Asymmetric synthesis of protected 2-keto-1,3-diol and 1,2,3-triol building blocks bearing a quaternary stereogenic center

Article abstract of DOI:10.1055/s-2001-15236

The asymmetric synthesis of protected 2-keto-1,3-diols 5 and 1,2,3-triols 6 bearing a quaternary stereogenic center starting from 2,2-dimethyl-1,3-dioxan-5-one (1) is described. The stereogenic centers are generated by sequential α-alkylation of 1 using the SAMP/RAMP hydrazone method and stereoselective reduction of ketones 5 with L-selectride. The products are obtained in good yields and high diastereomeric and enantiomeric excesses.

Full text of DOI:10.1055/s-2001-15236

1406
PAPER
Asymmetric Synthesis of Protected 2-Keto-1,3-diol and 1,2,3-Triol Building
Blocks Bearing a Quaternary Stereogenic Center
A
symmetric Synth
i
esis of
e
Protected
2
t
-Keto-
e
r1,2,3-Triol
B
E
uilding Blocks nders,* Anja Nühring, Jan Runsink, Gerhard Raabe
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, 52074 Aachen, Germany
Fax +49(241)8888127; E-mail: Enders@RWTH-Aachen.de
Received 2 April 2001
diffraction (Figure).14 The structure showed the twist-boat
Abstract: The asymmetric synthesis of protected 2-keto-1,3-diols 5
conformation of the six-membered dioxane ring, and the
and 1,2,3-triols 6 bearing a quaternary stereogenic center starting
two methyl groups in cis-position. This meant that the
electrophilic attack is again from the lithium-coordinated
from 2,2-dimethyl-1,3-dioxan-5-one (1) is described. The stereo-
genic centers are generated by sequential -alkylation of 1 using the
SAMP/RAMP hydrazone method and stereoselective reduction of side and therefore consistent with a metallo-retentive
mechanism.11 Further, NOE data showed this to apply
also for hydrazones 4a, c–f. The alkylation of 3 with iso-
ketones 5 with L-selectride. The products are obtained in good
yields and high diastereomeric and enantiomeric excesses.
Keywords: 2-keto-1,3-diols, 1,2,3-triols, asymmetric synthesis,
quaternary stereogenic center, SAMP/RAMP hydrazones.
propyl iodide lead to a nearly 1:1 mixture of both possible
epimers 4b at position 4, the metallo-retentive and the in-
verse one (Table 1), which could be separated by column
chromatography. Apparently, a sterically hindered elec-
A common structural feature of a large variety of polyox- trophile leads to a diminished stereo differentiation.
ygenated biologically active compounds is a tertiary alco-
hol moiety with a methyl group as one of the substituents.
For example, it is found in many nucleosides, such as tra-
chycladine A and B1 or in sugars such as L-mycarose,2
part of the antibiotic erythromycin,3 or L-vancosamine,4
part of glycopeptide vancomycin.5 General procedures for
the enantioselective formation of this characteristic
moiety6 are the 1,2-addition to a prochiral ketone,7 the Ja-
cobsen epoxidation of alkenes8 with subsequent cleavage
or the Sharpless-dihydroxylation9 of trisubstituted alk-
enes. A common drawback of these reactions is the need
to synthesize pure E- or Z-alkenes and further, the reduc-
tive opening of an epoxide or the removal of a hydroxy
group.
We now describe an efficient diastereo- and enantioselec-
tive synthesis of protected 2-keto-1,3-diols and 1,2,3-tri-
ols starting from the readily available dihydroxy acetone
equivalent 1,3-dioxan-5-one (1)10 employing the SAMP/
RAMP-hydrazone method.11,12
As shown in Scheme 1, our synthesis starts from 1,3-diox-
an-5-one 1, which was synthesized according to a litera-
ture procedure.13 In the first step, this ketone was
transformed to the corresponding RAMP-hydrazone 2.
Two alkylations at the - and ’-position with methyl io-
dide led to the RAMP-hydrazone 3 with the two methyl
substituents in a trans-relationship. The key step in our
synthesis was a subsequent third metalation and alkyla-
tion of 3 to install the quaternary stereocenter. The smooth
metalation of 3 was achieved with tert-butyllithium; and
the alkylation with various electrophiles led to the -qua-
ternary hydrazones 4 in excellent yields and diastereomer-
ic excesses (Table 1). One of the hydrazones 4g was a
colorless crystalline solid and could be analyzed by X-ray
Scheme 1 Reagents and conditions: a) RAMP, benzene, reflux; b)
1) t-BuLi, THF, –78°C, 2) MeI, –100°C to r.t.; c) 1) t-BuLi, THF, –
78°C, 2) MeI, –100°C to r.t.; d) 1) t-BuLi, THF, –78°C, 2) RX, –
100°C to r.t.; e) O3, CH2Cl2, –78°C; f) L-selectride, THF, –78°C to
r.t.
As shown in Scheme 2, in the case of (R,S,R)-4b, there are
NOE correlations between the methyl group at C-6 and
the methine proton of the isopropyl substituent at C-4, be-
tween one of the methyl groups at C-2 and the methine
proton at C-6, which in turn correlates with one hydrogen
of the -N-CH2-group of the auxiliary. These relation-
ships indicated a trans-orientation of the two methyl
groups at C-4 and C-6. Similar NOE measurements on
Synthesis 2001, No. 9, 29 06 2001. Article Identifier:
1437-210X,E;2001,0,09,1406,1414,ftx,en;Z03901SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Asymmetric Synthesis of Protected 2-Keto-1,3-diol and 1,2,3-Triol Building Blocks
1407
Table 1 Synthesis of -Quaternary Hydrazones 4
4
a
R
X
Yield E/Z (%)a de (%)a
(%)
Allyl
Br
I
99
40
39
89
81
76d
80d
82
31
33
9:1
1:1
96
96
96
96
83
96
96
96
96
71
b (4R)b i-Pr
b (4S)b i-Pr
O
I
10:1
10:1
1:2
O
cc
d
e
f
n-Hex
I
O
(R O)2CH(CH2)2
TBSO(CH2)3
Bn
I
N
O
N
I
1:1
Br
Cl
–
2:1
g
h
i
BnOCH2
10:1
10:1
10:1
Figure Crystal structure of hydrazone 4g
CH3(CO)(CH2)2
CH3C(OH)
CH=CH2
–
Table 2 Synthesis of -Quaternary Ketones 5
5
R
Yield (%)
de (%)a
96
a Determined by 13C NMR spectroscopy.
bAfter chromatographic separation of the diastereomers.
c SAMP was used as chiral auxiliary.
a
Allyl
33
66
76
83
72
86
92
79
d The epimer at C-4 was obtained (approx. 10%) after chromato-
graphic separation.
b (R,R)
i-Pr
96
b (S,R)
i-Pr
96
cb
d
e
n-Hex
96
(R,R,R)-4b showed a cis-configuration of the methyl
groups at C-4 and C-6.
(R O)2CH(CH2)2
TBSO(CH2)3
Bn
83
96
It was also possible to trap the azaenolate of hydrazone 3
in a Michael addition with an , -unsaturated ketone. The
product obtained was a mixture of the 1,2- (4i) and 1,4-ad-
dition product (4h) (de = 71% and > 96%, respectively).
The NOE data of these compounds showed both to have
the two methyl groups in the trans-position, which meant
that the attack of the electrophile was not metallo-reten-
tive. Apparently, a different relative configuration is ob-
served with Michael acceptors as electrophiles in this
system.15
f
96
g
BnOCH2
96
a Determined by 13C NMR spectroscopy.
b SAMP was used as chiral auxiliary.
tive yields and excellent diastereomeric and enantiomeric
excesses (Table 3). The acetal moiety could be cleaved by
treatment with TFA. This reaction was very fast and in the
case of 6f lead to the 1,2,3-triol 7 (Scheme 3).
Oxidative cleavage of the hydrazones 4 with ozone af-
forded the ketones 5 in good yields (Table 2). Hydrolysis
of the C=N double bond either with CuCl2 or under acidic
conditions was not effective. In the former case, the reac-
tion times were too long causing partial epimerization,
and in the latter, the acetal moiety was cleaved under the
acidic conditions.
In summary, the procedure described offers an efficient
diastereo- and enantioselective entry to protected 1,3-di-
hydroxy-2-ketones and 1,2,3-triols bearing a quaternary
stereocenter. Using the SAMP-/RAMP-hydrazone meth-
od it is possible to build up different diastereomers and
enantiomers. We are now using this method to synthesize
complex natural products.
Finally, the ketones 5 were reduced using L-selectride to
yield the acetal-protected 1,2,3-triols 6 in nearly quantita-
Scheme 2
Scheme 3
Synthesis 2001, No. 9, 1406–1414 ISSN 0039-7881 © Thieme Stuttgart · New York

1408
D. Enders et al.
PAPER
N-[(2’R)-2’-(Methoxymethyl)tetrahydro-1’H-1’-pyrrolyl]-N-
Table 3 Synthesis of Protected 1,2,3-Triols 6
[(4R,6R)-2,2,4,6-tetramethyl-1,3-dioxan-5-ylidene]amine (3)
To a stirred solution of crude N-[(2'R)-2'-(methoxymethyl)tetrahy-
dro-1H-1-pyrrolyl]-N-[(4R)-2,2,4-trimethyl-1,3-dioxan-5-ylidene]-
amine (8.875 g, 34.62 mmol) in anhyd THF (70 mL) was slowly
added t-BuLi (23.80 mL, 38.08 mmol) at –78°C and stirring contin-
ued for 4 h. The mixture was cooled to –100 °C and MeI (2.60 mL,
41.54 mmol) was added dropwise. After stirring for 1.5 h at
–100 °C, the reaction mixture was allowed to warm to r.t. over 15
h, and quenched with pH 7 buffer (100 mL). The aqueous phase was
extracted with Et2O (1 L) and the organic phase washed with brine
(100 mL). The combined aqueous phases were extracted with Et2O
(100 mL) and the combined organic layers were dried (MgSO4). Re-
moval of the solvent under reduced pressure and purification of the
residue by flash chromatography (silica gel; Et2O–pentane, 1:4) af-
forded 3 as a colorless oil; yield: 7.014 g (75% for two steps);
[ ]D26 = –105.3 (c 1.04, CHCl3). Further analytical data were consis-
tent with the literature data.10,12f
6
cb
d
e
R
Yield (%) de (%)a
ee (%)
96
n-Hex
96
96
83
96
96
60c
(R O)2CH(CH2)2 96
96
TBSO(CH2)3
Bn
quant.
96
f
76
94
96
g
BnOCH2
96
a Determined by 13C NMR spectroscopy.
b SAMP was used as chiral auxiliary.
c NaBH4 was used as reducing agent; the two epimers at C-5 were ob-
tained in a 4:1 ratio.
