A concise route to the C3-C23 fragment of the macrolide palmerolide A

Article abstract of DOI:10.1016/j.tet.2007.10.028

A concise route to the C3-C23 part of the macrolide palmerolide A was developed. This part features the 7,10,11-trihydroxy sector containing the 8E-double bond as well as the 14,16-diene subunit. The stereocenter at C-7 originated from a Noyori reduction on alkynone 8. The substrate 16 containing an enyne was obtained via a Claisen rearrangement. The vicinal diol at C10,C11 was created by a Sharpless asymmetric dihydroxylation. After selective protecting group manipulations the propargylic alcohol was reduced with Red-Al to the E-alkylic alcohol 26. The conjugated diene in the fragment 40 resulted from a Stille cross-coupling reaction between the vinylstannane derived?from alkyne 30 and the vinyl iodide 39. The latter could conveniently be prepared by an aldol/Wittig strategy.

Full text of DOI:10.1016/j.tet.2007.10.028

Available online at www.sciencedirect.com
Tetrahedron 63 (2007) 13006–13017
A concise route to the C3–C23 fragment of the
macrolide palmerolide A
*
€
Julia Jagel, Anke Schmauder, Michael Binanzer and Martin E. Maier
Institut fu€r Organische Chemie, Universita€t Tu€bingen, Auf der Morgenstelle 18, 72076 Tu€bingen, Germany
Received 11 July 2007; revised 25 September 2007; accepted 4 October 2007
Available online 7 October 2007
Abstract—A concise route to the C3–C23 part of the macrolide palmerolide Awas developed. This part features the 7,10,11-trihydroxy sector
containing the 8E-double bond as well as the 14,16-diene subunit. The stereocenter at C-7 originated from a Noyori reduction on alkynone 8.
The substrate 16 containing an enyne was obtained via a Claisen rearrangement. The vicinal diol at C10,C11 was created by a Sharpless asym-
metric dihydroxylation. After selective protecting group manipulations the propargylic alcohol was reduced with Red-Al to the E-alkylic
alcohol 26. The conjugated diene in the fragment 40 resulted from a Stille cross-coupling reaction between the vinylstannane derived from
alkyne 30 and the vinyl iodide 39. The latter could conveniently be prepared by an aldol/Wittig strategy.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
disconnection at the diene generates the two fragments 4 and
5. The syn stereochemistry in the enoate 4 should be avail-
able via an aldol reaction. The fragment 5 was traced back
to enyne 6.
A range of natural products rely on reactive functional
groups to confer biological activity.1 Thus, epoxide func-
tions are quite common such as in the amphidinolides2 or
fumagillin.3 Other natural products feature an electrophilic
exo-methylene butenolide as reactive Michael acceptor.4 Be-
sides these groups various natural products are known that
contain an enamide terminus. Prominent examples include
the benzolactone enamides.5 It seems likely that protonation
of the enamide double bond generates an electrophilic acyl-
iminium ion.6 Recently, the structure of a further macrolac-
tone enamide, palmerolide A (1) was described by Baker
et al.7 This natural product displayed selective and strong
antitumor activity (LC50¼18 nM) against melanoma cells
(Fig. 1). It could be shown that the mode of action on a mo-
lecular level is due to the inhibition of V-ATPase, which is an
important proton pump.8 In this regard palmerolide is related
to the benzolactone enamides. Due to the novel structural
features and the mode of action we became interested in a
total synthesis of palmerolide A. From a structural point of
view the unsaturated N-acyldienamine side chain, five ster-
eocenters, the unsaturated segments, and the 20-membered
macrolactone pose certain challenges. As with any macro-
lactone, classical lactonization reactions, alkylative lactoni-
zation (cf. Mitsunobu) or any other C–C bond formation on
suitable ester substrates can be considered.9 Our retrosyn-
thetic analysis was built upon a Horner–Wadsworth–Emmons
macrocyclization of a phosphonate of type 3. A further key
O
3
H
N
O
1
19
15
IM HWE or
Yamaguchi
7
O
OH
HO
O
palmerolide A (1)
O
NH2
11
palmerolide A revised (2): 7, 10, 11 inverted
O
O
O
P(OEt)2
3
O
H
MeO22C3
OTBS
OP1
P2O
cross-coupling
OP1
3
OMOM
P1O
7
OTBS
OTBS
MeO2C
+
P2O 10
6
5
4
11 OMOM
I
CO2Et
Keywords: Palmerolide; Asymmetric dihydroxylation; Claisen rearrange-
ment; Suzuki cross-coupling; Evans aldol; Protecting groups.
* Corresponding author. Tel.: +49 7071 2975247; fax: +49 7071 295137;
e-mail: martin.e.maier@uni-tuebingen.de
P1, P2 = SiR3
Figure 1. Original (1) and revised structure of palmerolide A (2) together
with retrosynthetic considerations.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.028

J. Ja€gel et al. / Tetrahedron 63 (2007) 13006–13017
13007
While our work was in progress the group of De Brabander
published the synthesis of the proposed structure of palmer-
olide A.10 Through chemical correlation they could show
that the structure of palmerolide A (1) has to be revised to
2. The macrocyclization was achieved by HWE olefination
to an enone with the formation of the C8–C9 double bond.
The stereocenter at C7 was created by a CBS reduction.11
The two stereocenters at C10 and C11 came from D-arabitol.
A further publication by Kaliappan and Gowrisankar 12 de-
scribed the synthesis of the C1–C9 and C15–C21 fragments.
Quite recently the Nicolaou–Chen group published the total
synthesis of the originally proposed and revised structures of
palmerolide A. Their synthesis relies on a ring-closing meta-
thesis reaction to form the C8–C9 double bond.13 In this
publication we report the synthesis of the C3–C23 fragment
40 of the originally proposed structure of palmerolide A via
the enyne 25 as a key intermediate.
giving alkyne 12. The stage called now for extension of the
carbon chain to an enyne. While this could be achieved via
a cross-coupling reaction, in the case at hand a Claisen rear-
rangement seemed more suitable.18 Accordingly, the anion
of alkyne 12 was reacted with acrolein to give the allylic
alcohol 13 as a mixture of diastereomers. A Johnson–Claisen
rearrangement19 using triethyl orthoacetate, a trace of pro-
pionic acid and heating of the mixture in xylene provided
a 79% yield of 1,4-unsaturated ester 14. Subsequently, ester
reduction to the primary alcohol 15 and protection of the
hydroxyl group delivered enyne 16.
Initially the asymmetric dihydroxylation was performed on
the ester 14. The idea was to use lactonization as a means to
differentiate the vicinal hydroxyl functions resulting from
the dihydroxylation.20 As it is known from the literature,
the double bond of enynes can be selectively dihydroxy-
lated.21,22 Using (DHQD)2PHAL as the ligand, Sharpless
dihydroxylation of enyne 14 generally yielded a mixture of
diol 17 and butyrolactone 18 (Scheme 2). Heating of this
mixture in toluene in presence of a trace of CSA converted
the diol 17 to the lactone 18. As we detected only one set of
signals in the 13C NMR spectrum of lactone 18, a high dia-
stereoselectivity for the hydroxylation reaction could be
inferred. The lactone allowed for a selective protection of
the 10-OH group (palmerolide numbering) as its tert-butyl-
diphenylsilyl ether 19. Reduction of the lactone 19 with
LiAlH4 in THF led to diol 20. However, this reduction was
accompanied by some cleavage of the tert-butyldiphenylsilyl
ether function yielding roughly a 3:1 mixture of 20 and 21.
Selective protection of the primary hydroxyl function, either
on the mixture of 20 and 21, or the separated compounds led
to compounds 22 and 23. We were surprised to see that treat-
ment of the diol 23 with tert-butyldiphenylsilyl chloride/
imidazole generated the alcohol 22 in a selective manner.
It should be noted that with tert-butyldimethylsilyl chloride
this reaction was not selective.
2. Results
The synthesis started with valerolactone that was opened
under basic conditions and alkylated with para-methoxy-
benzyl chloride to give the ester 7 (Scheme 1). The ester 7
could be converted to the alkynone 8 by reacting it with
the lithium anion of triisopropysilylacetylene in presence of
BF3$OEt2.14 At this stage a transfer hydrogenation accord-
ing to Noyori using the Ru catalyst containing the (R,R)-
diamine derivative 9 furnished a good yield of the propargylic
alcohol 10.15 According to GC analysis on the derived
alcohol 11 an ee-value of 98% was obtained. The absolute
configuration of alcohol 11 could be supported by Mosher
analysis.16,17 Two further steps via alkynol 11 served to pro-
tect the alcohol function and to liberate the terminal alkyne
O
OPMB
Li
Si(iPr)3
KOH, toluene
O
CO2PMB
PMB-Cl, reflux
(89%)
BF3·Et2O, THF
–80 °C (86%)
7
OTBS
AD-mix-β
cat. 9
TBSOTf
tBuOH/H2O
OPMB
O
OPMB
OH
iPrOH, 23 °C
lutidine, CH2Cl2
(72%, 2 steps)
MeSO2NH2
0 to 23 °C
OPMB
(69%)
EtO2C
Si(iPr)3
R
8
14
10 R = Si(iPr)3
CSA, toluene
TBAF
THF
OTBS
OTBS
80 °C
O
11 R = H
OH
O
+
OTBS
OTBS
1. nBuLi, THF
MeC(OEt)3
OPMB
17
OPMB
OH
OH
H+, xylene
CO2Et
2. LiBr, acrolein
THF, –80 °C
(74%)
18
H
OPMB
OPMB
reflux (79%)
13
12
OTBS
OH
O
O
LiAlH4
TBDPSCl, imidazole
(84%, 3 steps)
OTBS
OTBS
10
18
THF, 0 °C
OPMB
LiAlH4
THF, 0 °C
OTBDPS
OTBS
19
OPMB
14
OPMB
RO
OTBS
OH
EtO2C
OH
15 R = H
16 R = TBS
TBSCl, imidazole
(87%, 2 steps)
TBSCl
imidazole
Ts
N
Ru
N
OPMB
OPMB
Ph
Ph
RO
RO
OH
TBSO
20 R = TBDPS
21 R = H
TBDPSCl
imidazole
(75%)
22 R = TBDPS (45%, 2 steps)
H
9
23 R = H (42%, 2 steps)
Scheme 1. Synthesis of the enyne 16 via the alkynone 8 and Johnson–
Claisen rearrangement of the derived allylic alcohol 13 to the enoate 14.
Scheme 2. Synthesis of alkyne 22 via the lactone 18.

13008
J. Ja€gel et al. / Tetrahedron 63 (2007) 13006–13017
O
O
Based on the above results, we found it more convenient to
perform the dihydroxylation not on the ester 14 but rather on
the reduced derivative 16 of it. Using (DHQD)2PHAL as the
ligand, Sharpless dihydroxylation of eneyne 16 provided the
diol 23 in 77% yield (Scheme 3). Again, a high diastereo-
selectivity for the hydroxylation reaction could be concluded
from the 13C spectrum of diol 23. As we had found, a selec-
tive silylation of the propargylic hydroxyl group of diol 23 to
the silyl ether 22 was feasible. This allowed us to protect
OH-11 of 22 with the MOM group yielding the fully pro-
tected compound 24.23 A subsequent treatment of compound
24 with camphorsulfonic acid (CSA) in a CH2Cl2/MeOH
mixture removed the two tert-butyldimethylsilyl groups re-
sulting in diol 25. The free progargylic hydroxyl group of
25 allowed then for a reduction of the triple bond using
Red-Al (5.5 equiv). This way the allylic alcohol 26 was
obtained in 80% yield. Performing a selective oxidation of
the primary alcohol function10,24 of 26 using diacetoxy-
iodobenzene (2.2 equiv) and a catalytic amount of TEMPO
gave rise to the hydroxy aldehyde 27. The crude material
could be converted to the alkyne 29 using the Bestmann–
Ohira reagent, ketodiazophosphonate25 28. The overall yield
for this two-step transformation amounted to 51%. Finally,
the allylic alcohol function of 29 was reprotected with
tert-butyldimethylsilyl triflate, completing the synthesis of
the C3–C15 fragment 30.
O
OH
O
O
nBu2BOTf
iPr2NEt, CH2Cl2
–80 °C (72%)
I
N
O
I
+
I
N
O
H
31
33
32
OR
OTES
DIBAL
CH2Cl2
NaOMe
MeOH/CH2Cl2
CO2Me
I
OH
–80 °C (84%
)
36
34 R = H
TESCl, Et3N
(85%, 2 steps)
35 R = TES
Ph3P
CO2Me
38
OTES
Dess-Martin
I
O
toluene, 80 °C
(79%, 2 steps)
CH2Cl2, 23 °C
37
OTES
I
CO2Me
39
cross-coupling:
TBSO
OMOM
1. 9-BBN, THF, 0 °C
TBDPSO
OPMB
2. 39, PdCl2(dppf), Ph3As
Cs2CO3, DMF
23 °C, 72 h (67%)
30
H
or
1. Bu3SnH, PdCl2(PPh3)2
2. 39, Pd2(dba)3, Ph3As
DMF, 23 °C, 6 h (78%)
TBSO
OMOM
OTES
15
OTBS
23
AD-mix-β
tBuOH/H2O
MeSO2NH2
0 to 23 °C (77%)
10
CO2Me
OH
7
11
CH2(OMe)2, LiBr
16
16
TBDPSO
OPMB
40
pTsOH, 23 °C
(palmerolide numbering)
OPMB
OR
23 R = H
22 R = TBDPS
OH
OTBS
(82%)
TBSO
OMOM
OTES
1
9
TBDPSCl, imidazole
(75%)
14
CO2Me
5
17
10
41
TBDPSO
OPMB
OR
OMOM
OMOM
Scheme 4. Synthesis of the vinyl iodide 39 and its cross-coupling with the
vinylborane, prepared in situ from the alkyne 30, yielding the C3–C23 frag-
ment 40 of palmerolide A. The dihydro compound 41 is formed with an
excess of 9-BBN.
Red-Al
TBDPSO
OPMB
PMBO
THF, 0 °C
(80%)
TBDPSO
OH
26
CSA
24 R = TBS
OR
MeOH/CH2Cl2
(75%)
O
O
25 R = H
with phosphorane30 38 the enoate 39 was obtained (79%
over two steps). The crucial cross-coupling reaction between
the vinyl iodide 39 and a vinyl metal derivative of 30 turned
out to be quite difficult. In a model study, the tert-butyldime-
thylsilyl ether of pentenol was reacted under the typical
Heck conditions [Pd(OAc)2, Et3N, Cs2CO3, Bu4NBr,
DMF, 23 ꢀC]31 with vinyl iodide 34. While LC-MS analysis
indicated formation of the diene, there were three signals
with the correct mass. We surmised that double bond iso-
mers were formed. Analysis by 1H NMR did indeed show too
many olefinic signals. A practical solution could be devel-
oped building upon a Suzuki cross-coupling reaction.32
First, the alkyne 30 was reacted with 9-BBN in THF
(0 ꢀC, 36 h). Thereafter, the THF solution of the intermedi-
ate vinyl borane was added to a solution of the vinyl iodide
39 in DMF, containing PdCl2(dppf), CsCO3, AsPh3, and
a trace of water.33 Comparable results were obtained using
the combination of (Ph3P)4Pd, and a mixture of 2 N NaOH
and THF. The coupling reaction to give the key fragment
40 was complete within 72 h at room temperature. While the
NMR spectrum of the tetraene 40 turned out to be quite com-
plex, a characteristic signal appears at d¼6.16 ppm showing
(EtO)2P
OH
OMOM
28
PhI(OAc)2
TEMPO, CH2Cl2
N2
TBDPSO
OPMB
H
K2CO3, MeOH
(51%)
27
O
OR
OMOM
TBDPSO
OPMB
3
15
H
29 R = H
TBSOTf
lutidine (93%)
30 R = TBS
Scheme 3. Completion of the synthesis of C3–C15 fragment 30.
The synthesis of the C16–C23 fragment 39 relied on an
Evans aldol reaction of 4-iodo-3-methyl-3-butenal26 (31)
with the propionyloxazolidinone27 32 (Scheme 4). The chi-
ral auxiliary could be removed using NaOMe in a methanol/
CH2Cl2 mixture28 providing the hydroxyester 34. This was
followed by protecting the alcohol function using triethyl-
silyl chloride. Reduction of the ester 35 with DIBAL fur-
nished alcohol 36 that was then oxidized to the aldehyde
37 using the Dess–Martin periodinane.29 In a Wittig reaction

