Two-directional total synthesis of efomycine M and formal total synthesis of elaiolide

Article abstract of DOI:10.1016/j.tet.2008.01.114

The anti-inflammatory agent efomycine M (1) has been synthesized from macrodilactone 38 and vinyliodide 42 by a two-directional total synthesis in 17 steps over the longest linear sequence with an overall yield of 7%. The C₂-symmetric macrodiolide 38 has been prepared by Yamaguchi macrolactonization of seco-acid 26. The central stereopentad of 1 was obtained by a highly efficient anti-aldol reaction followed by a diastereoselective ketone reduction. Additionally, we have completed a formal total synthesis of elaiolide (3) by converting macrodiolide 37 into Paterson's methylketone 13.

Full text of DOI:10.1016/j.tet.2008.01.114

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4718e4735
www.elsevier.com/locate/tet
Two-directional total synthesis of efomycine M
and formal total synthesis of elaiolide
*
Roland Barth, Johann Mulzer
Institute of Organic Chemistry, University of Vienna, Wa¨hringerstrasse 38, 1090 Vienna, Austria
Received 16 August 2007; received in revised form 24 September 2007; accepted 17 October 2007
Available online 2 February 2008
Abstract
The anti-inflammatory agent efomycine M (1) has been synthesized from macrodilactone 38 and vinyliodide 42 by a two-directional total
synthesis in 17 steps over the longest linear sequence with an overall yield of 7%. The C2-symmetric macrodiolide 38 has been prepared by
Yamaguchi macrolactonization of seco-acid 26. The central stereopentad of 1 was obtained by a highly efficient anti-aldol reaction followed
by a diastereoselective ketone reduction. Additionally, we have completed a formal total synthesis of elaiolide (3) by converting macrodiolide
37 into Paterson’s methylketone 13.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
analysis.7 The natural product 2 itself has received much atten-
tion during the last years due to its antibiotic properties against
Gram-positive bacteria.4a Furthermore, compound 2 was
shown to possess anthelmintic activity against Trichonomonas
vaginalis,4a apoptosis inducing activities,8 immunosuppressive
activity9 and plant growth inhibitory activity.10
The demanding structure of elaiophylin (2) initiated several
synthetic approaches11 and total syntheses. Kinoshita et al.
completed the only total synthesis of the natural product 2
in 1986.12 One year before, Seebach et al. described the first
synthesis of 11,110-di-O-methylelaiophylidene (4), the di-
methyl aglycon of 2.13 Evans and Fitch14 and Paterson
et al.15 reported the syntheses of elaiolide (3), the elaiophylin
agylcon.
Before we started, there was no total synthesis of efomycine
M (1), which was surprising in view of its interesting structure
and promising biological profile. We are now pleased to report
a route that was efficient enough to provide sufficient amounts
of 1. Furthermore, it appears suitable for the preparation of
analogues for future SAR studies, which are indicated by the
fact that von Bonin et al. recently strongly disputed the postu-
lated mode of action of 1 via a pan-selectin antagonism,
although they fully confirmed the anti-inflammatory profile of
compound.16
Efomycines are a newly disclosed family of small molecules
that structurally mimic the binding site of selectin ligands.1
These E- and P-selectin is expressed in inflammatory skin dis-
eases such as psoriasis, atopic dermatitis or contact dermatitis
and mediates T cell rolling along blood vessels by their interac-
tion with T cell epitopes, which are represented by the sialyl
Lewisx (sLex) tetrasaccharide.2 This process results in the infil-
tration of T cells into the skin. The blockade of selectin ligands
by small-molecule antagonists is a new therapeutic approach
in dermatology to prevent the rolling of T cells and therefore
to prevent the occurrence of skin inflammation.
The most promising representative of this family, efomy-
cine M (1), is obtained semi-synthetically from naturally
occurring elaiophylin (2) by a base-catalyzed b-elimination
of the L-2-deoxyfucose moiety (Scheme 1).3 Elaiophylin (2)
was originally isolated from Streptomyces melanosporus in
1959 and one year later re-isolated from a related microorgan-
ism.4 The structure of 2 was elucidated by chemical degrada-
tion,5 spectroscopic methods6 and by X-ray crystallographic
* Corresponding author. Tel.: þ43 1 4277 52190; fax: þ43 1 4277 9521.
E-mail address: johann.mulzer@univie.ac.at (J. Mulzer).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.114

R. Barth, J. Mulzer / Tetrahedron 64 (2008) 4718e4735
2: R1 = L-deoxyfucose, R2 = H
(Elaiophylin)
4719
R1
O
R2O
O
O
3: R1 = H, R2 = H
(Elaiolide)
OH
O
O
OH
O
O
O
OR2
4: R1 = H, R2 = Me
(11,11'-Di-O-methylelaiophylidene)
R1
O
OH
O
OH
O
O
OH
O
OH
KHCO3, H2O
EtOH, EtOAc
52%
Efomycine M
2
O
1
Scheme 1. Semi-synthetic origin of efomycine M (1) from elaiophylin (2) by base-catalyzed b-elimination.
2. Retrosynthetic considerations
We also performed a formal total synthesis of elaiolide (3)
from bis-aldehyde 6 by a sequence of double Wittig olefina-
tion and double Wacker oxidation to generate bis-methyl-
ketone 13, which has previously been elaborated into elaiolide
(3) by the Paterson group.15a
The structure of efomycine M (1) features a 16-membered
macrodiolide core, a labile a,b-enone moiety and seven ster-
eogenic centres. The characteristic C2-symmetry of 1 inspired
us to aim for a two-directional strategy (Scheme 2).17 The
C11eC12 bond should be formed at a late stage of the synthe-
sis by the nucleophilic attack of an organometallic species 5,
which should be obtained from methyl (R)-3-hydroxybutyrate
7, to bis-aldehyde 6. The central macrodiolide core of 6 should
come from the dimerization of the corresponding seco-acid 8,
which would be formed from aldehyde 9 and phosphonate 10.
The central stereopentad 9 should be available by an aldol
reaction between b-ketoimide 12 and aldehyde 11 followed by
a diastereoselective ketone reduction.
3. Results and discussion
3.1. First generation synthesis of stereopentads 17 and 18
and preparations of seco-acids 25 and 26
Our synthesis started with an anti-selective aldol reaction
between b-ketoimide 12 and aldehyde 11a, which gave
b-hydroxyketone 14a in 80% yield and a diastereomeric ratio
of 95:5 as determined by HPLC (Scheme 3).18 The TBDPS
O
O
12
15
1
O
11
PG2O
O
OPG2
metal
+
1
OPG1
O
O
5
6
15
OMe
OH
O
PG3O
O
7
1
11
PG2O
OH
OH
8
12
1
4
1
O
OMe
9
5
PG3O
O
(EtO)2(O)P
+
O
OR
O
O
OR
O
O
PG2O
OPG4
10
O
9
13
Bn
R = TES
9
8
PG3O
+
N
O
O
O
O
O
11
12
Scheme 2. Retrosynthetic anaylsis of efomycine M (1) and of elaiolide precursors 13. PG¼protecting group.

4720
R. Barth, J. Mulzer / Tetrahedron 64 (2008) 4718e4735
O
O
O
O
O
O
OH
Cy2BCl, Me2NEt
Et2O, -78 °C
OR
+
O
N
O
N
OR
O
Bn
Bn
14a: R = TBDPS (80%)
14b: R = PMB (62%)
14c: R = TBS (56%)
11a: R = TBDPS
11b: R = PMB
11c: R = TBS
12
PMP
1. LiBH4, H2O
Et2O, 0 °C
O
O
OH OH
O
O
OH
NaBH(OAc)3, AcOH
MeCN, -40 °C
79%
14a
O
N
OTBDPS
2. PMPCH(OMe)2, ( )-CSA
CH2Cl2, RT
99% over 2 steps
OTBDPS
Bn
15
16
1. TBAF, THF, RT
2. TBSOTf, 2,6-lutidine
CH2Cl2, 0 °C
1. MOMCl, DIPEA
CH2Cl2, 0 °C
16
16
HO
OTBS
HO
OTBDPS
2. DIBAL-H
CH2Cl2, 0 °C
79% over 2 steps
3. DIBAL-H
CH2Cl2, -30 °C
77% over 3 steps
18
17
Scheme 3. Preparation of stereopentads 17 and 18.
protecting group gave the highest yields in comparison to
PMB (14b: 62%) and TBS (14c: 56%). b-Hydroxyketone
14a was selectively reduced to the anti-1,3-diol 15 with
NaBH(OAc)3 (79%, dr 96:4).19 The reductive removal of the
auxiliary with LiBH4 furnished a triol, which was protected re-
gioselectively as PMP-acetal 16 with PMPCH(OMe)2 (99%
over two steps). For the protection of the free 9-OH function,
we examined both an MOM and a TBS group. The MOM
group was introduced under standard conditions with
MOMCl/DIPEA. Before introducing the 9-OTBS group, the
primary TBDPS group was removed and the resulting diol
was di-TBS-protected (90% over two steps). Finally, both
PMP-acetals were reductively opened with DIBAL-H to give
fully protected stereopentads 17 (94%) and 18 (85%, based
on recovered starting material).
The primary alcohols 17 and 18 were oxidized with Desse
Martin periodinane as the corresponding Swern oxidation
resulted in a partial epimerization of the C6-methyl group of
aldehydes 19 and 20 (Scheme 4). The (2E,4E)-diene moiety
was formed in a single olefination step. Best results were ob-
tained from a HornereWadswortheEmmons reaction with
phosphonate 1020 and aldehydes 19 and 20, which gave the de-
sired E-olefins 21 and 22 in excellent yields (21: 85% and 22:
89%, over two steps) and 4E/4Z ratios of >50:1. The corre-
sponding Wittig olefination required repeated column chroma-
tography and resulted generally in lower yields.
OR2
OR2
DMP, CH2Cl2
10, LDA, THF
-78 °C RT
6
OR1
HO
OR1
O
RT
19: R1 = TBDPS, R2 = MOM
20: R1 = R2 = TBS
17: R1 = TBDPS, R2 = MOM
18: R1 = R2 = TBS
OH OR2
O
OR2
O
DDQ, CH2Cl2
pH 7 buffer, RT
OR1
MeO
OR1
RO
21: R1 = TBDPS, R2 = MOM
(85% over 2 steps)
23: R = Me, R1 = TBDPS, R2 = MOM
24: R = Me, R1 = R2 = TBS
22: R1 = R2 = TBS
LiOH, H2O
THF, 0 °C
(89% over 2 steps)
25: R = H, R1 = TBDPS, R2 = MOM
(88% over 2 steps)
26: R = H, R1 = R2 = TBS
(88% over 2 steps)
Scheme 4. Preparation of seco-acids 25 and 26.

R. Barth, J. Mulzer / Tetrahedron 64 (2008) 4718e4735
4721
O
O
O
N
O
TBSO
TBSO
O
TBSO HO
O
Bn
29
DIBAL-H, THF
-78 °C
PMBO
PMBO
N
PMBO
N
O
O
Bu2BOTf, NEt3
CH2Cl2, -78 °C
OMe
98%
Bn
27
28
30
86%
PMP
O
1. MOMCl, DIPEA
CH2Cl2, 0 °C
TBSO
OMOM
O
OMOM
OH
1. TBAF, THF, RT
PMBO
OH
2. LiBH4, H2O
Et2O, 0 °C
63% over 2 steps
2. DDQ, m.s. 4A
CH2Cl2, -10 °C
64% over 2 steps
31
32
PMP
O
O
OMOM
DIBAL-H, CH2Cl2
TBDSPCl, imidazole
17
0 °C
93%
DMAP, DMF, RT
97%
OTBDPS
33
Scheme 5. Second generation synthesis of stereopentad 17.
The preparation of both seco-acids 25 and 26 was com-
pleted by a sequence of PMB cleavage with DDQ and hydro-
lysis of the methyl ester with LiOH in THF/H2O (25: 88%, 26:
88%, over two steps, Scheme 4).
of the formation of dimer 35 were depending on the scale of
the reaction and varied between 23% (25: 1.0 mmol) and
78% (25: 0.1 mmol). The TBDPS groups of 35 were removed
with TBAF and the resulting primary bis-alcohol was oxidized
to the bis-aldehyde 37 in 90% over two steps. In the case of
macrolactone 36, the two primary TBS ethers were cleaved
with a diluted solution of HF$pyridine in THF and the result-
ing bis-alcohol was oxidized with DesseMartin periodinane to
bis-aldehyde 38 in 82% over two steps.
3.2. Second generation synthesis of stereopentad 17
To obtain an independent structural confirmation of frag-
ment 17, we performed a second synthesis from Weinreb am-
ide 27,21 which was reduced to aldehyde 28 (Scheme 5).22
A
stereoselective syn-aldol addition with imide 29 afforded ster-
eopentad 30 in 86% yield, diastereomerically pure as deter-
mined by 1H NMR.23 MOM protection and reductive
removal of the auxiliary afforded 31 (63% over two steps).
Cleavage of the TBS group and formation of the 1,3-PMP-ac-
etal gave 32 in 64% yield over two steps. The remaining pri-
mary hydroxyl group was protected as TBDPS-ether 33
(97%). Finally, reductive opening of the PMP-acetal with
DIBAL-H gave primary alcohol 17 (93%), identical in all
respects with the material obtained from the first synthesis
(cf. Scheme 3).
3.4. Preparation of the C12eC16 fragments 42 and 43
Methyl (R)-3-hydroxybutanoate (7) was alkylated with ethyl
´
iodide by a diastereoselective FratereSeebach reaction in 76%
yield and a diastereomeric ratio of 97:3 after distillation
(Scheme 7).26 The secondary alcohol was protected and the
methyl ester was reduced to alcohol 40 with DIBAL-H (99%).
Among several protecting groups tested (i.e., PMB, MOM,
TBS), the TIPS group was the best choice for the preparation
of the C12eC16 fragment and for a late stage cleavage. After
oxidation of alcohol 40 with DesseMartin periodinane, a
C1-homologation with TMSCHN2/n-BuLi gave alkyne 41 in
58% yield over two steps.27 Hydrozirconation/iodination fur-
nished (E)-vinyliodide 42 (66%).28 Alternatively, alkyne 41
was converted into stannane 43 by an AIBN-mediated hydro-
stannylation in 82% yield. Direct formation of vinyliodide 42
via a Takai iodoolefination proceeded with an excellent E/Z ratio
(>40:1),29 though in low yield (18%).
3.3. Yamaguchi dimerization and preparation of
macrodiolide cores 37 and 38
Initial attempts to dimerize seco-ester 23 or 24 with Otera’s
catalyst (34) failed to give the desired macrodiolides 35 and 36
and led to the corresponding seco-acids 25 and 26,
exclusively.24
In contrast, the dimerization of seco-acids 25 and 26 via the
modified YonemitsueYamaguchi protocol gave the desired di-
mers 35 and 36 in 47% and 59% yield, respectively (Scheme
6).25,14 In both cases, only minor amounts of the acyclic dimer
were isolated (35a: <5% and 36a: 19%) and it could be easily
reconverted into 25 and 26 by treatment with LiOH. The yields
3.5. C11eC12 bond formation and completion of the
synthesis of efomycine M (1)
Our initial strategy envisaged a CrCl2/NiCl2-mediated
NozakieHiyamaeKishi coupling between vinyliodide 42 and
bis-aldehydes 37 and 38, respectively (Scheme 8).30 Although

4722
R. Barth, J. Mulzer / Tetrahedron 64 (2008) 4718e4735
R1O
O
2,4,6-Cl3C6H2C(O)Cl, NEt3
OH OR2
R2O
O
O
OR2
O
toluene, RT
OR1
HO
OR1
O
then DMAP, RT
25: R1 = TBDPS, R2 = MOM
26: R1 = R2 = TBS
35: R1 = TBDPS, R2 = MOM (47%)
36: R1 = R2 = TBS (59%)
X
Bu Bu
Sn O Sn O
O
O
O
Bu
Bu
1. TBAF, THF, 0 °C
2. DMP, CH2Cl2, RT
90% over 2 steps
MOMO
TBSO
O
O
OMOM
OTBS
Bu
Bu
35
O
Sn O Sn
Bu Bu
X
O
O
O
O
34: X = NCS
37
R1O
O
O
O
O
1. HF.pyridine (7%)
THF, RT
R2O
OH
HO2C
O
OR2
36
OR1
2. DMP, CH2Cl2, RT
82% over 2 steps
38
35a: R1 = TBDPS, R2 = MOM (< 5%)
36a: R1 = R2 = TBS (19%)
Scheme 6. YonemitsueYamaguchi macrolactonization and preparation of bis-aldehydes 37 and 38.
1. TIPSOTf, 2,6-lutidine
CH2Cl2, 0 °C
LDA (3eq), THF
-40 °C
OTIPS
O
OH
O
OH
1. DMP, CH2Cl2, RT
HO
40
MeO
MeO
39
then EtI, -78 °C
76%
2. DIBAL-H, toluene
-78 °C
99% over 2 steps
2. TMSCHN2, nBuLi
Et2O, -78 °C
58% over 2 steps
7
OTIPS
OTIPS
OTIPS
Cp2Zr(H)Cl, THF, RT
then I2, THF, RT
66%
Bu3SnH, AIBN
PhH, Δ
Bu3Sn
I
41
43
42
41
82%
Scheme 7. Preparation of vinyliodide 42.
a test reaction of 42 with isobutyraldehyde in DMSO gave the
corresponding allylic alcohol in 82% yield as a 1:1 mixture of
diastereomers, all additions of vinyliodide 42 to bis-aldehydes
37 or 38 proceeded in disappointingly low yields. The best
result (34%) was achieved when bis-aldehyde 38 and iodide
42 were treated with a 20-fold excess of CrCl2 in DMF.
Next, we examined the addition of the corresponding orga-
nozinc derivative. Thus, following a protocol by Wipf et al. al-
kyne 41 was hydrozirconated and the organozirconium species
was transmetallated with Et2Zn.31 The organozinc compound
was added to 38. However, only traces (<5%) of the bis-allylic
alcohol 45 were obtained.
O
O
O
OTIPS
11
RO
O
OR
I
a or b
11
+
12
O
O
42
37: R = MOM
38: R = TBS
O
TIPSO
HO RO
O
O
O
OR OH
OTIPS
A satisfactory solution was finally achieved by halogenelith-
ium exchange of 42 with t-BuLi in Et2O and adding the resulting
vinyllithium species to bis-aldehyde 37 or 38, respectively. The vi-
nyllithium intermediate did not attack at the macrocycle carbonyls
even in the presence of a large excess so that the bis-allylic alcohols
44 and 45 were isolated in excellent yields (44: 83%, 45: 89%).
No stereoinduction was observed, as we obtained an insep-
arable yet inconsequential mixture of all three diastereomers
44: R = MOM
45: R = TBS
a: CrCl2, NiCl2, DMF, 0 °C
44: 18%, 45: 34%
b: tBuLi, Et2O, -78 °C
44: 83%, 45: 89%
Scheme 8. Two-directional C11eC12 bond formation.

