De novo synthesis of l -colitose and l -rhodinose building blocks

Article abstract of DOI:10.1021/jo201883k

A divergent, practical, and efficient de novo synthesis of fully functionalized l-colitose (3,6-dideoxy-l-galactose), 2-epi-colitose (3,6-dideoxy-l-talose), and l-rhodinose (2,3,6-trideoxy-l-galactose) building blocks has been achieved using inexpensive, commercially available (S)-ethyl lactate as the starting material. The routes center around a diastereoselective Cram-chelated allylation that provides a common homoallylic alcohol intermediate. Oxidation of this common intermediate finally resulted in the synthesis of the three monosaccharide building blocks.

Full text of DOI:10.1021/jo201883k

Article
pubs.acs.org/joc
De Novo Synthesis of L-Colitose and L-Rhodinose Building Blocks
Oliviana Calin, Rajan Pragani, and Peter H. Seeberger*
Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Muhlenberg 1, 14476 Potsdam, Germany,
̈
and Institute for Chemistry and Biochemistry, Freie Universitat Berlin, Arnimallee 22, 14195 Berlin, Germany
̈
S
* Supporting Information
ABSTRACT: A divergent, practical, and efficient de novo synthesis of fully
functionalized L-colitose (3,6-dideoxy-L-galactose), 2-epi-colitose (3,6-
dideoxy-L-talose), and L-rhodinose (2,3,6-trideoxy-L-galactose) building
blocks has been achieved using inexpensive, commercially available (S)-
ethyl lactate as the starting material. The routes center around a
diastereoselective Cram-chelated allylation that provides a common
homoallylic alcohol intermediate. Oxidation of this common intermediate finally resulted in the synthesis of the three
monosaccharide building blocks.
colitose (3,6-dideoxy-L-talose) and L-rhodinose (2,3,6-trideoxy-
L-galactose), which are closely related to L-colitose (Figure 1).
INTRODUCTION
■
Deoxysugars are commonly found in nature as a component of
plants, fungi, and bacteria. One particular class of deoxysugars,
the 3,6-dideoxyhexoses, are widespread in the O-specific side
chain of lipopolysaccharides of Gram-negative bacteria. These
sugars serve as antigenic determinants and are vital for bacterial
survival. L-Colitose (3,6-dideoxy-L-galactose; Figure 1) is a 3,6-
RESULTS AND DISCUSSION
■
The retrosynthetic analysis targeted functionalized L-colitose
building block 1 (Scheme 1) to be generated from acyclic
Scheme 1. Retrosynthetic Analysis of L-Colitose Building
Block 1
Figure 1. Rare sugar targets.
dideoxyhexose of particular interest since this monosaccharide
is specific to the O-antigen of a large range of Gram-negative
bacteria such as Escherichia coli O111,1 Salmonella enterica,2
Salmonella Adelaide,3 Salmonella greenside, and Vibrio cholerae,4
which are enteric pathogens responsible for many epidemics.
Furthermore, L-colitose is present in the O-specific poly-
saccharides of aerobic heterotrophic marine prokaryotes of the
genera Pseudoalteromonas.5 These prokaryotes produce a range
of biologically active products such as antibiotics, antitoxins,
and antitumor and antiviral agents. To evaluate the
immunological properties of L-colitose-containing bacterial
oligosaccharides and the potential of the corresponding
glycoconjugates as vaccines against bacteria, the development
of an efficient synthesis for functionalized L-colitose building
blocks remains essential. Previous syntheses of L-colitose
building blocks start mainly from expensive L-fucose6 and/or
require many steps.7 As part of our ongoing program aimed at
establishing efficient synthetic pathways for accessing fully
protected natural and non-natural monosaccharides,8 we report
a de novo synthesis of a L-colitose glycosylating agent starting
from inexpensive commercially available (S)-ethyl lactate.9 We
extend this synthetic methodology to the preparation of 2-epi-
precursor aldehyde 2. We envisioned obtaining differentially
protected aldehyde 2 via a dihydroxylation/oxidation sequence
of homoallylic alcohol 3 that could be obtained by allylation of
(S)-α-hydroxy aldehyde 4 under Cram-chelation control.10
Intermediate 4 could be synthesized in two steps starting from
(S)-ethyl lactate.
2-Naphthylmethyl (Nap) ether protection11 of the free
alcohol in (S)-ethyl lactate (5), which has the same
stereochemistry at C5 as the target L-colitose, followed by
reduction of the ester moiety with DIBAL afforded aldehyde 4
in 77% yield over two steps (Scheme 2). Introduction of the
remaining L-colitose carbon backbone and the C4 stereocenter
was accomplished via Cram-chelated controlled allylation of 412
with allyl trimethyl silane in the presence of SnCl4 in a
noncoordinating solvent (DCM).13 This reaction provided
desired homoallylic alcohol 3 (dr = 14:1) in 91% yield. The
absolute stereochemistry of the newly formed chiral center was
assigned by Mosher ester analysis.14
Received: September 26, 2011
Published: December 12, 2011
© 2011 American Chemical Society
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Scheme 2. Synthesis of Homoallylic Alcohol 3
Scheme 3. Upjohn Dihydroxylation of Homoallylic Alcohol
3
With olefin 3 in hand, we investigated the stereoselective
introduction of the C2-OH group using a Sharpless asymmetric
dihydroxylation (AD; Table 1).15 Thus, substrate 3 was treated
with the appropriate AD-mix β reagent in tert-BuOH/water in
order to afford the corresponding 2,4-anti intermediate.
Surprisingly, the reaction was not stereoselective, and the
target triol was obtained as a 1:1 mixture of 2,4-syn and 2,4-anti
diastereoisomers (Table 1, entry 1). The use of AD-mix α,
which should favor the formation of 2,4-syn triol, also exhibited
very low diastereoselectivity (Table 1, entry 2). At least modest
diastereoselectivity in line with the selectivity achieved in the
Sharpless dihydroxylation reaction of simple terminal olefins16
was expected.
The absolute configuration of the newly introduced C2-OH
was established using Rychnovsky’s acetonide method20
(Scheme 4). Selective protection of the primary alcohol on
Scheme 4. Synthesis of the C2−C4 Acetonides 8a and 9a
One strategy that has been used to alter the diastereose-
lectivity in the Sharpless AD of homoallyllic alcohol substrates
is to introduce different protecting groups on the homoallylic
alcohol. Unfortunately, substrates 6 and 7 containing benzoyl
ester and silyl ether protective groups also showed very poor
diastereoselectivities ranging from 1:1.3 to 1:2 (Table 1, entries
3−6). The low diastereoselectivity was suspected to be a result
of the sterically encumbering C4 and C5 substituents. Thus, it
is likely that the substrate cannot fit in the active site of the
chiral catalyst and thereby allows for the nonselective
dihydroxylation to become the dominant mechanism. Others
have reported poor diastereoselectivities for the Sharpless AD
of homoallylic alcohol, ether, and ester substrates previously.17
The lack of selectivity when enlisting the Sharpless catalyst
prompted us to use the Upjohn dihydroxylation18 due its lower
cost (Scheme 3).19 Consequently, homoallylic alcohol 3 was
treated at room temperature with OsO4−NMO in tetrahy-
drofuran/water to furnish an 1:1 mixture of 2,4-anti triol 8 and
2,4-syn triol 9. Gratifyingly, 8 and 9 could be separated by silica
gel column chromatography to afford triol 8 in 49% yield and
diastereoisomer 9 in 44% yield.
substrate 8 as a TBDPS ether followed by treatment of the
intermediate diol with 2,2-DMP in presence of PPTS afforded
acetonide 8a. According to the C13 chemical shifts of the
acetonide methyl groups and quaternary carbon, it was
determined that 8a had a 2,4-anti configuration. Having
established the absolute configuration of C4 through Mosher
ester analysis of alcohol 3, the absolute configuration of C2 in
triol 8 was thus determined to be S. The same procedure was
applied to triol 9 to afford acetonide 9a. The 13C NMR data
was consistent with the assignment of a 2,4-syn configuration
for 9a and, thus, an R-configured C2 stereocenter.
Having set and defined all the necessary stereocenters in triol
8, the synthesis of L-colitose 1 was completed (Scheme 5).
