd,
J = 11.0, 17.4 Hz, 1 H), 5.16 (d, J = 10.7 Hz, 1 H), 5.15 (d, J = 17.5
Hz, 1 H), 5.10 (s, 2 H), 4.49 (d, J = 16.7 Hz, 1 H), 4.44 (d, J = 16.7
Hz, 1 H), 3.91 (dd, J = 5.7, 11.5 Hz, 1 H), 3.80 (s, 3 H), 3.76 (dd,
J = 7.7, 11.4 Hz, 1 H), 1.36 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 158.28, 156.99, 140.84, 136.17,
131.70, 128.37, 127.90, 127.83, 127.33, 114.45, 113.71, 69.33,
67.26, 65.97, 55.24, 48.99, 20.32.
(S)-4-Ethyl-4-methyloxazolidin-2-one (4)
To a solution of 3 (84 mg, 0.814 mmol) and DMAP (1 mg, 0.081
mmol) in CH2Cl2 (24 mL) were added Et3N (205 mg, 0.28 mL, 2.03
mmol) and triphosgene (82 mg, 0.276 mmol). The solution was
stirred at r.t. for 2 h and solvent was removed in vacuo. The residue
was purified by flash chromatography (silica gel, PE–EtOAc 1:1) to
afford known compound 4; yield: 74 mg (70%).
HRMS (EI): m/z calcd for C21H25NO4 (M+): 355.1783; found:
355.1781.
[a]D23 –1.44 (c 7.3, EtOH) {lit.7 [a]D12 +1.0 (c 5.92, EtOH) (46% ee,
R-isomer)}.
Anal. Calcd for C21H25NO4: C, 70.96; H, 7.09. Found: C, 70.74; H,
6.86.
IR (film): 3286, 1743, 1483, 1462, 1399, 1273, 1197, 1039, 945,
772 cm–1.
1H NMR (500 MHz, CDCl3): d = 5.08 (br s, 1 H), 4.15 (d, J = 8.5
Hz, 1 H), 4.05 (d, J = 8.4 Hz, 1 H), 1.62 (q, J = 7.6 Hz, 1 H), 1.34
(s, 3 H), 0.96 (t, J = 7.5 Hz, 3 H).
(S)-2-[(Benzyloxycarbonyl)(4-methoxybenzyl)amino]-2-meth-
ylbut-3-enal (9)
Oxalyl chloride (1.28 g, 0.885 mL, 10.1 mmol) was added dropwise
to a solution of DMSO (1.58 g, 1.44 mL, 20.2 mmol) in dry CH2Cl2
(15 mL) at –60 °C. After 30 min, 8 (1.545 g, 4.35 mmol) in CH2Cl2
(2 mL) was added dropwise. The solution was stirred between –60
and –40 °C for 1.5 h and then cooled to –60 °C. Triethylamine (2.33
g, 3.2 mL, 23 mmol) was added and the cold bath was removed. Af-
ter warming to r.t., Et2O (30 mL) was added and the mixture was fil-
tered. Then, H2O was added and the mixture was extracted with
Et2O. The organic layers were washed with brine and dried
(MgSO4). Crude product 1.617 g (>100%) was obtained and direct-
ly used for the next step. For analytical purposes, some crude prod-
uct was purified by flash chromatography (silica gel, PE–EtOAc
4:1 → 2:1 → 1:1) to afford the desired product 9 as a colorless oil.
tert-Butyl (S)-[1-(Hydroxymethyl)-1-methylpropyl]carbamate
(6)
To a solution of 4 (74 mg, 0.57 mmol) and DMAP (14 mg, 0.11
mmol) in CH2Cl2 were added Et3N (115 mg, 0.16 mL, 1.14 mmol)
and (Boc)2O (188 mg, 0.855 mmol) at 0 °C. The solution was
warmed to r.t., stirred overnight, quenched with sat. aq NaHCO3,
and extracted with EtOAc. The organic layers were washed with
brine and dried (Na2SO4). After removal of the solvent, the crude
product was purified by flash chromatography (silica gel, PE–
EtOAc 5:1) to afford 5; yield: 120 mg (91%).
1H NMR (500 MHz, CDCl3): d = 4.08 (d, J = 8.7 Hz, 1 H), 3.89 (d,
J = 8.7 Hz, 1 H), 2.07 (m, 1 H), 1.65 (m, 1 H), 1.55 (s, 9 H), 1.51 (s,
3 H), 0.91 (t, J = 7.4 Hz, 3 H).
Rf = 0.38 (hexanes–EtOAc, 4:1).
IR (film): 2994, 2956, 2836, 2368, 2339, 1734, 1684, 1613, 1514,
1354 cm–1.
A solution of 5 (37 mg, 0.161 mmol) and Cs2CO3 (54 mg, 0.166
mmol) in MeOH (2 mL) was stirred at r.t. for 1 d and quenched with
H2O. After extracting with EtOAc, the organic layers were washed
with brine and dried (MgSO4). The solvent was removed and the
crude product was purified by flash chromatography (silica gel, PE–
EtOAc 5:1 → 2:1) to afford known compound 6; yield: 22 mg
(67%).
1H NMR (300 MHz, CDCl3): d = 9.39 (s, 1 H), 7.15–7.47 (m, 5 H),
7.16 (d, J = 8 Hz, 2 H), 6.83 (d, J = 8 Hz, 2 H), 5.87 (dd, J = 11, 18
Hz, 1 H), 5.35 (d, J = 11 Hz, 1 H), 5.25 (d, J = 18 Hz, 1 H), 5.18 (s,
2 H), 4.46 (AB, 2 H), 3.80 (s, 3 H), 1.38 (s, 3 H).
Because of hindered rotation of the carbamate bond, the carbon
spectrum was very complex.
HRMS (EI): m/z calcd for C21H23NO4 (M+): 353.1627; found
353.1625.
[a]D23 –3.87 (c 2.2, MeOH) {lit.8 [a]D25 +4.1 (c 1.00, MeOH)}.
