Open chain chiral macrolide building blocks by opening of deoxygenated 1,6-anhydrosugars with 1,3-propanedithiol

Article abstract of DOI:10.1080/07328300802691851

Chiral building blocks for macrolides and related natural products are obtained from 1,6-anhydrosugars by conversion of the bicyclic acetals 2 or 12 into the open chain chiral 1,3-dithianes 6 and 13. Branched precursors can be obtained by opening of the C

Full text of DOI:10.1080/07328300802691851

Journal of Carbohydrate Chemistry, 28:64–77, 2009
ꢀC
Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328300802691851
Open Chain Chiral Macrolide
Building Blocks by Opening
of Deoxygenated 1,6-
Anhydrosugars with
1,3-Propanedithiol
Karsten Krohn, Ishtiaq Ahmed, Dietmar Gehle,
and Mohammed Al Sahli
Department of Chemistry, University of Paderborn, Paderborn, Germany
Chiral building blocks for macrolides and related natural products are obtained from
1,6-anhydrosugars by conversion of the bicyclic acetals 2 or 12 into the open chain
chiral 1,3-dithianes 6 and 13. Branched precursors can be obtained by opening of the
ˇ
Cerny´ epoxide 1 with the 1,3-dithiane anion to yield 7, followed by ring opening with
1,3-propanedithiol to the bis-1,3-dithiane 8.
Keywords 1,6-Anhydrosugars, Chiral building blocks, Ring opening with 1,3-
ˇ
propandithiol, 1,3-Dithianes, Cerny´ epoxides
INTRODUCTION
In connection with investigations to use 1,6-anhydrosugars and their
derivatives as chiral starting materials for more complex targets such as
macrolides,[1−3] we probed the opening of a number of 1,6-anhydrosugar
derivatives with different degrees of substitution and deoxygenation with 1,3-
propanedithiol. In this proton- or Lewis acid-catalyzed reaction (Sch. 1), the
cyclic acetals of the anhydrosugars A are converted with good yields into open
chain 1,3-dithianes B in a smooth and reliable reaction.
This conversion has several advantages. No new chiral centers are formed
during the dithiane formation, the stereogenic centers present in the sugar
Received August 26, 2008; accepted December 16, 2008.
Address correspondence to Karsten Krohn, Department of Chemistry, University
of Paderborn, Warburger Str. 100, D-33098 Paderborn, Germany. E-mail: karsten.
krohn@uni-paderborn.de
64

Open Chain Chiral Macrolide Building Blocks
65
6
O
SH
O
R
R''
HS
BF3
1
2
5
4
S
3
1
5
2
6
4
3
HO
.
Et2O
R
R''
OH R'
S
R'
A
B
Scheme 1: Lewis acid-catalyzed opening of 1,6-anhydrosugars A with 1,3-propanedithiol to
afford open chain 1,3-dithianes B.
molecule generally do not epimerize under these conditions, and double bonds
are also not affected. Moreover, the chemically reactive groups on both ends
of the linear fragment B allow incorporation into larger units. Both the left
and right ends of the molecule can be converted into either nucleophiles or
electrophiles. Thus, the inherent C-H acidity of 1,3-dithiane allows conversion
into a nucleophile after deprotonation and formation of new C C bonds in the
reaction with various electrophiles. This dithiane reactivity was pioneered by
the work of Corey and Seebach[4] and has been compiled in a recent review
by Yus et al.[5] Particularly interesting is the formation of the 1,3-dioxygen
pattern by reaction with terminal epoxides as shown by Smith et al.[6,7] Ap-
plications of this approach in natural products synthesis have been demon-
strated, inter alia, by Redlich et al.,[8] Smith et al.,[9,10] Guo et al.,[11] Hodges
and Procter,[12] and Kochetkov et al.[13−15] Boron trifluoride etherate in dilute
solution at rt has been effectively used by Procter et al.[11,16] and Kochetkov
et al.[13,14] including incorporation of the resulting 1,3-dithianes into target
molecules. Alternatively, the 1,3-dithiane can also be converted into an elec-
trophilic aldehyde group.
On the left side of the molecule, the hydroxyl groups at C-5 and C-6, hidden
in the cyclic acetal of the anhydrosugar A, are liberated in B and open the door
to a number of subsequent transformations. For instance, cleavage of the diol
generates reactive aldehydes and terminal epoxides are easily obtained via
the primary tosylate.[17] Protection of the diols as cyclic acetals or esters is also
possible.
RESULTS AND DISCUSSION
The aim of the present study was to provide these functionalized stereotri-
ads of type B with different degrees of substitution, branching, and deoxy-
genation for potential use as building blocks for macrolides and other target
molecules. The first series started from the benzyloxy-alcohol 2,[18−20] read-
ily available by reaction of epoxide 1[21] with dimethyl cuprate (Sch. 2). The
anhydrosugar 2 has been used in a number of further transformations and
applications in natural product chemistry,[22−26] but in a different way than

K. Krohn et al.
66
6
O
7
OH
3
6
O
O
O
1
O
3
OH
2
O
O
3
5
1
6
5
5
4
1
+
a
4
2
S3'
4'
2
c
4
BnO
CH3
BnO
BnO
BnO
2'
O
OH
1' S
OH
5'
6'
1
2
3
7
d
b
d
b
5''
2''
6''
O
OAc
OAc
3''S
S 1''
O
OBn CH3
4
OBn
3'
S
1
2
3'
S
1
4'
5'
HO
3
5
4'
5'
2'
HO
5
BnO
BnO
CH3
2'
OH OH
S
1'
OH OH 1' S
O
OAc
6'
6'
8
6
5
4
Scheme 2: a) CuI (4 eq.), MeLi (8 eq.), Et2O/THF, −10◦C to 20◦C, 12 h, 67%; b) Ac2O, pyridine,
DMAP, 85%; c) 1,3-dithiane (1 eq.), n-BuLi, (1 eq.), THF, −78◦C to 20◦C, 71%; d) HS(CH2)3SH (1.5
eq.), BF3.Et2O (2.1 eq.), 4 h, rt, 77%.