J. Ja€gel et al. / Tetrahedron 63 (2007) 13006–13017
13009
coupling constants of 14.9 and 10.2 Hz, respectively. This
signal was assigned to 15-H (palmerolide numbering). In or-
der to improve the efficiency of the Suzuki cross-coupling,
the hydroboration of alkyne 30 was also performed with
an excess of 9-BBN (3 equiv). While the subsequent cross-
coupling of the intermediate borane with 39 using the previ-
ous conditions [PdCl2(dppf) (5 mol %), AsPh3 (5 mol %),
Cs2CO3 (2 equiv), trace of water, in DMF] proceeded
cleanly, careful analysis of the product by NMR and LC-MS
showed it to be the 9,10-dihydro derivative 41. The forma-
tion of 41 might be explained by protonation of the initial
vinyl borane with excess of 9-BBN followed by hydrobora-
tion of the resulting terminal alkene. Accordingly, we also
examined the Stille cross-coupling34 to produce 40. Using
palladium catalysis, the alkyne 30 was converted to the
corresponding vinyl stannane.35,36 Coupling of the crude
stannane with vinyl iodide 39 in presence of Pd2(dba)3
(20 mol %), AsPh3 (40 mol %) in DMF furnished tetraene
40 as well. Since these conditions gave 40 in higher yield
and purity this is our preferred method for this case.
cuvette, 25 ꢀC. Solvents were distilled prior to use; petro-
leum ether with a boiling range of 40–60 ꢀC was used.
Reactions were generally run under an argon atmosphere.
4.1.1. para-Methoxybenzyl-5-[(para-methoxybenzyl)-
oxy]pentanoate (7). To a stirred solution of tetrahydro-2H-
pyran-2-one (valerolactone, 2.2 mL, 24.14 mmol) and KOH
(4.8 g, 85 mmol, 3.5 equiv) in toluene (50 mL) was added
para-methoxybenzyl chloride37 (16 mL, 118 mmol, 4.9 equiv)
in one portion. The mixture was refluxed for 48 h (130 ꢀC)
with a Dean-Stark trap. After addition of water, the layers
were separated and the aqueous layer was extracted twice
with Et2O. The combined organic layers were washed with
saturated NaHCO3 and NaCl solution, dried over MgSO4,
filtered, and concentrated. The residue was purified by flash
chromatography (petroleum ether/EtOAc, 10:1) to give 7.7 g
(89%) of ester 7 as yellow oil. Rf¼0.30 (petroleum ether/
1
EtOAc, 5:1); H NMR (400 MHz, acetone-d6): d [ppm]¼
1.53–1.69 (m, 2H, 4-H), 1.69–1.79 (m, 2H, 3-H), 2.32 (t,
J¼7.3 Hz, 2H, 2-H), 3.41 (t, J¼6.1 Hz, 2H, 5-H), 3.77 (s,
6H, CH3O), 4.37 (s, 2H, PMB CH2), 5.02 (s, 2H, PMB
CH2), 6.85–6.93 (m, 4H, CHar, meta), 7.24–7.36 (m, 4H,
CHar, ortho); 13C NMR (100 MHz, CDCl3): d [ppm]¼21.6
(C-3), 29.0 (C-4), 33.9 (C-2), 55.1 (OCH3), 65.8 (PMB
CH2), 69.3 (C-5), 72.4 (PMB CH2), 113.6 (CHar, meta),
113.8 (CHar, meta), 128.1 (Car), 129.1 (CHar, ortho), 129.9
(CHar, ortho), 130.5 (Car), 159.0 (Car, para), 159.5 (Car,
para), 173.3 (C-1); HRMS (ESI): [M+Na]+ calcd for
C21H26O5 381.16725, found 381.16712.
3. Conclusion
A convergent and efficient synthesis of the C3–C23 frag-
ment of palmerolide A was developed. The stereocenters
in the C3–C15 building block 30 were created by catalytic
methods. The carbon skeleton of 30 originated from valero-
lactone, acetylene, acrolein, and triethyl orthoacetate. The
enyne 14 was obtained via a Claisen rearrangement on the
allylic alcohol 13. A derivative of 14 was subjected to a
Sharpless asymmetric dihydroxylation. Key to the synthesis
was a selective silylation of the propargylic alcohol in the
diol 22. Using the free hydroxyl group at C7 allowed for a
Red-Al mediated reduction of the triple bond of 25 to the
E allyl alcohol 26. A Stille cross-coupling reaction between
the vinylstannane, generated from alkyne 30 and the vinyl
iodide 39, which was prepared via an Evans aldol strategy,
delivered the C3–C23 fragment 40 of palmerolide A (1).
While the revised structure of palmerolide A requires the
enantiomer of 30, adaption of the presented strategy should
now enable the total synthesis of palmerolide A.
4.1.2. 7-[(para-Methoxybenzyl)oxy]-1-(triisopropylsilyl)-
hept-1-yn-3-one (8). To a stirred solution of ethynyl(triiso-
propyl)silane (7.5 mL, 33.5 mmol, 2 equiv) in THF (60 mL)
at ꢂ80 ꢀC was added nBuLi (13.5 mL, 1 M in hexane,
33.5 mmol, 2 equiv) dropwise. After stirring at this temper-
ature for 45 min, a vigorously stirred solution of pentanoate
7 (6.0 g, 17.0 mmol) and BF3$Et2O (2 mL, 17 mmol) in
THF (30 mL) was added slowly. After stirring for 12 h the
mixture was diluted with Et2O and treated with saturated
NH4Cl solution. The layers were separated and the aqueous
layer was extracted twice with Et2O. The combined organic
layers were washed with 1 M NaOH solution, H2O and NaCl
solution, dried over MgSO4, filtered, and concentrated in
vacuo. The crude product was purified by flash chromato-
graphy (petroleum ether/EtOAc, 10:1) to give 5.8 g (86%)
of alkynone 8 as light yellow oil. Rf¼0.57 (petroleum
ether/EtOAc, 5:1); 1H NMR (400 MHz, acetone-d6): d
[ppm]¼1.05–1.19 (m, 21H, Si(CH(CH3)2)), 1.56–1.64 (m,
2H, 6-H), 1.71–1.81 (m, 2H, 5-H), 2.62 (t, J¼7.3 Hz, 2H,
4-H), 3.44 (t, J¼6.1 Hz, 2H, 7-H), 3.77 (s, 3H, CH3O),
4.39 (s, 2H, PMB CH2), 6.88 (d, J¼8.7 Hz, 2H, CHar,
meta), 7.24 (d, J¼8.7 Hz, 2H, CHar, ortho); 13C NMR
(100 MHz, CDCl3): d [ppm]¼10.9 (Si(CH(CH3)2)), 18.4
(Si(CH(CH3)2)), 20.9 (C-5), 28.9 (C-6), 45.2 (C-4), 55.1
(CH3O), 69.4 (C-7), 72.5 (PMB CH2), 95.3 (C-1), 104.1
(C-2), 113.6 (CHar, meta), 129.1 (CHar, ortho), 130.5 (Car),
159.0 (Car, para), 187.5 (C-3); HRMS (ESI): [M+Na]+ calcd
for C24H38O3Si 425.24824, found 425.24834.
4. Experimental
4.1. General
1H and 13C NMR: Bruker Avance 400, spectra were recorded
at 295 K either in CDCl3 or acetone-d6. Chemical shifts are
calibrated to the residual proton and carbon resonance of the
solvent: CDCl3 (dH 7.25, dC 77.0 ppm); acetone-d6 (dH
2.40, dC 29.8 ppm). HRMS (FT-ICR): Bruker Daltonic
APEX 2 with electron spray ionization (ESI). Analytical
LC-MS: HP 1100 Series connected with an ESI MS detector
Agilent G1946C, positive mode with fragmentor voltage
of 40 eV, column: Nucleosil 100–5, C-18 HD, 5 mm,
70ꢁ3 mm Machery-Nagel, eluent: NaCl solution (5 mM)/
acetonitrile, gradient: 0–10–15–17–20 min with 20–80–
80–99–99% acetonitrile, flow: 0.5 mL minꢂ1. Flash chro-
matography: J. T. Baker silica gel 43–60 mm. Thin-layer
4.1.3. (3R)-7-[(para-Methoxybenzyl)oxy]-1-(triisopropyl-
silyl)hept-1-yn-3-ol (10). To a stirred solution of alkynone
8 (5.0 g, 12.4 mmol) in propan-2-ol (135 mL) the com-
plex RuCl[(R,R)-NTsCH(Ph)CH(Ph)NH2(h6-cymene) (9)
chromatography: Machery-Nagel Polygram Sil G/UV254
Perkin–Elmer 341 Polarimeter, Na-lamp, 589 nm, 1 dm
.

