A carbohydrate-based approach for the total synthesis of (-)-dinemasone B, (+)-4a-epi-dinemasone B, (-)-7-epi-dinemasone B, and (+)-4a,7-di-epi-dinemasone B

Article abstract of DOI:10.1021/jo4015694

(-)-Dinemasone B was isolated by Krohn and co-workers from a culture of the endophytic fungus Dinemasporium strigosum and has shown promising antimicrobial activity. Described herein is the first total synthesis of (-)-dinemasone B, (+)-4a-epi-dinemasone B, (-)-7-epi-dinemasone B, and (+)-4a,7-di-epi-dinemasone B. Their absolute configurations were also determined. The developed synthesis features a stereoselective reduction of C-glycosidic ketone, lactonization, and E-olefination of aldehyde starting from d-glucose.

Full text of DOI:10.1021/jo4015694

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Article
A Carbohydrate-Based Approach for the Total Synthesis
of (-)-Dinemasone B, (+)-4a-epi-Dinemasone B, (-)-7-
epi-Dinemasone B, and (+)-4a,7-diepi-Dinemasone B
Xiaochao Xue, Zhaojun Yin, Xiangbao Meng, and Zhongjun Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4015694 • Publication Date (Web): 29 Aug 2013
Downloaded from http://pubs.acs.org on August 30, 2013
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A Carbohydrate-Based Approach for the Total Synthesis of (−)-Dinemasone B,
(+)-4a-epi-Dinemasone B, (−)-7-epi-Dinemasone B, and (+)-4a,7-diepi-Dinemasone B
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Xiaochao Xue, Zhaojun Yin, Xiangbao Meng,* and Zhongjun Li*
The State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical
Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, P. R.
China
xbmeng@bjmu.edu.cn; zjli@bjmu.edu.cn
TOC/Abstract Graphic:
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ABSTRACT:
(−)-Dinemasone B was isolated by Krohn and co-workers from a culture of the
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endophytic fungus Dinemasporium strigosum and has shown promising antimicrobial
activity. Described herein is the first total synthesis of (−)-dinemasone B,
(+)-4a-epi-dinemasone B, (−)-7-epi-dinemasone B, and (+)-4a,7-diepi-dinemasone B. Their
absolute configurations were also determined. The developed synthesis features a
stereoselective reduction of C-glycosidic ketone, lactonization and E-olefination of
aldehyde starting from D-glucose.
INTRODUCTION:
(−)-Dinemasone B (1) and (−)-dinemasone C (2) were first reported by Krohn and
co-workers as two naturally occurring antibiotics with biological activities against the
Bacillus megaterium (gram-positive), Microbotryum violaceum (fungus) and Chlorella
fusca (alga). These compounds were isolated by these researchers from a culture of the
endophytic fungus Dinemasporium strigosum, which was obtained from the roots of
1
Calystegia sepium in 2008 (Figure 1). Because of the presence of the stereogenic
hexahydropyrano[4,3-b]pyran-5(7H)-one structure, these metabolites are challenging
targets for synthesis.
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Figure 1. Structures of (−)-dinemasone B (1) and (−)-dinemasone C (2)
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2
In 2010, Snider and co-workers accomplished the first total synthesis of (±)-dinemasone
C (2), but studies towards the synthesis of (−)-dinemasone B (1) have not been described.
Herein, we present the first stereocontrolled total synthesis of 1 utilizing a chiral substrate
for the efficient construction of the core structure.
RESULTS AND DISCUSSION:
Total Synthesis of (−)-Dinemasone B
Our retrosynthetic analysis of (−)-dinemasone B (1) is outlined in Scheme 1. The
E-alkene would be produced via a Takai-Utimoto reaction with benzyl protected aldehyde 3,
and δ-lactone 3 could be obtained by intramolecular hydrolysis of the hydroxyl nitrile 4.
The key C7 stereocenter of 4 could be introduced through a stereoselective reduction of
C-glycosidic ketone 5, which could be derived from D-glucose.
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Scheme 1. Retrosynthetic Analysis of (−)-Dinemasone B (1)
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The investigation began with the 1,2:5,6-di-O-isopropylidene-D-glucofuranose 6, which
3
was commercially available or could be easily synthesized from D-glucose. Protection of
hydroxyl group with benzyl bromide in the presence of sodium hydride, followed by
+
cleavage of the isopropylidene groups with Dowex H resin in hot water, afforded 8 in
4
5-7
excellent yield. Further treatment of 8 with acetylacetone in NaHCO
acetylization by Ac O/pyridine smoothly produced C-glycosidic ketone 5 in 78% yield for
two steps, as shown in Scheme 2.
3
solution and
2
Scheme 2. Synthesis of C-Glycosidic Ketone 5
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With ketone 5 in hand, a careful survey of conditions for the stereoselective reduction
was conducted (Table 1). Reduction of 5 with sodium borohydride in the presence of
AcOH yielded a mixture of alcohols 9 and 10 in poor selectivity (Table 1, entries 1 and 2),
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8
-10
which were similar to the results reported in literature. Later, it was found that the major
1
1-13
product 10 (S-isomer) could be obtained by the Corey-Bakshi-Shibata reduction
R)-Me-CBS as the catalyst (Table 1, entries 3 and 4), especially when catecholborane was
used as the reductant (Ratio: 9/10 = 06:94) (Table 1, entry 4). According to the literature,
with
(
1
4
the selectivity for S-isomer should be better when (R)-Bu-CBS is used. However, a slight
decrease in selectivity is observed (Table 1, entry 5).
For the synthesis of the R-isomer, the CBS catalyzed reduction using various reductants
provided poor stereoselectivity, affording at best a 2:1 ratio of 9 and 10 (Table 1, entries
6
~8). Other bulky reductants, including combinations of lithium borohydride with
1
5-18
19
20-22
TarB-H,
DIBAL-H, and L-Selectride/Ti(OiPr)
4
in THF,
gave varying ratios of the
two stereoisomers in an unpredictable manner. Under most conditions, poor yields of
R-isomer 9 were achieved (Table 1, entries 9~12). Serendipitously, changing the solvent to
toluene when using L-Selectride/Ti(OiPr)
4
, improved the stereoselective reduction to give
the R-isomer as the major isomer (Table 1, entry 13).
