Horner-Wadsworth-Emmons reactions as a facile entry to biogenetic key substructures

Article abstract of DOI:10.1055/s-2005-863705

One-pot Horner-Wadsworth-Emmons reactions are used to synthesize α,β-enones with two configurationally independent stereogenic centers. These intermediates are used for the construction of polyketide and monosaccaride fragments. In particular, novel approaches to the branched pentoses mycarose and arcanose are described.

Full text of DOI:10.1055/s-2005-863705

CLUSTER
685
Horner–Wadsworth–Emmons Reactions as a Facile Entry to Biogenetic Key
Substructures
E
ntry to B
o
iogenetic
K
e
h
y
S
ubstructu
a
r
es nn Mulzer,* Andreas Sieg, Christoph Brücher, Dieter Müller, Harry J. Martin
Institut für Organische Chemie, Währingerstrasse 38, 1090 Wien, Austria
Fax +43(1)427752189; E-mail: johann.mulzer@univie.ac.at
Received 30 November 2004
HO
Me
O
O
Abstract: One-pot Horner–Wadsworth–Emmons reactions are
used to synthesize a,b-enones with two configurationally indepen-
dent stereogenic centers. These intermediates are used for the con-
struction of polyketide and monosaccaride fragments. In particular,
novel approaches to the branched pentoses mycarose and arcanose
are described
(n + 1)
SCoA
Me
Me
Me
n
Me
SCoA
SCoA
- n CO2
O
O
O
O
Keywords: polyketides, enones, carbonyl reduction, hydrobora-
tion, mycarose, arcanose
Me
Me
Me
(eq 1)
R1
R2
*
*
*
*
*
OH
OH
Biogenetic aldol-type C-C-connections are abundant in
the formation of polyketide and carbohydrate polyol me-
tabolites,1 as illustrated in equations 1 and 2 in Scheme 1.
PO
OH
O
OH
OH
OH
OH
In search of a non-aldol non-biomimetic pathway to these
important structural patterns, we found that the venerable
Horner–Wadsworth–Emmons (HWE) reaction2 can be
developed into a one-pot highly connective process
(Scheme 2).3 As shown in equation 3 in Scheme 2, an a-
chiral ester A is connected across a phosphonate B with an
a-chiral aldehyde C to form E-enone D, which has two
stereogenic centers at C-1 and C-5, respectively, both with
unambiguously defined configuration and fully indepen-
dent from each other. X and Y can be heteroatoms or
carbon appendages, most simply a methyl group. To cap-
italize on the synthetic potential of the enone moiety we
sought for stereocontrolled reduction to convert D into the
allylic alcohol E, which should then undergo stereocon-
trolled hydroboration to generate stereopentad F with de-
fined stereochemistry (equation 4 in Scheme 2). To test
the viability of this approach stereopentad 1, and polypro-
pionate fragments 3 and 4 were envisaged as lead struc-
tures. Additionally hexitol 2 was considered as a
monosaccharide type target.
(eq 2)
*
*
+
*
*
H
O
OH
OH
OH
OH
Scheme 1 Biogenesis of polypropionates and hexitols
O
H
R1
R2
+
P(O)(OEt2)
+
*
X
*
Y
OEt
O
Me
B
A
C
O
R1
R2
(eq 3)
(eq 4)
*
Y
*
X
Me
D
OH
OH OH
H
BH3
R1
R2
R1
R2
D
*
X
*
*
*
*
*
*
*
Me
Y
X
Me
Y
F
E
Scheme 2 HWE-carbonyl reduction–hydroboration sequence
To prepare stereopentad 1 (Figure 1) which corresponds
to the C1-C7-fragment 5 of monensin4 and to the C5-C11-
fragment 6 of lonomycin A (Figure 2),5 ester 7 was con-
verted into phosphonate 8 which was treated in situ with
aldehyde 9 to give enone 10 E-selectively in good yield.
TBS-deprotection and reduction with diborane furnished
syn-alcohol 11 selectively, which was converted into ace-
tonide 12 and subjected to hydroboration (Scheme 3). Ste-
reopentad 1 was formed stereoselectively in high yield.