(E)-N-{(4R,6R)-4-Allyl-2,2,4,6-tetramethyl-1,3-dioxan-5-
ylidene}-N-[(2’R)-2’-(methoxymethyl)tetrahydro-1’H-1’-
pyrrolyl]amine (4a); Typical Procedure
All reagents were of commercial quality used from freshly opened
containers. Solvents were dried and purified by conventional meth-
ods prior to use. THF was freshly distilled under Ar from Na/Pb al-
loy. t-BuLi (1.5 M in hexane) and L-selectride (1 M in THF) were
purchased from Merck, Darmstadt. Preparative column chromatog-
raphy: Merck silica gel 60, particle size 0.040–0.063 mm (230–400
mesh, flash). Analytical TLC: Silica gel 60 F254 plates, Merck,
Darmstadt. Optical rotation values were measured using a Perkin–
Elmer P 241 polarimeter, solvents used were of Merck UVASOL
quality. Microanalyses were obtained with a Heraeus CHN-O-
RAPID elemental analyzer. Mass spectra: Varian MAT 212 (EI 70
To a stirred solution of 3 (1.352 g, 5.00 mmol) in anhyd THF (10
mL), t-BuLi (4.70 mL, 7.50 mmol) was slowly added at –78°C. Af-
ter stirring for 4 h, the reaction mixture was cooled to –100°C, allyl
bromide (0.72 mL; 8.50 mmol) was added dropwise, and the mix-
ture was stirred for another hour. Then the mixture was allowed to
warm to r.t. over 15 h and quenched with pH 7 buffer (30 mL). The
aqueous phase was extracted with Et2O (300 mL) and the organic
phase washed with brine (30 mL). The combined aqueous phases
were extracted with Et2O (30 mL) and the combined organic layers
were dried (MgSO4). Removal of the solvent under reduced pres-
sure and purification of the residue by flash chromatography (SiO2;
Et2O–pentane, 1:4) afforded 4a as a pale yellow oil; yield: 1.543 g
(99%).
1
eV). IR spectra: Perkin–Elmer FT/IR 1750. H NMR spectra (300
MHz, 400 MHz and 500 MHz), 13C NMR (75 MHz, 100 MHz and
125 MHz): Varian Gemini 300, Varian Inova 400 or Varian Unity
500 (solvent C6D6, TMS as internal standard). Reactions were con-
ducted using standard Schlenk techniques under Ar at r.t.
[ ]D25 = –53.8 (c 1.32, CHCl3).
IR (film): = 2982, 2937, 2873, 2828, 1378, 1370, 1254, 1232,
1206, 1182, 1168, 1153, 1107, 1021, 1001, 913 cm–1.
N-(2,2-Dimethyl-1,3-dioxan-5-ylidene)-N-[(2’R)-2-
(methoxymethyl)tetrahydro-1’H-1’-pyrrolyl]amine (2)
A stirred solution of 2,2-dimethyl-1,3-dioxan-5-one (1) (15.417 g,
77.00 mmol, w = 65%) and (–)-(R)-1-amino-2-methoxymethylpyr-
rolidine (RAMP; 12.151 g, 70.00 mmol, w = 75%) in benzene (200
mL) was refluxed for 16 h using a Dean-Stark trap. The solvent was
removed under reduced pressure and the crude hydrazone was ob-
tained as a brown oil. High vacuum distillation (92°C/0.015 mbar)
afforded 2 as an orange oil; yield: 15.732 g (93%); [ ]D26 = –225.8
(c 1.26, CHCl3). Further analytical data were consistent with the lit-
erature data.10,12f
1H NMR (300 MHz): = 1.36 [d, 3H, J = 0.55 Hz, C(CH3)CH3],
1.46 [d, 3H, J = 0.55 Hz, C(CH3)CH3], 1.54 (d, 3H, J = 6.05 Hz,
CHCH3), 1.66 (s, 3H, CCH3), 1.50–1.76 (m, 4H, NCH2CH2,
NCHCH2), 1.96 (m, 1H, CHHCH=CH2), 2.50 (m, 1H, NCHcis
Htrans), 2.77 (m, 1H, NCHcisHtrans), 2.89 (m, 1H, CHHCH=CH2),
3.12 (s, 3H, OCH3), 3.16 (m, 1H, NCH), 3.18 (m, 1H, CHHOCH3),
3.34 (m, 1H, CHHOCH3), 4.43 (q, 1H, J = 6.32 Hz, CHCH3), 5.13–
5.28 (m, 2H, CH=CH2), 6.07 (m, 1H, CH=CH2).
13C NMR (75 MHz): = 17.63 (CHCH3), 21.96 (NCH2CH2), 26.08
(CCH3), 26.78 (NCHCH2), 28.57, 29.22 [C(CH3)2], 43.70
(CH2CH=CH2), 57.66 (NCH), 58.65 (NCH2), 67.39, 67.70 (OCH3,
CHCH3), 74.86 (CH2OCH3), 78.68 (CCH3), 100.13 [C(CH3)2],
117.31 (CH=CH2), 135.24 (CH=CH2), 175.01 (C=N).
N-[(2’R)-2’-(Methoxymethyl)tetrahydro-1H-1-pyrrolyl]-N-
[(4R)-2,2,4-trimethyl-1,3-dioxane-5-ylidene]amine
To a stirred solution of 2 (8.484 g, 35.00 mmol) in anhyd THF (70
mL) was slowly added t-BuLi (24.10 mL, 38.50 mmol) at –78°C
and stirring continued for 4 h. The mixture was cooled to –100 °C
and MeI (2.62 mL, 42.00 mmol) was added dropwise. After stirring
for 1.5 h at –100 °C, the reaction mixture was allowed to warm to
r.t. over 15 h, and quenched with pH 7 buffer (100 mL). The aque-
ous phase was extracted with Et2O (1 L) and the organic phase
washed with brine (100 mL). The combined aqueous phases were
extracted with Et2O (100 mL) and the combined organic layers were
dried (MgSO4). Removal of the solvent under reduced pressure
gave the crude product as a yellow oil, which was used in the next
step without further purification.
MS: m/z (%) = 295 (4, M+ – CH3), 265 (M+ – CH2OCH3), 212 (12),
211 (100, M+ – C3H5 – C3H6O), 182 (10), 139 (56), 114 (57), 113
(16), 112 (60), 94 (19), 85 (11), 70 (58), 59 (69, C3H7O+), 55 (13),
+
54 (10), 45 (29, CH2OCH3 ).
Anal. Calcd for C17H30N2O3 (310.4): C, 65.77; H, 9.74; N, 9.02.
Found: C, 65.82; H, 9.53; N, 9.34.
(E/Z)-N-{(4R,6R)-4-Isopropyl-2,2,4,6-tetramethyl-1,3-dioxan-5-
ylidene}-N-[(2'R)-2'-(methoxymethyl)tetrahydro-1'H-1'-pyrrolyl-
]amine (4b)
Prepared from 3 (0.811 g, 3.00 mmol), anhyd THF (6 mL), t-BuLi
(2.80 mL, 4.50 mmol), and isopropyl iodide (0.51 mL; 5.10 mmol).
Flash chromatography (SiO2; Et2O–pentane, 1:4) afforded a diaste-
reomeric mixture of (R,S,S)-4b and (R,S,R)-4b both as colorless
Synthesis 2001, No. 9, 1406–1414 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Protected 2-Keto-1,3-diol and 1,2,3-Triol Building Blocks
1409
oils; yield: 0.371 g (40%) of (E/Z)-(2’R,4R,6R)-4b; [ ]D25 –86.3 (c
1.23, CHCl3); 0.352 g (39%) of (E)-(2'R,4S,6R)-4b; [ ]D25 = –182.9
(c 0.97, CHCl3).
(E)-N-{(4S,6S)-4-Hexyl-2,2,4,6-tetramethyl-1,3-dioxan-5-
ylidene}-N-[(2'S)-2'-(methoxy-methyl)tetrahydro-1'H-1'-
pyrrolyl]amine (4c)
Prepared from 3 (0.854 g, 3.00 mmol; w = 95%), anhyd THF (6
mL), t-BuLi (2.80 mL, 4.50 mmol), and hexyl iodide (0.75 mL, 5.10
mmol). Flash chromatography (SiO2; Et2O–pentane, 1:4) afforded
4c as a colorless oil; yield: 0.942 g (89%).
IR (film): = 2981, 2938, 2875, 1370, 1204, 1181, 1147, 1115,
1046, 1001 cm–1.
MS: m/z (%) = 312 (16, M+), 267 (14, M+ – CH2OCH3), 212 (13),
211 (100, M+ – C3H7 – C3H6O), 116 (11), 114 (27), 112 (57), 96
[ ]D25 = +31.7 (c 1.25, CHCl3).
(14), 70 (48), 59 (49, C3H7O+), 55 (12), 45 (20, CH2OCH3 ).
+
IR (film): = 2982, 2956, 2932, 2872, 1378, 1269, 1231, 1200,
1170, 1155, 1113 cm–1.
Major Diastereomer (E)-(2'R,4R,6R)-4b
1H NMR (400 MHz): = 1.15 [d, 3H, J = 7.15 Hz, CH(CH3)CH3],
1.17 [d, 3H, J = 6.86 Hz, CH(CH3)CH3], 1.29 [d, 3H, J = 0.55 Hz,
C(CH3)CH3], 1.55–1.62 (m, 3H, NCH2CH2, NCHCHH), 1.56 [d,
3H, J = 0.55 Hz, C(CH3)CH3], 1.62 (s, 3H, CCH3), 1.68 (d, 3H,
J = 6.59 Hz, CHCH3), 1.91 (m, 1H, NCHCHH), 2.26 (m, 1H, NC-
HcisHtrans), 2.51 [sept, 1H, J = 6.87 Hz, CH(CH3)2], 2.89 (m, 1H,
NCHcisHtrans), 3.14 (s, 3H, OCH3), 3.20 (m, 1H, CHHOCH3), 3.42
(m, 1H, NCH), 3.48 (dd, 1H, J = 4.12/8.79 Hz, CHHOCH3), 4.62 (q,
1H, J = 6.59 Hz, CHCH3).
1H NMR (300 MHz): = 0.90 (m, 3H, CH2CH3), 1.34 [m, 8H,
(CH2)4], 1.38 [s, 3H, C(CH3)CH3], 1.49 [s, 3H, C(CH3)CH3], 1.55
(d, 3H, J = 6.31 Hz, CHCH3), 1.66 (s, 3H, CCH3), 1.58–1.83 (m, 3H,
NCH2CH2, NCHCHH), 1.88 [m, 1H, CHH(CH2)4CH3], 2.05 (m,
1H, NCHCHH), 2.41 [m, 1H, CHH(CH2)4CH3], 2.48 (m, 1H, NC-
HcisHtrans), 2.78 (m, 1H, NCHcisHtrans), 3.17 (s, 3H, OCH3), 3.22 (m,
2H, NCH, CHHOCH3), 3.43 (m, 1H, CHHOCH3), 4.43 (q, 1H,
J = 6.32 Hz, CHCH3).