13010
J. Ja€gel et al. / Tetrahedron 63 (2007) 13006–13017
(95 mg, catalytic amount), dissolved in a minimal amount of
CH2Cl2 (0.7 mL), was added. The mixture was stirred at
room temperature for 5 h. The solvent was removed and
the brown residue purified by flash chromatography (petro-
leum ether/EtOAc, 9:1) to give 3.5 g (69%) of propargylic
alcohol 10 as brown oil. Some starting material (1.5 g,
3.8 mmol) could be recovered. Rf¼0.38 (petroleum ether/
EtOAc, 5:1); [a]D20 ꢂ1.6 (c 1.00, CH2Cl2); 1H NMR
(400 MHz, acetone-d6): d [ppm]¼1.02–1.07 (m, 21H,
Si(CH(CH3)2)), 1.50–1.77 (m, 6H, 4-H, 5-H, 6-H), 1.94 (s,
1H, OH), 3.43 (t, J¼6.4 Hz, 2H, 7-H), 3.78 (s, 3H, CH3O),
4.36 (t, J¼6.5 Hz, 1H, 3-H), 4.41 (s, 2H, PMB CH2), 6.86
(d, J¼8.7 Hz, 2H, CHar, meta), 7.24 (d, J¼8.4 Hz, 2H,
CHar, ortho); 13C NMR (100 MHz, CDCl3): d [ppm]¼11.1
(Si(CH(CH3)2)), 18.6 (Si(CH(CH3)2)), 21.9 (C-5), 29.3 (C-
6), 37.7 (C-4), 55.3 (CH3O), 62.9 (C-3), 69.9 (C-7), 72.5
(PMB CH2), 85.5 (C-1), 108.7 (C-2), 113.7 (CHar, meta),
129.2 (CHar, ortho), 130.7 (Car), 159.1 (Car, para); HRMS
(ESI): [M+Na]+ calcd for C24H40O3Si 427.26389, found
427.26373.
d6): d [ppm]¼0.12 (s, 3H, Si(CH3)2), 0.14 (s, 3H,
Si(CH3)2), 0.90 (s, 9H, C(CH3)3), 1.47–1.74 (m, 6H, 4-H,
5-H, 6-H), 2.86–2.92 (m, 1H, 1-H), 3.43 (t, J¼6.1 Hz, 2H,
7-H), 3.76 (s, 3H, CH3O), 4.39 (s, 2H, PMB CH2), 4.40–
4.44 (m, 1H, 3-H), 6.87 (d, J¼8.7 Hz, 2H, CHar, meta),
7.25 (d, J¼8.4 Hz, 2H, CHar, ortho); 13C NMR (100 MHz,
CDCl3): d [ppm]¼ꢂ5.1 (Si(CH3)2), ꢂ4.6 (Si(CH3)2), 18.2
(C(CH3)3), 21.8 (C-5), 25.8 (C(CH3)3), 29.4 (C-6), 38.3
(C-4), 55.2 (CH3O), 62.7 (C-3), 70.0 (C-7), 72.0 (C-1), 72.5
(PMB CH2), 85.6 (C-2), 113.7 (CHar, meta), 129.2 (CHar,
ortho), 130.7 (Car), 159.0 (Car, para); HRMS (ESI): [M+Na]+
calcd for C21H34O3Si 385.21694, found 385.21671.
4.1.6. (6R)-6-{[tert-Butyl(dimethyl)silyl]oxy}-10-[(para-
methoxybenzyl)oxy]dec-1-en-4-yne-3-ol (13). A solution
of alkyne 12 (3.38 g, 9.31 mmol) in THF (45 mL) was
treated at ꢂ80 ꢀC with nBuLi (8.2 mL, 1 M in hexane,
20.48 mmol, 2.2 equiv). The mixture was stirred for 30 min,
then warmed to room temperature. Now, LiBr (650 mg,
7.45 mmol, 0.8 equiv) was added and the mixture stirred
until the LiBr was dissolved. It was then cooled to ꢂ80 ꢀC
before acrolein (1.44 mL, 20.48 mmol, 2.2 equiv) in THF
(15 mL) was slowly added over a period of 30 min. After ad-
ditional stirring for 2 h at ꢂ80 ꢀC the reaction was quenched
by addition of aqueous NH4Cl solution and the mixture
warmed to room temperature. The layers were separated
and the aqueous layer was extracted twice with Et2O. The
combined organic layers were washed with saturated NaCl
solution, dried over MgSO4, filtered, and concentrated in
vacuo. The crude product was purified by flash chromato-
graphy (petroleum ether/EtOAc, 10:1) to give 2.88 g (74%)
of the allylic alcohol 13 as light yellow oil. Rf¼0.38 (petro-
4.1.4. (3R)-7-[(para-Methoxybenzyl)oxy]hept-1-yn-3-ol
(11). To a stirred solution of propargylic alcohol 10 (3.45 g,
8.53 mmol) in THF (25 mL) was added TBAF (9.7 mL, 1 M
in THF, 9.7 mmol, 1.13 equiv). After stirring for 3 h at room
temperature the reaction was quenched with saturated
NaHCO3 solution. The layers were separated and the aque-
ous layer was extracted twice with Et2O. The combined
organic layers were washed with saturated NaCl solution,
dried over MgSO4, filtered, and concentrated to give 3.6 g
of crude product as yellow oil. The residue was used without
further purification. GC analysis of 11 (fused silica column,
30% Lipodex E in PS255, 0.13 mm film, 80 ꢀC, isothermal,
carrier gas 50 kPa H2) indicated an ee of 98%. An analytical
amount was purified by flash chromatography (petroleum
ether/EtOAc, 5:1). Rf¼0.13 (petroleum ether/EtOAc, 5:1);
1
leum ether/EtOAc, 5:1); [a]2D0 +28.4 (c 1.00, CH2Cl2); H
NMR (400 MHz, CDCl3): d [ppm]¼0.08, 0.11 (2s, 3H each,
Si(CH3)2), 0.88 (s, 9H, C(CH3)3), 1.38–1.76 (m, 6H, 7-H,
8-H, 9-H), 2.03 (s, 1H, OH), 3.43 (t, J¼6.5 Hz, 2H, 10-H),
3.79 (s, 3H, CH3O), 4.38 (t, J¼6.0 Hz, 1H, 6-H), 4.42 (s,
2H, PMB CH2), 4.82–4.92 (m, 1H, 3-H), 5.19 (d, J¼
10.2 Hz, 1H, 1-H), 5.42 (d, J¼17.0 Hz, 1H, 1-H), 5.86–
6.00 (m, 1H, 2-H), 6.86 (d, J¼8.7 Hz, 2H, CHar, meta),
7.25 (d, J¼8.4 Hz, 2H, CHar, ortho); 13C NMR (100 MHz,
CDCl3): d [ppm]¼ꢂ5.0 (Si(CH3)2), ꢂ4.5 (Si(CH3)2), 18.2
(C(CH3)3), 21.9 (C-8), 25.8 (C(CH3)3), 29.3 (C-9), 38.2
(C-7), 55.2 (CH3O), 62.8 (C-6), 63.1 (C-3), 69.8 (C-10),
72.5 (PMB CH2), 82.6 (C-4), 88.1 (C-5), 113.7 (CHar,
meta), 116.3 (C-1), 129.2 (CHar, ortho), 130.6 (Car), 136.9
(C-2), 159.1 (Car, para); HRMS (ESI): [M+Na]+ calcd for
C24H38O4Si 441.24316, found 441.24239.
1
[a]2D0 +2.7 (c 1.00, CH2Cl2); H NMR (400 MHz, acetone-
d6): d [ppm]¼1.47–1.75 (m, 6H, 4-H, 5-H, 6-H), 2.25 (s,
1H, OH), 2.43 (d, J¼2.0 Hz, 1H, 1-H), 3.43 (t, J¼6.5 Hz,
2H,
7-H),
3.78
(s,
3H,
CH3O),
4.29–4.36
(m, 1H, 3-H), 4.41 (s, 2H, PMB CH2), 6.86 (d, J¼8.4 Hz,
2H, CHar, meta), 7.24 (d, J¼8.4 Hz, 2H, CHar, ortho); 13C
NMR (100 MHz, CDCl3): d [ppm]¼21.8 (C-5), 29.2 (C-6),
37.3 (C-4), 55.2 (CH3O), 62.1 (C-3), 69.8 (C-7), 72.5 (PMB
CH2), 72.9 (C-1), 84.9 (C-2), 113.7 (CHar, meta), 129.2
(CHar, ortho), 130.5 (Car), 159.1 (Car, para); HRMS
(ESI): [M+Na]+ calcd for C15H20O3 271.13047, found
271.13080.
4.1.5. (3R)-3-{[tert-Butyl(dimethyl)silyl]oxy}-7-[(para-
methoxybenzyl)oxy]-hept-1-yne (12). To a stirred solution
of hept-1-yn-3-ol 11 (2 g crude, max. 5 mmol) in CH2Cl2
(31 mL)wasadded2,6-lutidine (1.83 mL, 15 mmol, 3 equiv).
After cooling to 0 ꢀC, TBSOTf (1.3 mL, 5.48 mmol,
1.1 equiv) was added dropwise and the mixture was stirred
for 20 min at this temperature. The mixture was diluted
with CH2Cl2 and the organic layer was washed with H2O,
1 N HCl, and saturated NaHCO3 solution, dried over
MgSO4, filtered, and concentrated in vacuo. The residue
was purified by flash chromatography (petroleum ether/
EtOAc, 10:1) to give 2.1 g (72%, over 2 steps) of silyl ether
12 as colorless oil. Rf¼0.68 (petroleum ether/EtOAc, 5:1);
[a]2D0 +32.0 (c 1.00, CH2Cl2); 1H NMR (400 MHz, acetone-
4.1.7. Ethyl-(4E,8R)-8-{[tert-butyl(dimethyl)silyl]oxy}-
12-[(para-methoxybenzyl)oxy]dodec-4-en-6-ynoate (14).
A mixture of alcohol 13 (2.0 g, 5.0 mmol), triethylorthoace-
tate (4.6 mL, 25 mmol, 5 equiv), and propionic acid (3 drops)
in xylene (25 mL) was refluxed (150 ꢀC) for 2 h. After cool-
ing, the mixture was concentrated under reduced pressure
and the residue purified by flash chromatography (petroleum
ether/EtOAc, 15:1) to give 1.9 g (79%) of 1,4-unsaturated
ester 14 as light yellow oil. Rf¼0.65 (petroleum ether/
EtOAc, 5:1); [a]D20 +22.0 (c 1.00, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d [ppm]¼0.08, 0.10 (2s, 3H each,
Si(CH3)2), 0.88 (s, 9H, C(CH3)3), 1.23 (t, J¼7.1 Hz, 3H,
CH3CH2O), 1.36–1.75 (m, 6H, 9-H, 10-H, 11-H), 2.32–2.45
(m, 4H, 2-H, 3-H), 3.42 (t, J¼6.6 Hz, 2H, 12-H), 3.78 (s, 3H,