Me
O
Me
O
OH
OH
Me
OH
OTIPS
HO Me
OH
Me
Me
Me
OH
OH
1
2
Me
O
OH
OH
OBz
O
Me
Me
Me
Me
OBn Me
Me
Me
SYNLETT 2005, No. 4, pp 0685–0692
Advanced online publication: 22.02.2005
0
4.
0
3.
2
0
0
5
3
4
DOI: 10.1055/s-2005-863705; Art ID: Y04504ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1

686
J. Mulzer et al.
CLUSTER
Table 1 Carbonyl Reduction of Enones 13
HO
H
Et
7
OBOM
OH
Me
Me
Me
O
O
O
Me
H
OPG
OPG
O
H
Me
O
7
OMe OBn
OMe
CO2H
H
Me
OBOM
Me
Me
Me
OBOM
Me
O
MeO2C
1
O
conditions
14 (syn)
Ph
1
OPG
Me
Me
Me
Me
OH
OH
5
Me
Me
Monensin
13
OMe
11
Me
15 (anti)
Me
OMe
Me
Me
Me
Me
Me
Me
Me
O
OMe
O
O
O
13
a
PG
Conditions
Ratio 14:15 Yield (%)
Me
HO Me
3
CO2H
1
5
MeO
TBS
Zn(BH4)2, Et2O
NaBH4, EtOH
N-Selectride, THF
L-Selectride, THF
LAH, Et2O
1.4:1
1.5:1
2.7:1
6.1:1
9.0:1
1.0:1
78
83
95
86
79
40
OH
Me
Me
O
O
3
OMe OH
5
OH
O
Lonomycin A
11
HO
Me
Me
Me
Me
Me
6
Figure 2
b
c
TIPS
Tr
LAH, N-Selectride,
THF
LAH, Et2O
1:5.0
1:5.2
81
95
O
O
a
(EtO)2(O)P
N-Selectride
MeO
OTBS
OTBS
Me
Me
Me
8
7
PG
O
H
O
Met
O
PGO
Me
b
c,d
O
TIPSO
OTBS
Me
H
Me
Me
OTIPS
O
Me
Me
Me
Me
Me
Me
9
H
H
10
BOMO
BOMO
Chelate Cram (syn!)
Felkin-Anh (anti!)
OH
O
O
OTIPS
Me
OTIPS
Me
f
e
Figure 3
1
OH
Me
11
Me
Me
Me
with L-selectride, and lithium aluminium hydride, where-
as bulky protecting groups such as TIPS or Tr lead to sig-
nificant Felkin–Anh preference. The free alcohol induces
the chelate Cram mechanism and, under appropriate con-
ditions gives the syn-product exclusively (Table 2). A
similarly detailed study on the hydroboration6 (Scheme 4,
Scheme 5) revealed that the 3,5-anti-diols 20, 28, 31 and
34 are formed with high selectivity from 19 and the 1,3-
acetonides 12, 30 and 33. The remaining olefins form the
3,5-anti-products with much lower selectivity. Thus, all
the olefins are attacked by the borane from the si-si-face.
This result excludes internal delivery processes, because
in this case the selectivity should strongly depend on the
configuration the C-3-OH. Therefore we suggest that free
alcohols 19, 14c and 15a, with the first equivalent of di-
borane, form a boronate, which is then further attacked at
the double bond by a second diborane molecule. The
stereochemical outcome may be rationalized on the basis
of conformational studies of the starting materials. For
12
Scheme 3 Reagents and conditions: a) diethylethanephosphonate,
LDA, Et2O, –78 °C, 30 min, 80%; b) i. Ba(OH)2, THF–water (v/v
40:1), 22 °C, 30 min; ii. 9, 0 °C, 7 h, 65%; c) HF–pyridine, THF, 0 °C,
45 min, 79%; d) Zn(BH4)2, Et2O, 0 °C, 45 min, 90%; e) 2,2-di-
methoxypropane, camphorsulfonic acid, CH2Cl2, 60 min, 22 °C,
99%; f) i. BH3·DMS, THF, 22 °C, 60 min; ii. NaOH, 30% H2O2, 0 °C,
90 min, 64%
Encouraged by this result we used enones 13 and 16 in a
systematic model study on the stereoselectivity of the
carbonyl reduction (Table 1 and Table 2).