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Table 1. Stereoselective Reduction of Ketone 5
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ꢀ
a
Yield (%)
Entry
Reagent
Solvent
MeOH
T[°C]
t[h]
b
(
9/10 Ratio)
98 (33:67)
96 (45:55)
99 (26:74)
99 (06:94)
98 (10:90)
99 (64:36)
98 (36:64)
99 (29:71)
89 (50:50)
87 (12:88)
91 (50:50)
90 (86:14)
92 (95:05)
c
d
1
2
3
4
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9
NaBH
NaBH
4
4
, AcOH
0
0.5
0.5
1.0
1.0
1.0
1.0
1.0
1.0
0.5
1.0
0.5
0.5
0.5
c
d
, AcOH
CH
2
Cl
2
0
e
c
(R)-Me-CBS, BMS
THF
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-78
-78
-78
-78
e
c
(R)-Me-CBS, CB
toluene
toluene
THF
e
c
(R)-Bu-CBS, CB
e
c
(S)-Me-CBS, BMS
e
c
(S)-Me-CBS, CB
toluene
toluene
THF
e
c
(S)-Bu-CBS, CB
c
f
LiBH
4
, TarB-H
c
f
1
1
0
1
DIBAL-H, Ti(OiPr)
4
toluene
THF
c
f
f
L-Selectride, Ti(OiPr)
4
4
c
12
L-Selectride, Ti(OiPr)
CH
2
Cl
2
c
f
1
3
L-Selectride, Ti(OiPr)
4
toluene
a
b
1
Yield of isolated product. Ratios of 9/10 were determined by H NMR analysis.
c
Reductants: NaBH
4 4
(2.0 eq.), BMS (3.0 eq.), CB (3.0 eq.), LiBH (2.0 eq.), DIBAL-H (1.1
d
e
eq.), L-Selectride (1.1 eq.). Amount of AcOH (2.0 eq.). The CBS catalysts (1.5 eq.).
f
4
Chelating agent: TarB-H (2.0 eq.), Ti(OiPr) (4.0 eq.). BMS = Borane dimethyl sulfide
complex, CB = Catecholborane, DIBAL-H = Diisobutylaluminum hydride, L-Selectride =
Lithium tri-Sec-butylborohydride.
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Both the absolute configurations of alcohols 9 and 10 were determined by NMR studies
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of the MPA esters.
After alcohol 9 was obtained successfully, protection of 9 with TBDPS ether under the
condition of TBDPSCl/imidozale afforded 11 in quantitative yield. Removal of the acetate
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ester followed by acetalization with PhCH(OMe)
gave alcohol 12 in 89% yield. Treatment of 12 with trifluoromethanesulfonic anhydride in
CH Cl at 0°C, followed by subsequent substitution reaction with
2
in the presence of p-toluenesulfonic acid
2
2
N
S 2
2
5
n-tetrabutylammonium cyanide, provided 13, and deprotection of the TBDPS ether with
tetrabutylammonium fluoride produced hydroxyl nitrile 4 in 91% yield over three steps
(
Scheme 3).
Scheme 3. Synthesis of the Hydroxyl Nitrile 4
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To synthesize (−)-dinemasone B (1), the δ-lactone must be constructed first. We
designed several synthesis pathways (Scheme 4). In the designed Path A, reduction of the
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nitrile 13 to aldehyde 14 with DIBAL-H
or Red-Al under cold condition, followed by
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the removal of the silyl ether, would form the unstable hydroxyl aldehyde M-1, which
could cyclize automatically to form the hemiacetal 15. Lactone 16 would be obtained after
oxidation, but the cyano group failed to be converted to aldehyde probably due to steric
hindrance.
In Path B, when hydroxyl nitrile 4 was heated with DBU in toluene at 80 °C, allowing
for intramolecular condensation of the alcohol with cyanide to afford the intermediate
2
9
M-2. Following acidolysis, lactone 16 could be obtained. However, when hydroxyl nitrile
4 was treated with DBU, no desired product was observed, only epimerization product 17
was obtained in 34% yield, along with unreacted substrate. Thus Path B was also
abandoned.
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Scheme 4. Construction of Lactones 16 and 19
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ꢀ
Path C converted compound 4 to carboxylic acid 18 by treatment with alkaline hydrogen
3
0
peroxide in a mixture of water and ethanol at 90 °C, during which epimerization of the
carboxylic group occurred. Subsequent lactonization with EDCI and DMAP afforded the
lactone 19 in 88% yield, which was an epimer of lactone 16.
Path D under more mild alkalinity and temperature transformed hydroxyl nitrile 4 into
31
the non-epimerized amide 20 quantitatively. And fortunately, refluxing of 20 in
chlorobenzene under a continuous stream of nitrogen afforded the corresponding lactone 16
in 78% yield by elimination of ammonia, as shown in Scheme 4, Path D.
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Scheme 5. Synthesis of the E-Alkene 22
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Reductive ring opening of the cyclic benzyliene acetal of 16 by treatment with
3
2
BH
3 2
•THF/Bu BOTf gave the corresponding primary alcohol 21 in 94% yield. Oxidation
of 21 by DIB/TEMPO smoothly furnished benzyl protected aldehyde 3. And Takai-Utimoto
3
3,34
Reaction
of 3 led to the desired E-alkene 22 in 78% yield with a high selectivity (E/Z >
95:05), as shown in Scheme 5.
The last step was the deprotection of 22. Various conditions were tested for the selective
3
5
3
removal of benzyl groups (Table 2). When BCl was used, only trace amount of product
3
6
was obtained (Table 2, entry 1). Treatment with DDQ at room temperature did not
produce any product (Table 2, entry 2). When refluxing with DDQ or treatment with
37
Na/Naphthalene as a single-electron reductant, only trace amount of product was
observed (Table 2, entries 3 and 4). Hydrogenolysis attempts to selectively remove the
benzyl groups also reduced the alkene even when using 1-methyl 1,4-cyclohexadiene as a
hydrogen donor (Table 2, entries 5~8).
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Table 2. Results of De-O-Benzylation of 22
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Entry
Conditions
, -78 °C, 0.5 h
Results
trace
a
1
2
3
4
5
6
7
BCl
3
, CH
2
Cl
2
a
b
DDQ, CH
2
2
Cl
Cl
2
2
-H
-H
2
2
O, rt, 12 h
O, reflux, 6 h
-
a
DDQ, CH
trace
trace
Na/Naphthalene, THF, -78 °C, 0.5 h
Pd/C, H (4.5 atm), THF, rt, 0.5 h
c
c
c
2
23 (96%)
23 (97%)
23 (99%)
Pd(OH)
Pd(OH)
Pd(OH)
2
2
2
/C. H
/C, H
2
2
(4.5 atm), THF, rt, 0.5 h
(1.0 atm), THF, rt, 0.5 h
/C, 1-Methyl-1,4-Cyclohexadiene,
c
8
23 (89%)
THF, rt, 0.5 h
a
b
c
Amount of Agents: BCl
3
(2.5 eq.), DDQ (2.0 eq.). No reaction. Yield of isolated product.
DDQ = 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone.
After the failed deprotection of 22, we adjusted the protecting groups. Removal of the
benzylidene and benzyl group in 16 by hydrogenolysis, followed by protection of 24 with
trimethyl chlorosilane, gave lactone 25 in 99% yield over two steps, and the trimethylsilyl
3
8
group could be removed by hydrolysis under mild conditions. Selective oxidative removal
39-41
of the TMS group on primary alcohol using Collins oxidation,
followed by
4
2-44
Kocieński-Julia olefination
with the use of LiHMDS in DMF, afforded the desired
E-alkene (E:Z = 94:06) (optimization of E-alkene, see below). Removal of the TMS groups
in the presence of 2% (v/v) trifluoroacetic acid afforded (−)-dinemasone B (1) in 73% yield
for three steps (Scheme 6).