described here. Interestingly, in the opening of the epoxide with the dimethyl
cuprate reagent,[22] the formation of the open chain keto diol 3 was observed
as a side reaction. This unusual reaction was previously observed in a similar
transformation[27] and seems to be of general importance.
In the 13C NMR spectrum of the diol 3, the signals at δ = 85.0 ppm for the
methylene carbon at C-3 and at δ = 212.7 for the carbonyl carbon at C-4 were
particularly characteristic. The structures of the alcohols 2 and 3 were further
confirmed by conversion to the respective monoacetate 4 and the diacetate 5.
The crucial opening of both the five- and six-membered rings in the anhy-
drosugar 2 was effected by treatment of the cyclic acetal 2 with a slight excess
of 1,3-propanedithiol in the presence of boron trifluoride dietherate at rt to
afford the desired 1,3-dithiane derivative 6 in 77% yield (Sch. 2). In addition
to occurrence of the new signals for the 1,3-dithiane ring (δ = 1.69–174, 1.93–
1.96 [2 × m, 2 × 2 H, 4ꢁ,6ꢁ-H]), the coupling pattern of the protons at C-1 and
C-2 were typical for an open chain arrangement of 6 in contrast to the rigid
structure in 2. The constitution of 6 was further fully confirmed by the mass
spectrum and the HRMS spectrum with m/z = 358.12751 (calc. 358.12726).
This 1,2-dioxo-3-methyl stereotriad has the great advantage that the two oxy-
gens are chemically differentiated and allow regioselective derivatizations, for
instance, selective glycosylation. The stereotriad with the correct absolute con-
figuration present in 6 and differentiated vicinal hydroxyl groups (e.g., selec-
tively monoglycosylated diols) is present in a number of macrolide antibiotics
such as cytovaricin H,[28,29] yokonolide A,[30] and antibiotic A 82548A.[31]
Next we tried the nucleophilic opening of the epoxide 1 with the 1,3-
dithiane anion. Epoxides react smoothly with 1,3-dithiane anions[5] and
sugar epoxides have often been subjected to this transformation either

Open Chain Chiral Macrolide Building Blocks
67
extramolecularly[32] or intramolecularly.[33] However, to the best of our know-
ˇ
ledge, they have not yet been added to Cerny´ epoxides such as 1. As expected,
the reaction of epoxide 1 with the lithium salt of 1,3-dithiane went smoothly
and the adduct 7 was isolated in 71% yield after chromatographic purifica-
tion. In building block 7, the dithiane moiety introduces a branching of the
linear chain (after ring opening) and the dithiane group can serve to modify
the nature of the side chain in great variety. The amphidinolides[34−36] and the
pinolidoxins[37] are just two examples of macrocyclic bioactive natural products
containing such a branching in combination with the absolute configuration of
the other stereocenters in building block 7. Finally, we demonstrated that ring
opening of the sugar is no problem with the highly functionalized molecule 7 by
reaction with 1,3-propandithiol in the presence of boron trifluoride dietherate
to afford the bis-dithiane 8 in 77% yield.
Next, we wanted to probe the ring opening via conversion to the 1,3-
dithianes on a more highly deoxygenated molecule. As a model, we selected
the tertiary alcohol 12. The synthesis started from the readily available di-
tosylate 9,[24,38] which was oxidized in high yield to the ketone 10, using the
perruthenate (TPAP) reagent[39] (Sch. 3). Several procedures for the reductive
removal of the two tosyl groups using Raney nickel[40,41] or superhydride[42]
have been described. However, in our hands, the reduction of 10 was best per-
formed using activated zinc dust and ammonium acetate as proposed by Belyk
et al.[43] to afford the ketone 11 in 85% yield. The subsequent Grignard reaction
with methylmagnesium chloride gave the tertiary alcohol 12 stereoselectively
in 90% yield with exclusive attack of the nucleophile from the less hindered
bottom side of the molecule.
Finally, the ring opening by reaction of 12 with 1,3-propanedithiol was per-
formed as described above to afford the chiral 1,3-dithiane derivative 13 in
O
O
O
O
O
O
a
b
Ts O
OTs
Ts O
OTs
OH
O
O
11
4'
9
10
6
O
3'
O
5'
6'
OH
5
S
c
d
OH
1
2
5
4
2'
HO
6
1
3
3
4
2
S
1'
7
HO
13
12
Scheme 3: a) RuCl3·3 H2O (1 mol%), NaBrO3 (65 mol%), MeCN:AcOH (10:1), 0◦C, 4 h, 93%; b)
◦
¨
Zn, NH4OAc (25 eq.), THF, 0 C to rt, 22 h then K2CO3, 24 h, 85%; c) MeMgCl (1.1Aq.), Et2O,
−20◦C to rt, 30 min, 90%, 100% de; d) HS(CH2)3SH (1.5 eq.), BF3·Et2O (2.1 eq.), 3 h, RT, 68%.