13C NMR (75 MHz): = 14.35 (CH2CH3), 17.71 (CHCH3), 21.92
(NCH2CH2), 23.21 (CH2CH3), 24.58 (CH2CH2CH3), 26.01, 29.18,
29.33 [CCH3, C(CH3)2], 27.54 (NCHCH2), 30.21, 32.54
[(CH2)2CH2CH2CH3], 39.93 [C(CH)3CH2], 57.50 (NCH2), 58.74
(OCH3), 67.53 (NCH), 67.90 (CHCH3), 75.64 (CH2OCH3), 79.15
(CCH3), 99.80 [C(CH3)2], 174.70 (C=N).
13C NMR (100 MHz):
= 16.86 (CHCH3), 17.55, 18.39
[CH(CH3)2], 22.87 (NCH2CH2), 25.41 (CCH3), 26.67, 30.83
[C(CH3)2], 27.15 (NCHCH2), 35.26 [CH(CH3)2], 52.97 (NCH2),
58.73 (OCH3), 67.32 (NCH), 67.50 (CHCH3), 75.88 (CH2OCH3),
79.21 (CCH3), 98.28 [C(CH3)2], 164.76 (C=N).
Anal. Calcd for C17H32N2O3 (312.5): C, 65.35; H, 10.32; N, 8.97.
Found: C, 65.51; H, 10.49; N, 9.26.
MS: m/z (%) = 354 (14, M+), 309 (31, M+ – CH2OCH3), 211 (19, M+
– C6H13 – C3H6O), 167 (12), 138 (26), 116 (19), 114 (15), 112 (100),
70 (66), 59 (61, C3H7O+), 55 (14), 45 (18, CH2OCH3).
Major Diastereomer (Z)-(2'R,4R,6R)-4b
1H NMR (400 MHz): = 1.04 [d, 3H, J = 6.86 Hz, CH(CH3)CH3],
1.09 [d, 3H, J = 6.86 Hz, CH(CH3)CH3], 1.35 [d, 3H, J = 0.55 Hz,
C(CH3)CH3], 1.44 [d, 3H, J = 0.55 Hz, C(CH3)CH3], 1.54 (d, 3H,
J = 6.32 Hz, CHCH3), 1.55–1.62 (m, 2H, NCH2CH2), 1.65 (s, 3H,
CCH3), 1.73 (m, 1H, NCHCHH), 1.96 (m, 1H, NCHCHH), 2.47 (m,
1H, NCHcisHtrans), 2.79 (m, 1H, NCHcisHtrans), 3.07 [m, 1H,
CH(CH3)2], 3.14 (s, 3H, OCH3), 3.19 (m, 1H, CHHOCH3), 3.36
(dd, 1H, J = 3.85/8.79 Hz, CHHOCH3), 3.42 (m, 1H, NCH), 4.36 (q,
1H, J = 6.32 Hz, CHCH3).
Anal. Calcd for C20H38N2O3 (354.5): C, 67.76; H, 10.80; N, 7.90.
Found: C, 67.65; H, 11.20; N, 8.21.
(E/Z)-N-{(4R,6R)-4-[2'-(1',3'-Dioxolane-2'-yl)ethyl]-2,2,4,6-
tetramethyl-1,3-dioxan-5-ylidene}-N-[(2''R)-2''-
(methoxymethyl)tetrahydro-1''H-1''-pyrrolyl]amine (4d)
Prepared from 3 (0.811 g, 3.00 mmol), anhyd THF (6 mL), t-BuLi
(2.80 mL, 4.50 mmol), and 1,3-dioxolane-2-yl-ethyliodide (1.163 g,
5.10 mmol). Flash chromatography (SiO2; Et2O–pentane, 1:1) af-
forded an (E/Z)-mixture of 4d (E/Z = 1:2) as a pale yellow oil; yield:
0.898 g (81%).
13C NMR (100 MHz):
= 15.92 (CHCH3), 17.46, 18.75
[CH(CH3)2], 21.84 (NCH2CH2), 25.75 (CCH3), 26.98 (NCHCH2),
27.73, 29.19 [C(CH3)2], 34.47 [CH(CH3)2], 57.41 (NCH2), 58.62
(OCH3), 67.75, 68.26 (NCH, CHCH3), 74.94 (CH2OCH3), 80.79
(CCH3), 99.78 [C(CH3)2], 175.89 (C=N).
[ ]D25 = –77.8 (c 1.06, CHCl3).
IR (film): = 2982, 2937, 2876, 1379, 1370, 1233, 1208, 1169,
1129, 1036, 1011, 989 cm–1.
MS: m/z (%) = 371 (17, M+ + 1), 370 (M+), 326 (17, M+ + 1 –
CH2OCH3), 325 (86, M+ – CH2OCH3), 267 (24), 211 (24, M+ –
C5H9O2 – C3H6O), 154 (51), 145 (16), 116 (17), 114 (17), 112 (100),
110 (16), 99 (16), 73 (21), 70 (58), 59 (43, C3H7O+), 55 (10), 45 (20,
Minor Diastereomer (E)-(2'R,4S,6R)-4b
1H NMR (400 MHz): = 1.15 [d, 3H, J = 7.15 Hz, CH(CH3)CH3],
1.17 [d, 3H, J = 6.86 Hz, CH(CH3)CH3], 1.29 [d, 3H, J = 0.55 Hz,
C(CH3)CH3], 1.55–1.62 (m, 3H, NCH2CH2, NCHCHH), 1.56 [d,
3H, J = 0.55 Hz, C(CH3)CH3], 1.62 (s, 3H, CCH3), 1.68 (d, 3H,
J = 6.59 Hz, CHCH3), 1.91 (m, 1H, NCHCHH), 2.26 (m, 1H, NC-
HcisHtrans), 2.51 [sept, 1H, J = 6.87 Hz, CH(CH3)2], 2.89 (m, 1H,
NCHcisHtrans), 3.14 (s, 3H, OCH3), 3.20 (m, 1H, CHHOCH3), 3.42
(m, 1H, NCH), 3.48 (dd, 1H, J = 4.12/8.79 Hz, CHHOCH3), 4.62 (q,
1H, J = 6.59 Hz, CHCH3).
+
CH2OCH3 ).
Anal. Calcd for C19H34N2O5 (370.5): C, 61.60; H, 9.25; N, 7.56.
Found: C, 61.51; H, 9.04; N, 8.00.
(Z)-(2''R,4R,6R)-4d
1H NMR (400 MHz): = 1.29 [d, 3H, J = 0.55 Hz, C(CH3)CH3],
1.44 [d, 3H, J = 0.55 Hz, C(CH3)CH3], 1.51 (d, 3H, J = 6.04 Hz,
CHCH3), 1.64 (s, 3H, CCH3), 1.54–1.73 (m, 2H, NCH2CH2), 1.88
[m, 1H, CHHCH(OCH2)2], 2.01–2.30 [m, 4H, NCHCH2,
C(CH3)CHHCHH], 2.48 (m, 1H, NCHcisHtrans), 2.67 [m, 1H,
C(CH3)CHHCH2], 2.78 (m, 1H, NCHcisHtrans), 3.24 (s, 3H, OCH3),
3.20–3.60 [m, 7H, NCH, CH2OCH3, CH(OCH2)2], 4.33 (q, 1H,
J = 6.05 Hz, CHCH3), 4.96 [pent, 1H, J = 4.95 Hz, CH(OCH2)2].
13C NMR (100 MHz):
= 16.67 (CHCH3), 17.14, 18.24
[CH(CH3)2], 20.29 (CCH3), 22.75 (NCH2CH2), 25.99, 30.46
[C(CH3)2], 26.97 (NCHCH2), 35.47 [CH(CH3)2], 52.70 (NCH2),
58.69 (OCH3), 67.24 (NCH), 67.61 (CHCH3), 75.76 (CH2OCH3),
81.48 (CCH3), 98.57 [C(CH3)2], 166.97 (C=N).
Anal. Calcd for C17H32N2O3 (312.5): C, 65.35; H, 10.32; N, 8.97.
Found: C, 65.43; H, 10.52; N, 9.39.
13C NMR (100 MHz): = 17.79 (CHCH3), 22.80 (NCH2CH2), 25.82
(CCH3), 27.51 (NCHCH2), 29.07, 29.25 [C(CH3)2], 29.42
(CH2CH2CH), 34.27 (CH2CH2CH), 57.52 (NCH2), 58.68 (OCH3),
64.73 [-(OCH2)2-], 67.55, 67.88 (NCH, CHCH3), 75.79
Synthesis 2001, No. 9, 1406–1414 ISSN 0039-7881 © Thieme Stuttgart · New York

1410
D. Enders et al.
PAPER
(E/Z)-N-{(4R,6R)-4-Benzyl-2,2,4,6-tetramethyl-1,3-dioxan-5-
(CH2OCH3), 78.59 (CCH3), 99.85 [C(CH3)2], 105.20 [CH-
(OCH2)2-], 174.01 (C=N).
ylidene}-N-[(2'R)-2'-(methoxymethyl)tetrahydro-1'H-1'-
pyrrolyl]amine (4f)
(E)-(2’’R,4R,6R)-4d
Prepared from 3 (0.811 g, 3.00 mmol), anhyd THF (6 mL), t-BuLi
(2.80 mL, 4.50 mmol), and benzyl bromide (0.61 g, 5.10 mmol).
Flash chromatography (SiO2; Et2O–pentane, 1:9) afforded an (E/Z)-
mixture of 4f (E/Z = 2:1) as a colorless oil; yield: 0.866 g (80%).
1H NMR (400 MHz): = 1.28 [s, 3H, C(CH3)CH3], 1.49 [s, 3H,
C(CH3)CH3], 1.63 (d, 3H, J = 6.32 Hz, CHCH3), 1.64 (s, 3H,
CCH3), 1.54–1.73 (m, 2H, NCH2CH2), 1.88 [m, 1H,
CHHCH(OCH2)2],
2.01–2.30
[m,
5H,
NCHCH2,
[ ]D25 = –75.2 (c 1.12, CHCl3).
C(CH3)CH2CHH], 2.43 (m, 1H, NCHcisHtrans), 2.86 (m, 1H, NC-
HcisHtrans), 3.13 (s, 3H, OCH3), 3.20–3.60 [m, 7H, NCH, CH2OCH3,
CH(OCH2)2], 4.65 (q, 1H, J = 6.05 Hz, CHCH3), 4.97 [pent, 1H,
J = 4.94 Hz, CH(OCH2)2].
13C NMR (100 MHz): = 17.23 (CHCH3), 22.80 (NCH2CH2), 25.48
(CCH3), 27.01 (NCHCH2), 28.91, 29.03 [C(CH3)2], 30.69
(CH2CH2CH), 35.38 (CH2CH2CH), 57.52 (NCH2), 58.68 (OCH3),
64.68 [-(OCH2)2-], 67.18, 67.46 (NCH, CHCH3), 75.75
(CH2OCH3), 77.20 (CCH3), 98.52 [C(CH3)2], 105.49 [CH-
(OCH2)2-], 164.77 (C=N).
