New chiral building blocks and branched 1,6-anhydro sugars from regio- and stereoisomeric Cerny epoxides

Article abstract of DOI:10.1002/ejoc.200500242

The tandem epoxide→allyl alcohol rearrangement-cuprate cross-coupling previously described for the Cerny epoxide 1, to yield the allyl alcohol 2, was extended to the regioisomeric epoxy-tosylate 3, to yield allyl alcohol 4, and to the stereoisomeric epoxi

Full text of DOI:10.1002/ejoc.200500242

FULL PAPER
New Chiral Building Blocks and Branched 1,6-Anhydro Sugars from
[‡]
ˇ
Regio- and Stereoisomeric Cerný Epoxides
Karsten Krohn,*[a] Dietmar Gehle,[a] and Ulrich Flörke[a]
Dedicated to Prof. Dieter Arlt on the occasion of his 70th birthday
ˇ
Keywords: 1,6-Anhydro sugars / Chiral building blocks / Branched sugars / Cerný epoxides / Gilman cuprates / Epoxide
rearrangement / Vinyl tosylate cross coupling
The tandem epoxideǞallyl alcohol rearrangement–cuprate
cross-coupling previously described for the Cerný epoxide 1,
to yield the allyl alcohol 2, was extended to the regioisomeric
epoxy-tosylate 3, to yield allyl alcohol 4, and to the stereoiso-
meric epoxide 5 to afford the allyl alcohols of type 6. Further
transformation of the products from this new two-step one-
pot reaction afforded regio- and stereodiverse branched 1,6-
anhydrosugars of potential use as building blocks in natural
product synthesis.
ˇ
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
absolutely uncertain in view of the unknown stereoelec-
tronic requirements of the two sequential reactions.[1]
Introduction
In a previous communication,[1] we reported on a new
tandem epoxideǞallyl alcohol rearrangement–cuprate
cross-coupling reaction, induced by treatment of the
[2]
ˇ
“Cerný” epoxide 1 (dioxirane at C-3,4) with Gilman cup-
rates, to afford the synthetically valuable allyl alcohol 2 (R
= methyl, ethyl, n-butyl). This allyl alcohol could be con-
verted to numerous new branched 1,6-anhydrosugars, steri-
cally complementary to hitherto known branched sugar de-
rivatives. The conversion of an intermediate allyl alcohol (2,
R = OTs) to the methylated compound (R = methyl) sup-
ported the mechanism of initial deprotonation at C-2 by an
excess of the basic Gilman cuprate, followed by epox-
ideǞallyl alcohol rearrangement. The C–H acidity at C-2
of the tosylate 1 may be increased by the presence of the
electron-withdrawing O-tosyl group, facilitating the subse-
quent epoxideǞallyl alcohol rearrangement. In addition,
complexation of the anomeric oxygen with the lithium cat-
ion of the Gilman cuprate might direct the attack of the
base at 2-H.
Scheme 1. Tandem epoxideǞallyl alcohol rearrangement–cuprate
cross-coupling of Cerný epoxides 1, 3, and 5 with Gilman cuprates.
ˇ
To exploit the great potential of the new tandem reaction
and to extend the stereochemical diversity of available chi-
ral building blocks, we now report on investigations to
probe the reaction on the regioisomeric 2,3-epoxide 3 and
the stereoisomeric 3,4-epoxide 5 (Scheme 1). The outcome
of the desired formation of the allyl alcohols 4 and 6 was
Results and Discussion
The synthesis of the required epoxide 3 started with glu-
cal (7), which was converted into the iodo-1,6-anhydrosugar
8 as described by Czernecki et al.[3] (Scheme 2). The further
steps to 3 included silylation and base-catalyzed cyclization
of the α-hydroxy iodide 8 to silylated epoxide 9 according
to Samadi et al.[4] Desilylation of the TBS ether 9 to the
alcohol 10 using tetrabutylammonium fluoride (TBAF) was
followed by tosylation to afford 3 in 86% combined yield.
[‡] Highly Deoxygenated Sugars, 4. Part 3: Ref.[1]
[a] Department Chemie, University of Paderborn,
Warburger Straße 100, 33098 Paderborn, Germany
E-mail: Karsten.Krohn@uni-paderborn.de
Eur. J. Org. Chem. 2005, 4557–4562
DOI: 10.1002/ejoc.200500242
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4557

K. Krohn, D. Gehle, U. Flörke
FULL PAPER
iodolevoglucosan (8) also results in epoxide 12, through in-
termediate 10. Surprisingly, the chemistry of this easily
available epoxide 12 was only occasionally exploited and its
use as the starting material for the synthesis of 3-substituted
-mannose derivatives was the most noteworthy transfor-
mation.[12] The tandem epoxideǞallyl alcohol rearrange-
ment–tosylate cross coupling reaction with 5 would not
only permit alkylation at C-2 but also generate the inverse
stereochemistry at C-4 with respect to alcohol 2, available
from epoxide 1 (see Scheme 1).
Scheme 2. a) (Bu3Sn)2O, 3-Å molecular sieves, acetonitrile, reflux,
6 h; b) I2, room temp., 12 h, 68–79%; c) TBSCl, imidazole, DMF,
room temp., 4 h; d) NaH (3 equiv.), 2 h, 85%; e) TBAF, THF, room
temp., 20 min, 95%; f) TsCl, Et3N, DMAP, CH2Cl2, room temp.,
2 h, 91%.
