Synthesis of N-Bz-protected D-daunosamine and D-Ristosamine by silica gel promoted intramolecular conjugate addition of trichloroacetimidates obtained from osmundalactone and its epimer

Article abstract of DOI:10.1002/ejoc.200901402

Trichloroacetimidates prepared from osmundalactone and its epimer unexpectedly undergo intramolecular conjugate addition during silica gel chromatography to produce oxazolines in excellent yields. The novel, simple synthesis of N-Bz-protected D-daunosamin

Full text of DOI:10.1002/ejoc.200901402

FULL PAPER
DOI: 10.1002/ejoc.200901402
Synthesis of N-Bz-Protected
D
-Daunosamine and -Ristosamine by Silica Gel
D
Promoted Intramolecular Conjugate Addition of Trichloroacetimidates obtained
from Osmundalactone and Its Epimer
Yoshitaka Matsushima*[a] and Jun Kino[a]
Keywords: Nucleophilic addition / Heterocycles / Natural products / Amino sugars
Trichloroacetimidates prepared from osmundalactone and its
epimer unexpectedly undergo intramolecular conjugate ad-
dition during silica gel chromatography to produce oxazol-
ines in excellent yields. The novel, simple synthesis of N-
Bz-protected -daunosamine and -ristosamine from these
oxazolines is described in this paper.
D
D
Recently, we reported the application of trichloroacet-
imidate-mediated functionalization for providing a simple
and useful method for the stereoselective synthesis of poly-
functionalized carbocycles such as 3-hydroxy-substituted 2-
aminocycloalkanecarboxylates.[12]
The purpose of this study was to utilize trichloroacet-
imidate-mediated functionalization for the introduction of
nitrogen functionality in the stereoselective synthesis of
polyfunctionalized heterocycles such as deoxyamino sugars.
This paper describes a methodology applicable for the con-
struction of polyfunctionalized carbocyclic systems, a novel
route to 3-amino-2,3,6-trideoxy sugars, especially for dau-
nosamine and ristosamine, which are the amino sugar con-
stituents of daunomycin and other antibiotics.[13]
Introduction
Amino sugars, especially deoxyamino sugars, are found
in clinically important antibiotics such as antimicrobial
macrolides and anthracycline antitumor antibiotics.[1] In
most instances, the sugar components of these antibiotics
are essential for biological activity; however, the functions
of the sugar moieties have not been investigated thus far.[2]
We envisaged that modification of the sugar moieties of
these antibiotics may serve as a tool for investigating the
significance of amino sugars and the structure–activity rela-
tionship and for elucidating the biosynthetic route of anti-
biotics.[3,4] For this purpose, a versatile and synthetic route
for deoxyamino sugars is highly desirable. We were espe-
cially interested in developing a new synthetic route to de-
oxyamino sugars from nonsugar materials.[5–7]
Similar to deoxyamino sugars, 1,2- and 1,3-amino
alcohol moieties are often found in natural products and
potent drugs. These moieties have also been used as syn-
thetic intermediates. An effective method for the introduc-
tion of functionality into acyclic olefinic systems is re-
quired. While a variety of stereoselective synthetic methods
have been developed for 1,2-amino alcohol moieties,[8] there
are relatively few methods for 1,3-amino alcohols.[9] We ob-
served the intramolecular conjugate addition of γ-trichloro-
acetimidoyloxy-α,β-unsaturated esters during the course of
developing a simple synthetic strategy for deoxyamino
sugars.[6,10] We investigated the potential of trichloroacet-
imidate-mediated functionalization for the introduction of
nitrogen functionality[11] into the β-carbon of γ- and δ-
hydroxy-α,β-unsaturated esters, a new method to synthesize
1,2- or 1,3-amino alcohol moieties in an acyclic system.[7]
Results and Discussion
For the synthesis of polyfunctionalized heterocyclic com-
pounds such as deoxyamino sugars, we prepared amino
alcohol moieties with lactones by employing the intramo-
lecular conjugate addition of trichloroacetimidates to α,β-
unsaturated lactones. We assumed that osmundalactone
and its epimer would be suitable substrates for deoxyamino
sugars having a 3,4-cis-amino alcohol moiety, especially
daunosamine and ristosamine.
From the retrosynthetic analysis of N-Bz--daunosamine
(1) and N-Bz--ristosamine (2), as shown in Scheme 1, we
found that 1 and 2 could be obtained from preceding lac-
tones 3 and 4 with the oxazoline moiety, respectively. In
fact, racemic oxazoline 2 was reported as the precursor of
1.[14] Oxazoline intermediates 3 and 4 in turn could be ob-
tained from 4-epi-osmundalactone (5) and osmundalactone
(6) by the key intramolecular conjugate addition of the cor-
responding trichloroacetimidates.[6,10,11] 4-epi-Osmunda-
lactone (5) and osmundalactone (6) individually could be
prepared from chiral starting materials 7 and 8 by lactone
formation, accompanied by geometrical isomerization
[a] Department of Chemistry, Hamamatsu University School of
Medicine,
Handayama, Hamamatsu 431-3192, Japan
Fax: +81-53-435-2319
E-mail: ymatsu@hama-med.ac.jp
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901402.
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Silica Gel Promoted Intramolecular Conjugate Addition of Trichloroacetimidates
(trans to cis) of the double bond.[15] Compound 7 was
known to be obtained from the commercially available ethyl
sorbate by Sharpless asymmetric dihydroxylation, following
Pd-catalyzed etheration, as previously reported,[7] whereas
chiral starting material 8 was also known to be derived
from ethyl sorbate by Shi’s asymmetric epoxidation[16] and
epoxide ring opening,[17] as reported in the literature.
Scheme 1. Retrosynthetic analysis of N-Bz--daunosamine (1) and
N-Bz--ristosamine (2).
Scheme 2. Synthesis of N-Bz--daunosamine (1) from chiral
alcohol 7.