R. Barth, J. Mulzer / Tetrahedron 64 (2008) 4718e4735
4723
The MOM protected macrodiolide core 35 could be, how-
ever, converted into the corresponding TBS protected macro-
cycle 36 (Scheme 10). This was performed by a three-step
sequence of TMSBr-mediated MOM cleavage, followed by
cleavage of the primary TBDPS groups with TBAF and per-
protection as TBS ether with TBSOTf in 63% yield over three
steps. It should be mentioned that in this case the cleavage of
the MOM group proceeded smoothly at low temperature with-
out the formation of side products. Additionally, the use of
TMSBr at low temperature gave by far the best results for
the MOM cleavage reaction.31
O
O
TIPSO
HO
O
O
O
O
OH
OTIPS
O
O
44
H+ or Lewis acid
O
This failure of the MOM route turned our attention to the
TBS-protected bis-allylic alcohol 45. The allylic hydroxyl
groups were oxidized with DesseMartin periodinane to the
bis-enone 47 in 82% yield (Scheme 11). The attempted global
deprotection with TBAF resulted in the elimination of the
OTBS group and gave the (10E,12E)-bis-dieneone. AcOH-
buffered TBAF gave no reaction. Eventually, the global depro-
tection step was smoothly effected with a 70% solution of
HF$pyridine in MeCN to provide efomycine M (1) in 17 steps
over the longest linear sequence in a total yield of 7%. All
TIPSO
O
O
O
O
O
O
OTIPS
O
up to 65%
46
Scheme 9. Attempted cleavage of the MOM-protecting group.
of 44 and 45 in a 1:1:2 ratio for both the NozakieHiyamae
Kishi reaction and the vinyllithium addition.
The final steps of the total synthesis envisaged the cleavage
of the protecting groups and oxidation of the bis-allylic alco-
hol to the enone moiety. In the case of 44, it was possible to
perform the oxidation step with DesseMartin periodinane or
MnO2 and to cleave the TIPS protecting groups with TBAF.
However, all attempts to remove the MOM groups under
Brønsted or Lewis acid conditions failed. The free allylic alco-
hol trapped the intermediate oxonium species under formation
of the cyclic methylene acetal 46 in up to 65% yield (Scheme
9). Prior protection of the free alcohol as TBS ether or prior
oxidation to the enone did not help. In both cases decomposi-
tion of the starting material during the attempted MOM cleav-
age was observed.
1
spectroscopic data of our synthetic material, i.e., H NMR,
13C NMR, IR, HRMS and the optical rotation were in com-
plete agreement with the data obtained from an authentic
efomycine M (1) sample.33
4. Formal total synthesis of elaiolide (3)
The successful syntheses of macrodiolide aldehydes 37 and
38 encouraged us to tackle the formal total synthesis of elaio-
lide (3, Scheme 12). The synthesis of methylketones 13 and 51
should also allow an additional access towards the preparation
TBDPSO
O
1. TMSBr, CH2Cl2, -50 °C
2. TBAF, THF, RT
3. TBSOTf, 2,6-lutidine
CH2Cl2, 0 °C
MOMO
O
O
OMOM
36
O
OTBDPS
63% over 3 steps
35
Scheme 10. Conversion of macrodilactone 35 into macrodiolide 36.
O
TIPSO
HO RO
O
O
OR OH
OTIPS
DMP
CH2Cl2, 0 °C
82%
O
45: R = TBS
O
Efomycine M
1
TIPSO
O
RO
O
O
O
OR
O
OTIPS
HF.pyridine
MeCN, RT
70%
47: R = TBS
Scheme 11. Completion of the total synthesis of efomycine M (1).

4724
R. Barth, J. Mulzer / Tetrahedron 64 (2008) 4718e4735
O
O
O
Ph3PCH3Br, nBuLi
RO
O
O
OR
RO
O
O
OR
THF, -40 °C
RT
O
O
O
37: R = MOM
38: R = TBS
48: R = MOM (92%)
49: R = TBS (78%)
O
PdCl2, CuCl, O2
DMF, H2O
1. TMSBr, CH2Cl2
-50 °C
TESO
O
O
OTES
13
48
2. TESOTf, 2,6-lutidine
CH2Cl2, 0 °C
85% over 2 steps
67%
O
elaiolide precursor
50
O
PdCl2, CuCl, O2
DMF, H2O
O
OR
O
O
OR O
49
80%
O
51: R = TBS
O
ODEIPS
1.
52
18 steps
[ref. 15a]
LiHMDS, THF, -78 °C
3
13
OBz
2. HF.pyridine
pyridine, THF, H2O
O
[ref. 15a]
Scheme 12. Formal total synthesis of elaiolide (3) by a double Wacker oxidation.
of efomycine M (1) analogues in future. Our syntheses started
from macrocycles 37 and 38, which were homologated by a
Wittig olefination with methylene triphenylphosphorane in ex-
cellent yields (48: 92% and 49: 78%, respectively). The MOM
protecting group of 48 was then exchanged for a TES group.
In this respect, the use of TMSBr for the MOM cleavage
gave best results.32 The TES group was introduced via the cor-
responding triflate to give 50 in 85% yield over two steps. Fi-
nally, a double Wacker oxidation furnished bis-methylketone
13 in 67% yield.34 Additionally, TBS-protected olefin 49
was directly oxidized to bis-methylketone 51 by means of
a double Wacker oxidation in 80% yield.34 Our formal total
synthesis of elaiolide (3) was achieved in 16 steps in an overall
yield of 9%. The analytical data of bis-methylketone 13 were
in complete agreement with those described for Paterson’s
intermediate.15a
6. Experimental
6.1. General experimental procedures
1H and 13C NMR spectra were measured in CDCl3 at 300 K
on a Bruker Avance DRX 400 or DRX 600 at 400.1 MHz
(100.6 MHz) or 600.1 MHz (150.9 MHz), respectively. Chemi-
cal shifts were referenced to residual CHCl3 (dH¼7.26) and
CDCl3 (dC¼77.0). All chemical shifts are given in parts per
million and all coupling constants in hertz. Assignment of pro-
ton resonances was confirmed by correlated spectroscopy. IR
spectra were recorded as thin films on a silicon disc on a
PerkineElmer 1600 FT-IR spectrometer. Mass spectra were
measured on a Micro mass, trio 200 Fisions Instruments.
High-resolution mass spectra (HRMS) were performed with
a Finnigan MAT 8230 with a resolution of 10,000. Optical
rotations were measured on a PerkineElmer 351 polarimeter
in a 1 dm cell. Melting points were measured on a Reichert
Thermovar and were uncorrected. Analytical HPLC was per-
formed on a Jasco System (PU-980 pump, UV 975 and RI
930) using a Nucleosil 50 column (5 mm, Ø 4 mmꢀ250 mm)
at ambient temperature. Preparative HPLC was performed
on a Dynamix Model SD-1 equipped with a Model UV-1 ab-
5. Conclusion
In conclusion, we completed the first total synthesis of efo-
mycine M (1) in 17 steps over the longest linear sequence in
7% overall yield. This two-directional convergent approach
was also applied to a formal total synthesis of elaiolide (3).
Our synthesis should also allow the preparation of simplified
analogues, which is currently underway in our laboratories.
In this connection, side-chain modifications as well as stereo-
chemical variations are considered and will be reported in due
course.
˚
sorbance detector using a Supersphere (60 A pore size, 4 mm
particle size, Ø 25 mmꢀ250 mm) at ambient temperature.
The reaction progress was checked on precoated TLC
plates (Merck Kieselgel 60 F254). Spots were visualized under
254 nm UV light and/or by dipping the TLC plate into

R. Barth, J. Mulzer / Tetrahedron 64 (2008) 4718e4735
4725
a solution of 20 g (NH4)6Mo7O24$4H2O and 0.5 g CeSO4$7H2O
in 400 mL 10% H2SO4 followed by heating with a hot gun.
Column chromatography was performed with Merck silica gel
60 (230e400 mesh). All solvents (hexane, ethyl acetate,
CH2Cl2, Et2O) were distilled prior to use. All reactions were
performed under an atmosphere of argon using oven-dried
glassware and standard syringe/septa techniques. THF and
Et2O were distilled from sodium/benzophenone and toluene
from sodium. CH2Cl2 was dried over P2O5. CH3CN, DMF,
NEt3, Me2NEt, i-Pr2NH, i-Pr2NEt and 2,6-lutidine were
distilled from CaH2.
(CH), 127.8 (2ꢀCH), 127.4 (CH), 75.0 (CH), 68.3 (CH2),
66.3 (CH2), 55.4 (CH), 53.0 (CH), 47.4 (CH), 38.0 (CH2),
35.9 (CH), 26.9 (3ꢀCH3), 19.2 (C), 13.8 (CH3), 12.8 (CH3),
8.9 (CH3); IR (thin film): 3503, 2931, 2858, 1780, 1718,
1696, 1359, 702 cmꢂ1; HRMS [MNaþ] calcd: 638.2914,
found: 638.2922.
6.2.2. (R)-4-Methylphenyl-3-[(2R,3R,4S,5S,6R)-7-
(tert-butyldiphenylsilanyloxy)-3,5-dihydroxy-2,4,6-
trimethylheptanoyl]-oxazolidin-2-one (15)
To a stirred suspension of NaBH(OAc)3 (24.0 g, 146.4 mmol)
in 120 mL MeCN under argon atmosphere at ꢂ45 ꢁC was added
80 mL AcOH. After stirring for 10 min at ꢂ45 ꢁC, a solution of
b-hydroxyketone 14a (10.83 g, 17.59 mmol) in 35 mL MeCN
was added dropwise. The reaction mixture was allowed to
warm up to ꢂ15 ꢁC within 4 h and was stirred at this temperature
until TLC indicated complete consumption of the starting mate-
rial. The reaction was quenched by the slow addition of 50 mL of
a saturated solution of NaHCO3 and was neutralized with solid
NaHCO3. The organic layer was separated and the aqueous
phase was extracted four times with ethyl acetate. The combined
organic layers were washed with a saturated solution of
NaHCO3, dried over Na2SO4, filtered and concentrated under re-
duced pressure. The crude product was purified by flash column
chromatography (hexane/ethyl acetate, 2:1) to give diol 15
(8.62 g, 79%) as a highly viscous oil. Rf¼0.23 (hexane/ethyl ac-
etate, 2:1); [a]2D0 ꢂ52.7 (c 0.77, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d¼7.67 (m, 4H, Harom), 7.21e7.47 (series of m, 11H,
6.2. Total synthesis of efomycine M (1)
6.2.1. (2R,4S,5S,6R)-1-[(R)-4-Phenylmethyl-2-oxo-
oxazolidin-3-yl]-7-(tert-butyldiphenylsilanyloxy)-5-hydroxy-
2,4,6-trimethylheptane-1,3-dione (14a)
To
a stirred solution of b-ketoimide 12 (5.77 g,
19.94 mmol) in 95 mL Et2O was added a solution of chlorodi-
cyclohexylborane (1.0 M in hexane, 23.0 mL, 23.0 mmol) at
0 ꢁC. Me2NEt (3.05 mL, 28.15 mmol) was added dropwise
and the resulting yellow suspension was stirred at 0 ꢁC for
90 min. After cooling to ꢂ78 ꢁC, a solution of freshly pre-
pared aldehyde 14a (6.46 g, 19.78 mmol) in 12 mL Et2O
was added dropwise. The reaction mixture was stirred at
ꢂ78 ꢁC for 6 h and was then allowed to warm up to þ4 ꢁC
within 12 h. The reaction was quenched with 80 mL of a satu-
rated solution of NH4Cl. The organic phase was separated and
concentrated under reduced pressure. The remaining yellow
oil was dissolved in 80 mL MeOH and 80 mL of pH 7 phos-
phate buffer and cooled to 0 ꢁC. H2O2 (16 mL, 30%) was
added cautiously and the reaction mixture was stirred for
60 min at 0 ꢁC. After dilution with CH2Cl2, the organic phase
was separated and the aqueous phase was extracted four times
with CH2Cl2. The combined organic phases were dried over
Na2SO4, filtered and concentrated under reduced pressure.
Purification of the residue by flash column chromatography
(hexane/ethyl acetate, 3:1) provided b-hydroxyketone 14a
(10.83 g, 89%) as a colourless highly viscous oil, which still
Harom), 4.74 (m, 1H, NCH), 4.27 (m, 1H, CHOH), 4.21 (ddwt,
J¼9.1 Hz, 1H, CHAHBPh), 4.16 (dd, J¼9.1, 3.0 Hz, 1H,
CHBHAPh), 4.04(dq, J¼9.5, 6.9 Hz, 1H, CHCH3), 3.87(brd, J¼
7.5 Hz, 1H, CHOH), 3.78 (dd, J¼10.1, 3.9 Hz, 1H, CHAHBOSi),
3.69 (dd, J¼10.1, 4.5 Hz, 1H, CHBHAOSi), 3.27 (dd, J¼13.4,
3.3 Hz, 1H, CHAHBO), 3.00 (br s, 1H, OH), 2.81 (br s, 1H,
OH), 2.80 (dd, J¼13.3, 9.6 Hz, 1H, CHBHAO), 1.74e1.87 (m,
2H, 2ꢀCHCH3), 1.12 (d, J¼6.9 Hz, 3H, CH3CH), 1.07 (s, 9H,
t-Bu), 1.04 (d, J¼7.0 Hz, 3H, CH3CH), 0.90 (d, J¼7.0 Hz, 3H,
CH3CH); 13C NMR (100 MHz, CDCl3): d¼176.8 (C), 153.5
(C), 135.7 (CH), 135.6 (CH), 135.3 (C), 133.1 (C), 132.9 (C),
129.8 (CH), 129.8 (CH), 129.4 (CH), 128.9 (CH), 127.8
(2ꢀCH), 127.3 (CH), 75.8 (CH), 73.5 (CH), 68.9 (CH2), 66.1
(CH2), 55.3 (CH), 40.0 (CH), 38.0 (CH2), 36.7 (CH), 36.7
(CH), 26.9 (3ꢀCH3), 19.2 (C), 14.3 (CH3), 10.3 (CH3), 10.0
(CH3); IR (thin film): 3480 (br), 2963, 1931, 2858, 1783, 1699,
1472, 1455, 1428, 1390, 1350, 1212, 1112, 1019, 972, 738,
702 cmꢂ1; HRMS [MNaþ] calcd: 640.3070, found: 640.3043.
1
contained 9% of 12 as determined by H NMR. A sample
was additionally purified by preparative HPLC (hexane/
i-PrOH, 97.5:2.5, flow: 80 mLꢀminꢂ1, tR¼7.0 min). Rf¼0.28
1
(hexane/ethyl acetate, 3:1); [a]2D0 ꢂ51.6 (c 1.13, CH2Cl2); H
NMR (400 MHz, CDCl3): d¼7.63e7.67 (m, 4H, Harom),
7.18e7.45 (m, 11H,
H
arom), 4.91 (q, J¼7.3 Hz, 1H,
CHCH3), 4.75 (m, 1H, NCH), 4.22 (t, J¼9.1 Hz, 1H,
CHAHBPh), 4.16 (dd, J¼9.1, 2.9 Hz, 1H, CHBHAPh), 4.07
(ddd, J¼9.5, 3.0, 2.0 Hz, 1H, CHOH), 3.75 (dd, J¼10.1,
4.2 Hz, 1H, CHAHBOSi), 3.65 (dd, J¼10.1, 5.9 Hz, 1H,
CHBHAOSi), 3.31 (dd, J¼13.3, 3.0 Hz, 1H, CHAHBO), 2.92
(dq, J¼9.5, 7.0 Hz, 1H, CHCH3), 2.79 (dd, J¼13.3, 9.6 Hz,
1H, CHBHAO), 2.59 (d, J¼3.1 Hz, 1H, OH), 1.76 (m, 1H,
CHCH3), 1.49 (d, J¼7.3 Hz, 3H, CH3CH), 1.05 (s, 12H,
CH3CH overlapped by t-Bu), 0.90 (d, J¼7.0 Hz, 3H,
CH3CH); 13C NMR (100 MHz, CDCl3): d¼211.1 (C), 170.9
(C), 153.4 (C), 135.7 (CH), 135.6 (CH), 135.2 (C), 133.2
(C), 133.0 (C), 129.8 (CH), 129.7 (CH), 129.4 (CH), 129.0
6.2.3. (2S,3S,4R,5S,6R)-7-(tert-Butyldiphenylsilanyloxy)-
2,4,6-trimethylheptane-1,3,5-triol
LiBH4 (300 mg, 13.77 mmol) was added in small portions
over a period of 3 h to a stirred solution of diol 15 (7.13 g,
11.54 mmol) in 120 mL Et2O and H2O (0.27 mL,
14.98 mmol) at 0 ꢁC. The reaction was quenched with
30 mL H2O. The organic layer was separated and the aqueous
layer was extracted four times with CH2Cl2. The combined or-
ganic layers were dried over MgSO4, filtered and concentrated
under reduced pressure. The crude product was purified by