Having epoxide-tosylate 3 in hand, the stage was set to
try the tandem epoxideǞallyl alcohol rearrangement–cupr-
ate cross-coupling reaction. To our delight, epoxide 3 was
smoothly converted into the allyl alcohol 4 by treatment
with the methyl Gilman cuprate (Scheme 3). The yield was
lower (64%) than in the conversion of 1 to 2 (92%),[1] but
the product was a single stereoisomer. Similar to the pre-
viously described regioisomeric allyl alcohol 2,[1] the oxi-
dation to the corresponding α,β-unsaturated ketone 11 was
achieved in 94% yield using PDC as the oxidant. Both the
alcohol 4 and the enone 11 have been synthesized pre-
viously by different routes, and both compounds are of
great pharmaceutical interest. The allyl alcohol 4 was pre-
pared in connection with α-glucosidase inhibition and can-
cer metastasis inhibitors.[5] The enone 11 was used in a for-
mal synthesis of (+)-grandisol from levoglucosenone[6] and
mentioned in a number of patents as part of an investiga-
tion of immuno-suppressing and anti-inflammatory
agents.[7–10] The further transformations of the densely
packed functional groups in 4 and 11 are part of a future
communication.
Scheme 4. a) NaOMe (4 equiv.), CH2Cl2, (12 h), 95%; b) TsCl,
Et3N, DMAP, CH2Cl2, 2 h, 92%; c) CuCN (4 equiv.), RLi
(8 equiv.), Et2O/THF, –78 °C (1 h) to –20 °C (2 h), 84%;
d) TMEDA (0.6 equiv.), ethyl chlorocarbonate (1.2 equiv.),
CH2Cl2, (0.5 h), 90%; e) OsO4, NMO, acetone/H2O, 58 %.
The reaction of epoxide 5 with the Gilman cuprate was
performed as described previously for compound 1[1] to
yield methylated allyl alcohol 6b in 84% isolated yield as
the only product. To further probe the generality of the
reaction, 5 was also reacted with the corresponding n-butyl
Gilman cuprate to afford the butyl compound 6c in 68%
yield in addition to 22% of the nonalkylated allyl alcohol
6a. The product 6a may be formed by hydrolysis of an inter-
mediate metalated vinyl species.
Scheme 3. a) CuCN (4 equiv.), MeLi (8 equiv.), Et2O/THF, –78 °C
(1 h) to –20 °C (2 h), 64%; b) PDC, CH2Cl2, 18 h, 94%.
Next, we wanted to test the feasibility of the tandem ep-
Many more functional group transformations are await-
oxideǞallyl alcohol rearrangement–cuprate cross-coupling ing the study of the chemistry of the allyl alcohols of type
reaction on the stereoisomeric 3,4-epoxide 5. Epoxide 5 is 6, complementary in stereochemistry to the product 2, de-
not directly available from levoglucosan (1). However, al- scribed in the previous communication.[1] In this paper, only
ˇ
ready in 1965 Cerný and coworkers discovered the base- one preliminary experiment was performed analysing the
catalyzed Payne rearrangement of epoxy alcohol 10, easily inverse stereochemical influence of the anhydro bridge and
available from levoglucosan or as shown in Scheme 2, to the an axially orientated carbonate at C-4. Thus, the mixed car-
regioisomeric epoxy alcohol 12, as shown in Scheme 4.[11] bonate 13 was subjected to the Upjohn osmylation condi-
The equilibrium lies almost entirely on the side of epoxide tions yielding a ca. 1.5:1 (NMR) mixture of the respective
12, possibly due to stabilizing chelation of 2-OH to the α and β cis-diols 14 and 15. This result perfectly reflects the
bridged oxygen. It is worth noting that base treatment of stereochemical situation with the opposing effect of the ax-
4558
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 4557–4562

New Chiral Building Blocks and Branched 1,6-Anhydro Sugars
FULL PAPER
ial anhydro bridge and the axial substituents at C-4, shield-
ing the 2,3-double bond to attack from both the top and
bottom sides.[13–15]
Finally, we wanted to extend the use of the tosylate 5,
readily available from the Payne rearrangement product 12.
In the reaction of 5 with Normant cuprates, we expected
the formation of a C-3 methylated product, in agreement
with the Fürst–Plattner rules, leading to the respective 3,4-
diaxial products (Scheme 5).[16] However, to our surprise,
the reaction of 5 with methylmagnesium chloride, in the
presence of catalytic amounts of copper iodide, led to meth-
ylation at C-4 to afford alcohol 16 in 89% yield with equa-
torial substituents at C-3 and C-4. This is one of the very
rare examples[17] in which the violation of the Fürst–
Plattner rules is reported for a carbon nucleophile in the
field of 1,6-anhydrosugars. Reports in the literature state
that “hard” nucleophiles strictly open in a trans-diaxial
manner, whereas “soft” ones occasionally open equatori-
ally.[14,15] Since the Normant cuprates are more on the
“soft” side, our surprising result is in line with this explana-
tion. The structure of 16 was confirmed by analysis of the
3
1H NMR spectrum, showing a coupling of J3,4 = 7.5 Hz
for trans-diaxial protons. Also the strong NOE correlation
of 4-H with 2-H confirmed this assignment.
Figure 1. The molecular structure of 17. Selected bond lengths [Å]
and angles [°]: C1–O3 1.435(3), C2–O4 1.183(3), C6–O6 1.406(4),
C7–O6 1.444(4), C1–C2 1.515(4), C1–C6 1.520(4), C2–C3 1.506(4),
C3–C4 1.513(4), C3–C5 1.523(4), C5–C7 1.504(4); C5–O5–C6
102.3(2), C6–O6–C7 106.4(2).
with endo H-6. The stereochemical outcome is in agreement
with the strong shielding of the top-side of the molecule,
also clearly visible in the X-ray structure 17 (see Figure 1).