J. Ja€gel et al. / Tetrahedron 63 (2007) 13006–13017
13011
CH3O), 4.11 (q, J¼7.1 Hz, 2H, CH3CH2O), 4.36–4.45 (m,
3H, 8-H, PMB CH2), 5.51 (d, J¼16.0 Hz, 1H, 5-H), 5.99–
6.11 (m, 1H, 4-H), 6.85 (d, J¼8.7 Hz, 2H, CHar, meta),
7.20 (d, J¼8.7 Hz, 2H, CHar, ortho); 13C NMR (100 MHz,
CDCl3): d [ppm]¼ꢂ5.1 (Si(CH3)2), ꢂ4.5 (Si(CH3)2), 14.2
(OCH2CH3), 18.2 (C(CH3)3), 21.9 (C-10), 25.8 (C(CH3)3),
28.1 (C-3), 29.3 (C-11), 33.3 (C-2), 38.4 (C-9), 55.2 (CH3O),
60.4 (C-8), 63.3 (OCH2CH3), 69.9 (C-12), 72.5 (PMB CH2),
82.4 (C-6), 90.2 (C-7), 110.6 (C-5), 113.7 (CHar, meta),
129.1 (CHar, ortho), 130.7 (Car), 141.6 (C-4), 159.0 (Car,
para), 172.5 (C-1); HRMS (ESI): [M+Na]+ calcd for
C28H44O5Si 511.28502, found 511.28510.
(1-OSi(CH3)2C(CH3)3), 18.3 (8-OSi(CH3)2C(CH3)3), 22.0
(C-10), 25.8 (1-OSi(CH3)2C(CH3)3), 25.9 (8-OSi(CH3)2-
C(CH3)3), 29.4 (C-3), 29.4 (C-11), 31.7 (C-2), 38.5 (C-9),
55.3 (CH3O), 62.2 (C-8), 63.3 (C-1), 70.0 (C-12), 72.5
(PMB CH2), 82.8 (C-6), 89.5 (C-7), 109.5 (C-5), 113.7
(CHar, meta), 129.2 (CHar, ortho), 130.7 (Car), 143.9 (C-4),
159.1 (Car, para); HRMS (ESI): [M+Na]+ calcd for
C32H56O4Si2 583.36093, found 583.35994.
4.1.10. Ethyl (4R,5R,8R)-8-{[tert-butyl(dimethyl)silyl]-
oxy}-4,5-dihydroxy-12-[(para-methoxybenzyl)oxy]dodec-
6-ynoate (17) and (50R)-50-{(1R,4R)-4-{[tert-butyl(dime-
thyl)silyl]oxy}-1-hydroxy-8-[(para-methoxybenzyl)oxy]-
oct-2-ynyl}dihydrofuran-20(3H)-one (18). (DHQD)2PHAL
(30.9 mg, cat.), K3Fe(CN)6 (3.9 g, 11.5 mmol, 3 equiv),
K2CO3 (1.6 g, 11.5 mmol, 3 equiv), and K2OsO2(OH)4 (7 mg,
cat.) were dissolved in a 1:1 mixture of water (20 mL) and
tert-butyl alcohol (20 mL). MeSO2NH2 (374 mg, 3.9 mmol,
1 equiv) was added and the vigorously stirred solution was
cooled to 0 ꢀC. At this point unsaturated ester 14 (1.9 g,
3.9 mmol) was added in one portion and the mixture allowed
to warm to room temperature within 4 h. Stirring was con-
tinued for 10 h before the reaction was quenched by addition
of solid Na2SO3 (5.6 g). The solution was extracted twice
with EtOAc. The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo. The residue,
a mixture of ester and lactone, was used in the following
step without further purification.
4.1.8. (4E,8R)-8-{[tert-Butyl(dimethyl)silyl]oxy}-12-
[(para-methoxybenzyl)oxy]dodec-4-en-6-yn-1-ol (15).
To a stirred suspension of LiAlH4 (29 mg, 0.737 mmol,
1.2 equiv) in THF (2 mL) at 0 ꢀC was added dropwise a solu-
tion of ester 14 (300 mg, 0.614 mmol) in THF (5 mL). After
being stirred for 10 min, the reaction was quenched by addi-
tion of H2O (0.03 mL), 1 M NaOH (0.03 mL), and H2O
(0.1 mL). After filtration the solvent was evaporated. The
crude product was used without further purification. Rf¼
0.08 (petroleum ether/EtOAc, 6:1); [a]2D0 +26.1 (c 1.00,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d [ppm]¼0.09, 0.11
(2s, 3H each, Si(CH3)2), 0.89 (s, 9H, C(CH3)3), 1.41–1.78
(m, 8H, 2-H, 9-H, 10-H, 11-H), 2.13–2.23 (m, 2H, 3-H),
3.43 (t, J¼6.5 Hz, 2H, 12-H), 3.62 (t, J¼6.4 Hz, 2H, 1-H),
3.79 (s, 3H, CH3O), 4.37–4.48 (m, 3H, 8-H, PMB CH2),
5.46–5.55 (m, 1.40 Hz, 1H, 5-H), 6.01–6.14 (m, 1H, 4-H),
6.86 (d, J¼8.7 Hz, 2H, CHar, meta), 7.24 (d, J¼8.7 Hz,
2H, CHar, ortho); 13C NMR (100 MHz, CDCl3): d
[ppm]¼ꢂ5.0 (Si(CH3)2), ꢂ4.5 (Si(CH3)2), 18.2 (C(CH3)3),
22.0 (C-10), 25.8 (C(CH3)3), 29.3 (C-3), 29.4 (C-11), 31.5
(C-2), 38.5 (C-9), 55.2 (CH3O), 62.0 (C-8), 63.3 (C-1),
70.0 (C-12), 72.5 (PMB CH2), 82.7 (C-6), 89.7 (C-7), 109.9
(C-5), 113.7 (CHar, meta), 129.2 (CHar, ortho), 130.7 (Car),
143.4 (C-4), 159.0 (Car, para); HRMS (ESI): [M+Na]+ calcd
for C26H42O4Si 469.27446, found 469.27487.
To a stirred solution of dihydroxy ester 17 (crude, max.
3.9 mmol) in toluene (135 mL) was added CSA (100 mg,
cat.) and the mixture was stirred at 80 ꢀC for 6 h. After cool-
ing, the mixture was treated with solid CaCO3 (220 mg).
After filtration, the solution was concentrated in vacuo and
the residue, lactone 18, was used without further purifica-
tion. Rf¼0.15 (petroleum ether/EtOAc, 5:1); 1H NMR
(400 MHz, CDCl3): d [ppm]¼0.07, 0.10 (2s, 3H each,
Si(CH3)2), 0.88 (s, 9H, SiC(CH3)3), 1.37–1.70 (m, 6H, 5-H,
6-H, 7-H), 2.06–2.35 (m, 2H, 40-H), 2.40–2.60 (m, 2H, 30-
H), 3.43 (t, J¼6.4 Hz, 2H, 8-H), 3.79 (s, 3H, CH3O), 4.36
(t, J¼6.2 Hz, 1H, 4-H), 4.41 (s, 2H, PMB CH2), 4.42–4.57
(m, 2H, 1-H, 50-H), 6.86 (d, J¼8.7 Hz, 2H, CHar, meta),
7.24 (d, J¼8.4 Hz, 2H, CHar, ortho); 13C NMR (100 MHz,
CDCl3): d [ppm]¼ꢂ5.1 (Si(CH3)2), ꢂ4.6 (Si(CH3)2), 18.2
(SiC(CH3)3), 21.8 (C-40), 23.4 (C-6), 25.7 (SiC(CH3)3),
28.1 (C-30), 29.3 (C-7), 38.1 (C-5), 55.3 (CH3O), 62.7 (C-4),
64.7 (C-1), 69.8 (C-8), 72.5 (PMB CH2), 80.0 (C-2), 81.4
(C-50), 88.9 (C-3), 113.7 (CHar, meta), 129.3 (CHar, ortho),
130.6 (Car), 159.1 (Car, para), 176.6 (C-20).
4.1.9. (4E,8R)-1,8-Di-{[tert-butyl(dimethyl)silyl]oxy}-
12-[(para-methoxybenzyl)oxy]dodec-4-en-6-yne (16).
To a stirred solution of alcohol 15 (253 mg crude, max.
0.614 mmol) in DMF (6 mL) were added imidazole
(64 mg, 0.960 mmol, 1.5 equiv) and DMAP (cat.). At 0 ꢀC
TBSCl (110 mg, 0.737 mmol, 1.2 equiv) was added and
the mixture stirred for 3 h before it was diluted with Et2O.
Then H2O was added and after separation of the layers,
the organic layer was washed with saturated NaCl solution,
dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography (petroleum
ether/EtOAc, 10:1) to give 300 mg (87%, over 2 steps) of
silyl ether 16 as yellow oil. Rf¼0.70 (petroleum ether/
EtOAc, 6:1); [a]D20 +18.9 (c 1.00, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d [ppm]¼0.03 (s, 6H, 1-OSi(CH3)2),
0.09, 0.11 (2s, 3H each, Si(CH3)2), 0.88 (s, 9H, 1-
OSi(CH3)2C(CH3)3), 0.89 (s, 9H, 8-OSi(CH3)2C(CH3)3),
1.39–1.75 (m, 8H, 2-H, 9-H, 10-H, 11-H), 2.10–2.20 (m,
2H, 3-H), 3.43 (t, J¼6.6 Hz, 2H, 12-H), 3.59 (t, J¼6.2 Hz,
2H, 1-H), 3.79 (s, 3H, CH3O), 4.38–4.46 (m, 3H, 8-H, PMB
CH2), 5.43–5.52 (m, 1H, 5-H), 6.02–6.14 (m, 1H, 4-H), 6.86
(d, J¼8.7 Hz, 2H, CHar, meta), 7.25 (d, J¼8.4 Hz, 2H, CHar,
ortho); 13C NMR (100 MHz, CDCl3): d [ppm]¼ꢂ5.3 (1-
OSi(CH3)2), ꢂ5.0 (8-OSi(CH3)2, ꢂ4.5 (8-OSi(CH3)2), 18.3
4.1.11. (50R)-50-{(1R,4R)-4-{[tert-Butyl(dimethyl)silyl]-
oxy}-1-{[tert-butyl(diphenyl)silyl]oxy}-8-[(para-methoxy-
benzyl)oxy]oct-2-ynyl}dihydrofuran-20(3H)-one (19). To
a stirred solution of lactone 18 (1.73 g crude, max.
3.635 mmol, 1 equiv) in CH2Cl2 (22 mL) was added imida-
zole (727 mg, 5.2 mmol, 3 equiv). At 0 ꢀC TBDPSCl
(1.4 mL, 2.6 mmol, 1.5 equiv) was added and the mixture
stirred for 4 h. This was followed by the addition of saturated
NaCl solution and separation of the layers. The aqueous layer
was extracted twice with CH2Cl2. The combined organic
layers were dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by flash chromatography
(petroleum ether/EtOAc, 8:1) to give 2.19 g (84%, over 3

13012
J. Ja€gel et al. / Tetrahedron 63 (2007) 13006–13017
steps) of silyl ether 19 as light yellow oil. Rf¼0.60 (petroleum
ether/EtOAc, 3:1); 1H NMR (400 MHz, CDCl3): d [ppm]¼
0.04, 0.05 (2s, 3H each, Si(CH3)2), 0.85 (s, 9H,
Si(CH3)2C(CH3)3), 1.06 (s, 9H, Si(Ph)2C(CH3)3), 1.20–1.60
(m, 6H, 5-H, 6-H, 7-H), 2.18–2.35 (m, 2H, 40-H), 2.36–2.67
(m, 2H, 30-H), 3.38 (t, J¼6.4 Hz, 2H, 8-H), 3.77 (s, 3H,
CH3O), 4.19 (t, J¼6.2 Hz, 1H, 4-H), 4.40 (s, 2H, PMB
CH2), 4.41–4.54 (m, 2H, 1-H, 50-H), 6.85 (d, J¼8.7 Hz,
2H, CHar, meta), 7.24 (d, J¼8.4 Hz, 2H, CHar, ortho), 7.30–
7.45 (m, 6H, phenyl), 7.60–7.73 (m, 4H, phenyl); 13C
NMR (100 MHz, CDCl3): d [ppm]¼ꢂ5.2 (Si(CH3)2), ꢂ4.6
(Si(CH3)2), 18.1 (Si(CH3)2C(CH3)3), 19.3 (Si(Ph)2C(CH3)3),
21.8 (C-6), 22.6 (C-40), 25.7 (Si(CH3)2C(CH3)3), 26.8
(Si(Ph)2C(CH3)3), 27.9 (C-30), 29.3 (C-7), 38.0 (C-5), 55.2
(CH3O), 62.6 (C-4), 65.5 (C-1), 69.9 (C-8), 72.5 (PMB
CH2), 80.3 (C-2), 80.6 (C-50), 88.7 (C-3), 113.7 (CHar, meta),
127.5 (phenyl), 127.8 (phenyl), 129.2 (CHar, ortho), 129.8
(phenyl), 130.0 (phenyl), 130.7 (CHar), 132.6 (phenyl),
132.8 (phenyl), 135.7 (phenyl), 135.9 (phenyl), 159.0 (Car,
para), 176.7 (C-20).
CH2Cl2. The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography (petroleum ether/EtOAc,
15:1) to give 1.25 g (75%) of alcohol 22 as light yellow
oil. Rf¼0.53 (petroleum ether/EtOAc, 6:1); [a]2D0 ꢂ10.3 (c
1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3): d [ppm]¼
0.02 (s, 6H, 1-OSi(CH3)2), 0.03 (s, 6H, 8-OSi(CH3)2),
0.84 (s, 9H, 1-OSi(CH3)2C(CH3)3), 0.88 (s, 9H, 8-
OSi(CH3)2C(CH3)3), 1.06 (s, 9H, OSi(Ph)2C(CH3)3), 1.17–
1.91 (m, 10H, 2-H, 3-H, 9-H, 10-H, 11-H), 2.64 (s, 1H,
OH), 3.36 (t, J¼6.7 Hz, 2H, 12-H), 3.57–3.64 (m, 3H, 1-
H, 4-H), 3.79 (s, 3H, CH3O), 4.11 (t, J¼5.6 Hz, 1H, 8-H),
4.27 (d, J¼6.4 Hz, 1H, 5-H), 4.42 (s, 2H, PMB CH2), 6.87
(d, J¼8.7 Hz, 2H, CHar, meta), 7.25 (d, J¼8.7 Hz, 2H,
CHar, ortho), 7.29–7.45 (m, 6H, phenyl), 7.63–7.76 (m,
4H, phenyl); 13C NMR (100 MHz, CDCl3): d [ppm]¼ꢂ5.3
(1-OSi(CH3)2), ꢂ5.1 (8-OSi(CH3)2), ꢂ4.5 (8-OSi(CH3)2),
18.1 (1-OSi(CH3)2C(CH3)3), 18.3 (8-OSi(CH3)2C(CH3)3),
19.3 (OSi(Ph)2C(CH3)3), 21.8 (C-10), 25.7 (8-
OSi(CH3)2C(CH3)3), 26.0 (1-OSi(CH3)2C(CH3)3), 26.9
(OSi(Ph)2C(CH3)3), 28.8 (C-11), 29.1 (C-2), 29.3 (C-3),
38.0 (C-9), 55.2 (CH3O), 62.6 (C-8), 63.3 (C-1), 68.1 (C-
5), 70.0 (C-12), 72.5 (PMB CH2), 74.8 (C-4), 82.0 (C-6),
88.5 (C-7), 113.7 (CHar, meta), 127.4 (phenyl), 127.7 (phen-
yl), 129.2 (CHar, ortho), 129.6 (phenyl), 129.9 (phenyl),
130.7 (Car), 133.0 (phenyl), 133.3 (phenyl), 135.8 (phenyl),
136.0 (phenyl), 159.1 (Car, para); HRMS (ESI): [M+Na]+
calcd for C48H76O6Si3 855.48419, found 855.48473.
4.1.12. (4R,5R,8R)-8-{[tert-Butyl(dimethyl)silyl]oxy}-5-
{[tert-butyl(diphenyl)silyl]oxy}-12-[(para-methoxybenz-
yl)oxy]dodec-6-yne-1,4-diol (20) and (4R,5R,8R)-8-{[tert-
butyl(dimethyl)silyl]oxy}-12-[(para-methoxybenzyl)-
oxy]dodec-6-yne-1,4,5-triol (21). A suspension of LiAlH4
(80 mg, 2.1 mmol, 1.5 equiv) in THF (15 mL) was cooled
to 0 ꢀC and a solution of lactone 19 (1.0 g, 1.4 mmol,
1 equiv) in THF (20 mL) was added dropwise. The mixture
was stirred for 15 min. This was followed by the addition
of saturated NH4Cl solution and separation of the layers.
The aqueous layer was extracted twice with EtOAc. The
combined organic layers were dried over MgSO4, filtered,
and concentrated in vacuo. The crude mixture of diol 20
and triol 21 was used in the following step without further pu-
rification. Rf (20)¼0.15 (petroleum ether/EtOAc, 3:1); Rf
(21)¼0.01 (petroleum ether/EtOAc, 3:1).
4.1.14. (4R,5R,8R)-1,8-Di-{[tert-butyl(dimethyl)silyl]-
oxy}-12-[(para-methoxybenzyl)oxy]dodec-6-yne-4,5-diol
(23). (DHQD)2PHAL (4.3 mg, cat.), K3Fe(CN)6 (532 mg,
1.6 mmol, 3 equiv), K2CO3 (226 mg, 1.6 mmol, 3 equiv),
and K2OsO2(OH)4 (1 mg, cat.) were dissolved in a 1:1 mix-
ture of water (3 mL) and tert-butyl alcohol (3 mL). MeS-
O2NH2 (52 mg, 0.54 mmol, 1 equiv) was added and the
vigorously stirred solution was cooled to 0 ꢀC. At this point
the enyne 16 (300 mg, 0.53 mmol) was added in one portion
and the mixture allowed to warm to room temperature within
4 h. Stirring was continued for 10 h before the reaction was
quenched by addition of solid Na2SO3 (770 mg). The solu-
tion was extracted twice with EtOAc. The combined organic
layers were dried over MgSO4, filtered, and concentrated
in vacuo. The residue was purified by flash chromatography
(petroleum ether/EtOAc, 6:1) to give 243 mg (77%) of diol
23 as light yellow oil. Rf¼0.25 (petroleum ether/EtOAc,
4.1.13. (4R,5R,8R)-1,8-Di-{[tert-butyl(dimethyl)silyl]-
oxy}-5-{[tert-butyl(diphenyl)silyl]oxy}-12-[(para-meth-
oxybenzyl)oxy]dodec-6-yne-4-ol (22).
4.1.13.1. By selective silylation of the primary alcohol
function of diol 20. A crude mixture of diol 20 and triol 21
(1.0 g, max. 1.4 mmol) was dissolved in DMF (13 mL) fol-
lowed by the addition of imidazole (145 mg, 2.1 mmol,
1.5 equiv) and DMAP (cat.). At 0 ꢀC TBSCl (250 mg,
1.55 mmol, 1.1 equiv) was added and the mixture was stirred
for 1 h at room temperature before it was diluted with Et2O.
Now, H2O was added and after separation of the layers, the
organic layer was washed with saturated NaCl solution,
dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography (petroleum
ether/EtOAc, 9:1) to give 525 mg (45%, over 2 steps) of al-
cohol 22 and 350 mg (42%, over 2 steps) of diol 23 as light
yellow oils.
1
6:1); [a]2D0 +20.2 (c 1.00, CH2Cl2); H NMR (400 MHz,
CDCl3): d [ppm]¼0.06 (s, 6H, 1-OSi(CH3)2), 0.08, 0.11 (2s,
3H each, Si(CH3)2), 0.88 (s, 9H, 1-OSi(CH3)2C(CH3)3), 0.89
(s, 9H, 8-OSi(CH3)2C(CH3)3), 1.34–1.92 (m, 10H, 2-H, 3-H,
9-H, 10-H, 11-H), 3.42 (t, J¼6.5 Hz, 2H, 12-H), 3.52–3.73
(m, 3H, 4-H, 1-H), 3.79 (s, 3H, CH3O), 4.16 (d, J¼6.9 Hz,
1H, 5-H), 4.35 (t, J¼5.7 Hz, 1H, 8-H), 4.41 (s, 2H, PMB
CH2), 6.86 (d, J¼8.7 Hz, 2H, CHar, meta), 7.24 (d,
J¼8.4 Hz, 2H, CHar, ortho); 13C NMR (100 MHz, CDCl3):
d [ppm]¼ꢂ5.4 (1-OSi(CH3)2), ꢂ5.0 (8-OSi(CH3)2), ꢂ4.5
(8-OSi(CH3)2), 18.2 (1-OSi(CH3)2C(CH3)3), 18.3 (8-OSi-
(CH3)2C(CH3)3), 21.9 (C-10), 25.8 (8-OSi(CH3)2C(CH3)3),
25.9 (1-OSi(CH3)2C(CH3)3), 28.9 (C-11), 29.3 (C-2),
30.3 (C-3), 38.2 (C-9), 55.2 (CH3O), 62.8 (C-8), 63.5
(C-1), 66.3 (C-5), 69.9 (C-12), 72.5 (PMB CH2), 74.6
(C-4), 82.2 (C-6), 87.8 (C-7), 113.7 (CHar, meta), 129.2
(CHar, ortho), 130.6 (Car), 159.1 (Car, para); HRMS
4.1.13.2. By selective silylation of diol 23. To a stirred
solution of diol 23 (1.18 g, 2 mmol) in CH2Cl2 (10 mL)
was added imidazole (405 mg, 6.0 mmol, 3 equiv). After
cooling to 0 ꢀC TBDPSCl (0.58 mL, 2.2 mmol, 1.1 equiv)
was added and the mixture stirred for 3 h. This was followed
by the addition of saturated NaCl solution and separation
of the layers. The aqueous layer was extracted twice with