Clearly, the syn-alcohols 14 and 17 are the result of a che-
late Cram mechanism, whereas the anti-diastereomers 15
and 18 result from a Felkin–Anh attack (Figure 3). The
data collected in Table 1 and Table 2 show how the pro-
tective group at the C-1-OH and the reagent bear on the
stereochemical outcome of the reaction. The TBS-protect-
ed enone 13 shows increasing chelate Cram selectivity
Synlett 2005, No. 4, 685–692 © Thieme Stuttgart · New York

CLUSTER
Entry to Biogenetic Key Substructures
687
Table 2 Carbonyl Reduction of Enone 16
TIPSO
OH
OH
OTBS
OBOM
OH
OH
3
OTBS
1
OTIPS
Me
Me
Me
Me
OH
OH
20
5
20:21 = 10:1
OBOM
Me
O
Me
Me
Me
Me
62%
Me
Me
conditions
17 (syn)
TIPSO
BOMO
OH
OH
OH
OTBS
OH
19
Me
Me
OBOM
Me
OH
16
Me
Me
Me
Me
Me
Me
21
Me
OH
OTr
18 (anti)
OBOM
Me
OH
OTr
Conditions
Ratio 17:18
3.5:1
Yield (%)
22
22:23 = 2.2:1
L-Selectride, THF
NaBH4, EtOH
LAH, Et2O
91
95
95
74
93
84
94
85%
Me
Me
BOMO
OH
OH
OTr
4.6:1
14c
7.0:1
Me
Me
Me
Me
Me
Me
23
DIBALH, THF
Zn(BH4)2, Et2O
Me4NBN(OAc)3
BH3, THF
22:1
BOMO
OH
OH
OTBS
47:1
>99:1
>99:1
OBOM
Me
OH
OTBS
24
24:25 = 2.9:1
Me
Me
85%
BOMO
OH
OH
OTBS
15a
instance the crystal stucture of alcohol 14c (Figure 4) may
serve as a model for the acyclic alcohol derivatives. It
shows a sickle like conformation which is the result of
A1,3-strain7 between the C-4-methyl group and the stereo-
genic centers at C-2 and C-6, respectively. This effect
places one substituent on each center on top of the 4,5-ole-
fin plane; in 14c these residues are 6-methyl and 3-
OBRR¢, which hinder the attack from the top face and di-
rect the borane to the bottom face (si-si-face) with low se-
lectivity. If, however, as in 19, both positions are occupied
by bulky residues (OBRR¢ and CH2OTIPS), the facial
preference for the si-si-face was quite high. The ace-
tonides 12 and 33 were studied by 1H NMR ROESY ex-
periments, which revealed ground state conformations in
which due to A1,3-strain effects the olefin side chain
adopts a skew conformation with respect to the acetonide
(Figure 5 and Figure 6). The re-re-face of the olefin is
shielded by the acetonide ring. The configurations of the
stereogenic centers at C-2 and C-6 have no influence on
the stereochemical course.
Me
Me
Me
25
OBOM
Me
OPiv OTBS
Me
22 + 23
22:23 = 1.1:1
Me
82%
26
OBOM
Me
OPiv OTBS
Me
22 + 23
24:25 = 1.4:1
Me
82%
27
Scheme 4 Stereocontrol of the hydroboration of acyclic olefins 19,
14c, 15a, 26 and 27
As a further synthetic application, fragment ent-14c nicely
matches the C-5-C-11-part of the ansamycin macbecin I
(Figure 7).8
A more extensive application of the HWE methodology is
aiming for a total synthesis of the polyol antibiotic zinco-
phorin.9 Our retrosynthetic analysis envisaged the con-
struction of the carbon skeleton from the fragments 36, 37
and 4, which should be connected by a HWE olefination
between C-9 and C-10 and a Julia–Lythgoe olefination
between a C-16 aldehyde and a C-17-sulfone (Scheme 6).