4726
R. Barth, J. Mulzer / Tetrahedron 64 (2008) 4718e4735
flash column chromatography (hexane/ethyl acetate, 1:1) to
give the triol (4.48 g, 87%) as a colourless, highly viscous
gel. Rf¼0.21 (hexane/ethyl acetate, 1:1); [a]2D0 þ2.9 (c 1.23,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d¼7.63e7.68 (m,
4H, Harom), 7.37e7.47 (m, 6H, Harom), 3.93 (dd, J¼9.7,
1.7 Hz, 1H, CHO), 3.81 (m, 1H, CHO), 3.76 (dd, J¼10.0,
4.0 Hz, 1H, CHO), 3.64e3.70 (m, 3H, 3ꢀCHO), 3.48 (br s,
2H, 2ꢀOH), 3.30 (d, J¼2.7 Hz, 1H, OH), 1.68e1.94 (series
of m, 3H, 3ꢀCHCH3), 1.06 (s, 9H, t-Bu), 1.05 (d, J¼
7.2 Hz, 3H, CH3CH), 0.88 (d, J¼7.0 Hz, 3H, CH3CH), 0.68
(d, J¼6.9 Hz, 3H, CH3CH); 13C NMR (100 MHz, CDCl3):
d¼135.8 (CH), 135.5 (CH), 133.0 (C), 132.8 (C), 129.9 (CH),
129.8 (CH), 127.8 (CH), 127.8 (CH), 77.2 (CH), 76.9 (CH),
69.5 (CH2), 68.9 (CH2), 37.1 (CH), 36.9 (CH), 36.9 (CH), 26.9
(3ꢀCH3), 19.2 (C), 13.2 (CH3), 10.8 (CH3), 10.2 (CH3); IR:
(thin film) 3392 (br), 2962, 2931, 2856, 1780, 1428, 1166,
1113, 702 cmꢂ1; HRMS [Mþꢂt-Bu] calcd: 387.1992, found:
387.1999.
with 30 mL of a saturated solution of NH4Cl and dilution with
30 mL of CH2Cl2, the organic layer was separated and the
aqueous layer was extracted four times with CH2Cl2. The
combined organic layers were dried over MgSO4, filtered
and concentrated in vacuo. Purification with flash column
chromatography gave the diol (1.51 g, 99% over two steps)
as viscous oil. Rf¼0.17 (hexane/ethyl acetate, 1:1); [a]D20
þ43.8 (c 1.22, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d¼7.38 (m, 2H, Harom), 6.88 (m, 2H, Harom), 5.47 (s, 1H,
OCHO), 4.11 (dd, J¼11.2, 4.7 Hz, 1H, CHAHBO), 3.88 (dd,
J¼10.1, 2.0 Hz, 1H, CHO), 3.87 (m, 1H, CHOH), 3.80 (s,
3H, OCH3), 3.75 (dd, J¼10.5, 3.9 Hz, 1H, CHAHBOH), 3.70
(m, 1H, CHBHAOH), 3.53 (t, J¼11.1 Hz, 1H, CHBHAO),
2.74 (br d, J¼2.8 Hz,1H, OH), 2.07e2.17 (m, 2H, OH,
CHCH3), 1.89 (ddq, J¼10.4, 7.1, 2.1 Hz, 1H, CHCH3), 1.82
(m, 1H, CHCH3), 0.98 (d, J¼7.0 Hz, 3H, CH3CH), 0.96 (d,
J¼7.1 Hz, 3H, CH3CH), 0.77 (d, J¼7.7 Hz, 3H, CH3CH);
13C NMR (100 MHz, CDCl3): d¼159.9 (C), 131.3 (C),
127.4 (CH), 113.6 (CH), 101.1 (CH), 82.3 (CH), 74.6 (CH),
73.2 (CH2), 67.9 (CH2), 55.3 (CH3), 36.7 (CH), 36.5 (CH),
30.4 (CH), 12.0 (CH3), 10.5 (CH3), 9.2 (CH3); IR (thin
film): 3402 (br), 2967, 1518, 1250, 1032 cmꢂ1; HRMS [Mþ]
calcd: 324.1937, found: 324.1942.
6.2.4. (2R,3S,4S)-1-(tert-Butyldiphenylsilanyloxy)-
4-[(2S,4S,5S)-2-(4-methoxyphenyl)-5-methyl-[1,3]-
dioxan-4-yl]-2-methylpentan-3-ol (16)
Triol (2.10 g, 4.72 mmol) was dissolved in 50 mL CH2Cl2.
Freshly distilled PMPCH(OMe)2 (1.0 mL, 5.86 mmol) was
added followed by the addition of (ꢃ)-CSA (49 mg,
0.21 mmol). The reaction mixture was stirred at room temper-
ature for 60 min and then quenched by the addition of 20 mL
of a saturated solution of NaHCO3. The organic layer was sep-
arated and the aqueous layer was extracted three times with
CH2Cl2. The combined organic phases were dried over
MgSO4, filtered and concentrated in vacuo to give 16 quanti-
tatively. As it was not possible to separate the remaining
p-methoxybenzaldehyde from PMP-acetal 16 by flash column
chromatography, the crude product was used in the next step
without any further purification. 1H NMR (400 MHz,
CDCl3): d¼7.67 (m, 4H, Harom), 7.33e7.45 (series of m,
8H, Harom), 6.88 (m, 2H, Harom), 5.50 (s, 1H, OCHO), 4.09
(dd, J¼11.1, 4.6 Hz, 1H, CHAHBO), 3.93 (dt, J¼8.5, 3.1 Hz,
1H, CHOH), 3.88 (dd, J¼10.3, 1.8 Hz, 1H, CHO), 3.80 (s,
3H, OCH3), 3.75 (dd, J¼10.0, 4.4 Hz, 1H, CHAHBOSi), 3.67
(dd, J¼10.0, 5.5 Hz, 1H, CHBHAOSi), 3.52 (ddwt,
J¼11.1 Hz, 1H, CHBHAO), 2.62 (d, J¼4.0 Hz, 1H, OH), 2.07
(m, 1H, CHCH3), 1.77e1.86 (m, 2H, 2ꢀCHCH3), 1.05 (s, 9H,
t-Bu), 0.96 (d, J¼7.0 Hz, 3H, CH3CH), 0.92 (d, J¼7.0 Hz,
3H, CH3CH), 0.71 (d, J¼6.7 Hz, 3H, CH3CH); 13C NMR
(100 MHz, CDCl3): d¼159.8 (C), 135.6 (CH), 133.2 (C),
132.0 (CH), 131.6 (C), 129.7 (CH), 127.7 (CH), 113.5 (CH),
100.9 (CH), 81.8 (CH), 73.3 (CH2), 68.5 (CH2), 55.3 (CH3),
36.7 (CH), 36.2 (CH), 30.4 (CH), 26.9 (t-Bu), 19.2 (C), 11.9
(CH3), 10.0 (CH3), 9.6 (CH3).
6.2.6. (2S,4S,5S)-4-[(1R,2S,3R)-2,4-Bis-
(tert-butyldimethylsilanyloxy)-1,3-dimethylbutyl]-
2-(4-methoxyphenyl)-5-methyl-1,3-dioxinane
2,6-Lutidine (2.40 mL, 20.60 mmol) and TBSOTf (1.95 mL,
8.49 mmol) were added to a stirred solution of the diol (1.02 g,
3.14 mmol) in 30 mL CH2Cl2 at 0 ꢁC. After 90 min, the reac-
tion was quenched by the addition of 20 mL of a saturated
solution of NaHCO3. The organic layer was separated and the
aqueous layer was extracted three times with CH2Cl2. The com-
bined organic phases were dried over MgSO4, filtered and
concentrated under reduced pressure. The crude product was
purified by flash column chromatography (hexane/ethyl ace-
tate, 30:1) to give the di-TBS ether (1.59 g, 91%) as a colourless
oil. Rf¼0.65 (hexane/ethyl acetate, 7:1); [a]2D0 þ22.4 (c 1.52,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d¼7.40 (m, 2H, Harom),
6.87 (m, 2H, Harom), 5.47 (s, 1H, OCHO), 4.12 (dd, J¼10.9,
4.5 Hz, 1H, CHAHBO), 4.01 (dd, J¼8.7, 1.0 Hz, 1H, CHO),
3.80 (s, 3H, OCH3), 3.75 (br d, J¼9.9 Hz, 1H, CHO), 3.49 (t,
J¼11.1, CHO), 3.47 (dd, J¼9.7, 8.3 Hz, 1H, CHAHBO), 3.39
(dd, J¼9.8, 6.9 Hz, 1H, CHBHAO), 2.05 (m, 1H, CHCH3),
1.79e1.90 (m, 2H, 2ꢀCHCH3), 0.92 (s, 9H, t-Bu), 0.91 (d,
J¼7.1 Hz, 3H, CH3CH), 0.88 (s, 9H, t-Bu), 0.80 (d,
J¼6.8 Hz, 3H, CH3CH), 0.74 (d, J¼6.7 Hz, 3H, CH3CH),
0.07 (s, 3H, CH3Si), 0.06 (s, 3H, CH3Si), 0.03 (s, 6H,
2ꢀCH3Si); 13C NMR (100 MHz, CDCl3): d¼159.7 (C),
131.7 (C), 127.2 (CH), 113.4 (CH), 100.3 (CH), 80.8 (CH),
73.3 (CH2), 71.4 (CH), 66.1 (CH2), 55.3 (CH3), 38.4 (CH),
38.3 (CH), 30.4 (CH), 26.4 (3ꢀCH3), 25.9 (3ꢀCH3), 18.6
(C), 18.2 (C), 12.3 (CH3), 9.9 (CH3), 9.1 (CH3), ꢂ3.4 (CH3),
ꢂ4.1 (CH3), ꢂ5.2 (CH3), ꢂ5.3 (CH3); IR (thin film): 2956,
2930, 2857, 1519, 1472, 1463, 1386, 1250, 1109, 1093, 1039,
835, 775 cmꢂ1; HRMS [Mþꢂt-Bu] calcd: 495.2962, found:
495.2967.
6.2.5. (2R,3S,4S)-4-[(2S,4S,5S)-2-(4-Methoxyphenyl)-5-
methyl[1,3]dioxan-4-yl]-2-methylpentane-1,3-diol
Crude PMP-acetal 16 (2.94 g, calcd as 4.72 mmol) was dis-
solved in 35 mL THF. A solution of TBAF (1.0 M in THF,
9.40 mL, 9.40 mmol) was added at 0 ꢁC and the reaction mix-
ture was stirred at room temperature for 24 h. After quenching