IR (film): = 2982, 2935, 2873, 2828, 1454, 1379, 1370, 1230,
1202, 1165, 1104, 1055, 1021, 992, 701, cm-1.
MS: m/z (%) = 360 (4, M+), 315 (2, M+ – CH2OCH3), 212 (13), 211
(100, M+ – C7H7 – C3H6O), 114 (23), 112 (19), 70 (19), 59 (19,
+
C3H7O+), 45 (10, CH2OCH3 ).
Anal. Calcd for C21H32N2O3 (360.5): C, 69.97; H, 8.95; N, 7.77.
Found: C, 69.96; H, 8.66; N, 7.97.
(Z)-(2''R,4R,6R)-4f
1H NMR (400 MHz): = 1.31 [s, 3H, C(CH3)CH3], 1.35 [s, 3H,
C(CH3)CH3], 1.49 (d, 3H, J = 6.32 Hz, CHCH3), 1.64 (s, 3H,
CCH3), 1.66 (m, 2H, NCH2CH2), 1.79 (m, 1H, NCHCHH), 1.97
(m, 1H, NCHCHH), 2.54 (m, 1H, NCHcisHtrans), 2.85 (m, 1H,
NCHcisHtrans), 3.06 (s, 3H, OCH3), 3.25 (m, 2H, NCH, CHHOCH3),
3.35 (m, 1H, CHHOCH3), 3.37 (d, 1H, J = 13.19 Hz, CHHC6H5),
3.68 (d, 1H, J = 13.18 Hz, CHHC6H5), 4.25 (q, 1H, J = 6.32 Hz,
CHCH3), 7.10–7.50 (m, 5H, C6H5).
13C NMR (100 MHz): = 17.30 (C-7), 22.27 (C-2), 26.21 (C-13),
26.63 (C-3), 28.18 (C-14), 29.06 (C-11), 44.45 (C-15), 57.90 (C-1),
58.47 (C-6), 67.31 (C-4), 67.74 (C-8), 74.37 (C-5), 78.93 (C-10),
100.13 (C-12), 126.32 (C-19), 127.18 (C-17, C-21), 131.40 (C-18,
C-20), 138.25 (C-16), 174.96 (C-9).
(E/Z)-N-{(4R,6R)-4-(3'-{[1'-(tert-Butyl)-1',1'-dimethylsilyloxy]-
propyl-}2,2,4,6-tetramethyl-1,3-dioxan-5-ylidene}-N-[(2''R)-2''-
(methoxymethyl)tetrahydro-1''H-1''-pyrrolyl]amine (4e)
Prepared from 3 (0.811 g, 3.00 mmol), anhyd THF (6 mL), t-BuLi
(2.80 mL, 4.50 mmol), and 1-tert-butyl-1,1-dimethylsilyloxypropyl
iodide (1.163 g, 5.10 mmol). Flash chromatography (SiO2; Et2O–
pentane, 1:1) afforded an (E/Z)-mixture of 4e (E/Z = 1:2) as a pale
yellow oil; yield: 0.898 g (81%).
[ ]D25 = –77.8 (c 1.06, CHCl3).
IR (film): = 2981, 2954, 2933, 2858, 1254, 1233, 1171, 1102,
1043, 836, 776, cm–1.
MS: m/z (%) = 443 (27, M+ + 1), 442 (87, M+), 398 (25, M+ + 1 –
CH2OCH3), 397 (88, M+ – CH2OCH3), 339 (12), 226 (27), 211 (M+
– C3H6OTBS – C3H6O), 116 (22), 114 (15), 112 (100), 85 (35), 75
(E)-(2''R,4R,6R)-4f
1H NMR (400 MHz): = 1.10 [s, 3H, C(CH3)CH3], 1.48 [s, 3H,
C(CH3)CH3], 1.53 (m, 2H, NCH2CH2), 1.62 (d, 3H, J = 6.60 Hz,
CHCH3), 1.63 (s, 3H, CCH3), 1.66 (m, 1H, NCHCHH), 1.97
(m, 1H, NCHCHH), 2.12 (m, 1H, NCHcisHtrans), 2.85 (m, 1H,
NCHcisHtrans), 3.12 (d, 1H, J = 13.46 Hz, CHHC6H5), 3.17 (s, 3H,
OCH3), 3.21 (dd, 1H, J = 7.42/9.07 Hz, CHHOCH3), 1.39 (d, 1H,
J = 13.46 Hz, CHHC6H5), 3.52 (dd, 1H, J = 4.40/9.07 Hz,
CHHOCH3), 3.58 (m, 1H, NCH), 4.56 (q, 1H, J = 6.60 Hz, CHCH3),
7.10–7.50 (m, 5H, C6H5).
+
(19), 73 (19), 70 (55), 59 (45, C3H7O+), 45 (13, CH2OCH3 ).
Anal. Calcd for C23H46N2O4Si (442.7): C, 62.40; H, 10.47; N, 6.33.
Found: C, 62.35; H, 10.38; N, 6.70.
13C NMR (100 MHz): = –5.06, –5.02 (C-18, C-19), 17.24, 17.81
(C-7), 18.54 (C-20), 21.90, 22.87 (C-2), 25.57, 25.94 (C-13), 26.18,
26.20 (C-21 to C-23), 27.14, 27.31, 27.76, 28.11 (C-3, C-16), 28.84,
28.97, 29.29, 30.75 (C-11, C-14), 35.92, 37.26 (C-15), 53.13, 57.44
(C-1), 58.71 (C-6), 63.97, 64.22 (C-17), 67.29, 67.49, 67.55, 67.89
(C-4, C-8), 75.43, 75.81 (C-5), 77.39, 78.90 (C-10), 98.47, 99.81
(C-12), 165.09, 174.38 (C-9).
13C NMR (100 MHz): =16.95 (C-7), 23.11 (C-2), 25.26 (C-13),
27.44 (C-3), 29.03 (C-14), 30.63 (C-11), 46.51 (C-15), 53.52 (C-1),
58.76 (C-6), 67.40 (C-4), 67.57 (C-8), 75.95 (C-5), 77.90 (C-10),
98.50 (C-12), 125.96 (C-19), 127.18 (C-17, C-21), 132.47 (C-18, C-
20), 138.74 (C-16), 163.34 (C-9).
(Z)-(2''R,4R,6R)-4e
1H NMR (400 MHz): = 0.09 [s, 3H, Si(CH3)CH3], 0.10 [s, 3H,
Si(CH3)CH3], 1.00 [s, 9H, C(CH3)3], 1.34 [s, 3H, C(CH3)CH3], 1.46
[s, 3H, C(CH3)CH3], 1.53 (d, 3H, J = 6.32 Hz, CHCH3), 1.64 (s, 3H,
CCH3), 1.54–1.72 (m, 3H, NCH2CH2, NCHCHH), 1.78–2.06 (m,
(E)-N-{(4S,6R)-4-[(Benzyloxy)methyl]-2,2,4,6-tetramethyl-1,3-
dioxan-5-ylidene}-N-[(2'R)-2'-(methoxymethyl)tetrahydro-1'H-1'-
pyrrolyle]amine (4g)
4H,
NCHCHH,
CHHCH2CH2OTBS),
2.16
[m,
1H,
CHH(CH2)2OTBS], 2.48 (m, 1H, NCHcisHtrans), 2.79 (m, 1H, NC-
HcisHtrans), 3.14 (s, 3H, OCH3), 3.20 (m, 1H, NCH), 3.42–3.49 (m,
2H, CH2OCH3), 3.69 (m, 2H, CH2OTBS), 4.40 (q, 1H, J = 6.32 Hz,
CHCH3).
To a stirred solution of 3 (4.661 g, 16.38 mmol) in anhyd THF (35
mL), t-BuLi (15.35 mL, 24.57 mmol) was slowly added at –78°C.
After stirring continued for 4 h, the reaction mixture was cooled to
–100°C and benzyloxymethyl chloride (3.85 g, 25 mmol) was add-
ed dropwise and stirred for another hour. Then the mixture was al-
lowed to warm to r.t. over 15 h and quenched with pH 7 buffer (100
mL). The aqueous phase was extracted with Et2O (1 L) and the or-
ganic phase washed with brine (100 mL). The combined aqueous
phases were extracted with Et2O (100 mL) and the combined organ-
ic layers were dried (MgSO4). Removal of the solvent under re-
duced pressure and purification of the residue by flash
chromatography (Al2O3; Et2O–pentane, 1:4) afforded 4g as a color-
less solid; yield: 5.216 g (82%).
(E)-(2''R,4R,6R)-4e
1H NMR (400 MHz): = 0.10 [s, 3H, Si(CH3)CH3], 0.11 [s, 3H,
Si(CH3)CH3], 1.00 [s, 9H, C(CH3)3], 1.31 [s, 3H, C(CH3)CH3], 1.51
[s, 3H, C(CH3)CH3], 1.64 (s, 3H, CCH3), 1.65 (d, 3H, J = 6.59 Hz,
CHCH3), 1.54–1.72 (m, 3H, NCH2CH2, NCHCHH), 1.78–2.06 (m,
4H, NCHCHH, CHHCH2CH2OTBS), 2.26 (m, 1H, NCHcisHtrans),
2.42 [m, 1H, CHH(CH2)2OTBS], 2.91 (m, 1H, NCHcisHtrans), 3.21
(s, 3H, OCH3), 3.20 (m, 1H, NCH), 3.42–3.49 (m, 2H, CH2OCH3),
3.69 (m, 2H, CH2OTBS), 4.67 (q, 1H, J = 6.59 Hz, CHCH3).
[ ]D26 = +12.2 (c 1.16, CHCl3).
Synthesis 2001, No. 9, 1406–1414 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Protected 2-Keto-1,3-diol and 1,2,3-Triol Building Blocks
1411
IR (in CHCl3): = 2984, 2936, 2873, 1497, 1453, 1378, 1369, 1320,
1286, 1232, 1217, 1184, 1114, 1028, 973, 917, 755, 698 cm–1.
2.08 (m, 1H, NCHcisHtrans), 2.80 (m, 1H, NCHcisHtrans), 3.14 (s, 3H,
OCH3), 3.14 (m, 1H, CHHOCH3), 3.27 (m, 1H, CHHOCH3), 3.30
(m, 1H, NCH), 4.43 (d, 1H, J = 0.91 Hz, OH), 4.61 (q, 1H, J = 6.71
Hz, CHCH3), 5.22 (dd, 1H, J = 2.44/10.68 Hz, CH=CHH), 5.69 (dd,
1H, J = 2.44/17.39 Hz, CH=CHH), 6.69 (dd, 1H, J = 10.68/17.40
Hz, CH=CH2).