Figure 4 Crystal structure of 14c
Synlett 2005, No. 4, 685–692 © Thieme Stuttgart · New York

688
J. Mulzer et al.
CLUSTER
TIPSO
TIPSO
OH
O
O
O
O
OTIPS
Me
O
O
O
O
O
O
Me
Me
Me
Me
Me
Me
28
28:29 > 95:5
64%
Me
Me
Me
Me
OH
12
29
BOMO
BOMO
OH
O
O
O
O
OBOM
Me
Figure 6 ROESY analysis of 12 (atom distances in pm)
Me
Me
Me
Me
Me
Me
31
31:32 > 95:5
69%
Me
OH
5
OBOM
OH
OTr
5
Me
O
30
11
Me
Me
Me
OCONH2
NH
32
Me
Me
Me
O
ent-14c
Me
OMe
O
TIPSO
TIPSO
OH
O
O
O
O
11
OMe
OTIPS
Me
MeO
Me
Me
Me
Me
Me
Me
Macbecin I
34
34:35 > 95:5
Figure 7
70%
Me
OH
33
Me
OH
OH
OH OH OH
10
35
O
O
1
Scheme 5 Diastereomeric ratio for the hydroboration of acetonides
12, 30 and 33
16
Me
Me
Me
Me
Me
Me
OH
25
Zincophorin
Me
O
OH
1
9
10
(EtO)2(O)P
OBn
BzO
O
O
16
Me
Me
Me
Me
36
37
OH
HO
17
Me
Me
OH
25
4
Figure 5 ROESY analysis of 33 (atom distances in pm)
Scheme 6
Stereotriad 43 was transformed into into aldehyde 44
which was subjected to an Evans aldol addition12 to fur-
nish adduct 45 with high stereoselectivity. Removal of the
auxiliary and of the THP protecting group led to diol 38,
which under Mitsunobu conditions cyclized to tetrahydro-
pyran 41 exclusively. This result indicated that the path
via 39 was the favored one, which means that the bulky
phosphonium group was attached to the less hindered C-
The synthesis of the tetrahydropyran fragment 36 was
centered around a Mitsunobu cyclization10 of diol 38,
which, in principle could give either 41 or its diastereomer
42, depending on whether activated intermediate 39 or 40
was formed preferentially (Scheme 7). Thus, 38 was pre-
pared from known precursor11 43 in good overall yield
and stereocontrol along the route shown in Scheme 8.
Synlett 2005, No. 4, 685–692 © Thieme Stuttgart · New York

CLUSTER
Entry to Biogenetic Key Substructures
689
OH
OH
3-alcohol function and the more hindered C-7-hydroxyl
group acted as the nucleophile. Desilylation and oxidation
furnished aldehyde 36. Separately, phosphonate 37 was
prepared from the known aldehyde 4813 as shown in
Scheme 9, and connected with 36 to form the enone 3.
Evans–Carreira reduction14 should generate anti-diol 51,
however, the ensuing hydroboration, which underlies
doubly stereodifferentiating influences from both sides,
has yet to be performed. In the end aldehyde 52 should be
generated. The missing C-17-C-25-fragment 56 was pre-
pared as shown in Scheme 10. The carbonyl reduction of
55 to 56 was performed with the CBS reagent15 with 80%
de. The exchange of the terminal hydroxyl for a phenyl-
sulfonyl group should generate 57. With the intermediates
52 and 57 in hands we would intersect Danishefsky’s
synthesis.9 Alternatively, the C-7-C-13-segment of zinco-
phorin can readily be prepared in form of acetonide 58
from compound 15c (Scheme 11).
BzO
OTBS
Me
Me
38
Me
Me
Me
Me
Ph3PO
OPPh3
BzO
HO
OTBS
BzO
OH
OTBS
Me
Me
Me
40
39
Me
Me
Me
Me
BzO
O
OTBS
BzO
O
OTBS
The HWE reduction sequence is also suitable for control-
ling remote stereogenic centers, as demonstrated in the to-
tal synthesis of the macrodiolide antibiotic tartrolon B16
(Scheme 12). The retrosynthetic disconnection leads to
the mono-secoacid precursor 59, which was assembled
via an aldol addition of ketone 60 to aldehyde 61. Ketone
60 was prepared via the HWE route shown in Scheme 12.