K. Krohn et al.
68
68% yield after chromatographic purification. The structure elucidation was
performed by comparison with related compounds.[13] In particular, the new
signals for the dithiane protons at δ = 2.7–2.8, 2.9–3.0, and 4.3 ppm were char-
acteristic. The 2-D NMR spectra fully confirmed the structure. The tertiary
alcohol with vicinal methylene groups present in building block 13 is a fre-
quently occurring motive in natural products. For example, within a pyranose
ring it can be found in the songistatins (altohyrtins),[44−46] in trisphaerolide
A,[47] or within macrocyclic compounds such as in the dermocanarins.[48,49]
In conclusion, we have shown that anhydrosugars with different groups
such as free secondary or tertiary hydroxyl groups, benzyloxy, 1,3-dithianyl,
or methyl groups can be converted effectively to the open chain 1,3-dithiane
ˇ
derivatives. Branched side chains can be introduced easily by reaction of Cerny´
epoxides with 1,3-dithiane anions.
EXPERIMENTAL
For general methods and instrumentations see reference 3.
4-O-Benzyl-2-methyl-1,6-anhydro-β-D-glucopyranose (2)
A solution of CuI (7.1 g, 37.6 mmol, 4 eq.) in dried THF (25 mL) was treated
under argon at −10◦C with a solution of methyllithium (1.6 M in diethyl ether,
54 mL, 73.7 mmol, 8 eq.). The mixture was stirred at 0◦C for10 min and the
epoxide (1)[21] (2.2 g, 9.4 mmol) in dried THF (30 mL) was added drop-wise. Af-
ter 40 min of stirring at 0◦C, the reaction mixture was warmed to rt and stirred
for another 12 h. The mixture was then diluted with diethyl ether (50 mL)
and saturated NH4Cl solution (50 mL) was added. The mixture was vigorously
stirred for another 1 h. The organic layer was separated and the aqueous layer
was extracted with diethyl ether (3 × 10 mL). The combined organic phase
was dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue obtained was purified by column chromatography (PE/EtOAc 7:3)
to obtain benzyl ether 2 as a colorless oil (1.57 g, 6.35 mmol, 67% yield) along
with a very polar ring opened ketone 3 as colorless oil in 23% yield (574 mg,
2.16 mmol). [α]D = −33.2◦ (c 0.78, CHCl3). 1H NMR (200 MHz, CDCl3): δ = 1.19
(d, J7,2 = 7.5 Hz, 3 H, CH3), 1.87 (q, J7,2 = 7.4 Hz, 1 H, 2-H), 3.34 (s, 1 H, 3-H),
3.67–3.74 (m, 2 H, 6-H), 4.07 (d, J4,3 = 7.3 Hz, 1 H, 4-H), 4.58 (d, J5,6a = 5.1 Hz,
1 H, 5-H), 4.67 (s, 2 H, Ar-CH2), 5.38 (s, 1 H, 1-H), 7.36–7.38 (m, 5 H, Ar-H).
13C NMR (50 MHz, CDCl3): δ = 15.4 (q, C-7), 41. 6 (d, C-2), 65.7 (t, C-Ar), 71.7
(t, C-6), 71.8 (d, C-3), 75.0 (d, C-4), 79.7 (d, C-5), 104.9 (d, C-1), 128.0 (d, C-Ar),
128.8 (d, C-Ar), 138.5 (s, C-Ar). IR (Film): ν˜ = 3458 (O−H), 2956 (C−H), 1547
(C-H), 1472 (C−H), 1371 (C−H), 1222 (C−O). MS (EI, 70 eV): m/z (%) = 250
(9) [M+], 208 (22), 168 (18), 151 (7), 126 (4), 91 (100), 57 (12). HREIMS: Calc.
for C14H18O4 250.29034. Found 250.29018.

Open Chain Chiral Macrolide Building Blocks
69
(2S,3R)-1,2-Dihydroxy-3-benzyloxy-6-methylheptan-4-one (3)
[α]D = +53.9 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3): 0.92 (d, J8,2
= 6.4 Hz, 3 H, 8-H), 0.94 (d, J1,2 = 6.4 Hz, 3 H, 1-H), 2.19 (m, 1 H, 2-H), 2.47
(m, 2 H, 3-H), 2.91 (m, 1 H, 5-H), 3.46 (m, 1 H, 7a-H), 3.56 (m, 1 H, 6-H), 3.70
(br, 1 H, 7b-H), 4.56 (d, Jgem = 8.4 Hz, 2 H, CH2-Ar), 7.29–7.37 (m, 5 H, Ar-H).
