Synthesis of (Z)-Trisubstituted olefins by decarboxylative Grob-Type fragmentations: Epothilone D, discodermolide, and peloruside A

Article abstract of DOI:10.1002/chem.200901567

Methyl-branched (Z)-trisubstituted olefins are found in many polyketides with interesting biological activity, such as epothilone D (1), discodermolide (3), and peloruside A (2). Despite the employment of numerous different strategies, this motif has often been the weak point in total synthesis. Thus, we present a novel hydroxideinduced Grob-type fragmentation as an easy access to trisubstituted olefins. In our case, β-mesyloxy δ-lactones with three stereogenic centers were chosen whose fragmentation underlies a high stereoelectronic control. Major challenges in the syntheses were the instailation of quaternary stereocenters, achieved by enzymatic desymmetrization of meso-diesters and by aluminiumpromoted stereoselective rearrangement of chiral epoxides, respectively. Different aldol strategies were developed for the formation of the fragmentation precursors. Additionally a short survey about nucleophilic additions to aldehydes with quaternary α-centers is presented.

Full text of DOI:10.1002/chem.200901567

FULL PAPER
DOI: 10.1002/chem.200901567
Synthesis of (Z)-Trisubstituted Olefins by Decarboxylative Grob-Type
Fragmentations: Epothilone D, Discodermolide, and Peloruside A
Kathrin Prantz and Johann Mulzer*[a]
Abstract: Methyl-branched (Z)-trisub-
stituted olefins are found in many poly-
ketides with interesting biological ac-
tivity, such as epothilone D (1), disco-
dermolide (3), and peloruside A (2).
Despite the employment of numerous
different strategies, this motif has often
been the weak point in total synthesis.
Thus, we present a novel hydroxide-
induced Grob-type fragmentation as an
easy access to trisubstituted olefins. In
our case, b-mesyloxy d-lactones with
three stereogenic centers were chosen
whose fragmentation underlies a high
stereoelectronic control. Major chal-
lenges in the syntheses were the instal-
lation of quaternary stereocenters, ach-
ieved by enzymatic desymmetrization
of meso-diesters and by aluminium-
promoted stereoselective rearrange-
ment of chiral epoxides, respectively.
Different aldol strategies were devel-
oped for the formation of the fragmen-
tation precursors. Additionally a short
survey about nucleophilic additions to
aldehydes with quaternary a-centers is
presented.
Keywords: discodermolide
· epo-
thilone D · Grob fragmentation ·
natural products · peloruside A ·
polyketides
Introduction
One of the major challenges for a synthetic organic chemist
is the stereoselective formation of carbon–carbon bonds and
carbon–carbon double bonds, respectively. Especially in
polyketides, such as epothilone D (1), discodermolide (3),
and peloruside A (2), methyl-branched (Z)-trisubstituted
olefins are an important structural motif. These natural
products are potent antitumor agents and like paclitaxel
they have a stabilizing effect on microtubules. Owing to
their pharmacological importance, their synthesis has been
investigated intensively in the last decade. For the genera-
tion of the crucial trisubstituted (Z)-olefinic subunits a
manifold of synthetic approaches has been devised, which
rely on carbonyl olefination, olefin metathesis, alkyne func-
tionalization, allylic rearrangements, and cross-coupling
chemistry.[1] Many of these protocols show low yield and ste-
reoselectivity, and employ toxic and/or expensive reagents.
This raises the question why simple E2 eliminations and in
particular the well-known Grob fragmentation has never
been considered before,[2] especially as it has had an impres-
sive revival in the synthesis of cyclic olefins.[3]
Herein we report a novel hydroxide-induced decarboxyla-
tive Grob-type fragmentation for the stereoselective synthe-
sis of trisubstituted double bonds.[4] This strategy utilizes d-
lactones such as 4 as fragmentation precursors that feature
three stereogenic centers, one of them quaternary, with the
indicated relative configuration (Scheme 1).[5] Upon hydrox-
ide addition a tetrahedral intermediate (5) is generated,
which undergoes fragmentation under extrusion of carbon
dioxide and the mesylate to form the desired (Z)-olefin.
Stereoelectronically, clean fragmentation can be expected if
the hydroxyl anion attacks axially and the lactone adopts a
chair conformation with the OMs-substituent in an equatori-
[a] K. Prantz, Prof. J. Mulzer
Institute of Organic Chemistry, University of Vienna
Wꢀhringerstrasse 38, 1090 Vienna (Austria)
Fax : (+43)1-4277-52189
E-mail: johann.mulzer@univie.ac.at
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901567.
Chem. Eur. J. 2010, 16, 485 – 506
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485

Scheme 1. Grob-type hydroxide induced fragmentation of lactone 4.
Ms=methanesulfonyl.
Scheme 3. Model study. a) LDA, HMPA, then PhCHO, THF, À788C; 1m
KOH, then HCl, 08C, 64% (2 steps); b) [Pd(PPh3)4], allyl acetate,
K2CO3, BnEt3NCl, EtOAc/H2O, 98%, d.r. 4:1; c) NaBH4, MeOH, 08C,
97%; d) MsCl, Et3N, Et2O, À108C; e) KOH, MeOH, 08C, >95% (2
steps). HMPA=hexamethylphosphoramide.
al position.[6] This provides an antiperiplanar arrangement of
the oxygen lone pair and the bonds to be broken during the
course of the reaction, which may be facilitated by introduc-
ing a bulky residue R2 cis to the OMs as a conformational
anchor.
AHCTUNGTRENNUNG
The natural compounds 1–3 can be traced back to the
known precursors 7–9, which can be gained from fragmenta-
tion precursors 10–12 (Scheme 2). As the d-hydroxy group
in 10 and 12 is homochiral, lactones 10 and 12 have to be
prepared in a diastereo- and enantioselective manner. Thus,
an additional synthetic challenge lies in the enantioselective
generation of aldol-type quaternary centers, for which differ-
ent strategies had to be developed.
Encouraged by this positive result we turned our attention
to natural product synthesis, and, consequently to an
enantioACHTNUTRGNEsNUG elective synthesis of fragmentation precursors 10–
12.
Epothilone D (first-generation approach): The first strategy
towards fragmentation precursor 10 was in analogy to the
test system. Therefore a Cram-chelate-controlled Mukai-
AHCTUNGTREGyNNUN ama aldol reaction was performed with enol ether 21 and
known aldehyde 19,[8] derived in three steps from (S)-ethyl
lactate. A single diastereoisomer 22 was generated in excel-
lent yield,[9,10] which was deprotected to form lactone 23
Scheme 4. Synthesis of lactone 23. a) MgBr2·Et2O, CH2Cl2, À108C, 96%;
b) K2CO3, methanol, RT, then HCl, quant. TMS=trimethylsilyl.
Scheme 2. Retrosynthetic analysis. TBS=tert-butyldimethylsilyl, PMB=
para-methoxybenzyl.
Results and Discussion
(Scheme 4).