Experimental Section
General: For general methods and instrumentation see ref.[20] and
the preceding paper.[1]
1,6-Anhydro-2-deoxy-2-iodo-β-
D
-glucopyranose
(2-Iodolevogluco-
san) (8): M.p. 101 °C (ref.[3] m.p. 101–103 °C). [α]2D0 = +10.1 (c =
[21]
0.92 in MeOH), (ref.
+10, c = 1.0, MeOH).).
Scheme 5. Fürst–Plattner rule opposed opening of epoxide 5 fol-
lowed by conversion to alcohol 18. a) MeMgCl (4 equiv.), CuI (10
mol-%), THF, 40 °C, 12 h, 89%; b) RuCl3·3 H2O (1 mol-%), Na-
BrO3 in H2O (0.65 equiv.), acetonitrile/AcOH, 0 °C, 4 h, 99%; c)
MeMgCl, Et2O, 0 °C, 45 min, 93%.
1,6:2,3-Dianhydro-4-O-tert-butyldimethylsilyl-β-D-mannopyranose
(9): M.p. 55 °C (ref. m.p. 54–56 °C[4]). [α]2D0 = –22.8 (c = 0.99 in
CH2Cl2), (ref. –23 (c = 1.0, CH2Cl2)[4]).
1,6:2,3-Dianhydro-β-D-mannopyranose (10): A solution 9 (2.0 g,
7.74 mmol) in dry THF was treated with tetrabutylammonium
fluoride (TBAF, 2.68 g, 8.5 mmol, 1.1 equiv.). After 1 h, the mix-
ture was concentrated and the residue was filtered through a batch
of silica gel (CH2Cl2/5% diethyl ether) to afford the epoxide 10
(1.05 g, 7.35 mmol, 95%) as colorless crystals. Aqueous workup
leads to loss of products due to the remarkable water solubility of
Next, the alcohol 16 was almost quantitatively oxidized
to the ketone 17 using catalytic amounts of ruthenium tri-
chloride and sodium bromate as the cooxidant.[18,19] Suit-
able crystals for X-ray analysis were obtained from the
ketone 17 and the molecule in the crystal is shown in Fig-
ure 1, confirming the “anti-Fürst–Plattner” addition of the
methyl group at C-4 and its equatorial position.
The ketone 17 can serve to prepare further branched
sugars and stereochemical “triads” for natural product syn-
thesis. The reaction of 17 with methylmagnesium chloride
afforded a single tertiary alcohol 18 isolated in 93% yield
as a colorless solid. The equatorial position of the methyl
the unprotected epoxide. M.p. 70 °C (ref.[22] 68–70 °C). [α]2D0
+32.9 (c = 1.0, MeOH), [ref.[22] +33.8 (c = 1.02, MeOH)].
=
1,6:2,3-Dianhydro-4-O-p-tolylsulfonyl-β-D-mannopyranose (3):
A
solution of 10 (2.9 g, 20.1 mmol) in dry CH2Cl2 (50 mL) was
treated with triethylamine (5.2 mL, 40.2 mmol, 2 equiv.) and
DMAP (cat.). Tosyl chloride (7.6 g, 40.2 mmol, 2 equiv.) was then
added to the cooled (0 °C) mixture in portions. After 2 h at 22 °C,
the conversion was complete and the mixture was poured into ice
group is in agreement with the missing NOE correlation water. Colorless needles of 3 formed, which were filtered off and
Eur. J. Org. Chem. 2005, 4557–4562
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K. Krohn, D. Gehle, U. Flörke
FULL PAPER
dried to yield 3; (5.45 g, 18.2 mmol, 91%); m.p. 136 °C, (ref.[11] 137–
138 °C). [α]2D0 = –38.0 (c = 1.2, CHCl3), [ref.[11] –37 (c = 1.0,
CHCl3)]. 1H NMR (500 MHz, CDCl3): δ = 2.49 (s, 3 H, Ar–CH3),
3.10 (ddd, J3,2 = 3.6, J3,4 = 1.5, J3,5 = 0.8 Hz, 1 H, 3-H), 3.47 (ddd,
J2,3 = 3.6, J2,1 = 3.3, J2,4 = 0.8 Hz, 1 H, 2-H), 3.73–3.75 (m, 2 H,
6-H), 4.53 (m, 1 H, 5-H), 4.65 (d, J4,3 = 1.5 Hz, 1 H, 4-H), 5.72 (d,
J1,2 = 3.3 Hz, 1 H, 1-H), 7.42 (d, JAr,Ar = 8.3 Hz, 2 H, Ar-H), 7.87
(d, JAr,Ar = 8.3 Hz, 2 H, Ar-H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 21.7 (q, Ar–CH3), 47.1 (d, C-3), 54.4 (d, C-2), 65.6 (t, C-6),
71.8 (d, C-5), 74.1 (d, C-4), 97.4 (d, C-1), 127.9, 130.2 (d, 4×C–
Ar), 133.1 (s, S–CAr), 145.7 (s, CAr–CH3) ppm.
phases were dried (Na2SO4), evaporated at reduced pressure, and
purified by column chromatography (CH2Cl2/acetone, 95:5).
1,6-Anhydro-3,4-dideoxy-4-methyl-β-D-threohex-3-enopyranose (4):
Amounts of reagents: 3 (500 mg, 1.7 mmol) in dried THF (20 mL);
CuCN (600 mg, 6.7 mmol, 4 equiv.) in dried diethyl ether (20 mL);
methyllithium (1.6  in diethyl ether, 8.4 mL, 13.4 mmol, 8 equiv.).