13C NMR (125 MHz, CDCl3): 23.0 (q, C-8), 23.1 (q, C-1), 23.9 (d, C-2), 48.7 (t,
C-3), 63.3 (t, C-7), 69.3 (d, C-6), 73.8 (t, CH2-Bn), 85.0 (d, C-5), 128.4 (d, C-Ar),
128.5 (d, C-Ar), 128.6 (d, C-Ar), 129.0 (d, C-Ar), 137.4 (d, C-Ar), 144.5 (s, C-Ar),
212.7 (s, C-4). IR (Film): ν˜ = 3413 (brs, O−H), 2956 (m, C−H), 2910 (m, C−H),
2897 (m, C−H), 1712 (C=O), 1458 (m, C−H), 1254 (s, C-H), 1177 (s, C-O). MS
(EI, 70 eV): m/z (%) = 266 (30) [M+], 248 (48), 181 (4), 159 (24), 91 (32), 57
(100), 43 (66). HREIMS: Calc. for C15H22O4 266.15194. Found 266.15183.
4-O-Benzyl-2-methyl-3-acetoxy-1,6-anhydro-β-D-glucopyranose
(4)
A solution of compound 2 (100 mg, 0.40 mmol) in pyridine (0.5 mL) was
treated with acetic anhydride (0.1 mL) and DMAP (10 mg). The solution
was kept at 20◦C for 2 h, quenched by addition of 2 N HCl (2 mL), and ex-
tracted with diethyl ether (3 × 20 mL). The combined organic phase was
dried (Na2SO4) and filtered, and the solvent was removed under reduced pres-
sure. The residue was purified by column chromatography on silica gel (elu-
tion petroleum ether/EtOAc 7:3) to afford the monoacetate 4 as an oil (98 mg,
0.33 mmol, 85%).
1
[α]D = −38.6 (c 1.1, CH2Cl2). H NMR (200 MHz, CDCl3): δ = 1.23 (d, J7,2
= 7.6 Hz, 3 H, CH3), 1.88 (m, 1 H, 2-H), 2.09 (s, 3H, OAc), 3.27 (s, 1 H, 3-H),
3.71–4.01 (m, 2 H, 6-H), 4.23 (m, 1H, 5-H), 4.58 (d, Jgem = 6.6 Hz, 2 H, CH2-
Ar), 4.80 (m, 1H, 4-H), 5.34 (s, 1 H, 1-H), 7.30–7.42 (m, 5 H, Ar-H). 13C NMR
(50 MHz, CDCl3): δ = 15.4 (q, C-7), 21.7 (q, C-8, OAc), 38.6 (d, C-2), 65.1 (t,
C-6), 71.5 (d, C-3), 71.9 (t, C-9, CH2-Bn), 74.8 (d, C-5), 78.1 (d, C-4), 104.0
(d, C-1), 128.1 (d, C-Ar), 128.8 (d, C-Ar), 138.2 (s, C-Ar), 170.5 (C=O, ester).
IR (Film): ν˜ =2967 (C−H), 1731 (C=O, ester), 1517 (C-H), 1376 (C−H), 1243
(C−O). MS (EI, 70 eV): m/z (%) = 292 (2) [M+], 208 (38), 168 (16), 151 (20),
126 (16), 91 (100), 67(14). HREIMS: Calc. for C16H20O5 292.13107. Found 292.
13128.
(2S,3R)-1,2-Diacetoxy-3-benzyloxy-6-methylheptan-4-one (5)
A solution of diol 3 (100 mg, 0.37 mmol) in pyridine (0.5 mL) was treated
with acetic anhydride (0.1 mL) and DMAP (10 mg). The solution was kept at
20◦C for 2 h, quenched by addition of 2 N HCl (2 mL), and extracted with di-
ethyl ether (3 × 20 mL). The combined organic phase was dried (Na2SO4) and
filtered, and the solvent was removed under reduced pressure. The residue

K. Krohn et al.
70
was purified by column chromatography on silica gel (elution petroleum
ether/EtOAc 7:3) to afford the diacetate 5 as an oil (108 mg, 0.308 mmol,
83%).
1
[α]D = +22.8 (c 1.0, CH2Cl2). H NMR (500 MHz, CDCl3): δ = 0.89 (d, J8,6
= 3.5 Hz, 3 H, 8-H), 0.92 (d, J1,2 = 3.5 Hz, 3 H, 1-H), 2.00 ( s, 3 H, 9-H), 2.03
( s, 3 H, 10-H), 2.18 (m, 1 H, 2-H), 2.35 (d, J5,6 = 5.4 Hz, 2 H, 3-H), 2.27 (br,
1 H, 5-H), 4.22–4.32 (m, 2 H, 7-H), 4.54 (d, Jgem = 6.8 Hz, 2H, CH2-Bn), 5.36
(m, 1 H, 6-H), 7.34–736 (m, 5 H, Ar-H). 13C NMR (125 MHz, CDCl3): δ = 21.0
(q, C-8), 21.1 (q, C-1), 22.9 (q, C-9), 23.0 (q, C-10), 23.9 (d, C-2), 48.0 (t, C-3),
62.3 (t, C-7) 71.2 (d, C-6), 73.4 (t, CH2-Bn), 82.6 (d, C-5), 128.5, (d, C-Ar) 128.6
(d, C-Ar), 128.9 (d, C-Ar), 137.0 (s, C-Ar), 170.3 (s, C-9), 170.9 (s, C-10), 209.1
(s, C-4). IR (Film): ν˜ = 2958 (C−H), 1747 (C=O, ester), 1558 (C-H), 1461 (C−H),
1371 (C−H), 1222 (C−O). MS (EI, 70 eV): m/z (%) = 350 (1) [M+], 279 (2), 265
(8), 247 (2), 184 (4), 168 (74), 153 (44), 125 (20), 91 (100), 85 (46), 57 (16).