Me
Me
41
42
Scheme 7
OH
OTHP
a
OTBS
OTBS
O
Me
Me
43
Me
Me
O
O
OH
O
44
a
b
OBn
O
N
b
48
Me
49
OBn
OH
Bn
O
OTHP
Me
OTHP
c–e EtO2C
O
OH
O
OTBS
OTBS
c
(EtO)2(O)P
16
9
Me
Me
Me
EtO
45
Me
OBn
Me
Me
OBn
46
50
37
f
Me
O
OH
O
OH
OTHP
O
d
9
16
7
BzO
O
N
OTBS
O
Me
Me
Me
Me
Me
Me
Me
OBn
Me
Me
Me
3
Bn
47
OH
OH
g-k
l
m,n
BzO
O
36
41
38
Me
Me
Me
OBn
Scheme 8 Reagents and conditions: a) DHP, CH2Cl2, PPTS, 22 °C,
40 h, 89%; b) i. ozone, MeOH, –78 °C; ii. TPP, 22 °C, 16 h; iii.
diethylmethanephosphonate, NaH, THF, –15 °C, 1 h; iv. 44, THF, 0–
22 °C, 3 h, 92%; c) EtOH, Raney-nickel, H2, 1 bar, 22 °C, 5 h, 99%;
d) DIBALH (1.2 M in toluene), THF, –70 °C to 0 °C, 2 h, 99%; e)
oxalylchloride, DMSO, Ni-PrEt2, CH2Cl2, –78 °C to 50 °C, 20 min,
95%; f) (4R)-N-propionyl-4-benzyl-oxazolidinone, dibutylborontri-
flate, Et3N, CH2Cl2, –65 °C, 90 min, 97%; g) i. tributylborane, propio-
nic acid, THF, 22 °C, 90 min; ii. lithiumborohydride (1 M in THF),
0–22 °C, 14 h, 89%; h) benzoylchloride, pyridine, –15 °C to 22 °C, 3
h, 88%; k) Me2AlCl (1 M in hexane), CH2Cl2, –25 °C, 2 h, 88%; l)
TPP, DEAD, toluene, 22 °C, 16 h, 56%; m) PPTS, MeOH, 22 °C, 16
h, 95%; n) see e), 95%
51
O
OR
OR
OR
13
16
O
7
MeO
O
Me
Me
Me
Me
52
Scheme 9 Reagents and conditions: a) (4R)-N-propionyl-4-benzyl-
oxazolidinone, dibutylborontriflate, Et3N, CH2Cl2, –65 °C, 90 min,
94%; b) Ti(OEt)4, EtOH, reflux, 14 h, 95%; c) diethylethanephos-
phonate, LDA, Et2O, –78 °C, 30 min; 67%; d) i. Ba(OH)2, THF–wa-
ter (v/v 40:1), 22 °C, 1 h; ii. 36, 0 °C, 16 h, 65%
Synlett 2005, No. 4, 685–692 © Thieme Stuttgart · New York

690
J. Mulzer et al.
CLUSTER
TBSO
17
O
TBSO
O
O
21
a
20
P(OEt)2
17
Me
OH
11
O
20
O
21
Me
Me
Me
Me
Me
O
O
O
O
Me
55
53
Me
Me
54
9
O
3
O
Na
O
B
PhO2S
OR
TBSO
OH
O
21
O
b
19
Me
Me
Me
O
O
1
Me
Me
Me
Me
Me
Me
57
56
OH
Scheme 10 Reagents and conditions: a) i. Ba(OH)2, THF, 22 °C, 1
h; ii. 54, 0 °C, 16 h, 82%; b) (S)-CBS catalyst (0.1 equiv), BH3·THF
(1 M in THF), THF, 0 °C, 10 min, 69%
Tartrolon B
20
Me
O
OTBDPS
Me
11
H
O
O
20
Me
61
a,b
7
13
OH
11
O
15c
TrO
OBOM
OTBDPS
+
9
Me
Me
Me
O
58
PMBO
3
Me
Scheme 11 Reagents and conditions: a) i. BH3–DMS, THF, 0 °C, 4
h; ii. H2O2, NaOH, 22 °C, 90 min, 85%; b) 2,2-dimethoxypropane,
camphorsulfonic acid, CH2Cl2, 60 min, 22 °C, 98%
9
Me
59
TBSO
PMBO
3
Me
TBSO
The crucial carbonyl reduction to allylic alcohol 64 was
achieved with 10:1 selectivity with the CBS reagent.