The first stage of our study was the synthesis of the inter-
mediary 4-epi-osmundalactone (5) from the chiral starting
material, δ-hydroxy-α,β-unsaturated ester 7 (Scheme 2).[7] after charging crude 10 on the silica gel column improved
Ester 7 was hydrolyzed with 2  sodium hydroxide in 2- the yield of oxazoline 3 up to 85% in this transformation.
propanol, and the resulting crude carboxylic acid was suc-
To the best of our knowledge, trichloroacetimidates are
cessively subjected to δ-lactonization in the presence of rarely affected by silica gel. Therefore, their isolated yields
2,4,6-trichlorobenzoyl chloride and pyridine to give the α,β- are seldom affected by the deprotection of the trichloroacet-
unsaturated-δ-lactone congener 9 (90% yield in 2 steps), ac- imidate group during chromatography. In addition, conju-
companied by successful trans/cis isomerization.[15] The p- gate addition has never been observed during silica gel
methoxyphenyl (PMP) group was oxidatively cleaved by ce- chromatography thus far. This might be attributed to the
ric ammonium nitrate (CAN) to give 5, which was obtained conformational regulation of the trichloroacetimidate being
in 82% yield.[18] The spectroscopic data (1H and 13C NMR, close to the reaction site, because the reactant lactone itself
IR) and optical rotation of 5 were identical to those re- is cyclic and besides the methyl group is substituted on the
ported in the literature.[19]
opposite site. From the viewpoint of green chemistry, our
For the intramolecular conjugate addition, 5 was trans- finding that silica gel promotes intramolecular conjugate
formed into the corresponding trichloroacetimidate 10 by addition could be very important, because conjugate ad-
treating it with a catalytic amount of 1,8-diazabicyclo- ditions are inherently atom economic, and the use of silica
[5.4.0]undec-7-ene (DBU) and an excess amount of tri- promotes conjugate additions. However, only few studies on
chloroacetonitrile in acetonitrile. Resulting crude 10, whose heteroconjugate additions promoted by silica gel have been
structure was confirmed by 1H NMR spectroscopy, was reported thus far.[20]
subjected to silica gel chromatography for purification, as
With objective intermediary oxazoline 3 in hand, the
reported previously. However, 10 was not practically ob- semifinal manipulation of our work was the transformation
tained in the expected fractions. Fortunately, desired oxaz- into N-Bz-γ-lactone 11; the known exact precursor[21] of 3-
oline 3 (73% in 2 steps) was found after close analysis of amino-2,3,6-trideoxyhexose, namely, daunosamine. Thus
the more polar fractions. During chromatography, a silica far,[14] the hydrolysis of the oxazoline ring of compound 3
gel promoted intramolecular conjugate addition unexpec- and the spontaneous formation of the γ-lactone were real-
tedly occurred and, consequently, 10 was directly trans- ized by heating the compound with 3  hydrochloric acid
formed into desired oxazoline 3. Further investigation in ethanol, followed by evaporation to afford the corre-
showed that regulation of the retention period of the eluent sponding γ-lactone hydrochloride. This was immediately
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Y. Matsushima, J. Kino
FULL PAPER
suspended in acetone and treated with a saturated aqueous the intramolecular conjugate addition to occur in the same
solution of sodium hydrogen carbonate and benzoyl chlo- manner as that described above. As a result, 14 was also
ride to produce desired N-Bz-γ-lactone 11 in 78% yield in successfully transformed into desired oxazoline 4 (81% in 2
2 steps. Finally, the half reduction of lactone 11 was steps).
achieved by using diisobutylaluminium hydride (DIBAL) in
Finally, a three-step process was used, which was the
tetrahydrofuran (THF)/hexane at –60 °C to produce N-Bz- same at that used in the case of N-Bz--daunosamine, to
protected -daunosamine (1, 33% yield). The spectroscopic afford N-Bz-protected -ristosamine (2). Acidic hydrolysis
data (1H and 13C NMR, IR) and the optical rotation of of compound 9 along with its transformation into γ-lactone
resulting compound 1 were identical to those reported in was achieved by heating the compound with 3  hydrochlo-
the literature.[21,22]
ric acid in ethanol. The obtained crude γ-lactone hydro-
For another type of 3-amino-2,3,6-trideoxyhexose, ristos- chloride was benzoylated to give N-Bz-γ-lactone 15 in 81%
amine, we first synthesized intermediary osmundalactone 6 yield in 2 steps. Finally, half reduction of lactone 15 was
from the chiral starting material δ-hydroxy-α,β-unsaturated achieved by using DIBAL in THF/hexane at –60 °C to give
ester (8), which was prepared from ethyl sorbate as reported 2 (59% yield). The spectroscopic data (1H and 13C NMR,
in the literature (Scheme 3).[16,17] Ester 8 was hydrolyzed, IR) and optical rotation of resulting 2 were identical to
and the obtained crude carboxylic acid was successively those reported in the literature.[21,24]
transformed into α,β-unsaturated-δ-lactone 13 by treating
it with 2,4,6-trichlorobenzoyl chloride in pyridine (48% in
3 steps) along with trans/cis isomerization.[15] The benzyl
group of lactone 13 was cleaved by aluminium chloride to
give 6 in 86% yield. The spectroscopic data (1H and 13C
NMR, IR) and optical rotation of obtained 6 were identical
to those reported in the literature.[19,23]
Conclusions
In conclusion, we have succeeded in developing a very
concise route for the synthesis of N-Bz-protected -daunos-
amine and -ristosamine by silica gel promoted intramolec-
ular conjugate addition of γ-trichloroacetimidates obtained
from osmundalactone and its epimer. This shows that our
synthetic strategy is applicable for the synthesis of 3-amino-
2,4,6-trideoxysugars from nonsugar chiral starting materi-
als. Further synthetic studies using this type of intramolecu-
lar conjugate addition, especially from the viewpoint of
green chemistry, are in progress and will be reported in due
course.