1H NMR (500 MHz, CDCl3): d = 4.63 (br s, 1 H), 3.65 (d, J = 11.5
Hz, 1 H), 3.59 (d, J = 11.5 Hz, 1 H), 1.70–1.78 (m, 1 H), 1.52–1.60
(m, 1 H), 1.43 (s, 9 H), 1.15 (s, 3 H), 0.90 (t, J = 7.5 Hz, 3 H).
Anal. Calcd for C21H23NO4: C, 71.36; H, 6.56. Found: C, 71.52; H,
6.80.
13C NMR (125 MHz, CDCl3): d = 156.28, 79.76, 69.48, 57.05,
29.00, 28.30, 21.95, 7.79.
(S)-3-[(Benzyloxycarbonyl)(4-methoxybenzyl)amino]-3-meth-
ylhexa-1,4E-diene (10)
A solution of 0.5 M KHMDS in toluene (14.6 mL, 7.3 mmol) was
added dropwise over a period of 45 min to a solution of 9 (1.617 g
crude, directly from above reaction, 4.35 mmol) and 5-ethylsulfo-
nyl-1-phenyl-1H-tetrazole (1.55 g, 6.53 mmol) in dry DME (65
mL) at –60 °C under Ar. The mixture was stirred for 20 min before
H2O (20 mL) was added. The cold bath was removed and the mix-
ture was slowly allowed to reach ambient temperature. The mixture
was extracted with Et2O and the combined organic layers were
(S)-2-[(Benzyloxycarbonyl)(4-methoxybenzyl)amino]-2-meth-
ylbut-3-en-1-ol (8)
A suspension of (S)-2-(4-methoxybenzyl)amino-2-methylbut-3-en-
1-ol 1 (3.76 g, 17.0 mmol), benzyl chloroformate (3.48 g, 2.91 mL,
20.4 mmol), and NaHCO3 (3.85 g, 45.9 mmol) in H2O (24 mL) was
stirred at r.t. for 4 h. The mixture was diluted with H2O and extract-
ed with EtOAc, and the organic layers were dried (MgSO4). After
Synthesis 2005, No. 19, 3335–3345 © Thieme Stuttgart · New York

3342
B. M. Trost et al.
PAPER
washed with brine and dried (MgSO4). After removal of the solvent
in vacuo, the crude product was purified by flash chromatography
(silica gel, PE–EtOAc 19:1) to afford the desired product 10 as a
colorless oil; yield: 1.195 g (75% from 8).
EtOAc and the combined organic layers were dried (MgSO4). The
two diastereomeric acetonides were isolated by flash chromatogra-
phy (silica gel, PE–EtOAc 2:1).
First eluted acetonide 13a
Colorless oil.
[a]D23 +5.75 (c 1.26, CHCl3).
Rf = 0.52 (hexanes–EtOAc, 4:1).
IR (film): 2937, 1702, 1612, 1512, 1395, 1350, 1240, 1174 cm–1.
Yield: 92 mg (60%).
[a]D23 +23.11 (c 1.05, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.21–7.38 (m, 5 H), 7.13 (d, J =
8.5 Hz, 2 H), 6.82 (d, J = 8.5 Hz, 2 H), 5.99 (dd, J = 10.5, 17.6 Hz,
1 H), 5.57 (d, J = 15.9 Hz, 1 H), 5.46 (dq, J = 6.1, 15.6 Hz, 1 H),
5.12 (s, 2 H), 5.01 (d, J = 11.2 Hz, 1 H), 5.00 (d, J = 17.3 Hz, 1 H),
4.51 (s, 2 H), 3.80 (s, 3 H), 1.64 (d, J = 5.9 Hz, 3 H), 1.53 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 158.24, 156.34, 143.22, 136.73,
135.08, 132.48, 128.26, 127.85, 127.69, 123.79, 113.61, 111.67,
66.81, 63.80, 55.21, 48.78, 23.38, 17.77.
Rf = 0.45 (hexanes–EtOAc, 1:1).
IR (film): 3477, 2984, 2935, 1697, 1612, 1513, 1247, 1043 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.26–7.38 (m, 5 H), 7.13 (d, J =
8.4 Hz, 2 H), 6.82 (d, J = 8.6 Hz, 2 H), 5.19 (d, J = 12.2 Hz, 1 H),
5.13 (d, J = 12.2 Hz, 1 H), 4.76 (d, J = 16.6 Hz, 1 H), 4.57 (d, J =
7.8 Hz, 1 H), 4.37 (d, J = 16.6 Hz, 1 H), 3.84–3.96 (m, 1 H), 3.80
(s, 3 H), 3.58 (q, J = 5.9 Hz, 2 H), 2.39 (dt, J = 5.6, 14.4 Hz, 1 H),
2.26 (dt, J = 6.6, 14.4 Hz, 1 H), 1.59 (s, 3 H), 1.36 (s, 3 H), 1.35 (s,
3 H), 1.13 (d, J = 6.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 158.51, 156.47, 136.20, 131.75,
128.42, 128.30, 128.19, 128.13, 113.77, 107.90, 84.09, 73.34,
67.31, 62.73, 59.04, 55.17, 48.98, 41.20, 27.30, 26.84, 20.08, 19.16.
Anal. Calcd for C23H27NO3: C, 75.59; H, 7.45; N, 3.83. Found: C,
75.67; H, 7.48; N, 3.90.
(S)-3-[(Benzyloxycarbonyl)(4-methoxybenzyl)amino]-3-meth-
ylhex-4E-en-1-ol (11)
A solution of 9-BBN-H (244 mg, 2.01 mmol) in THF (3 mL) was
added slowly to a solution of 10 (488 mg, 1.34 mmol) in THF (1.5
mL) at 0 °C and the mixture was heated at 60 °C for 2.5 h. Cooling
to 0 °C again, 3.0 M aq NaOAc (1.34 mL, 4.0 mmol) and 30% H2O2
(1.21 mL, 10.7 mmol) were added and the mixture was stirred at r.t.
for 10 min and then at 60 °C for 1 h. After cooling to r.t., the mixture
was extracted with Et2O. The combined organic layers were washed
with brine and dried (MgSO4). After removal of the solvent in vac-
uo, the crude product was purified by flash chromatography (silica
gel, PE–EtOAc 3:1 → 2:1) to afford the desired product 11 as a col-
orless oil; yield: 415 mg (81%).