Strategically, a building block with a C2 nonparticipating
protecting group (Bn) was targeted as L-colitose is naturally
Table 1. Survey of Dihydroxylation Attempts
a,b
entry
substrate
conditions
dr
1
2
3
4
5
6
3
3
6
6
7
AD-mix β, tBuOH/H2O (1:1), 0 °C, 12 h
AD-mix α, tBuOH/H2O (1:1), 0 °C, 12 h
AD-mix β, tBuOH/H2O (1:1), 0 °C, 48 h
AD-mix α, tBuOH/H2O (1:1), 0 °C, 12 h
AD-mix β, tBuOH/H2O (1:1), 0 °C, 12 h
AD-mix α, tBuOH/H2O (1:1), 0 °C, 12 h
1:1
1.5:1
2:1
2:1
1.3:1
1.7:1
7
a
b
1
Ratios determined by H NMR. Major and minor diastereomers of the product mixtures were not determined
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2,4-syn triol 9 was converted in three steps to primary alcohol
13 in 50% overall yield. A major undesired byproduct of this
reaction sequence was the formation of the C2−C4 six-
membered benzylidene acetal.24 The six-membered ring forms
more easily here (in contrast to the conversion of the 2,4-anti
triol 8 to 10) due to the formation of a six-membered acetal
where all substituents occupy equatorial positions. Oxidation of
primary alcohol 13 gave aldehyde 14 in 85% yield. Following 2-
naphthylmethyl cleavage in the presence of DDQ, treatment of
the intermediate acetal with trichloroacetonitrile and DBU
afforded 2-epi-colitose trichloroacetimidate 15 in 84% overall
yield as a 9:1 α/β mixture. Coupling constant analysis of the
major α-anomer (3JH1,H2 < 1.0 Hz) of 15 is consistent with an
equatorial-equatorial proton coupling.
Scheme 5. Synthesis of L-Colitose Building Block 1
L-Rhodinose building block 18 was prepared because of the
presence of this motif in different classes of polyketides with
antitumor and antibacterial activity25 (Scheme 7). After
Scheme 7. Synthesis of L-Rhodinose Building Block 18
only found α-linked to other sugars. An electron-withdrawing
protecting group (Bz) was to be placed in the C4 position to
stabilize the electron rich deoxysugar building block. Thus, triol
8 was converted selectively to five-membered benzylidene
acetal 10. The remaining hydroxyl group in 10 was
benzoylated, and the benzylidene was regioselectively opened
using BH3·THF/TMSOTf to afford primary alcohol 11 in 71%
yield over three steps. Although alcohol 11 could not be
converted to corresponding aldehyde 2 using Swern21 or
Parikh−Doering22 conditions, Dess−Martin periodinane23
provided aldehyde 2 in 92% yield. Removal of the 2-
naphthylmethyl protecting group in 2 with DDQ led to the
corresponding hemiacetal, which was treated with trichlor-
oacetonitrile in the presence of DBU to give L-colitose
trichloroacetimidate 1 as a 1.6:1 α/β mixture in 79% yield
over two steps. Coupling constant analysis of the α-anomer
(3JH1,H2 = 3.2 Hz) and β-anomer (3JH1,H2 = 7.6 Hz) of imidate 1
are consistent with an axially oriented H2, confirming the C13
acetonide analysis of intermediate 8.
protection of secondary alcohol 3 as a benzoyl ester,
rhodium-catalyzed hydroboration26 in the presence of
catecholborane furnished alcohol 16 in 95% yield over two
steps. Parikh−Doering oxidation of alcohol 16 to the
corresponding aldehyde followed by cleavage of the 2-
naphthylmethyl protecting group in the presence of DDQ
and in situ cyclization afforded intermediary hemiacetal 17 as an
1:1 α/β anomeric mixture in 85% yield over two steps. Since L-
rhodinosyl acetates have been shown to be efficient
glycosylating agents,27 hemiacetal 17 was quantitatively
converted into the corresponding glycosylating agent by
treatment with acetic anhydride and pyridine. Thus, L-
rhodinosyl acetate 18 was prepared in eight steps and 57%
overall yield starting from inexpensive (S)-ethyl lactate.
Scheme 6. Synthesis of 2-epi-Colitose Building Block 15
CONCLUSION
■
In summary, we have developed a practical synthesis of a fully
functionalized L-colitose glycosylating agent in 10 steps with
18% overall yield starting from commercially available (S)-ethyl
lactate. The divergent route also allowed us to prepare two
other congeners of L-colitose: a 2-epi-colitose building block
(11% overall yield) and a L-rhodinose building block (57%
overall yield) from advanced intermediate 3. The key step of
this synthesis is the allylation reaction under Cram-chelated
control that introduces the hydroxyl group at C4 in a
stereoselective manner. This approach could be extended to
As a means to access derivatives of carbohydrates that are not
found in nature, the de novo approach was applied toward the
synthesis of 2-epi-colitose building block 15 (Scheme 6). Such
non-natural analogues serve as important probes when
determining the epitope of oligosaccharide antigens. Thus,
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alcohol 3 (4.8 g, 18.7 mmol, 91%) as a colorless oil: [α]20 +39.6 (c
the preparation of other natural and non-natural 3,6-dideoxy L-
and D-hexoses. This methodology will be of particular use for
the synthesis of natural products and for the basis of
oligosaccharide conjugate vaccines against bacteria that contain
the respective glycans on their surface.
D
0.42, CHCl3); Rf 0.67 (toluene/acetone = 80:20); 1H NMR (400
MHz, CDCl3) δ 7.84−7.78 (m, 4H), 7.51−7.45 (m, 3H), 5.93−5.83
(m, 1H), 5.13− 5.07 (m, 2H), 4.83 (d, J = 11.6 Hz, 1H), 4.62 (d, J =
11.6 Hz, 1H), 3.58−3.54 (m, 1H), 3.53−3.47 (m, 1H), 2.54 (bs, 1H),
2.40−2.34 (m, 1H), 2.26−2.19 (m, 1H), 1.25 (d, J = 6.0 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 135.9, 134.9, 133.4, 133.1, 128.4, 128.0,
127.8, 126.6, 126.3, 126.0, 125.9, 117.4, 77.7, 74.4, 71.3, 37.7, 15.6; IR
(thin film) 3249, 2976, 2924, 2853, 1670, 1641, 1605, 1509, 1374,
1325 cm−1; HRMS(ESI) m/z calcd for (M + Na)+ C17H20O2Na
279.1361, found 279.1358.
EXPERIMENTAL SECTION
■
General Experimental Details. Commercial grade reagents and
solvents were used without further purification except as indicated
below. All reactions were conducted under an Ar atmosphere. The
term “concentrated” refers to the removal of solvents and other
volatile material using a rotary evaporator while maintaining a water
bath temperature under 40 °C. The compounds purified by flash
chromatography are further concentrated by the removal of residual
solvent under high vacuum (<0.2 mbar). Analytical thin layer
chromatography (TLC) was performed on Kieselgel 60 F254 glass
plates precoated with a 0.25 mm thickness of silica gel. The TLC
plates were visualized with UV light and by staining with Hanessian
solution (ceric sulfate and ammonium molybdate in aqueous sulfuric
acid) or potassium permanganate solution (potassium permanganate
in basic aqueous solution). Column chromatography was performed
using Kieselgel 60 (230−400 mesh) silica gel with a typical 50−100:1
weight ratio of silica gel to crude product.
The absolute configuration of the C4-hydroxyl group for compound
1
3 was assigned by H NMR analysis of the Mosher ester.
(4S,5S)-4-O-(Benzoyl)-5-(naphthalen-2-ylmethoxy)hexene
(6). A solution of alcohol 3 (827 mg, 3.23 mmol) in pyridine (16 mL)
was treated at 0 °C with BzCl (0.75 mL, 6.45 mmol). After 2 h of
stirring at rt the mixture was concentrated. The crude was diluted with
DCM and washed with HCl, water, and brine. The organic layer was
dried over MgSO4 and concentrated. Flash column chromatography
(cyclohexane/AcOEt = 100:0 to 70:30) gave benzoate 6 (1.16 g, 3.2
(S)-Ethyl 2-(Naphthalen-2-ylmethoxy)propanoate (SI1). At 0
°C, a solution of (S)-ethyl lactate (5.0 mL, 44 mmol) and 2-
naphthylmethyl bromide (10.6 g, 48 mmol, 1.1 equiv) in DMF (146
mL) was treated with NaH (60% in mineral oil, 1.9 g, 48 mmol). The
reaction mixture was stirred at rt for 2 h and quenched by adding
ethanol. The reaction was extracted with Et2O. The combined organic
extracts were washed with H2O and brine, dried over MgSO4, and
concentrated under reduced pressure. The crude product was purified
by flash column chromatography (cyclohexane/AcOEt = 100:0 to
90:10) to yield the naphthyl ether (10.6 g, 41 mmol, 94%) as a yellow
mmol, 100%) as a colorless oil: [α]20 −6.5 (c 1, CHCl3); Rf 0.68
D
(cyclohexane/AcOEt = 70:30); 1H NMR (400 MHz, CDCl3) δ 8.06−
8.04 (m, 2H), 7.82−7.76 (m, 4H), 7.58−7.54 (m, 1H), 7.46−7.41 (m,
5H), 5.86−5.76 (m, 1H), 5.32−5.27 (m, 1H), 5.11 (dd, J = 17.2 Hz,
1.2 Hz, 1H), 5.03 (m, 1H), 4.82 (d, J = 12.0 Hz, 1H), 4.70 (d, J = 12.0
Hz, 1H), 3.82 (dq, J = 1.2, 6.4 Hz, 1H), 2.63−2.57 (m, 1H), 2.53−
2.45 (m, 1H), 1.27 (d, J = 6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3)
δ 166.3, 136.1, 133.9, 133.3, 133.09, 133.04, 130.5, 129.8 (2C), 128.4
(2C), 128.2, 128.0, 127.8, 126.5, 126.1, 125.99, 125.94, 117.9, 75.5,
74.8, 71.4, 34.5, 15.6; IR (thin film) 3059, 2979, 2934, 2867, 1716,
1643, 1602, 1584, 1509, 1491, 1451, 1373, 1349, 1314, 1272 cm−1;
HRMS(ESI) m/z calcd for (M + Na)+ C24H24O3Na 383.1623, found
383.1598.