Experimental Section
General Information: NMR spectra were recorded with a JEOL
GSX-270 spectrometer. 1H NMR and 13C NMR chemical shifts
are reported in δ values based on internal tetramethylsilane (δH
0 ppm) or solvent signal (CDCl3 δC = 77.0 ppm; C6D6 δH
=
=
7.15 ppm; [D6]DMSO δC = 39.5 ppm) as reference. IR spectra were
recorded with a HORIBA FT-720 Fourier-transform infrared spec-
trometer. Optical rotations were measured with a Rudolph Re-
search Analytical AUTOPOL V polarimeter. Mass spectra were
measured with a Shimadzu LCMS-IT-TOF mass spectrometer.
Flash silica gel column chromatography was carried out on Kanto
Chemical Co., Inc., Silica Gel 60 N (spherical, neutral, 40–50 mm).
(4R,5R)-4-(p-Methoxyphenoxy)-5-methyl-2-hexen-5-olide (9): To a
solution of 7[7] (206.9 mg, 0.738 mmol) in 2-propanol (2.0 mL) was
added 2  NaOH (1.0 mL, 2.0 mmol), and the reaction mixture
was stirred for 2.5 h at room temperature. The reaction mixture
was concentrated in vacuo. To the residue was added 2  HCl, and
the mixture was extracted with EtOAc. The extract was washed
with brine, dried (MgSO4), and concentrated in vacuo. To an ice-
cold solution of the thus obtained crude carboxylic acid in dry
pyridine (1.5 mL) was added dropwise 2,4,6-trichlorobenzoyl chlo-
ride (135 µL, 0.864 mmol), and the mixture was stirred for 1.5 h
under a dry atmosphere (calcium chloride tube). The reaction mix-
ture was diluted with EtOAc and washed successively with satu-
rated aqueous NaHCO3 and brine, dried (MgSO4), and concen-
trated in vacuo. The residue was purified by flash column
Scheme 3. Synthesis of N-Bz--ristosamine (2) from chiral epoxide
12.
Next, for the key intramolecular conjugate addition, 6
was transformed into the corresponding trichloroacetimid-
ate 14 by treating it with a catalytic amount of DBU and an
excess amount of trichloroacetonitrile in acetonitrile. Thus
obtained crude 14 was charged onto a silica gel column for chromatography (hexane/EtOAc, 1:1) to give lactone 9 (155.4 mg,
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Silica Gel Promoted Intramolecular Conjugate Addition of Trichloroacetimidates
90% yield, 2 steps) as a colorless solid. An analytical sample (color-
less rod) was obtained by recrystallization from EtOAc/hexane;
(3R,4R,5R)-3-Benzamido-5-hydroxy-4-hexanolide (11): To a solu-
tion of oxazoline 3 (276.4 mg, 1.01 mmol) in EtOH (19 mL) was
added 3  HCl (19 mL, 57 mmol), and the reaction mixture was
heated (bath temp 75 °C) for 12 h. The reaction mixture was con-
m.p. 62.0–63.5 °C. [α]2D4.7 = –369 (c = 0.630, CHCl ). IR (KBr): ν
˜
3
= 2954, 1736, 1718, 1508, 1242, 1225, 1107, 1059, 1030, 982, 958,
822, 771 cm–1. 1H NMR (270 MHz, CDCl3): δ = 6.98 (dd, J = 4.9, centrated in vacuo. To the suspension of the residue in acetone
9.8 Hz, 1 H, 3-H), 6.93–6.81 (m, 4 H, Ar), 6.18 (d, J = 9. 8 Hz, 1 (6.5 mL) and saturated aqueous NaHCO3 (16 mL) was added
H, 2-H), 4.73 (dq, J = 3.4, 6.6 Hz, 1 H, 5-H), 4.62 (dd, J = 3.4,
4.7 Hz, 1 H, 4-H), 3.78 (s, 3 H, OMe), 1.56 (d, J = 6.6 Hz, 3 H, 5-
Me) ppm. 13C NMR (67.8 MHz, CDCl3): δ = 162.9, 155.0, 151.0,
142.0, 123.7, 117.5, 114.9, 76.1, 69.3, 55.8, 15.8 ppm. C13H14O4
(234.25): calcd. C 66.66, H 6.02; found C 66.51, H 6.12.
dropwise benzoyl chloride (390 µL, 3.35 mmol), and the mixture
was stirred for 4 h at room temperature. The mixture was acidified
with 2  HCl and extracted with EtOAc. The extract was dried
(MgSO4) and concentrated in vacuo. The residue was purified by
flash column chromatography (hexane/EtOAc, 1:2) to give 11
(197.7 mg, 78%) as a colorless solid. An analytical sample (color-
less needle) was obtained by recrystallization from EtOAc/hexane;
m.p. 143.0–146.5 °C {ref.[22a] m.p. 147 °C; ref.[20b] m.p. 143–144 °C;
(4R,5R)-4-Hydroxy-5-methyl-2-hexen-5-olide (4-epi-Osmundalact-
one) (5): To a cooled (bath temp. –25 °C) solution of 9 (69.2 mg,
0.295 mmol) in acetonitrile (3.0 mL) and water (0.75 mL) was
added ceric ammonium nitrate (416 mg, 0.759 mmol), and the mix-
ture was stirred for 15 min. The mixture was filtered through a pad
of silica gel and eluted with hexane/EtOAc (1:5), and the filtrate
was concentrated in vacuo. The residue was purified by flash col-
umn chromatography (hexane/EtOAc, 1:3) to give 5 (31.0 mg, 82%)
as a colorless solid. An analytical sample (colorless powder) was
obtained by recrystallization from Et2O; m.p. 49.5–53.5 °C {ref.[19]
(+)-5, m.p. 48–53 °C}. [α]2D6.6 = –230 (c = 0.550, H2O) {ref.[19] (+)-
ref.[22e] m.p. 148–149 °C; cf. ref.[14] (Ϯ)–11, 137–139 °C}. [α]2D8.7
=
+18.9 (c = 1.01, EtOH) {ref.[22b] [α]2D6 = –19.4 (c = 1.0, EtOH);
ref.[22e] [α]1D8 = –19.7 (c = 1.02, EtOH)}. IR (KBr): ν = 3465, 3338,
˜
2937, 1774, 1641, 1537, 1269, 1203, 1151, 1039, 694, 663, 633 cm–1.