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Scheme 6. Total Synthesis of (−)-Dinemasone B (1)
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The reaction conditions for the olefination of aldehyde 26 were explored and the results
3
3,34
are summarized in Table 3. First, Takai-Utimoto olefination
of 26 gave a mixture of
E/Z alkene, even when DMF was introduced (Table 3, entries 1 and 2). As temperature
increased (65°C) or decreased (0°C), no product was observed (Table 3, entries 3 and 4).
4
5-48
And the Wittig reaction
also did not yield the product due to the steric hindrance of the
substrate (Table 3, entries 5 and 6). Later, we found that high selectivity for E- double
4
2-44
bond could be achieved by the Kocieński-Julia olefination
(Table 3, entries 7~10),
4
3
especially with the use of LiHMDS in DMF at -35°C (Table 3, entry 9).
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Table 3. Results of the Olefination of Aldehyde 26
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
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55
56
57
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60
T
Yield
Ratio
Entry
Reagent and Solvent
a
b
[
°C]
25
25
0
(%)
(E/Z)
87:13
41:59
-
1
2
CH
CH
CH
CH
3
3
3
3
CHI
CHI
CHI
CHI
2
2
2
2
, CrCl
, CrCl
, CrCl
, CrCl
2
2
2
2
, THF
62
65
•DMF, THF
, THF
c
3
-
4
, THF
65
trace
-
d
c
5
Ph
Et
3
P=CHCH
3
, THF
-78
-78
-78
-60
-35
-35
-
-
d
d
d
d
d
c
6
3
P=CHCH
3
, THF
-
-
e
7
Julia agent, LiHMDS, THF
76
72
73
70
55:45
90:10
94:06
83:17
e
8
Julia agent, LiHMDS, DMF
e
9
Julia agent, LiHMDS, DMF
e
f
10
Julia agent, LiHMDS, DMF/HMPA
a
b
1
Yield of isolated product. Ratios of E/Z products were determined by H NMR analysis.
c
d
No reaction. Reactions were set up at the indicated temperatures and then allowed to
e
f
warm to room temperature. Julia agent = 5-ethylsulfonyl-1-phenyl-1H-tetrazole. A
mixture solvent of DMF and HMPA at 4:1 ratio (v/v). LiHMDS = Lithium
bis(trimethylsilyl)amide, HMPA = Hexamethyl phosphoric triamide. Aldehyde 26 was not
isolated and made in situ, then reacted immediately due to its poor stability.
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9
1
1
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1
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4
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4
4
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5
5
6
1
13
The H NMR and C NMR spectra of the synthesized (−)-dinemasone B (1) were
identical to those reported for the naturally isolated product. The optical rotation was also
25
D
25
in good agreement (synthetic 1: [α] = -28.2 (c = 1.00, CH
2
Cl
2
); natural 1: [α]D = -27.0 (c
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
=
2 2
0.97, CH Cl )).
Total Synthesis of (+)-4a-epi-Dinemasone B
Using a similar approach, catalytic hydrogenolysis of lactone 19 with Pd(OH)
2
/C in THF
and protection of the hydroxyl groups of 28 with TMS gave lactone 29 in 93% yield for
3
9-41
two steps. Selective oxidative deprotection of the primary alcohol TMS group,
3
3,34
Takai-Utimoto olefination
3 2 2
using CH CHI in the presence of CrCl in THF, and removal
of the remaining TMS groups afforded (+)-4a-epi-dinemasone B (30) in 67% yield over
three steps with an excellent selectivity (E/Z > 95:05) (Scheme 7).
Scheme 7. Total Synthesis of (+)-4a-epi-Dinemasone B (30)
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Total Synthesis of (−)-7-epi-Dinemasone B and (+)-4a,7-diepi-Dinemasone B
Meanwhile, (−)-7-epi-dinemasone B (39) and (+)-4a,7-diepi-dinemasone B (44) were
obtained with an excellent selectivity from the (S)-alcohol 10 using the same method
described above. The synthetic details were shown in Scheme 8.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 8. Total Synthesis of (−)-7-epi-Dinemasone B (39) and
(+)-4a,7-diepi-Dinemasone B (44) from (S)-Alcohol 10
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2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
All the configurations of (−)-dinemasone B (1), (+)-4a-epi-dinemasone B (30),
(−)-7-epi-dinemasone B (39) and (+)-4a,7-diepi-dinemasone B (44) were confirmed by
49
NOESY analysis, which were in agreement with that of the MPA esters, as shown in
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 2.
Figure 2. The NOESY experiments of (−)-dinemasone B (1) and its epimers
CONCLUSION:
In summary, we have achieved the stereoselective total syntheses of (−)-dinemasone B,
(+)-4a-epi-dinemasone B, (−)-7-epi-dinemasone B and (+)-4a,7-diepi-dinemasone B for the
first time starting from D-glucose derivative and the absolute configurations of these
compounds were established. The total synthesis of (−)-dinemasone B (1) proceeded in 18
steps in 29% overall yield, with the stereoselective reduction of C-glycosidic ketone,
lactonization and Kocieński-Julia olefination as the key steps. The stereoselectivity of the
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process and the high overall yield make the method one of the most practical alternatives to
synthesize optically pure hexahydropyrano[4,3-b]pyran-5(7H)-one systems. Further studies
towards the total synthesis of (−)-dinemasone C are currently underway.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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39
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44
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EXPERIMENTAL SECTION:
(
2R,3S,4R,4aS,7R,8aS)-Hexahydro-3,4-dihydroxy-7-methyl-2-[(1E)-prop-1-enyl]pyran
o[4,3-b]pyran-5(7H)-one (1): To a solution of celite (1.88 g, 4g per g(CrO )) and pyridine
759 µL, 9.38 mmol) in DCM (5 mL) was added chromium (VI) oxide (469 mg, 4.69
3
(
mmol), the mixture was stirred at rt for 1 h then cooled to 0°C. Then a solution of lactone
25 (210 mg, 469 µmol) in DCM (5 mL) was added and stirred for 2 h. The reaction mixture
was filtered through a pad of silica, concentrated in vacuum affording an unstable aldehyde,
which was used immediately without further purification.
To a solution of 5-ethylsulfonyl-1-phenyl-1H-tetrazole (134 mg, 563 µmol) in DMF (2
mL) was added LiHMDS (1 M in THF/Ethylbenzene, 516 µL, 516 µmol) at -35°C. This
was immediately followed by addition of aldehyde in DMF (3 mL) via cannula. The
reaction was allowed to warm slowly to rt and stirred for 10 h before it was diluted with
DCM and water. The organic layers were separated and the aqueous layers were extracted
with DCM. The combined organic layers were washed with brine, dried over Na
2 4
SO ,
filtered and concentrated.