The next objective was the introduction of the quaternary
center by a diastereoselective allylic alkylation, which was
first tested with allyl acetate. The biphasic “achiral” Tsuji–
Trost conditions, developed for test system 14 with pallad-
Model studies: For a proof of principle, a simplified racemic
test system was used (Scheme 3). Therefore, lactone 14 was
prepared by addition of the dianion of acetoacetate 13 to
benzaldehyde followed by saponification. The quaternary
center was introduced by a biphasic Trost–Tsuji allylation.[7]
This turned out to be the only protocol mild enough for this
kind of transformation, as in homogeneous organic solvents
or by direct reaction of the enolate with an allyl halogenide
the very base sensitive lactone 14 eliminated water to form
cinnamic acid derivatives. After reduction of the b-carbonyl
group, the major diastereomer 16 was isolated by column
chromatography and mesylated to give 17. Treatment with
sodium hydroxide in methanol at 08C gave (Z)-olefin 18 as
the only product in almost quantitative yield.
AHCTUNGTREGiNNUN um-tetrakis(triphenylphosphane) as the catalyst, gave a 3:1-
ratio of easily separable diastereoisomers 24a and 24b in ex-
cellent yield (Scheme 5); the relative configuration of the
two diastereoisomers was determined via NOE difference
spectroscopy.
Despite extensive optimizations concerning the palladium
source, choice of ligands, solvent system, and bases, the best
diastereomeric ratio never exceeded 7:2 in favor of 24a
(Table 1).[11]
Also intramolecular allylation, as described by Trost and
Stoltz, was tested (Scheme 6).[12] Therefore the potassium
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Synthesis of (Z)-Trisubstituted Olefins
FULL PAPER
from which compound 33 was isolated by chromatography
(Scheme 8). Mesylation and fragmentation as before deliv-
ered pure (Z)-olefin 34 in 91% yield. If the diastereomeric
d -lactone mixture was used, 34 was isolated as the only ole-
finic product, though in correspondingly lower yield. In a
simple, efficient, and high-yielding four-step endgame, olefin
34 was converted to compound 38, which has been an im-
portant intermediate in several approaches to epothilone D
and proved identical with an authentic sample in every
respect.[19]
Scheme 5. Tsuji–Trost allylation with allyl acetate. a) see Table 1.
Table 1. Conditions and results for Tsuji–Trost allylation with allyl acetate.
Pd/Ln*
[Pd(PPh3)4]
[Pd2A(dba)3]·CHCl3, (R,R)-Trost DACH
Base
Solvent
Yield [%]
24a/24b
Epothilone D (second-genera-
tion approach): To achieve a
higher degree of stereoselectiv-
ity, a second strategy was devel-
oped, which relies on an enzy-
G
K2CO3
LDA
H2O/EtOAc
THF
98
3:1
–
G
R
lactone
opening
82
60
75
G
2A
2A(dba)3]·CHCl3, (R,R)-Trost DACH
2A(dba)3]·CHCl3, (S,S)-Trost DACH
2A(dba)3]·CHCl3, (S,S)-Trost DACH
LiHMDS
DBU
LiHMDS
DBU
THF
toluene
THF
1:2
2:3
3:1
7:2
N
N
G
R
matic
desymmetrization
of
N
C
toluene
92
meso-malonate 39.[14] Hydroly-
Scheme 6. Intramolecular Tsuji–Trost allylation. a) Allyl chloroformate,
2A
KOtBu, THF, À788C, 95%; b) [Pd (dba)3]·CHCl3, 25, toluene, À788C,
G
76%, 24a/24b 4:1. dba=dibenzylideneacetone.
Scheme 7. Allylation
with
elaborated
allylic
carbonate
30.
a) EtO2CCH2P(O)
toluene, À788C, 95%; c) LG-Cl, pyridine, RT, 88%; d) see Table 2.
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, Troc=2,2,2-trichloroethyl car-
bonate.
ACHTUNGTERN(NUNG OEt)2, DBU, LiCl, CH3CN, RT, 84%; b) DIBALH,
enolate of 23 was trapped as allyl carbonate 26, which could
be used in the allylation without any additional base or
other additives, and the diastereomeric ratio was increased
to 4:1.
AHCTUNGTRENNUNG
After this, the introduction of the quaternary center with
the fully substituted allylic carbonate was tackled, and also
the carbonate leaving group was varied in the optimization
process. Known aldehyde 27[13a] was olefinated by means of
a Horner–Wadsworth–Emmons reaction under Masamune–
Roush conditions[13b] to provide pure (E)-enoate 28
(Scheme 7), which was converted to a variety of allylic car-
bonates 30. The allylation was performed with three achiral
and two chiral catalysts. The best result is the one shown in
the last row, which uses the simplest ingredients (Table 2).
The seemingly trivial task to reduce the b-ketone stereo-
selectively was more troublesome than expected and gave
sis with pig liver esterase (PLE) to mono acid 40 and selec-
tive reduction of the carboxylate gave alcohol 41
(Scheme 9), a general building block whose allylic append-
age can be modified in the desired manner.[15]
En route to our target molecule 38, a cross metathesis of
41 with olefin 42 was investigated first, but despite variation
of catalyst, solvent, reaction time, and temperature, the
yield never exceeded 40% (Scheme 10).[16] Next we tried
carbonyl olefination and oxidized 41 to lactol 44. However,
neither Julia–Lythgoe nor Wittig conditions gave any reac-
tion.[17]
disappointing
1:1
mixtures
under all conditions. Most prob-
ably the 6-sidechain was not an
efficient conformational anchor.
Efforts to introduce the thiazo-
lylidene moiety earlier proved
unsuccessful. Finally, carbonyl
reduction and hydrogenation of
the diastereomeric mixture with
Adamꢂs catalyst gave a mixture
of d-lactone-3,4-diastereomers,
Table 2. Conditions and results for Tsuji–Trost allylation with elaborated allyl carbonates.
Pd/Ln*
[Pd(PPh3)4]
[Pd2A(dba)3]·CHCl3, (R,R)-Trost DACH
[Pd2A(dba)3]·CHCl3, (S,S)-Trost DACH
(PPh3)4]
(PPh3)4]
(PPh3)4]
(PPh3)4]
(PPh3)4]
OLG
Base
Solvent
Yield [%]
31a/31b
G
OTroc
OTroc
OTroc
OTroc
OC(O)CH2Cl
OC(O)OEt
OC(O)OEt
OC(O)OEt
K2CO3
DBU
DBU
DBU
DBU
DBU
–
H2O/EtOAc
toluene
toluene
toluene
toluene
toluene
H2O/EtOAc
H2O/EtOAc
97
60
54
41
17
34
85
97
3:1
2:3
3:2
3:1
4:1
4:1
4:1
4:1
A
U
A
U
[Pd
[Pd
[Pd
[Pd
[Pd
N
K2CO3
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487

J. Mulzer and K. Prantz
Scheme 8. Fragmentation and conversion into northern fragment 38.
a) NaBH4, MeOH, 08C, 98%; b) PtO2, H2, EtOAc, 1 atm, RT, quant.;
chromatographic separation of diastereomers; c) MsCl, Et3N, Et2O, 0 8C;
d) KOH, methanol, 08C, 91% (2 steps); e) TBSOTf, 2,6-lutidine, CH2Cl2,
RT, quant.; f) DDQ, CH2Cl2, RT, 98%; g DMP, NaHCO3, CH2Cl2,
quant.; h) (2-methyl-thiazol-4-yl)methyltributylphosphonium chloride,
nBuLi, THF, À78 to 608C, 93%. DDQ=2,3-dichloro-5,6-dicyano-1,4-
benzoquinone, DMP=Dess–Martin periodinane.