oil: [α]D −62.6 (c 0.96, CHCl3); Rf 0.50 (cyclohexane/AcOEt =
20
1
80:20); H NMR (400 MHz, CDCl3) δ 7.90−7.77 (m, 4H), 7.54−
7.39 (m, 3H), 4.86 (d, J = 12.0 Hz, 1H), 4.62 (d, J = 12.0 Hz, 1H),
4.28−4.15 (m, 2H), 4.10 (q, J = 6.8 Hz, 1H), 1.46 (d, J = 6.8 Hz, 3H),
1.30 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 173.4, 135.2,
133.3, 133.2, 128.3, 128.0, 127.8, 126.9, 126.2, 126.08, 126.07, 74.1,
72.2, 61.0, 18.8, 14.4; IR (thin film) 3055, 2982, 2936, 1742, 1445,
1369, 1270 cm−1; HRMS(ESI) m/z calcd for (M + Na)+ C16H18O3Na
281.1154, found 281.1158.
(S)-2-(Naphthalen-2-ylmethoxy)propanal (4). To a solution of
2-naphthylmethyl ether SI1 (8.1 g, 31 mmol) in DCM (314 mL) was
added 1 M DIBAL solution in cyclohexane (34.5 mL, 34 mmol) at
−78 °C. After 1.5 h the reaction was quenched with methanol (80
mL) and was warmed to rt. A solution of potassium sodium tartrate
was added, and the mixture was stirred overnight and extracted with
DCM. The combined organic extracts were washed with H2O, dried
over MgSO4, and concentrated. Flash column chromatography
(cyclohexane/AcOEt = 100:0 to 90:10) on silica gel gave aldehyde
(4S,5S)-4-O-(tert-Butyldimethylsilyl)-5-(naphthalen-2-
ylmethoxy)hexene (7). A solution of alcohol 3 (150 mg, 0.58
mmol) in DCM (6 mL) was treated at 0 °C with 2,6-lutidine (0.14
mL, 1.1 mmol) and TBSOTf (0.2 mL, 0.9 mmol). After 2.5 h, the
reaction mixture was quenched with a saturated aq solution of
NaHCO3 (20 mL) and extracted with DCM. The combined organic
extracts were dried over MgSO4 and concentrated. Flash column
chromatography on silica gel (hexanes/AcOEt = 100:0 to 90:10)
afforded compound 7 (200 mg, 0.55 mmol, 95%) as a colorless oil:
4 (5.5 g, 25.6 mmol, 82%) as a colorless oil: [α]20 −34.5 (c 0.58,
1
[α]20 +1.4 (c 1.0, CHCl3); Rf 0.48 (hexanes/AcOEt = 90:10); H
D
D
1
CHCl3); Rf 0.75 (toluene/acetone = 80:20); H NMR (400 MHz,
NMR (400 MHz, CDCl3) δ 7.91−7.71 (m, 4H), 7.48−7.45 (m, 3H),
5.90−5.70 (m, 1H), 5.09−5.00 (m, 2H), 4.76 (d, J = 12.0 Hz, 1H),
4.69 (d, J = 12.0 Hz, 1H), 3.80−3.76 (m, 1H), 3.60−3.50 (m, 1H),
2.46−2.39 (m, 1H), 2.19−2.12 (m, 1H), 1.17 (d, J = 6.4 Hz, 3H), 0.62
(s, 9H), 0.01 (s, 3H), −0.02 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
136.6, 136.2, 133.4, 133.0, 128.1, 127.9, 127.8, 126.2, 126.1, 125.9,
125.8, 116.7, 77.5, 74.0, 71.3, 36.5, 26.0 (3C), 18.2, 14.2, −4.33,
−4.36; IR (thin film) 3058, 2953, 2926, 2855, 1729, 1642, 1603, 1509,
1462, 1377 cm−1; HRMS(ESI) m/z calcd for (M + Na)+
C23H34O2SiNa 393.2226, found 393.2231.
(2S,4S,5S)-5-(Naphthalen-2-ylmethoxy)hexane-1,2,4-triol (8)
and (2R,4S,5S)-5-(naphthalen-2-ylmethoxy)hexane-1,2,4-triol
(9). At 0 °C, N-methylmorpholin-N-oxide (2.5 g, 21 mmol) was
added to a solution of 3 (2.7 g, 10 mmol) in THF/H2O (53 mL, 2:1).
After 15 min, OsO4 (2.5 wt % solution in tert-butanol, 130 μL, 0.010
mmol) was added, and the mixture was stirred at rt overnight. After
dilution with AcOEt, the organic layer was washed with Na2S2O3, HCl,
CDCl3) δ 9.70 (d, J = 1.6 Hz, 1H), 7.93−7.75 (m, 4H), 7.58−7.43 (m,
3H), 4.83 (d, J = 12.0 Hz, 1H), 4.76 (d, J = 12.0 Hz, 1H), 3.95 (qd, J =
6.8, 1.6 Hz, 1H), 1.36 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 203.4, 134.9, 133.3, 133.2, 128.5, 128.0, 127.8, 127.0, 126.4,
126.2, 125.8, 79.5, 72.2, 15.4; IR (thin film) 3448, 3055, 2980, 2932,
2854, 2801, 2706, 1733, 1602, 1509, 1445, 1373, 1330 cm−1;
HRMS(ESI) m/z calcd for (M + Na)+ C14H14O2Na 237.0891,
found 237.0885.
(2S,3S)-2-(Naphthalen-2-ylmethoxy)hex-5-en-3-ol (3). SnCl4
(2.6 mL, 23 mmol) was added at −78 °C to a solution of aldehyde 4
(4.4 g, 20 mmol) in DCM (100 mL). After 15 min, allyltrimethylsilane
(3.6 mL, 23 mmol) was added, and the mixture was stirred at −78 °C
for 2 h, quenched with H2O, and warmed to rt. The mixture was
extracted with DCM, and the combined organic extracts were washed
with brine, dried over MgSO4, and concentrated. Flash column
chromatography on silica gel (hexanes/AcOEt = 90:10) afforded
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and water, dried over MgSO4, and concentrated. Flash column
chromatography (cyclohexane/AcOEt = 80:20) on silica gel afforded
2,4-anti triol 8 (1.5 g, 5.1 mmol, 49%) and the 2,4-syn triol 9 (1.3 g, 4.6
mmol, 44%) as white foams.
(2S,4S,5S)-5-(Naphthalen-2-ylmethoxy)hexane-1,2,4-triol
(8). [α]20D +35.2 (c 0.45, CHCl3); Rf 0.50 (toluene/acetone = 30:70);
1H NMR (400 MHz, CDCl3) δ 7.84−7.76 (m, 4H), 7.49−7.38 (m,
3H), 4.84 (d, J = 11.6 Hz, 1H), 4.60 (d, J = 11.6 Hz, 1H), 4.01−3.96
(m, 1H), 3.77−3.74 (m, 1H), 3.63 (dd, J = 11.2, 3.6 Hz, 1H), 3.54−
3.46 (m, 2H), 2.64 (bs, 3H), 1.70 (ddd, J = 14.4, 8.8, 3.2 Hz, 1H), 1.57
(ddd, J = 14.4, 9.2, 3.6 Hz, 1H), 1.23 (d, J = 6.0 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 135.6, 133.3, 133.1, 128.5, 128.0, 127.8, 126.7,
126.3, 126.1, 125.9, 78.5, 72.5, 71.3, 69.6, 67.0, 35.4, 15.6; IR (thin
film) 3372, 3054, 2923, 2871, 1712, 1633, 1602, 1509, 1453, 1401,
1375 cm−1; HRMS(ESI) m/z calcd for (M + Na)+ C17H22O4Na
313.1416, found 313.1435.
solution of NaHCO3, and filtered through Celite. The mixture was
extracted with DCM, and the combined organic layers were washed
with water and brine, dried over MgSO4, and concentrated. Flash
column chromatography on silica gel (hexanes/AcOEt = 80:20) gave
acetonide 9a (130 mg, 0.23 mmol, 95%) as a colorless oil: [α]D20 −0.7
1
(c 1.0, CHCl3); Rf 0.23 (hexanes/EtOAc = 90:10); H NMR (400
MHz, CDCl3) δ 7.85−7.80 (m, 4H), 7.72−7.65 (m, 3H), 7.54−7.32
(m, 10H), 4.80 (2d, J = 12.4, 12.4 Hz, 2H), 4.01−3.95 (m, 2H), 3.74
(dd, J = 10.4, 5.2 Hz, 1H), 3.62−3.52 (m, 2H), 1.59−1.51 (m, 1H),
1.42 (2s, 6H), 1.35−1.26 (m, 1H), 1.17 (d, J = 6.4 Hz, 3H), 1.07 (s,
9H); 13C NMR (101 MHz, CDCl3) δ 136.7, 135.8 (3C), 133.8, 133.4,
133.0, 129.75, 129.73, 128.1, 127.9, 127.8, 127.74 (3C), 127.73 (3C),
126.3, 126.1, 126.0, 125.8, 98.6, 77.0, 72.3, 71.9, 69.8, 67.7, 30.1, 28.9,
27.0 (3C), 19.9, 19.4, 15.3; IR (thin film) 3069, 3051, 2989, 2958,
2930, 2858, 1112 cm−1; HRMS(ESI) m/z calcd for (M + Na)+
C36H44O4SiNa 591.2907, found 591.2953.