J. Ja€gel et al. / Tetrahedron 63 (2007) 13006–13017
13013
(ESI): [M+Na]+ calcd for C32H58O6Si2 617.36641, found
617.36628.
PMB), 55.7 (CH3OCH2), 62.1 (C-8), 62.8 (C-1), 66.4 (C-5),
69.9 (C-12), 72.6 (PMB CH2), 80.6 (C-4), 83.3 (C-7), 87.6
(C-6), 97.1 (CH3OCH2O), 113.8 (CHar, meta), 127.4 (phenyl),
127.7 (phenyl), 129.3 (CHar, ortho), 129.7 (phenyl), 129.9
(phenyl), 130.6 (Car), 133.0 (phenyl), 133.7 (phenyl), 135.8
(phenyl), 136.1 (phenyl), 159.1 (Car, para); HRMS (ESI):
[M+Na]+ calcd for C38H52O7Si 671.33745, found 671.33814.
4.1.15. (4R,5R,8R)-1,8-Di-{[tert-butyl(dimethyl)silyl]-
oxy}-5-{[tert-butyl(diphenyl)silyl]oxy}-12-[(para-meth-
oxybenzyl)oxy]-4-(methoxymethoxy)dodec-6-yne (24). To
a stirred solution of 6-yne-4-ol 22 (1.2 g, 1.44 mmol) in
CH2(OCH3)2 (22 mL), were added LiBr (46 mg, 0.4 equiv)
and para-toluenesulfonic acid (46 mg, 0.2 equiv) at room
temperature and followed by stirring of the mixture for 4
days. The mixture was treated with saturated NaCl solution
and extracted twice with Et2O. The combined organic layers
were dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by flash chromatography (petro-
leum ether/EtOAc, 10:1) to give 1.03 g (82%) of MOM ether
24 as light yellow oil. Rf¼0.60 (petroleum ether/EtOAc,
4.1.17. (4R,5R,6E,8R)-5-{[tert-Butyl(diphenyl)silyl]oxy}-
12-[(para-methoxybenzyl)oxy]-4-(methoxymethoxy)do-
dec-6-ene-1,8-diol (26). To a stirred solution of alkynediol
25 (470 mg, 0.72 mmol) in THF (25 mL) was added at 0 ꢀC
a solution of Red-Al (1.2 mL, 65% in toluene, 4.0 mmol,
5.5 equiv). The mixture was allowed to warm to room tem-
perature and stirring was continued for 12 h. After being
quenched with 1 N HCl, the mixture was extracted twice
with Et2O. The combined organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by flash chromatography (petro-
leum ether/EtOAc, 1:3) to give 375 mg (80%) of allylic alco-
hol 26 as light yellow oil. Rf¼0.20 (petroleum ether/EtOAc,
1:3); [a]2D0 +8.7 (c 1.00, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d [ppm]¼1.06 (s, 9H, Si(Ph)2C(CH3)3), 1.17–1.69
(m, 10H, 2-H, 3-H, 9-H, 10-H, 11-H), 3.23 (s, 3H, CH3O-
CH2O), 3.32–3.43 (m, 3H, 4-H, 12-H), 3.56 (t, J¼6.2 Hz,
2H, 1-H), 3.79 (s, 3H, CH3O), 3.88–3.99 (m, 1H, 8-H),
4.30–4.49 (m, 5H, 5-H, CH3OCH2O, PMB CH2), 5.40–5.53
(m, 1H, 6-H), 5.54–5.66 (m, 1H, 7-H), 6.86 (d, J¼8.7 Hz,
2H, CHar, meta), 7.24 (d, J¼8.4 Hz, 2H, CHar, ortho), 7.29–
7.48 (m, 6H, phenyl), 7.57–7.71 (m, 4H, phenyl); 13C NMR
(100 MHz, CDCl3): d [ppm]¼19.3 (Si(Ph)2C(CH3)3), 22.0
(C-10), 26.1 (C-11), 27.0 (Si(Ph)2C(CH3)3), 29.0 (C-3),
29.6 (C-2), 36.6 (C-9), 55.2 (CH3O PMB), 55.7 (CH3O-
CH2O), 62.8 (C-1), 69.9 (C-12), 72.2 (C-8), 72.5 (PMB
CH2), 74.4 (C-5), 81.3 (C-4), 97.0 (CH3OCH2O), 113.7
(CHar, meta), 127.5 (phenyl), 127.6 (phenyl), 128.8 (CHar,
ortho), 129.3 (C-6), 129.7 (phenyl), 129.8 (phenyl), 130.6
(Car), 133.7 (phenyl), 133.9 (phenyl), 135.3 (C-7), 135.9
(phenyl), 135.9 (phenyl), 159.1 (Car, para); HRMS (ESI):
[M+Na]+ calcd for C38H54O7Si 673.35310, found
673.35320.
1
6:1); [a]2D0 ꢂ4.0 (c 1.00, CH2Cl2); H NMR (400 MHz,
CDCl3): d [ppm]¼0.03 (s, 6H, 1-OSi(CH3)2), 0.04 (s, 6H,
8-OSi(CH3)2), 0.84 (s, 9H, 1-OSi(CH3)2C(CH3)3), 0.89 (s,
9H, 8-OSi(CH3)2C(CH3)3), 1.05 (s, 9H, OSi(Ph)2C(CH3)3),
1.18–2.01 (m, 10H, 2-H, 3-H, 9-H, 10-H, 11-H), 3.20 (s,
3H, CH3OCH2O), 3.31–3.46 (m, 3H, 4-H, 12-H), 3.53–3.69
(m, 2H, 1-H), 3.79 (s, 3H, CH3O), 4.14–4.26 (m, 1H, 8-H),
4.34–4.55 (m, 5H, 5-H, CH3OCH2O, PMB CH2), 6.86 (d, J¼
8.7 Hz, 2H, CHar, meta), 7.25 (d, J¼8.4 Hz, 2H, CHar, ortho),
7.29–7.45 (m, 6H, phenyl), 7.61–7.75 (m, 4H, phenyl); 13C
NMR (100 MHz, CDCl3): d [ppm]¼ꢂ5.3 (1-OSi(CH3)2),
ꢂ4.5 (8-OSi(CH3)2), 18.1 (1-OSi(CH3)2C(CH3)3), 18.3 (8-
OSi(CH3)2C(CH3)3), 19.2 (OSi(Ph)2C(CH3)3), 21.8 (C-10),
25.8 (8-OSi(CH3)2C(CH3)3), 26.0 (1-OSi(CH3)2C(CH3)3),
26.9 (OSi(Ph)2C(CH3)3), 27.0 (C-11), 29.2 (C-3), 29.4 (C-
2), 38.2 (C-9), 55.2 (CH3O PMB), 55.5 (CH3OCH2), 62.7
(C-8), 63.3 (C-1), 66.2 (C-5), 70.0 (C-12), 72.5 (PMB
CH2), 80.8 (C-4), 82.3 (C-6), 87.6 (C-7), 96.9 (CH3OCH2O),
113.7 (CHar, meta), 127.4 (phenyl), 127.6 (phenyl), 129.1
(CHar, ortho), 129.5 (phenyl), 129.8 (phenyl), 130.7 (Car),
133.3 (phenyl), 133.4 (phenyl), 135.8 (phenyl), 135.9 (phen-
yl), 159.4 (Car, para); HRMS (ESI): [M+Na]+ calcd for
C50H80O7Si3 899.51041, found 899.51123.
4.1.16. (4R,5R,8R)-5-{[tert-Butyl(diphenyl)silyl]oxy}-12-
[(para-methoxybenzyl)oxy]-4-(methoxymethoxy)dodec-
6-yne-1,8-diol (25). The fully protected dodec-6-yne derivative
24 (930 mg, 1.06 mmol) was dissolved in a 1:1 mixture of
methanol (8 mL) and CH2Cl2 (8 mL). CSA (cat.) was added
and the mixture stirred at room temperature for 4 h. The reac-
tion was quenched with saturated NaHCO3 solution and the
mixture extracted twice with CH2Cl2. The combined organic
layers were dried over MgSO4, filtered, and concentrated
in vacuo. The residue was purified by flash chromatography
(petroleum ether/EtOAc, 1:3) to give 470 mg (69%) of diol
25 as light yellow oil. Rf¼0.37 (petroleum ether/EtOAc, 1:3);
4.1.18. (4R,5R,6E,8R)-5-{[tert-Butyl(diphenyl)silyl]oxy}-
8-hydroxy-12-[(para-methoxybenzyl)oxy]-4-(methoxy-
methoxy)dodec-6-enal (27). To a stirred solution of 1,8-diol
26 (50 mg, 0.077 mmol) in CH2Cl2 (5 mL) was added a solid
mixture of PhI(OAc)2 (55 mg, 0.17 mmol, 2.2 equiv) and
TEMPO (3 mg, 0.017 mmol, 0.22 equiv). After stirring at
air for 6 h, TLC showed complete conversion to the alde-
hyde. The reaction was quenched with 10% Na2S2O3 solu-
tion and the product was extracted twice with CH2Cl2. The
combined organic layers were washed with NaHCO3 solu-
tion and water, dried over MgSO4, filtered, and concentrated
in vacuo. The residue was used without further purification.
An analytical sample was subjected to flash chromatography
(petroleum ether/EtOAc, 1.5:1). Rf¼0.48 (petroleum ether/
1
[a]2D0 ꢂ22.5 (c 1.00, CH2Cl2); H NMR (400 MHz, CDCl3):
d [ppm]¼1.05 (s, 9H, Si(Ph)2C(CH3)3), 1.27–1.80 (m, 10H,
2-H, 3-H, 9-H, 10-H, 11-H), 3.27 (s, 3H, CH3OCH2O), 3.39
(t, J¼6.6 Hz, 2H, 12-H), 3.50–3.58 (m, 1H, 4-H), 3.62 (t,
J¼5.7 Hz, 2H, 1-H), 3.79 (s, 3H, CH3O), 4.01–4.18 (m, 1H,
8-H), 4.41 (s, 2H, PMB CH2), 4.46–4.66 (m, 3H, 5-H, CH3O-
CH2O), 6.86 (d, J¼8.7 Hz, 2H, CHar, meta), 7.24 (d, J¼7.1 Hz,
2H, CHar, ortho), 7.30–7.49 (m, 6H, phenyl), 7.63–7.78 (m,
4H, phenyl); 13C NMR (100 MHz, CDCl3): d [ppm]¼19.2
(OSi(Ph)2C(CH3)3), 21.8 (C-10), 26.8 (OSi(Ph)2C(CH3)3),
27.0 (C-3), 28.7 (C-11), 29.3 (C-2), 37.1 (C-9), 55.3 (CH3O
1
EtOAc, 1:2); H NMR (400 MHz, CDCl3): d [ppm]¼1.07
(s, 9H, Si(Ph)2C(CH3)3), 1.17–1.70 (m, 8H, 3-H, 9-H, 10-
H, 11-H), 2.36–2.56 (m, 2H, 2-H), 3.21 (s, 3H, CH3OCH2O),
3.27–3.36 (m, 1H, 4-H), 3.40 (t, J¼6.6 Hz, 2H, 12-H), 3.79
(s, 3H, CH3O PMB), 3.91–4.00 (m, 1H, 8-H), 4.29–4.39
(m, 3H, 5-H, CH3OCH2O), 4.41 (s, 2H, PMB CH2), 5.43–
5.73 (m, 2H, 6-H, 7-H), 6.86 (d, J¼8.7 Hz, 2H, CHar,