Anal. Calcd for C26H35NO6: C, 68.25; H, 7.71; N, 3.06. Found: C,
68.45; H, 7.67; N, 3.07.
Second eluted acetonide 13b
Colorless oil.
Yield: 46 mg (30%).
[a]D25 +39.23 (c 1.28, CHCl3).
Rf = 0.33 (hexanes–EtOAc, 1:1).
IR (film): 3474, 2985, 2835, 1695, 1613, 1513, 1395 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.22–7.36 (m, 5 H), 7.17 (d, J =
8.8 Hz, 2 H), 6.82 (d, J = 8.5 Hz, 2 H), 5.18 (d, J = 12.5 Hz, 1 H),
5.12 (d, J = 12.7 Hz, 1 H), 4.85 (d, J = 17.1 Hz, 1 H), 4.39 (d, J =
7.8 Hz, 1 H), 4.36 (d, J = 17.1 Hz, 1 H), 3.82–3.96 (m, 1 H), 3.79
(s, 3 H), 3.46–3.63 (m, 2 H), 2.80–2.96 (m, 1 H), 1.58–1.76 (m, 1
H), 1.39 (s, 3 H), 1.38 (s, 3 H), 1.33 (s, 3 H), 1.31 (d, J = 5.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 158.24, 156.54, 136.51, 132.64,
128.35, 127.87, 127.72, 113.63, 107.60, 85.32, 73.13, 66.90, 61.95,
59.01, 55.16, 49.35, 39.30, 27.36, 26.93, 20.26, 20.07.
[a]D23 –1.75 (c 1.20, CHCl3).
Rf = 0.47 (hexanes–EtOAc, 1:1).
IR (film): 3449, 2937, 2836, 1698, 1612, 1513, 1454, 1397, 1247
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.20–7.36 (m, 5 H), 7.10 (d, J =
8.8 Hz, 2 H), 6.82 (d, J = 8.8 Hz, 2 H), 5.60 (d, J = 15.9 Hz, 1 H),
5.48 (dq, J = 5.9, 15.7 Hz, 1 H), 5.13 (s, 2 H), 4.55 (d, J = 16.4 Hz,
1 H), 4.42 (d, J = 16.4 Hz, 1 H), 3.80 (s, 3 H), 3.60 (m, 2 H), 2.26
(m, 2 H), 1.63 (d, J = 5.9 Hz, 3 H), 1.44 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 158.24, 156.54, 136.62, 136.28,
132.35, 128.34, 127.82, 123.40, 113.63, 66.86, 61.91, 59.53, 55.17,
48.86, 41.89, 24.37, 17.78.
Anal. Calcd for C26H35NO6: C, 68.25; H, 7.71; N, 3.06. Found: C,
68.07; H, 7.66; N, 3.04.
Benzyl (4-Methoxybenzyl)((1S)-1-methyl-3-oxo-1-{(4S,5S)-
2,2,5-trimethyl[1,3]dioxolan-4-yl}propyl)carbamate (14a, from
the First Eluted Acetonide 13a)
Anal. Calcd for C23H29NO4: C, 72.04; H, 7.62; N, 3.65. Found: C,
71.92; H, 7.69; N, 3.57.
Dess–Martin periodinane (177 mg, 0.42 mmol) was added to a so-
lution of the first eluted acetonide 13a (128 mg, 0.28 mmol) in
CH2Cl2 (3 mL) and the mixture was stirred at ambient temperature
for 15 min before the entire mixture was transferred to a flash col-
umn and eluted (hexanes–EtOAc, 4:1) to afford 14a as a colorless
oil; yield: 124 mg (97%).
Benzyl [(1S)-3-Hydroxy-1-methyl-1-(2,2,5-trimethyl[1,3]diox-
olan-4-yl)propyl](4-methoxybenzyl)carbamate (13a and 13b)
A solution of 4% OsO4 in H2O (0.11 mL, 0.017 mmol) was added
to a solution of 11 (129 mg, 0.336 mmol), NMO (59 mg, 0.504
mmol), and DABCO (56 mg, 0.504 mmol) in acetone (2.4 mL) and
H2O (0.6 mL) at 0 °C. The solution was stirred at r.t. overnight be-
fore sat. NaHSO3 (0.4 mL) was added and the mixture stirred for a
further 10 min. The mixture was diluted with brine and extracted
with EtOAc. The combined organic layers were washed with brine
and dried (MgSO4), and the solvent was removed in vacuo to afford
a 2:1 mixture of triol 12a/12b. The mixture was dissolved in ace-
tone (1.6 mL) and PTSA·H2O (3.0 mg, 0.016 mmol) and 2,2-
dimethoxypropane (66 mg, 78 mL, 0.63 mmol) were added. The
mixture was stirred at ambient temperature overnight before
quenching with sat. NaHCO3. The aqueous layer was extracted with
Rf = 0.60 (hexanes–EtOAc, 1:1).
IR (film): 2985, 2935, 1717, 1694, 1623, 1512, 1247 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.64 (t, J = 2.5 Hz, 1 H). 7.24–7.40
(m, 5 H), 7.10 (d, J = 8.8 Hz, 2 H), 6.81 (d, J = 8.8 Hz, 2 H), 5.19
(d, J = 12.0 Hz, 1 H), 5.14 (d, J = 12.0 Hz, 1 H), 4.84 (d, J = 16.6
Hz, 1 H), 4.49 (d, J = 7.6 Hz, 1 H), 4.48 (d, J = 16.6 Hz, 1 H), 3.76–
3.92 (m, 1 H), 3.79 (s, 3 H), 3.24 (dd, J = 2.2, 16.4 Hz, 1 H), 2.96
(dd, J = 2.3, 16.0 Hz, 1 H), 1.41 (s, 3 H), 1.35 (s, 3 H), 1.33 (s, 3 H),
1.11 (d, J = 5.9 Hz, 3 H).