(2S,3S)-3-(Naphthalen-2-ylmethoxy)-1-((S)-2-phenyl-1,3-di-
oxolan-4-yl)butan-2-ol (10). Triol 8 (1.30 g, 4.5 mmol), CuSO4
(2.10 g, 14 mmol) and CSA (52 mg, 0.22 mmol) were suspended in
CH3CN/THF (46 mL, 1:1). At 0 °C, benzaldehyde dimethyl acetal
(6.7 mL, 45 mmol) was added, and the mixture was stirred for 10 min,
neutralized with NaHCO3 and filtered through Celite. The mixture
was extracted with DCM and the combined organic layers were
washed with water and brine, dried over MgSO4, and concentrated.
Flash column chromatography on silica gel (hexanes/AcOEt/Et3N =
80:19:1) gave 1,2-hemiacetal 10 (1.42 g, 3.7 mmol, 83%) as a 9:1
(2R,4S,5S)-5-(Naphthalen-2-ylmethoxy)hexane-1,2,4-triol
(9). [α]20D +25.0 (c 0.65, CHCl3); Rf 0.59 (toluene/acetone = 30:70);
1H NMR (400 MHz, CDCl3) δ 7.86−7.77 (m, 4H), 7.51−7.43 (m,
3H), 4.84 (d, J = 11.6 Hz, 1H), 4.60 (d, J = 11.6 Hz, 1H), 3.99−3.94
(m, 1H), 3.79−3.74 (m, 1H), 3.63 (dd, J = 11.2, 3.6 Hz, 1H), 3.52−
3.42 (m, 2H), 3.24 (s, 1H), 2.36 (s, 2H), 1.66−1.59 (m, 2H), 1.22 (d,
J = 6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 135.5, 133.3, 133.1,
128.5, 128.0, 127.8, 126.7, 126.4, 126.2, 125.9, 78.5, 75.2, 71.8, 71.3,
66.7, 35.3, 15.4; IR (thin film) 3367, 3054, 2923, 2870, 1712, 1633,
1602, 1509, 1449, 1400, 1374 cm−1; HRMS(ESI) m/z calcd for (M +
Na)+ C17H22O4Na 313.1416, found 313.1426.
mixture of diastereoisomers: [α]20 +1.44 (c 1.0, CHCl3); Rf 0.25
D
(hexanes/AcOEt = 70:30); 1H NMR (400 MHz, CDCl3) δ 7.91−7.68
(m, 4H), 7.53−7.42 (m, 5H), 7.41−7.33 (m, 3H), 5.82 (s, 1H), 4.84
(d, J = 12.0 Hz, 1H), 4.61 (d, J = 12.0 Hz, 1H), 4.51−4.48 (m, 1H),
4.18 (dd, J = 8.0, 6.8 Hz, 1H), 3.81−3.71 (m, 2H), 3.49−3.43 (m,
1H), 2.65 (dd, J = 4.0, 0.8 Hz, 1H), 1.96−1.86 (m, 1H), 1.76 (ddd, J =
15.6, 10.4, 5.2 Hz, 1H), 1.24 (d, J = 6.4 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 137.8, 135.6, 133.2, 132.9, 129.2, 128.3 (2C), 128.2,
127.8, 127.7, 126.5 (2C), 126.4, 126.1, 125.9, 125.7, 103.7, 78.3, 75.0,
72.14, 71.10, 70.6, 37.0, 15.5; IR (thin film) 3474, 3053, 2952, 2924,
2874, 1087, 1067 cm−1; HRMS(ESI) m/z calcd for (M + Na)+
C24H26O4Na 401.1729, found 401.1734.
Stereochemical Proof of 8: Synthesis of (2S,4S,5S)-1-(tert-
Butyldiphenylsilyloxy)-2,4-isopropanedioxy-5-(naphthalen-2-
ylmethoxy)-hexane (8a). To a mixture of triol 8 (100 mg, 0.34
mmol), imidazole (28 mg, 0.41 mmol), and DMAP (9 mg, 0.07
mmol) in DCM (3.4 mL) was added TBDPSCl (100 μL, 0.38 mmol).
The mixture was stirred for 18 h at rt, then diluted with DCM, washed
with a saturated aq solution of NH4Cl, water, and brine, and dried over
MgSO4. Following removal of the solvents in vacuo, the crude product
was run through a plug of silica gel (hexanes/AcOEt = 100:0 to 70:30)
to furnish 180 mg of crude silyl ether. The crude silyl ether dissolved
in anhydrous DCM (3.5 mL) was treated with PPTS (17 mg, 0.07
mmol) and 2,2-DMP (220 μL, 1.7 mmol). The mixture was stirred at
rt for 4 h and neutralized with an aq saturated solution of NaHCO3.
The mixture was extracted with DCM, and the combined organic
layers were washed with water and brine, dried over MgSO4, and
concentrated. Flash column chromatography on silica gel (hexanes/
AcOEt = 80:20) gave acetonide 8a (163 mg, 0.29 mmol, 83%) as a
colorless oil: [α]D20 −11.7 (c 2.0, CHCl3); Rf 0.23 (hexanes/EtOAc =
(2S,4S,5S)-5-(Benzyloxy)-6-hydroxy-2-(naphthalen-2-
ylmethoxy)hexan-3-yl Benzoate (11). At 0 °C, BzCl (0.8 mL, 6.8
mmol) was added to the solution of hemiacetal 10 (1.3 g, 3.43 mmol)
in pyridine (16 mL). The mixture was stirred at rt for 2 h and
concentrated. The crude was dissolved in DCM and washed with HCl
and water. The organic layer was dried over MgSO4 and concentrated
to give the ester. The crude ester in DCM (35 mL) was treated at 0 °C
with a 1 M BH3 solution in THF (10.2 mL, 10.2 mmol). After 15 min
TMSOTf (62 μL, 0.34 mmol) was added, and the mixture was
warmed slowly at rt. After 1 h, the reaction mixture was cooled to 0
°C, quenched with MeOH (8.5 mL) and Et3N (0.35 mL), and
concentrated. The crude oil was diluted in DCM, washed with water
and brine, dried over MgSO4, and concentrated. Flash column
chromatography (hexanes/AcOEt = 70:30) on silica gel afforded
1
90:10); H NMR (600 MHz, CDCl3) δ 7.83−7.80 (m, 4H), 7.71−
7.69 (m, 3H), 7.50−7.36 (m, 10H), 4.83 (d, J = 12.0 Hz, 1H), 4.79 (d,
J = 12.0 Hz, 1H), 3.99−3.93 (m, 1H), 3.89−3.86 (m, 1H), 3.74 (dd, J
= 10.8, 6.0 Hz, 1H), 3.64 (dd, J = 10.8, 4.2 Hz, 1H), 3.60−3.54 (m,
1H), 1.74 (ddd, J = 15.6, 10.2, 6.6 Hz, 1H), 1.53 (ddd, J = 15.6, 9.6,
6.0 Hz, 1H), 1.41 (2s, 6H), 1.18 (d, J = 6.6 Hz, 3H), 1.08 (s, 9H); 13C
NMR (151 MHz, CDCl3) δ 136.7, 135.85 (2C), 135.81 (2C), 133.9,
133.8, 133.4, 133.0, 129.73, 129.71, 128.1, 127.9, 127.8, 127.73 (2C),
127.71 (2C), 126.3, 126.1, 126.0, 125.8, 100.5, 76.4, 71.8, 70.4, 67.9,
66.9, 30.5, 26.9 (3C), 25.0, 24.8, 19.4, 15.6; IR (thin film) 3069, 3051,
2989, 2958, 2930, 2858, 1112 cm−1; HRMS(ESI) m/z calcd for (M +
Na)+ C36H44O4SiNa 591.2907, found 591.2894.