The residue was dissolved in DCM (5 mL) and trifluoroacetic acid (100 µL, 2% v/v)
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1
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1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
was added dropwise at rt. After stirring 30 min, the reaction mixture was concentrated, and
purified by flash column chromatography (CHCl
3
-Acetone, 4:1) to afford 1 (78 mg, 69%)
= 0.2 (CHCl -Acetone,
); H NMR (400 MHz, CDCl ) δ 5.87
(dq, J = 15.6 Hz, 6.8 Hz, 1H), 5.50 (dd, J = 15.6 Hz, 6.8 Hz, 1H), 4.36 (m, 1H), 4.15 (dt, J
and Z-isomer S3 (5 mg, 4%). Data for 1 (an amorphous solid): R
f
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
D
5
1
4
:1); mp 157-158°C; [α] = -28.2 (c = 1.0, CH
2
Cl
2
3
=
=
9.2 Hz, 2.8 Hz, 1H), 4.03 (d, J = 11.2 Hz, 1H), 3.69 (dt, J = 5.2 Hz, 9.2 Hz, 1H), 3.64 (t, J
9.2 Hz, 1H), 3.55 (t, J = 8.0 Hz, 1H), 3.00 (t, J = 4.0 Hz, 1H), 2.60 (br s, 1H), 2.47 (ddd,
J = 14.8 Hz, 8.8 Hz, 3.6 Hz, 1H), 1.77 (ddd, J = 14.8 Hz, 12.0 Hz, 2.8 Hz, 1H), 1.75 (d, J =
1
3
6
.4 Hz, 3H), 1.42 (d, J = 6.0 Hz, 3H) ppm; C NMR (100 MHz, CDCl
3
) δ 173.4, 131.7,
1
27.8, 81.3, 73.5, 72.8, 72.2, 71.4, 44.9, 37.1, 20.6, 18.2 ppm; HRMS (ESI-FT-ICR): m/z
+
+
19 5 5
Calcd for C12H O [M+H] 243.1227, Found: 243.1228; C12H18NaO [M+Na] 265.1046,
Found: 265.1046.
(2R,3S,4R,4aS,7R,8aS)-Hexahydro-3,4-dihydroxy-7-methyl-2-[(1Z)-prop-1-enyl]pyran
o[4,3-b]pyran-5(7H)-one (S3) (an amorphous solid): R = 0.2 (CHCl -Acetone, 4:1); mp
); H NMR (400 MHz, CDCl ) δ 5.86 (m, 1H),
f
3
2
D
5
1
1
80-181°C; [α] = -50.0 (c = 0.4, CHCl
3
3
5.40 (t, J = 9.6 Hz, 1H), 4.37 (m, 1H), 4.18 (dt, J = 9.2 Hz, 3.2 Hz, 1H), 4.01 (d, J = 13.2
Hz, 1H), 3.97 (t, J = 8.8 Hz, 1H), 3.73 (dt, J = 4.8 Hz, 9.2 Hz, 1H), 3.67 (t, J = 9.2 Hz, 1H),
3
.02 (t, J = 4.0 Hz, 1H), 2.47 (ddd, J = 15.2 Hz, 9.2 Hz, 4.0 Hz, 1H), 2.44 (br s, 1H), 1.77
(ddd, J = 15.2 Hz, 12.0 Hz, 2.8 Hz, 1H), 1.75 (d, J = 6.8 Hz, 3H), 1.42 (d, J = 6.4 Hz, 3H)
1
3
3
ppm; C NMR (100 MHz, CDCl ) δ 173.4, 131.2, 127.2, 76.0, 73.5, 72.9, 72.5, 71.5, 45.0,
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+
3
19 5
7.1, 20.6, 14.1 ppm; HRMS (ESI-FT-ICR): m/z Calcd for C12H O [M+H] 243.1227,
+
Found: 243.1226; C12
H18NaO
5
[M+Na] 265.1046, Found: 265.1045.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
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(
2S,3S,4R,4aR,7R,8aS)-Hexahydro-3,4-di-benzyloxy-7-methyl-2-(formyl)pyrano[4,3-b]
pyran-5(7H)-one (3): To a stirred solution of 21 (170 mg, 412 µmol) in dry DCM (10 mL)
at rt was added PhI(OAc) (266 mg, 825 µmol) and TEMPO (65 mg, 412 µmol). The
resulting mixture was stirred for 12 h, and then quenched with a mixture of saturated
aqueous solution of NaHCO (5 mL) and Na (5 mL). The resulting mixture was
extracted with DCM, dried over Na SO and concentrated. The crude residue was purified
by flash column chromatography (PE-EtOAc, 1:1) to afford aldehyde 3 (156 mg, 92%) as a
2
3
2 2 3
S O
2
4
2
D
5
1
colorless syrup: R
MHz, CDCl ) δ 9.56 (d, J = 0.4 Hz, 1H), 7.37~7.26 (m, 10H), 4.78 (d, J = 11.2 Hz, 1H),
.68~4.61 (m, 3H), 4.28 (m, 1H), 4.20 (m, 1H), 4.13 (t, J = 6.7 Hz, 1H), 4.03 (m, 1H), 3.87
(d, J = 6.6 Hz, 1H), 3.00 (dd, J = 4.8 Hz, 4.1 Hz, 1H), 2.30 (ddd, J = 14.5 Hz, 7.5 Hz, 3.0
f 3
= 0.4 (PE-Acetone, 1:1); [α] = +4.0 (c = 1.0, CHCl ); H NMR (400
3
4
1
3
Hz, 1H), 1.87 (ddd, J = 14.4 Hz, 11.5 Hz, 6.3 Hz, 1H), 1.39 (d, J = 6.2 Hz, 3H) ppm; C
NMR (100 MHz, CDCl ) δ 198.4, 169.8, 137.8, 137.5, 128.7, 128.6, 128.3, 128.2, 128.1,
3
81.9, 74.0, 73.6, 72.4, 70.7, 42.5, 37.0, 21.0 ppm; HRMS (ESI-FT-ICR): m/z Calcd for
+
C
24
H26NaO
6
[M+Na] 433.1622, Found: 433.1630.
(R)-6-O-Benzyl-7,9-O-benzylidene-5-cyano-4,8-anhydro-1,3,5-tri-deoxy-D-erythro-L-gl
uco-nonitol (4): To a solution of 13 (1.34 g, 2.07 mmol) in THF (50 mL) were added acetic
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
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5
5
5
5
5
6
acid (592 µL, 10.35 mmol) and tetrabutylammonium fluoride (1M in THF, 20.7 mL, 20.70
mmol) at 50°C, and was stirred for 24 h. The reaction mixture was passed through a short
plug of silica gel (PE-EtOAc, 1:1). The filtrate was concentrated, and the residue was
subjected to flash column chromatography (PE-EtOAc, 1:1) to afford alcohol 4 (839 mg,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
5
1
quant.) as a colorless syrup: R
NMR (400 MHz, CDCl ) δ 7.49~7.25 (m, 10H), 5.63 (s, 1H), 4.85 (d, J = 13.1 Hz, 1H),
.75 (d, J = 12.4 Hz, 1H), 4.29 (dd, J = 10.4 Hz, 4.8 Hz, 1H), 4.03 (m, 1H), 3.99 (t, J = 9.4
Hz, 1H), 3.85~3.77 (m, 3H), 3.41 (dt, J = 4.9 Hz, 9.6 Hz, 1H), 3.19 (dd, J = 5.3 Hz, 2.1 Hz,
f 3
= 0.3 (PE-EtOAc, 1:1); [α] = -62.5 (c = 2.6, CHCl ); H
D
3
4
1
1
H), 1.99 (ddd, J = 14.3 Hz, 9.3 Hz, 1.8 Hz, 1H), 1.73 (br s, 1H), 1.53 (ddd, J = 13.8 Hz,
1
3
3
0.2 Hz, 3.1 Hz, 1H), 1.22 (d, J = 6.2 Hz, 3H) ppm; C NMR (100 MHz, CDCl ) δ 137.7,
137.3, 129.2, 128.6, 128.4, 128.1, 127.9, 126.2, 117.1, 101.7, 80.6, 74.6, 73.4, 72.9, 71.8,
6
8.5, 64.3, 42.6, 41.0, 24.5 ppm; HRMS (ESI-FT-ICR): m/z Calcd for C24H27NNaO
5
+
[
M+Na] 432.1781, Found: 432.1788.