Synthesis 2005, No. 19, 3335–3345 © Thieme Stuttgart · New York

PAPER
Ring Opening of Isoprene Monoxide – Asymmetric Synthesis of Branched Amino Sugars
3343
13C NMR (75 MHz, CDCl3): d = 183.05, 158.66, 156.21, 136.05,
131.30, 128.48, 128.26, 128.21, 128.14, 113.91, 108.37, 83.36,
73.13, 67.49, 61.68, 55.19, 50.61, 48.91, 27.31, 26.71, 20.34, 20.02.
[a]D25 +8.36 (c 4.26, CHCl3).
IR (film): 3493, 1685, 1514, 1399, 1247, 1041 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.28–7.34 (m, 5 H), 7.14 (d, J =
8.5 Hz, 2 H), 6.82 (d, J = 8.8 Hz, 2 H), 5.20 (d, J = 12.5 Hz, 1 H),
5.13 (d, J = 12.2 Hz, 1 H), 5.01 (dd, J = 1.0, 5.4 Hz, 1 H), 4.92 (d,
J = 17.5 Hz, 1 H), 4.59 (d, J = 17.1 Hz, 1 H), 4.30 (s, 1 H), 4.06–
4.16 (m, 1 H), 3.79 (s, 3 H), 3.37 (s, 3 H), 2.70 (dd, J = 1.0, 14.7 Hz,
1 H), 1.89 (d, J = 10.0 Hz, 1 H), 1.79 (dd, J = 5.4, 14.9 Hz, 1 H),
1.41 (s, 3 H), 1.18 (br s, 3 H).
13C NMR (100 MHz, CDCl3): d = 158.45, 156.35, 136.36, 131.19,
128.44, 128.16, 128.09, 128.01, 113.78, 103.22, 88.97, 67.19,
66.49, 65.98, 55.21, 54.84, 48.56, 44.67, 22.94, 22.14.
Anal. Calcd for C26H33NO6: C, 68.55; H, 7.30; N, 3.07. Found: C,
68.56; H, 7.18; N, 3.08.
Benzyl (4-Methoxybenzyl)((1S)-1-methyl-3-oxo-1-{(4R,5R)-
2,2,5-trimethyl[1,3]dioxolan-4-yl}propyl]carbamate (14b, from
the Second Eluted Acetonide 13b)
Dess–Martin periodinane (101 mg, 0.24 mmol) was added to a so-
lution of the second eluted acetonide 13b (72 mg, 0.16 mmol) in
CH2Cl2 (2 mL) and the mixture was stirred at ambient temperature
for 15 min before the entire mixture was transferred to a flash col-
umn and eluted (hexanes–EtOAc 4:1) to afford 14b as a colorless
oil; yield: 70 mg (98%).
Anal. Calcd for C24H31NO6 + 3 wt% CH2Cl2: C, 65.52; H, 7.12; N,
3.16. Found: C, 65.80; H, 6.85; N, 3.26.
[a]D28 +24.50 (c 0.96, CHCl3).
(R)-1-{(2R,3S)-3-[(Benzyloxycarbonyl)(4-methoxybenzyl)ami-
no]-5-methoxy-3-methyltetrahydrofuran-2-yl}ethanol (15b1
and 15b2)
Rf = 0.49 (hexanes–EtOAc, 2:1).
IR (film): 2986, 2935, 1722, 1694, 1613, 1514, 1247 cm–1.
To the solution of 14b (403 mg, 0.885 mmol) in MeOH (9 mL) was
added PTSA·H2O (34 mg, 0.18 mmol). The mixture was stirred
overnight and quenched with sat. aq NaHCO3. The aqueous layer
was extracted with EtOAc and the combined organic layers were
washed with brine and dried (MgSO4). The two anomers were iso-
lated by flash chromatography (silica gel, PE–EtOAc 4:1 → 3:1).
1H NMR (300 MHz, CDCl3): d = 9.62 (t, J = 2.4 Hz, 1 H), 7.20–7.36
(m, 5 H), 7.13 (d, J = 8.8 Hz, 2 H), 6.82 (d, J = 8.5 Hz, 2 H), 5.16
(d, J = 12.5 Hz, 1 H), 5.10 (d, J = 12.5 Hz, 1 H), 4.78 (d, J = 17.1
Hz, 1 H), 4.47 (d, J = 17.1 Hz, 1 H), 4.29 (d, J = 8.1 Hz, 1 H), 3.90–
4.00 (m, 1 H), 3.79 (s, 3 H), 3.72–3.82 (m, 1 H), 2.22 (dd, J = 2.7,
15.6 Hz, 1 H), 1.49 (s, 3 H), 1.37 (s, 3 H), 1.36 (s, 3 H), 1.24 (d, J =
5.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 19.95, 21.64, 26.80, 27.33, 48.74,
49.16, 55.19, 60.77, 67.23, 72.96, 84.91, 107.97, 113.73, 127.84,
127.99, 128.39, 131.73, 136.17, 156.33, 158.40, 200.53.
First eluted anomer 15b1
Colorless oil.
Yield: 163 mg (43%).
[a]D24 –20.29 (c 4.3, CHCl3).
Anal. Calcd for C26H33NO6: C, 68.55; H, 7.30; N, 3.07. Found: C,
68.56; H, 7.18; N, 3.08.
IR (film): 3484, 1693, 1612, 1514, 1460, 1400, 1365, 1300, 1248,
1175, 1144, 1104, 1031, 1002, 950 cm–1.
(S)-1-{(2S,3S)-3-[(Benzyloxycarbonyl)(4-methoxybenzyl)ami-
no]-5-methoxy-3-methyltetrahydrofuran-2-yl}ethanol (15a1
and 15a2)
To the solution of 14a (509 mg, 1.12 mmol) in MeOH (10 mL) was
added PTSA·H2O (41 mg, 0.22 mmol). The mixture was stirred
overnight and quenched with sat. aq NaHCO3. The aqueous layer
was extracted with EtOAc and the combined organic layers were
washed with brine and dried (MgSO4). The two anomers were iso-
lated by flash chromatography (silica gel, PE–EtOAc 3:1).