Yield of 4: colorless oil (155 mg, 1.1 mmol, 64%). [α]2D0 = –69.3 (c
1
= 1.09, MeOH). H NMR (500 MHz, CDCl3): δ = 1.75 (s, 3 H, 7–
H), 2.13 (br. s, 1 H, OH), 3.75 (dd, J6a,6b = 6.6, J6a,5 = 4.0 Hz, 1
H, 6a-H), 3.79 (d, J6b,6a = 6.6 Hz, 1 H, 6b-H), 4.29 (s, 1 H, 2-H),
4.44 (d, J5,6a = 4.0 Hz, 1 H, 5-H), 5.32 (s, 1 H, 3-H), 5.49 (s, 1 H,
1,6:3,4-Dianhydro-β-D
-altropyranose (12): NaOMe (137 mL of a 1-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 19.0 (q, C-7), 69.0
0.8  solution, 100 mmol, 4 equiv.) was added to a stirred solution
of iodolevoglucosan (8) (7.5 g, 27.6 mmol) in CH2Cl2 (350 mL) at
room temp. with a dropping funnel over a period of 1 h. After 12 h,
the solution was neutralized to pH = 7 by addition of HCl (10%).
The aqueous phase was extracted with EtOAc (10×25 mL) and
the combined organic phases were dried (Na2SO4), filtered, and
concentrated to obtain the epoxide 12 (3.45 g, 23.9 mmol, 87%) as
a solid, which can be used without any further purification. M.p.
159 °C (ref.[23] 161–162 °C). [α]2D0 = –120 (c = 1.3, H2O), [ref.[23]
(d, C-2), 69.9 (t, C-6), 74.8 (d, C-5), 100.6 (d, C-1), 122.2 (d, C-3),
139.1 (s, C-4) ppm. IR (Film): ν = 3411 (s, O–H), 2980 (s, C–H),
˜
2924 (m, C–H), 1677 (w, C=C), 1461 (m, C–H), 1365 (s, C–H),
1360 (s, C–H), 1251 (s, C–O), 1011 (s, C–O) cm–1. MS (EI, 70 eV):
m/z (%) = 142 (55) [M+], 111 (21), 99 (90), 95 (77), 82 (100), 71
(58), 57 (55), 43 (82) 29 (20). HRMS (EI): calcd. for C7H10O3
142.0629; found 142.0629. C7H10O3 (142.15): calcd. C 59.14, H
7.09; found C 58.76, H 7.00.
1,6-Anhydro-2,3-dideoxy-2-methyl-β-D-erythrohex-2-enopyranose
1
–121 (c = 0.6, H2O)]. H NMR (500 MHz, MeOD): δ = 2.92 (dd,
J3,2 = 3.0, J3,4 = 3.5 Hz, 1 H, 3-H), 3.22 (d, J4,3 = 3.5 Hz, 1 H, 4-
(6b): Amounts of reagents: 5 (502 mg, 1.7 mmol) in dry THF
(20 mL); CuCN (600 mg, 6.7 mmol, 4 equiv.) in dry diethyl ether
(20 mL); methyllithium (1.6  in diethyl ether, 8.4 mL, 13.4 mmol,
H), 3.70 (d, J2,3 = 3.0 Hz, 1 H, 2-H), 3.81 (dd, J6a,6b = 7.4, J6a,5
=
4.4 Hz, 1 H, 6a-H), 4.08 (d, J6b,6a = 7.4 Hz, 1 H, 6b-H), 4.69 (d,
J5,6a = 4.4 Hz, 1 H, 5-H), 5.22 (s, 1 H, 1-H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 50.1 (d, C-4), 51.0 (d, C-3), 65.4 (d, C-2),
66.8 (t, C-6), 69.7 (d, C-5), 99.4 (C-1) ppm.
8 equiv.). Yield: 6b, 202 mg, colorless oil (1.42 mmol, 85%). [α]2D0
=
1
+131.7 (c = 1.35, MeOH). H NMR (500 MHz, CDCl3): δ = 1.77
(s, 3 H, H–CH3), 2.35 (br. s, 1 H, OH), 3.45 (dd, J6a,6b = 7.7, J6a,5
= 1.9 Hz, 1 H, 6a-H), 3.63 (ddd, J4,5 = 3.0, J4,3 = 5.9, J4,6 = 1.3 Hz,
1 H, 4-H), 3.91 (dd, J6b,6a = 7.7, J6b,5 = 7.0 Hz, 1 H, 6b-H), 4.64
(dddd, J5,4 = 3.0, J5,6a = 1.9, J5,6b = 7.0, J5,3 = 1.6 Hz, 1 H, 5-H),
5.30 (s, 1 H, 1-H), 5.45 (ddd, J3,4 = 5.9, J3,5 = 1.6, J3,1 = 3.0 Hz, 1
H, 3-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 18.7 (q, C-7), 63.0
(t, C-6), 67.1 (d, C-4), 76.5 (d, C-5), 99.4 (d, C-1), 119.6 (d, C-3),
1,6:3,4-Dianhydro-2-O-p-toluolsulfonyl-β-D-altropyranose (5):
A
solution of 12 (3.1 g, 21.5 mmol) in dried CH2Cl2 (50 mL) was
treated with triethylamine (5.5 mL, 43.0 mmol, 2 equiv.) and
DMAP (cat.). Tosyl chloride (8.2 g, 43.0 mmol, 2 equiv.) was added
to the cooled (0 °C) mixture in portions. After 2 h at room temp.
the conversion was complete and the mixture was poured into ice
water while stirring. The colorless needles were filtered off to yield
5 (5.90 g, 19.8 mmol, 92%); m.p. 101 °C, (ref.[24] 102–103 °C).