R. Barth, J. Mulzer / Tetrahedron 64 (2008) 4718e4735
4727
6.2.7. (2S,3S,4R,5S,6R)-5,7-Bis-(tert-butyldimethyl-
silanyloxy)-3-(4-methoxybenzyloxy)-2,4,6-trimethyl-
heptan-1-ol (18)
atmosphere at 0 ꢁC and stirred for 30 min. Phosphonate 10
(1.55 g, 6.56 mmol) was dissolved in 30 mL THF and cooled
to ꢂ78 ꢁC under argon atmosphere. The freshly prepared solu-
tion of LDA was added dropwise at ꢂ78 ꢁC and the reaction
mixture was allowed to warm up to ꢂ20 ꢁC within 3 h. The
reaction mixture was re-cooled to ꢂ78 ꢁC and a solution of
aldehyde 20 (2.56 g, 4.63 mmol) in 15 mL THF was added
dropwise. The reaction mixture was allowed to warm up to
room temperature overnight and was quenched by the addition
of 40 mL of a saturated solution of NH4Cl. The organic layer
was separated and the aqueous layer was extracted three times
with Et2O. The combined organic phases were dried over
MgSO4, filtered and concentrated under reduced pressure.
Purification by flash column chromatography (hexane/ethyl
acetate, 15:1) gave diene 22 (2.61 g, 89% over two steps) as
a colourless viscous oil. Rf¼0.29 (hexane/ethyl acetate,
10:1); [a]2D0 ꢂ2.0 (c 0.82, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d¼7.24e7.31 (m, 3H, Harom, C3eH), 6.88 (m, 2H,
A solution of DIBAL-H (1.5 M in toluene, 5.0 mL,
7.50 mmol) was added to a stirred solution of the PMP-acetal
(1.40 g, 2.53 mmol) in 24 mL CH2Cl2 at ꢂ30 ꢁC under argon
atmosphere. The reaction mixture was allowed to warm up to
ꢂ10 ꢁC within 3 h and was then quenched by the addition of
a saturated solution of Na/K/tartrate. The organic phasewas sep-
arated and the aqueous phase was extracted three times with
CH2Cl2. The combined organic phases were dried over
MgSO4, filtered and concentrated in vacuo. The crude product
was purified by flash column chromatography to give alcohol
18 (0.97 g, 69%, 85% based on the recovered starting material)
as colourless oil together with 0.26 g of recycled starting mate-
rial. Rf¼0.26 (hexane/ethyl acetate, 7:1); [a]2D0 ꢂ6.2 (c 1.10,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d¼7.26 (m, 2H, Harom),
6.87 (m, 2H, Harom), 4.60, 4.54 (AB system, J¼10.2 Hz, 2H,
OCH2Ph), 4.00 (br d, J¼6.3 Hz, 1H, CHO), 3.83 (dddwdt,
11.0, 3.9 Hz, 1H, CHAHBOH), 3.80 (s, 3H, OCH3), 3.59
(dddwdt, J¼11.0, 5.8 Hz, 1H, CHBHAOH), 3.47 (ddwt,
J¼5.4 Hz, 1H, CHOSi), 3.42 (t, J¼9.6 Hz, 1H, CHAHBOSi),
3.34 (dd, J¼9.6, 5.6 Hz, 1H, CHBHAOSi), 2.90 (dd, J¼6.2,
5.1 Hz, 1H, OH), 1.91e2.02 (m, 2H, 2ꢀCHCH3), 1.75 (m,
1H, CHCH3), 1.08 (d, J¼7.3 Hz, 3H, CH3CH), 1.06 (d,
J¼7.3 Hz, 3H, CH3CH), 0.91 (s, 9H, t-Bu), 0.89 (s, 9H, t-Bu),
0.84 (d, J¼6.8 Hz, 3H, CH3CH), 0.10 (s, 3H, CH3Si), 0.07 (s,
3H, CH3Si), 0.04 (s, 6H, 2ꢀCH3Si); 13C NMR (100 MHz,
CDCl3): d¼159.3 (C), 130.5 (C), 129.3 (CH), 113.9 (CH),
86.6 (CH), 75.3 (CH2), 71.5 (CH), 66.0 (CH2), 65.5 (CH2),
55.3 (CH3), 42.8 (CH), 37.7 (CH), 37.2 (CH), 26.1 (3ꢀCH3),
25.9 (3ꢀCH3)18.5 (C), 18.2 (C), 15.6 (CH3), 11.7 (CH3), 10.7
(CH3), ꢂ3.4 (CH3), ꢂ4.4 (CH3), ꢂ5.4 (2ꢀCH3); IR (thin
film): 3448 (br), 2956, 2929, 2857, 1515, 1473, 1465, 1251,
1086, 1043, 836, 774 cmꢂ1; HRMS [Mþ] calcd: 554.3823,
found: 554.3814.
Harom), 6.24 (m, 2H, C4eH, C5eH), 5.78 (d, J¼15.4 Hz,
1H, C2eH), 4.57, 4.52 (AB system, J¼10.4 Hz, 2H, OCH2Ph),
4.01 (br d, J¼5.6 Hz, 1H, C9eH), 3.81 (s, 3H, OCH3), 3.74 (s,
3H, C1eOCH3), 3.41 (t, J¼9.6 Hz, 1H, C11eHA), 3.32 (dd,
J¼9.6, 5.3 Hz, 1H, C11eHB), 3.25 (dd, J¼7.5, 3.3 Hz, 1H,
C7eH), 2.71 (m, 1H, C6eH), 1.84 (m, 1H, C8eH), 1.72 (m,
1H, C10eH), 1.13 (d, J¼6.8 Hz, 3H, C6eCH3), 1.05 (d,
J¼7.1 Hz, 3H, C8eCH3), 0.93 (s, 9H, t-Bu), 0.88 (s, 9H,
t-Bu), 0.84 (d, J¼6.8 Hz, 3H, C10eCH3), 0.08 (s, 3H, CH3Si),
0.07 (s, 3H, CH3Si), 0.02 (s, 3H, CH3Si), ꢂ0.03 (s, 3H,
CH3Si); 13C NMR (100 MHz, CDCl3): d¼167.6 (C), 159.1 (C),
146.5 (CH), 145.3 (CH), 131.0 (CH), 129.1 (CH), 128.7 (CH),
119.1 (CH), 113.8 (CH), 85.2 (CH), 75.0 (CH2), 70.0 (CH),
66.4 (CH2), 55.3 (CH3), 51.4 (CH3), 43.4 (CH), 40.5 (CH), 37.4
(CH), 26.0 (6ꢀCH3), 18.3 (C), 18.3 (C), 18.2 (CH3), 11.8 (CH3),
11.2 (CH3), ꢂ3.7 (CH3), ꢂ4.7 (CH3), ꢂ5.2 (CH3), ꢂ5.3 (CH3);
IR (thin film): 2955, 2930, 2857, 1722 (br), 1516, 1250, 1142,
1072, 1042, 836, 774 cmꢂ1; HRMS [Mþꢂt-Bu] calcd:
577.3381, found: 577.3394.
6.2.8. (2R,3R,4R,5S,6R)-5,7-Bis-(tert-butyldimethyl
silanyloxy)-3-(4-methoxybenzyloxy)-2,4,6-trimethylheptanal
(20) and (2E,4E)-(6S,7S,8R,9S,10R)-9,11-bis-
6.2.9. (2E,4E)-(6S,7S,8R,9S,10R)-9,11-Bis-
(tert-butyldimethylsilanyloxy)-7-hydroxy-6,8,10-
(tert-butyldimethylsilanyloxy)-7-(4-methoxybenzyloxy)-
6,8,10-trimethylundeca-2,4-dienoic acid methyl ester (22)
DesseMartin periodinane (3.54 g, 8.35 mmol) was added
in one portion to a stirred solution of alcohol 18 (2.57 g,
4.63 mmol) in 50 mL CH2Cl2 at 0 ꢁC. The reaction mixture
was stirred at 0 ꢁC for 30 min and for 4 h at room temperature.
The reaction was quenched by the addition of 20 mL of
a 1.0 M solution of Na2S2O3 and neutralized with 30 mL of
a saturated solution of NaHCO3. The organic phase was sepa-
rated and the aqueous phase was extracted three times with
CH2Cl2. The combined organic layers were dried over
MgSO4, filtered over a short column of silica gel and concen-
trated in vacuo. The crude product 20 (2.56 g) was used in the
next step without any further purification.
trimethylundeca-2,4-dienoic acid methyl ester (24)
DDQ (581 mg, 2.559 mmol) was added in small portions to
a vigorously stirred solution of PMB-ether 22 (935 mg,
1.472 mmol) in 40 mL DCM and 15 mL of a 1.0 M pH 7 phos-
phate buffer over a period of 4 h. Stirring was continued until
TLC indicated complete consumption of the starting material.
The reaction was quenched with 50 mL of a saturated solution
of NaHCO3 and the organic layer was separated. The aqueous
layer was extracted four times with CH2Cl2. The combined or-
ganic phases were dried over MgSO4, filtered and concen-
trated in vacuo. The crude product was purified by flash
column chromatography (hexane/ethyl acetate, 10:1) to give
seco-ester 24 (741 mg, 98%) as a slightly yellow oil.
Rf¼0.20 (hexane/ethyl acetate, 10:1); [a]2D0 ꢂ20.6 (c 0.86,
1
A solution of LDA was prepared by adding a solution of
n-BuLi (2.5 M in hexane, 2.65 mL, 6.63 mmol) to a solution
of i-Pr2NH (0.93 mL, 6.64 mmol) in 15 mL THF under argon
CH2Cl2); H NMR (400 MHz, CDCl3): d¼7.30 (dd, J¼15.4,
10.0 Hz, 1H, C3eH), 6.17e6.29 (m, 2H, C4eH, C5eH),
5.80 (d, J¼15.4 Hz, 1H, C2eH), 3.87 (t, J¼4.2 Hz, 1H,

4728
R. Barth, J. Mulzer / Tetrahedron 64 (2008) 4718e4735
C9eH), 3.73 (s, 3H, OCH3), 3.71 (m, 1H, C7eH), 3.50 (dd,
J¼9.8, 6.4 Hz, 1H, C11eHA), 3.45 (dd, J¼9.8, 6.0 Hz, 1H,
C11eHB), 3.04 (d, J¼1.7 Hz, OH), 2.41 (m, 1H, C6eH),
1.89 (m, 1H, C10eH), 1.77 (m, 1H, C8eH), 0.97 (d,
J¼7.1 Hz, 3H, C8eCH3), 0.96 (d, J¼6.8 Hz, 3H, C6eCH3),
0.93 (d, J¼6.9 Hz, 3H, C10eCH3), 0.91 (s, 9H, t-Bu), 0.98
(s, t-Bu), 0.09 (s, 3H, CH3Si), 0.08 (s, 3H, CH3Si), 0.04 (s,
3H, CH3Si), 0.03 (s, 3H, CH3Si); 13C NMR (100 MHz,
CDCl3): d¼167.6 (C), 147.8 (CH), 145.4 (CH), 128.2 (CH),
119.2 (CH), 77.6 (CH), 74.9 (CH), 66.0 (CH2), 51.4 (CH3),
40.7 (CH), 39.5 (CH), 37.9 (CH), 26.2 (3ꢀCH3), 25.9
(3ꢀCH3), 18.4 (C), 18.2 (C), 16.4 (CH3), 13.0 (CH3), 11.1
(CH3), ꢂ3.8 (CH3), ꢂ4.0 (CH3), ꢂ5.4 (2ꢀCH3); IR (thin
film): 3503, 2956, 2930, 2885, 2858, 1723 (br), 1645, 1258,
1142, 1091, 1045, 1004, 837, 775 cmꢂ1; HRMS [Mþꢂt-Bu]
calcd: 457.2806, found: 457.2798.
toluene. The cloudy solution was stirred at room temperature
for 4 h. A solution of N,N-dimethylaminopyridine (140 mg,
1.146 mmol) in 6 mL toluene was added over a period of
8 h with a syringe pump and stirring was continued overnight.
The resulting slightly yellow suspension was quenched with
10 mL of a 1.0 M solution of KHSO4. The organic phase
was separated and the aqueous phase was extracted three times
with Et2O. The combined organic layers were dried over
MgSO4, filtered and concentrated under reduced pressure. Pu-
rification with flash column chromatography (hexane/ethyl ac-
etate, 30:1) gave macrodiolide 36 (161 mg, 59%) as colourless
needles together with uncyclized dimer 36a (51 mg, 19%).
Rf¼0.22 (hexane/ethyl acetate, 15:1); [a]2D0 þ46.4 (c 1.30,
CH2Cl2); mp: 174e175 ꢁC; 1H NMR (400 MHz, CDCl3):
d¼6.93 (dd, J¼15.3, 11.1 Hz, 2H, C3eH), 5.98 (dd, J¼15.0,
11.1 Hz, 2H, C4eH), 5.63 (dd, J¼15.0, 9.9 Hz, 2H, C5eH),
5.58 (d, J¼15.3 Hz, 2H, C2eH), 4.94 (br d, J¼10.1 Hz, 2H,
C7eH), 3.74 (dd, J¼6.8, 1.7 Hz, 2H, C9eH), 3.47 (dd,
J¼9.8, 7.6 Hz, 2H, C11eHA), 3.38 (dd, J¼9.8, 6.9 Hz, 2H,
C11eHB), 2.42 (m, 2H, C6eH), 1.93 (m, 2H, C8eH), 1.76
(m, 2H, C10eH), 1.05 (d, J¼6.6 Hz, 6H, C6eCH3), 0.96 (d,
J¼7.2 Hz, 6H, C8eCH3), 0.91 (s, 18H, t-Bu), 0.86 (s, 18H,
t-Bu), 0.84 (d, J¼6.8 Hz, 6H, C10eCH3), 0.15 (s, 6H,
CH3Si), 0.05 (s, 6H, CH3Si), 0.02 (s, 6H, CH3Si), 0.01 (s,
6H, CH3Si); 13C NMR (100 MHz, CDCl3): d¼167.6 (C),
145.2 (CH), 144.5 (CH), 130.7 (CH), 121.3 (CH), 76.9
(CH), 73.7 (CH), 66.0 (CH2), 42.5 (CH), 39.0 (CH), 38.7
(CH), 26.3 (3ꢀCH3), 25.9 (3ꢀCH3), 18.7 (C), 18.2 (C), 16.3
(CH3), 10.4 (CH3), 10.2 (CH3), ꢂ3.6 (CH3), ꢂ4.3 (CH3),
ꢂ5.3 (CH3), ꢂ5.3 (CH3); IR (thin film): 2956, 2943, 2930,
2885, 2856, 1709 (br), 1643, 1472, 1385, 1251, 1225, 1150,
1123, 1118, 1106, 1044, 1006, 849, 837, 776 cmꢂ1; HRMS
[MNaþ] calcd: 987.6393, found: 987.6381.
6.2.10. (2E,4E)-(6S,7S,8R,9S,10R)-9,11-Bis-(tert-
butyldimethylsilanyloxy)-7-hydroxy-6,8,10-
trimethylundeca-2,4-dienoic acid (26)
A solution of LiOH$H2O (170 mg, 4.051 mmol) in 11 mL
H2O was added to a solution of 24 (741 mg, 1.493 mmol) in
24 mL THF at 0 ꢁC. The reaction mixture was allowed to
warm up to room temperature and was stirred for 24 h. The
reaction was quenched by the dropwise addition of AcOH
(0.37 mL, 6.65 mmol) at 0 ꢁC. The organic layer was separated
and the aqueous layer was four times extracted with CH2Cl2.
The combined organic layers were dried over MgSO4, filtered
and concentrated invacuo. Purification by flash column chroma-
tography (hexane/ethyl acetate, 3:1) gave seco-acid 26 (649 mg,
90%) as a slightly yellow, highly viscous gum. Rf¼0.17 (hexane/
1
ethyl acetate, 3:1); [a]2D0 ꢂ24.3 (c 1.08, CH2Cl2); H NMR
(400 MHz, CDCl3): d¼7.37 (m, 1H, C3eH), 6.27 (m, 2H,
C4eH, C5eH), 5.79 (d, J¼15.3 Hz, 1H, C2eH), 3.87 (t,
J¼4.1 Hz, 1H, C9eH), 3.74 (dd, J¼8.7, 2.1 Hz, 1H, C7eH),
3.51 (dd, J¼9.8, 6.4 Hz, 1H, C11eHA), 3.46 (dd, J¼9.8,
5.9 Hz, 1H, C11eHB), 2.43 (m, 1H, C6eH), 1.90 (m, 1H,
C10eH), 1.78 (m, 1H, C8eH), 0.98 (d, J¼6.9 Hz, C8eCH3),
0.97 (d, J¼6.6 Hz, C6eCH3), 0.94 (d, J¼6.9 Hz, C10eCH3),
0.91 (s, 9H, t-Bu), 0.89 (s, 9H, t-Bu), 0.10 (CH3Si), 0.09
(CH3Si), 0.04 (CH3Si), 0.04 (CH3Si); 13C NMR (100 MHz,
CDCl3): d¼172.1 (C), 148.9 (CH), 147.4 (CH), 128.1 (CH),
118.8 (CH), 77.9 (CH), 75.0 (CH), 66.0 (CH2), 40.8 (CH),
39.5 (CH), 37.8 (CH), 26.2 (3ꢀCH3), 25.9 (3ꢀCH3), 18.4 (C),
18.2 (C), 16.4 (CH3), 13.1 (CH3), 11.2 (CH3), ꢂ3.8 (CH3),
ꢂ4.0 (CH3), ꢂ5.4 (2ꢀCH3); IR (thin film): 3470 (v br), 2956,
2929, 2858, 1691, 1639, 1257, 1089, 1048, 1004, 836,
6.2.12. (3E,5E,11E,13E)-(7S,8S,15S,16S)-8,16-Bis-
[(1R,2S,3R)-2-(tert-butyldimethylsilanyloxy)-4-hydroxy-1,3-
dimethylbutyl]-7,15-dimethyl-1,9-dioxacyclohexadeca-
3,5,11,13-tetraene-2,10-dione
A solution of HF$pyridine (70%, 1.17 mL, 6.54 mmol) in
1.40 mL pyridine was added to a solution of compound 36
(243 mg, 0.252 mmol) in 6.0 mL THF under argon atmosphere
at 0 ꢁC. The reaction mixture was stirred at room temperature
until TLC indicated complete consumption of the starting mate-
rial (approximately 3 days). The reaction was quenched by the
addition of a saturated solution of NaHCO3 and diluted with
CH2Cl2. The organic layer was separated and the aqueous layer
was extracted four times with CH2Cl2. The combined organic
phases were dried over MgSO4, filtered and concentrated under
reduced pressure. Purification with flash column chromatogra-
phy (hexane/ethyl acetate, 3:1) gave the bis-diol (159 mg,
86%) as colourless needles. Rf¼0.32 (hexane/ethyl acetate,
2:1); [a]2D0 þ19.8 (c 0.43, CH2Cl2); mp: 159e161 ꢁC; 1H
NMR (400 MHz, CDCl3): d¼6.93 (dd, J¼15.3, 11.1 Hz, 2H,
C3eH), 6.01 (dd, J¼15.0, 11.2 Hz, 2H, C4eH), 5.61 (dd,
J¼15.0, 9.9 Hz, 2H, C5eH), 5.61 (d, J¼15.4 Hz, 2H, C2eH),
4.87 (d, J¼10.2 Hz, 2H, C7eH), 3.86 (dd, J¼5.8, 1.5 Hz, 2H,
C9eH), 3.45 (m, 4H, C11eH), 2.43 (m, 2H, C6eH), 2.03 (m,
774 cmꢂ1
443.2657.
;
HRMS [Mþꢂt-Bu] calcd: 443.2649, found:
6.2.11. (3E,5E,11E,13E)-(7S,8S,15S,16S)-8,16-Bis-
[(1R,2S,3R)-2,4-bis-(tert-butyldimethylsilanyloxy)-1,3-
dimethylbutyl]-7,15-dimethyl-1,9-dioxacyclohexadeca-
3,5,11,13-tetraene-2,10-dione (36)
NEt3 (160 mL, 1.148 mmol) and 2,4,6-trichlorobenzoyl-
chloride (110 mL, 0.704 mmol) were added to a stirred solu-
tion of seco-acid 26 (285 mg, 0.569 mmol) in 35 mL