1H NMR (270 MHz, CDCl3): δ = 7.83–7.75 (m, 2 H, Ar), 7.60–
7.41 (m, 3 H, Ar), 6.63 (br. d, J = 6.2 Hz, 1 H, NH), 4.82 (dddd,
J = 3.6, 4.4, 7.0, 8.9 Hz, 1 H, 3-H), 4.37 (dd, J = 2.8, 3.4 Hz, 1 H,
4-H), 4.16 (ddq, J = 2.7, 6.4, 6.4 Hz, 1 H, 5-H), 3.18 (dd, J = 9.0,
18.2 Hz, 1 H, one of 2-H), 2.59 (dd, J = 4.3, 18.2 Hz, 1 H, one of
2-H), 2.18 (d, J = 6.2 Hz, 1 H, OH), 1.35 (d, J = 6.6 Hz, 3 H, Me)
ppm. 13C NMR (67.8 MHz, CDCl3): δ = 175.2, 167.7, 133.0, 132.3,
128.8, 127.0, 88.9, 67.9, 49.0, 35.1, 19.3 ppm. C13H15NO4 (249.26):
calcd. C 62.64, H 6.07, N 5.62; found C 62.48, H 6.12, N 5.58.
5, [α]3D3 = +230.6 (c = 0.51, H O)}. IR (KBr): ν = 3448, 1711, 1387,
˜
2
1263, 1115, 1061, 989, 958, 833 cm–1. 1H NMR (270 MHz, CDCl3):
δ = 7.02 (dd, J = 5.8, 9.6 Hz, 1 H, 3-H), 6.11 (d, J = 9. 8 Hz, 1 H,
2-H), 4.54 (dq, J = 2.7, 6.7 Hz, 1 H, 5-H), 4.03 (ddd, J = 2.8, 5.8,
9.4 Hz, 1 H, 4-H), 2.21 (d, J = 9.4 Hz, 1 H, OH), 1.51 (d, J =
6.8 Hz, 3 H, 5-Me) ppm. 13C NMR (67.8 MHz, CDCl3): δ = 163.8,
144.5, 122.8, 77.1, 63.0, 15.7 ppm. C6H8O3 (128.13): calcd. C 56.24,
H 6.29; found C 56.20, H 6.33.
3-Benzamido-2,3,6-trideoxy-D-lyxo-hexopyranose (N-Bz-D-Daunos-
amine) (1): To a solution of lactone 11 (64.5 mg, 0.259 mmol) in
dry THF (10 mL) was added dropwise DIBAL (0.98  in hexane,
1.32 mL, 1.29 mmol) under an argon atmosphere at –60 °C, and
the reaction mixture was stirred for 1 h at –60 to –50 °C. The reac-
tion was quenched by the dropwise addition of acetone/MeOH
(1:1, 2.5 mL), and the mixture was warmed gradually to room tem-
perature with stirring for ca. 1 h. The mixture was filtered through
a pad of Celite. The filter cake was washed with acetone/MeOH
(1:1), and then the filtrate was concentrated in vacuo. The residue
was purified by flash column chromatography (EtOAc) to give 1
(21.7 mg, 33%). An analytical sample (colorless rod) was obtained
by recrystallization from EtOAc/hexane; m.p. 151.0–154.0 °C
{ref.[22a] m.p. 151.5–153 °C; ref.[22c] m.p. 152–154 °C; ref.[22d] m.p.
153–155 °C; ref.[22e] m.p. 154–156 °C; ref.[22f] m.p. 146–149 °C; cf.
ref.[14] (Ϯ)–1, 137–139 °C}. [α]2D6.9 = +128 (immediately after prepa-
ration), [α]2D3.0 = +93.5 (after 3 h, constant) (c = 0.149, EtOH)
{ref.[22a] [α]2D6 = –106 (EtOH); ref.[22c] [α]2D2 = –106.7 (c = 0.22,
EtOH); ref.[22d] [α]2D0 = –109 (c = 0.08, EtOH); ref.[22e] [α]2D0 = –108
(c = 0.093, EtOH); ref.[22f] [α]2D5 = –87.8 to –61.8 (c = 0.50, EtOH,
(3aR,4R,7aR)-2-Trichloromethyl-3a,4,7,7a-tetrahydro-4-methylpyr-
ano[4,3-d]oxazol-6-one (3): To a cooled (bath temp. – 45 °C) solu-
tion of 5 (160.9 mg, 1.26 mmol) and trichloroacetonitrile (1.26 mL,
12.6 mmol) in dry acetonitrile (4.8 mL) was added dropwise DBU
(95.0 µL, 0.635 mmol), and the mixture was stirred for 15 min un-
der a dry atmosphere (calcium chloride tube). The reaction mixture
was poured into a cold saturated aqueous solution of NH4Cl and
extracted with EtOAc. The extract was washed successively with
saturated aqueous NH4Cl and brine, dried (MgSO4), and concen-
trated in vacuo. Thus obtained crude 10 [(4R,5R)-4-trichloroacet-
imidoyloxy-5-methyl-2-hexen-5-olide] was subjected to flash column
chromatography: 1H NMR (270 MHz, CDCl3): δ = 8.50 (br. s, 1
H, NH), 7.13 (dd, J = 5.6, 9.6 Hz, 1 H, 3-H), 6.27 (d, J = 9. 8 Hz,
1 H, 2-H), 5.31 (dd, J = 2.9, 5.4 Hz, 1 H, 4-H), 4.78 (dq, J = 2.9,
6.6 Hz, 1 H, 5-H), 1.56 (d, J = 6.6 Hz, 3 H, 5-Me)] ppm. The
conditions for chromatography were as follows: SiO2: 80 g, sol-
vents: hexane/EtOAc = 1:1 to 1:3. Elution with polar solvents (hex-
ane/EtOAc, 1:3) was started ca. 30 min after charging the column
with crude 10. Oxazoline 3 (291.7 mg, 85% yield, 2 steps) was ob-
tained as a colorless solid through an intramolecular conjugate ad-
dition. An analytical sample (colorless rod) was obtained by
recrystallization from EtOAc/hexane; m.p. 197.5–199.3 °C {ref.[14]
(Ϯ)–3, 178–181 °C}. [α]2D5.7 = +88.7 (c = 0.565, CHCl3). IR (KBr):
3 h)}. IR (KBr): ν = 3442, 3330, 2974, 1637, 1577, 1525, 1489,
˜
1350, 1279, 1248, 1192, 1165, 1082, 1016, 982, 930, 692 cm–1. 1H
and 13C NMR spectra of this material were identical with those
reported in the literature.[21] C13H17NO4 (251.28): calcd. C 62.14,
H 6.82, N 5.57; found C 61.81, H 6.85, N 5.49.