5
,7,9-Tri-O-acetyl-6-O-benzyl-4,8-anhydro-1,3-di-deoxy-D-glycero-D-gulo-non-2-ulose
(5): To a solution of S1 (3.0 g, 9.67 mmol) in pyridine (30 mL) was added acetic anhydride
(15 mL). After stirred at rt for 12 h, The reaction mixture was cooled to 0°C, and added
methanol dropwise, then concentrated at reduced pressure, the residue was washed with 1
M HCl (aq.), extracted with DCM. The combined organic layers were washed with
3 2 4
saturated NaHCO (aq.) and brine, dried over Na SO and concentrated, purification with
flash column chromatography (PE-EtOAc, 3:1), afforded ketone 5 (4.22 g, quant.) as an
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D
5
amorphous solid: R
f
= 0.5 (PE-EtOAc, 1:1); mp 123-125°C; [α] = -18.3 (c = 1.1, CHCl
3
);
1
H NMR (400 MHz, CDCl
3
) δ 7.35~7.22 (m, 5H), 5.06 (t, J = 9.6 Hz, 1H), 4.91 (t, J = 9.6
Hz, 1H), 4.61 (s, 2H), 4.17 (dd, J = 12.4 Hz, 5.2 Hz, 1H), 4.02 (dd, J = 12.4 Hz, 2.4 Hz,
H), 3.89 (ddd, J = 9.6 Hz, 8.8 Hz, 3.2 Hz, 1H), 3.70 (t, J = 9.2 Hz, 1H), 3.57 (ddd, J =
12.4 Hz, 5.2 Hz, 2.4 Hz, 1H), 2.75 (dd, J = 16.8 Hz, 8.8 Hz, 1H), 2.46 (dd, J = 16.8 Hz, 3.2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1
3
Hz, 1H), 2.16 (s, 3H), 2.06 (s, 3H), 1.96 (s, 6H) ppm; C NMR (100 MHz, CDCl
3
) δ 205.8,
1
70.9, 170.0, 169.6, 138.0, 128.6, 128.0, 127.8, 81.8, 76.2, 74.6, 74.2, 73.4, 70.1, 62.5, 45.6,
+
9
31.3, 21.0, 20.9 ppm; HRMS (ESI-FT-ICR): m/z Calcd for C22H28NaO [M+Na] 459.1626,
Found: 459.1616.
3-O-Benzyl-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (7): Diacetone D-glucose 6
12.00 g, 46.13 mmol) was dissolved in THF (30 mL) and sodium hydride (5.54 g, 138.4
(
mmol) was added. After stirred at 0°C for 30 min, benzyl bromide (6.58 mL, 55.36 mmol)
was added, the mixture was stirred at 40°C for 10 h. Then the reaction was quenched by
addition of methanol dropwise, the solvent was removed under reduced pressure and the
residue was dissolved in DCM and washed with 1 M HCl (aq.). The aqueous layers were
extracted with DCM, and the combined organic layers were washed with saturated
3 2 4
NaHCO (aq.) and brine, dried over Na SO , filtered, evaporated, and purified by flash
column chromatography (PE-EtOAc, 8:1) to give benzyl ether 7 (16.15 g, quant.) as a
1
colorless syrup: R
f
= 0.5 (PE-EtOAc, 2:1); H NMR (400 MHz, CDCl
3
) δ 7.37~7.25 (m,
5
H), 5.89 (d, J = 3.6 Hz, 1H), 4.67 (d, J = 12.0 Hz, 1H), 4.62 (d, J = 12.0 Hz, 1H), 4.57 (d,
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5
5
5
5
5
6
J = 4.0 Hz, 1H), 4.37 (dt, J = 7.7 Hz, 6.0Hz, 1H), 4.15 (dd, J = 7.8 Hz, 3.1 Hz, 1H); 4.10
(dd, J = 8.6 Hz, 6.2 Hz, 1H), 4.02 (d, J = 2.9 Hz, 1H), 4.00 (dd, J = 8.5 Hz, 5.8 Hz, 1H),
1
3
1
1
3
.48 (s, 3H), 1.42 (s, 3H), 1.37 (s, 3H), 1.30 (s, 3H) ppm; C NMR (100 MHz, CDCl ) δ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
37.7, 128.5, 127.9, 127.7, 111.8, 109.0, 105.4, 82.7, 81.8, 81.4, 72.6, 72.4, 67.5, 26.9, 26.8,
+
26.3, 25.5 ppm; HRMS (ESI-FT-ICR): m/z Calcd for C19
H26NaO
6
[M+Na] 373.1622,
Found: 373.1628.
3-O-Benzyl-D-glucopyranose (8): To a solution of benzyl ether 7 (10.0 g, 28.56 mmol) in
+
H
2
O (50 mL) was added DOWEX 50WX8-400 resin (H form) (20.0 g). The reaction
mixture was heated to 70°C for 12 h, then the resin was filtered off and the filtrate
f 3 3
concentrated, yielded 8 (7.56 g, 98%) as an amorphous solid: R = 0.3 (CHCl -CH OH, 6:1);
1
mp 119-120°C; H NMR (400 MHz, DMSO-d
6
) δ 7.41~7.22 (m, 5H), 6.65 (d, J = 3.6 Hz,
1
H), 5.04 (s, 2H), 4.81 (d, J = 12.0 Hz, 1H), 4.77 (d, J = 12.0 Hz, 1H), 4.50 (s, 1H), 4.33 (t,
J = 7.2 Hz, 1H), 3.68 (ddd, J = 7.6 Hz, 5.2 Hz, 1.2 Hz, 1H), 3.45 (m, 1H), 3.27~3.18 (m,
1
3
2
9
6
H), 3.14~3.05 (m, 2H) ppm; C NMR (100 MHz, DMSO-d ) δ 139.7, 127.9, 127.4, 127.0,
6.9, 85.3, 76.7, 74.8, 73.6, 69.9, 61.1 ppm; HRMS (ESI-FT-ICR): m/z Calcd for
+
C
13
H18NaO
6
[M+Na] 293.0996, Found: 293.1000.