R. Barth, J. Mulzer / Tetrahedron 64 (2008) 4718e4735
4729
2H, C10eH), 1.63e1.84 (br m, 4H, C8eH, OH), 1.06 (d,
J¼6.6 Hz, 6H, C6eCH3), 1.01 (d, J¼7.2 Hz, 6H, C10eCH3),
0.91 (s, 18H, t-Bu), 0.85 (d, J¼6.9 Hz, 6H, C8eCH3), 0.13 (s,
6H, CH3Si), 0.06 (s, 6H, CH3Si); 13C NMR (100 MHz,
CDCl3): d¼168.0 (C), 145.4 (CH), 144.5 (CH), 131.0 (CH),
121.4 (CH), 77.6 (CH), 74.3 (CH), 66.2 (CH2), 42.4 (CH), 39.1
(CH), 38.5 (CH), 26.1 (3ꢀCH3), 18.4 (C), 16.2 (CH3), 11.3
(CH3), 9.2 (CH3), ꢂ3.9 (CH3), ꢂ4.5 (CH3); IR (thin film):
3483 (br), 2928, 1716, 1636, 1473, 1387, 1301, 1252, 1221,
1184, 1047, 998, 866, 837, 773 cmꢂ1; HRMS [Mþꢂt-Bu] calcd:
679.4062, found: 679.4076.
of EtI (7.50 mL, 93.77 mmol) in 15 mL THF was added drop-
wise. The reaction was stirred at ꢂ78 ꢁC for 4 h and then
allowed to warm up to room temperature overnight. After
quenching with 70 mL of a saturated solution of NH4Cl, the or-
ganic layer was separated and the aqueous layer was extracted
four times with Et2O. The combined organic layers were dried
over Na2SO4, filtered and concentrated under reduced pressure.
Purification by bulb-to-bulb distillation (bp 72 ꢁC at 3 mmHg)
gave compound 39 (2.99 g, 76%) as a colourless liquid. [a]D20
1
ꢂ4.5 (c 1.63, CHCl3); H NMR (400 MHz, CDCl3): d¼3.92
(m, 1H, CHOH), 3.72 (s, 3H, OCH3), 2.46 (d, J¼6.9 Hz, 1H,
OH), 2.32 (dt, J¼8.5, 6.0 Hz, 1H, CHCH2), 1.59e1.75 (m,
2H, CH2CH3), 1.22 (d, J¼6.3 Hz, 3H, CH3CH), 0.92 (t,
J¼7.5 Hz, 3H, CH3CH2); 13C NMR (100 MHz, CDCl3):
d¼175.8 (C), 68.1 (CH), 54.3 (CH3), 51.5 (CH), 22.6 (CH2),
21.5 (CH3), 11.7 (CH3); IR (thin film): 3401 (br), 2972, 1737
(br), 1456, 1171, 995, 799 cmꢂ1; HRMS [MþꢂMe] calcd:
131.0708, found: 131.0711.
6.2.13. (2S,3R,4R)-3-(tert-Butyldimethylsilanyloxy)-4-
{(4E,6E,12E,14E)-(2S,3S,10S,11S)-10-[(1R,2R,3S)-2-(tert-
butyldimethylsilanyloxy)-1,3-dimethyl-4-oxobutyl]-3,11-
dimethyl-8,16-dioxo-1,9-dioxacyclohexadeca-4,6,12,14-
tetraen-2-yl}-2-methylpentanal (38)
DesseMartin periodinane (320 mg, 0.754 mmol) was added
in one portion to a stirred solution of the bis-alcohol (122 mg,
0.165 mmol) in 5 mL CH2Cl2 at 0 ꢁC. The reaction mixture
was stirred at room temperature for 4 h before being quenched
with 4 mL of a 1.0 M solution of Na2S3O3 and 10 mL of a satu-
rated solution of NaHCO3. The organic layer was separated and
the aqueous layer was extracted three times with CH2Cl2. The
combined organic layers were dried over MgSO4, filtered and
concentrated in vacuo. Purification by flash column chromatog-
raphy (hexane/ethyl acetate, 5:1) gave bis-aldehyde 38 (114 mg,
94%) as colourless crystals. Rf¼0.23 (hexane/ethyl acetate,
2,6-Lutidine (6.00 mL, 51.51 mmol) and TIPSOTf
(6.20 mL, 23.06 mmol) were added to a stirred solution of alco-
hol 39 (2.99 g, 20.45 mmol) in 21 mL CH2Cl2 at 0 ꢁC. The reac-
tion mixture was stirred for 2 h and then quenched by the
addition of 20 mL of a saturated solution of NH4Cl. The organic
layer was separated and the aqueous layer was extracted two
times with CH2Cl2. The combined organic layers were dried
over MgSO4, filteredand concentrated invacuo. The crude prod-
uct was used in the next step without any further purification.
A solution of DIBAL-H (1.5 M in toluene, 48.0 mL,
72.0 mmol) was added to a stirred solution of the TIPS-
protected ester (calcd as 20.45 mmol) in 80 mL toluene
at ꢂ78 ꢁC. The reaction mixture was allowed to warm up
to ꢂ50 ꢁC within 2 h. After quenching with 50 mL of a saturated
solution of Na/K/tartrate, the organic layer was separated and
the aqueous phase was extracted three times with Et2O. The
combined organic phases were dried over MgSO4, filtered and
concentrated under reduced pressure. The crude product was pu-
rified by flash column chromatography (hexane/ethyl acetate,
7:1) followed by vacuum distillation (bp: 125 ꢁC at 4 mmHg)
to give alcohol 40 (5.58 g, 99% over two steps) as a colourless
liquid. Rf¼0.20 (hexane/ethyl acetate, 7:1); [a]2D0 ꢂ8.0 (c 1.34,
5:1); [a]2D0 þ124.8 (c 0.99, CH2Cl2); mp: 126 ꢁC; H NMR
1
(250 MHz, CDCl3): d¼9.70 (s, 2H, C11eH), 6.95 (dd, J¼15.3,
11.1 Hz, 2H, C3eH), 6.00 (dd, J¼15.1, 11.1 Hz, 2H, C4eH),
5.63 (dd, J¼15.0, 10.0 Hz, 2H, C5eH), 5.60 (d, J¼15.4 Hz,
2H, C2eH), 4.99 (d, J¼10.2 Hz, 2H, C7eH), 4.17 (dd, J¼7.1,
2.1 Hz, 2H, C9eH), 2.42 (m, 4H, C6eH, C10eH), 2.00 (m,
2H, C8eH), 1.14 (d, J¼7.0 Hz, 6H, C10eCH3), 1.06 (d,
J¼6.6 Hz, 6H, C6eCH3), 0.98 (d, J¼7.1 Hz, 6H, C8eCH3),
0.87 (s, 18H, t-Bu), 1.14 (s, 6H, CH3Si), ꢂ0.03 (s, 6H,
CH3Si); 13C NMR (63 MHz, CDCl3): d¼204.9 (CH), 167.6
(C), 145.6 (CH), 144.5 (CH), 130.9 (CH), 121.2 (CH), 76.5
(CH), 72.8 (CH), 50.1 (CH), 42.4 (CH), 38.8 (CH), 26.1
(3ꢀCH3), 18.4 (C), 16.2 (CH3), 10.0 (CH3), 7.4 (CH3), ꢂ4.2
(2ꢀCH3); IR (thin film): 2930, 2885, 2857, 1721, 1717, 1642,
1258, 1220, 1146, 1107, 1028, 999, 838; HRMS [Mþꢂt-Bu]
calcd: 675.3749, found: 675.3738.
1
CH2Cl2); H NMR (400 MHz, CDCl3): d¼4.16 (dq, J¼6.3,
3.8 Hz, 1H, CHOSi), 3.94 (dt, J¼11.2, 3.3 Hz, 1H, CHAHBO),
3.63 (m, 1H, CHBHAO), 2.87 (dd, J¼7.2, 3.8 Hz, 1H, OH),
1.43e1.62 (m, 2H, CH2CH3), 1.29 (d, J¼6.3 Hz, CH3CH),
1.09 (s, 21H, 3ꢀCH(CH3)2), 0.96 (t, J¼7.5 Hz, 3H, CH3CH2);
13C NMR (100 MHz, CDCl3): d¼72.9 (CH), 62.5 (CH2), 48.6
(CH), 22.3 (CH3), 21.7 (CH2), 18.2 (3ꢀCH(CH3)2), 12.7
(CH3); IR (thin film): 3429, 2962, 2944, 2868, 1053, 1032,
1013, 883, 678 cmꢂ1; HRMS [MþeMe] calcd: 259.2093,
found: 259.2084.
6.2.14. (2R,3R)-2-Ethyl-3-hydroxybutyric acid methyl ester
(39), (2R,3R)-2-ethyl-3-triisopropylsilanyloxybutyric acid
methyl ester and (2S,3R)-2-ethyl-3-triisopropylsilanyl-
oxybutan-1-ol (40)
A solution of LDA was prepared by adding a solution of
n-BuLi (2.5 M in hexane, 32.30 mL, 80.75 mmol) to a solution
of i-Pr2NH (11.40 mL, 81.34 mmol) in 70 mL THF at 0 ꢁC and
stirred for 30 min. A solution of (R)-3-hydroxybutyric acid
methyl ester (7, 3.16 g, 26.75 mmol) in 15 mL THF was added
at ꢂ50 ꢁC and stirred for 3.5 h. During that period, the slightly
yellow reaction mixture was allowed to warm up to ꢂ20 ꢁC.
The reaction mixture was re-cooled to ꢂ78 ꢁC and a solution
6.2.15. (2R,3R)-2-Ethyl-3-triisopropylsilanyloxybutyr-
aldehyde and [(1R,2S)-2-ethyl-1-methylbut-3-ynyloxy]-
triisopropylsilane (41)
DesseMartin periodinane (5.50 g, 12.97 mmol) was added
to a stirred solution of alcohol 40 (2.57 g, 9.36 mmol) in
25 mL CH2Cl2 at 0 ꢁC. The reaction mixture was stirred at

4730
R. Barth, J. Mulzer / Tetrahedron 64 (2008) 4718e4735
room temperature for 3 h. After quenching with 25 mL of
a 1.0 M solution of Na2S2O3, the reaction mixture was neutral-
ized with 40 mL of a saturated solution of NaHCO3. The or-
ganic layer was separated and the aqueous layer was
extracted three times with CH2Cl2. The combined organic
layers were dried over MgSO4, filtered over a short column
of silica gel and concentrated under reduced pressure. The
crude product was used in the next step without any further
purification.
(d, J¼14.4 Hz, 1H, CHI]CH), 3.94 (dq, J¼6.2, 3.6 Hz, 1H,
CHOSi), 1.95 (ddt, J¼9.8, 6.1, 3.8 Hz, 1H, CHCH2), 1.54e
1.64 (m, 1H, CHAHBCH3), 1.29e1.40 (m, 1H, CHBHACH3),
1.11 (d, J¼6.2 Hz, 3H, CH3CH), 1.06 (s, 21H, 3ꢀCH(CH3)2),
0.86 (t, J¼7.4 Hz, 3H, CH3CH2); 13C NMR (100 MHz,
CDCl3): d¼147.5 (CH), 75.3 (CH), 70.6 (CH), 56.8 (CH),
22.4 (CH2), 21.1 (CH3), 18.2 (3ꢀCH(CH3)2), 12.7 (CH3); IR
(thin film): 2961, 2943, 2866, 1463, 1155, 1131, 1108, 1054,
998, 951, 882, 677 cmꢂ1
353.0798, found: 353.0807.
;
HRMS [Mþꢂi-Pr] calcd:
A solution of TMSCHN2 (2.0 M in Et2O, 5.80 mL,
11.60 mmol) was diluted with 20 mL Et2O at ꢂ78 ꢁC. A solu-
tion of n-BuLi (2.5 M in hexane, 4.70 mL, 11.75 mmol) was
added dropwise over a period of 10 min and stirring was contin-
ued for 3 h. A solution of crude aldehyde (calcd as 9.36 mmol) in
5 mL THF was added dropwise. The reaction mixture was first
stirred at ꢂ78 ꢁC for 30 min and then at 0 ꢁC overnight. The
reaction was quenched with 20 mL of a saturated solution of
NH4Cl. The organic phase was separated and the aqueous phase
was extracted with hexane/Et2O (1:1). The combined organic
phases were dried over MgSO4, filtered and concentrated under
reduced pressure. Purification with flash column chromatogra-
phy (hexane) gave alkyne 41 (1.46 g, 58% over two steps) as
a colourless liquid. Rf¼0.63 (hexane); [a]2D0 þ13.3 (c 1.04,
6.2.17. (3E,5E,11E,13E)-(7S,8S,15S,16S)-8,16-Bis-[(E)-
(1R,2S,3R,7S,8R)-2-(tert-butyldimethylsilanyloxy)-7-ethyl-
4-hydroxy-1,3-dimethyl-8-triisopropylsilanyloxynon-5-
enyl]-7,15-dimethyl-1,9-dioxacyclohexadeca-3,5,11,13-
tetraene-2,10-dione (45) and (3E,5E,11E,13E)-
(7S,8S,15S,16S)-8,16-bis-[(E)-(1R,2R,3S,7S,8R)-2-(tert-
butyldimethylsilanyloxy)-7-ethyl-1,3-dimethyl-4-oxo-8-
triisopropylsilanyloxynon-5-enyl]-7,15-dimethyl-1,9-
dioxacyclohexadeca-3,5,11,13-tetraene-2,10-dione (47)
t-BuLi (1.7 M in pentane, 0.54 mL, 0.918 mmol) was added
dropwise to a stirred solution of vinyliodide 42 (180 mg,
0.454 mmol) in 4.5 mL Et2O at ꢂ78 ꢁC. The reaction mixture
was stirred at ꢂ78 ꢁC for 20 min and at 0 ꢁC for 10 min before
being re-cooled to ꢂ78 ꢁC. A solution of bis-aldehyde 38
(128 mg, 0.175 mmol) in 6.0 mL Et2O was added dropwise
and the reaction mixture was stirred at ꢂ78 ꢁC for 20 min
and at 0 ꢁC for 20 min. The reaction was quenched with
5.0 mL of a saturated solution of NH4Cl. The organic layer
was separated and the aqueous layer was extracted four times
with Et2O. The combined organic layers were dried over
MgSO4, filtered and concentrated under reduced pressure.
Purification by flash column chromatography (hexane/ethyl
acetate, 10:1) gave bis-allylic alcohol 45 (198 mg, 89%) as
an inseparable mixture of diastereomers (dr¼2:1:1); Rf¼0.27
(hexane/ethyl acetate, 10:1).
1
CH2Cl2); H NMR (400 MHz, CDCl3): d¼4.12 (dq, J¼6.2,
3.9 Hz, 1H, CHOSi), 2.38 (ddt, J¼10.5, 3.8, 2.5 Hz, 1H,
CHCH2), 2.06 (d, J¼2.5 Hz, 1H, HCC), 1.75 (ddq, J¼13.0,
7.4, 3.8 Hz, 1H, CHAHBCH3), 1.36e1.47 (m, 1H, CHBHACH3),
1.23 (d, J¼6.2 Hz, 3H, CH3CH), 1.06 (s, 21H, 3ꢀCH(CH3)2),
1.04 (t, J¼7.4 Hz, 3H, CH3CH2); 13C NMR (100 MHz,
CDCl3): d¼85.7 (C), 70.4 (CH), 70.0 (CH), 41.9 (CH), 21.3
(CH2), 19.5 (CH3), 18.1 (3ꢀCH(CH3)2), 12.5 (CH3); IR (thin
film): 3314, 2964, 2944, 2892, 2868, 1464, 1109, 998, 883,
680, 636 cmꢂ1; HRMS [Mþꢂi-Pr] calcd: 225.1675, found:
225.1670.
6.2.16. [(E)-(1R,2S)-2-Ethyl-4-iodo-1-methylbut-3-
enyloxy]-triisopropylsilane (42)
DesseMartin periodinane (362 mg, 0.854 mmol) was added
in one portion to a stirred solution of the diastereomeric mixture
of bis-allylic alcohol 45 (198 mg, 0.155 mmol) in 10 mL
CH2Cl2 at 0 ꢁC. The reaction mixture was stirred at room
temperature for 6 h before being quenched with 4 mL of
a 1.0 M solution of Na2S3O3 and 10 mL of a saturated solution
of NaHCO3. The organic layer was separated and the aqueous
layer was extracted three times with CH2Cl2. The combined or-
ganic layerswere dried over MgSO4, filtered and concentrated in
vacuo. Purification by flash column chromatography (hexane/
ethyl acetate, 15:1) gave bis-enone 47 (162 mg, 82%) as a highly
viscous gum. Rf¼0.20 (hexane/ethyl acetate, 15:1); [a]2D0 þ96.6
Cp2ZrCl2 (1.04 g, 3.56 mmol) was dissolved in 10 mL THF
at 0 ꢁC. A solution of DIBAL-H (2.30 mL, 3.45 mmol) was
added dropwise and the resulting suspension was stirred for
1 h at 0 ꢁC. The supernatant liquid was removed with a syringe.
The remaining white solid was washed with 5 mL THF and
taken up in 10 mL THF. A solution of alkyne 41 (795 mg,
2.961 mmol) in 5 mL THF was added to the stirred suspension
of Schwartz reagent resulting in a homogenous orange solu-
tion after stirring for 1 h at room temperature. A solution of
I2 (960 mg, 3.782 mmol) in 5 mL THF was added dropwise
and stirring was continued for 5 min. The reaction was
quenched with 6 mL of a 1.0 M solution of Na2S2O3. Hexane
(10 mL) was added and the organic phase was separated. The
aqueous phase was extracted two times with hexane. The com-
bined organic phases were dried over MgSO4, filtered and con-
centrated under reduced pressure. Purification of the crude
product by flash column chromatography (hexane) gave
(E)-vinyliodide 42 (776 mg, 66%) as colourless oil. Rf¼0.78
1
(c 0.65, CH2Cl2); H NMR (600 MHz, CDCl3): d¼6.90 (dd,
J¼15.3, 11.2 Hz, 2H, C3eH), 6.79 (dd, J¼15.9, 9.4 Hz, 2H,
C13eH), 6.16 (d, J¼15.9 Hz, 2H, C12eH), 5.97 (dd, J¼15.0,
11.2 Hz, 2H, C4eH), 5.57 (d, J¼15.3 Hz, 2H, C2eH), 5.56
(dd, J¼15.1, 11.3 Hz, 2H, C5eH), 4.96 (d, J¼10.0 Hz, 2H,
C7eH), 4.03 (m, 4H, C9eH, C15eH), 3.11 (m, 2H, C10eH),
2.38 (m, 2H, C6eH), 2.12 (m, 2H, C14eH), 1.96 (m, 2H, C8eH),
1.74 (m, 2H, C14eCHAHB), 1.45 (m, 2H, C14eCHBHA), 1.12 (d,
J¼7.0 Hz, 6H, C10eCH3), 1.10 (d, J¼6.3 Hz, C15eCH3), 1.06
(hexane); [a]2D0 þ3.7 (c 1.84, CH2Cl2); H NMR (400 MHz,
1
CDCl3): d¼6.38 (dd, J¼14.4, 9.7 Hz, 1H, CH]CHI), 5.97