13014
J. Ja€gel et al. / Tetrahedron 63 (2007) 13006–13017
meta), 7.24 (d, J¼6.9 Hz, 2H, CHar, ortho), 7.29–7.47 (m,
6H, phenyl), 7.58–7.71 (m, 4H, phenyl), 9.70 (s, 1H, 1-H);
13C NMR (100 MHz, CDCl3): d [ppm]¼19.3 (OSi(Ph)2-
C(CH3)3), 22.1 (C-10), 22.3 (C-3), 27.0 (OSi(Ph)2C(CH3)3),
29.6 (C-11), 36.7 (C-9), 40.5 (C-2), 55.3 (CH3O PMB), 55.7
(CH3OCH2O), 70.0 (C-12), 72.1 (C-8), 72.5 (PMB CH2),
74.0 (C-4), 80.6 (C-5), 97.1 (CH3OCH2O), 113.7 (CHar,
meta), 127.5 (phenyl), 127.7 (phenyl), 128.2 (C-6), 129.2
(CHar, ortho), 129.7 (phenyl), 129.9 (phenyl), 130.7 (Car),
133.6 (phenyl), 133.8 (phenyl), 135.5 (C-7), 135.9 (phenyl),
135.9 (phenyl), 159.1 (Car, para), 202.3 (C-1).
3.32–3.45 (m, 3H, 5-H, 13-H), 3.79 (s, 3H, CH3O PMB),
4.01–4.11 (m, 1H, 9-H), 4.22–4.32 (m, 2H, CH3OCH2O),
4.33–4.38 (m, 1H, 6-H), 4.42 (s, 2H, PMB CH2), 5.53–5.68
(m, 2H, 7-H, 8-H), 6.86 (d, J¼8.7 Hz, 2H, CHar, meta),
7.22–7.28 (m, 2H, CHar, ortho), 7.29–7.46 (m, 6H, phenyl),
7.56–7.73 (m, 4H, phenyl); 13C NMR (100 MHz, CDCl3):
d [ppm]¼ꢂ4.9 (Si(CH3)2), ꢂ4.4 (Si(CH3)2), 14.9 (C-3),
18.2 (Si(CH3)2C(CH3)3), 19.3 (Si(Ph)2C(CH3)3), 21.9 (C-
11), 25.9 (Si(CH3)2C(CH3)3), 27.1 (Si(Ph)2C(CH3)3), 28.4
(C-12), 29.8 (C-4), 38.2 (C-10), 55.3 (CH3O PMB), 55.5
(CH3OCH2O), 68.4 (C-1), 70.2 (C-13), 72.5 (C-9), 73.0
(PMP CH2), 73.6 (C-6), 79.9 (C-5), 84.3 (C-2), 97.0 (CH3O-
CH2O), 113.7 (CHar, meta), 127.2 (C-7), 127.5 (phenyl),
127.6 (phenyl), 129.2 (CHar, ortho), 129.6 (phenyl), 129.8
(phenyl), 130.8 (Car), 133.7 (phenyl), 133.9 (phenyl), 135.6
(C-8), 135.9 (phenyl), 136.0 (phenyl), 159.1 (Car, para);
HRMS (ESI): [M+Na]+ calcd for C45H66O6Si2 781.42901,
found 781.43091.
4.1.19. (5R,6E,8R,9R)-8-{[tert-Butyl(diphenyl)silyl]oxy}-1-
[(para-methoxybenzyl)oxy]-9-(methoxymethoxy)tridec-6-
en-12-yn-5-ol(29). Diethyl-1-diazo-2-oxopropylphosphonate
(28) (25 mg, 0.12 mmol, 1.5 equiv) was added to a stirred so-
lution of hydroxy aldehyde 27 (max. 0.077 mmol, 1 equiv,
crude) and K2CO3 (20 mg, 2 equiv) and stirring was contin-
ued for 12 h. The reaction mixture was diluted with Et2O and
washed with NaHCO3 solution. The organic layer was dried
over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by flash chromatography (petroleum ether/
EtOAc, 1.5:1) to give 25 mg (51%, over 2 steps) of alkynol 29
as light yellow oil. Rf¼0.60 (petroleum ether/EtOAc, 1:1);
4.1.21. (4S)-3-[(2S,30R,50E)-30-Hydroxy-60-iodo-20,50-di-
methyl-5-hexenoyl]-4-isopropyl-1,3-oxazolidin-2-one
(33). To a solution of (3E)-4-iodo-3-methyl-3-buten-1-ol26
(2.02 g, 9.54 mmol) in CH2Cl2 (50 mL) was added NaHCO3
(4.00 g, 47.70 mmol, 5 equiv) followed by Dess–Martin
periodinane (15% in CH2Cl2, 21.78 mL, 10.49 mmol,
1.1 equiv)atroomtemperature. After20 min, a1:1:1solution
(50 mL) of saturated Na2S2O3 solution, saturated NaHCO3
solution, and water was added and the mixture stirred vigor-
ously for 30 min. The aqueous layer was extracted twice
with CH2Cl2. The combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo. To the resulting
oil Et2O was added, the white solid formed was filtered and
the filtrate was concentrated again. The crude aldehyde 31
was used for the aldol reaction without further purification.
To a solution of 4-isopropyl-3-propionyl-1,3-oxazolidin-
2-one27 (32) (1.59 g, 8.59 mmol, 0.9 equiv) in CH2Cl2
(17 mL) was added di-n-butylboryl triflate (1 M in CH2Cl2,
9.54 mL, 9.54 mmol, 1.0 equiv) at 0 ꢀC. The resulting brown
solution was stirred for 10 min, then iPr2NEt (1.78 mL,
10.49 mmol, 1.1 equiv) was added, resulting in a color
change from red to light yellow. The mixture was stirred
for 1 h at 0 ꢀC and cooled to ꢂ80 ꢀC. Now, a solution of
the above aldehyde 31 in CH2Cl2 (3 mL) was added and stir-
ring was continued for 1 h at ꢂ80 ꢀC. The reaction mixture
was allowed to warm to 0 ꢀC over 30 min and strirred for
30 min at this temperature. The reaction was quenched
with pH 7 phosphate buffer (10 mL), MeOH (35 mL), finally
treated with a mixture of MeOH/H2O2 (2:1, 35 mL), allowed
to warm to room temperature and stirred for 1 h. Most of the
organic solvents were removed by rotary evaporation and
the aqueous layer was extracted twice with diethyl ether.
The combined extracts were washed with saturated NaHCO3
solution, saturated NaCl solution, dried over NaSO4, filtered,
and concentrated in vacuo. The crude product was purified
by flash chromatography (petroleum ether/ethyl acetate,
3:1) to afford the aldol product 33 (2.48 g, 72% over two
steps) as a light yellow oil. Rf¼0. 36 (petroleum ether/EtOAc,
1
[a]2D0 +8.1 (c 1.00, CH2Cl2); H NMR (400 MHz, CDCl3):
d [ppm]¼1.07 (s, 9H, Si(Ph)2C(CH3)3), 1.16–1.70 (m, 8H,
2-H, 3-H, 4-H, 10-H), 1.90 (s, 1H, 13-H), 2.12–2.36 (m, 2H,
11-H), 3.21 (s, 3H, CH3OCH2O), 3.39 (t, J¼6.6 Hz, 2H, 1-H),
3.49–3.56 (m, 1H, 9-H), 3.78 (s, 3H, CH3O PMB), 3.89–4.02
(m, 1H, 5-H), 4.32–4.47 (m, 5H, 8-H, CH3OCH2O, PMB
CH2), 5.47–5.57 (m, 1H, 7-H), 5.58–5.67 (m, 1H, 6-H), 6.86
(d, J¼8.4 Hz, 2H, CHar, meta), 7.21–7.27 (m, 2H, CHar,
ortho), 7.29–7.47 (m, 6H, phenyl), 7.58–7.72 (m, 4H, phenyl);
13C NMR (100 MHz, CDCl3): d [ppm]¼14.6 (C-11), 19.0
(OSi(Ph)2C(CH3)3), 21.8 (C-3), 26.7 (OSi(Ph)2C(CH3)3),
28.2 (C-2), 29.3 (C-10), 36.4 (C-4), 55.0 (CH3O PMB), 55.4
(CH3OCH2O), 68.3 (C-13), 69.7 (C-1), 71.8 (C-5), 72.2
(PMB CH2), 73.4 (C-8), 79.5 (C-9), 83.8 (C-12), 96.8 (CH3O-
CH2O), 113.5 (CHar, meta), 127.2 (phenyl), 127.3 (phenyl),
128.2 (C-7), 128.9 (CHar, ortho), 129.4 (phenyl), 129.5 (phen-
yl), 130.4 (Car), 133.3 (phenyl), 133.6 (phenyl), 135.0 (C-6),
135.6 (phenyl), 135.7 (phenyl), 158.8 (Car, para); HRMS
(ESI): [M+Na]+ calcd for C39H52O6Si 667.34254, found
667.34281.
4.1.20. (5R,6R,7E,9R)-9-{[tert-Butyl(dimethyl)silyl]oxy}-
6-{[tert-butyl(diphenyl)silyl]oxy}-13-[(para-methoxybenz-
yl)oxy]-5-(methoxymethoxy)tridec-7-en-1-yne (30). To a
stirred solution of alkynol 29 (77 mg, 0.12 mmol) in CH2Cl2
(1 mL), 2,6-lutidine (47 mL, 0.36 mmol, 3 equiv) was added.
At 0 ꢀC TBSOTf (42 mL, 0.18 mmol, 1.5 equiv) was added
dropwise and the mixture stirred for 40 min. The mixture
was diluted with CH2Cl2 and the organic layer washed
with H2O, 1 N HCl, and saturated NaHCO3 solution, dried
over MgSO4 and filtered. The filtrate was concentrated in va-
cuo and the residue purified by flash chromatography (petro-
leum ether/EtOAc, 10:1) to give 85 mg (93%) of alkyne 30
as colorless oil. Rf¼0.48 (petroleum ether/EtOAc, 10:1);
1
3:1); [a]2D0 +50.2 (c 1.02, CH2Cl2); H NMR (400 MHz,
1
[a]2D0 +7.4 (c 1.00, CH2Cl2); H NMR (400 MHz, CDCl3):
CDCl3): d [ppm]¼0.85 (d, J¼7.1 Hz, 3H, CH(CH3)2), 0.90
(d, J¼7.1 Hz, 3H, CH(CH3)2), 1.25 (d, J¼7.1 Hz, 3H, 20-
CH3), 1.86 (d, J¼0.8 Hz, 3H, 50-CH3), 2.24–2.37 (m, 2H,
40-H, CH(CH3)2), 2.39–2.49 (m, 1H, 40-H), 2.77 (br s, 1H,
OH), 3.71–3.80 (m, 1H, 20-H), 4.05–4.13 (m, 1H, 30-H),
d [ppm]¼0.00, 0.02 (2s, 3H each, Si(CH3)2), 0.86 (s, 9H,
Si(CH3)2C(CH3)3), 1.07 (s, 9H, Si(Ph)2C(CH3)3), 1.14–
1.67 (m, 8H, 4-H, 10-H, 11-H, 12-H), 1.88 (t, J¼2.5 Hz,
1H, 1-H), 2.07–2.33 (m, 2H, 3-H), 3.17 (s, 3H, CH3OCH2O),