Me
60
To generate monosaccharide polyols HWE reactions with
the glyceraldehyde derivatives 69 and 77 were investigat-
ed. As shown in Scheme 13 a variety of hydroxylated
enone derivatives were obtained E-selectively with ac-
ceptable yields.
O
7
OPMB
OTBS
Me
O
OPMB
a
(EtO)2(O)P
7
OTBS
Me
Me
Me
Me
62
63
65
O
As a specific target the branched pentoses mycarose and
arcanose were chosen, which are monosaccharide compo-
nents in the antibiotics erythromycin D17 and lankamy-
cin,18 respectively (Figure 8).
OH
OTBS
Me
OH
OPMB
OTBS
OPMB
b
c
Me
Me
64
The synthesis of L-methyl-mycaro-pyranoside is de-
scribed in Scheme 14. Chelate controlled reduction of
enone 72 furnished the anti-diol derivative 79, which was
MOM protected. Removal of the acetonide and tritylation
at the primary position furnished the free alcohol at C-2,
which served for a syn-directed epoxidation to give 80.
Reductive epoxide opening at the less hindered position
led to 81, which on glycol cleavage and treatment with
methanol and acid gave the pyranose as an anomeric mix-
ture 82, which was separated by HPLC. The analytical
data of the b-anomer were in good agreement with those
reported in the literature.19
PMP
O
OTBS
O
OTBS PMBO
OH
f,g,f
d
e
60
Me
Me
Me
Me
66
67
Scheme 12 Reagents and conditions: a) i. LiOH, THF–H2O (40:1),
22 °C, 1 h; ii. aldehyde, 0 °C, 16 h, 90%; b) (S)-CBS catalyst (0.1
equiv), BH3·THF (1 M in THF), THF, 0 °C, 10 min, 84%; c) hydrazi-
ne hydrate, O2, Cu(OAc)2, 95%; d) DDQ, MS 4 Å, CH2Cl2, 76%, e)
DIBALH, CH2Cl2, 40 °C to –10 °C, 91%; f) oxalylchloride, DMSO,
Ni-PrEt2, CH2Cl2, –78 °C to 50 °C, 20 min, 92%; g) i. MeMgBr, Et2O;
ii. see f), 83%
The synthesis of the corresponding arcanosyl derivative
(Scheme 15) started with the Felkin–Anh selective reduc-
tion of 70 to the syn-diol derivative 83, which was syn ep-
oxidized to 84. Degradation of the acetonide to the
aldehyde 85 and reductive opening of the epoxy-aldehyde
with zinc led to hydroxy aldehyde 86, which was convert-
ed into ketal 87 with ethylene glycol. O-Methylation with
methyltriflate and treatment with methanol and acid gave
pyranoside 89 as an anomeric mixture, from which the
b-anomer was isolated by HPLC in pure form. As men-
tioned above, free arcanose is not a natural product, and
the only characterization of the methyl pyranoside is its
combustion analysis.18 The absolute and relative configu-
ration of arcanose, which, to our knowledge, has never
Synlett 2005, No. 4, 685–692 © Thieme Stuttgart · New York

CLUSTER
Entry to Biogenetic Key Substructures
691
OH
O
OH
O
a
Me
b
Me
70
H
O
O
O
O
O
O
Me
O
O
Me
84
O
TBDPSO
TBDPSO
69
Me
P(OEt)2
Me
Me
83
O
O
O
O
65%
OR
68
Me
OR
Me
Me
Me
Me
Me
O
O
O
O
OH
MOMO
O
70
O
c
O
Me
d
Me
O
O
O
Me OH
TBDPSO
Me
TBDPSO
69
Me
BnO
P(OEt)2
85
86
60%
Me
Me
Me
Me
BnO
MOMO
MOMO
72
71
e
f
Me
Me
O
O
O
O
O
Me OMe
Me OH
TBDPSO
TBDPSO