R. Barth, J. Mulzer / Tetrahedron 64 (2008) 4718e4735
4731
(s, 42H, 6ꢀi-Pr), 1.03 (d, J¼7.2 Hz, 6H, C8eCH3), 0.95 (d,
J¼6.6 Hz, 6H, C6eCH3), 0.86 (s, 18H, 2ꢀt-Bu), 0.86 (t, J¼
7.3 Hz, 6H, C14eCH2CH3), 0.09 (s, 6H, 2ꢀCH3Si), ꢂ0.02
(s, 6H, 2ꢀCH3Si); 13C NMR (151 MHz, CDCl3): d¼202.4
(C), 167.3 (C), 148.7 (CH), 145.0 (CH), 144.1 (CH), 131.0 (CH),
130.8 (CH), 121.6 (CH), 76.0 (CH), 75.9 (CH), 70.9 (CH),
53.1 (CH), 47.3 (CH), 42.4 (CH), 37.8 (CH), 26.2 (3ꢀCH3),
22.2 (CH2), 21.0 (CH3), 18.4 (C), 18.2 (6ꢀCH3), 16.1 (CH3),
13.1 (CH3), 12.6 (3ꢀCH), 12.5 (CH3), 10.9 (CH3), ꢂ3.7
(CH3), ꢂ3.9 (CH3); IR (thin film): 2963, 2951, 2944, 2867,
1717, 1109, 1085, 1056, 998 cmꢂ1; HRMS [MNaþ] calcd:
1291.8779, found: 1291.8795.
period. The reaction was quenched by the addition of 20 mL
of a saturated solution of NaHCO3. The organic layer was sep-
arated and the aqueous layer was extracted three times with
CH2Cl2. The combined organic phases were dried over
MgSO4, filtered and concentrated under reduced pressure. Pu-
rification by flash column chromatography (hexane/ethyl ace-
tate, 7:1) gave the MOM-ether (780 mg, 83% over two steps)
as a colourless oil. Rf¼0.36 (hexane/ethyl acetate, 5:1); [a]D20
þ20.3 (c 1.18, CHCl3); 1H NMR (400 MHz, CDCl3):
d¼7.66 (m, 4H, Harom), 7.32e7.43 (series of m, 8H, Harom),
6.85 (m, 2H, Harom), 5.46 (s, 1H, OCHO), 4.70, 4.62 (AB sys-
tem, J¼5.9 Hz, 1H, OCH2O), 4.14 (dd, J¼11.1, 4.6 Hz, 1H,
CHAHBO), 3.95 (dd, J¼10.1, 1.3 Hz, 1H, CHO), 3.81 (part
A of dd, J¼1.8 Hz, 0.5H, CHO), 3.79 (s, 3.5H, part B of dd,
OCH3), 3.64 (dd, J¼9.9, 8.9 Hz, 1H, CHAHBOSi), 3.54 (dd,
J¼9.9, 5.1 Hz, 1H, CHBHAOSi), 3.52 (d, J¼10.6 Hz, 1H,
CHBHAO), 3.28 (s, 3H, OCH3), 2.10 (m, 1H, CHCH3),
1.86e1.98 (m, 2H, 2ꢀCHCH3), 1.03 (s, 9H, t-Bu), 0.90 (d,
J¼7.0 Hz, 3H, CH3CH), 0.78 (d, J¼7.1 Hz, 3H, CH3CH),
0.76 (d, J¼7.0 Hz, 3H, CH3CH); 13C NMR (100 MHz,
CDCl3): d¼159.6 (C), 135.6 (CH), 135.6 (CH), 133.9 (C),
129.5 (CH), 127.6 (CH), 127.2 (CH), 113.5 (CH), 100.6
(CH), 99.0 (CH2), 81.5 (CH), 79.2 (CH), 73.4 (CH2), 66.4
(CH2), 55.9 (CH3), 55.3 (CH3), 37.2 (CH), 36.2 (CH), 30.5
(CH), 26.8 (t-Bu), 19.2 (C), 12.0 (CH3), 10.0 (CH3), 9.1
(CH3); IR (thin film): 2959, 2931, 2857, 1616, 1518, 1462,
1428, 1385, 1250, 1171, 1157, 1113, 1092, 1039, 972, 825,
703 cmꢂ1; HRMS [MþꢂMeOH] calcd: 549.2672, found:
549.2665.
6.2.18. Efomycine M (1)
Bis-enone 47 (57 mg, 44.8 mmol) was dissolved in 2.0 mL of
THF and 3.0 mL of MeCN in a polyethylene vessel and the so-
lution was cooled to 0 ꢁC. HF$pyridine complex (70%,
0.15 mL, 5.77 mmol) was added dropwise and the reaction mix-
ture was allowed to warm up to room temperature. Stirring was
continued for 72 h. The reaction was quenched by the addition
of 0.5 mL of a saturated solution of NaHCO3 and one spatula
of solid NaHCO3. The precipitate was filtered off over Celite
and washed excessively with CH2Cl2. The crude product was
concentrated in vacuo. Purification by flash column chromatog-
raphy (hexane/ethyl acetate, 1:6) gave 23 mg (70%) efomycine
M (1) as a colourless solid. Rf¼0.33 (ethyl acetate); [a]D20
1
þ104.3 (c 1.1, MeOH); H NMR (600 MHz, CDCl3, 7 mg):
d¼6.95 (dd, J¼15.3, 11.2 Hz, 2H, C3eH), 6.72 (dd, J¼15.8,
9.6 Hz, 2H, C13eH), 6.23 (d, J¼15.8 Hz, 2H, C12eH), 6.04
(dd, J¼15.0, 11.2 Hz, 2H, C4eH), 5.64 (dd, J¼15.0, 9.8 Hz,
2H, C5eH), 5.60 (d, J¼15.5 Hz, 2H, C2eH), 5.08 (dd, J¼
10.3, 1.6 Hz, 2H, C7eH), 3.81 (m, 2H, C15eH), 3.74 (br dd,
J¼9.3, 2.6 Hz, 2H, C9eH), 3.31 (br s, 2H, C9eOH), 2.89 (dq,
J¼7.1, 2.7 Hz, 2H, C10eH), 2.48 (tq, J¼10.0, 6.6 Hz, 2H,
C6eH), 2.03 (m, 2H, C14eH), 1.94 (m, 2H, C8eH), 1.61 (m,
2H, C14eCHAHB), 1.42 (br m, 2H, C14eCHBHA), 1.17 (d,
J¼6.3 Hz, 6H, C15eCH3), 1.16 (d, J¼7.1 Hz, 6H, C10eCH3),
1.03 (d, J¼6.7 Hz, 6H, C6eCH3), 0.92 (d, J¼7.0 Hz, 6H,
C8eCH3), 0.86 (t, J¼7.4 Hz, 6H, C14eCH2CH3); 13C NMR
(151 MHz, CDCl3): d¼203.2 (C), 168.4 (C), 147.6 (CH),
145.2 (CH), 144.5 (CH), 131.3 (CH), 131.0 (CH), 121.1 (CH),
76.6 (CH), 71.5 (CH), 69.5 (CH), 52.4 (CH), 45.5 (CH), 41.5
(CH), 36.0 (CH), 23.5 (CH2), 21.3 (CH3), 15.3 (CH3), 11.9
(CH3), 9.3 (CH3), 9.2 (CH3); IR (thin film): 3470 (br), 2963,
1703, 1699, 1695, 1683, 1652, 1634, 1222, 1183, 1145,
997 cmꢂ1; HRMS [MNaþ] calcd: 751.4397, found: 751.4374.
6.3.2. (2S,3S,4R,5S,6R)-7-tert-Butyldiphenylsilanoxy-
3-(4-methoxybenzyloxy)-5-methoxymethoxy-2,4,6-
trimethylheptan-1-ol (17)
DIBAL-H (1.5 M in toluene, 11.5 mL, 17.25 mmol) was
added within 5 min to a stirred solution of the PMP-acetal
(3.33 g, 5.49 mmol) in 65 mL CH2Cl2 at ꢂ5 ꢁC. The reaction
mixture was stirred at 0 ꢁC for 50 min and then quenched by
the addition of 40 mL of a saturated solution of Na/K/tartrate.
The organic phase was separated and extracted three times
with CH2Cl2. The combined organic layers were dried over
MgSO4, filtered and concentrated under reduced pressure. Pu-
rification by flash column chromatography (hexane/ethyl ace-
tate, 3:1) gave alcohol 17 (3.15 g, 94%) as a colourless oil.
Rf¼0.27 (hexane/ethyl acetate, 3:1); [a]2D0 þ5.7 (c 1.62,
CHCl3); 1H NMR (400 MHz, CDCl3): d¼7.67 (m, 4H, Harom),
7.35e7.45 (series of m, 6H, Harom), 7.28 (m, 2H, Harom), 6.85
(m, 2H, Harom), 4.85, 4.65 (AB system, J¼6.4 Hz, 2H,
OCH2O), 4.74, 4.60 (AB system, J¼10.6 Hz, 2H, OCH2Ar),
3.96 (dd, J¼9.5, 1.5 Hz, 1H, CHO), 3.84 (dd, J¼7.9, 1.5 Hz,
1H, CHO), 3.78 (s, 3H, OCH3), 3.67 (dd, J¼11.1, 7.2 Hz,
1H, CHO), 3.62 (dd, J¼11.0, 3.5 Hz, 1H, CHO), 3.55 (m,
2H, 2ꢀCHO), 3.39 (s, 3H, OCH3), 3.02 (br s, 1H, OH),
1.91e1.97 (series of m, 2H, 2ꢀCHCH3), 1.82 (m, 1H,
CHCH3), 1.06 (s, 9H, t-Bu), 0.93 (2ꢀdwt, J¼7.4 Hz, 6H,
2ꢀCH3), 0.75 (d, J¼6.9 Hz, 3H, CH3); 13C NMR (100 MHz,
CDCl3): d¼159.1 (C), 135.5 (CH), 133.6 (C), 133.6 (C),
130.9 (C), 129.6 (CH), 129.2 (CH), 127.7 (CH), 113.8 (CH),
6.3. Formal total synthesis of elaiolide (3)
6.3.1. tert-Butyl-(2R,3S,4S)-3-methoxymethoxy-4-
(2S,4S,5S)-4-methoxyphenyl-5-methyl-[1,3]-dioxan-
4-yl-2-methylpentyloxydiphenylsilane
DIPEA (1.62 mL, 9.30 mmol) and MOMCl (0.71 mL,
9.35 mmol) were added to a stirred solution of crude alcohol
16 (1.023 g, calcd as 1.55 mmol) in 10 mL CH2Cl2 at 0 ꢁC.
The reaction mixture was stirred for 36 h and the temperature
was allowed to warm up to room temperature during that

4732
R. Barth, J. Mulzer / Tetrahedron 64 (2008) 4718e4735
98.3 (CH2), 83.5 (CH), 81.3 (CH), 74.2 (CH2), 66.8 (CH2),
66.1 (CH2), 55.7 (CH3), 55.2 (CH3), 39.0 (CH), 38.9 (CH),
37.4 (CH), 26.9 (t-Bu), 19.2 (C), 14.9 (CH3), 10.9 (CH3),
9.1 (CH3); IR (thin film): 3488 (br), 2931, 1514, 1472,
1428, 1248, 1141, 1112, 1085, 1035, 823 cmꢂ1; HRMS
[Mþꢂt-Bu] calcd: 551.2829, found: 551.2818.
the aqueous phase was extracted three times with Et2O. The
combined organic layers were dried over MgSO4, filtered
and concentrated in vacuo. Purification by flash column chro-
matography gave diene 21 (2.86 g, 96%, E/Z >50:1) as
a highly viscous oil. Rf¼0.55 (hexane/ethyl acetate, 3:1);
1
[a]2D0 ꢂ38.6 (c 1.32, CH2Cl2); H NMR (400 MHz, CDCl3):
d¼7.64e7.69 (m, 4H, Harom), 7.34e7.45 (m, 6H, Harom),
7.26e7.33 (m, 1H, C3eH), 7.22 (m, 2H, Harom), 6.82 (m,
6.3.3. (2R,3R,4R,5S,6R)-7-(tert-Butyldiphenylsilanyloxy)-3-
(4-methoxybenzyloxy)-5-methoxymethoxy-2,4,6-
2H,
Harom), 6.23 (m, 2H, C4eH, C5eH), 5.80 (d,
trimethylheptanal (19) and (2E,4E)-(6S,7S,8R,9S,10R)-11-
(tert-butyldiphenylsilanyloxy)-7-(4-methoxybenzyloxy)-9-
methoxymethoxy-6,8,10-trimethylundeca-2,4-dienoic acid
methyl ester (21)
J¼15.3 Hz, 1H, C2eH), 4.77, 4.62 (AB system, J¼6.4 Hz,
2H, C9eOCH2), 4.57, 4.51 (AB system, J¼10.7 Hz, 2H,
C7eOCH2), 3.91 (dd, J¼8.7, 1.5 Hz, 1H, C9eH), 3.78 (s,
3H, OCH3), 3.75 (s, 3H, OCH3), 3.65 (dd, J¼6.7, 2.5 Hz,
1H, C7eH), 3.57 (t, J¼9.7 Hz, 1H, C11eHA), 3.51 (dd,
J¼10.1, 5.9 Hz, 1H, C11eHB), 3.35 (s, 3H, OCH3), 2.60
(ddqwtq, J¼10.1, 6.8 Hz, 1H, C6eH), 1.92 (m, 1H,
C10eH), 1.84 (m, 1H, C8eH), 1.07 (d, J¼6.8 Hz, 3H, C6e
CH3), 1.06 (s, 9H, t-Bu), 0.91 (d, J¼7.0 Hz, 3H, C8eCH3),
0.76 (d, J¼6.9 Hz, 3H, C10eCH3); 13C NMR (100 MHz,
CDCl3): d¼167.7 (C), 158.9 (C), 147.1 (CH), 145.4 (CH),
135.6 (CH), 135.5 (CH), 133.7 (C), 133.7 (C), 131.3 (C),
129.6 (CH), 128.9 (CH), 127.9 (CH), 127.7 (CH), 119.0
(CH), 113.7 (CH), 98.4 (CH2), 82.3 (CH), 80.5 (CH), 73.7
(CH2), 66.4 (CH2), 55.6 (CH3), 55.2 (CH3), 51.4 (CH3), 41.6
(CH), 38.9 (CH), 37.2 (CH), 26.9 (t-Bu), 19.2 (C), 17.5
(CH3), 10.9 (CH3), 9.6 (CH3); IR (thin film): 2931, 1718,
1642, 1614, 1514, 1429, 1302, 1248, 1143, 1112, 1035, 824,
741, 703 cmꢂ1; HRMS [MþꢂMeOH] calcd: 656.3533, found:
656.3526.
DesseMartin periodinane (6.67 g, 15.73 mmol) was added
in one portion to a stirred solution of alcohol 17 (3.012 g,
4.947 mmol) in 40 mL CH2Cl2 at 0 ꢁC. The reaction mixture
was stirred for 30 min at 0 ꢁC and for 6 h at room temperature.
The reaction was quenched with 40 mL of a 1.0 M solution of
Na2S2O3 and 20 mL of a saturated solution of NaHCO3. Solid
NaHCO3 was added in small portions until two clear phases
were obtained. The organic phase was separated and the aque-
ous phase was extracted three times with CH2Cl2. The com-
bined organic phases were dried over MgSO4, filtered and
concentrated under reduced pressure. Purification by flash
column chromatography (hexane/ethyl acetate, 4:1) gave alde-
hyde 19 (2.629 g, 88%) as a colourless oil. The product was
used in the next step immediately. 1H NMR (400 MHz,
CDCl3): d¼9.83 (d, J¼2.7 Hz, 1H, HCO), 7.65 (m, 4H,
Harom), 7.34e7.45 (series of m, 6H, Harom), 7.21 (m, 2H,
Harom), 6.82 (m, 2H, Harom), 4.84, 4.64 (AB system,
J¼6.4 Hz, 2H, OCH2O), 4.64, 4.49 (AB system, J¼10.7 Hz,
2H, OCH2O), 4.12 (dd, J¼8.0, 1.6 Hz, 1H, CHO), 3.99 (dd,
J¼9.5, 1.7 Hz, 1H, CHO), 3.78 (s, 3H, OCH3), 3.55 (m, 2H,
CHAHBOSi), 3.38 (s, 3H, OCH3), 2.72 (ddq, J¼9.7, 7.0,
2.7 Hz, 1H, CHCH3), 1.92 (m, 1H, CHCH3), 1.79 (m, 1H,
CHCH3), 1.07 (d, J¼7.0 Hz, 3H, CH3CH), 1.04 (s, 9H,
t-Bu), 0.93 (d, J¼7.1 Hz, 3H, CH3CH), 0.73 (d, J¼6.9 Hz,
3H, CH3CH); 13C NMR (100 MHz, CDCl3): d¼204.9 (CH),
159.0 (C), 135.6 (CH), 135.5 (CH), 133.7 (C), 133.7 (C),
130.9 (C), 129.7 (CH), 128.9 (CH), 127.7 (CH), 113.7 (CH),
98.7 (CH2), 80.8 (CH), 79.7 (CH), 73.4 (CH2), 66.0 (CH2),
55.7 (CH3), 55.2 (CH3), 50.3 (CH), 38.8 (CH), 37.4 (CH),
26.9 (t-Bu), 19.2 (C), 11.8 (CH3), 10.5 (CH3), 9.1 (CH3).
A solution of LDA was prepared by the addition of n-BuLi
(2.5 M in hexane, 2.80 mL, 7.0 mmol) to a solution of DIPA
(1.0 mL, 7.12 mmol) in 10 mL THF at 0 ꢁC and stirred for
25 min. A solution of phosphonate 10 (1.7 g, 7.20 mmol) in
45 mL THF was cooled to ꢂ78 ꢁC and the freshly prepared so-
lution of LDA was added dropwise. The reaction mixture was
stirred for 3.5 h and the temperature was allowed to warm up
to ꢂ20 ꢁC during that period. The reaction mixture was re-
cooled to ꢂ78 ꢁC and a solution of aldehyde 19 (2.629 g,
4.332 mmol) in 15 mL THF was added dropwise within
5 min. The reaction mixture was stirred overnight and the tem-
perature was allowed to warm up to room temperature during
that period. The reaction was quenched with 30 mL of a satu-
rated solution of NH4Cl. The organic layer was separated and
6.3.4. (2E,4E)-(6S,7S,8R,9S,10R)-11-(tert-Butyldiphenyl-
silanyloxy)-7-hydroxy-9-methoxymethoxy-6,8,10-trimethyl-
undeca-2,4-dienoic acid methyl ester (23)
DDQ (320 mg, 1.497 mmol) was added in small portions
over a period of 3 h to a vigorously stirred solution of PMB-
ether 21 (520 mg, 0.755 mmol) in 15 mL CH2Cl2 and 10 mL
of a 0.5 M pH 7 phosphate buffer at room temperature. The re-
action mixture was then stirred overnight. The reaction was
quenched with 10 mL of a saturated solution of NaHCO3
and diluted with 20 mL CH2Cl2 and 20 mL H2O. Solid
NaHCO3 was added in small portions until two homogenous
phases were obtained. The organic phase was separated and
the aqueous phase was extracted four times with CH2Cl2.
The combined organic layers were dried over MgSO4, filtered
and concentrated in vacuo. Purification by flash column chro-
matography (hexane/ethyl acetate, 7:1) gave seco-ester 23
(398 mg, 91%) as a highly viscous oil. Rf¼0.45 (hexane/ethyl
acetate, 3:1); [a]D20 þ2.3 (c 1.00, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d¼7.64 (m, 4H, Harom), 7.35e7.45 (m, 6H, Harom),
7.28e7.34 (m, 1H, C3eH), 6.20e6.29 (m, 2H, C4eH, C5eH),
5.81 (d, J¼15.3 Hz, 1H, C2eH), 4.77, 4.61 (AB system,
J¼6.2 Hz, 2H, C9eOCH2O), 3.82 (dd, J¼8.5, 2.9 Hz, 1H,
C9eH), 3.73 (s, 3H, OCH3), 3.69 (m, 1H, C7eH), 3.53 (br
d, J¼7.1 Hz, 2H, C11eHAHB), 3.41 (br d, J¼3.0 Hz, 1H,
C7eOH), 3.37 (s, 3H, OCH3), 2.42 (m, 1H, C6eH), 1.91 (m,
1H, C10eH), 1.80 (m, 1H, C8eH), 1.05 (s, 9H, t-Bu), 0.92 (d,
J¼6.9 Hz, 3H, C6eCH3), 0.85 (d, J¼6.9 Hz, 3H, C8eCH3),