HREIMS: Calc. for C19H26O6 350.17294. Found 350.17303.
(2R,3S,4R,5R)-3-(Benzyloxy)-5-(1,3-dithian-2-yl)hexane-1,2,4-
triol (6)
To a solution of D-glucopyranose 2 (200 mg, 0.80 mmol) in absolute CH2Cl2
(10 mL) at 0◦C was added 1,3-propanedithiol (0.12 mL 1.20 mmol, 1.5 eq.)
and BF3·Et2O (0.20 mL, 1.68 mmol, 2.1 eq.). The mixture was stirred at rt
for 3 h. After complete conversion of the starting material (TLC monitor-
ing), saturated NaHCO3 solution (15 mL) was added and the mixture was
stirred for 30 min. The organic layer was separated and the aqueous layer
was extracted with EtOAc (5 × 10 mL). The combined organic phase was
dried over MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (PE/EtOAc 3:1) to
obtain triol 6 (2.65 g, 11.3 mmol) as a colorless oil (215 mg, 0.60 mmol, 77%
yield).
[α]D = −18.5 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 1.16 (d, J6,5
=
6.8 Hz, 3 H, 6-H), 1.69–174, 1.93–1.96 (2 × m, 2 H, 5ꢁ-H), 2.10–2.14 (m, 1 H,
5-H), 2.58–2.72 (m, 4 H, 4ꢁ,6ꢁ-H), 3.57 (dd, J3,2 = 1.8 Hz, J3,4 = 3.1 Hz 1 H, 3-
H), 3.63–3.66 (m, 1 H, 1a-H), 3.72–3.79 (m, 1 H, 1b-H), 3.88–3.98 (m, 6 H, 2-H,
4-H, 2ꢁ-H,OH), 4.57 (d, Jgem = 11.3 Hz, 1 H, 11-H, CH2-Bn), 4.69 (d, Jgem = 11.3
Hz, 1 H, 11-H, CH2-Bn), 7.23–7.33 (m, 5H, Ar-H). 13C-NMR (125 MHz, CDCl3):
δ = 12.8 (q, C-6, CH3), 26.0 (t, C-5ꢁ), 30.4 (t, C-4ꢁ), 31.0 (t, C-6ꢁ), 40.4 (d, C-5),
52.5 (d, C-2ꢁ), 63.6 (t, C-1), 71.9 (d, C-4), 72.0 (d, C-2), 72.9 (t, C-11, CH2-Bn),
77.9 (d, C-3), 128.0 (d, C-Ar), 128.4 (d, C-Ar), 128.5 (d, C-Ar), 137.6 (s, C-Ar).
IR (Film): ν˜ = 3405 (brs, O−H), 2898 (C−H), 1633 (C−H), 1454 (C-H), 1276
(C−O). MS (EI, 70 eV): m/z (%) = 358 (10) [M+], 327 (2), 297 (3), 267 (6), 249
(12), 219 (4), 176 (8), 159 (48), 119 (88), 91 (100), 75 (8), 41 (6), 27 (2). HREIMS:
Calc. for C17H26O4S2 358.12726. Found 358.12751.

Open Chain Chiral Macrolide Building Blocks
71
4-O-Benzyl-2-(1,3-dithian-2-yl)-1,6-anhydro-β-D-glucopyranose
(7)
To a solution of 1,3-dithiane (102 mg, 0.85 mmol) in dried THF at −20◦C
(ice/NaCl) was added n-BuLi (23% in hexane, 0.40 mL, 0.85 mmol). After stir-
ring for 1 h at −20◦C, the solution was cooled to −78◦C and the epoxide 1
(200 mg, 0.85 mmol) was added. The reaction mixture was warmed to rt and
stirred overnight. To quench the reaction, saturated NH4Cl (5 mL) was added.
The organic layer was separated and the aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The combined organic phase was dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue obtained was
purified by column chromatography (PE/EtOAc 7:3) to obtain compound 7 as
colorless oil in 71% yield (213 mg, 0.60 mmol).