6
-O-Benzyl-4,8-anhydro-1,3-di-deoxy-D-glycero-D-gulo-non-2-ulose (S1): To a solution
of 8 (5.0 g, 18.51 mmol) in H O (75 mL) were added sodium bicarbonate (2.33 g, 27.77
2
mmol) and pentane-2,4-dione (2.29 mL, 22.21 mmol). After refluxed for 48 h, the reaction
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8
9
+
mixture was treated with DOWEX 50WX8-400 resin (H form), The resin was filtered off
and the filtrate was concentrated to dry, purification with flash column chromatography
(
(
CHCl
CHCl
3
3
-CH
3
3
OH, 20:1) afforded S1 (4.48 g, 78%) with an amorphous solid: R
f
= 0.5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
D
5
1
-CH
OH, 6:1); mp 87-88°C; [α] = +10.9 (c = 1.1, Acetone); H NMR (400 MHz,
Acetone-d
6
) δ 7.42~7.23 (m, 5H), 4.94 (d, J = 11.6 Hz, 1H), 4.90 (d, J = 11.6 Hz, 1H), 4.45
(
d, J = 5.6 Hz, 1H), 4.39 (d, J = 4.8 Hz, 1H), 3.78 (ddd, J = 11.6 Hz, 6.0 Hz, 3.2 Hz, 1H),
3
.73 (dt, J = 3.2 Hz, 9.2 Hz, 1H), 3.63 (m, 1H), 3.57 (t, J = 6.4 Hz, 1H), 3.52 (dt, J = 4.8 Hz,
9.2 Hz, 1H), 3.40 (t, J = 8.8 Hz, 1H), 3.30 (ddd, J = 9.6 Hz, 5.2 Hz, 2.8 Hz, 1H), 3.25 (dt, J
5.6 Hz, 8.8 Hz, 1H), 2.86 (dd, J = 15.6 Hz, 2.8 Hz, 1H), 2.50 (dd, J = 15.6 Hz, 8.8 Hz,
=
1
3
1
H), 2.14 (s, 3H) ppm; C NMR (100 MHz, Acetone-d
6
) δ 206.8, 140.7, 128.8, 128.4,
127.9, 87.7, 81.3, 77.1, 75.2, 74.8, 72.0, 63.0, 47.0, 30.5 ppm; HRMS (ESI-FT-ICR): m/z
+
+
Calcd for C16
23 6 6
H O [M+H] 311.1489, Found: 311.1489; C16H22NaO [M+Na] 333.1309,
Found: 333.1307.
5
,7,9-Tri-O-acetyl-6-O-benzyl-4,8-anhydro-1,3-di-deoxy-D-erythro-L-galacto-nonitol
(
9): To a solution of ketone 5 (100 mg, 0.23 mmol) in toluene (30 mL) was added Titanium
(IV) isopropoxide (274 µL, 0.92 mmol) at rt, after stirred for 30 min, the mixture was
cooled to -78°C, then added L-Selectride (1 M in THF, 253 µL, 253 µmol). The reaction
was quenched by addition of saturated NH
added, the mixture was extracted with DCM, and the combined organic layers were washed
with saturated NaHCO (aq.) and brine, dried over Na SO , filtered, evaporated, and
4
Cl (aq.) after 30 min, then 1 M HCl (aq.) was
3
2
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
purified by flash column chromatography (PE-EtOAc, 1:1) to give alcohol 9 (92.43 mg,
2
5
f
92%, R/S > 95:05) as an amorphous solid: R = 0.2 (PE-EtOAc, 1:1); mp 72-73°C; [α] =
D
1
-
22.2 (c = 2.2, CHCl
3
); H NMR (400 MHz, CDCl
3
) δ 7.35~7.22 (m, 5H), 5.08 (t, J = 9.6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Hz, 1H), 4.97 (t, J = 9.6 Hz, 1H), 4.61 (s, 2H), 4.17 (dd, J = 12.4 Hz, 5.2 Hz, 1H), 4.10 (dd,
J = 12.4 Hz, 2.4 Hz, 1H), 4.09 (m, 1H), 3.69 (t, J = 9.2 Hz, 1H), 3.65 (dt, J = 2.8 Hz, 9.2
Hz, 1H), 3.57 (ddd, J = 10.0 Hz, 5.2 Hz, 2.4 Hz, 1H), 2.08 (s, 3H), 1.99 (s, 3H), 1.97 (s,
1
3
3
3
H), 1.66~1.51 (m, 3H), 1.20 (d, J = 6.4 Hz, 3H) ppm; C NMR (100 MHz, CDCl ) δ
171.0, 169.8, 169.6, 138.0, 128.6, 127.9, 127.8, 81.8, 76.2, 75.5, 74.4, 73.0, 70.2, 64.2, 62.7,
+
3
4
9
9.7, 23.9, 21.0, 20.9 ppm; HRMS (ESI-FT-ICR): m/z Calcd for C22H30NaO [M+Na]
61.1782, Found: 461.1793.
5
,7,9-Tri-O-acetyl-6-O-benzyl-4,8-anhydro-1,3-di-deoxy-D-erythro-L-talo-nonitol (10):
To a stirred solution of (R)-2-methyl-CBS-oxazoborolidine (1 M in toluene, 516 µL, 516
µmol) in toluene (10 mL) was added catecholborane (1 M in THF, 1.03 mL, 1.03 mmol) at
0
°C. The reaction mixture was stirred for 10 min, then the solution of 5 (150 mg, 344 µmol)
in toluene (5 mL) was added. The mixture was warmed to rt and stirred for 1 h. Quenched
by addition of saturated NH Cl (aq.), then 1 M HCl (aq.) (10 mL) was added, the mixture
was extracted with DCM, and the combined organic layers were washed with saturated
NaHCO (aq.) and brine, dried over Na SO , filtered, evaporated, and purified by flash
column chromatography (PE-EtOAc, 1:1) to give alcohol 10 (149.2 mg, quant., S/R = 94:06)
4
3
2
4
2
D
5
as an amorphous solid: R
f
= 0.2 (PE-EtOAc, 1:1); mp 111-112°C; [α] = -8.0 (c = 1.0,
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8
9
1
CHCl
3 3
); H NMR (400 MHz, CDCl ) δ 7.35~7.22 (m, 5H), 5.02 (t, J = 9.6 Hz, 1H), 4.93 (t,
J = 9.6 Hz, 1H), 4.61 (s, 2H), 4.20 (d, J = 12.0 Hz, 1H), 4.03 (dd, J = 12.4 Hz, 7.2 Hz, 1H),
3
9
.98 (m, 1H), 3.67 (t, J = 9.6 Hz, 1H), 3.63 (dt, J = 9.6 Hz, 2.4 Hz, 1H), 3.57 (dt, J = 2.4 Hz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
.2 Hz, 1H), 3.16 (br s, 1H), 2.07 (s, 3H), 1.99 (s, 3H), 1.98 (s, 3H), 1.69~1.56 (m, 2H),
1
3
1.18 (d, J = 6.4 Hz, 3H) ppm; C NMR (100 MHz, CDCl
3
) δ 170.8, 169.7, 169.5, 137.9,
1
2
28.6, 128.0, 127.8, 81.5, 79.1, 76.2, 74.4, 73.4, 70.3, 67.8, 62.9, 39.7, 23.5, 21.0, 20.9,
+
0.8 ppm; HRMS (ESI-FT-ICR): m/z Calcd for C22
H
31
O
9
[M+H] 439.1963, Found:
+
439.1972; C22
H30NaO
9
[M+Na] 461.1782, Found: 461.1789.