138.9 (s, C-2). IR (Film): ν = 3400 (s, O–H), 2969 (s, C–H), 2908
˜
(m, C–H), 1679 (w, C=C), 1450 (m, C–H), 1369 (s, C–H), 1259 (s,
C–O), 1086 (s, C–O) cm–1. MS (EI, 70 eV): m/z (%) = 142 (52)
[M+], 111 (24), 99 (100), 95 (55), 82 (95), 71 (55), 57 (58), 43 (72)
[α]2D0 = –68 (c = 0.36, CHCl3), [ref.[24] –70 (c = 1.35, CHCl3)]. H
1
NMR (500 MHz, CDCl3): δ = 2.49 (s, 3 H, Ar–CH3), 3.05 (dd, J3,2 29 (30). HRMS (EI): calcd. for C7H10O3 142.0629; found 142.0630.
= 2.4, J3,4 = 3.5 Hz, 1 H, 3-H), 3.15 (bd, J4,3 = 3.5 Hz, 1 H, 4-H), C7H10O3 (142.15): calcd. C 59.14, H 7.09; found C 59.76, H 7.56.
3.88 (dd, J6a,6b = 7.6, J6a,5 = 4.4 Hz, 1 H, 6a-H), 4.13 (d, J6b,6a
=
1,6-Anhydro-2-butyl-2,3-dideoxy-β- -erythrohex-2-enopyranose
D
7.6 Hz, 1 H, 6b-H), 4.51 (dd, J2,3 = 2.4, J2,1 = 2.6 Hz, 1 H, 2-H),
4.73 (dd, J5,6a = 4.4, J5,4 = 0.8 Hz, 1 H, 5-H), 5.26 (d, J1,2 = 2.6 Hz,
(6c): Amounts of reagents: 5 (500 mg, 1.68 mmol) in THF (20 mL);
CuCN [600 mg, 6.7 mmol, 4 equiv. in dry diethyl ether (10 mL)];
butyllithium (1.54  in hexane, 8.78 mL, 13.4 mmol, 8 equiv.).
Yield of 6c: colorless oil (209 mg, 1.14 mmol, 68%). [α]2D0 = +94.3
1 H, 1-H), 7.39 (d, JAr,Ar = 8.3 Hz, 2 H, Ar–H), 7.87 (d, JAr,Ar
=
8.3 Hz, 2 H, Ar–H) ppm. 13C NMR (125 MHz, CDCl3): δ = 21.7
(q, Ar–CH3), 49.0 (d, C-3), 49.7 (d, C-4), 67.5 (t, C-6), 69.9 (d, C-
5), 71.8 (d, C-2), 97.1 (d, C-1), 128.0, 130.2 (d, 4×C–Ar), 133.0 (s,
S–CAr), 145.6 (s, CAr–CH3) ppm.
1
(c = 0.86, MeOH). H NMR (500 MHz, CDCl3): δ = 0.93 (t, J10,9
= 7.3 Hz, 3 H, 10-H), 1.30–1.38 (m, 2 H, 9-H), 1.41–1.48 (m, 2 H,
8-H), 2.05–2.10 (m, 2 H. 7-H), 2.15 (br. s, 1 H, OH), 3.41 (dd, J6a,6b
= 7.7, J6a,5 = 2.0 Hz, 1 H, 6a-H), 3.66 (ddd, J4,5 = 3.4, J4,3 = 2.9,
J4,6a = 1.2 Hz, 1 H, 4-H), 3.92 (dd, J6b,6a = 7.7, J6b,5 = 6.5 Hz, 1
H, 6b-H), 4.65 (ddd, J5,6a = 2.0, J5,6b = 6.5, J5,4 = 3.4 Hz, 1 H, 5-
General Procedure for the Reaction of Epoxides with the Gilman
Cuprate: A suspension of CuCN (4 equiv.) in freshly distilled dry
diethyl ether was treated under argon at –78 °C with a solution of
the respective organolithium compound (8 equiv.) over a period of
5 min. The solution was then allowed to warm to 0 °C. During this
time the suspension became transparent. After stirring for 10 min
at 0 °C, the mixture was cooled to –78 °C and a solution of the
respective epoxide was added in dry THF. The resulting yellow
solution was stirred at –78 °C for 1 h and was then allowed to warm
up to –20 °C. After complete conversion of the starting material
(ca. 2 h, at –20 °C, TLC monitoring) the reaction was quenched by
dropwise addition of water (15 mL) and then with a saturated
aqueous NH4Cl (15 mL) solution. The biphasic mixture was stirred
until the aqueous phase turned blue. The aqueous phase was
washed with diethyl ether (5×20 mL) and the combined ethereal
H), 5.34 (d, J1,3 = 0.9 Hz, 1 H, 1-H), 5.46 (dd, J3,4 = 2.9, J3,1
=
0.9 Hz, 1 H, 3-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 13.8 (q,
C-10), 22.2 (t, C-9), 29.0 (t, C-8), 32.6 (t, C-7), 63.0 (t, C-6), 67.2
(d, C-4), 76.8 (d, C-5), 99.0 (d, C-1), 118.6 (d, C-3), 142.9 (s, C-
2) ppm. IR (Film): ν = 3402 (m, O–H), 2966 (m, C–H), 2924 (m,
˜
C–H), 2865 (m, C–H), 1693 (m, C=C), 1591 (m, C–H), 1455 (s, C–
H), 1366 (s, C–H), 1172 (s, C–O), 980 (s, C–O) cm–1. MS (EI, 70
eV): m/z (%) = 184 (48) [M+], 155 (9),141 (18), 111 (21), 95 (78),
85 (55), 82 (100), 81 (90), 71 (40) 68 (38), 57 (92), 55 (82), 43 (60),
41 (80) 27 (30). HRMS (EI): calcd. for C10H16O3; 184.1099; found
184.1101. C10H16O3 (184.23): calcd. C 65.19; H 8.75; found C
65.86; H 8.92.