J. Ja€gel et al. / Tetrahedron 63 (2007) 13006–13017
13015
4.19 (dd, J¼9.1, 3.0 Hz, 1H, 5-H), 4.28 (t, J¼8.7 Hz, 1H,
5-H), 4.44 (dt, J¼3.4, 8.4 Hz, 1H, 4-H), 6.02 (s, 1H, H-60);
13C NMR (100 MHz, CDCl3): d [ppm]¼11.6 (20-CH3),
14.6 (CH(CH3)2), 17.9 (CH(CH3)2), 24.0 (50-CH3), 28.3
(CH(CH3)2), 42.1 (C-20), 44.1 (C-40), 58.2 (C-4), 63.3 (C-
5), 69.0 (C-30), 77.4 (C-60), 144.7 (C-50), 153.5 (C-2),
176.9 (C-10); HRMS (ESI): [M+Na]+ calcd for
C14H22INO4 418.04857, found 418.04898.
a dropwise fashion. After 1.5 h the reaction was quenched
with saturated Na, K-tartrate solution and the mixture stirred
vigorously at room temperature for 1 h. The aqueous layer
was extracted twice with CH2Cl2 and the combined organic
layers were dried over NaSO4, filtered, and concentrated in
vacuo. Flash chromatography (petroleum ether/EtOAc,
10:1) of the residue provided hexenol 36 (0.96 g, 84%) as a
colorless oil. Rf¼0. 38 (petroleum ether/ethyl acetate, 10:1);
1
[a]2D0 +6.0 (c 1.00, CH2Cl2); H NMR (400 MHz, CDCl3):
4.1.22. Methyl (2S,3R,5E)-3-hydroxy-6-iodo-2,5-di-
methyl-5-hexenoate (34). To a solution of aldol product
33 (1.38 g, 3.48 mmol) in CH2Cl2 (30 mL) at ꢂ30 ꢀC was
added dropwise NaOMe (0.5 M in MeOH, 8.35 mL,
4.18 mmol, 1.2 equiv). The reaction mixture was allowed
to warm to 0 ꢀC and stirred for 10 min at this temperature be-
fore saturated NH4Cl (9 mL) solution was added. The aque-
ous layer was extracted twice with CH2Cl2 and the combined
organic layers were dried over NaSO4, filtered, and concen-
trated in vacuo to afford 1.35 g of the crude product. The
residue was used for the next reaction without further purifi-
cation. For analytical purposes a small amount was purified
by flash chromatography (petroleum ether/ethyl acetate,
4:1). Rf¼0. 27 (petroleum ether/EtOAc, 4:1); [a]2D0 +20.4
d [ppm]¼0.57 (q, J¼7.6 Hz, 6H, CH3CH2Si), 0.81 (d, J¼
6.9 Hz, 3H, 2-CH3), 0.94 (t, J¼8.8 Hz, 9H, CH3CH2Si),
1.83 (d, J¼0.9 Hz, 3H, 5-CH3), 1.84–1.93 (m, 1H, 2-H),
2.38 (dd, J¼6.6, 0.6 Hz, 2H, 4-H), 2.46–2.51 (m, 1H, OH),
3.48–3.56 (m, 1H, 1-H), 3.59–3.68 (m, 1H, 1-H), 3.96 (dt,
J¼6.7, 2.9 Hz, 1H, 3-H), 5.92–5.99 (m, 1H, 6-H); 13C
NMR (100 MHz, CDCl3): d [ppm]¼5.0 (CH3CH2Si), 6.9
(CH3CH2Si), 11.4 (2-CH3), 24.1 (5-CH3), 39.6 (C-2), 43.1
(C-4), 65.7 (C-1), 72.9 (C-3), 77.7 (C-6), 144.5 (C-5);
HRMS (ESI): [M+Na]+ calcd for C14H29IO2Si 407.08737,
found 407.08736.
4.1.25. (2S,5E)-6-Iodo-2,5-dimethyl-3-[(triethylsilyl)-
oxy]-5-hexenal (37). To a solution of alcohol 36 (0.32 g,
0.84 mmol) in CH2Cl2 (16 mL) was added NaHCO3 (0.25 g,
2.95 mmol, 3.5 equiv) at room temperature, followed by
Dess–Martin periodinane (15% in CH2Cl2, 2.00 mL,
0.96 mmol, 1.1 equiv). After 30 min, saturated Na2S2O3 so-
lution (8 mL) was added and the mixture was stirred vigor-
ously for 30 min. The aqueous layer was extracted twice
with CH2Cl2 and the combined organic layers were dried
over Na2SO4, filtered, and concentrated in vacuo. To the re-
sulting oil was added Et2O, the white solid formed was fil-
tered off, and the filtrate concentrated in vacuo. The crude
aldehyde 37 was used for the subsequent Wittig reaction
without further purification. For analytical purposes a small
amount was purified by flash chromatography (petroleum
ether/EtOAc, 12:1). Rf¼0.56 (petroleum ether/ethyl acetate
1
(c 1.00, CH2Cl2); H NMR (400 MHz, CDCl3): d [ppm]¼
1.18 (d, J¼7.1 Hz, 3H, CH3C-2), 1.85 (s, 3H, 5-CH3),
2.24–2.41 (m, 2H, 4-H), 2.43–2.58 (m, 1H, 2-H, OH), 3.68
(s, 3H, OCH3), 4.00–4.08 (m, 1H, 3-H), 6.01 (s, 1H, 6-H);
13C NMR (100 MHz, CDCl3): d [ppm]¼10.9 (2-CH3),
23.9 (5-CH3), 43.9 (C-2), 43.9(C-4), 51.9 (OCH3), 69.2
(C-3), 77.5 (C-6), 144.4 (C-5), 176.0 (C-1); HRMS (ESI):
[M+Na]+ calcd for C9H15IO3 320.99581, found 320.99586.
4.1.23. Methyl (2S,3R,5E)-6-iodo-2,5-dimethyl-3-[(tri-
ethylsilyl)oxy]-5-hexenoate (35). After cooling a solution
of crude hydroxyester 34 in CH2Cl2 (22 mL) to 0 ꢀC, Et3N
(1.45 mL, 10.44 mmol, 3.0 equiv) was added. A catalytic
amount of DMAP was added and the reaction mixture was
stirred for 10 min before triethylsilyl chloride (1.17 mL,
6.96 mmol, 2.0 equiv) was added dropwise. The reaction
mixture was allowed to warm to room temperature. After
20 h the reaction was quenched with water. The aquous layer
was extracted twice with diethyl ether and the combined or-
ganic layers were washed with saturated NaCl solution,
dried over NaSO4, filtered, and concentrated in vacuo. The
crude product was purified by flash chromatography (petro-
leum ether/EtOAc, 20:1) to afford silyl ether 35 (1.22 g, 85%
over two steps) as a colorless oil. Rf¼0. 45 (petroleum ether/
ethyl acetate, 20:1); [a]2D0 +14.2 (c 1.00, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d [ppm]¼0.55 (q, J¼8.1 Hz, 6H,
CH3CH2Si), 0.93 (t, J¼7.9 Hz, 9H, CH3CH2Si), 1.12 (d,
J¼6.9 Hz, 3H, 2-CH3), 1.85 (d, J¼0.9 Hz, 3H, 5-CH3),
2.38 (d, J¼6.6 Hz, 2H, 4-H), 2.40–2.46 (m, 1H, 2-H), 3.66
(s, 3H, OCH3), 4.22 (dt, J¼6.6, 4.5 Hz, 1H, 3-H), 5.95–
5.97 (m, 1H, 6-H); 13C NMR (100 MHz, CDCl3): d [ppm]¼
5.0 (CH3CH2Si), 6.8 (CH3CH2Si), 10.8 (2-CH3), 24.1 (5-
CH3), 44.6 (C-4), 45.8 (C-2), 51.6 (OCH3), 70.9 (C-3), 78.1
(C-6), 144.4 (C-5), 175.2 (C-1); HRMS (ESI): [M+Na]+
calcd for C15H29IO3Si 435.08229, found 435.08235.
1
12:1); H NMR (400 MHz, CDCl3): d [ppm]¼0.55 (q, J¼
7.9 Hz, 6H, CH3CH2Si), 0.92 (t, J¼7.9 Hz, 9H, CH3CH2Si),
1.08 (d, J¼7.1 Hz, 3H, 2-CH3), 1.85 (d, J¼1.0 Hz, 3H,
5-CH3), 2.31–2.46 (m, 3H, 2-H, 4-H), 4.30 (dt, J¼6.7,
3.3 Hz 1H, 3-H), 5.96–6.01 (m, 1H, 6-H), 9.73 (s, 1H, 1-H);
13C NMR (100 MHz, CDCl3): d [ppm]¼5.0 (CH3CH2Si),
6.8 (CH3CH2Si), 7.5 (2-CH3), 24.2 (5-CH3), 44.9 (C-4),
51.0 (C-2), 69.6 (C-3), 78.4 (C-6), 144.4 (C-5), 204.6 (C-1).
4.1.26. Methyl (2E,4R,5R,7E)-8-iodo-2,4,7-trimethyl-
5-[(triethylsilyl)oxy]-2,7-octadienoate (39). (Methoxy-
carbonyl)ethylidenetriphenylphosphorane30 38 (0.50 g,
1.43 mmol, 1.7 equiv) was added to a solution of aldehyde
37 in toluene (10 mL). The reaction mixture was stirred for
5 h at 80 ꢀC, cooled to room temperature, filtered, and con-
centrated in vacuo. The crude product was purified by flash
chromatography (petroleum ether/EtOAc, 20:1) to afford di-
enoate 39 (0.30 g, 79% over two steps) as a colorless oil.
Rf¼0. 47 (petroleum ether/ethyl acetate, 20:1); [a]2D0 +28.4
1
(c 1.00, CH2Cl2); H NMR (400 MHz, CDCl3): d [ppm]¼
0.56 (q, J¼7.9 Hz, 6H, CH3CH2Si), 0.94 (t, J¼7.9 Hz, 9H,
CH3CH2Si), 0.98 (d, J¼6.9 Hz, 3H, 4-CH3), 1.82 (m, 6H,
2-CH3, 7-CH3), 2.27–2.41 (m, 2H, 6-H), 2.46–2.57 (m, 1H,
4-H), 3.69–3.74 (m, 4H, OCH3, 5-H), 5.90–5.93 (m, 1H, 8-
H), 6.60–6.65 (m, 1H, 3-H); 13C NMR (100 MHz, CDCl3):
d [ppm]¼5.1 (CH3CH2Si), 6.9 (CH3CH2Si), 12.7 (2-CH3),
4.1.24. (2R,3R,5E)-6-Iodo-2,5-dimethyl-3-[(triethylsilyl)-
oxy]-5-hexen-1-ol (36). To a solution of ester 35 (1.22 g,
2.96 mmol) in CH2Cl2 (30 mL) at ꢂ80 ꢀC was added DIBAL
(1 M in hexane, 8.88 mL, 8.88 mmol, 3.0 equiv) in