Stereochemical Proof of 9: Synthesis of (2R,4S,5S)-1-(tert-
Butyldiphenylsilyloxy)-2,4-isopropanedioxy-5-(naphthalen-2-
ylmethoxy)-hexane (9a). To a mixture of triol 9 (70 mg, 0.24
mmol), imidazole (20 mg, 0.28 mmol), and DMAP (6 mg, 0.05
mmol) in DCM (2.5 mL) was added TBDPSCl (70 μL, 0.26 mmol).
The mixture was stirred for 18 h at rt, then diluted with DCM, washed
with a saturated aq solution of NH4Cl, water, and brine, and dried over
MgSO4. Following removal of the solvents in vacuo, the crude product
was run through a plug of silica gel (hexanes/AcOEt = 100:0 to 70:30)
to furnish 125 mg of crude silyl ether. The crude silyl ether dissolved
in acetone (3.5 mL) was treated with CuSO4 (115 mg, 0.72 mmol),
PPTS (12 mg, 0.05 mmol), and 2,2-DMP (150 μL, 1.2 mmol). The
mixture was stirred at rt for 10 min, neutralized with an aq saturated
alcohol 11 (1.4 g, 2.9 mmol, 86% over 2 steps) as a white foam: [α]20
+29.4 (c 1.2, CHCl3); Rf 0.31 (hexanes/AcOEt = 70:30); H NMR
D
1
(400 MHz, CDCl3) δ 8.07 (d, J = 7.6 Hz, 2H), 7.81−7.75 (m, 4H),
7.58 (t, J = 7.6 Hz, 1H), 7.47−7.41 (m, 5H), 7.37−7.21 (m, 5H), 5.60
(ddd, J = 10.4, 4.4, 2.4 Hz, 1H), 4.80 (d, J = 12.0 Hz, 1H), 4.71 (d, J =
12.0 Hz, 1H), 4.56 (d, J = 10.8 Hz, 1H), 4.51 (d, J = 10.8 Hz, 1H),
3.85−3.76 (m, 2H), 3.63−3.57 (m, 1H), 3.57−3.48 (m, 1H), 2.13
(ddd, J = 14.8, 9.2, 2.4 Hz, 1H), 1.94 (dd, J = 14.8, 10.4, 3.6 Hz, 1H),
1.79 (bs, 1H), 1.26 (d, J = 6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3)
δ 166.2, 139.1, 138.2, 133.3, 133.1, 133.0, 130.3, 129.8 (2C), 128.6
(2C), 128.5 (2C), 128.21 (2C), 128.20, 128.0, 127.9, 127.7, 126.5,
126.1, 126.0, 125.9, 76.6, 75.2, 72.8, 72.4, 71.3, 64.4, 32.0, 15.4; IR
(thin film) 3470, 3060, 2976, 2927, 2871, 1714, 1621, 1601, 1584,
1509, 1487, 1458, 1450, 1376, 1343 cm−1; HRMS(ESI) m/z calcd for
(M + H)+ C31H33O5 485.2328, found 485.2326.
(2S,3S,5S)-5-(Benzyloxy)-2-(naphthalen-2-ylmethoxy)-6-ox-
ohexan-3-yl Benzoate (2). Alcohol 11 (1.00 g, 2.0 mmol), Dess−
Martin periodinane (2.63 g, 6.2 mmol), and pyridine (1.7 mL, 20.6
874
dx.doi.org/10.1021/jo201883k | J. Org. Chem. 2012, 77, 870−877

The Journal of Organic Chemistry
Article
mmol) in DCM (9 mL) were stirred at rt for 1 h. After addition of a
saturated aq solution of Na2S2O3 (10 mL) and a saturated aq solution
of NaHCO3 (10 mL), the mixture was stirred for additional 15 min.
The mixture was extracted with DCM, and the organic layer was
washed with H2O, dried over MgSO4, and concentrated. Flash column
chromatography (cyclohexane/AcOEt = 100:0 to 80:20) on silica gel
Hz, 3H, H6-α); 13C NMR (151 MHz, CDCl3) δ 166.1, 165.9, 161.59,
161.57, 138.0, 137.8, 133.42, 133.40, 130.0, 129.9 (2C), 129.8 (4C),
128.66 (3C), 128.61, 128.53 (3C), 128.50, 127.92, 127.90 (2C), 127.8
(2C), 100.1 (1JC1−H1 = 168.1 Hz, C1-β), 94.1 (1JC1−H1 = 178.4 Hz, C1-
α), 91.6 (CCl3), 91.1 (CCl3), 73.5 (C2-β), 73.0 (CH2-β), 72.2 (C2-α),
71.3 (CH2-α), 71.2 (C4-β), 70.7 (C4-α), 70.1 (C5-β), 68.0 (C5-α),
34.0 (C3-β), 29.8 (C3-α), 16.69 (C6-β), 16.62 (C6-α); IR (thin film)
3406, 3344, 2926, 2857, 1718, 1671, 1601, 1497, 1452, 1359 cm−1;
HRMS(ESI) m/z calcd for (M + Na)+ C22H22Cl3NO5Na 508.0461,
found 508.0434.
afforded aldehyde 2 (886 mg, 1.84 mmol, 92%) as white foam: [α]20
D
1
−19.4 (c 0.64, CHCl3); Rf 0.57 (cyclohexane/AcOEt = 70:30); H
NMR (400 MHz, CDCl3) δ 9.66 (d, J = 2.0 Hz, 1H), 8.06−8.02 (m,
2H), 7.83−7.73 (m, 4H), 7.61−7.55 (m, 1H), 7.48−7.41 (m, 5H),
7.34−7.19 (m, 5H), 5.61 (ddd, J = 10.4, 4.4, 2.4 Hz, 1H), 4.79 (d, J =
12.4 Hz, 1H), 4.70 (d, J = 12.4 Hz, 1H), 4.59 (d, J = 11.2 Hz, 1H),
4.53 (d, J = 11.2 Hz, 1H), 3.89−3.80 (m, 2H), 2.17 (ddd, J = 14.4,
10.4, 3.2 Hz, 1H), 2.04 (ddd, J = 14.4, 10.4, 2.4 Hz, 1H), 1.17 (d, J =
6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 203.4, 166.1, 137.0,
135.8, 133.38, 133.30, 133.1, 130.0, 129.90 (2C), 128.6 (2C), 128.5
(4C), 128.28, 128.27, 128.0, 127.8, 126.6, 126.1, 126.0, 125.9, 80.6,
74.8, 73.5, 71.5, 71.4, 30.5, 15.3; IR (thin film) 3061, 3032, 2976, 2926,
2864, 2714, 1718, 1601, 1585, 1509, 1495, 1452, 1377 cm−1;
HRMS(ESI) m/z calcd for (M + Na)+ C31H30O5Na 505.1991,
found 505.1970.
(2S,3S)-3-(Naphthalen-2-ylmethoxy)-1-((R)-2-phenyl-1,3-di-
oxolan-4-yl)butan-2-ol (12). Using the same procedure as for
compound 10, benzylidene acetal 12 was synthesized starting from
triol 9 (1.2 g, 4.1 mmol) in 61% yield as a 1.6:1 diatereoisomeric
mixture: [α]20 +17.0 (c 1.0, CHCl3); Rf 0.37 (hexanes/AcOEt =
D
1
70:30); H NMR (400 MHz, CDCl3) δ 7.85−7.78 (m, 8H), 7.50−
7.44 (m, 10H), 7.38−7.36 (m, 6H), 5.96 (s, 1H), 5.80 (s, 1H), 4.84 (d,
J = 11.6 Hz, 2H), 4.63 (d, J = 11.6 Hz, 2H), 4.47−4.40 (m, 2H), 4.28
(dd, J = 8.0, 6.0 Hz, 1H), 4.13 (dd, J = 7.6, 6.8 Hz, 1H), 3.78−3.67 (m,
4H), 3.65−3.59 (m, 2H), 2.99 (d, J = 2.4 Hz, 1H), 2.89 (d, J = 2.8 Hz,
1H), 2.00−1.80 (m, 4H), 1.27 (2d, J = 6.4 Hz, J = 6.8 Hz, 6H); 13C
NMR (101 MHz, CDCl3) δ 138.2, 137.6, 135.89, 135.88, 133.3 (2C),
133.1 (2C), 129.4, 129.2, 128.5 (2C), 128.4 (2C), 128.3 (2C), 127.9
(2C), 127.8 (2C), 126.7, 126.67, 126.66, 126.4 (3C), 126.3 (2C),
126.1 (2C), 125.96, 125.95, 104.2, 103.3, 77.6, 77.4, 75.4, 74.7, 72.9,
71.2 (2C), 70.9 (2C), 70.2, 35.9, 35.5, 15.25, 15.22; IR (thin film)
3496, 3056, 2924, 2871, 1087, 1068 cm−1; HRMS(ESI) m/z calcd for
(M + Na)+ C24H26O4Na 401.1729, found 401.1750.