5
,7,9-Tri-O-acetyl-6-O-benzyl-2-O-t-butyldiphenylsilyl-4,8-anhydro-1,3-di-deoxy-D-ery
thro-L-galacto-nonitol (11): To a solution of alcohol 9 (4.77 g, 10.89 mmol) in DCM (30
mL) were added imidazole (1.85 g, 27.23 mmol) and tert-butylchlorodiphenylsilane (3.35
mL, 13.07 mmol). The reaction mixture was stirred at rt for 2 h. Then washed with brine,
the aqueous layers were extracted with DCM, and the combined organic layers were dried
over Na
2
SO
4
, filtered, evaporated, and purified by flash column chromatography
= 0.4 (PE-EtOAc, 3:1);
) δ 7.69~7.22 (m, 15H), 5.04 (t, J
9.6 Hz, 1H), 4.84 (t, J = 9.6 Hz, 1H), 4.60 (d, J = 11.6 Hz, 1H), 4.56 (d, J = 11.6 Hz, 1H),
.15 (m, 1H), 4.09 (dd, J = 12.4 Hz, 4.4 Hz, 1H), 3.73 (dd, J =12.4 Hz, 2.4 Hz, 1H), 3.51 (t,
J = 9.2 Hz, 1H), 3.48 (dt, J = 1.6 Hz, 10.0 Hz, 1H), 3.05 (ddd, J = 10.0 Hz, 4.0 Hz, 2.0 Hz,
(
PE-EtOAc, 5:1) to give 11 (7.36 g, quant.) as a colorless syrup: R
f
2
5
1
3 3
[α] = +1.8 (c = 4.4, CHCl ); H NMR (400 MHz, CDCl
D
=
4
1
H), 2.03 (s, 3H), 2.02 (s ,3H), 1.94 (s, 3H), 1.60 (ddd, J = 14.4 Hz, 9.6 Hz, 1.2 Hz, 1H),
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
.49 (ddd, J = 14.4 Hz, 10.4 Hz, 2.4 Hz, 1H), 1.08 (d, J = 6.4 Hz, 3H), 1.06 (s, 9H) ppm;
1
3
C NMR (100 MHz, CDCl
3
) δ 171.0, 169.9, 169.4, 138.1, 136.0, 134.7, 134.4, 129.8,
1
2
29.7, 128.5, 127.9, 127.8, 127.7, 127.6, 82.1, 75.5, 74.9, 74.1, 73.4, 69.7, 66.1, 62.3, 41.8,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
7.2, 24.6, 21.1, 20.9, 19.5 ppm; HRMS (ESI-FT-ICR): m/z Calcd for C38H48NaO Si
+
[M+Na] 699.2960, Found: 699.2975.
6
-O-Benzyl-2-O-t-butyldiphenylsilyl-4,8-anhydro-1,3-di-deoxy-D-erythro-L-galacto-non
itol (S2): To a solution of 11 (6.97 g, 10.31 mmol) in methanol (50 mL) was added
catalytic sodium, the reaction mixture was stirred at 50°C for 2 h. The solution was
+
neutralized with DOWEX 50WX8-400 resin (H form). The resin was filtered off and the
filtrate concentrated to afford S2 (5.67 g, quant.) as a colorless syrup, which was directly
2
5
f 3 3
used without further purification: R = 0.2 (CHCl -CH OH, 30:1); [α] = +5.2 (c = 2.3,
D
1
CHCl
3
); H NMR (400 MHz, CD
3
OD) δ 7.73~7.26 (m, 15H), 4.89 (s, 2H), 4.25 (m, 1H),
3.65 (d, J = 3.3 Hz, 2H), 3.56~3.47 (m, 2H), 3.28 (t, J = 8.9 Hz, 1H), 3.14 (t, J = 9.2 Hz,
1
H), 3.00 (dt, J = 9.7 Hz, 3.3 Hz, 1H), 2.16 (ddd, J = 14.0 Hz, 9.7 Hz, 1.4 Hz, 1H), 1.38
13
(ddd, J = 14.0 Hz, 10.4 Hz, 2.6 Hz, 1H), 1.05 (s, 9H), 1.02 (d, J = 6.1 Hz, 3H) ppm; C
NMR (100 MHz, CD
3
OD) δ 140.4, 137.0, 136.9, 135.9, 135.3, 130.7, 130.6, 129.1, 129.0,
1
28.6, 128.4, 128.3, 88.1, 80.8, 77.5, 76.0, 75.5, 71.3, 67.4, 62.4, 43.2, 27.7, 25.1, 20.2 ppm;
+
6
HRMS (ESI-FT-ICR): m/z Calcd for C32H42NaO Si [M+Na] 573.2643, Found: 573.2653.
(
R)-6-O-Benzyl-7,9-O-benzylidene-2-O-t-butyldiphenylsilyl-4,8-anhydro-1,3-di-deoxy-
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D-erythro-L-galacto-nonitol (12): To a solution of S2 (5.15 g, 9.36 mmol) and
3
benzaldehyde dimethyl acetal (2.11 mL, 14.04 mmol) in CH CN (50 mL) was added
p-toluenesulfonic acid monohydrate (89.02 mg, 468 µmol) at rt. After stirring for 8 h, the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
reaction mixture was quenched by addition of triethylamine and the reaction was
concentrated, and purified by flash column chromatography (PE-EtOAc, 5:1) to give
25
f
alcohol 12 (5.32g, 89%) as a colorless syrup: R = 0.2 (PE-EtOAc, 5:1); [α] = +8.0 (c =
D
1
2
.5, CHCl
3
); H NMR (400 MHz, CDCl
3
) δ 7.70~7.31 (m, 20H), 5.53 (s, 1H), 5.02 (d, J =
11.6 Hz, 1H), 4.70 (d, J = 11.6 Hz, 1H), 4.12 (m, 1H), 4.10 (dd, J = 10.4 Hz, 4.8 Hz, 1H),
3
8
.60 (dd, J = 10.4 Hz, 9.2 Hz, 1H), 3.59 (ddd, J = 9.6 Hz, 8.8 Hz, 2.4 Hz, 1H), 3.57 (t, J =
.8 Hz, 1H), 3.52 (t, J = 8.8 Hz, 1H), 3.27 (t, J = 8.8 Hz, 1H), 3.16 (ddd, J = 9.2 Hz, 8.8 Hz,
4.8 Hz, 1H), 2.32 (br s, 1H), 2.13 (ddd, J = 14.0 Hz, 9.6 Hz, 1.6 Hz, 1H), 1.38 (ddd, J =
1
3
1
4.0 Hz, 10.4 Hz, 2.4 Hz, 1H), 1.05 (s, 9H), 1.04 (d, J = 6.0 Hz, 3H) ppm; C NMR (100
MHz, CDCl ) δ 138.6, 137.6, 136.1, 134.9, 134.3, 129.7, 129.6, 129.1, 128.7, 128.4, 128.2,
3
128.1, 127.6, 127.5, 126.1, 101.2, 82.7, 82.4, 76.7, 74.8, 74.3, 70.2, 69.0, 66.0, 42.5, 27.2,
+
2
4.6, 19.5 ppm; HRMS (ESI-FT-ICR): m/z Calcd for C39
H46NaO
6
Si [M+Na] 661.2956,
Found: 661.2969.