1H NMR (500 MHz, CDCl3): d = 7.16–7.38 (m, 7 H), 6.82 (d, J =
8.3 Hz, 2 H), 5.14 (AB, 2 H), 4.97 (br s, 1 H), 4.84 (d, J = 16.2 Hz,
1 H), 4.39 (d, J = 16.5 Hz, 1 H), 4.33 (s, 1 H), 3.77–3.86 (m, 1 H),
3.79 (s, 3 H), 3.45 (s, 3 H), 2.84 (d, J = 12.0 Hz, 1 H), 2.59 (d, J =
8.7 Hz, 1 H), 1.99 (dd, J = 6.1, 12.7 Hz, 1 H), 1.32 (s, 3 H), 1.21 (s,
3 H).
13C NMR (125 MHz, CDCl3): d = 158.58, 156.10, 136.70, 130.82,
128.51, 128.50, 127.94, 127.78, 113.69, 104.23, 89.75, 67.19,
66.03, 65.70, 55.92, 55.19, 49.54, 43.25, 21.57, 21.03.
First eluted anomer 15a1
Colorless oil.
Anal. Calcd for C24H31NO6: C, 67.11; H, 7.27; N, 3.26. Found: C,
66.91; H, 7.12; N, 3.25.
Yield: 150 mg (31%).
[a]D25 –35.08 (c 10.2, CHCl3).
Second eluted anomer 15b2
Colorless oil.
IR (film): 3463, 1694, 1613, 1514, 1456, 1397, 1357, 1297, 1248,
1190, 1146, 1098, 1046, 970, 912, 841, 776, 738, 699 cm–1.
Yield: 200 mg (53%).
[a]D24 –53.40 (c 4.1, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.25–7.35 (m, 5 H), 7.13 (d, J =
8.5 Hz, 2 H), 6.86 (d, J = 8.8 Hz, 2 H), 5.17 (d, J = 12.5 Hz, 1 H),
5.12 (d, J = 12.5 Hz, 1 H), 4.60 (t, J = 5.2 Hz, 1 H), 4.56 (d, J = 9.8
Hz, 2 H), 3.81–3.89 (m, 1 H), 3.79 (s, 3 H), 3.36 (s, 3 H), 3.02 (d,
J = 11.2 Hz, 1 H), 2.81 (dd, J = 6.1, 15.4 Hz, 1 H), 1.93 (dd, J = 4.9,
15.4 Hz, 1 H), 1.62 (s, 3 H), 1.18 (d, J = 6.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 158.55, 156.23, 136.30, 128.42,
127.98, 127.88, 127.36, 113.95, 105.06, 89.76, 69.26, 67.10, 65.80,
55.69, 55.20, 48.43, 44.30, 21.52, 20.36.
IR (film): 3498, 1692, 1613, 1514, 1460, 1401, 1358, 1298, 1245,
1200, 1175, 1142, 1111, 1062, 1039, 1006 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.28–7.38 (m, 5 H), 7.20 (d, J =
8.1 Hz, 2 H), 6.83 (d, J = 8.7 Hz, 2 H), 5.19 (d, J = 12.3 Hz, 1 H),
5.15 (d, J = 12.2 Hz, 1 H), 5.03 (d, J = 6.7 Hz, 1 H), 4.60 (d, J = 16.5
Hz, 1 H), 4.49 (d, J = 16.1 Hz, 1 H), 4.18 (br s, 1 H), 3.78–3.88 (m,
1 H), 3.78 (s, 3 H), 3.34 (s, 3 H), 2.79 (dd, J = 6.8, 12.1 Hz, 1 H),
1.73 (d, J = 12.2 Hz, 1 H), 1.52 (s, 3 H), 1.10 (br s, 3 H).
13C NMR (125 MHz, CDCl3): d = 171.15, 158.70, 156.50, 136.05,
131.37, 128.52, 128.36, 128.21, 114.00, 104.41, 90.71, 67.55,
66.56, 65.39, 55.40, 55.20, 49.63, 43.57, 21.03 (2 C).
Anal. Calcd for C24H31NO6: C, 67.11; H, 7.27; N, 3.26. Found: C,
66.84; H, 7.15; N, 3.24.
Second eluted anomer 15a2
Colorless oil.
Anal. Calcd for C24H31NO6: C, 67.11; H, 7.27; N, 3.26. Found: C,
66.90; H, 7.14; N, 3.25.
Yield: 225 mg (47%).
Synthesis 2005, No. 19, 3335–3345 © Thieme Stuttgart · New York

3344
B. M. Trost et al.
PAPER
(2R,3R,4S,6S)-6-Methoxy-4-(4-methoxybenzylamino)-2,4-di-
1-[(3S)-3-Amino-5-methoxy-3-methyltetrahydrofuran-2-
yl]ethanol (16)
methyltetrahydropyran-3-ol (17)
The solution of 15 in MeOH (0.05 M) with Pd(OH)2/C (20 wt% on
dry base, <50 wt% H2O, 0.20 equiv) was stirred under 35 psi H2 for
24 h. The mixture was filtered (washed with MeOH) and the solvent
was removed in vacuo. The crude product was purified by flash
chromatography (silica gel, EtOAc–MeOH–Et3N 100:5:10) to af-
ford the desired product 16 as a white wax-like solid.
Acetyl chloride (110 mg, 0.1 mL, 1.41 mmol) was added to MeOH
(2 mL). After stirring for 15 min, the solution was added to 14b (46
mg, 0.101 mmol). The solution was stirred for 2.5 d and quenched
with sat. aq NaHCO3. After extraction with EtOAc, the organic lay-
ers were washed with brine and dried (Na2SO4). After removal of
the solvent, the crude product was purified by flash chromatography
(silica gel, PE–EtOAc 2:1, with 5 vol% Et3N) to afford the desired
product 17 as a single diastereomer; yield: 17 mg (57%).
16a2: Following the above procedure, compound 15a2 was con-
verted into 16a2 with the following quantities of reagents and sol-
vent: 15a2 (42 mg, 0.098 mmol), Pd(OH)2/C (20 wt% on dry base,
<50 wt% H2O, 14 mg, 9.8 mmol), and MeOH (2.0 mL) under 35 psi
H2. The reaction was complete in 20 h and the crude product was
purified by flash chromatography (silica gel, EtOAc–MeOH–Et3N
100:5:10) to afford the desired compound 16a2; yield: 14 mg
(82%).