Scheme 11. Conversion of alcohol 41 into aldehyde 50. a) TESCl, py, RT,
quant; b) Grubbs–Hoveyda cat, 42, CH2Cl2, reflux, 93%; c) O3, PPh3,
PPTS, CH2Cl2, À788C, quant.; d) LiHMDS, 51, THF, À78 to À308C,
96%; e) PPTS, MeOH, RT, 92%; f) PtO2, H2, EtOAc, 99%; g) DMP,
CH2Cl2, 08C, 91%. TES=triethylsilyl, BT=2-benzothiazolyl, PPTS=
pyridinium p-toluenesulfonate, HMDS=hexamethyldisilazane.
Scheme 9. Conversion of malonate 39 into alcohol 41. a) PLE, 0.05m
KH2PO4, 90%; b) ClC(O)OMe, Et3N, THF, 08C; NaBH4, MeOH, 08C,
75%.
Scheme 12. Synthesis of the C7–C21 epothilone D fragment 38.
a) LiHMDS, THF, À788C, then 50, MgBr2·Et2O, 91%; b) catecholborane,
THF, À108C, 88%; c) LiOH, THF, 08C; d) EDC·HCl, DMAP, CH2Cl2,
94% (2 steps); e) DMP, NaHCO3, CH2Cl2, 94%; f) NaBH4, MeOH,
À788C, 93%; g) MsCl, Et3N, Et2O, 0 8C; h) LiOH, THF, 08C, 81%;
i) TBSOTf, 2,6-lutidine, CH2Cl2, RT, quant. EDC=1-ethyl-3-(3-dimethyl-
Scheme 10. Cross-metathesis to elongate the allyl moiety of alcohol 41.
a) (COCl)2, DMSO, Et3N, CH2Cl2, À78 to 08C; b) Ph3PCH3, KOtBu,
THF, 08C to RT, 87%; c) Grubbs–Hoveyda, CH2Cl2, 458C, <40%; d)
O3, PPh3, CH2Cl2, À788C, quant.
AHCTUNGERTGaNNUN minopropyl)carbodiimide, DMAP=4-(dimethylamino)pyridine.
As the free alcohol seemed to be the source of all incon-
venience, it was protected as a TES-ether and indeed, both
elongation strategies worked smoothly and furnished 43 in
high yields (Scheme 11). From 43, aldehyde 50 was obtained
by desilylation, hydrogenation and oxidation.
as TiCl4 or SnCl4, a chelated transition state could not be en-
forced and without activation the reaction was sluggish and
low yielding. For the substrate controlled syn-reduction cat-
echolborane proved best and furnished only syn-dihydroxy
Next, aldehyde 50 was activated with freshly prepared
MgBr2·Et2O, and then added to the lithium enolate of
ketone 52. Adduct 53 was obtained as a single (13R)-diaste-
reomer in 91% yield, presumably via a Felkin-like transition
state 54 (Scheme 12). Even with stronger Lewis acids such
ester 55, whereas with LiBH4, ZnACHTUNGTER(UNNG BH4)2, or BEt3/NaBH4 the
selectivity was not satisfactory.[18] Saponification and lactoni-
zation led to lactone 56. As (13S)-configuration was re-
quired for clean fragmentation, inversion at C13 was ach-
ieved by an oxidation–reduction sequence to give 10. Trans-
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Synthesis of (Z)-Trisubstituted Olefins
FULL PAPER
formation to mesylate 57 set the stage for the fragmentation
reaction. KOH in methanol opened the lactone to form the
methyl ester, whereas LiOH, KOH, and NaOH in THF
gave the desired (Z)-olefin 7 exclusively in about 80%
yield, from which epothilone fragment 38 was obtained by
silylation.
To investigate the stereoelectronic demands of the frag-
mentation, we turned to lactone 56 (Scheme 13). Due to the
axial configuration of the 13-OH, a Grob-type fragmenta-
Scheme 14. Fragmentation of lactones 63 and 64. a) Me4NBHACHTUNGTRENNUNG(OAc)3,
CH3CN/AcOH, À308C, 87%; b) LiOH, THF, 08C; c) EDC·HCl, DMAP,
CH2Cl2, 85% (2 steps); d) DMP, NaHCO3, CH2Cl2, 94%; e) NaBH4,
MeOH, À788C, 90%; f) MsCl, Et3N, Et2O, 0 8C; g) LiOH, THF, 08C,
64% (65), 36% (66), 52% (67).
Scheme 13. Fragmentation of lactone 56. a) MsCl, Et3N, Et2O, 0 8C;
b) LiOH, THF, 08C, 38% (60) and 52% (61); c) DMF, reflux, 85%.
of 1 are available from intermediate 53 using the same frag-
mentation protocol.
tion in a chair conformation (58a) should be impossible. On
the other hand, boat conformation 58b might stereoelec-
tronically be suitable to undergo fragmentation, however,
the species itself is energetically unfavorable. Nevertheless,
olefin 60 (38%) was obtained under the usual conditions,
alongside b-lactone 61 (52%). This result may be rational-
ized by assuming that lactone 56 under the action of base
first forms carboxylate 59, which undergoes both fragmenta-
tion to (E)-olefin 60 and SN2 cyclization to b -lactone 61.[20]
On thermolysis 61 gave 60 as well, so that, overall, olefin 60
is obtained from 56 in pure (E)-geometry and about 80%
combined yield. In effect, this result underlines the versatili-
ty of our method, as both the (Z)- and the (E)-olefin are
available from lactone 56 along analogous routes.
Do we need d-lactones as fragmentation precursors or
would an acyclic derivative also do? To test this possibility
intermediate 55 was regioselectively protected as 15-OTIPS
ether and mesylated to give 69 (Scheme 15). All attempts to
convert the ester into the carboxylate either by using vari-
ous hydroxides, KOTMS or the Krapcho protocol
failed.[22,23] However, after reducing the ester to the alde-
hyde, fragmentation gave olefin 71 in excellent yield. Not-
withstandingly, the lactone route appears more reliable, as
inversion of the b-OH and regioselective protection of the
d-OH position might be problematic in acyclic molecules.
Variation of the temperature in the fragmentation of 56
did not significantly alter the ratio of olefin and b-lactone,
however, with increasing temperature the amount of the
olefin was slightly enhanced. Changing the leaving group
from OMs to OTs and OTf gave similar product distribu-
tions. The instability of the triflate led to slightly lower
yields though.