4-O-Benzoyl-2-O-benzyl-3,6-dideoxy-L-galactohexopyra-
nose (SI2). At 0 °C, DDQ (917 mg, 4.04 mmol) was added to a
solution of aldehyde 2 (650 mg, 1.34 mmol) in DCM/MeOH (135
mL, 9:1). The mixture was slowly warmed to rt and stirred for 3 h,
then diluted with Et2O, and quenched with saturated aq solutions of
NaHCO3 and Na2S2O3. After separation of the layers, the organic layer
was washed with H2O, dried over MgSO4, and concentrated. Flash
column chromatography (hexanes/AcOEt = 70:30) on silica gel gave a
1:1 α/β mixture of the target hemiacetal (SI2) (383 mg, 1.12 mmol)
(2S,4S,5R)-5-(Benzyloxy)-6-hydroxy-2-(naphthalen-2-
ylmethoxy)hexan-3-yl Benzoate (13). Using the same procedure
as for compound 11, alcohol 13 was synthesized starting from
benzylidene acetal 12 (0.90 g, 2.4 mmol) in 82% yield as a white foam:
[α]20D +3.6 (c 0.8, CHCl3); Rf 0.25 (cyclohexane/AcOEt = 70:30); 1H
NMR (400 MHz, CDCl3) δ 8.03 (m, 2H), 7.85−7.72 (m, 4H), 7.60−
7.54 (m, 1H), 7.50−7.40 (m, 5H), 7.26 −7.21 (m, 5H), 5.42−5.35 (m,
1H), 4.81 (d, J = 12.0 Hz, 1H), 4.66 (d, J = 12.0 Hz, 1H), 4.52 (d, J =
11.6 Hz, 1H), 4.47 (d, J = 11.6 Hz, 1H), 3.85−3.70 (m, 2H), 3.64−
3.50 (m, 2H), 2.17−2.08 (m, 2H), 1.87 (bs, 1H), 1.24 (d, J = 6.4 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 166.2, 138.1, 135.9, 133.3,
133.19, 133.10, 130.2, 129.8 (2C), 128.5 (4C), 128.2, 128.0, 127.9
(2C), 127.85, 127.81, 126.6, 126.2, 126.03, 126.02, 76.7, 74.7, 73.0,
71.3, 71.2, 63.7, 30.7, 15.3; IR (thin film) 3469, 3060, 2926, 2871,
1714, 1602, 1584, 1509, 1495, 1451, 1375, 1345 cm−1; HRMS(ESI)
m/z calcd for (M + Na)+ C31H32O5Na 507.2147, found 507.2164.
(2S,3S,5R)-5-(Benzyloxy)-2-(naphthalen-2-ylmethoxy)-6-ox-
ohexan-3-yl Benzoate (14). Using the same procedure as for
compound 2, aldehyde 14 was synthesized starting from alcohol 13
(720 mg, 1.48 mmol) in 85% yield as white foam: [α]20D +4.0 (c 0.62,
CHCl3); Rf 0.53 (cyclohexane/AcOEt = 70:30); 1H NMR (400 MHz,
CDCl3) δ 9.58 (d, J = 1.2 Hz, 1H), 8.06−7.95 (m, 2H), 7.87−7.70 (m,
4H), 7.54 (t, J = 7.6 Hz, 1H), 7.47−7.38 (m, 5H), 7.23−7.19 (m, 5H),
5.54−5.50 (m, 1H), 4.78 (d, J = 12.0 Hz, 1H), 4.65 (d, J = 12.0 Hz,
1H), 4.56 (d, J = 11.6 Hz, 1H), 4.44 (d, J = 11.6 Hz, 1H), 3.86 (td, J =
5.6, 1.2 Hz, 1H), 3.78−3.72 (m, 1H), 2.29 (ddd, J = 14.8, 5.6, 4.4 Hz,
1H), 2.17 (ddd, J = 14.8, 8.8, 5.6 Hz, 1H), 1.21 (d, J = 6.4 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 203.3, 165.8, 137.1, 135.8, 133.3,
133.2, 133.1, 130.12, 129.8 (2C), 128.6 (2C), 128.5 (2C), 128.3,
128.14, 128.12 (2C), 128.0, 127.8, 126.6, 126.2, 126.04, 126.02, 80.5,
74.1, 72.4, 71.8, 71.3, 30.3, 15.0; IR (thin film) 3061, 2978, 2930, 2866,
2714, 1718, 1601, 1584, 1509, 1495, 1452, 1377, 1338 cm−1;
HRMS(ESI) m/z calcd for (M + Na + MeOH)+ C32H34O6Na
537.2253, found 537.2243.
4-O-Benzoyl-2-O-benzyl-3,6-dideoxy-L-talohexopyranose
(SI3). At 0 °C, DDQ (520 mg, 2.3 mmol) was added to a solution of
aldehyde 14 (370 mg, 0.76 mmol) in DCM/MeOH (76 mL, 9:1). The
mixture was slowly warmed to rt and stirred for 3 h, then diluted with
Et2O, and quenched with NaHCO3 and Na2S2O3. After separation of
the layers, the organic layer was washed with H2O, dried over MgSO4,
and concentrated. Flash column chromatography (hexanes/AcOEt =
70:30) on silica gel gave a 1:1 α/β mixture of hemiacetal SI3 (247 mg,
in 83% yield as a colorless oil: [α]20 −29.6 (c 2.0, CHCl3); Rf 0.28
D
(hexanes/AcOEt = 60:40); 1H NMR (400 MHz, CDCl3) δ 8.08−8.03
(m, 4H), 7.61−7.57 (m, 2H), 7.48−7.44 (m, 4H), 7.33−7.24 (m,
10H), 5.35 (d, J = 2.8 Hz, 1H, H1-α), 5.24−5.21 (m, 1H, H4-α),
5.19−5.17 (m, 1H, H4-β), 4.78 (2d, J = 7.2 Hz, J = 11.6 Hz, 2H, H1-β,
CH2Ph-β), 4.70−4.58 (m, 2H, CH2Ph-β, CH2Ph-α), 4.55 (d, J = 11.6
Hz, 1H, CH2Ph-α), 4.36 (qd, J = 6.4, 1.2 Hz, H5-α), 3.93−3.58 (m,
2H, H5-β, H2-α), 3.57 (ddd, J = 5.2, 11.6, 7.6 Hz, 1H, H2-β), 3.08 (bs,
1H, OH-β), 2.85 (bs, 1H, OH-α), 2.45 (ddd, J = 14.4, 5.2, 3.2 Hz, 1H,
H3-βeq), 2.24 (dddd, J = 13.6, 3.6, 4.8, 0.8 Hz, 1H, H3-αeq), 2.15 (ddd,
J = 13.6, 11.6, 3.2 Hz, 1H, H3-αax), 1.81 (ddd, J = 14.4, 11.6, 3.2 Hz,
1H, H3-βax), 1.26 (d, J = 6.4 Hz, 3H, H6-β), 1.18 (d, J = 6.4 Hz, 3H,
H6-α); 13C NMR (101 MHz, CDCl3) δ 166.1, 166.0, 138.2, 137.6,
133.3, 133.2, 130.1, 129.99, 129.93 (2C), 129.8 (2C), 128.58 (2C),
128.56 (3C), 128.50 (2C), 128.06 (2C), 128.04 (2C), 127.96 (2C),
127.8, 98.9 (1JC1−H1 = 163.9 Hz, C1-β), 91.0 (1JC1−H1 = 175.0 Hz, C1-
α), 74.5 (C2-β), 72.8 (C2-α), 72.7 (CH2-β), 71.6 (C4-α), 71.3 (C4-
β), 71.0 (CH2-α), 70.9 (C5-β), 65.2 (C5-α), 34.0 (C3-β), 28.4 (C3-α),
16.8 (C6-β), 16.5 (C6-α); IR (thin film) 3417, 3064, 3032, 2982,
2937, 2874, 1715, 1267 cm−1; HRMS(ESI) m/z calcd for (M + Na)+
C20H22O5Na 365.1365, found 365.1363.