[a]D24 = +100.73 (c 1.2, CHCl3).
IR (film): 3432, 3344, 1513, 1457, 1247, 1176, 1155, 1117, 1045,
997, 780 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.25 (d, J = 8.9 Hz, 2 H), 6.86 (d,
J = 8.7 Hz, 2 H), 4.74 (d, J = 4.2 Hz, 1 H), 4.21 (q, J = 6.6 Hz, 1 H),
3.80 (s, 3 H), 3.73 (d, J = 11.6 Hz, 1 H), 3.58 (d, J = 11.6 Hz, 1 H),
3.33 (s, 3 H), 3.27 (d, J = 7.2 Hz, 1 H), 1.87 (d, J = 14.8 Hz, 1 H),
1.79 (br d, J = 8.8 Hz, 1 H), 1.70 (dd, J = 4.4, 14.6 Hz, 1 H), 1.23
(d, J = 6.5 Hz, 3 H), 1.22 (s, 3 H).
[a]D24 +132.03 (c 1.37, CHCl3).
IR (film): 3354 (br), 1648, 1602, 1450, 1381, 1199, 1147, 1098,
1034, 997, 923, 869, 842 cm–1.
1H NMR (500 MHz, CDCl3): d = 5.02 (dd, J = 2.0, 5.5 Hz, 1 H),
3.81 (dq, J = 4.4, 6.3 Hz, 1 H), 3.61 (d, J = 4.3 Hz, 1 H), 3.39 (s, 3
H), 2.16 (dd, J = 5.6, 13.3 Hz, 1 H), 1.89 (br s, 3 H), 1.86 (dd, J =
2.1, 13.4 Hz, 1 H), 1.26 (d, J = 6.5 Hz, 3 H), 1.25 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 103.94, 90.72, 66.63, 58.08,
55.09, 49.75, 23.46, 20.60.
13C NMR (125 MHz, CDCl3): d = 158.47, 133.34, 129.35, 113.79,
99.23, 73.44, 62.03, 55.26, 55.14, 54.21, 45.79, 33.10, 23.11, 17.13.
(2R,3R,4S,6S)-4-Amino-6-methoxy-2,4-dimethyltetrahydropy-
ran-3-ol (18)
A solution of 17 (32 mg, 0.108 mmol) and suspension of Pd(OH)2/
C (20 wt%, with 50 wt% H2O, 15 mg, 0.011 mmol) in MeOH (2
mL) was stirred under 50 psi H2 at r.t. for 20 h. After filtration and
removal of the solvent in vacuo, the residue was purified by flash
chromatography (silica gel, EtOAc–MeOH–Et3N 100:5:10) to af-
ford the desired product 18; yield: 20 mg (100%).
[a]D25 +127.27 (c 0.9, MeOH).
IR (film): 3366, 1122, 1050, 997 cm–1.
1H NMR (500 MHz, CDCl3): d = 4.74 (d, J = 4.4 Hz, 1 H), 4.26 (q,
J = 6.6 Hz, 1 H), 3.35 (s, 3 H), 3.01 (s, 1 H), 1.93 (br s, 3 H), 1.85
(dd, J = 4.4, 14.4 Hz, 1 H), 1.54 (d, J = 14.4 Hz, 1 H), 1.25 (d, J =
6.6 Hz, 3 H), 1.15 (s, 3 H).
1H NMR (500 MHz, CDCl3 with stoichiometric TMSCl and D2O):
d = 4.83 (d, J = 3.3 Hz, 1 H), 4.04 (q, J = 6.1 Hz, 1 H), 3.63 (s, 1 H),
3.40 (s, 3 H), 2.04 (dd, J = 3.8, 14.9 Hz, 1 H), 1.78 (d, J = 14.8 Hz,
1 H), 1.46 (s, 3 H), 1.31 (d, J = 6.3 Hz, 3 H).
1H NMR (500 MHz, pyridine-d5): d = 4.85 (d, J = 3.9 Hz, 1 H), 4.47
(q, J = 6.6 Hz, 1 H), 3.32 (s, 3 H), 3.29 (s, 1 H), 2.19 (dd, J = 4.4,
13.9 Hz, 1 H), 1.69 (d, J = 13.9 Hz, 1 H), 1.48 (d, J = 6.5 Hz, 3 H),
1.40 (s, 3 H).
1H NMR (500 MHz, MeOH-d4): d = 4.72 (d, J = 3.5 Hz, 1 H), 4.13
(q, J = 6.6 Hz, 1 H), 3.33 (s, 3 H), 3.03 (s, 1 H), 1.87 (dd, J = 4.2,
14.4 Hz, 1 H), 1.53 (d, J = 14.4 Hz, 1 H), 1.21 (d, J = 6.6 Hz, 3 H),
1.13 (s, 3 H).
16b1: Following the above procedure, compound 15b1 was con-
verted into 16b1 with the following quantities of reagents and sol-
vent: 15b1 (43 mg, 0.100 mmol), Pd(OH)2/C (20 wt% on dry base,
<50 wt% H2O, 14 mg, 0.010 mmol), and MeOH (2.0 mL) under 35
psi H2. The reaction was complete in 25 h and the crude product was
purified by flash chromatography (silica gel, EtOAc–MeOH–Et3N
100:5:10) to afford the desired compound 16b1; yield: 13 mg
(74%).
[a]D24 +55.66 (c 1.3, CHCl3).
IR (film): 3375, 1598, 1439, 1377, 1203, 1140, 1095, 1027, 996,
924 cm–1.
1H NMR (500 MHz, CDCl3): d = 5.02 (dd, J = 1.9, 5.9 Hz, 1 H),
4.00 (dq, J = 2.3, 6.6 Hz, 1 H), 3.43 (s, 3 H), 3.42 (d, J = 2.4 Hz, 1
H), 2.43 (br s, 3 H), 2.16 (dd, J = 5.9, 13.4 Hz, 1 H), 1.93 (dd, J =
1.9, 13.5 Hz, 1 H), 1.28 (s, 3 H), 1.27 (d, J = 6.6 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 104.04, 89.24, 66.13, 58.26,
55.18, 49.17, 27.29, 20.39.