Two additional diastereoisomers can easily be gained
from 53 by reducing ketone 53 to anti-diol 62
(Scheme 14),[21] from which lactones 63 and 64 were avail-
able by saponification and Steglich lactonization. Fragmen-
tation of 63 via the chair transition state cleanly led to (E)-
olefin 65, whereas 64 gave b-lactone 66 and (Z)-olefin 67, as
expected. Thus four diastereomers of the northern fragment
Scheme 15. Fragmentation of open chain precursor 70. a) TIPSOTf, 2,6-
lutidine, CH2Cl2, RT, 85%; b) MsCl, Et3N, Et2O, RT, 96%; c) DIBAL-H,
toluene, À788C, 87%; d) DMP, NaHCO3, CH2Cl2, 08C, 94%; e) LiOH,
THF, 08C, 82%. TIPS=triisopropylsilyl.
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489

J. Mulzer and K. Prantz
Evans–Carreira anti-reduction transformed 78 to the stereo-
pentad 79 (Scheme 18).
For the preparation of the d-lactone, the primary neopent-
AHCTUNGTREGyNNNU l position in 79 had to be oxidized to the acid and then cy-
clized to the lactone. Thus, the TBS ether was cleaved with
HF·pyridine to get triol 80. To our surprise, the oxidation of
80 with one equivalent of DMP cleanly furnished ketone 81,
which impressively demonstrates the inaccessibility of the
neopentyl position (Scheme 19). As an additional test, triol
Scheme 16. Fragmentation of 57 using organolithium species. a) PhLi,
THF, À788C, 43% (72a), 20% (7), b) MeLi, THF, À788C, 23% (72b),
51% (7).
Phenyl- and methyllithium were also tested in the frag-
mentation of lactone 57 (Scheme 16). Both gave the (Z)-
olefin, either in form of the carbonate 72 or the unprotected
alcohol 7. However, when fragmentation of 56 was attempt-
ed with these organolithium species, only decomposition
was observed. This result again underlines the need for a
chairlike transition state.
Discodermolide: In this case, the required quaternary ste-
reocenter was generated by the organoaluminum-promoted
rearrangement of OTBS-protected epoxy-geraniol (73) to
aldehyde 74, which was obtained under complete chirality
transfer (Scheme 17).[24]
Scheme 19. Selective oxidation of triol 80. a) 35% HF·py, CH3CN, RT,
92%; b) DMP, NaHCO3, CH2Cl2, 08C, 65%; c) 2,2-dimethoxypropane,
CSA, CH2Cl2, RT, 88%.
80 was converted into acetonide 82, which again shows that
the primary alcohol site is the least reactive one.
Alternatively, 82 was prepared from 79 via TBS-ether 83
(Scheme 20). A two-step oxidation of 82 led to the acid,
Scheme 17. Yamamotoꢂs organoaluminum-promoted rearrangement to
generate aldehyde 75. a) MABR, CH2Cl2, À78 to 08C, quant., 95%ee.
An anti–anti-selective Paterson aldol addition of 75 with
known ethyl ketone 77,[26] gave multigram quantities of
aldol adduct 78 in good yield and excellent selectivity.
Scheme 20. Synthesis of the discodermolide fragmentation precursor 12.
a) 2,2-Dimethoxypropane, CSA, CH2Cl2, RT, 86%; b) 35% HF·py,
CH3CN, RT, 97%; c) IBX, EtOAc, reflux, 86%; d) 2-methyl-2-butene,
NaClO2, NaH2PO4, tert-butanol/H2O, RT, quant.; e) CSA, CH2Cl2, RT,
83%. CSA=camphorsulfonic acid, IBX=2-iodoxybenzoic acid.
which spontaneously cyclized to lactone 12 upon treatment
with CSA.
Due to severe steric hindrance, the mesylation of d-lac-
tone 12 required an excess of mesyl chloride and DMAP.
Upon treatment with lithium hydroxide the mesylate cleanly
furnished (Z)-olefin 86 via the chair transition state
Scheme 18. Synthesis of the stereopentad 79. a) Cy2BCl, Et3N, then 75,
Et2O, À78 to 08C, 76%; b) Me4NBH
A
94% (b.r.s.m.). Cy=cyclohexyl.
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Synthesis of (Z)-Trisubstituted Olefins
FULL PAPER
ous stereogenic centers were to be generated by aldol strat-
egy.
First aldolization with b-ketoimide 96 was attempted,[28,29]
but even under a variety of conditions no product was ob-
served. This is not surprising as the combination of 95 and
96 results in a mismatched transition state (98), with unfav-
orable syn-pentane interaction (Scheme 24).
Scheme 21. Fragmentation of 12 and conversion to acid 90. a) MsCl,
DMAP, py, CH2Cl2, RT; b) LiOH, THF, RT, 88% (2 steps); c) TBSOTf,
2,6-lutidine, CH2Cl2, RT, quant.; d) mCPBA, NaOAc, CH2Cl2, À208C,
92%; e) HIO4·2H2O, THF/Et2O, 0 8C, 90%; f) 2-methyl-2-butene,
NaClO2, NaH2PO4, tert-butyl alcohol/H2O, RT, quant. mCPBA=meta-
chloroperbenzoic acid.
(Scheme 21). After silylation of the secondary alcohol a
three-step oxidation of the terminal olefin led to acid 90,
from which the key intermediates of both Patersonꢂs and
Smithꢂs discodermolide syntheses were prepared.
Thus, Patersonꢂs aryl ester 91 and methyl ester 9 are avail-
able by esterification of acid 90 under Steglich conditions or
treatment with diazomethane, respectively (Scheme 22).[26b]
Scheme 24. Unsuccessful aldolization of aldehyde 95 with diketoimide 96.
i) Bu2BOTf, Et3N, then 95, CH2Cl2, À78 to 08C; or ii) Sn
ACHTUNGTRENNUNG(OTf)2,
Et3N,then 95, CH2Cl2, À78 to 08C.
Next, ethyl ketone 102 was tried; but again we face a mis-
matched situation, though with considerably less steric inter-
action. Thus, the Nozaki–Hiyama/Peterson protocol was
used to prepare (Z)-diene 100 from 101, which was convert-
ed to ethyl ketone 102 (Scheme 25).[30] On trying to convert
102 into the (Z)-enolborinate, (À)-diisopinocampheylboron-
triflate failed to react,[31a] whereas dibutylboron triflate
smoothly gave an aldol adduct (103),[31b] which, based on lit-
erature precedence, could either be 103a or 103b.[31c] The
latter one was more likely, because with a-chiral aldehydes,
(Z)-enolborinates normally form anti-Felkin adducts via
transition state TS B. The Felkin transition state TS A[26a] is
destabilized by a syn-pentane interaction.
On determining the configurations of the newly formed
stereogenic centers in 103, C17 was shown to have the de-
sired R configuration via the corresponding Mosher esters
(Scheme 26).[32] For further assignments, adduct 103 was
converted into acetal 105 by syn reduction with catecholbor-
ane and reaction with anisaldehyde dimethyl acetal. NOE
signals definitely proved an 17,18-anti-arrangement and
hence, the aldol adduct has the unexpected structure 103c!