[α]D = −23.3 (c 0.8, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 1.93 (m, 1H,
2ꢁ-H), 2.00–2.10 (m, 2 H, 5ꢁ-H), 2.72–2.79 (m, 2 H, 4ꢁ-H), 2.83–2.91 (m, 2 H,
6 -H), 2.97 (d, J2 ,2 = 6.4 Hz, 1 H, 2ꢁ-H), 3.40 (brs, 1 H, 3-H), 3.68 (dd, J6a,6b
ꢁ
= 7.5 Hz, J6a,5 = 5.3 Hz, 1 H, 6a-H), 4.01 (d, J6b,6a = 7.5 Hz, 1 H, 6b-H), 4.27
(d, J4,3 = 9.9 Hz ,1 H, 4-H), 4.31 (brs, 1H, OH), 4.56 (d, J5,6a = 5.3 Hz, 1 H,
5-H), 4.61 (d, J11a,11b = 11.8 Hz, 1 H, 11a, CH2-Bn), 4.68 (d, J11b,11a = 11.8
Hz, 1 H, 11b, CH2-Bn), 5.91 (s, 1H, 1-H), 7.26–7.37 (m, 5H, Ar-H). 13C NMR
(125 MHz, CDCl3): δ = 25.7 (t, C-5ꢁ), 28.5 (t, C-4ꢁ), 28.9 (t, C-6ꢁ), 45.4 (d, C-2ꢁ),
48.7 (d, C-2), 66.4 (t, C-6), 67.1 (d, C-3), 71.7 (t, C-11, CH2-OBn), 75.5 (d, C-5),
79.6 (d, C-4), 101.4 (d, C-1), 127.8 (d, C-Ar), 127.9 (d, C-Ar), 128.0 (d, C-Ar),
128.3 (d, C-Ar), 128.4 (d, C-Ar), 137.8 (s, C-Ar). IR (Film): ν˜ =3444 (brs, O−H),
2896 (C−H), 1619 (C−H), 1454 (C-H), 1461 (C−H), 1371 (C−H), 1276 (C−O),
1039 (C−O). MS (EI, 70 eV): m/z (%) = 354 (14) [M+], 308 (2), 263 (10), 234
(26), 217 (4), 161 (10), 119 (96), 91 (100), 47 (14), 35 (6). HREIMS: Calc. for
C17H22O4S2 354.09595. Found 354.09605.
(2R,3S,4R)-3-(Benzyloxy)-5,5-di(1,3-dithian-2-yl)pentane-1,2,4-
triol (8)
The reaction was carried out according to the procedure as described for
compound 6. Dithiane 7 (100 mg, 0.28 mmol) in CH2Cl2 (10 mL) was re-
acted with 1,3-propanedithiol (0.042 mL, 0.42 mmol, 1.5 eq.) and BF3-Et2O
(0.075 mL, 0.60 mmol, 2.1 eq.) to afford triol 8 (91 mg, 0.20 mmol, 68% yield).
m.p = 64–65◦C. [α]D = −10.7 (c 0.9, CH2Cl2). 1H NMR (500 MHz, CDCl3):
δ = 1.84 (m, 2 H, 5ꢁ-H), 2.05 (m, 2 H, 5ꢁ-H), 2.38 (m, 1 H, 5-H), 2.71–3.05 (m,
8 H, 4ꢁ-H, 4ꢁꢁ-H, 6ꢁ-H, 6ꢁꢁ-H), 3.41 (brs, 1 H, OH), 3.72 (m, 1 H, 1a-H), 3.82 (m,
1 H, 1b-H), 4.13 (m, 2 H, 2-H,3-H), 4.58 (d, J2 ,5 = 1.8 Hz, 1 H, 2ꢁ-H), 4.75 (d,
ꢁ
J2 ,5 = 1.8 Hz, 1 H, 2ꢁꢁ-H), 4.78 (s, 2H, CH2-Bn), 7.26–7.39 (m, 5H, Ar-H). 13C
ꢁꢁ
NMR (125 MHz, CDCl3): δ = 25.8 (t, C-5ꢁ), 25.9 (t, C-5ꢁꢁ), 31.3 (t, C-4ꢁ), 31.4 (t,
C-4ꢁꢁ, 31.7 (t, C-6ꢁ), 32.2 (t, C-6ꢁꢁ), 48.6 (d, C-2ꢁ) , 49.9 (d, C-2ꢁꢁ), 51.8 (d, C-5),

K. Krohn et al.
72
63.7 (t, C-1), 68.8 (d, C-4), 72.2 (t, C-10, CH2-OBn), 72.3 (d, C-2), 78.0 (d, C-3),
127.8 (d, C-Ar), 128.1 (d, C-Ar), 128.3 (d, C-Ar), 128.4 (d, C-Ar), 128.5 (d, C-
Ar), 137.9 (s, C-Ar). IR (Film): ν˜ = 3421 (brs, O−H), 2896 (C−H), 1654 (C−H),
1424 (C-H), 1287 (C−H), 1047 (C−O). MS (EI, 70 eV): m/z (%) = 462 (10) [M+],
444 (2) 383 (2), 356 (4), 355 (26), 343 (12), 265 (6), 251 (82), 197 (4), 177 (12),
145 (22), 119 (100), 91 (72), 75 (52). HREIMS: Calc. for C20H30O4S4 462.10269.
Found 462.10225.