(4S,5R)-4-Benzyloxy-5-methyl-2-hexen-5-olide (13): To a cooled
(bath temp. –20 °C) solution of epoxide 12[16] (756.6 mg,
4.84 mmol) and benzyl alcohol (1.25 mL, 12.1 mmol) in dry
CH2Cl2 (15 mL) was added dropwise BF3·OEt2 (1.20 mL,
9.72 mmol), and the mixture was stirred for 1 h at room tempera-
ture. To the mixture was added water, and the mixture was ex-
tracted with EtOAc and washed successively with saturated aque-
ous NaHCO3 and brine, dried (MgSO4), and concentrated in
vacuo. The residue was purified by flash column chromatography
(hexane/EtOAc, 5:1) to give 8 contaminated with benzyl alcohol.
[A small amount of pure 8 (ethyl (2E,4S,5R)-4-benzyloxy-5-hy-
ν = 2991, 1743, 1660, 1348, 1284, 1254, 1107, 1036, 999, 804, 793,
˜
673 cm–1. 1H NMR (270 MHz, CDCl3): δ = 5.07 (dd, J = 1.7,
10.0 Hz, 1 H, 3a-H), 4.94 (ddd, J = 1.9, 5.6, 10.0 Hz, 1 H, 7a-H),
4.49 (dq, J = 1.7, 6.6 Hz, 1 H, 4-H), 3.08 (dd, J = 1.9, 16.0 Hz, 1
H, one of 7-H), 2.72 (dd, J = 5.7, 16.1 Hz, 1 H, one of 7-H), 1.56
(d, J = 6.6 Hz, 3 H, 4-Me) ppm. 13C NMR (67.8 MHz, CDCl3): δ
= 168.7, 163.8, 85.7, 81.7, 74.1, 63.4, 32.6, 15.9 ppm. C8H8Cl3NO3
(272.51): calcd. C 35.26, H 2.96, N 5.14; found C 35.05, H 2.99, N
5.07.
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Y. Matsushima, J. Kino
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droxyhex-2-enoate)(colorless oil) obtained during flash column
CDCl3): δ = 163.2, 148.6, 120.7, 79.0, 67.7, 18.1 ppm. C6H8O3
(128.13): calcd. C 56.24, H 6.29; found C 56.21, H 6.33.
chromatography was used for several analyses: [α]2D5.7 = +64.1 (c =
0.605, CHCl ). IR (neat): ν = 3464, 2979, 1718, 1657, 1454, 1369,
˜
3
(3aS,4R,7aS)-2-Trichloromethyl-3a,4,7,7a-tetrahydro-4-methylpyr-
ano[4,3-d]oxazol-6-one (4): To a cooled (bath temp. –45 °C) solu-
tion of 6 (209.8 mg, 1.64 mmol) and trichloroacetonitrile (1.70 mL,
17.0 mmol) in dry acetonitrile (7.5 mL) was added dropwise DBU
(123 µL, 0.822 mmol), and the mixture was stirred for 20 min under
a dry atmosphere (calcium chloride tube). The reaction mixture
was poured into cold saturated aqueous NH4Cl and extracted with
EtOAc. The extract was washed successively with saturated aque-
ous NH4Cl and brine, dried (MgSO4), and concentrated in vacuo.
Thus obtained crude 14 [(4S,5R)-4-trichloroacetimidoyloxy-5-
methyl-2-hexen-5-olide] was subjected to flash column chromatog-
1300, 1275, 1178, 1095, 1041, 698 cm–1. 1H NMR (270 MHz,
CDCl3): δ = 7.41–7.26 (m, 5 H, Ar), 6.91 (dd, J = 6.7, 15.9 Hz, 1
H, 3-H), 6.07 (dd, J = 1.1, 15.8 Hz, 1 H, 2-H), 4.65 (d, J = 11.8 Hz,
1 H, one of benzyl), 4.42 (d, J = 11.8 Hz, 1 H, one of benzyl), 4.23
(q, J = 7.2 Hz, 2 H, CH2CH3), 4.03–3.89 (m, 1 H, 5-H), 3.91 (ddd,
J = 1.2, 3.7, 6.7 Hz, 1 H, 4-H), 2.19 (br. d, J = 4.9 Hz, 1 H, OH),
1.31 (t, J = 7.2 Hz, 3 H, CH2CH3), 1.16 (d, J = 6.4 Hz, 3 H,
CH(OH)CH3) ppm. 13C NMR (67.8 MHz, CDCl3) δ = 165.7,
143.9, 137.6, 128.5, 127.9, 127.8, 124.8, 81.9, 71.3, 69.2, 60.6, 17.9,
14.2 ppm. HRMS (ESI-TOF): calcd. for C15H21O4 [M +H]+
265.1440; found 265.1474.] To a solution of thus obtained crude
product in 2-propanol (10 mL) was added 2  NaOH (5.0 mL,
10 mmol), and the reaction mixture was stirred for 2.5 h at room
temperature. After an additional amount of 2  NaOH (3.0 mL,
6.0 mmol), the reaction mixture was stirred for 1 h. The reaction
mixture was concentrated in vacuo. The residue was washed with
CHCl3 for removal of benzyl alcohol. After acidification (pH ca.