Obviously, both transition states TS A and TS B are flawed
by unfavorable interactions; the system has dodged this sit-
uation by isomerizing the initially formed (Z)-borinate to
the (E)-isomer and then using the favorable Felkin transi-
tion state TS C.
Scheme 22. Conversion into Patersonꢂs intermediates 91 and 9. a) 2,6-di-
methylphenol, DIC, DMAP, CH2Cl2, RT (99%); b) CH2N2, MeOH, RT
(quant.). DIC = N,N’-diisopropylcarbodiimide.
To intersect Smithꢂs intermediate 92, the C16–C21 (east-
ern) part of discodermolide had to be attached to 90. First,
the C16 methyl group was introduced via the Oppolzer
sultam 93 (Scheme 23).[27] Then the auxiliary was removed
to yield aldehyde 95, from which the missing four contigu-
After the convergent approaches had failed, a stepwise
strategy was finally successful. Aldehyde 95 was subjected
to a syn selective Evansꢂ aldol addition which gave 108 with
excellent selectivity (Scheme 27).[33] Silyl protection and re-
ductive removal of the auxiliary furnished alcohol 110,
Scheme 23. Generation of aldehyde 95. a) (1R)-camphore-2,10-sultam,
DIC, DMAP, CH2Cl2, RT, 96%; b) NaHMDS, MeI, THF, À788C, 89%;
c) DIBALH, CH2Cl2, À1008C, 94%.
Chem. Eur. J. 2010, 16, 485 – 506
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491

J. Mulzer and K. Prantz
Scheme 27. Conversion to Smithꢂs discodermolide fragment 92.
a) Bu2BOTf, Et3N, then 95, CH2Cl2, À78 to 08C, 65% (99% b.r.s.m.);
b) TBSOTf, 2,6-lutidine, CH2Cl2, RT, quant.; c) LiBH4, Et2O, MeOH,
08C, 86%; d) IBX, DMSO, RT; e) (R,R)-diisopropyl tartrate (E)-crotyl-
Scheme 25. Paterson-type aldol addition with ethyl ketone 102. a) IBX,
EtOAc, RT; b) CrCl3, LiAlH4, (1-bromoallyl)trimethylsilane, THF, 08C
to RT, then KOH, 08C, 90% (over 2 steps); c) DDQ, CH2Cl2, RT, 93%;
d) DMP, NaHCO3, CH2Cl2, RT; e) EtMgBr, Et2O, 0 8C, 89%; f) DMP,
NaHCO3, CH2Cl2, RT, 99%; g) Bu2BOTf, Et3N, then 95, CH2Cl2, À78 to
08C, 89% (b.r.s.m.).
boronate, toluene, À78 to 08C, 87%; f) VO
ACHTUNGTRENNUN(G acac)2, tBuOOH, CH2Cl2,
08C, 87% (2 steps); g) HIO4·2H2O, Et2O/THF, 08C, then NaBH4, metha-
nol, 08C 51% b.r.s.m.; h) anisaldehyde dimethyl acetal, CSA, CH2Cl2,
RT, 86 %.
Peloruside A: For the synthesis of Ghoshꢂs peloruside A in-
termediate 121 an enzymatic desymmetrization was used to
generate the quaternary center in mono acid 114
(Scheme 28).[37] Conversion to alcohol 115 by reduction via
the mixed anhydride was followed by oxidation to aldehyde
Scheme 26. Conversion to discodermolide fragment 105. a) Catechol-
borane, THF, À108C, 65%; b) PMPCH
ACHTUGNTREN(NUNG OMe)2, CSA, CH2Cl2, RT, 99%.
which was oxidized to the aldehyde. This compound was
then used in a Roush crotylation to create the missing two
stereocenters.[34] Oxidative cleavage of the terminal olefin,
by a vanadium-mediated epoxidation,[35] was followed by re-
duction and led to the C19,21-diol 113. Protection of the
diol led to PMP-acetal 92, whose analytical data were in full
agreement with those reported by Smith and co-workres.[36]
Scheme 28. Synthesis of the C15–C19 peloruside A fragment 121.
a) ClC(O)OMe, Et3N, THF, 08C; NaBH4, MeOH, 08C, 83%; b) IBX,
DMSO, RT, 80%; c) 122, Bu2BOTf, Et3N, then 116, CH2Cl2, À78 to 08C,
85%; d) LiBH4, Et2O, MeOH, 08C, 80%; e) K2CO3, MeOH, RT, 1n
HCl, quant.; f) MsCl, DMAP, CH2Cl2, RT, 99%; g) LiOH, dioxane, RT,
83%; h) BnBr, Ag2O, TBAI, quant.; i) TFA, CH2Cl2, RT, 91%. TFA=tri-
fluoroacetic acid.
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Synthesis of (Z)-Trisubstituted Olefins
FULL PAPER
116 which was used in a syn-selective aldol addition with ox-
azolidinone 122.[38] Reductive removal of the auxiliary was
optimized carefully to avoid the spontaneous cyclization of
dihydroxy ester 118 to lactone 11, which is immediately re-
duced to inseparable product mixtures under the conditions.
Instead, base induced saponification of 118 was used to
obtain d-lactone 11, which was mesylated and fragmented
via the chair transition state 119 to give (Z)-olefin 8. Now
only a change of protecting groups was required to intercept
intermediate 121.[39,40]
Nucleophile additions to an aldehyde with quaternary a-
center: When we observed the unusual behaviour of alde-
hyde 50 in the aldol addition, we decided to investigate this
kind of substrates further. Thus, starting from aldehyde 123,
easily accessible by oxidation of alcohol 41, a variety of ally-
lation protocols were tested (Scheme 29, Table 3). With allyl
silanes or stannanes the stereochemical outcome correlated
with the nature of the Lewis acid, giving the Cram chelate
product 124b with TiCl4, SnCl4, and MgBr2·Et2O and the
Felkin product 124a with BF3.[41] In the Brown or Roush al-
lylation adduct 124a was preferred, and the influence of the
chiral ligand was of minor importance.[42] Thus we conclude
that substrate control overruled reagent control and the
chiral ligands can only modify this basic trend. The relative
configuration of 124a,b was verified via the corresponding
b-lactones.
Scheme 30. Paterson aldol additions of aldehyde 123. a) Cy2BCl, Et3N,
then 123, Et2O, À78 to 08C, 87%, 9:1; b) Bu2BOTf, Et3N, then 123,
CH2Cl2, À78 to 08C, 15% (98% b.r.s.m.), 4:1; c) Cy2BCl,Et3N, then 123,
Et2O, À78 to 08C, quant., 5:4; d) Bu2BOTf, Et3N, then 123, CH2Cl2, À78
to 08C, 20% (80% b.r.s.m.), 1:1.