13016
J. Ja€gel et al. / Tetrahedron 63 (2007) 13006–13017
14.6 (4-CH3), 24.4 (7-CH3), 38.6 (C-4), 45.4 (C-6), 51.7
(OCH3), 73.5 (C-5), 77.9 (C-8), 127.0 (C-2), 144.5 (C-7),
144.8 (C-3), 168.6 (C-1); HRMS (ESI): [M+Na]+ calcd for
C18H33IO3Si 475.11359, found 475.11377.
CH2), 5.44–5.66 (m, 3H, 10-, 15-, 16-H), 5.72–5.79 (m, 1H,
8-H), 6.16 (dd, J¼14.9, 10.9 Hz, 1H, 9-H), 6.71 (d, J¼
10.2 Hz, 1H, 3-H), 6.86 (d, J¼8.7 Hz, 2H, CHar, meta),
7.24 (d, J¼6.4 Hz, 2H, CHar, para), 7.29–7.45 (m, 6H, phen-
yl), 7.56–7.71 (m, 4H, phenyl); 13C NMR (400 MHz, CDCl3):
d [ppm]¼ꢂ4.8 (17-OSi(CH3)2), ꢂ4.3 (17-OSi(CH3)2), 5.1
(SiCH2CH3), 6.9 (SiCH2CH3), 12.6 (2-CH3), 13.6 (4-CH3),
17.0 (7-CH3), 18.2 (17-OSiC(CH3)3), 18.6 (14-OSiC(CH3)3),
19.4 (C-11), 21.9 (C-19), 25.9 (17-OSiC(CH3)3), 27.1 (14-
OSiC(CH3)3), 29.7 (C-12), 29.8 (C-20), 37.9 (C-18), 38.2
(C-4), 46.0 (C-6), 51.6 (OCH3, ester), 55.3 (PMB CH3),
55.5 (MOM CH3), 70.2 (C-21), 72.5 (PMB CH2), 73.1 (C-
17), 73.7 (C-5), 74.0 (C-14), 81.8 (C-13), 96.9 (MOM
CH2), 113.8 (PMB, meta), 126.3 (C-2), 126.7 (C-9), 127.5
(phenyl), 127.5 (C-15), 127.6 (phenyl), 128.0 (C-8), 129.2
(PMB, ortho), 129.6 (phenyl), 129.7 (phenyl), 130.9 (PMB),
131.5 (C-7), 132.9 (C-10), 133.8 (phenyl), 134.1 (phenyl),
135.5 (C-16), 135.9 (phenyl), 135.9 (phenyl), 146.1 (C-3),
159.1 (PMB, para), 168.8 (C-1); HRMS (ESI): [M+Na]+
calcd for C63H100O9Si3 1107.65674, found 1107.65705.
4.1.27. Methyl (2E,4R,5R,7E,9E,13R,14R,15E,17R)-17-
{[tert-butyl(dimethyl)silyl]oxy}-14-{[tert-butyl(diphenyl)-
silyl]oxy}-21-[(para-methoxybenzyl)oxy]-13-(methoxy-
methoxy)-2,4,7-trimethyl-5-[(triethylsilyl)oxy]henicosa-
2,7,9,15-tetraenoate (40).
4.1.27.1. Via Suzuki coupling. To a stirred solution of
enyne 30 (10 mg, 0.013 mmol, 1 equiv) in THF (0.15 mL)
was added 9-BBN (34 mL, 0.5 M in THF, 0.017 mmol,
1.3 equiv) at 0 ꢀC. After stirring for 36 h at room temperature
the vinyl borane solution was used in the following coupling
step without further purification. To a stirred solution of dien-
oate39(8 mg,0.017 mmol,1.3 equiv)inDMF(0.2 mL)were
added AsPh3 (0.3 mg, 5 mol %), PdCl2(dppf) (0.8 mg,
5 mol %), Cs2CO3 (14 mg, 0.034 mmol, 2 equiv), and 2
drops of water at room temperature. After addition of the
vinyl borane solution stirring was continued for 72 h at
room temperature. The reaction was quenched with saturated
NH4Cl solution and the aqueous layer extracted twice with
EtOAc. The combined organic extracts were dried over
MgSO4, filtered, and concentrated in vacuo. The crude prod-
uct was purified by flash chromatography (petroleum ether/
EtOAc, 12:1) to afford 9 mg (67% over 2 steps) of coupling
product 40 as colorless oil. According to LC-MS this com-
pound contains the 9,10-dihydro derivative as a by-product.
The dihydro compound 41 was the only product when 9-
BBN was used in excess (3 equiv).
Compound 41: Rf¼0.45 (petroleum ether/EtOAc, 10:1);
[a]2D0 +64.5 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d [ppm]¼ꢂ0.01, 0.01 (2s, 3H each, Si(CH3)2), 0.57 (q,
J¼8.1 Hz, 6H, CH3CH2Si), 0.86 (s, 9H, Si(CH3)2C(CH3)3),
0.89–0.96 (m, 9H, CH3CH2Si), 0.97 (m, 3H, 4-CH3), 1.05 (s,
9H, Si(Ph)2C(CH3)3), 1.15–1.71 (m, 15H, 7-CH3, 10-,11-
,12-,18-,19-,20-H), 1.80 (s, 3H, 2-CH3), 1.88–1.99 (m, 2H,
9-H), 2.06–2.25 (m, 2H, 6-H), 2.48–2.61 (m, 1H, 4-H),
3.12–3.23 (m, 4H, 13-H, CH3OCH2O), 3.39 (t, J¼6.7 Hz,
2H, 21-H), 3.68–3.76 (m, 4H, OCH3, 5-H), 3.79 (s, 3H, PMB
OCH3), 4.01–4.09 (m, 1H, 17-H), 4.20–4.36 (m, 3H, 14-H,
CH3OCH2O), 4.41 (s, 2H, PMB CH2), 5.16 (t, J¼6.6 Hz,
1H, H-8), 5.48–5.67 (m, 2H, 15-,16-H), 6.73 (d, J¼
10.2 Hz, 1H, 3-H), 6.86 (d, J¼8.7 Hz, 2H, CHar, meta), 7.25
(d, J¼8.7 Hz, 2H, CHar, para), 7.29–7.45 (m, 6H, phenyl),
7.56–7.71 (m, 4H, phenyl); 13C NMR (400 MHz, CDCl3):
d [ppm]¼ꢂ4.9 (17-OSi(CH3)2), ꢂ4.4 (17-OSi(CH3)2), 5.1
(SiCH2CH3), 6.9 (SiCH2CH3), 12.5 (2-CH3), 13.4 (4-CH3),
16.5 (7-CH3), 18.2 (17-OSiC(CH3)3), 19.3 (14-OSiC(CH3)3),
21.9 (C-19), 25.6 (C-11), 25.9 (17-OSiC(CH3)3), 27.0 (14-
OSiC(CH3)3), 28.1 (C-9), 29.3 (C-10), 29.8 (C-12, C-20),
37.6 (C-18), 38.1 (C-4), 45.8 (C-6), 51.6 (OCH3, ester), 55.2
(PMB CH3), 55.4 (MOM CH3), 70.2 (C-21), 72.5 (PMB
CH2), 73.1 (C-17), 73.5 (C-5), 74.0 (C-14), 81.2 (C-13), 96.8
(MOM CH2), 113.7 (PMB, meta), 126.0 (C-2), 127.4 (phenyl),
127.6 (phenyl), 127.6 (C-15), 128.1 (C-8), 129.2 (PMB, ortho),
129.6 (phenyl), 129.7 (phenyl), 130.8 (PMB), 131.4 (C-7),
133.8 (phenyl), 134.1 (phenyl), 135.2 (C-16), 135.9 (phenyl),
146.4 (C-3), 159.1 (PMB, para), 168.8 (C-1). HRMS:
[M+Na]+ calcd for C63H102O9Si3 1109.7239, found 1109.7403.
4.1.27.2. Via Stille coupling. To a stirred solution of al-
kyne 30 (10 mg, 0.013 mmol, 1 equiv) in THF (0.15 mL) was
added PdCl2(PPh3)2 (0.17 mg, 200 mmol, 15 mol %) at room
temperature. Thereafter, Bu3SnH (10 mL, 0.038 mmol,
3 equiv) was added dropwise. After stirring for 10 min at
room temperature TLC showed complete conversion to the
vinylstannane. After evaporation of volatiles the residue
can be used in the following coupling step without further
purification. To a stirred solution of vinyl iodide 39
(5.5 mg, 0.012 mmol, 1.2 equiv) and the stannane (10 mg,
0.01 mmol, 1 equiv) in DMF (0.2 mL) were added AsPh3
(1.3 mg, 0.4 equiv) and Pd2(dba)3 (2 mg, 0.2 equiv) at room
temperature. Stirring was continued for 6 h. For the work-up,
water was added and the mixture extracted with diethyl ether
(2ꢁ10 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo. The residue
was purified by flash chromatography (petroleum ether/
EtOAc, 20:1) to give 8 mg (78%) of coupling product 40.
Compound 40: Rf¼0.43 (petroleum ether/EtOAc, 10:1);
[a]2D0 +41.0 (c 0.47, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d [ppm]¼ꢂ0.01, 0.01 (2s, 3H each, Si(CH3)2), 0.57 (q,
J¼8.1 Hz, 6H, CH3CH2Si), 0.84 (s, 9H, Si(CH3)2C(CH3)3),
0.86 (t, J¼2.2 Hz, 9H, CH3CH2Si), 0.99 (d, J¼6.9 Hz, 3H,
4-CH3), 1.05 (s, 9H, Si(Ph)2C(CH3)3), 1.25–1.62 (m, 8H,
12-,18-,19-,20-H), 1.72 (s, 3H, 7-CH3), 1.78–1.80 (m, 3H,
2-CH3), 1.95–2.38 (m, 4H, 6-, 11-H), 2.48–2.59 (m, 1H, 4-
H), 3.12–3.25 (m, 4H, 13-H, CH3OCH2O), 3.38 (t, J¼
6.7 Hz, 2H, 21-H), 3.72 (s, 3H, OCH3), 3.74–3.77 (m, 1H,
5-H), 3.79 (s, 3H, PMB OCH3), 3.98–4.07 (m, 1H, 17-H),
4.17–4.36 (m, 3H, 14-H, CH3OCH2O), 4.41 (s, 2H, PMB
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie is gratefully
acknowledged. We thank Graeme Nicholson (Institute of
Organic Chemistry) for measuring the HRMS spectra.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.10.028.

J. Ja€gel et al. / Tetrahedron 63 (2007) 13006–13017
13017
21. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483–2547.
References and notes
22. The synthesis of (ꢂ)-pinellic acid which also contains a 1,2,5-
trihydroxy-3-ene subunit was recently described featuring a
related dihydroxylation of an enyne: Naidu, S. V.; Kumar, P.
Tetrahedron Lett. 2007, 48, 2279–2282.
23. Gras, J.-L.; Chang Kong Win, Y.-Y.; Guerin, A. Synthesis 1985,
74–75.
24. De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.;
Piancatelli, G. J. Org. Chem. 1997, 62, 6974–6977.
25. (a) Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D.
Synth. Commun. 1987, 17, 1709–1716; (b) Roth, G. J.; Liepold,
1. Drahl, C.; Cravatt, B. F.; Sorensen, E. J. Angew. Chem. 2005,
117, 5936–5958; Angew. Chem., Int. Ed. 2005, 44, 5788–5809.
2. Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77–93.
3. (a) Zhang, Y.; Griffith, E. C.; Sage, J.; Jacks, T.; Liu, J. O. Proc.
Natl. Acad. Sci. U.S.A. 2000, 97, 6427–6432; (b) Yamaguchi,
J.; Toyoshima, M.; Shoji, M.; Kakeya, H.; Osada, H.;
Hayashi, Y. Angew. Chem. 2006, 118, 803–807; Angew.
Chem., Int. Ed. 2006, 45, 789–793 and references therein.
ꢀ
˜
€
4. Siedle, B.; Garcıa-Pineres, A. J.; Murillo, R.; Schulte-Monting,
J.; Castro, V.; R€ungeler, P.; Klaas, C. A.; Da Costa, F. B.; Kisiel,
W.; Merfort, I. J. Med. Chem. 2004, 47, 6042–6054.
5. Yet, L. Chem. Rev. 2003, 103, 4283–4306.
€
B.; Muller, S. G.; Bestmann, H. J. Synthesis 2004, 59–62; (c)
Pietruszka, J.; Witt, A. Synthesis 2006, 4266–4268.
26. Marshall, J. A.; Eidam, P. Org. Lett. 2004, 6, 445–448.
27. (a) Gage, J. R.; Evans, D. A. Org. Synth. 1989, 68, 77–82; (b)
Nerz-Stormes, M.; Thornton, E. R. J. Org. Chem. 1991, 56,
2489–2498; (c) Palaty, J.; Abbott, F. S. J. Med. Chem. 1995,
38, 3398–3406; (d) Guerlavais, V.; Carroll, P. J.; Joullie,
M. M. Tetrahedron: Asymmetry 2002, 13, 675–680.
28. Baker, R.; Castro, J. L. J. Chem. Soc., Chem. Commun. 1989,
378–381.
6. Xie, X.-S.; Padron, D.; Liao, X.; Wang, J.; Roth, M. G.; De
Brabander, J. K. J. Biol. Chem. 2004, 279, 19755–19763.
7. Diyabalanage, T.; Amsler, C. D.; McClintock, J. B.; Baker, B. J.
J. Am. Chem. Soc. 2006, 128, 5630–5631.
8. (a) Nishi, T.; Forgac, M. Nat. Rev. Mol. Cell Biol. 2002, 3, 94–
103; (b) Junge, W.; Nelson, N. Science 2005, 308, 642–644;
(c) Beyenbach, K. W.; Wieczorek, H. J. Exp. Biol. 2006,
209, 577–589.
29. Boeckman, R. K., Jr.; Shao, P.; Mullins, J. J. Org. Synth. 2000,
77, 141–152.
9. Parenty, A.; Moreau, X.; Campagne, J. M. Chem. Rev. 2006,
106, 911–939.
30. (a) Werkhoven, T. M.; Van Nispen, R.; Lugtenburg, J. Eur. J.
Org. Chem. 1999, 2909–2914; (b) Xie, L.; Takeuchi, Y.;
Cosentino, L. M.; Lee, K.-H. J. Med. Chem. 1999, 42, 2662–
2672.
10. Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J. K. J. Am.
Chem. Soc. 2007, 129, 6386–6387.
11. Corey, E. J.; Helal, C. J. Angew. Chem. 1998, 110, 2092–2118;
Angew. Chem., Int. Ed. 1998, 37, 1986–2012.
31. Bhatt, U.; Christmann, M.; Quitschalle, M.; Cluas, E.; Kalesse,
M. J. Org. Chem. 2001, 66, 1885–1893.
12. Kaliappan, K. P.; Gowrisankar, P. Synlett 2007, 1537–1540.
13. Nicolaou, K. C.; Guduru, R.; Sun, Y.-P.; Banerji, B.; Chen,
D. Y. K. Angew. Chem. 2007, 119, 6000–6004; Angew.
Chem., Int. Ed. 2007, 46, 5896–5900.
14. Thornton, P. D.; Burnell, D. J. Org. Lett. 2006, 8, 3195–3198.
15. (a) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1997, 119, 8738–8739; (b) Noyori, R.;
Yamakawa, M.; Hashiguchi, S. J. Org. Chem. 2001, 66,
7931–7944; (c) Marshall, J. A.; Eidam, P.; Schenck, H. Org.
Synth. 2007, 84, 120–128.
16. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092–4096.
17. The configurational analysis was performed on ent-11 obtained
using ent-9 as catalyst; see Supplementary data.
18. See for example: Mulzer, J.; Berger, M. J. Org. Chem. 2004, 69,
891–898.
19. (a) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brockson,
T. J.; Li, T.-T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem.
Soc. 1970, 92, 741–743; (b) Gonzalez, F. B.; Bartlett, P. A.
Org. Synth. 1986, 64, 175–181; Org. Synth., Coll. Vol. 1990,
7, 175–180.
20. (a) Wang, Z.-M.; Zhang, X.-L.; Sharpless, K. B.; Sinha, S. C.;
Sinha-Bagchi, A.; Keinan, E. Tetrahedron Lett. 1992, 33,
6407–6410; (b) Sinha, S. C.; Sinha, A.; Yazbak, A.; Keinan,
E. J. Org. Chem. 1996, 61, 7640–7641.
32. For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995,
95, 2457–2483; (b) Chemler, S. R.; Trauner, D.; Danishefsky,
S. J. Angew. Chem. 2001, 113, 4676–4701; Angew. Chem.,
Int. Ed. 2001, 40, 4544–4568; (c) Darses, S.; Genet, J.-P. Eur.
J. Org. Chem. 2003, 4313–4327; (d) Bellina, F.; Carpita, A.;
Rossi, R. Synthesis 2004, 2419–2440; (e) Suzuki, A. Chem.
Commun. 2005, 4759–4763; (f) Nicolaou, K. C.; Bulger,
P. G.; Sarlah, D. Angew. Chem. 2005, 117, 4516–4563;
Angew. Chem., Int. Ed. 2005, 44, 4442–4489.
33. See for example: Zhu, B.; Panek, J. S. Org. Lett. 2000, 2, 2575–
2578.
34. Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997,
50, 1–652.
35. (a) Betzer, J.-F.; Delaloge, F.; Muller, B.; Pancrazi, A.; Prunet,
J. J. Org. Chem. 1997, 62, 7768–7780; (b) Cuzzupe, A. N.;
Hutton, C. A.; Lilly, M. J.; Mann, R. K.; McRae, K. J.;
Zammit, S. C.; Rizzacasa, M. A. J. Org. Chem. 2001, 66,
€
2382–2393; (c) Vaz, B.; Alvarez, R.; Bruckner, R.; de Lera,
A. R. Org. Lett. 2005, 7, 545–548.
36. For a review, see: Smith, N. D.; Mancuso, J.; Lautens, M.
Chem. Rev. 2000, 100, 3257–3282.
37. Amin, S.; Hecht, S. S.; Hoffman, D. J. Org. Chem. 1981, 46,
2394–2398.