O
O
g
EtO
EtO
P(OEt)2
69
EtO
EtO
87
88
43%
OMe
OMe
Me
74
73
O
OR
O
O
OR
O
Me
89
HO
69
P(OEt)2
L-Methyl-arcano-pyranoside
62%
Me
Me
Scheme 15 Reagents and conditions: a) MgBr2·OEt2, THF,
Zn(BH4)2 (0.6 M in THF), –18 °C, 75 min, 77% (selectivity 11:1); b)
mCPBA, CH2Cl2, phosphate buffer, 0–22 °C, 2 h, 98%; c) i. p-TsOH,
MeOH–H2O (3:1), THF, 22 °C, 3 d, 99%; ii. Pd(OAc)4, CH2Cl2,
22 °C, 30 min; d) Al-Hg, THF, H2O, 16 °C, 3d, 72%; e) oxalic acid,
MeCN–ethyleneglycol (4:1), 22 °C, 4 h, 72%; f) BuLi (1.6 M in he-
xane), THF, MeOTf, –50 °C, 4 h, 95%; g) i. TBAF (1 M in THF),
THF, 22 °C, 6 d, 92%; ii. p-TsOH, MeOH–water (3:1), THF, 22 °C,
3 d, 84%, anomeric ratio b:a = 2:1
76
75
OR
O
O
OR
O
OBn
OBn
O
P(OEt)2
77 OTBS
66%
Me
Me
OTBS
75
78
Scheme 13 HWE olefination of aldehydes 69 and 77 (R = TBDPS)
In conclusion, we have shown that the HWE olefination in
combination with stereo- and regiocontrolled modifica-
tions of the enone intermediate is an efficient method for
preparing polypropionate and monosaccharide fragments.
In this way the HWE methodology may be a welcome
supplement to the established aldol strategy.12 Additional
potential of the HWE approach, however, lies in stereo-
controlled additions to the double bond or in sigmatropic
rearrangements of the corresponding allylic alcohol.
These possibilities are currently considered for natural
product syntheses in our laboratory.
OH
MOMO
Me
OTr
O
b
a
Me
72
O
OBn Me
O
OBn Me
OH
79
80
MOMO
Me
OH
OH
O
c
d
OMe
Me
HO
OH OH
Me
HO
Me
81
82
L-Methyl-mycaro-pyranoside
Acknowledgment
Scheme 14 Reagents and conditios: a) LiAlH4 (0.67 M in THF),
THF, –20 °C, 2 h, 83% (selectivity 6:1); b) i. MOMCl, CH2Cl2, 0 °C,
48 h, 93%; ii. formic acid, MeOH–H2O (2:1), 22 °C, 2 d, 95%; iii.
TrCl, CH2Cl2, Et3N, DMAP, 22 °C, 16 h, 84%; iv. mCPBA, CH2Cl2,
phosphate buffer, 0–22 °C, 2 h, 95%; c) i. LiAlH4 (0.67 M in THF),
Et2O, reflux, 14 h, 60%; ii. Na, NH3, Et2O, –78 °C, 15 min, 82%; d)
i. PTS, MeOH–H2O (3:1), THF, 22 °C, 3 d, 99%; ii. Pd(OAc)4,
CH2Cl2, 22 °C, 30 min; iii. acetylchloride, MeOH, 22 °C, 90 min,
81% (anomeric ratio b:a = 3:1)
We thank Dr. J. W. Bats, University of Frankfurt, for performing the
crystal structure analysis of compound 14c.
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its 4-epimer cladinose.20 The 1H NMR, 13C NMR, and MS
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structure 89.
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Synlett 2005, No. 4, 685–692 © Thieme Stuttgart · New York

692
J. Mulzer et al.
CLUSTER
O
O
OH
Me
Me
Me
Me
Me
OH
Me
HO
Me
Me
Et
OAc
Me
OH
Me
OMe
Me
NMe2
Me
HO
O
O
O
O
O
O
3
3
Me
OMe
OH
O
O
O
O
Me
Me
Me
Me
OH
4
O
O
Me
Me
OAc
Lankamycin
[3-(4-O-acetyl)-L-arcanosyl]
Erythromycin D
(3-L-mycarosyl)
Figure 8
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Synlett 2005, No. 4, 685–692 © Thieme Stuttgart · New York