R. Barth, J. Mulzer / Tetrahedron 64 (2008) 4718e4735
4733
0.79 (d, J¼6.9 Hz, 3H, C10eCH3); 13C NMR (100 MHz,
CDCl3): d¼167.7 (C), 149.0 (CH), 145.5 (CH), 135.6
(CH), 135.5 (CH), 133.6 (C), 133.6 (C), 129.7 (CH), 129.7
(CH), 127.7 (CH), 118.9 (CH), 99.0 (CH2), 81.6 (CH),
73.0 (CH), 65.9 (CH2), 56.2 (CH3), 51.4 (CH3), 40.3 (CH),
37.5 (CH), 36.3 (CH), 26.9 (t-Bu), 19.2 (C), 16.2 (CH3),
10.2 (CH3), 9.4 (CH3); IR (thin film): 3503, 2962, 2931,
2858, 1718, 1642, 1429, 1262, 1142, 1112, 1090, 1028,
1005, 824, 741 cmꢂ1; HRMS [Mþꢂt-Bu] calcd: 479.2254,
found:479.2243.
was separated and the aqueous phase was extracted three times
with CH2Cl2. The combined organic layers were dried over
MgSO4, filtered and concentrated in vacuo. Purification by
flash column chromatography (hexane/ethyl acetate, 5:1)
gave macrodiolide 35 (130 mg, 47%) as a highly viscous oil.
It should be mentioned that an up-scaling of the reaction
was accompanied with a decrease of the yield. Rf¼0.32 (hex-
ane/ethyl acetate, 2:1); [a]2D0 þ29.0 (c 1.07, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d¼7.66 (m, 8H, Harom), 7.34e7.43 (m,
12H, Harom), 6.96 (dd, J¼15.3, 11.2 Hz, 2H, C3eH), 6.03
(dd, J¼15.0, 11.2 Hz, 2H, C4eH), 5.70 (dd, J¼15.0, 9.9 Hz,
2H, C5eH), 5.57 (d, J¼15.4 Hz, 2H, C2eH), 5.08 (d,
J¼10.3 Hz, 2H, C7eH), 4.72, 4.57 (AB system, J¼6.3 Hz,
4H, C9eOCH2), 3.72 (dd, J¼9.9, 8.6 Hz, 2H, C11eHA),
3.54 (m, 4H, C9eH, C11eHB), 3.28 (s, 6H, C9eOCH3), 2.50
(ddq, J¼10.2, 9.9, 6.3 Hz, 2H, C6eH), 1.98 (m, 2H, C8eH),
1.89 (m, 2H, C10eH), 1.05 (d, J¼6.6 Hz, 6H, C6eCH3),
1.03 (s, 18H, t-Bu), 0.91 (d, J¼7.0 Hz, 6H, C8eCH3), 0.83
(d, J¼6.9 Hz, 6H, C10eCH3); 13C NMR (100 MHz, CDCl3):
d¼167.7 (C), 145.5 (CH), 144.8 (CH), 135.6 (CH), 135.6
(CH), 134.1 (C), 134.0 (C), 130.7 (CH), 129.5 (2ꢀCH),
127.6 (2ꢀCH), 121.2 (CH), 99.6 (CH2), 80.4 (CH), 76.3
(CH), 66.4 (CH2), 55.8 (CH3), 42.1 (CH), 37.5 (CH), 36.3
(CH), 26.8 (t-Bu), 19.2 (C), 16.0 (CH3), 10.2 (CH3), 9.6
(CH3); IR (thin film): 2964, 2931, 1715, 1221, 1140, 1112,
1034, 999, 877, 744, 702 cmꢂ1; HRMS [MNaþ] calcd:
1095.5814, found: 1095.5821.
6.3.5. (2E,4E)-(6S,7S,8R,9S,10R)-11-(tert-Butyldiphenyl-
silanyloxy)-7-hydroxy-9-methoxymethoxy-6,8,10-trimethyl-
undeca-2,4-dienoic acid (25)
A solution of LiOH$H2O (99 mg, 2.359 mmol) in 4.8 mL
H2O was added to a stirred solution of methyl ester 23
(480 mg, 0.844 mmol) in 7.0 mLTHFat 0 ꢁC. The reaction mix-
ture was allowed to warm up to room temperature and was
stirred for 24 h. The reaction was quenched by the addition of
AcOH (0.30 mL, 5.20 mmol) at 0 ꢁC. The organic layer was
separated and the aqueous layer was extracted four times with
CH2Cl2. The combined organic layers were dried over
MgSO4, filtered and concentrated in vacuo. Purification by flash
column chromatography (hexane/ethyl acetate, 2:1) gave seco-
acid 25 (455 mg, 97%) as a slightly yellow, highly viscous gum.
Rf¼0.22 (hexane/ethyl acetate, 2:1); [a]2D0 þ2.8 (c 1.02,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d¼7.64 (m, 4H, Harom),
7.35e7.46 (m, 7H, Harom, C3eH), 6.23e6.33 (m, 2H, C4eH,
C5eH), 5.80 (d, J¼15.3 Hz, 1H, C2eH), 4.77, 4.61 (AB system,
J¼6.2 Hz, 2H, C9eOCH2O), 3.82 (dd, J¼8.5, 2.9 Hz, 1H,
C9eH), 3.71 (3.71, dd, J¼9.6, 1.7 Hz, 1H, C7eH), 3.53 (br d,
J¼7.1 Hz, 2H, C11eHAHB), 3.38 (s, 3H, OCH3), 2.45 (m, 1H,
C6eH), 1.92 (m, 1H, C10eH), 1.81 (m, 1H, C8eH), 1.06 (s,
9H, t-Bu), 0.93 (d, J¼6.8 Hz, 3H, C6eCH3), 0.86 (d,
J¼6.9 Hz, 3H, C8eCH3), 0.79 (d, J¼6.9 Hz, C10eCH3); 13C
NMR (100 MHz, CDCl3): d¼172.0 (C), 150.1 (CH), 147.6
(CH), 135.6 (CH), 135.5 (CH), 133.6 (C), 133.6 (C), 129.7
(CH), 129.7 (CH), 127.7 (CH), 127.7 (CH), 118.5 (CH), 99.0
(CH2), 81.7 (CH), 73.1 (CH), 65.9 (CH2), 56.2 (CH3), 40.3
(CH), 37.5 (CH), 36.3 (CH), 26.9 (t-Bu), 19.2 (C), 16.2 (CH3),
10.2 (CH3), 9.4 (CH3); IR (thin film): 3480, 2962, 2931, 2858,
6.3.7. (3E,5E,11E,13E)-(7S,8S,15S,16S)-8,16-Bis-
((1S,2S,3R)-4-hydroxy-2-methoxymethoxy-1,3-
dimethylbutyl)-7,15-dimethyl-1,9-dioxacyclohexadeca-
3,5,11,13-tetraene-2,10-dione
A solution of TBAF (1.0 M in THF, 0.50 mL, 0.50 mmol)
was added to a stirred solution of bis-TBDPS ether 35
(122 mg, 1.136 mmol) in 4 mL THF at 0 ꢁC. The reaction mix-
ture was stirred for 3 days and the temperature was allowed to
warm up to room temperature during that period. The reaction
was quenched by the addition of 5 mL of a saturated solution
of NH4Cl and diluted with Et2O. The organic phase was sep-
arated and the aqueous phase was extracted four times with
EtOAc. The combined organic layers were dried over
MgSO4, filtered and concentrated in vacuo. Purification by
flash column chromatography (hexane/ethyl acetate, 1:1.25)
gave the bis-diol (64 mg, 94%) as white needles. Rf¼0.14
1688, 1112, 1027, 702 cmꢂ1
577.2961, found: 577.2951.
;
HRMS [MNaþ] calcd:
1
6.3.6. (3E,5E,11E,13E)-(7S,8S,15S,16S)-8,16-Bis-
[(1S,2S,3R)-4-(tert-butyldiphenylsilanyloxy)-2-
(hexane/ethyl acetate, 1:1); [a]2D0 þ27.5 (c 0.49, CH2Cl2); H
NMR (400 MHz, CDCl3): d¼6.91 (dd, J¼15.2, 11.2 Hz, 2H,
C3eH), 6.02 (dd, J¼15.0, 11.2 Hz, 2H, C4eH), 5.68 (dd,
J¼15.0, 9.9 Hz, 2H, C5eH), 5.60 (d, J¼15.4 Hz, 2H, C2eH),
4.97 (d, J¼10.2 Hz, 2H, C7eH), 4.72 (s, 4H, C9eOCH2),
3.47e3.54 (m, 6H, C9eH, C11eH), 3.42 (s, 6H, C9eOCH3),
2.51 (ddq, J¼10.1, 9.9, 6.6 Hz, 2H, C6eH), 1.86e2.01 (m,
4H, C8eH, C10eH), 1.05 (d, J¼6.6 Hz, 6H, C6eCH3), 0.91
(d, J¼7.0 Hz, 6H, C8eCH3), 0.78 (d, J¼6.9 Hz, 6H,
C10eCH3), OH unidentified; 13C NMR (100 MHz, CDCl3):
d¼168.0 (C), 145.6 (CH), 144.8 (CH), 130.8 (CH), 121.4
(CH), 100.1 (CH2), 80.9 (CH), 76.2 (CH), 64.5 (CH2), 56.4
(CH3), 42.1 (CH), 36.6 (CH), 36.3 (CH), 16.0 (CH3), 9.8
methoxymethoxy-1,3-dimethylbutyl]-7,15-dimethyl-1,9-
dioxacyclohexadeca-3,5,11,13-tetraene-2,10-dione (35)
NEt3 (0.21 g, 1.507 mmol) and 2,4,6-trichlorobenzoyl-
chloride (120 mL, 0.768 mmol) were added to a stirred solu-
tion of seco-acid 25 (290 mg, 0.523 mmol) in 18 mL toluene
at room temperature. The reaction mixture was stirred for
2.5 h. A solution of 4-dimethylaminopyridine (300 mg,
2.456 mmol) in 4 mL toluene was added over a period of
3 h with a syringe pump and the reaction mixture was stirred
overnight. The reaction was quenched by the addition of
12 mL of a 1.0 M solution of KHSO4. The organic phase