1,6-Anhydro-2,4-di-O-tosyl-β-D-ribohexapyrano-3-ulose (10)
A solution of ditosylate 9[24,38] (30.2 g, 64.2 mmol) in acetonitrile (90 mL)
was treated under argon at 0◦C with acetic acid (18.6 mL) and RuCl3·3 H2O
(150 mg, 0.64 mmol, 1 mol%) and a solution of NaBrO3 (6.3 g, 41.7 mmol) in
water (30 mL) was then added drop-wise with vigorous stirring over 2.5 h. The
temperature should not exceed 10◦C. After stirring for 2 h at 0◦C, 2-propanol
(1 mL) was added and stirring was continued for 1 h. The mixture was diluted
with EtOAc (350 mL) and the organic phase was washed with a 10% aqueous
solution of Na2S2O3 (2 × 50 mL). The organic phase was washed successively
with water (50 mL), saturated NaHCO3 solution (3 × 50 mL), and brine (50
mL). The solution was dried (MgSO4) and filtered, and the solvent was re-
moved at reduced pressure to afford the ketone 10 as an oil (28.3 g, 60.3 mmol,
1
94%). [α]D = −21.6◦ (c 1.5, MeOH). H NMR (500 MHz, CDCl3): δ = 2.48 (s, 6
H, 2 × Ar–CH3), 3.80 (dd, J6a,6b = 8.5 Hz, J6a,5 = 5.0 Hz, 1 H, 6a-H), 3.92 (dd,
J6b,6a = 8.5 Hz, J6b,5 = 1.0 Hz, 1 H, 6b-H), 4.52 (d, J2,1 = 1.2 Hz, 1 H, 2-H),
4.69 (d, J4,5 = 1.0 Hz, 1 H, 4-H), 4.90 (ddd, J5,6a = 5.0 Hz, J5,6b = 1.0 Hz, J5,4
= 1.0 Hz, 1 H, 5-H), 5.62 (d, J1,2 = 1.2 Hz, 1 H, 1-H), 7.33–7.38 (m, 4 H, Ar-H),
7.75–7.78 (m, 4 H, Ar-H). 13C NMR (125 MHz, CDCl3): δ = 21.0 (q, CH3–Ar),
21.7 (q, CH3–Ar), 66.7 (t, C-6), 76.9 (d, C-5), 77.6 (d, C-2), 79.3 (d, C-4), 101.3
(d, C-1), 127.9, 128.0, 128.1, 128.3, 129.9, 130.0 (d, C-Ar), 132.5, 132.4 (s, C-
Ar), 145.7, 145.8 (s, C-Ar), 190.7 (s, C-3). IR (Film): ν˜ = 2965 (m, C–H), 2924
(m, C–H), 2913 (m, C–H), 1750 (s, C=O), 1594 (s, C=C), 1372 (s, S–O2) 1196
(s, C–H), 1175 (s, C–H), 1129 (m, C–O), 1089 (m, C–O), 1015 (s, C–O), 989 (s,
C–H). MS (EI, 70 eV): m/z (%) = 468 (5) [M+], 313 (47), 172 (12), 155 (99),
142 (29), 113 (23), 91 (100), 85 (7), 65 (19), 57 (9), 29 (5). HREIMS: Calc. for
C20H20O9S2468.0548. Found 468.0549. Anal C20H20O9S2 (468.5) Calc. C, 51.27;
H, 4.30. Found: C, 51.37; H, 4.22.
1,6-Anhydro-2,4-dideoxy-β-D-glycerohexopyrano-3-ulose (11)
Zinc dust (250 g) was activated by stirring with diluted HCl (600 mL, 1.5%)
at rt for 45 min. The aqueous phase was decanted, and the residue was washed
with THF or diethyl ether (600 mL) and subsequently dried under high vac-
uum. For detosylation, part of the activated zinc dust (90 g) was suspended

Open Chain Chiral Macrolide Building Blocks
73
in dry THF (450 mL) in a three-necked flask. Dry NH4OAc (103 g, 1.34 mol,
25 eq.) was added and the mixture was stirred for 45 min at rt. A solution of
ditosylate 10 (26.0 g, 55.5 mmol) in THF (200 mL) was then added drop-wise at
0–5◦C over 2.5 h. The mixture was then stirred for 20 h at rt (TLC monitoring)
and filtered, and the zinc washed with THF (500 mL). The filtrate was treated
with K2CO3 (100 g) and stirred for a further 24 h. The salt was filtered off and
washed with THF (200 mL) and the solvent was removed at reduced pressure.
The residue was purified by column chromatography on silica gel to afford the
ketone 11 (5.9 g, 46.7 mmol, 85%) as an oil.
1
[α]D = −103◦ (c = 0.81, CHCl3). H NMR (500 MHz, CDCl3): δ = 2.40 (d,
J4a,4b = 16.8 Hz, 1 H, 4a-H), 2.50 (m, 2 H, 2-H), 2.71 (ddd, J4b,4a = 16.8 Hz,
J4b,5 = 5.0 Hz, J4b,2b = 2.0 Hz, 1 H, 4b-H), 3.76 (m, 1 H, 6a-H), 3.80 (m, 1 H,
6b-H), 4.79 (t, J5,4 = 5.0 Hz, 1 H, 5-H), 5.73 (t, J1,2 = 1.6 H, 1-H). 13C NMR
(125 MHz, CDCl3): δ = 46.9 (t, C-4), 48.6 (t, C-2), 69.6 (t, C-6), 72.2 (d, C-5),
100.5 (d, C-1), 204.5 (s, C-3). IR (Film): ν˜ = 2965 (m, C–H), 2893 (m, C–H),
2889 (m, C–H), 1713 (s, C=O), 1594 (s, CH), 1408 (s, C–H), 1367 (s, C–O), 1284
(s, C–H), 1139 (s, CO), 1036 (s, C–O), 989 (s, C–H), 860 (s, C–H). MS (EI, 70 eV):
m/z (%) = 128 (8) [M+], 111 (9), 100 (6), 97 (5), 86 (8), 83 (7), 82 (100), 71 (10),
70 (9), 69 (6), 58 (12), 57 (59), 55 (14), 54 (11), 44 (6), 43 (42), 42 (62), 41 (19), 31
(17), 29 (22), 27 (18). HREIMS: Calc. for C6H8O3: 128.0473. Found: 128.0439.