13C NMR (125 MHz): = 15.48 (C-7), 22.69 (C-2), 23.07 (C-18),
24.72 (C-14), 26.61 (C-3), 27.15 (C-11), 30.05 (C-13), 52.61 (C-1),
58.79 (C-6), 67.13 (C-4), 67.96 (C-8), 76.25 (C-5), 78.36, 82.11 (C-
10, C-15), 97.58 (C-12), 112.72 (C-17), 145.13 (C-16), 165.95 (C-
9).
1H NMR (500 MHz): = 1.25 (d, 3H, J = 6.10 Hz, CHCH3), 1.39 [d,
3H, J = 0.61 Hz, C(CH3)CH3], 1.42 [d, 3H, J = 0.61 Hz,
CCH3(CH3)], 1.52 (s, 3H, CCH3), 1.57 [m, 1H, NCH(CH2)CHcis
Htrans], 1.70–1.82 (m, 2H, NCH2CH2), 1.97 [m, 1H,
NCH(CH2)CHcisHtrans], 2.40 (m, 1H, NCHcisHtrans), 2.80 [m, 2H,
NCHcisHtrans, NCH(CH2)], 3.10 (dd, 1H, J = 7.63/9.16 Hz,
CHHOCH3), 3.15 (s, 3H, OCH3), 3.27 (dd, 1H, J = 3.96/9.16 Hz,
CHHOCH3), 3.58 [d, 1H, J = 9.77 Hz, C(CH3)CHHO], 4.18 [d, 1H,
J = 9.77 Hz, C(CH3)CHHO], 4.45 (q, 1H, J = 6.10 Hz, CHCH3),
4.55 (d, 1H, J = 18.92 Hz, OCHHC6H5), 4.59 (d, 1H, J = 18.92 Hz,
OCHHC6H5), 7.32–7.36 (m, 5H, C6H5).
13C NMR (125 MHz): = 17.39 (CHCH3), 21.77 (NCH2CH2),
25.08, 26.18 [C(CH3)2], 27.16 (NCHCH2), 29.42 (CCH3), 57.25
(NCH2), 58.57 (NCH), 67.43, 68.00 (OCH3, CHCH3), 73.60, 74.74,
75.64 (CH2OCH3, CH2OCH2C6H5), 80.21 (CCH3), 99.95
[C(CH3)2], 127.06, 127.24, 128.28, 139.61 (Carom.), 173.85 (C=N).
MS: m/z (%) = 295 (1, M+ – CH2OCH3), 212 (25), 211 (100, M+ –
RAMP), 167 (50), 114 (38, C6H12ON+), 112 (17, C6H8O2 ), 82 (11),
+
71 (16, C4H7O+), 70 (45, C4H8N+), 59 (10, C3H7O+), 57 (10,
C3H5O+), 55 (21), 45 (11, CH2OCH3 ).
+
Anal. Calcd for C18H32N2O4 (340.5): C, 63.50; H, 9.47; N, 8.23.
Found: C, 63.28; H, 9.56; N, 8.54.
MS: m/z (%) = 390 (M+, 26), 345 (M+ – CH2OCH3, 27), 212 (11),
211 (100), 115 (14), 114 (26), 112 (18), 91 (51), 70 (21), 59 (17).
(4R,6R)-4-Allyl-2,2,4,6-tetramethyl-1,3-dioxan-5-one (5a)
A solution of 4a (0.310 g, 1.00 mmol) in CH2Cl2 (20 mL) at –78°C
was ozonolyzed for 7 min. After flushing with a stream of Ar and
warming to r.t., the reaction mixture was concentrated under re-
duced pressure. Purification of the residue by flash chromatography
(Et2O–pentane, 1:9) afforded 5a as a pale yellow oil; yield: 0.065 g
(33%); [ ]D25 = +180.5 (c 0.93, CHCl3).
Anal. Calcd for C22H34N2O4 (390.5): C, 67.66; H, 8.78; N, 7.17.
Found: C, 67.81; H, 8.75; N, 7.13.
(E)-2-{(4S,6R)-5-[(2'R)-2'-(Methoxymethyl)tetrahydro-1'H-1'-
pyrrolylimino]-2,2,4,6-tetramethyl-1,3-dioxan-4-yl}-butane-2-one
(4h) and (E)-(2R/S)-2-{(4S,6R)-5-[(2'R)-2'-
IR (film): = 2988, 1741, 1373, 1232, 1210, 1166, 1024, cm–1.
(Methoxymethyl)tetrahydro-1'H-1'-pyrrolylimino]-2,2,4,6-
tetramethyl-1,3-dioxan-4-yl}-3-butene-2-ol (4i)
1H NMR (400 MHz): = 1.23 [d, 3H, J = 0.55 Hz, C(CH3)CH3],
1.28 (d, 3H, J = 6.59 Hz, CHCH3), 1.34 (s, 3H, CCH3), 1.38 [d, 3H,
J = 0.55 Hz, C(CH3)CH3], 2.34 (m, 1H, CHHCH=CH2), 2.52 (m,
1H, CHHCH=CH2), 4.04 (q, 1H, J = 6.60 Hz, CHCH3), 5.05 (m,
1H, CH=CHH), 5.08 (m, 1H, CH=CHH), 5.92 (m, 1H, CH=CH2).
13C NMR (100 MHz): = 15.66 (CHCH3), 24.94, 29.32 [C(CH3)2],
25.07 (CCH3), 43.58 (CH2CHCH2), 71.14 (CHCH3), 81.61 (CCH3),
100.15 [C(CH3)2], 118.34 (CH=CH2), 133.21 (CH=CH2), 211.00
(C=O).
Prepared according to the typical procedure using 3 (0.88 g, 3.30
mmol), anhyd THF (7 mL), t-BuLi (3.10 mL, 5.00 mmol), and eth-
ylvinyl ketone (0.45 mL, 5.60 mmol). Flash chromatography (SiO2;
Et2O–petroleum ether, 1:1) afforded a diastereomeric mixture of 4h
and 4i, both as sticky yellow oils; yield: 0.35 g of 4h (31%);
[ ]D27 = –173.4 (c 0.99, CHCl3); 0.37 g of 4i (33%); [ ]D27 = –286.2
(c 0.99, CHCl3).
MS: m/z (%) = 198 (1, M+), 157 (10, M+ – C3H5), 140 (12), 114 (17),
99 (12, M+ – C3H5 – C3H6O), 98 (49), 97 (11), 86 (53), 67 (10), 59
(32, C3H7O+), 58 (100), 56 (89), 45 (15).
(E)-4h
IR (film): = 2982, 2938, 2874, 1719, 1371, 1206, 1179, 1117,
1000 cm–1.
1H NMR (500 MHz): = 1.33 [s, 3H, C(CH3)CH3], 1.49 (s, 3H,
CCH3), 1.51 [s, 3H, C(CH3)CH3], 1.51–1.58 (m, 3H, NCH2CH2,
NCHCHH), 1.62 (d, 3H, J = 6.71 Hz, CHCH3), 1.73 [s, 3H,
C(O)CH3], 1.87 (m, 1H, NCHCHH), 2.23 (m, 1H, NCHcisHtrans),
2.47–3.30 [m, 4H, H3CC(O)(CH2)2], 2.90 (m, 1H, NCHcisHtrans),
3.14 (s, 3H, OCH3), 3.19 (m, 1H, CHHOCH3), 3.44 (m, 2H, NCH,
CHHOCH3), 4.73 (q, 1H, J = 6.71 Hz, CHCH3).
13C NMR (125 MHz): = 16.88 (CHCH3), 22.87 (NCH2CH2), 25.73
[C(CH3)CH3], 26.58 (CCH3), 27.09 (NCHCH2), 29.46 [C(O)CH3],
30.56 [C(CH3)CH3], 35.47, 38.81 [(CH2)2C(O)CH3], 53.03 (NCH2),
58.79 (OCH3), 67.23 (NCH), 67.71 (CHCH3), 76.08 (CH2OCH3),
77.97 (CCH3), 98.60 [C(CH3)2], 166.14 (C=N), 205.87 (C=O).
Anal. Calcd for C11H18O3 (198.3): C, 66.64; H, 9.15. Found: C,
66.90; H, 9.69.
(4R,6R)-4-Hexyl-2,2,4,6-tetramethyl-1,3-dioxan-5-one (5c)
A solution of 4c (0.200 g, 0.56 mmol) in CH2Cl2 (20 mL) at –78°C
was ozonolyzed for 5 min. After flushing with a stream of Ar and
warming to r.t., the reaction mixture was concentrated under re-
duced pressure. Purification of the residue by flash chromatography
(Et2O–pentane, 1:9) afforded 5c as a colorless oil; yield: 0.113 g
(83%); [ ]D25 = –158.77 (c 1.09, CHCl3).
IR (film): = 2987, 2955, 2929, 2860, 1739, 1373, 1234, 1216,
1202, 1167 cm–1.
MS: m/z (%) = 340 (12, M+), 295 (40, M+ – CH2OCH3), 211 (20, M+
1H NMR (300 MHz): = 0.87 (t, 3H, J = 6.87 Hz, CH2CH3), 1.23
[m, 7H, CHH(CH2)3], 1.26 [d, 3H, J = 0.55 Hz, C(CH3)CH3]; 1.32
(d, 3H, J = 6.59 Hz, CHCH3), 1.39 (s, 3H, CCH3), 1.41 [d, 3H,
J = 0.55 Hz, C(CH3)CH3], 1.58 [m, 2H, C(CH3)CHHCHH], 1.85
[m, 1H, C(CH3)CHH], 4.06 (q, 1H, J = 6.59 Hz, CHCH3).
– RAMP), 124 (59), 116 (35), 114 (20, C6H12ON+), 112 (100,
C6H8O2 ), 82 (10), 70 (81, C4H8N+), 59 (55, C3H7O+), 45 (13,
+
+
CH2OCH3 ).
+
HRMS: m/z calcd for C18H32N2O4 : 340.236.207. Found:
13C NMR (75 MHz): = 14.30 (CH2CH3), 15.73 (CHCH3), 23.02,
23.81 [(CH2)2CH3], 25.01, 25.61, 29.50 [CCH3, C(CH3)2], 30.01,
32.11 [(CH2)2(CH2)2CH3], 39.76 [C(CH3)CH2], 71.27 (CHCH3),
81.94 (CCH3), 100.19 [C(CH3)2], 212.21 (C=O).
340.236357
(E)-4i
IR (film): = 3424, 2984, 2941, 2874, 1372, 1181, 1127, 1005 cm–1.
1H NMR (500 MHz): = 1.31 [s, 3H, C(CH3)CH3], 1.36 (m, 1H,
NCHCHH), 1.44 [s, 3H, C(CH3)CH3], 1.45–1.50 (m, 2H,
NCH2CH2), 1.58 [d, 3H, J = 0.92 Hz, C(OH)CH3], 1.68 (m, 1H,
NCHCHH), 1.69 (d, 3H, J = 6.71 Hz, CHCH3), 1.72 (s, 3H, CCH3),
MS: m/z (%) = 227 (1, M+ – CH3), 184 (13), 129 (37), 86 (80), 59
(21, C3H7O+), 58 (82), 57 (10), 56 (100), 55 (11), 45 (10).