1) with 2  HCl, the mixture was extracted with Et2O. The extract
was washed with brine, dried (MgSO4), and concentrated in vacuo.
To an ice-cold solution of thus obtained crude carboxylic acid
(650.3 mg, mmol) in dry pyridine (6.0 mL) was added dropwise
2,4,6-trichlorobenzoyl chloride (480 µL, 3.07 mmol), and the mix-
ture was stirred for 1.5 h under a dry atmosphere (calcium chloride
tube). The reaction mixture was diluted with EtOAc and washed
successively with saturated aqueous NaHCO3 and brine, dried
(MgSO4), and concentrated in vacuo. The residue was purified by
flash column chromatography (hexane/EtOAc, 2:1) to give lactone
13 (506.1 mg, 48% yield, 3 steps) as a colorless oil. [α]2D5.6 = +95.0
(c = 1.03, CHCl3) {ref.[15] (+)-13, [α]25 = +97.4 (c = 0.35, CHCl3);
1
raphy. H NMR (270 MHz, CDCl3) δ 8.59 (br. s, 1 H, NH), 6.93
(dd, J = 2.9, 9.9 Hz, 1 H, 3-H), 6.14 (dd, J = 1.6, 9.9 Hz, 1 H, 2-
H), 5.45 (ddd, J = 1.6, 2.9, 7.8 Hz, 1 H, 4-H), 4.74 (dq, J = 6.5,
7.7 Hz, 1 H, 5-H), 1.51 (d, J = 6.4 Hz, 3 H, 5-Me)] ppm. The
conditions for chromatography were as follows: SiO2: 80 g, sol-
vents: hexane/EtOAc, 5:1 to 2:1. Elution with polar solvents (hex-
ane/EtOAc, 2:1) was started ca. 1 h after charging the column with
crude 14. Oxazoline 4 (361.7 mg, 81% yield, 2 steps) was obtained
as a colorless solid. An analytical sample (colorless rod) was ob-
tained by recrystallization from EtOAc/hexane; m.p. 179.0–
179.2 °C. [α]2D5.5 = +34.4 (c = 0.515, CHCl ). IR (KBr): ν = 1755,
˜
3
1657, 1250, 1005, 989, 835, 802, 663 cm–1. 1H NMR (270 MHz,
C6D6): δ = 3.68 (ddd, J = 6.8, 9.4, 9.4 Hz, 1 H, 7a-H), 3.55 (dd, J
= 8.3, 9.4 Hz, 1 H, 3a-H), 3.42 (dq, J = 6.3, 8.3 Hz, 1 H, 4-H),
2.50 (dd, J = 6.9, 15.5 Hz, 1 H, one of 7-H), 1.85 (dd, J = 9.3,
15.5 Hz, 1 H, one of 7-H), 0.87 (d, J = 6.2 Hz, 3 H, 4-Me) ppm.
13C NMR (67.8 MHz, CDCl3): δ = 168.7, 162.8, 85.7, 82.7, 73.3,
62.9, 33.3, 18.0 ppm. C8H8Cl3NO3 (272.51): calcd. C 35.26, H 2.96,
N 5.14; found C 34.97, H 3.09, N 5.08.
ref.[15] (–)-13, [α]25– = 97.8 (c = 0.32, CHCl )}. IR (neat): ν = 2983,
˜
3
1738, 1726, 1454, 1387, 1236, 1113, 1076, 1030, 737, 700 cm–1. H
1
(3S,4S,5R)-3-Benzamido-5-hydroxy-4-hexanolide (15): To a solution
of 4 (280.2 mg, 1.03 mmol) in EtOH (19 mL) was added 3  HCl
(19 mL, 57 mmol), and the reaction mixture was heated (bath temp
75 °C) for 12 h. The reaction mixture was concentrated in vacuo.
To the suspension of the residue in acetone (6.5 mL) and saturated
aqueous NaHCO3 (16 mL) was added dropwise benzoyl chloride
(400 µL, 3.45 mmol), and the mixture was stirred for 4.5 h at room
temperature. The mixture was acidified with 2  HCl and extracted
with EtOAc. The extract was dried (MgSO4) and concentrated in
vacuo. The residue was purified by flash column chromatography
(hexane/EtOAc, 1:2) to give 15 (207.7 mg, 81%) as a colorless solid.
An analytical sample (colorless powder) was obtained by
recrystallization from EtOAc/hexane; m.p. 153.0–154.0 °C (ref.[24a]
m.p. 152–154 °C; ref.[24b] m.p. 149 °C). [α]2D8.7 = –41.4 (c = 1.12,
NMR (270 MHz, CDCl3): δ = 7.44–7.30 (m, 5 H, Ar), 6.87 (dd, J
= 2.1, 10.0 Hz, 1 H, 3-H), 6.00 (dd, J = 1.8, 9.9 Hz, 1 H, 2-H),
4.71 (d, J = 11.8 Hz, 1 H, one of benzyl), 4.63 (d, J = 11.8 Hz, 1
H, one of benzyl), 4.47 (dq, J = 6.4, 8.5 Hz, 1 H, 5-H), 3.99 (ddd,
J = 2.0, 2.0, 8.6 Hz, 1 H, 4-H), 1.45 (d, J = 6.4 Hz, 3 H, 5-Me)
ppm. 13C NMR (67.8 MHz, CDCl3): δ = 162.9, 145.9, 136.8, 128.7,
128.3, 128.0, 121.0, 77.2, 73.9, 72.1, 18.3 ppm. HRMS (ESI-TOF):
calcd. for C13H15O3 [M + H]+ 219.1021; found 219.1037.