1,6-Anhydro-2,4-dideoxy-3-methyl-β-D-threo-hexopyranose (12)
A solution of ketone 12 (1.1 g, 8.6 mmol) in dry diethyl ether (180 mL) was
treated drop-wise at −20◦C with a solution of MeMgCl (9.5 mmol, 1.1 eq.) in
THF (3.2 mL). After stirring for 20 min at rt (TLC monitoring), Na2SO4·10 H2O
(5 g) was added portion-wise. The mixture was filtered, the solvent removed at
reduced pressure, and the residue purified by flash chromatography on silica
gel (CH2Cl2/acetone 95:5) to afford the alcohol 12 (1.15 g, 7.98 mmol, 90%) as
an oil.
1
[α]D = −53◦ (c = 0.77, MeOH). H NMR (500 MHz, CDCl3): δ = 1.20 (s, 3
H, 7-H), 1.83–1.96 (m, 3 H, 2a,b-H, 4a-H), 2.03 (ddd, J4b,4a = 14.5 Hz, J4b,5
=
4.3 Hz, J4b,6a = 1.7 Hz, 1 H, 4b-H), 3.40 (s, 1 H, OH), 3.73 (ddd, J6a,6b = 7.0
Hz, J6a,5 = 4.9 Hz, J6a,4b = 1.7 Hz, 1 H, 6a-H), 4.34 (d, J6b,6a = 7.0 Hz, 1 H,
6b-H), 4.58 (m, 1 H, 5-H), 5.68 (brs, 1 H, 1-H). 13C NMR (125 MHz, CDCl3):
δ = 31.5 (q, C-7), 41.9 (t, C-4), 44.3 (t, C-2), 68.0 (t, C-6), 68.3 (s, C-3), 72.8 (d,
C-5), 101.2 (d, C-1). IR (Film): ν˜ = 3467 (s, OH), 2970 (m, C–H), 2918 (m, C–H),
2898 (m, C–H), 1503 (w, C–H), 1377 (m, C–H), 1351 (m, C–H), 1268 (s, C–H),
1170 (s, C–O), 1118 (s, C–O), 1093 (s, C–O), 1062 (s, C–O). MS (EI, 70 eV):
m/z (%) = 144 (9) [M+], 126 (69), 97 (59), 89 (37), 87 (70), 71 (42), 69 (56),
59 (48), 57 (96), 55 (70), 43 (100), 41 (71), 39 (33), 29 (41). HREIMS: Calc. for
C7H12O3144.0786. Found 144.0778. Anal. C7H12O3 (144.17): Calc. C, 58.32; H,
8.39. Found C, 58.49; H, 8.85.

K. Krohn et al.
74
(2S,4S)-4-((1,3-Dithian-2-yl)methyl)pentane-1,2,4-triol (13)
As solution of hexopyranose 12 (220 mg, 1.72 mmol) in dry CH2Cl2 (15 mL)
was treated at 0◦C with 1,3-propanedithiol (0.26 mL, 2.58 mmol, 1.5 eq.) and
BF3·Et2O (0.46 mL, 3.61 mmol, 2.1 eq.). Workup was done as described for 6 to
afford the triol 13 as an oil (295 mg, 1.17 mmol, 68%). [α]D = +21.5◦ (c = 0.27,
CDCl3). 1H NMR (500 MHz, CDCl3): δ = 1.28 (s, 3 H, 5-H), 2.02 (dd, J6a,6b = 6.5
Hz, J6a,2 = 6.4 Hz, 1 H, 6a-H), 2.08–2.15 (m, 5 H, 6b-H, 3-H, 5ꢁ-H), 2.77–2.85,
ꢁ
2.91–3.02 (2 × m, 2 × 2 H, 4ꢁ-H, 6ꢁ-H), 3.85 (ddd, J1a,1b = 10.0 Hz, J1a,2 = 2.0
Hz, J1a,3a = 1.4 Hz, 1 H, 1a-H), 3.89 (dd, J1b,1a = 10.0 Hz, J1b,2 = 4.0 Hz, 1 H,
1b-H), 4.31 (t, J2 ,5 = 6.4 Hz, 1 H, 2ꢁ-H), 4.47 (ddd, J2,1a = 2.0 Hz, J2,1b = 4.0 Hz,
ꢁ
J2,3a = 8.4 Hz, 1 H, 2-H). 13C NMR (125 MHz, CDCl3): δ = 25.4 (t, C-5ꢁ), 27.3
(q, C-5), 30.8, 31.0 (2 × t, C-4ꢁ, C-6ꢁ), 43.3 (d, C-2ꢁ), 46.2 (t, C-3), 46.3 (t, C-6),
73.4 (d, C-2), 74.2 (t, C-1), 82.1 (s, C-4). IR (Film): ν˜ = 3469 (brs, OH), 2974 (m,
C–H), 2910 (m, C–H), 2897 (m, C–H), 1371 (m, C–H), 1349 (m, C–H), 1272 (s,
C–H), 1170 (s, C–O), 1112 (s, C–O), 1089 (s, C–O). MS (EI, 70 eV): m/z (%) =
234 (74) [M+ – H2O], 216 (18), 188 (19), 173 (40), 159 (70), 133 (53), 127 (32),
119 (81), 106 (35), 101 (90), 98 (50), 83 (69), 73 (33), 55 (29), 45 (33), 43 (100),
41 (61).
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