Synthesis 2001, No. 9, 1406–1414 ISSN 0039-7881 © Thieme Stuttgart · New York

1412
D. Enders et al.
PAPER
Anal. Calcd for C14H26O3 (242.4): C, 69.38; H, 10.81. Found: C,
69.23; H, 10.97.
(CH2CH2CH2), 71.29 (CHCH3), 81.70 (CCH3), 100.20 [C(CH3)2],
212.07 (C=O).
MS: m/z (%) = 315 (M+ – CH3), 216 (15), 215 (100, M+ – C6H15Si),
185 (12), 173 (25), 171 (21), 159 (65), 143 (26), 130 (11), 129 (89),
117 (14), 101 (10), 86 (61), 85 (57), 75 (88), 73 (21), 59 (20,
C3H7O+), 58 (53), 56 (31), 45 (11).
(4R,6R)-4-[2’-(1’,3’-Dioxolane-2’-yl)ethyl]-2,2,4,6-tetramethyl-
1,3-dioxan-5-one (5d)
A solution of 4d (0.370 g, 1.00 mmol) in CH2Cl2 (20 mL) at –78°C
was ozonolyzed for 7 min. After flushing with a stream of Ar and
warming to r.t., the reaction mixture was concentrated under re-
duced pressure. Purification of the residue by flash chromatography
(Et2O–pentane, 1:1) afforded a diastereomeric mixture of (4R,6R)-
5d and (4S,6R)-5d as a colorless oil; yield: 0.186 g (72%).
Anal. Calcd for C17H34O4Si (330.5): C, 61.77; H, 10.37. Found: C,
61.99; H, 10.29.
(4R,6R)-4-Benzyl-2,2,4,6-tetramethyl-1,3-dioxan-5-one (5f)
A solution of 4f (0.360 g, 1.00 mmol) in CH2Cl2 (20 mL) at –78°C
was ozonolyzed for 7 min. After flushing with a stream of Ar and
warming to r.t., the reaction mixture was concentrated under re-
duced pressure. Purification of the residue by flash chromatography
(Et2O–pentane, 1:9) afforded 5f as a colorless oil; yield: 0.228 g
(92%); [ ]D25 = +196.2 (c 1.22, CHCl3).
[ ]D25 = +128.1 (c 1.10, CHCl3).
IR (film): = 2986, 1738, 1374, 1235, 1216, 1168, 1148, 1126,
1034 cm–1.
MS: m/z (%) = 257 (1, M+ – 1), 143 (10, M+ – CH3), 101 (12,
+
C5H9O2 ), 100 (97), 99 (15, M+ – C5H9O2 – C3H6O), 86 (100), 73
(78), 59 (17, C3H7O+), 58 (95), 56 (60), 45 (30).
IR (film): = 2987, 1740, 1372, 1233, 1166, 1120, 1024, 701 cm–1.
Anal. Calcd for C13H22O5 (258.3): C, 60.45; H, 8.58. Found: C,
60.19; H, 8.59.
1H NMR (400 MHz): = 1.11 [d, 3H, J = 0.55 Hz, C(CH3)CH3],
1.17 (d, 3H, J = 6.60 Hz, CHCH3), 1.34 [d, 3H, J = 0.55 Hz,
C(CH3)CH3], 1.37 (s, 3H, CCH3), 2.80 [d, 1H, J = 13.19 Hz,
C(CH3)CHH], 3.05 [d, 1H, J = 13.46 Hz, C(CH3)CHH], 3.64 (q, 1H,
J = 6.60 Hz, CHCH3), 7.08 (m, 1H, CHarom.), 7.14 (m, 2H, CHarom.),
7.28 (m, 2H, CHarom.).
13C NMR (100 MHz): = 15.23 (CHCH3), 24.72, 25.75, 29.34
[CCH3, C(CH3)2], 45.23 (CH2C6H5), 70.98 (CHCH3), 82.52
(CCH3), 100.27 [C(CH3)2], 126.58, 127.73, 131.25, 136.81 (C6H5),
210.90 (C=O).
Major Diastereomer (4R,6R)-5d
1H NMR (300 MHz): = 1.19 [s, 3H, C(CH3)CH3], 1.26 (d, 3H,
J = 6.60 Hz, CHCH3), 1.34 (s, 3H, CCH3), 1.36 [s, 3H, C(CH3)CH3],
1.82–1.91 [m, 2H, C(CH3)CHHCHH], 2.03 [m, 1H, C(CH3)CHH-
CHH], 2.15 [m, 1H, C(CH3)CHH], 3.36 [m, 2H, CH(OCH2)], 3.53
[m, 2H, CH(OCH2)], 4.00 (q, 1H, J = 6.59 Hz, CHCH3), 4.82 [t, 1H,
J = 4.67 Hz, CH(OCH2)2].
13C NMR (75 MHz): = 15.73 (CHCH3), 24.83, 25.43, 29.40
[CCH3, C(CH3)2], 28.73, 33.79 (CH2CH2CH), 64.74, 64.76 [-
(OCH2)2-], 71.18 (CHCH3), 81.26 (CCH3), 100.11 [C(CH3)2],
104.55 [CH-(OCH2)2-], 211.60 (C=O).
MS: m/z (%) = 248 (2, M+), 190 (57, M+ – C3H6O), 157 (78, M+ –
C7H7), 135 (20), 134 (50), 119 (16), 118 (14), 117 (19), 115 (15), 99
+
(37), 92 (18), 91 (32, C7H7 ), 86 (72), 59 (40, C3H7O+), 58 (100), 56
(58), 45 (15).
Minor Diastereomer (4S,6R)-5d
Anal. Calcd for C15H20O3 (248.3): C, 72.55; H, 8.12. Found: C,
72.50; H, 8.47.
1H NMR (300 MHz): = 1.20 [s, 3H, C(CH3)CH3], 1.28 (s, 3H,
CCH3), 1.31 (d, 3H, J = 6.87 Hz, CHCH3), 1.49 [s, 3H,
C(CH3)CH3], 1.78–1.85 [m, 2H, C(CH3)CHHCHH], 1.99 [m, 1H,
C(CH3)CHHCHH], 2.25 [m, 1H, C(CH3)CHH], 3.31 [m, 2H,
CH(OCH2)], 3.47 [m, 2H, CH(OCH2)], 4.11 (q, 1H, J = 6.59 Hz,
CHCH3), 4.76 [t, 1H, J = 4.12 Hz, CH(OCH2)2].
13C NMR (75 MHz): = 16.33 (CHCH3), 23.24, 24.91, 29.40
[CCH3, C(CH3)2], 27.99, 32.70 (CH2CH2CH), 64.81 [-(OCH2)2-],
71.08 (CHCH3), 81.85 (CCH3), 100.11 [C(CH3)2], 104.11 [CH-
(OCH2)2-], 212.40 (C=O).
(4S,6R)-4-[(Benzyloxy)methyl]2,2,4,6-tetramethyl-1,3-dioxan-
5-one (5g)
A solution of 4g (0.391 g, 1.00 mmol) in CH2Cl2 (20 mL) at –78°C
was ozonolyzed for 7 min. After flushing with a stream of Ar and
warming to r.t., the reaction mixture was concentrated under re-
duced pressure. Purification of the residue by flash chromatography
(Et2O–pentane, 1:4) afforded 5g as a colorless oil; yield: 0.219 g
(79%); [ ]D26 = +140.5 (c 1.01, CHCl3).
IR (film): = 1989, 1743, 1453, 1372, 1234, 1214, 1174, 1148,
1106, 1016, 738, 699 cm–1.
(4R,6R)-4-(3’-[1’-(tert-Butyl)-1’,1’-dimethylsilyloxypropyl]-
2,2,4,6-tetramethyl-1,3-dioxan-5-one (5e)
1H NMR (400 MHz): = 1.26 (s, 3H, CH2CCH3), 1.30 (d, 3H,
J = 6.6 Hz, CHCH3), 1.36 (d, 3H, J = 0.6 Hz, CCH3), 1.41 (d, 3H,
J = 0.6 Hz, CHCH3), 3.35 (d, 1H, J = 9.6 Hz, CH3CCHHO), 3.70 (d,
1H, J = 9.9 Hz, CH3CCHHO), 4.29 (q, 1H, J = 6.6 Hz, CHCH3),
4.37 (d, 1H, J = 12.4 Hz, OCHH), 4.41 (d, 1H, J = 12.4 Hz, OCHH),
7.08–7.29 (m, 5H, CH2C6H5).
13C NMR (125 MHz): = 15.52 (CHCH3), 22.43 (CCH3), 25.18,
29.50 [C(CH3)2], 71.30 (CHCH3), 73.60 (CH2C6H5), 75.80
(CH2OCH2C6H5), 82.45 (CCH3), 100.18 [C(CH3)2], 127.42,
127.47, 128.36, 138.78 (C6H5), 209.96 (C=O).
A solution of 4e (0.443 g, 1.00 mmol) in CH2Cl2 (20 mL) at –78°C
was ozonolyzed for 7 min. After flushing with a stream of Ar and
warming to r.t., the reaction mixture was concentrated under re-
duced pressure. Purification of the residue by flash chromatography
(Et2O–pentane, 1:9) afforded 5e as a colorless oil; yield: 0.284 g
(86%); [ ]D25 = +110.8 (c 1.05, CHCl3).
IR (film): = 2987, 2955, 2936, 2858, 1740, 1373, 1255, 1235,
1208, 1168, 1103, 1018, 837, 776 cm–1.
1H NMR (400 MHz): = 0.06 [s, 3H, Si(CH3)CH3], 0.07 [s, 3H,
Si(CH3)CH3], 0.98 [s, 9H, C(CH3)3], 1.22 [d, 3H, J = 0.55 Hz,
C(CH3)CH3], 1.28 (d, 3H, J = 6.87 Hz, CHCH3), 1.36 (s, 3H,
CCH3), 1.38 [d, 3H, J = 0.55 Hz, C(CH3)CH3], 1.56 [m, 1H,
C(CH3)CH2CHH], 1.68 [m, 1H, C(CH3)CHH], 1.79 [m, 1H,
C(CH3)CH2CHH], 1.93 [m, 1H, C(CH3)CHH], 3.54 (dt, 2H,
J = 0.82/6.59 Hz, CH2OSi), 4.02 (q, 1H, J = 6.87 Hz, CHCH3).
13C NMR (100 MHz): = –5.17 [OSi(CH3)2], 15.76 (CHCH3),
18.51 [C(CH3)3], 24.94, 25.50, 29.47 [CCH3, C(CH3)2], 26.16
[C(CH3)3], 27.49 (CH2CH2CH2), 35.98 (CH2CH2CH2), 63.52
MS: m/z (%) = 278 (M+), 179 (13), 149 (14), 107 (10), 99 (13), 92
(11), 91 (100), 86 (13), 59 (13), 58 (18), 56 (11).