4560
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4557–4562

New Chiral Building Blocks and Branched 1,6-Anhydro Sugars
FULL PAPER
1,6-Anhydro-2,3-dideoxy-β-
sis of byproduct: [α]2D0 = +154.2 (c = 0.59, MeOH). 1H NMR
(500 MHz, CDCl3): δ = 2.65 (br. s, 1 H, OH), 3.46 (dd, J6a,6b
D
-erythrohex-2-enopyranose (6a): Analy-
130.0 (2×d, 2×C–Ar), 133.0 (s, C–Ar), 145.4 (s, C–Ar) ppm. IR
(Film): ν = 3508 (br, O–H), 2960 (m, C–H), 2903 (m, C–H), 2898
˜
=
(m, C–H), 1589 (w, C=C), 1455 (m, C–S), 1356 (s, C–H), 1175 (s,
7.9, J6a,5 = 2.2 Hz, 1 H, 6a-H), 3.66 (m, 1 H, 4-H), 3.94 (dd, J6b,6a C–H), 1129 (s, C–H), 1020 (s, C–O), 953 (s, C–O), 917 (s, C–
= 7.9, J6b,5 = 6.6 Hz, 1 H, 6b-H), 4.67 (m, 1 H, 5-H), 5.57 (d, J1,2
H) cm–1. MS (CI, isobutane): m/z (%) = 315 (5) [M+ + 1], 159 (80),
= 3.4 Hz, 1 H, 1-H), 5.85 (m, 1 H, 3-H), 6.03 (ddd, J2,1 = 3.4, J2,3 155 (62), 113 (100), 91 (74), 85 (40), 83 (77), 71 (30), 57 (22), 55
= 9.5, J2,4 = 0.6 Hz, 1 H, 2-H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 62.6 (t, C-6), 67.2 (d, C-4), 76.9 (d, C-5), 95.5 (d, C-1), 126.3
(56), 43 (26). C14H18O6S (314.35): calcd. C 53.49, H 5.77; found C
53.56, H 5.71.
(d, C-3), 130.1 (d, C-2) ppm. IR (Film): ν = 3436 (s, O–H), 2965
˜
1,6-Anhydro-4-deoxy-4-methyl-2-O-p-tolylsulfonyl-β-D-lyxopyranos-
(s, C–H), 2918 (s, C–H), 2893 (s, C–H), 1734 (m, C=C), 1636 (m,
C–H), 1387 (s, C–H), 1175 (s, C–O), 1093 (s, C–O), 1056 (s, C–O),
984 (s, C–O) cm–1. MS (EI, 70 eV): m/z (%) = 128 (10) [M+], 97
(14), 85 (40), 81 (19), 70 (28), 68 (100), 57 (57), 54 (20), 41 (27), 39
(21), 29 (21), 27 (17). HRMS (EI): calcd. For C6H8O3 128.0473,
found 128.0473. C6H8O3 (128.13) calcd. C 56.24, H 6.29; found C
55.87, H 6.61.
3-ulose (17): A solution of 16 (1.00 g, 3.2 mmol) in acetonitrile
(10 mL) was treated at 0 °C with AcOH (0.93 mL) and
RuCl3·3H2O (8 mg, 0.03 mmol, 1 mol-%) under argon. An aqueous
solution of NaBrO3 (320 mg, 2.1 mmol, 0.65 equiv. in 1.5 mL H2O)
was added dropwise to this mixture over a period of 2 h, keeping
the temperature below 10 °C. After the addition, the reaction was
stored for 2 h at 0 °C. After complete conversion (TLC monitoring)
the solution was diluted with EtOAc (50 mL) and extracted suc-
cessively with aqueous Na2S2O3 (2×15 mL, 10%), water (10 mL),
NaHCO3 (3×15 mL), and brine (10 mL). The dried (Na2SO4) or-
ganic phase was evaporated under reduced pressure to obtain
0.99 g of ketone 17 (99%, 3.17 mmol) as colorless crystals, which
1,6-Anhydro-3,4-dideoxy-4-methyl-β-D-glycerohex-3-enopyranos-2-
ulose (11): Allyl alcohol 4 (130 mg, 0.9 mmol) in dry CH2Cl2
(30 mL) was treated with PDC (400 mg, 1.9 mmol, 2 equiv.). The
mixture was stirred at room temp. for 24 h. After complete conver-
sion of the starting material, the solution was diluted by addition of
diethyl ether (50 mL), the inorganic product was filtered off (Celite,
washing with diethyl ether, 10 mL), and the filtrate evaporated at
reduced pressure. The residue was purified by flash chromatog-
raphy (CH2Cl2, 100:0 to 98:2) to yield enone 11 (119 mg,
0.85 mmol, 94%) as colorless crystals. [α]2D0 = –482 (c = 0.95,
were used without any further purification. M.p. 158 °C. [α]2D0
–38 (c = 0.94, CH2Cl2). H NMR (500 MHz, CDCl3): δ = 1.08 (d,
=
1
J7,4 = 6.9 Hz, 1 H, 7-H), 2.48 (s, 3 H, Ar–CH3), 2.06 (dt, J4,7
=
6.9, J4,6a = 1.0 Hz, 1 H, 4-H), 3.78 (ddd, J6a,6b = 8.0, J6a,5 = 4.8,