16b2: Following the above procedure, compound 15b2 was con-
verted into 16b2 with the following quantities of reagents and sol-
vent: 15b2 (38 mg, 0.088 mmol), Pd(OH)2/C (20 wt% on dry base,
<50 wt% H2O, 12 mg, 8.8 mmol), and MeOH (1.7 mL) under 35 psi
H2. The reaction was complete in 27 h and the crude product was
purified by flash chromatography (silica gel, EtOAc–MeOH–Et3N
100:5:10) to afford the desired compound 16b2; yield: 13 mg
(84%).
13C NMR (125 MHz, CDCl3): d = 99.18, 76.51, 62.17, 55.14, 50.29,
36.77, 27.84, 17.10.
[a]D24 –116.81 (c 1.3, CHCl3).
IR (film): 3362 (br), 1438, 1376, 1206, 1143, 1103, 1032, 974 cm–1.
Anal. Calcd for C8H17NO3: C, 54.84; H, 9.78; N, 7.99. Found: C,
54.68; H, 9.53; N, 7.90.
1H NMR (500 MHz, CDCl3): d = 5.14 (dd, J = 3.3, 5.7 Hz, 1 H),
4.05 (dq, J = 2.0, 6.5 Hz, 1 H), 3.44 (d, J = 2.0 Hz, 1 H), 3.39 (s, 3
H), 2.32 (br s, 3 H), 2.11 (dd, J = 5.7, 13.8 Hz, 1 H), 1.96 (dd, J =
3.3, 13.7 Hz, 1 H), 1.34 (s, 3 H), 1.31 (d, J = 6.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 102.95, 85.50, 65.51, 59.20,
55.24, 50.85, 26.52, 20.40.
(3aS,4S,6R,7aS)-6-Methoxy-1-(4-methoxybenzyl)-4,7a-dimeth-
ylhexahydropyrano[4,3-d]oxazol-2-one (19)
Acetyl chloride (385 mg, 0.35 mL, 4.9 mmol) was added to MeOH
(7 mL). After stirring for 15 min, the solution was added to 15a2
(151 mg, 0.35 mmol). The solution was stirred for 5 d and most of
the solvent was removed in vacuo. Then, sat. aq NaHCO3 was added
and the mixture was extracted with EtOAc. The organic layers were
washed with brine and dried (Na2SO4). After removal of the solvent,
the crude product was purified by flash chromatography (silica gel,
Anal. Calcd for C8H17NO3: C, 54.84; H, 9.78; N, 7.99. Found: C,
55.04; H, 10.00; N, 8.15.
Synthesis 2005, No. 19, 3335–3345 © Thieme Stuttgart · New York

PAPER
Ring Opening of Isoprene Monoxide – Asymmetric Synthesis of Branched Amino Sugars
3345
PE–EtOAc 2:1) to afford the desired product 19 as a single diaste-
reomer (colorless oil); yield: 113 mg (100%).
References
(1) Trost, B. M.; McEachern, E. J.; Toste, F. D. J. Am. Chem.
Soc. 1998, 120, 12702.
(2) Trost, B. M.; McEachern, E. J. J. Am. Chem. Soc. 1999, 121,
8649.
(3) Trost, B. M.; Bunt, R. C.; Lemoine, R.; Calkins, T. L. J. Am.
Chem. Soc. 2000, 122, 5968.
(4) Larksarp, C.; Alper, H. J. Am. Chem. Soc. 1997, 119, 3709.
(5) Trost, B. M.; Jiang, C. J. Am. Chem. Soc. 2001, 123, 12907.
(6) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121,
4545.
[a]D25 +27.60 (c 0.98, CHCl3).
IR (film): 1743, 1514, 1407, 1247, 1124, 1054 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.29 (d, J = 8.5 Hz, 2 H), 6.85 (d,
J = 8.8 Hz, 2 H), 4.46 (d, J = 15.4 Hz, 1 H), 4.21 (d, J = 15.4 Hz, 1
H), 4.18 (t, J = 5.7 Hz, 1 H), 3.90–3.94 (m, 2 H), 3.80 (s, 3 H), 3.22
(s, 3 H), 1.89 (dd, J = 5.4, 14.9 Hz, 1 H), 1.48 (dd, J = 6.1, 15.1 Hz,
1 H), 1.32 (d, J = 6.6 Hz, 3 H), 1.31 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 159.16, 157.76, 129.96, 129.50,
113.96, 96.96, 80.36, 62.86, 57.90, 55.25, 54.95, 43.67, 34.86,
25.90, 15.62.
(7) Yamada, S.; Terashima, S.; Achiwa, K. Chem. Pharm. Bull.
1965, 13, 751.
(8) Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J. M.;
Zurbano, M. M. J. Org. Chem. 1999, 64, 8220.
(9) (a) Smith, R. M.; Johnson, A. W.; Guthrie, R. D. J. Chem.
Soc., Chem. Commun. 1972, 361. (b) Johnson, A. W.;
Smith, R. M.; Guthrie, R. D. J. Chem. Soc., Perkin Trans. 1
1972, 2153. (c) Weringa, W. D.; Williams, D. H.; Feeney, J.;
Brown, J. P.; King, R. W. J. Chem. Soc., Perkin Trans. 1
1972, 443.
HRMS (EI): m/z calcd for C17H23NO5: 321.1576; found: 321.1574.
(3aS,4S,6R,7aS)-6-Methoxy-4,7a-dimethylhexahydropyra-
no[4,3-d]oxazol-2-one (20)
To the solution of 19 (16 mg, 0.050 mmol) in MeCN–H2O (1:1, 2
mL) was added CAN (71 mg, 0.13 mmol) at r.t. The solution was
stirred for 22 h and quenched with sat. aq NaHCO3. After extraction
with EtOAc, the organic layers were washed with brine and dried
(Na2SO4). The solvent was removed and the crude product was pu-
rified by flash chromatography (silica gel, PE–EtOAc 1:1 → 1:2) to
afford 20; yield: 5 mg (50%).
[a]D24 –11.25 (c 0.45, MeOH).
IR (film): 3298, 1749, 1056 cm–1.