132a and 132b. No reaction was observed when stronger
Lewis acids like TiCl4 were added to the aldehyde before-
hand (Scheme 31).
Table 3. Allylation of aldehyde 123.
Allyl reagent
LA
Yield [%]
124a/124b
Brown allylation [(À)-Ipc]
Brown allylation [(+)-Ipc]
Roush allylation [l-(+)-DIPT]
Roush allylation [d-(À)-DIPT]
allytrimethylsilane
allytrimethylsilane
allytributylstannane
allytributylstannane
51
quant.
69
60
84
85
quant.
87
3:1
20:1
8:1
20:1
>95:5
<5:95
1:2
Scheme 31. Aldol additions with lithium enolates to aldehyde 123. a)
LiHMDS, then 123, THF, À788C, 97% 132a, 72% 132b.
BF3·Et2O
TiCl4
TiCl4
MgBr2·Et2O
1:7
Under Mukaiyama conditions enol ethers 133a, b and al-
dehyde 123 formed the (S)-aldol adducts 134a and 134b in
moderate to low yields, but with excellent selectivity
(Scheme 32, Table 4). Short reaction times and TiCl4 as the
Lewis acid gave the best results.
Scheme 29. Allylation of aldehyde 123.
Subjecting aldehyde 123 to the Paterson aldol addition
with ketones 125 and 128 (Scheme 30), cases 1) and 2)
should represent the matched and 3) and 4) the mismatched
combinations, assuming that 123 exerts the same stereo-
chemical influence as in the boron-induced allylation reac-
tions. In fact, cases 1) and 2) gave a 9:1 and 4:1 selectivity,
whereas in cases 3) and 4) 1:1 mixtures were observed. This
basic trend apparently corroborates our theory, although the
configurations of the adducts were not rigorously proven.
Aldol additions with the lithium enolates of methyl
ketone 131a and 131b always led to the (R)-aldol adducts
Scheme 32. Mukaiyama aldol addition.
These optimized conditions were applied to the epothi-
lone substrates 135 and 50. Indeed pure (S)-aldol adduct 136
was obtained (Scheme 33), however in too low a yield to
make it a synthetically applicable step.
Aldol adducts 132a, b and 134a, b were converted into
the d-lactones via the corresponding syn- and anti-dihydroxy
Chem. Eur. J. 2010, 16, 485 – 506
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493

J. Mulzer and K. Prantz
Table 4. Mukaiyama aldol addition.
R
LA
SiR3
Yield [%]
H
H
H
H
H
H
OMe
MgBr2·Et2O
TiCl4
SnCl4
MgBr2·Et2O
SnCl4
TiCl4
TBS
TBS
TBS
TMS
TMS
TMS
TMS
no reaction
35
no reaction
no reaction
no reaction
42 (1h), 34 (2.5h)
59
TiCl4
Scheme 33. Mukaiyama aldol additions of aldehyde 50. a) 50, TiCl4, then
135, CH2Cl2, À788C, 23%.
Scheme 35. Fragmentations. a) i) MsCl, Et3N, Et2O, 0 8C; ii) LiOH, THF,
08C, 87% 145a, 74% 145b (2 steps); b) i) MsCl, Et3N, Et2O, 0 8C;
ii) LiOH, THF, 08C, 36% 146a, 50% 146b (2 steps); c) i) MsCl, Et3N,
Et2O, 0 8C; ii) LiOH, THF, 08C, 31% 147a, 27% 147b, 50% 148a, 28%
148b (2 steps); d) i) MsCl, Et3N, Et2O, 0 8C; ii) LiOH, THF, 08C, 25%
149a, 30% 149b, 9% 150a, 29% 150b (2 steps).
esters (Scheme 34). Besides serving for configurational as-
signments; the lactones were employed in the established
fragmentation protocol (Scheme 35).
The d-lactones 138 and 140, derived from the anti-diols,
fulfill all stereochemical requirements for the fragmentation
via the chair transition state and thus gave only the olefins.
In contrast, the d-lactones 142 and 144, derived from the
syn-diols would bear the leaving group in axial position and
thus make fragmentation via the chair transition state im-
possible. Indeed, they react presumably via the carboxylate,
and both olefin and b-lactone are obtained.
Conclusions
In conclusion, we have shown that decarboxylative Grob
fragmentation is an efficient and versatile tool for the ste-
reoselective preparation of chirally substituted (Z)-trisubsti-
tuted olefins as demonstrated by the formal synthesis of
epothilone D (1), discodermolide (3), and peloruside A (2).
The synthesis starts from chiral aldehydes such as 50, 75,
and 116, and uses their stereogenic information for the con-
struction of additional chiral centers on the chain. Fragmen-
tation primarily proceeds via the chair transition state, but
also acyclic fragmentation leads to olefinic products. The
olefin geometry is determined by the relative configuration
between the a- and b-centers and can thus be controlled by
the synthesis of the fragmentation precursor. Further advan-
tages of the approach lie in its high overall yield, stereocon-
trol, mild conditions and simple reagents. The method also
implies high connectivity and is compatible with aldol reac-
tions. Most steps of the sequence are rapidly performed and
the intermediates do not require purification. Additionally,
Scheme 34. Synthesis of the d-lactones. a) Me4NBHACTHNUTRGEN(NUG OAc)3, CH3CN/
AcOH, À308C, 75% 137a, 63% 137b; b) LiOH, THF, 08C;
c) EDC·HCl, DMAP, CH2Cl2, 75% 138a, 56% 138b (2 steps);
d) Me4NBH
G
e) LiOH, THF, 08C; f) EDC·HCl, DMAP, CH2Cl2, 82% 140a, 91% 140b
(2 steps); g) catecholborane, THF, À158C, 89% 141a, 88% 141b;
h) LiOH, THF, 08C; i) EDC·HCl, DMAP, CH2Cl2, 62% 142a, 72% 142b
(2 steps); j) catecholborane, THF, À158C, 89% 143a, 88% 143b;
k) LiOH, THF, 08C; l) EDC·HCl, DMAP, CH2Cl2, 81% 144a, 77% 144b
(2 steps).
494
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Synthesis of (Z)-Trisubstituted Olefins
FULL PAPER
129.4, 113.9, 76.5, 73.8, 71.1, 55.3, 51.5, 39.4, 14.9, 8.3 ppm; IR (film): n˜ =
2926, 1726, 1654, 1613, 1513, 1400, 1248, 1115 cmÀ1. HRMS (ESI): m/z:
[M]+ calcd for C16H20O5: 292.1311, found: 292.1307.
we were able to show that aldehydes with stereogenic qua-
ternary a-centers exhibit a strong substrate control on car-
bonyl additions.