Anal. Calcd for C16H22O4 (278.3): C, 69.04; H, 7.97. Found: C,
68.99; H, 7.80.
(4S,5R,6S)-4-Hexyl-2,2,4,6-tetramethyl-1,3-dioxan-5-ol (6c);
Typical Procedure
To a stirred solution of 5c (0.074 g, 0.31 mmol) in anhyd THF was
added L-selectride (0.46 mL, 0.46 mmol) at –78°C and the mixture
Synthesis 2001, No. 9, 1406–1414 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Protected 2-Keto-1,3-diol and 1,2,3-Triol Building Blocks
1413
stirred for 2 h. The reaction mixture was allowed to warm to r.t.
over 15 h and quenched with sat. NH4Cl. The aqueous phase was
extracted with Et2O (100 mL), the organic phase washed with brine
(5 mL) and dried (MgSO4). After concentration under reduced pres-
sure, the residue was dissolved in CH2Cl2 (10 mL), and 1 M NaOH
(2 mL) and aq 30% H2O2 (2 mL) were added. After stirring for 20
min, the reaction mixture was extracted with CH2Cl2 (100 mL). The
organic phase was washed with brine (5 mL) and dried (MgSO4).
After removal of the solvent under reduced pressure and purifica-
tion of the residue by flash chromatography (SiO2; Et2O–pentane,
1:1) afforded 6c as a pale yellow oil; yield: 0.072 g (96%).
13C NMR (75 MHz): = 15.55 (CHCH3), 23.11, 24.60, 35.23
[CCH3, C(CH3)2], 28.22, 31.95 [(CH2)2(CH2)3CH3], 64.44
(CHCH3), 64.87, 65.90 [(CH2)2CH3], 70.02 (CHOH), 76.85
(CCH3), 98.94 [C(CH3)2], 105.23 (C=O).
(4R,5S,6R)-4-(3'-[1'-(t-Butyl)-1',1'-dimethylsilyloxypropyl]-
2,2,4,6-tetramethyl-1,3-dioxan-5-ol (6e)
Prepared from 5e (0.265 g, 0.80 mmol), anhyd THF and L-selectride
(1.20 mL, 1.20 mmol). After concentration of the organic phase un-
der reduced pressure, the residue was dissolved in CH2Cl2 (20 mL)
and 1 M NaOH (4 mL) and aq 30% H2O2 (4 mL) were added. Flash
chromatography (SiO2; Et2O–pentane, 1:1) afforded 6e as a pale
yellow oil; yield: 0.265 g (quant.).
[ ]D25 = –28.2 (c 0.99, CHCl3).
IR (in CHCl3): = 2990, 2935, 2858, 1378, 1251, 1198, 1167, 1067,
1010, 999, 970, 758 cm–1.
[ ]D25 = +20.8 (c 1.05, CHCl3).
IR (film): = 2955, 2934, 2896, 2858, 1379, 1252, 1198, 1165,
1098, 1065, 1011, 837, 776 cm–1.
1H NMR (300 MHz): = 0.93 (t, 3H, J = 7.14 Hz, CH2CH3), 1.00–
1.60 [m, 10H, (CH2)5CH3], 1.24 (d, 3H, J = 6.31 Hz, CHCH3), 1.29
[d, 3H, J = 0.55 Hz, C(CH3)CH3], 1.33 (s, 3H, CCH3), 1.39 [d, 3H,
J = 0.55 Hz, C(CH3)CH3], 2.11 (d, 1H, J = 11.81 Hz, CHOH), 2.73
(dd, 1H, J = 1.10/11.81 Hz, CHOH), 3.99 (dq, 1H, J = 1.10/6.32 Hz,
CHCH3).
13C NMR (75 MHz): = 14.35 (CH2CH3), 17.97 (CHCH3), 23.09,
23.69 [(CH2)2CH3], 24.47, 24.63 [C(CH3)2], 30.39, 32.20
[(CH2)2(CH2)2CH3], 32.04 (CCH3), 38.37 [C(CH3)CH2], 64.56
(CHCH3), 71.11 (CHOH), 77.87 (CCH3), 98.77 [C(CH3)2].
1H NMR (400 MHz): = 0.06 [d, 6H, J = 0.82 Hz, Si(CH3)2], 0.98
[s, 9H, C(CH3)2], 1.21 (d, 3H, J = 6.04 Hz, CHCH3), 1.32 (s, 3H,
CCH3), 1.36 [d, 3H, J = 0.55 Hz, C(CH3)CH3], 1.38 [d, 3H, J = 0.55
Hz, C(CH3)CH3], 1.55 [m, 2H, C(CH3)CHHCHH], 1.67 [m, 1H,
C(CH3)CH2CHH], 1.79 [m, 1H, C(CH3)CHHCH2], 2.07 (d, 1H,
J = 11.81 Hz, CHOH), 2.76 (dd, 1H, J = 1.10/11.82 Hz, CHOH),
3.49 (m, 2H, CH2OSi), 4.08 (dq, 1H, J = 1.10/6.31 Hz, CHCH3).
13C NMR (100 MHz): = –5.18 [OSi(CH3)2], 17.87 (CHCH3),
18.46 [C(CH3)3], 24.59, 24.62, 31.98 [CCH3, C(CH3)2], 26.08
[C(CH3)3], 27.26 (CH2CH2CH2), 34.49 (CH2CH2CH2), 63.41
(CH2CH2CH2), 64.49 (CHCH3), 70.95 (CHOH), 77.54 (CCH3),
98.71 [C(CH3)2].
MS: m/z (%) = 229 (9, M+ – CH3), 169 (10), 159 (12, M+ – C6H13),
129 (50), 116 (13), 101 (13, M+ – C6H13 – C3H6O), 71 (14), 69 (16),
59 (100, C3H7O+), 58 (74), 57 (26), 55 (12).
Anal. calcd HRMS for C13H25O3 (M – CH3): 229.180370. Found:
229.180299.
MS: m/z (%) = 317 (12, M+ – CH3), 217 (34, M+ – C6H15Si), 199
(12), 173 (24), 159 (M+ – C6H15Si – C3H6O), 131 (13), 125 (81), 116
(15), 107 (12), 101 (17), 97 (12), 95 (17), 85 (98), 81 (15), 75 (77),
73 (23), 59 (100, C3H7O+), 58 (65), 57 (37), 55 (21).
(4R,5S,6R)-4-[2'-(1',3'-Dioxolan-2'-yl)ethyl]-2,2,4,6-tetramethyl-
1,3-dioxan-5-ol (6d)
Prepared from 5d (0.102 g, 0.39 mmol), anhyd THF and L-selec-
tride (0.59 mL, 0.59 mmol). Flash chromatography (SiO2; Et2O–
pentane, 1:1) afforded 6d as a pale yellow oil; yield: 0.099 g (96%).
Anal. Calcd for C17H36O4Si (332.6): C, 61.40; H, 10.91. Found: C,
61.69; H, 10.98.
(4R,5S,6R)-4-Benzyl-2,2,4,6-tetramethyl-1,3-dioxan-5-ol (6f)
Prepared from 5f (0.163 g, 0.66 mmol), anhyd THF and L-selectride
(0.98 mL, 0.98 mmol). After concentration under reduced pressure
the residue was dissolved in CH2Cl2 (20 mL) and 1 M NaOH (2 mL)
and H2O2 (2 mL) were added. Flash chromatography (SiO2; Et2O–
pentane, 1:1) afforded 6f as a pale yellow oil; yield: 0.124 g (76%).
[ ]D25 = +21.7 (c 1.05, CHCl3).
IR (in CHCl3): = 2984, 2936, 1378, 1246, 1215, 1174, 1078, 1034,
1004, 863 cm–1.
+
MS: m/z (%) = 245 (15, M+ – CH3), 145 (100), 101 (20, C5H9O2 ),
86 (17), 85 (24), 83 (41), 59 (19, C3H7O+), 58 (16), 57 (14), 55 (18),
45 (19).
[ ]D25 = +53.2 (c 1.09, CHCl3).
HRMS: m/z calcd for C12H21O5(M+ – CH3): 245.138899. Found:
245.138968.
IR (film): = 2988, 2936, 1454, 1378, 1236, 1196, 1175, 1143,
1130, 1083, 1071, 1043, 1012, 1000, 973, 754, 706 cm–1.
1H NMR (300 MHz): = 1.21 (d, 3H, J = 6.31 Hz, CHCH3), 1.29 (s,
3H, CCH3), 1.34 [d, 3H, J = 0.55 Hz, C(CH3)CH3], 1.39 [d, 3H,
J = 0.55 Hz, C(CH3)CH3], 1.99 (d, 1H, J = 11.26 Hz, CHOH), 2.74
(d, 1H, J = 13.74 Hz, CHHC6H5), 2.81 (d, 1H, J = 13.74 Hz,
CHHC6H5), 3.10 (dd, 1H, J = 1.64/1.26 Hz, CHOH), 4.00 (dq, 1H,
J = 1.65/6.32 Hz, CHCH3), 7.05–7.15 (m, 5H, C6H5).
13C NMR (75 MHz): = 16.80 (CHCH3), 23.96 (CCH3), 24.89,
30.97 [C(CH3)2], 45.06 (CH2C6H5), 64.16 (CHCH3), 69.45
(CHOH), 77.76 (CCH3), 98.56 [C(CH3)2], 125.81, 127.55, 130.00,
137.38 (C6H5).
Major Diastereomer (4R,5S,6R)-6d
1H NMR (300 MHz): = 1.19 (d, 3H, J = 6.31 Hz, CHCH3), 1.30 (s,
3H, CCH3), 1.36 [s, 6H, C(CH3)2], 1.80–2.03 [m, 4H,
C(CH3)CH2CH2], 2.13 (d, 1H, J = 11.81 Hz, CHOH), 2.73 (dd, 1H,
J = 1.10/11.81 Hz, CHOH), 3.39 (m, 2H, CHOCH2), 3.54 (m, 2H,
CHOCH2), 4.03 (dq, 1H, J = 1.10/6.32 Hz, CHCH3), 4.80 [pent, 1H,
J = 4.40 Hz, CH(OCH2)2].
13C NMR (75 MHz): = 17.85 (C-4), 24.44, 24.50, 31.95 (C-1, C-
2, C-8), 28.41, 31.95 (C-9, C-10), 64.58 (C-5), 64.87, 64.91 (C-12,
C-13), 71.11 (C-6), 77.38 (C-7), 98.94 (C-3), 104.86 (C-11).