J6a,4 = 1.0 Hz, 1 H, 6a-H), 3.83 (dd, J6b,6a = 8.0, J6b,5 = 0.8 Hz, 1
H, 6b-H), 4.68 (dd, J5,6a = 4.8, J5,6b = 0.8 Hz, 1 H, 5-H), 4.96 (dd,
J2,1 = 2.2, J = 2.2 Hz, 1 H, 2-H), 5.73 (d, J1,2 = 2.2 Hz, 1 H, 1-H),
7.38 (d, JAr,Ar = 8.0 Hz, 2 H, Ar–H), 7.89 (d, JAr,Ar = 8.0 Hz, 2 H,
Ar–H) ppm. 13C NMR (125 MHz, CDCl3): δ = 8.8 (q, C-7), 21.7
(q, CH3–Ar), 49.3 (d, C-4), 66.2 (t, C-6), 78.2 (d, C-5), 80.3 (d, C-
2), 101.8 (d, C-1), 128.1, 129.8 (2×d, 2×C–Ar), 133.3 (s, C–Ar),
1
MeOH). H NMR (500 MHz, CDCl3): δ = 2.07 (d, J7,3 = 1.6 Hz,
3 H, 7-H), 3.70 (dd, J6a,6b = 6.8, J6a,5 = 0.3 Hz, 1 H, 6a-H), 3.89
(dd, J6b,6a = 6.8, J6b,5 = 4.8 Hz, 1 H. 6b-H), 4.80 (d, J5,6b = 4.8 Hz,
1 H, 5-H), 5.29 (d, J1,3 = 1.4 Hz, 1 H, 1-H), 5.85 (dd, J3,7 = 1.4,
J3,1 = 1.6 Hz, 1 H, 3–H) ppm. 13C NMR (125 MHz, CDCl3): δ =
20.1 (q, C-7), 66.5 (t, C-6), 75.9 (d, C-5), 100.9 (d, C-1), 122.5 (d,
C-3), 161.0 (s, C-4), 189.2 (s, C-2) ppm. IR (Film): ν = 2979 (s, C–
˜
145.2 (s, C–Ar), 198.3 (s, C-3) ppm. IR (Film): ν = 2959 (m, C–H),
˜
H), 2893 (m, C–H), 2855 (m, C–H), 1748 (w, C=C), 1701 (s, C=C),
1677 (s, C=O), 1438 (m, C–H), 1381 (s, C–H), 1300 (s, C–H), 1261
(s, C–O), 1123 (s, C–O), 1066 (w, C–C), 961 (s, C–O) cm–1. MS (EI,
70 eV): m/z (%) = 140 (80) [M+], 99 (19), 97 (100), 82 (24), 71 (7),
69 (22), 57 (5), 55 (5), 53 (7), 43 (8), 41 (42), 29 (8), 27 (14). HRMS
(EI): calcd. for C7H8O3 140.04734; found 140.04734. C7H8O3
(140.15): calcd. C 59.99, H 5.75; found C 59.99, H 5.70.
2901 (m, C–H), 2860 (m, C–H), 1739 (w, C=O), 1579 (m, C–S),
1362 (s, C–H), 1170 (s, C–H), 1129 (s, C–H), 1041 (s, C–O), 968 (s,
C–O), 917 (s, C–H) cm–1. MS (EI, 70 eV): m/z (%) = 312 (30) [M+],
157 (88), 155 (68), 139 (14), 113 (40), 111 (100), 91 (94), 83 (90),
71 (39), 65 (50), 57 (22), 55 (93), 43 (28). HRMS (EI): calcd. for
C14H16O6S 312.0667; found 312.0654. C14H16O6S (312.34): calcd.
C 53.84, H 5.16; found C 53.91, H 4.68.
1,6-Anhydro-4-deoxy-4-methyl-2-O-p-tolylsulfonyl-β-D-idopyranose
Crystal Structure Determination of 17:[25] C14H16O6S, Mr = 312.3,
colorless crystal, size 0.05×0.06×0.45 mm³, orthorhombic, space
group P212121, a = 5.854(2), b = 7.770(3), c = 31.069(11) Å, V =
1413.2(9) ų, Z = 4, ρcalc = 1.468 g/cm³, F(000) = 656, T =
120(2) K. Bruker AXS SMART APEX,[26] graphite-monochro-
mated Mo-Kα radiation, µ = 0.254 mm–1, 14577 intensities collected
2.6 Ͻ Θ Ͻ 28.2°, h 7, k 10, –40 Ͻ l Ͻ 41, semi-empirical absorp-
tion correction[26] from equivalents, 3472 unique reflections. Struc-
ture solution[26] by direct methods, full-matrix least-squares refine-
ment[26] based on F² and 193 parameters, all but H atoms refined
anisotropically, H atoms refined with riding model on idealized
positions with Uiso = 1.2Ueq(C) and Uiso = 1.5 Ueq(C–methyl),
methyl groups were allowed to rotate but not to tip. Refinement
with correct assignment of absolute configuration [Flack parame-
ter[27] = 0.0(1)] converged at R1[I Ͼ 2σ(I)] = 0.054, wR2(all data)
= 0.068, max.(δ/σ) = 0.001, min./max. height in final ∆F map
–0.29/0.33 e/ų.
(16): A suspension of CuI (141 mg, 0.74 mmol, 10 mol-%) in abs.
THF (20 mL) was treated at –20 °C with MeMgCl (9.84 mL of a
3  solution in THF, 29.5 mmol, 4 equiv.). A solution of epoxide 5
(2.20 g, 7.38 mmol) in abs. THF (100 mL) was added to this. The
resulting mixture was kept at 40 °C for 12 h and after complete
conversion (TLC monitoring) it was diluted with EtOAc (200 mL).