(4S,5R)-4-Hydroxy-5-methyl-2-hexen-5-olide (6): To an ice-cooled
suspension of AlCl3 (756 mg, 5.67 mmol) in dry CH2Cl2 (11 mL)
was added a solution of 13 (495.1 mg, 2.27 mmol) in m-xylene
(2.0 mL), and the mixture was stirred for 1 h. The reaction mixture
was poured into cold saturated aqueous NH4Cl and extracted suc-
cessively with EtOAc and CHCl3. The extract was washed with
brine, dried (MgSO4), and concentrated in vacuo. The residue was
purified by flash column chromatography (hexane/EtOAc, 1:2) to
give 6 (248.7 mg, 86%) as a colorless solid. An analytical sample
(colorless plate) was obtained by recrystallization from Et2O; m.p.
75.0–78.5 °C {ref.[23c] (+)-6, m.p. 80 °C; ref.[23a] (–)-6, m.p. 82–
EtOH) (ref.[24b] [α]2D0 = +42 (c = 0.41, EtOH). IR (KBr): ν = 3334,
˜
2912, 1757, 1724, 1645, 1545, 1319, 1186, 1144, 1007, 714,
690 cm–1. 1H NMR (270 MHz, CDCl3): δ = 7.83–7.74 (m, 2 H,
Ar), 7.60–7.41 (m, 3 H, Ar), 6.62 (br. d, J = 7.1 Hz, 1 H, NH),
4.84 (dddd, J = 3.8, 4.6, 7.2, 9.0 Hz, 1 H, 3-H), 4.30 (dd, J = 3.7,
4.8 Hz, 1 H, 4-H), 4.07 (ddq, J = 4.6, 4.6, 6.4 Hz, 1 H, 5-H), 3.17
(dd, J = 9.1, 18.3 Hz, 1 H, one of 2-H), 2.76 (d, J = 4.3 Hz, 1 H,
OH), 2.61 (d, J = 4.7, 18.4 Hz, 1 H, one of 2-H), 1.38 (d, J =
6.4 Hz, 3 H, Me) ppm. 13C NMR (67.8 MHz, CDCl3): δ = 174.8,
167.7, 133.0, 132.3, 128.8, 127.0, 89.2, 68.2, 47.9, 35.5, 19.1 ppm.
C13H15NO4 (249.26): calcd. C 62.64, H 6.07, N 5.62; found C
62.44, H 5.93, N 5.59.
82.5 °C; ref.[23b] m.p. 82.5 °C; ref.[23d] m.p. 77–80 °C}. [α]2D5.9
=
+73.0 (c = 1.13, H2O) {ref.[23c] (+)-6, [α]2D2 = +65.8 (c = 0.16, H2O);
ref.[23a] (–)-6 [α]2D2 = –70.6 (c = 2.0, H2O); ref.[23b] [α]2D0 = –70.3 (c =
0.56, H2O); ref.[23d] [α]3D0 = –47.9 (c = 1.01, H O)}. IR (KBr): ν =
˜
2
3386, 2987, 1705, 1618, 1390, 1365, 1304, 1282, 1246, 1171, 1107,
1061, 1022, 964, 850, 808, 744, 469 cm–1. 1H NMR (270 MHz,
CDCl3): δ = 6.84 (dd, J = 2.2, 9.9 Hz, 1 H, 3-H), 5.99 (dd, J = 1.9, 3-Benzamido-2,3,6-trideoxy-D-ribo-hexofuranose (N-Bz-D-Ristos-
9.8 Hz, 1 H, 2-H), 4.38 (dq, J = 6.3, 8.9 Hz, 1 H, 5-H), 4.26 (dddd,
J = 2.0, 2.0, 6.9, 8.9 Hz, 1 H, 4-H), 2.35 (br. d, J = 6.8 Hz, 1 H,
OH), 1.49 (d, J = 6.2 Hz, 3 H, 5-Me) ppm. 13C NMR (67.8 MHz,
amine) (2): To a solution of 15 (63.7 mg, 0.256 mmol) in dry THF
(10 mL) was added dropwise DIBAL (0.98  in hexane, 1.30 mL,
1.28 mmol) under an argon atmosphere at –60 °C, and the reaction
2210
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2206–2211

Silica Gel Promoted Intramolecular Conjugate Addition of Trichloroacetimidates
Irie, J. Org. Chem. 1997, 62, 2275–2279; Y. Matsushima, T.
mixture was stirred for 1 h at –60 to –50 °C. The reaction was
quenched by the dropwise addition of acetone/MeOH (1:1, 2 mL),
and the mixture was warmed gradually to room temperature with
stirring for ca. 1 h. The mixture was filtered through a pad of Ce-
lite. The filter cake was washed with acetone/MeOH (1:1), and then
the filtrate was concentrated in vacuo. The residue was purified by
flash column chromatography (hexane/EtOAc, 1:5 to EtOAc) to 2
(37.6 mg, 59%). An analytical sample (colorless needle) was ob-
tained by recrystallization from acetone; m.p. 136.8–137.8 °C
{ref.[24a] m.p. 132–134 °C; ref.[24b] m.p. 131–133 °C}. [α]2D3.0 = –11.3
(after 10 min), + 25.8° (after 4 d, constant) (c = 0.257, EtOH)
{ref.[24a] [α]2D3.0 = –10 (after 10 min), –24° (after 3 h, constant) (c =
Nakayama, S. Tohyama, T. Eguchi, K. Kakinuma, J. Chem.
Soc. Perkin Trans. 1 2001, 569–577 and see also C. Rondot, P.
Retailleau, J. Zhu, Org. Lett. 2007, 9, 247–250 and references
cited therein; c) for Overman rearrangement, see: L. E. Over-
man, Acc. Chem. Res. 1980, 13, 218–224.