1H NMR (500 MHz, CDCl3): d = 4.79 (t, J = 6.0 Hz, 1 H), 4.04 (d,
J = 1.7 Hz, 1 H), 3.97 (dq, J = 1.6, 6.6 Hz, 1 H), 3.38 (s, 3 H), 2.06
(dd, J = 5.6, 15.0 Hz, 1 H), 1.67 (dd, J = 6.6, 15.0 Hz, 1 H), 1.43 (s,
3 H), 1.32 (d, J = 6.6 Hz, 3 H).
(10) Harada, K.; Ito, S.; Suzuki, M. Chem. Pharm. Bull. 1982, 30,
4288.
(11) (a) Williams, D. H.; Bardsley, B. Angew. Chem. Int. Ed.
1999, 38, 1172. (b) Malabarba, A.; Nicas, T. I.; Thompson,
R. C. Med. Res. Rev. 1997, 17, 69.
(12) (a) Dyong, I.; Friege, H. Chem. Ber. 1979, 112, 3273.
(b) Dyong, I.; Friege, H.; Luftmann, H.; Merten, H. Chem.
Ber. 1981, 114, 2669. (c) Hauser, F. M.; Ellenberger, S. R.
J. Org. Chem. 1986, 51, 50. (d) Cutchins, W. W.;
McDonald, F. E. Org. Lett. 2002, 4, 749.
(13) (a) Thang, T. T.; Winternitz, F. J. Chem. Soc., Chem.
Commun. 1979, 153. (b) Thang, T. T.; Winternitz, F.
Tetrahedron Lett. 1980, 21, 4495. (c) Brimacombe, J. S.;
Mengech, A. S.; Rahman, K. M. M.; Tucker, L. C. N.
Carbohydr. Res. 1982, 110, 207. (d) Ahmad, H. I.;
Brimacombe, J. S.; Mengech, A. S.; Tucker, L. C. N.
Carbohydr. Res. 1981, 93, 288. (e) Klemer, A.; Wilbers, H.
Liebigs Ann. Chem. 1987, 815. (f) Greven, R.; Jutten, P.;
Scharf, H.-D. Carbohydr. Res. 1995, 275, 83. (g) Smith, G.
R.; Giuliano, R. M. Carbohydr. Res. 2000, 323, 208.
(h) Fronza, G.; Fuganti, C.; Grasselli, P.; Pedrocchi-Fantoni,
G. Tetrahedron Lett. 1981, 22, 5073. (i) Hamada, Y.;
Kawai, A.; Shioiri, T. Tetrahedron Lett. 1984, 25, 5413.
(j) Hamada, Y.; Kawai, A.; Matsui, T.; Hara, O.; Shioiri, T.
Tetrahedron 1990, 46, 4823. (k) Nicolaou, K. C.; Mitchell,
H. J.; van Delft, F. L.; Rubsam, F.; Rodriguez, R. M. Angew.
Chem. Int. Ed. 1998, 37, 1871. (l) Nicolaou, K. C.; Baran, P.
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39, 2525. (m) Parker, K. A.; Chang, W. Org. Lett. 2003, 5,
3891.
1H NMR (500 MHz, D2O): d = 5.88 (br s, 1 H), 4.85 (dd, J = 5.7,
8.4 Hz, 1 H), 4.35 (d, J = 1.5 Hz, 1 H), 4.13 (dq, J = 1.5, 6.4 Hz, 1
H), 3.40 (s, 3 H), 2.20 (dd, J = 5.8, 15.3 Hz, 1 H), 1.70 (dd, J = 8.4,
15.3 Hz, 1 H), 1.39 (s, 3 H), 1.25 (d, J = 6.6 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 158.60, 97.19, 82.64, 63.44,
55.02, 54.71, 36.39, 28.28, 15.66.
(2S,3S,4S,6R)-4-Amino-6-methoxy-2,4-dimethyltetrahydropyr-
an-3-ol (21)
The solution of 20 (5 mg, 0.025 mmol) in 15% aq KOH (0.5 mL)
was refluxed for 2 h. After diluting with brine, the aqueous solution
was extracted with EtOAc thoroughly. The combined organic layers
were washed with brine and dried (Na2SO4). After removal of the
solvent, the residue was purified by flash chromatography (silica
gel, EtOAc–MeOH–Et3N 100:5:10) to afford known compound 21
as a colorless oil; yield: 3.5 mg (80%).
24
[a]D –105.12 (c 0.1, MeOH) {lit. [a]D –132 (c 1.4, MeOH)13g or
[a]D –118 (c 0.09, MeOH)9b}.
IR (film): 3357, 1726, 1287, 1126, 1051 cm–1.
(14) Ukai, T.; Kawazura, H.; Ishii, Y.; Bonnet, J. J.; Ibers, J. A. J.
Organomet. Chem. 1974, 65, 253.
1H NMR (500 MHz, CDCl3): d = 4.75 (d, J = 4.3 Hz, 1 H), 4.01 (q,
J = 6.4 Hz, 1 H), 3.32 (s, 3 H), 3.09 (s, 1 H), 1.83 (dd, J = 4.3, 13.9
Hz, 1 H), 1.59 (d, J = 13.8 Hz, 1 H), 1.37 (s, 3 H), 1.29 (d, J = 6.5
Hz, 3 H) [Lit.13g 1H NMR (300 MHz, CDCl3): d = 4.74 (d, J = 4.4
Hz, 1 H), 4.01 (q, J = 6.6 Hz, 1 H), 3.32 (s, 3 H), 3.02 (br, 1 H), 1.78
(dd, J = 4.4, 13.6 Hz, 1 H), 1.54 (d, J = 13.6 Hz, 1 H), 1.32 (s, 3 H),
1.29 (d, J = 6.6 Hz, 3 H)].
Acknowledgment
We thank the National Institutes of Health, General Medical Sci-
ences (GM-13598), and the National Science Foundation for their
generous support of our programs. Mass spectra were obtained from
the Mass Spectrometry Facility, University of San Francisco, sup-
ported by the NIH Division of Research Resources.
Synthesis 2005, No. 19, 3335–3345 © Thieme Stuttgart · New York