A sat. NH4Cl solution (80 mL) was added and the biphasic mixture
was stirred for 1 h. Extraction of the aqueous phase with EtOAc
(3×30 mL) and concentration of the dried (Na2SO4) combined or-
ganic phases led to a crude product which was purified by flash
column chromatography (CH2Cl2/acetone, 98:2). Yield of pyranose
16 (colorless crystals): 2.06 g (6.57 mmol, 89%); m.p. 141 °C. [α]2D0
1
= –79 (c = 0.84, MeOH). H NMR (500 MHz, CDCl3): δ = 1.06
(d, J7,4 = 6.9 Hz, 1 H, 7-H), 2.06 (m, 1 H, 4-H), 2.48 (s, 3 H, Ar–
CH3), 2.50 (br. s, 1-H, OH), 3.64 (ddd, J3,2 = 7.6, J3,4 = 7.5, J =
2.6 Hz, 1 H, 3-H), 3.68 (dd, J6a,6b = 7.7, J6a,5 = 5.2 Hz, 1 H, 6a-
H), 3.89 (d, J6b,6a = 7.7 Hz, 1 H, 6b-H), 4.27 (dd, J2,3 = 7.6, J2,1
=
1.7 Hz, 1 H, 2-H), 4.32 (dd, J5,6a = 5.2, J5,4 = 4.8 Hz, 1 H, 5-H),
5.31 (d, J1,2 = 1.7 Hz, 1 H, 1-H), 7.38 (d, JAr,Ar = 8.0 Hz, 2 H, Ar-
H), 7.87 (d, JAr,Ar = 8.0 Hz, 2 H, Ar-H) ppm. 13C NMR (125 MHz,
1,6-Anhydro-4-deoxy-3,4-dimethyl-2-O-p-tolylsulfonyl-β-D-talopyr-
anose (18): MeMgCl (0.35 mL, 3  solution in THF, 1.06 mmol,
1.1 equiv.) was added dropwise to a cooled (0 °C) solution of 17
CDCl3): δ = 12.9 (q, C-7), 21.7 (q, CH3–Ar), 40.3 (d, C-4), 64.9 (t, (300 mg, 0.96 mmol) in dried diethyl ether (30 mL). After complete
C-6), 72.0 (d, C-3), 77.5 (d, C-5), 83.7 (d, C-2), 99.6 (d, C-1), 128.0, conversion (45 min, TLC monitoring), water was added (10 mL).
Eur. J. Org. Chem. 2005, 4557–4562
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4561

K. Krohn, D. Gehle, U. Flörke
FULL PAPER
[9]
F. Kato, M. Kato, F. Tsukamoto, M. Tsukamoto (Ishihara
Sangyo Kaisha, Japan) JP 08059646, August 12, 1994; Chem.
Abstr. 1996, 125, 11351.
The aqueous phase was extracted with diethyl ether (2×5 mL) and
the dried (Na2SO4) combined organic phases were evaporated un-
der reduced pressure to obtain 293 mg of 18 (93%, 0.89 mmol) as
a colorless solid, which could be used without any further purifica-
tion. M.p. 108 °C. [α]2D0 = –61 (c = 0.81, MeOH). 1H NMR
(500 MHz, CDCl3): δ = 1.03 (d, J7,4 = 7.2 Hz, 1 H, 7-H), 1.09 (s,
3 H, 8-H), 2.04 (ddt, J4,7 = 7.2, J4,5 = 3.8, J4,6a = 0.9 Hz, 1 H, 4-
H), 2.48 (s, 3 H, Ar–CH3), 3.62 (dd, J6a,6b = 6.9, J6a,5 = 5.9 Hz, 1
H, 6a-H), 4.21 (dd, J5,6a = 5.9, J5,4 = 3.8 Hz, 1 H, 5-H), 4.31 (d,
J2,1 = 1.7 Hz, 1 H, 2-H), 4.36 (d, J6a,6a = 6.9 Hz, 1 H, 6b-H), 5.31
(d, J1,2 = 1.7 Hz, 1 H, 1-H), 7.38 (d, JAr,Ar = 8.0 Hz, 2 H, Ar–H),
7.87 (d, JAr,Ar = 8.0 Hz, 2 H, Ar–H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 9.1 (q, C-7), 21.7 (q, CH3–Ar), 25.7 (q, C-8), 42.3 (d,
C-4), 64.9 (t, C-6), 72.1 (s, C-3), 77.5 (d, C-5), 81.1 (d, C-2), 99.7
(d, C-1), 128.0, 129.8 (2×d, 2×C–Ar), 133.3 (s, C–Ar), 145.4 (s,
[10]
S. Mizukoshi, F. Kato, M. Tsukamoto (Jpn. Kokai Tokkyo
Koho) JP 06080565, March 22, 1994; Chem. Abstr. 1994, 121,
149078.
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M. Cerný, J. Pacak, J. Stanek, Collect. Czech. Chem. Commun.
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˜
A. Fürst, P. A. Plattner, in 12th Internat. Congress of Pure and
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C–H), 1155 (s, C–H), 1056 (s, C–O), 979 (s, C–O), 896 (s, C–
H) cm–1. MS (EI, 70 eV): m/z (%) = 328 (5) [M+], 257 (13), 173
(81), 157 (88), 155 (89), 139 (19), 127 (86), 113 (33), 111 (49), 109
(93), 99 (41), 91 (84), 85 (92), 83 (70), 71 (79), 57 (40), 55 (77), 43
(100). HRMS (EI): calcd. for C15H20O6S 328.0980; found 328.0973.
C15H20O6S (328.38): calcd. C 54.86, H 6.14; found C 55.13, H 6.20.
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[25] CCDC-267820 contains the supplementary crystallographic
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from The Cambridge Crystallographic Data Centre via
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Received: April 5, 2005
Published Online: September 8, 2005
4562
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4557–4562