[12] Y. Matsushima, J. Kino, Eur. J. Org. Chem. 2009, 1619–1624.
[13] For a recent synthesis of 3-amino-2,3,6-trideoxyhexose, see: K.
Gregory, G. K. Friestad, T. Jiang, G. M. Fioroni, Tetrahedron
2008, 64, 11549–11557, and references cited therein.
[14] Racemic oxazoline 2 and subsequent manipulation, see: W. R.
Roush, J. A. Straub, R. J. Brown, J. Org. Chem. 1987, 52, 5127–
5136.
[15] During our course of pursuing the effective synthesis of os-
mundalactones, an appealing method for δ-lactonization ac-
companied by trans/cis isomerization was reported. The
mechanism of trans/cis isomerization was suggested to occur
by pyridine-assisted addition–elimination in this paper. M.
Ono, X. Y. Zhao, Y. Shida, H. Akita, Tetrahedron 2007, 63,
10140–10148.
0.20, EtOH); ref.[24b] [α]2D5 = +28.0 (c = 0.23, EtOH)}. IR (KBr): ν
˜
= 3354, 3280, 2974, 1635, 1579, 1541, 1489, 1448, 1406, 1375, 1294,
1
1074, 1020, 964, 696 cm–1. H and 13C NMR spectra of this mate-
rial were identical with those reported in the literature.[21]
C13H17NO4 (251.28): calcd. C 62.14, H 6.82, N 5.57; found C
61.81, H 6.85, N 5.49.
[16] a) M. Frohn, M. Dalkiewicz, Y. Tu, Z.-X. Wang, Y. Shi, J. Org.
Chem. 1998, 63, 2948–2953; b) K. Uchida, K. Ishigami, H.
Watanabe, T. Kitahara, Tetrahedron 2007, 63, 1281–1287.
[17] M. Ono, C. Saotome, H. Akita, Tetrahedron: Asymmetry 1996,
7, 2595–2602.
[18] T. Fukuyama, A. A. Laird, L. M. Hotchkiss, Tetrahedron Lett.
1985, 26, 6291–6292.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra.
Acknowledgments
This work was supported by the Ministry of Education, Culture,
Sports, Science and Technology of Japan (17780089, Grant-in-Aid
for Scientific Research) and the 21st Century COE Program (Ham-
amatsu University School of Medicine, Medical Photonics). We are
grateful to Ms. N. Goto-Inoue of the Department of Molecular
Anatomy for measuring the high-resolution mass spectra. The au-
thors also thank the technical staff (Ms. M. Suzuki and Ms. M.
Toyama) for their support.
[19]
for selected literature on 4-epi-osmundalactone, which include
melting point data, see: S. V. Ley, A. Armstrong, D. Diez-
Martín, M. J. Ford, P. Grice, J. G. Knight, H. C. Kolb, A. Ma-
din, C. A. Marby, S. Mukherjee, A. N. Shaw, A. M. Z. Slawin,
S. Vile, A. D. White, D. J. Williams, M. Woods, J. Chem. Soc.
Perkin Trans. 1 1991, 667–689.
[20]
For a few examples of the use of silica gel in heteroconjugate
additions, see: a) for addition of amines to α,β-unsaturated es-
ters and nitriles: B. Basu, P. Das, I. Hossain, Synlett 2004,
2630–2632; b) for addition of amines to α,β-unsaturated
amides: L. You, S. Feng, R. An, X. Wang, D. Bai, Tetrahedron
Lett. 2008, 49, 5147–5149; c) for addition of thiols to α,β-un-
saturated ketones: H. Firouzabadi, N. Iranpoor, M. Jafarpour,
A. Ghaderi, J. Mol. Catal. A 2006, 249, 98–102; d) an intramo-
lecular version of the conjugate addition of thioamide to α,β-
unsaturated esters or amides to produce thiazolines was re-
ported: Z. Xu, T. Ye, Tetrahedron: Asymmetry 2005, 16, 1905–
1912.
[1] A. C. Weymouth-Wilson, Nat. Prod. Rep. 1997, 14, 99–110.
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[5] Y. Matsushima, J. Kino, Tetrahedron Lett. 2005, 46, 8609–8612.
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[7] Y. Matsushima, J. Kino, Tetrahedron 2008, 64, 3943–3952.
[8] S. C. Bergmeier, Tetrahedron 2000, 56, 2561–2576.
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Soc. 2003, 125, 11276–11282 and references cited therein.
[10] A few example of intramolecular conjugate additions of tri-
chloroacetimidates, which were prepared in situ, in a cyclic sys-
tem were reported: a) to α,β-unsaturated esters: J. R. Brown,
Y. Nishimura, J. D. Esko, Bioorg. Med. Chem. Lett. 2006, 16,
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Burgey, R. Vollerthum, Pure Appl. Chem. 1998, 70, 285–288; c)
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629–630.
[11] There are some useful reactions involving trichloroacetimidates
for the introduction of a nitrogen functionality; a) for electro-
phile-promoted intramolecular aminations of trichloroacetimi-
dates derived from allylic and homoallylic alcohols, see: H.-S.
Lee, S. H. Kang, Synlett 2004, 1673–1685 and references cited
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[21]
[22]
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[23]
[24]
Selected literature on osmundalactone, which include melting
point data: a) isolation of osmundarin and osmundalactone:
K. H. Hollenbeak, M. E. Kuehne, Tetrahedron 1974, 30, 2307–
2316; b) T. Murayama, T. Sugiyama, K. Yamashita, Agric. Biol.
Chem. 1986, 50, 2347–2351; c) M. Holzapfel, C. Kilpert, W.
Steglich, Liebigs Ann. Chem. 1989, 797–801; d) ref.[17]
.
Selected literature on N-Bz-ristosamine synthesis: a) M. Hi-
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Received: November 30, 2009
Published Online: February 25, 2010
Eur. J. Org. Chem. 2010, 2206–2211
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2211