4734
R. Barth, J. Mulzer / Tetrahedron 64 (2008) 4718e4735
(CH3), 9.0 (CH3); IR (thin film): 3401 (br), 2930, 1710, 1653,
1636, 1617, 1458, 1387, 1303, 1280, 1221, 1138, 1108, 1033,
999, 878 cmꢂ1; HRMS [MNaþ] calcd: 619.3458, found:
619.3464.
1031, 994, 952, 916, 875 cmꢂ1; HRMS [Mþ] calcd: 588.3662,
found: 588.3674.
6.3.9. (3E,5E,11E,13E)-(7S,8S,15S,16S)-8,16-Bis-
((1S,2S,3R)-2-hydroxy-1,3-dimethylpent-4-enyl)-7,15-
dimethyl-1,9-dioxacyclohexadeca-3,5,11,13-tetraene-2,10-
dione and (3E,5E,11E,13E)-(7S,8S,15S,16S)-8,16-bis-
((1R,2S,3R)-1,3-dimethyl-2-triethylsilanyloxypent-4-enyl)-
7,15-dimethyl-1,9-dioxacyclohexadeca-3,5,11,13-tetraene-
2,10-dione (50)
TMSBr (0.06 mL, 0.450 mmol) was added dropwise to
a stirred solution of bis-MOM-ether 48 (97 mg, 0.165 mmol)
in 16 mL CH2Cl2 at ꢂ55 ꢁC. Stirring was continued for
90 min and the reaction mixture was allowed to warm up to
ꢂ15 ꢁC. The reaction was quenched by the addition of 10 mL
of a saturated solution of NaHCO3. The organic phase was sep-
arated and the aqueous phase was extracted three times with
CH2Cl2. The combined organic layers were dried over
MgSO4, filtered and concentrated under reduced pressure. Fil-
tration over a short pad of silica gel (hexane/ethyl acetate, 3:1)
gave the bis-diol (75 mg, 91%) as a white solid. The product
6.3.8. (2S,3R,4S)-3-Methoxymethoxy-4-[(4E,6E,12E,14E)-
(2S,3S,10S,11S)-10-((1S,2R,3S)-2-methoxymethoxy-1,3-
dimethyl-4-oxobutyl)-3,11-dimethyl-8,16-dioxo-1,9-
dioxacyclohexadeca-4,6,12,14-tetraen-2-yl]-2-
methylpentanal (37) and (3E,5E,11E,13E)-(7S,8S,15S,16S)-
8,16-bis-((1S,2S,3R)-2-methoxymethoxy-1,3-dimethylpent-
4-enyl)-7,15-dimethyl-1,9-dioxacyclohexadeca-3,5,11,13-
tetraene-2,10-dione (48)
DesseMartin periodinane (390 mg, 0.920 mmol) was added
in one portion to a stirred solution of bis-diol (110 mg,
0.184 mmol) in 5 mL CH2Cl2 at 0 ꢁC. Stirring was continued
for 4 h at room temperature. The reaction was quenched by
the addition of 4 mL of a 1.0 M solution of Na2S2O3 and 6 mL
of a saturated solution of NaHCO3. The organic phase was sep-
arated and the aqueous phase was extracted three times with
CH2Cl2. The combined organic layers were dried over
MgSO4, filtered and concentrated under reduced pressure. Puri-
fication by flash column chromatography (hexane/ethyl acetate,
3:1) gave bis-aldehyde 37 (102 mg, 94%) as a white solid. The
product was immediately used in the next step.
1
was used in the next step without any further purification. H
NMR (400 MHz, CDCl3): d¼6.96 (dd, J¼15.4, 11.2 Hz, 2H,
C3eH), 6.07 (dd, J¼15.0, 11.2 Hz, 2H, C4eH), 5.93 (ddd,
J¼17.3, 10.4, 7.0 Hz, 2H, C11eH), 5.64 (dd, J¼15.0, 9.6 Hz,
2H, C5eH), 5.64 (d, J¼15.3 Hz, 2H, C2eH), 5.00e5.08 (6H,
C7eH, C12eH), 3.28 (br d, J¼8.8 Hz, 2H, C9eH), 2.74 (br s,
2H, C9eOH), 2.51 (ddq, J¼9.8, 9.6, 6.6 Hz, 2H, C6eH), 2.40
(m, 2H, C10eH), 1.94 (m, 2H, C8eH), 1.03 (d, J¼6.7 Hz, 6H,
C6eCH3), 1.00 (d, J¼6.9 Hz, 6H, C10eCH3), 0.91 (d,
J¼7.0 Hz, 6H, C8eCH3); 13C NMR (100 MHz, CDCl3):
d¼168.8 (C), 145.0 (CH), 144.5 (CH), 142.8 (CH), 131.5
(CH), 121.2 (CH), 114.0 (CH2), 77.4 (CH), 74.6 (CH), 41.4
(CH), 39.1 (CH), 36.0 (CH), 15.2 (CH3), 11.5 (CH3), 9.3 (CH3).
2,6-Lutidine (0.14 mL, 1.20 mmol) and TESOTf (0.11 mL,
0.487 mmol) were added dropwise to a stirred solution of the
bis-diol (75 mg, 0.150 mmol) in 9 mL CH2Cl2 at ꢂ30 ꢁC. The
reaction mixture was stirred for 60 min and the temperature
was allowed to warm up to ꢂ15 ꢁC during that period. The re-
action mixture was quenched by the addition of 5 mL of a sat-
urated solution of NaHCO3. The organic phase was separated
and the aqueous phase was extracted three times with CH2Cl2.
The combined organic layers were dried over MgSO4, filtered
and concentrated under reduced pressure. Purification by flash
column chromatography (hexane/ethyl acetate, 30:1) gave bis-
TES-ether 50 (101 mg, 93%) as colourless needles. Rf¼0.20
(hexane/ethyl acetate, 15:1); [a]2D0 þ96.5 (c 0.77, CH2Cl2);
mp: 145 ꢁC; 1H NMR (400 MHz, CDCl3): d¼6.94 (dd,
J¼15.4, 11.2 Hz, 2H, C3eH), 5.98 (dd, J¼15.0, 11.2 Hz,
2H, C4eH), 5.82 (ddd, J¼17.4, 10.2, 7.3 Hz, 2H, C11eH),
5.63 (dd, J¼15.0, 9.9 Hz, 2H, C5eH), 5.58 (d, J¼15.3 Hz,
2H, C2eH), 4.99e5.07 (m, 3H, C12eHAHB, C7eH), 3.47
(dd, J¼6.2, 4.3 Hz, 2H, C9eH), 2.35e2.44 (m, 4H, C6eH,
C10eH), 1.89 (m, 2H, C8eH), 1.01 (d, J¼6.6 Hz, 6H,
C10eCH3), 0.98 (d, J¼6.8 Hz, 6H, C6eCH3), 0.96 (d,
J¼7.2 Hz, 6H, C8eCH3), 0.94 (t, J¼7.9 Hz, 18H, CH3CH2),
0.62 (q, J¼7.8 Hz, 12H, CH2CH3); 13C NMR (100 MHz,
n-BuLi (2.5 M solution in hexane, 0.39 mL, 0.975 mmol)
was added dropwise to a stirred solution of methyl triphenyl-
phosphonium bromide (348 mg, 0.974 mmol) in 4.5 mL THF
at ꢂ45 ꢁC. Stirring was continued for 30 min and the temper-
ature was allowed to warm up to ꢂ35 ꢁC. Stirring was contin-
ued for further 5 min at 0 ꢁC. A solution of bis-aldehyde 37
(102 mg, 0.172 mmol) in 2.5 mL THF was added dropwise
and the reaction mixture was stirred at 0 ꢁC for 60 min and
at ambient temperature for 60 min. The reaction was quenched
by the addition of 5 mL of a saturated solution of NH4Cl and
diluted with 5 mL Et2O. The organic phase was separated and
the aqueous phase was extracted three times with Et2O. The
combined organic phases were dried over MgSO4, filtered
and concentrated in vacuo. Purification by flash column chro-
matography (hexane/ethyl acetate, 5:1) gave bis-olefin 48
(93 mg, 92%) as white crystals. Rf¼0.69 (hexane/ethyl acetate,
3:1); [a]2D0 þ88.0 (c 0.46, CH2Cl2); mp: 118 ꢁC; H NMR
1
(400 MHz, CDCl3): d¼6.93 (dd, J¼15.3, 11.2 Hz, 2H, C3eH),
5.60 (dd, J¼14.9, 11.3 Hz, 2H, C4eH), 5.95 (ddd, J¼17.4, 10.3,
7.1 Hz, 2H, C11eH), 5.66 (dd, J¼15.0, 9.9 Hz, 2H, C5eH), 5.59
(d, J¼15.4 Hz, 2H, C2eH), 5.07 (d, J¼9.7 Hz, 2H, C7eH), 5.05
(m, 2H, C12eHA), 5.01 (m, 2H, C12eHB), 4.65, 4.59 (AB sys-
tem, J¼6.5 Hz, 4H, C9eOCHAHBO), 3.39 (s, 6H, C9eOCH3),
3.19 (dd, J¼8.2, 3.2 Hz, 2H, C9eH), 2.40e2.50 (m, 4H,
C6eH, C10eH), 1.98 (m, 2H, C8eH), 1.04 (d, J¼6.6 Hz, 6H,
C6eCH3), 1.04 (d, J¼6.9 Hz, 6H, C10eCH3), 0.97 (d,
J¼7.1 Hz, 6H, C8eCH3); 13C NMR (100 MHz, CDCl3):
d¼167.6 (C), 145.4 (CH), 144.7 (CH), 142.4 (CH), 130.8
(CH), 121.3 (CH), 113.9 (CH2), 99.0 (CH2), 84.7 (CH), 75.9
(CH), 56.1 (CH), 42.2 (CH), 40.0 (CH), 36.2 (CH), 16.0
(CH3), 13.4 (CH3), 10.6 (CH3); IR (thin film): 2970, 2930,
2881, 17.8, 1638, 1616, 1301, 1221, 1180, 1141, 1101, 1070,

R. Barth, J. Mulzer / Tetrahedron 64 (2008) 4718e4735
4735
2. (a) Varki, A. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 7390; (b) Springer, T.
Cell 1994, 76, 301; (c) Butcher, E. C.; Picker, L. J. Science 1996, 272, 60.
3. Hammann, P.; Kretzschmar, G. Z. Naturforsch., B 1990, 45, 515.
4. (a) Arcamone, F. M.; Bertazzoli, C.; Ghione, M.; Scotti, T. G. Giorn.
Microbiol. 1959, 7, 207; (b) Arai, M. J. Antibiot. Ser. A 1960, 13, 46.
5. (a) Takahashi, S.; Arai, M.; Ohki, E. Chem. Pharm. Bull. 1967, 15, 1651;
(b) Takahashi, S.; Kurabayashi, M.; Ohki, E. Chem. Pharm. Bull. 1967,
15, 1657; (c) Takahashi, S.; Ohki, E. Chem. Pharm. Bull. 1967, 15, 1726.
6. Kaiser, H.; Keller-Schierlein, W. Helv. Chim. Acta 1981, 64, 407.
7. (a) Neupert-Laves, K.; Dobler, M. Helv. Chim. Acta 1982, 65, 262; (b)
Ley, S. V.; Neuhaus, D.; Williams, D. K. Tetrahedron Lett. 1982, 23, 1207.
8. Cui, C.; Wang, H.; Han, B.; Cai, B.; Luo, A.; Song, Y.; Zhou, P. Zhongguo
Kangshengsu Zazhi 2001, 26, 165.
CDCl3): d¼167.4 (C), 145.1 (CH), 144.6 (CH), 142.6 (CH),
130.7 (CH), 121.4 (CH), 114.2 (CH2), 78.4 (CH), 75.8 (CH),
42.4 (CH), 41.1 (CH), 37.4 (CH), 16.2 (CH3), 13.9 (CH3),
10.9 (CH3), 7.1 (CH3), 5.5 (CH2); IR (thin film): 2960, 2876,
1705, 1697, 1685, 1638, 1458, 1299, 1282, 1226, 1143,
1120, 1006, 912, 740; HRMS [Mþ] calcd: 728.4867, found:
728.4854.
6.3.10. (3E,5E,11E,13E)-(7S,8S,15S,16S)-8,16-Bis-
((1R,2R,3S)-1,3-dimethyl-4-oxo-2-triethylsilanyloxypentyl)-
7,15-dimethyl-1,9-dioxacyclohexadeca-3,5,11,13-tetraene-
2,10-dione (13)
9. Lee, S.-Y.; Kim, H.-S.; Kim, Y.-H.; Han, S.-B.; Kim, H.-M.; Hong, S.-D.;
Lee, J.-J. J. Microbiol. Biotechnol. 1997, 7, 272.
10. Igarashi, Y.; Yoshida, R.; Furumai, T. Shokubutsu no Seicho Chosetus
2002, 37, 63.
PdCl2 (3.5 mg, 0.020 mmol) and CuCl (13 mg, 0.131 mmol)
were added to a stirred suspension of 50 (33.7 mg, 0.046 mmol)
in 1.5 mL DMF, 0.3 mL THF and 0.3 mL H2O at room temper-
ature. O2 was bubbled through the reaction mixture for 15 min.
Stirring was continued for 120 h at room temperature under an
atmosphere of O2. The reaction mixture was then diluted with
3 mL H2O and 3 mL Et2O. The organic phase was separated
and the aqueous phase was extracted four times with EtOAc/
Et2O (1:1). The combined organic layers were dried over
MgSO4, filtered and concentrated under reduced pressure. Puri-
fication by flash column chromatography (hexane/ethyl acetate,
7:1) gave bis-methylketone 1315a (23.5 mg, 67%) as a white
crystalline solid. Additionally, mono-methylketone (5 mg,
14%) was isolated. Rf¼0.25 (hexane/ethyl acetate, 6.1); [a]D20
11. (a) Ziegler, F. E.; Tung, J. S. J. Org. Chem. 1991, 56, 6530; (b) Morita, A.;
Kuwahara, S. Tetrahedron Lett. 2007, 48, 3163.
12. (a) Toshima, K.; Tatsuta, K.; Kinoshita, M. Tetrahedron Lett. 1986, 27,
4741; (b) Toshima, K.; Tatsuta, K.; Kinoshita, M. Bull. Chem. Soc. Jpn.
1988, 61, 2369.
13. Seebach, D.; Chow, H.-F.; Jackson, R. F. W.; Lawson, K.; Sutter, M. A.;
Thaisrivongs, S.; Zimmermann, J. J. Am. Chem. Soc. 1985, 107, 5292.
14. Evans, D. A.; Fitch, D. M. J. Org. Chem. 1997, 62, 454.
15. (a) Paterson, I.; Lombart, H.-G.; Allerton, C. Org. Lett. 1999, 1, 19; (b)
Paterson, I.; Man, J. Tetrahedron Lett. 1997, 38, 695.
16. (a) von Bonin, A.; Buchmann, B.; Bader, B.; Rausch, A.; Venstrom, K.;
Schafer, M.; Grundemann, S.; Gunther, J.; Zorn, L.; Nubbemeyer, R.;
¨
¨
¨
Asadullah, K.; Zollner, T. M. Nat. Med. 2006, 12, 873; (b) Bader, B.;
von Bonin, A.; Buchmann, B.; Gay, J.; Gruendemann, S.; Guenther, J.;
Schaefer, M.; Spelling, T.; Zollner, T. M.; Zorn, L. Tetrahedron Lett.
2007, 48, 5984.
1
þ89.0 (c 0.71, CHCl3); H NMR (400 MHz, CDCl3): d¼6.94
17. (a) Barth, R.; Mulzer, J. Angew. Chem. 2007, 119, 5893; (b) Barth, R.;
Mulzer, J. Angew. Chem., Int. Ed. 2007, 46, 5791.
(dd, J¼15.3, 11.1 Hz, 2H, C3eH), 5.99 (dd, J¼15.1, 11.2 Hz,
2H, C4eH), 5.63 (dd, J¼15.0, 9.9 Hz, 2H, C5eH), 5.59 (d,
J¼15.4 Hz, 2H, C2eH), 4.94 (br d, J¼10.1 Hz, 2H, C7eH),
4.00 (dd, J¼6.1, 4.3 Hz, 1H, C9eH), 2.72 (dq, J¼7.1, 4.3 Hz,
2H, C10eH), 2.40 (m, 2H, C6eH), 2.18 (s, 6H, C12eH), 1.88
(m, 2H, C8eH), 1.11 (d, J¼7.1 Hz, 6H, C10eCH3), 1.01 (d,
J¼6.6 Hz, 6H, C6eCH3), 0.98 (d, J¼7.1 Hz, 6H, C8eCH3),
0.93 (t, J¼8.0 Hz, 18H, CH3CH2), 0.60 (q, J¼8.0 Hz, 12H,
CH2CH3); 13C NMR (100 MHz, CDCl3): d¼211.1 (C), 167.4
(C), 145.4 (CH), 144.4 (CH), 130.8 (CH), 121.3 (CH), 75.8
(CH), 74.8 (CH), 50.6 (CH), 42.4 (CH), 38.0 (CH), 29.3
(CH3), 16.2 (CH3), 11.5 (CH3), 10.6 (CH3), 7.0 (CH3), 5.3
(CH2); IR (thin film): 2952, 2876, 1718, 1707, 1226, 1144,
1125, 1005; HRMS [Mþ] calcd: 760.4766, found: 760.4781.
18. Evans, D.A.;Ng, H.P.;Clark, J.S.;Rieger, D.L. Tetrahedron1992, 48, 2127.
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20. Roush, W. R. J. Am. Chem. Soc. 1980, 102, 1390.
21. Weinrebamide30was a generous giftformDr. S. Mickel, Novartis AG Basel.
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Acknowledgements
R.B. acknowledges the Austrian Academy of Sciences. We
thank Dr. B. Buchmann, Schering AG, for providing us an
authentic sample of efomycine M (1) and for helpful discus-
sions. We thank Dr. H. Kahlig and S. Felsinger for recording
¨
of NMR spectra.
27. Miwa, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 107.
28. Hydrozirconation was performed according to the following procedure:
Huang, Z.; Negishi, E.-I. Org. Lett. 2006, 8, 3675.
29. Nitta, K.; Utimoto, K.; Takai, K. J. Am. Chem. Soc. 1986, 108, 7408.
30. For an excellent review see: Furstner, A. Chem. Rev. 1999, 99, 991.
¨
31. (a) Xu, W.; Wipf, P. Tetrahedron Lett. 1994, 35, 5197; (b) Review: Jahn,
H.; Wipf. Tetrahedron 1996, 52, 12853.
References and notes
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33. An authentic sample of efomycine M (1) was obtained from Dr. B. Buch-
mann, Schering AG.
1. Schon, M. P.; Krahn, T.; Schon, M.; Rodriguez, M.-L.; Antonicek, H.;
¨
¨
Schultz, J. E.; Ludwig, R. J.; Zollner, T. M.; Bischoff, E.; Bremm,
K.-D.; Schramm, M.; Henninger, K.; Kaufmann, R.; Gollnick, H. P. M.;
Parker, C. M.; Boehncke, W.-H. Nat. Med. 2002, 8, 366.
34. (a) Tsuji, J.; Nagashima, H.; Nemoto, H. Org. Synth. 1984, 62, 9; (b)
Tsuji, J. Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon:
Oxford, 1991; Vol. 7, p 449.