MS: m/z (%) = 235 (2, M+ – CH3), 159 (57, M+ – C7H7), 135 (27),
+
101 (46, M+ – C7H7 – C3H6O), 91 (28, C7H7 ), 59 (100, C3H7O+), 58
Minor Diastereomer (4S,5S,6R)-6d
1H NMR (300 MHz): = 1.01 (s, 3H, CCH3), 1.17 (d, 3H, J = 6.31
Hz, CHCH3), 1.23 [d, 3H, J = 0.55 Hz, C(CH3)CH3], 1.35 [d, 3H,
J = 0.55 Hz, C(CH3)CH3], 1.80–2.03 [m, 4H, C(CH3)CH2CH2], 2.17
(d, 1H, J = 11.54 Hz, CHOH), 2.63 (q, 1H, J = 0.83/11.54 Hz,
CHOH), 3.40 (m, 2H, CHOCH2), ), 3.54 (m, 2H, CHOCH2), 3.91
(dq, 1H, J = 0.83/6.32 Hz, CHCH3) 4.89 [pent, 1H, J = 4.67 Hz,
CH(OCH2)2].
(30), 57 (11).
Anal. calcd for C15H22O3 (250.3): C, 71.97; H, 8.86. Found: C,
71.94; H, 8.83.
(4S,5R/S,6R)-4-[(Benzyloxy)methyl]2,2,4,6-tetramethyl-1,3-
dioxan-5-ol (6g)
To a stirred solution of 5g (1.898 g, 6.82 mmol) in MeOH (100 mL)
was added NaBH4 (0.516 g, 13.64 mmol) at 0°C. The solution was
Synthesis 2001, No. 9, 1406–1414 ISSN 0039-7881 © Thieme Stuttgart · New York

1414
D. Enders et al.
PAPER
stirred for 4 h. After concentration under reduced pressure, the res-
idue was diluted with Et2O (100 mL) and the organic phase washed
with H2O and brine, and dried (MgSO4). The solvent was removed
under reduced pressure and purification of the residue by flash chro-
matography (silica gel; Et2O–pentane, 1:2) afforded a diastereomer-
ic mixture (4:1) of 6g as a colorless oil; yield: 1.801 g (94%).
[ ]D25 = +15.9 (c 1.01, CHCl3).
MS: m/z (%) = 192 (4, M+ – H2O), 148 (18), 135 (100), 119 (69, M+
– C7H7), 117 (14), 92 (54), 91 (50, C7H7 ), 75 (54), 58 (33), 57 (38),
45 (18).
+
Anal. calcd for C12H18O3 (210.3): C, 68.55; H, 8.63. Found: C,
68.71; H, 9.05.
Acknowledgement
IR (film): = 2989, 2936, 1454, 1380, 1248, 1202, 1169, 1152,
1090, 1055, 1005, 977 cm–1.
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 380) and the Fonds der Chemischen Industrie. We thank De-
gussa AG, BASF AG, Bayer AG and Aventis for the donation of
chemicals.
MS: m/z (%) = 279 (M+ – 1, 3), 265 (14), 165 (11), 158 (56), 101
(37), 92 (13), 91 (100), 59 (41), 58 (12).
Anal. calcd for C16H24O4 (280.4): C, 68.55; H, 8.63. Found: C,
68.38; H, 8.60.
References
Major Diastereomer (4R,5S,6R)-6g
1H NMR (500 MHz): = 1.21 (d, 3H, J = 6.41 Hz, CHCH3), 1.25 (s,
3H, CCH3), 1.39 (s, 3H, CCH3), 1.55 [s, 3H, CH(OH)CCH3], 2.04
(d, 1H, J = 10.98 Hz, OH), 3.27 [d, 1H, J = 9.16 Hz, C(CH3)CHHO],
3.33 (dd, 1H, J = 10.98/1.52 Hz, CHOH), 3.47 [d, 1H, J = 9.15 Hz,
C(CH3)CHHO], 3.98 (dq, 1H, J = 6.41/1.53 Hz, CH3CHCHOH),
4.19 (d, 1H, J = 12.21 Hz, OCHH), 4.27 (d, 1H, J = 12.21 Hz,
OCHH), 7.07–7.20 (m, 5H, CHarom.).
(1) Searle, P. A.; Molinski, T. F. J. Org. Chem. 1995, 60, 4296.
(2) Lear, M. J.; Hirama, M. Tetrahedron Lett. 1999, 40, 4897.
(3) Mulzer, J. Angew. Chem., Int. Ed. Engl. 1991, 30, 1452.
(4) (a) Greven, R.; Jütten, P.; Scharf, H.-D. Carbohydr. Res.
1995, 275, 83. (b) Nicolaou, K. C.; Mitchell, H. J.; van Delft,
F. L.; Rübsam, F.; Rodriguez, R. M. Angew. Chem., Int. Ed.
Engl. 1998, 37, 1871. (c) Nicolaou, K. C.; Mitchell, H. J.;
Jain, N. F.; Winssinger, N.; Hughes, R.; Bando, T. Angew.
Chem., Int. Ed. 1999, 38, 240.
13C NMR (100 MHz): = 17.54 (CHCH3), 23.72 (CCH3), 25.54,
31.65 [C(CH3)2], 65.14 (CHCH3), 68.59 (CHOH), 73.48
(CH2C6H5), 75.22 (CH2OCH2C6H5), 77.55 (CCH3), 98.93
[C(CH3)2], 127.73, 128.47, 128.54, 138.44 (C6H5).
(5) Nicolaou, K. C.; Boddy, C. N. C.; Bräse, S.; Winssinger, N.
Angew. Chem., Int. Ed. 1999, 38, 2097.
(6) Recent reviews: (a) Fuji, K. Chem. Rev. 1993, 93, 2037.
(b) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed.
Engl. 1998, 37, 388.
(7) (a) Weber, B.; Seebach, D. Angew. Chem., Int. Ed. Engl.
1992, 31, 84. (b) Weber, B.; Seebach, D. Tetrahedron 1994,
50, 6117.
Minor Diastereomer (4S,5R,6R)-6g
1H NMR (500 MHz): = 1.39 (d, 3H, J = 6.10 Hz, CHCH3), 1.40 (s,
3H, CCH3), 1.45 [s, 3H, CH(OH)CCH3], 1.47 (s, 3H, CCH3), 2.90
(d, 1H, J = 6.11 Hz, -OH), 3.36 [d, 1H, J = 9.16 Hz, C(CH3)CHHO],
3.38 (dd, 1H, J = 6.11/8.24 Hz, CHOH), 3.76 [d, 1H, J = 9.15 Hz,
C(CH3)CHHO], 3.93 (dq, 1H, J = 8.24/6.10 Hz, CHCH3), 4.12 (d,
1H, J = 11.90 Hz, OCHH-10), 4.17 (d, 1H, J = 11.90 Hz, OCHH-
10), 7.07–7.20 (m, 5H, CHarom.).
(8) Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, I.,
Ed.; VCH: New York, 1993.
(9) (a) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl.
1996, 35, 448. (b) Kolb, H. C.; Van Nieuwenhze, M. S.;
Sharpless, K. B. Chem. Rev. 1994, 94, 2483. (c) Morikawa,
K.; Park, J.; Andersson, P. G.; Hyshiyama, T.; Sharpless, K.
B. J. Am. Chem. Soc. 1993, 115, 8463.
13C NMR (125 MHz): = 19.76 (CHCH3), 25.49, 31.17 [C(CH3)2],
26.42 (CCH3), 68.37 (CHCH3), 73.73 (CH2C6H5), 75.41
(CH2OCH2C6H5), 77.55 (CCH3), 77.73 (CHOH), 98.93 [C(CH3)2],
127.73, 128.47, 128.54, 138.44 (C6H5).
(10) Bockstiegel, B. Dissertation; Technical University of
Aachen: Germany, 1989.
(2R,3S,4R)-4-Benzylpentane-1,2,3-triol (7)
To a stirred solution of 6f (0.201 g, 0.80 mmol) in THF (4 mL) was
added H2O (2 mL) and one drop of TFA at r.t. After stirring for 10
min, the reaction was quenched with concd aq ammonia (1 mL) and
H2O (3 mL). The reaction mixture was extracted with CH2Cl2 (100
mL), and the organic layer dried (MgSO4) and concentrated under
reduced pressure. Purification of the residue by flash chromatogra-
phy (SiO2; Et2O–pentane, 4:1) afforded 7 as a white solid; yield:
0.119 g (71%).
(11) (a) Enders, D. In Asymmetric Synthesis, Vol. 3B; Morrison,
J. D., Ed.; Academic Press: Orlando, 1984, 275. (b) Enders,
D.; Klatt, M. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995,
3368.
(12) For previous asymmetric syntheses based on 2 see:
(a) Enders, D.; Hundertmark, T. Tetrahedron Lett. 1999, 40,
4169. (b) Enders, D.; Hundertmark, T. Eur. J. Org. Chem.
1999, 751. (c) Enders, D.; Hundertmark, T.; Lampe, C.;
Jegelka, U.; Scharfbillig, I. Eur. J. Org. Chem. 1998, 2839.
(d) Enders, D.; Bockstiegel, B.; Gatzweiler, W.; Jegelka, U.;
Dücker, B.; Wortmann, L. Chimica Oggi 1997, 15, 20.
(e) Enders, D.; Jegelka, U. Tetrahedron Lett. 1993, 34, 2453.
(f) Enders, D.; Bockstiegel, B. Synthesis 1989, 493.
(13) Hoppe, D.; Schmincke, H.; Kleemann, H.-W. Tetrahedron
1989, 45, 687.
Mp 80°C.
[ ]D25 = +22.3 (c 1.04, CHCl3).
IR (KBr): = 3494, 3369, 1385, 1032 cm–1.
1H NMR (400 MHz): = 1.06 (s, 3H, CCH3), 1.21 (d, 3H, J = 6.31
Hz, CHCH3), 2.37 (d, 1H, J = 13.46 Hz, CHHC6H5), 2.73 [s, 1H,
C(CH3)OH], 2.86 (d, 1H, J = 13.46 Hz, CHHC6H5), 2.90 (dd, 1H,
J = 1.10/8.79 Hz, CHOH), 3.16 [d, 1H, J = 4.12 Hz, CH(CH3)OH],
3.19 (d, 1H, J = 8.79 Hz, CHOH), 4.11 [m, 1H, CH(CH3)OH], 7.09–
7.18 (m, 5H, C6H5).
(14) The crystal structure has been deposited at the Cambridge
Cryst. Data Centre (CCDC 162249), 12 Union Road,
Cambridge CB2 1EZ, UK.
(15) Enders, D.; Kownatka, D.; Hundertmark, T.; Prokopenko, O.
F.; Runsink, J. Synthesis 1997, 649.
13C NMR (100 MHz): = 20.82 [CH(OH)CH3], 23.56 (CCH3),
44.90 (CH2C6H5), 66.87 [CH(OH)CH3], 76.29 [C(OH)CH3], 77.46
(CHOH), 126.46, 128.14, 130.82, 137.47 (C6H5).
Synthesis 2001, No. 9, 1406–1414 ISSN 0039-7881 © Thieme Stuttgart · New York