(
R)-6-O-Benzyl-7,9-O-benzylidene-2-O-t-butyldiphenylsilyl-5-cyano-4,8-anhydro-1,3,5-
tri-deoxy-D-erythro-L-gluco-nonitol (13): To a solution of compound 12 (628 mg, 984
µmol) and pyridine (199 µL, 2.46 mmol) in DCM (10 mL) was added
trifluoromethanesulfonic anhydride (194 µL, 1.18 mmol) dropwise at 0°C. The reaction
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
was stirred for 2 h, after which time it was concentrated and passed through a short plug of
silica gel (PE-EtOAc, 20:1) to give triflate as an unstable, colorless syrup that was used
immediately without characterization. To a solution of the triflate in DCM (20 mL) was
added tetrabutylammonium cyanide (0.44 M in THF, 11.18 mL, 4.92 mmol) dropwise at rt.
The solution was allowed to stir for 12 h, then the mixture was concentrated to dryness, and
the residue was subjected to flash column chromatography (PE-EtOAc, 10:1) to afford 13
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
D
5
(
f
586 mg, 92%) as a colorless syrup: R = 0.4 (PE-EtOAc, 5:1); [α] = -29.3 (c = 4.5,
1
CHCl
3
); H NMR (400 MHz, CDCl
3
) δ 7.65~7.31 (m, 20H), 5.57 (s, 1H), 4.82 (d, J = 12.4
Hz, 1H), 4.72 (d, J = 12.4 Hz, 1H), 4.11 (ddq, J = 10.0 Hz, 2.0 Hz, 6.4 Hz, 1H), 4.04 (dd, J
10.4 Hz, 4.8 Hz, 1H), 3.88 (t, J = 9.6 Hz, 1H), 3.67 (t, J = 10.4 Hz, 1H), 3.65 (dt, J = 10.0
Hz, 2.0 Hz, 1H), 3.56 (dd, J = 9.6 Hz, 5.2 Hz, 1H), 3.01 (dd, J = 5.2 Hz, 2.0 Hz, 1H), 2.94
=
(ddd, J = 10.4 Hz, 9.6 Hz, 4.8 Hz, 1H), 1.90 (ddd, J = 14.4 Hz, 10.0 Hz, 2.0 Hz, 1H), 1.62
1
3
(
ddd, J = 14.4 Hz, 10.0 Hz, 2.0 Hz, 1H), 1.11 (d, J = 6.4 Hz, 3H), 1.03 (s, 9H) ppm; C
) δ 137.7, 137.3, 136.0, 135.8, 134.3, 134.1, 130.0, 129.9, 129.2,
28.6, 128.4, 128.1, 127.8, 127.8, 127.7, 126.2, 116.9, 101.6, 80.4, 74.7, 72.9, 72.9, 71.3,
NMR (100 MHz, CDCl
3
1
6
8.4, 66.3, 43.9, 40.9, 27.2, 24.5, 19.5 ppm; HRMS (ESI-FT-ICR): m/z Calcd for
+
C
40
H
45NNaO
5
Si [M+Na] 670.2959, Found: 670.2973.
(2R,4aR,5aS,7R,9aR,10R,10aS)-10-Benzyloxy-7-methyl-2-phenyl-hexahydro-4H-pyran
o[3',4':5,6]pyrano[3,2-d][1,3]dioxin-9(4aH)-one (16): A solution of amide 20 (200 mg,
4
68 µmol) in chlorobenzene (10 mL) was refluxed for 48 h, while a continuous stream of
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Page 29 of 54
The Journal of Organic Chemistry
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nitrogen was bubbled through the solution. After evaporation, the residue was purified by
flash column chromatography (PE-EtOAc, 2:1) to afford lactone 16 (150 mg, 78%) as an
25
f 3
amorphous solid: R = 0.2 (PE-EtOAc, 2:1); mp 201-203°C; [α] = +32.6 (c = 3.1, CHCl );
D
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3
H NMR (400 MHz, CDCl ) δ 7.44~7.19 (m, 10H), 5.60 (s, 1H), 4.91 (d, J = 12.8 Hz, 1H),
4.67 (d, J = 12.8 Hz, 1H), 4.37 (t, J = 9.4 Hz, 1H), 4.19 (m, 1H), 4.15 (dd, J = 10.4 Hz, 4.8
Hz, 1H), 4.07 (dt, J = 9.4 Hz, 3.2 Hz, 1H), 3.75 (dd, J = 9.7 Hz, 4.9 Hz, 1H), 3.69 (t, J =
1
0.2 Hz, 1H), 3.28 (dt, J = 4.8 Hz, 9.9 Hz, 1H), 2.87 (t, J = 3.9 Hz, 1H), 2.32 (ddd, J = 15.2
Hz, 9.5 Hz, 3.4 Hz, 1H), 1.58 (ddd, J = 15.2 Hz, 12.3 Hz, 3.2 Hz, 1H), 1.30 (s, J = 6.0 Hz,
1
3
3
1
3
H) ppm; C NMR (100 MHz, CDCl ) δ 168.9, 138.7, 137.7, 129.0, 128.6, 128.4, 128.0,
27.8, 126.2, 101.5, 79.0, 75.7, 73.7, 73.4, 72.8, 71.8, 68.5, 45.7, 37.4, 20.5 ppm; HRMS
+
(ESI-FT-ICR): m/z Calcd for C24
H
27
O
6
[M+H] 411.1802, Found: 411.1811; C24
H
26NaO
6
+
[
M+Na] 433.1622, Found: 433.1622.
(R)-7,9-O-Benzylidene-6-O-benzyl-5-cyano-4,8-anhydro-1,3,5-tri-deoxy-D-erythro-L-ga
lacto-nonitol (17): 1.8-Diazabicyclo[5.4.0]undec-7-ene (87.3 µL, 586 µmol) was added to
a solution of alcohol 4 (120 mg, 293 µmol) and toluene (5 mL). The reaction mixture was
heated to 80°C for 12 h. Then cooled to rt and diluted with DCM (5 mL) and quenched
with a saturated aqueous NaHCO
phase was extracted with DCM. The combined organic layers were dried over Na
filtered, and concentrated, which was purified by flash column chromatography (PE-EtOAc,
3
(10 mL). The organic layer was separated and aqueous
2
4
SO ,
4
:1) to afford 17 (41 mg, 34%) as an amorphous solid (76 mg of compound 4 was
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