Carbonic acid (E)-(S)-5-(tert-butyldimethylsilanyloxy)-4-methylpent-2-
enyl ester ethyl ester (30): To stirred solution of alcohol 29 (150 mg,
0.64 mmol) in pyridine (5 mL) was added ethyl chloroformate (73 mL,
0.76 mmol). The mixture was stirred at room temperature for 20 min,
then quenched with brine and layers were separated. The aqueous phase
was extracted with Et2O, the combined organic solutions were washed
with water, dried over MgSO4, and the solvent was evaporated. Purifica-
tion by column chromatography (hexane/ethyl acetate=10:1) yielded
ethyl carbonate 30 (170 mg; 88%). [a]2D0 =À9.2 (c=1.25, CH2Cl2);
1H NMR (400 MHz, CDCl3): d=5.76 (d, J=15.5, 6.9 Hz, 1H), 5.61 (dtd,
J=15.6, 6.4, 1.1 Hz, 1H), 4.57 (d, J=6.3 Hz, 2H), 4.19 (q. J=7.2 Hz,
2H), 3.49 (dd, J=9.9 6.3 Hz, 1H), 3.41 (dd, Hz, J=9.9,6.8 Hz, 1H), 2.35
(m, 1H), 1.30 (t, J=7.2 Hz, 3H), 1.00 (d, J=6.6 Hz, 3H), 0.88 (s, 9H),
0.03 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=155.0, 139.3, 123.0,
68.5, 67.6, 63.9, 39.0, 25.9, 18.3, 16.1, 14.3, À5.4 ppm; IR (film): n˜ = 2956,
2930, 2857, 1747, 1258, 1105 cmÀ1; HRMS (ESI): m/z: [M+Na]+ calcd for
C15H30O4SiNa: 325.1811, found: 325.1817.
Experimental Section
All reactions were carried out in oven-dried glassware under an argon
atmosphere, unless otherwise stated. Anhydrous acetonitrile was distilled
from CaH2. Anhydrous CH2Cl2 (DCM) was distilled over phosphorpent-
oxide under argon. Anhydrous THF (tetrahydrofuran) was purchased
(99.85%, water <50 ppm). Anhydrous diethyl ether was refluxed over
sodium/benzophenone ketyl. Triethylamine, diisopropylamine and 2,6-lu-
tidine were distilled from CaH2. Hexane and ethyl acetate for chromatog-
raphy were purified by distillation using a column. All other solvents
were HPLC grade. Reactions were magnetically stirred and monitored
by thin layer chromatography (TLC) with Merck silica gel 60-F254
plates. Flash column chromatography was performed with Merck silica
gel (0.04–0.063 mm, 240–400 mesh) under pressure. Yields refer to chro-
matographically and spectroscopically pure compounds, unless otherwise
stated. NMR spectra were recorded on either a Bruker Avance DRX 400
or 600 MHz spectrometer. Unless otherwise stated, all NMR spectra
were measured in CDCl3 solutions and referenced to the residual CHCl3
signal (1H, d=7.26 ppm, 13C, d=77.00 ppm). All 1H and 13C shifts are
given in ppm (s=singlet, d=doublet, t=triplet, q=quadruplet, m=mul-
tiplet, b=broad signal). Assignments of proton resonances were con-
firmed, when possible, by correlated spectroscopy. IR spectra were re-
corded as thin film on a silicon plate with a Perkin–Elmer 1600 FT-IR
spectrometer. Optical rotations were measured on a P 341 Perkin–Elmer
polarimeter at 208C. High-resolution mass spectra (HRMS) were per-
formed with a Finnigan MAT 8230 with a resolution of 10000. Compound
names were generated using AutoNom. The Supporting Information of
this paper includes experimental details for compounds 14–18, 24, 26, 28,
29, 39–42, 45–52, 80, 81, 99–105, 123, 124, 132–150 and NMR spectra of
all new compounds.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
chloride (34 mg, 0.15 mmol) in degassed water (4 mL) at 08C was added
carbonate 30 (453 mg, 1.5 mmol) in ethyl acetate (3 mL) and the mixture
was stirred for 15 min. A degassed suspension of 23 (650 mg, 1.8 mmol)
in ethyl acetate (3 mL) was added and stirring was continued for 15 min
before K2CO3 (270 mg, 1.95 mmol) in degassed water (2 mL) was added.
After stirring for 3 h, the reaction mixture was quenched with saturated
NH4Cl solution, and phases were separated. The aqueous phase was ex-
tracted with DCM and the combined organic layers were dried over
MgSO4 and the solvent was evaporated. The residue was purified by
column chromatography (hexane/ethyl acetate=3:1) to afford 31
(730 mg; 97%) as a 3:1 mixture as a pale yellow oil. Minor (31b: [a]D20
=
38.31 (c=0.95, CH2Cl2). 1H NMR (400 MHz, CDCl3): d=7.18 (d, J=
8.6 Hz, 2H), 6.86 (d, J=8,6 Hz, 2H), 5.43 (dd, J=15.5, 6.9 Hz, 1H), 5.28
(dt, J=15.3, 7.5 Hz, 1H), 4.48 (d, J=11.3 Hz, 1H), 4.44 (m, 1H), 4.31 (d,
J=11.6 Hz, 1H), 3.80 (s, 3H), 3.48 (m, 1H), 3.44 (dd, J=9.8, 6.1 Hz,
1H), 3.35 (dd, J=9.7, 6.9 Hz, 1H), 2.78 (dd, J=16.0, 6.2 Hz, 1H), 2.50
(dd, J=16.2, 4.5 Hz, 1H), 2.49 (m, 1H), 2.39 (dd, J=13.5, 8.2 Hz, 1H),
2.26 (m, 1H), 1.28 (d, J=6.3 Hz, 3H), 1.26 (s, 3H), 0.94 (d, J=6.8 Hz,
3H), 0.87 (s, 9H), 0.01 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=
204.5, 174.3, 159.5, 138.7, 130.2, 128.8, 123.0, 113.8, 76.8, 74.4, 70.5, 67.8,
57.9, 55.2, 43.6, 40.6, 39.2, 25.9, 20.3, 18.3, 16.6, 15.2, À5.3, À5.4 ppm; IR
(film): n˜ = 2955, 2930, 1716, 1613, 1514, 1250, 1082 cmÀ1. HRMS (ESI):
m/z: [MÀC4H9]+ calcd for C24H35O6Si: 447.2203, found: 447.2210. Major
(31a: [a]2D0 =À35.33 (c=0.3, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=
7.23 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 5.44 (dd, J=15.4,
7.0 Hz, 1H), 5.32 (dt, J=14.7, 7.4 Hz, 1H), 4.58 (d, J=11.6 Hz, 1H), 4.43
(d, J=11.6 Hz, 1H), 4.42 (m, 1H), 3.80 (s, 3H), 3.69 (dd, J=6.3, 3.4 Hz,
1H), 3.66 (dd, J=6.3, 3.8 Hz, 1H), 3.43 (dd, J=9.7, 5.9 Hz, 1H), 3.31
(dd, J=9.7, 7.2 Hz, 1H), 2.68 (dd, J=15.9, 3.3 Hz, 1H), 2.64 (dd, J=13.2,
6.6 Hz, 1H), 2.49 (dd, J=15.9, 10.9 Hz, 1H), 2,45 (dd, J=13.1, 8.0 Hz,
1H), 2.22 (m, 1H), 1.37 (s, 3H), 1.26 (d, J=6.3 Hz, 3H), 0.92 (d, J=
6.6 Hz, 3H), 0.87 (s, 9H), 0.01 ppm (s, 6H); 13C NMR (100 MHz,
CDCl3): d=206.2, 173.4, 159.4, 138.5, 129.6, 129.5, 123.3, 113.9, 75.6, 73.8,
71.0, 67.9, 56.7, 55.3, 40.7, 40.6, 39.3, 25.9, 23.0, 18.3, 16.6, 14.5, À5.3,
À5.4 ppm; IR (film): n˜ =2955, 2930, 1717, 1635, 1615, 1250 cmÀ1; HRMS
(ESI): m/z: [MÀC4H9]+ calcd for C24H35O6Si: 447.2203, found: 447.2212.