4-O-Benzoyl-2-O-benzyl-3,6-dideoxy-L-galactohexopyrano-
syltrichloroacetimidate (1). At 0 °C, DBU (11 μL, 0.07 mmol) and
Cl3CCN (190 μL, 1.89 mmol) were added to a solution of lactol SI2
(130 mg, 0.38 mmol) in DCM (1.5 mL). The reaction mixture was
stirred for 3 h at 0 °C and concentrated. Flash column
chromatography (hexanes/AcOEt/Et3N = 80:19:1) on silica gel
yielded imidate 1 (176 mg, 0.36 mmol) in 95% yield in an α/β
ratio of 1.6:1 as a colorless oil: [α]20 −24.4 (c 0.40, CHCl3); Rf 1α
D
0.68 (hexanes/AcOEt/Et3N = 70:29:1); Rf 1β 0.50 (hexanes/AcOEt/
Et3N = 70:29:1); 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H, NH-β),
8.61 (s, 1H, NH-α), 8.08−8.02 (m, 4H), 7.62−7.57 (m, 2H), 7.51−
7.45 (m, 4H), 7.31−7.20 (m, 10H), 6.56 (d, J = 3.2 Hz, 1H, H1-α),
5.87 (d, J = 7.6 Hz, 1H, H1-β), 5.33−5.30 (m, 1H, H4-α), 5.25−5.23
(m, 1H, H4-β), 4.80 (d, J = 11.6 Hz, 1H, CH2-β), 4.67−4.62 (m, 2H,
CH2-α, CH2-β), 4.57 (d, J = 12.0 Hz, 1H, CH2-α), 4.32 (qd, J = 6.8,
2.0 Hz, 1H, H5-α), 4.09−4.03 (m, 2H, H2-α, H5-β), 3.87 (ddd, J =
11.2, 7.6, 4.8 Hz, 1H, H2-β), 2.47 (ddd, J = 14.4, 4.8, 3.6 Hz, 1H,
H3eq-β), 2.38−2.27 (m, 2H, H3eq-α, H3a-α), 1.96 (ddd, J = 14.4, 11.2,
3.6 Hz, 1H, H3a-α), 1.29 (d, J = 6.4 Hz, 3H, H6-β), 1.20 (d, J = 6.8
875
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The Journal of Organic Chemistry
Article
0.72 mmol) in 94% yield as a colorless oil: [α]20 −49.9 (c 1.0,
mmol). After 1 h, the reaction mixture was quenched with a saturated
aq solution of Na2S2O3 (12 mL) and warmed to rt. The aq layer was
extracted with DCM. The combined organic layers were dried over
MgSO4 and concentrated. Flash column chromatography (hexanes/
AcOEt = 80:20) on silica gel afforded aldehyde SI4 (439 mg, 1.16
D
1
CHCl3); Rf 0.28 (hexanes/AcOEt = 70:30); H NMR (400 MHz,
CDCl3) δ 8.16−8.12 (m, 4H), 7.61−7.54 (m, 2H), 7.45−7.35 (m,
4H), 7.27−7.18 (m, 10H), 5.43 (s, 1H, H1-α), 5.13−5.10 (m, 1H, H4-
α), 5.05−5.03 (m, 1H, H4-β), 4.91−4.80 (dd, J = 12.4 Hz, J < 1.0 Hz,
1H, H1-β), 4.64 (d, J = 11.6 Hz, 1H, CH2-β), 4.58 (d, J = 11.6 Hz, 1H,
CH2-α), 4.54 (d, J = 11.6 Hz, 1H, CH2-α), 4.47 (qd, J = 6.4, 1.6 Hz,
1H, H5-α), 4.42 (d, J = 11.6 Hz, 1H, CH2-β), 4.26 (d, J = 12.4 Hz, 1H,
OH-β), 3.95 (qd, J = 6.4, 1.6 Hz, 1H, H5-β), 3.65−3.63 (m, 1H, H2-
β), 3.56−3.54 (m, 1H, H2-α), 3.15 (bs, 1H, OH-α), 2.74 (adt, J =
16.0, 2.4 Hz, 1H, H3-βeq), 2.41 (adtd, J = 15.4, 3.2, 1.2 Hz, 1H, H3-
αeq), 2.24 (adt, J = 15.4, 3.6 Hz, 1H, H3-αax), 1.91 (adt, J = 16.0, 3.6
Hz, 1H, H3-βax), 1.36 (d, J = 6.4 Hz, 3H, H6-β), 1.30 (d, J = 6.4 Hz,
3H, H6-α); 13C NMR (101 MHz, CDCl3) δ 166.63, 166.61, 138.0,
137.2, 133.1, 132.9, 130.3, 130.1, 130.08 (2C), 130.04 (2C), 128.4
(4C), 128.39 (2C), 128.32 (2C), 128.1 (2C), 127.9, 127.8 (2C),
127.5, 94.7 (1JC1−H1 = 164.8 Hz, C1-β), 93.1 (1JC1−H1 = 173.7 Hz, C1-
α), 72.9 (C5-β), 71.9 (C2-β), 71.7 (C2-α), 71.5 (CH2-β), 71.1 (CH2-
α), 68.7 (C4-α), 67.7 (C4-β), 65.2 (C5-α), 29.6 (C3-β), 26.4 (C3-α),
17.2 (C6-β), 16.8 (C6-α); IR (thin film) 3427, 3064, 3032, 2982,
2936, 2874, 1709, 1271, 1068 cm−1; HRMS(ESI) m/z calcd for (M +
Na)+ C20H22O5Na 365.1365, found 365.1387.
mmol, 98%) as a colorless oil: [α]20 −2.1 (c 0.80, CHCl3); Rf 0.44
D
1
(hexanes/EtOAc = 70:30); H NMR (400 MHz, CDCl3) δ 9.75 (s,
1H), 8.04 (d, J = 7.2 Hz, 2H), 7.85−7.72 (m, 4H), 7.58 (t, J = 7.2 Hz,
1H), 7.47 −7.42 (m, 5H), 5.34−5.23 (m, 1H), 4.82 (d, J = 12.0 Hz,
1H), 4.69 (d, J = 12.0 Hz, 1H), 3.83−3.77 (m, 1H), 2.53 (t, J = 7.6 Hz,
2H), 2.20−2.03 (m, 2H), 1.28 (d, J = 6.4 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 201.3, 166.3, 135.9, 133.36, 133.30, 133.1, 130.09,
129.8 (2C), 128.5 (2C), 128.2, 128.0, 127.8, 126.6, 126.2, 126.0, 125.9,
75.2, 75.0, 71.4, 40.3, 22.3, 15.3; IR (thin film) 3057, 2935, 2976, 2863,
2735, 1716, 1271 cm−1; HRMS(ESI) m/z calcd for (M + Na)+
C24H24O4Na 399.1572, found 399.1565.
4-O-Benzoyl-2,3,6-trideoxy-L-galactohexopyranose (17). At
0 °C, DDQ (760 mg, 3.30 mmol) was added to a solution of aldehyde
SI4 (439 mg, 1.10 mmol) in DCM/MeOH (22 mL, 9:1). The mixture
was slowly warmed to rt, stirred for 3 h, diluted with Et2O, and
quenched with a saturated aq solution of NaHCO3 and a saturated aq
solution of Na2S2O3. After separation of the layers, the organic layer
was washed with H2O, dried over MgSO4, and concentrated. Flash
column chromatography (hexanes/AcOEt = 70:30) on silica gel gave
an inseparable 1:1 α/β mixture of hemiacetal 17 (230 mg, 0.97 mmol)
4-O-Benzoyl-2-O-benzyl-3,6-dideoxy-L-talohexopyranosyl-
trichloroacetimidate (15). At 0 °C, DBU (9 μL, 0.06 mmol) and
Cl3CCN (146 μL, 1.46 mmol) were added to a solution of lactol SI3
(100 mg, 0.29 mmol) in DCM (1.1 mL). The reaction mixture was
stirred for 3 h at 0 °C and concentrated. Flash column
chromatography (hexanes/AcOEt/Et3N = 80:19:1) on silica gel
yielded imidate 15 (127 mg, 0.26 mmol) in 89% yield in an α/β
in 87% yield as a colorless oil: [α]20 −14.7 (c 1.0, CHCl3); Rf 0.45
D
(hexanes/AcOEt = 50:50); 1H NMR (400 MHz, CDCl3) δ 8.14−8.10
(m, 4H), 7.60−7.55 (m, 2H), 7.47−7.43 (m, 4H), 5.42 (d, J = 2.4 Hz,
1H, H1-α), 5.09−5.07 (m, 1H, H4-α), 5.01−4.98 (m, 1H, H4-β), 4.88
(dd, J = 9.2, 2.4 Hz, 1H, H1-β), 4.38 (qd, J = 6.4, 1.2 Hz, 1H, H5-α),
3.87 (qd, J = 6.4, 1.2 Hz, 1H, H5-β), 3.15 (bs, 1H, OH-β), 2.66 (bs,
1H, OH-α), 2.31−2.14 (m, 2H, H3-α, H3-β), 2.08−1.61 (m, 6H, H2-
α, H3-α, H3-β, H2-β, H2-β, H2-α), 1.27 (d, J = 6.4 Hz, 3H, H6-β),
1.18 (d, J = 6.4 Hz, 3H, H6-α); 13C NMR (101 MHz, CDCl3) 166.31,
166.30, 133.2, 133.1, 130.4, 130.2, 129.9 (2C), 129.8 (2C), 128.55
(2C), 128.54 (2C), 96.3 (C1-β), 91.8 (C1-α), 73.1 (C5-β), 70.1 (C4-
α), 68.7 (C4-β), 65.4 (C5-α), 27.8 (C2-β), 27.4 (C3-β), 24.4 (C2-α),
22.4 (C3-α), 17.48 (C6-β), 17.47 (C6-α); IR (thin film) 3416, 3064,
2980, 2938, 2863, 1715, 1601, 1584, 1450, 1384, 1358 cm−1;
HRMS(ESI) m/z calcd for (M + Na)+ C13H16O4Na 259.0946,
found 259.0983.
ratio of 9:1 as a colorless oil: [α]20 −31.4 (c 0.75, CHCl3); Rf 0.56
D
1
(hexanes/AcOEt/Et3N = 70:29:1); H NMR (400 MHz, CDCl3) δ
8.55 (s, 1H, NH), 8.03−7.96 (m, 2H), 7.49−7.41 (m, 1H), 7.30−7.21
(m, 2H), 7.19−7.09 (m, 5H), 6.39 (s, 1H, H1), 5.06−5.04 (m, 1H,
H4), 4.56 (d, J = 11.6 Hz, 1H, CH2Ph), 4.48 (d, J = 11.6 Hz, 1H,
CH2Ph), 4.30 (qd, J = 6.8, 1.6 Hz, 1H, H5), 3.63−3.61 (m, 1H, H2),
2.40 (dddd, J = 15.6, 3.2, 2.8, 1.6 Hz, 1H, H3eq), 2.17 (ddd, J = 15.6,
4.0, 3.6 Hz, 1H, H3a), 1.21 (d, J = 6.8 Hz, 3H, H6); 13C NMR (151
MHz, CDCl3) δ 166.6, 160.6, 137.8, 133.0, 130.2, 130.0 (2C), 128.4
(2C), 128.3 (2C), 127.7 (2C), 127.6, 96.3 (1JC1−H1 = 180.9 Hz, C1),
90.9 (CCl3), 71.5 (C4), 70.0 (C5), 68.1 (C2), 67.9 (CH2), 27.5 (C3),
16.9 (C6); IR (thin film) 3336, 2925, 2854, 1715, 1670, 1602, 1492,
1452, 1366 cm−1; HRMS(ESI) m/z calcd for (M + Na)+
C22H22Cl3NO5Na 508.0461, found 508.0434.
(2S,3S)-6-Hydroxy-2-(naphthalen-2-ylmethoxy)hexan-3-yl
Benzoate (16). A solution of alkene 6 (620 mg, 1.72 mmol) and
Rh(PPh3)3Cl (56 mg, 0.06 mmol) in THF (14 mL) was cooled to 0
°C. Catecholborane 1 M in THF (5.1 mL, 5.1 mmol) was added and
the reaction was stirred at 0 °C for 3 h. After dilution with THF/
MeOH (7 mL, 1:1) and addition of 3 M solution of NaOH (4 mL)
and an aq solution 35% H2O2 (4 mL), the reaction was stirred
overnight and quenched with a saturated solution of Na2SO3 (10 mL).
After dilution with Et2O, the organic layer was washed with NaHCO3
and brine, dried over MgSO4, and concentrated. Flash column
chromatography (cyclohexane/AcOEt/Et3N = 80:19:1) on silica gel
afforded alcohol 16 (620 mg, 1.63 mmol, 95%) as a colorless oil:
[α]20D −5.2 (c 1.0, CHCl3); Rf 0.28 (cyclohexane/AcOEt = 70:30); 1H
NMR (400 MHz, CDCl3) δ 8.07−8.04 (m, 2H), 7.81−7.75 (m, 4H),
7.58−7.54 (m, 1H), 7.47−7.42 (m, 5H), 5.31−7.27 (m, 1H), 4.82 (d, J
= 12.0 Hz, 1H), 4.69 (d, J = 12.0 Hz, 1H), 3.83−3.77 (m, 1H), 3.66 (t,
J = 6.4 Hz, 2H), 3.37−3.83 (m, 1H), 1.94−1.77 (m, 2H), 1.69−1.54
(m, 2H), 1.27 (d, J = 6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
166.5, 136.0, 133.3, 133.1, 133.0, 130.4, 129.8 (2C), 128.5 (2C), 128.2,
128.0, 127.8, 126.5, 126.1, 126.0, 125.9, 76.0, 75.1, 71.4, 62.7, 28.8,
26.1, 15.5; IR (thin film) 3422, 3058, 2952, 2933, 2870, 1715, 1601,
1584, 1450, 1376, 1341 cm−1; HRMS(ESI) m/z calcd for (M + Na)+
C24H26O4Na 401.1729, found 401.1737.
1-O-Acetyl-4-O-benzoyl-L-rhodinopyranose (18). Ac2O (3.4
mL, 36 mmol) was added at 0 °C to a solution of hemiacetal 17 (172
mg, 0.72 mmol) in pyridine (6 mL). The mixture was stirred at rt for 2
h, and the solvents were removed. The crude product was
coevaporated with toluene to give quantitatively rhodinosyl acetate
18 (200 mg, 0.72 mmol) as an oil in an α/β ratio of 41:59: [α]20
−8.4 (c 0.95, CHCl3); Rf 0.28 (hexanes/AcOEt = 70:30); H NMR
D
1
(400 MHz, CDCl3) δ 8.14−8.09 (m, 4H), 7.60−7.56 (m, 2H), 7.48−
7.44 (m, 4H), 6.25 (s, 1H, H1-α), 5.80 (dd, J = 9.6, 2.4 Hz, 1H, H1-β),
5.11 (as, 1H, H4-α), 5.03 (ad, J = 1.6 Hz, 1H, H4-β), 4.22 (qd, J = 6.4,
1.2 Hz, 1H, H5-α), 3.97 (qd, J = 6.4, 1.6 Hz, 1H, H5-β), 2.27−2.19
(m, 1H, H3-β), 2.15 (s, 3H, CH3CO-β), 2.13 (s, 3H, CH3CO-α),
2.08−1.99 (m, 2H, H2-α, H3-α), 1.96−1.85 (m, 3H, H3-α, H2-β, H3-
β), 1.79−1.72 (m, 1H, H2-β), 1.68−1.65 (m, 1H, H2-α), 1.28 (d, J =
6.4 Hz, 3H, H6-β), 1.20 (d, J = 6.4 Hz, 3H, H6-α); 13C NMR (101
MHz, CDCl3) δ 169.8, 169.5, 166.2, 166.2, 133.3, 133.2, 130.2, 130.1,
129.9 (2C), 129.8 (2C), 128.6 (2C), 128.5 (2C), 94.4 (1JC1−H1 = 161.7
Hz, C1-β), 92.1 (1JC1−H1 = 177.5 Hz, C1-α), 73.9 (C5-β), 69.4 (C4-α),
68.5 (C4-β), 67.8 (C5-α), 27.1 (C3-β), 25.0 (C2-β), 23.2 (C2-α), 22.8
(C3-α), 21.4 (2C, CH3CO), 17.4 (C6-α), 17.3 (C6-β); IR (thin film)
3064, 2983, 2963, 2939, 2868, 1745, 1714, 1601, 1584, 1491, 1450,
1366, 1329 cm−1; HRMS(ESI) m/z calcd for (M + Na)+ C15H18O5Na
301.1052, found 301.1064.
ASSOCIATED CONTENT
■
(2S,3S)-2-(Naphthalen-2-ylmethoxy)-6-oxohexan-3-yl Ben-
zoate (SI4). To a solution of alcohol 16 (450 mg, 1.19 mmol),
DIPEA (1 mL, 5.9 mmol) and DMSO (0.8 mL, 11.9 mmol) in DCM
(6 mL) at 0 °C was added SO3·pyridine complex (568 mg, 3.60
S
* Supporting Information
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
876
dx.doi.org/10.1021/jo201883k | J. Org. Chem. 2012, 77, 870−877

The Journal of Organic Chemistry
Article
(b) Bonini, C.; Chiummiento, L.; Pullez, M.; Solladie, G.; Colobert, F.
J. Org. Chem. 2004, 69, 5015−5022.
(18) Van Rheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.
1976, 17, 1973−1976.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: peter.seeberger@mpikg.mpg.de.
(19) Upjohn dihydroxylation performed on substrate 6 (C4-OBz)
afforded inseparable mixture of diastereosiomers with poor levels of
diastereoselectivity ranging from 1.3:1 to 1.6:1 when the temperature
is decreasing from rt to 0 °C.
(20) (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990,
31, 945−948. (b) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron
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2480−2482.
ACKNOWLEDGMENTS
■
The authors gratefully thank the Max Planck Society for
funding, the Marie Curie ITN FP7 project CARMUSYS
(PITN-GA-2008-213592) for a doctoral fellowship (O.C.), and
the Alexander von Humbolt Foundation for a postdoctoral
research fellowship (R.P.). We thank Dr. S. Eller for insightful
discussions and Dr. F. Levesque and Dr. M. Schlegel for
́
critically editing the manuscript.
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