6-[(2S,3S)-2-Hydroxy-3-(4-methoxybenzyloxy)butyl]-2,2,5-trimethyl-
ACHTUNGTRENNUNG[1,3]dioxin-4-one (22): Aldehyde 19 (800 mg, 4 mmol) in DCM (12 mL)
under argon at À108C was incubated with MgBr2·Et2O (2.1 g, 8 mmol)
for 30 min. Silyl enol ether 21 (1420 mg, 6 mmol) in DCM (5 mL) was
added and stirring continued for 1 h. A saturated NH4Cl solution was
added, layers were separated and the aqueous layer extracted with DCM.
The combined DCM layers were dried over MgSO4 and solvent removed
under reduced pressure. Column chromatography (hexane/ethyl ace-
tate=1:1) to yield aldol adduct 22 as pale yellow oil (1.34 mg; 96%).
1
[a]2D0 =15.8 (c=1.2, CH2Cl2). H NMR (400 MHz, CDCl3): d=7.25 (d, J=
8.6 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 4.62 (d, J=11.1 Hz, 1H), 4.36 (d,
J=11.1 Hz, 1H), 3.81 (s, 3H), 3.75–3.70 (m, 1H), 3.43 (dt, J=11.6,
6.2 Hz, 1H), 2. 53 (dd, J=14.2, 6.2 Hz, 1H), 2.44 (m, 1H), 2.35 (dd, J=
14.3, 9.1 Hz, 1H), 1.84 (s, 3H), 1.64 (s, 3H), 1.63 (s, 3H), 1.24 ppm (d,
J=6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=162.9, 159.4, 129.9,
113.9, 104.9, 102.3, 76.8, 72.5, 70.7, 55.3, 34.9, 25.8, 24.4, 15.5, 10.3 ppm;
IR (film): n˜ = 3468, 2936, 1721, 1647, 1514, 1248 cmÀ1.HRMS (ESI): m/z:
[M]+ calcd for C19H26O6: 350.1729, found: 350.1737.
(S)-6-[(S)-1-(4-Methoxybenzyloxy)ethyl]-3-methyldihydropyran-2,4-dione
(23): To a solution of lactone 22 (650 mg, 1.85 mmol) in methanol
(12 mL) was added K2CO3 (385 mg, 2.78 mmol) and the mixture was
stirred overnight. The solvent was evaporated and ice and 2n HCl was
added to the residue. The acidic layer was extracted with Et2O repeatedly
and the combined ethereal phases dried over MgSO4. After removal of
the solvent under reduced pressure lactone 23 (550 mg; quant.) was iso-
lated as a yellow solid and used without further purification. [a]2D0 =À29.5
(c=0.8, CHCl3); 1H NMR (400 MHz, CDCl3): d=7.23 (d, J=8.6 Hz,
2H), 6.88 (d, J=8.6 Hz, 2H), 4.64 (dt, J=8.8, 4.0 Hz, 1H), 4.58 (d, J=
11.4 Hz, 1H), 4.42 (d, J=11.4 Hz, 1H), 3.80 (s, 3H), 3.70 (ddd, J=12.7,
6.4, 3.8 Hz, 1H), 3.41 (q, J=6.6 Hz, 1H), 2.72 (dd, J=18.0, 4.2 Hz, 1H),
2.60 (dd, J=18.0, 8.9 Hz, 1H), 1.31 (d, J=6.8 Hz, 3H), 1.29 ppm (d, J=
6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=200.8, 169.7, 159.0, 129.8,
AHCTUNGTERG(NNUN 3S,4S,6S)-3-[(E)-(S)-5-(tert-Butyldimethylsilanyloxy)-4-methylpent-2-
enyl]-4-hydroxy-6-[(S)-1-(4-methoxybenzyloxy)ethyl]-3-methyltetrahy-
dropyran-2-one (32): To b-keto lactone 31 (220 mg, 0.44 mmol) in metha-
nol (9 mL) at 08C was added NaBH4 (17 mg, 0.44 mmol) and the solution
was stirred for 1.5 h. The reaction mixture was quenched with saturated
NH4Cl solution, the organic layer was separated, and the aqueous layer
was extracted with DCM. The combined organic solutions were dried
over MgSO4 and the solvent was evaporated. Purification by column
chromatography (hexane/ethyl acetate=3:1) yielded the reduction prod-
Chem. Eur. J. 2010, 16, 485 – 506
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
495

J. Mulzer and K. Prantz
uct 32 (218 mg; 98%). [a]2D0 =23.41 (c=0.85, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=7.26 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H),
5.47 (m, 2H), 4.63 (d, J=11.4 Hz, 1H), 4.43 (d, J=11.4 Hz, 1H), 4.42 (m,
1H), 3.82 (m, 1H), 3.80 (s, 3H), 3.56 (ddd, J=12.6, 6.3, 3.3 Hz, 1H), 3.46
(dd, J=9.6, 6.3 Hz, 1H), 3.39 (dd, J=9.8, 6.8 Hz, 1H), 2.55 (dd, J=13.6,
5.8 Hz, 1H), 2.40 (dd, J=13.9, 6.1 Hz, 1H), 2.29 (m,1H), 2.16 (ddd, J=
14.2, 7.1, 4.3 Hz, 1H), 1.98 (dt, J=14.1, 7.1 Hz, 1H), 1.20 (d, J=6.6 Hz,
3H), 1.20 (s, 3H), 0.96 (d, J=6.8 Hz, 3H), 0.88 (s, 9H), 0.02 ppm (s,
6H); 13C NMR (100 MHz, CDCl3): d=175.2, 159.4, 137.4, 129.7, 129.4,
129.2, 124.7, 113.9, 78.3, 75.0, 70.8, 70.4, 68.0, 55.2, 47.1, 39.4, 37.4, 28.9,
25.9, 21.0, 18.3, 16.6, 14.6, À5.3, À5.4 ppm; IR (film): n˜ = 3435, 2956,
2856, 1732, 1514, 1463, 1250, 1089, 1036 cmÀ1; HRMS (ESI): m/z: [M]+
calcd for C28H46O6: 506.3069, found: 506.3055.
(hexane/ethyl acetate=20:1) yielded the protected triole 35 (185 mg;
quant.) as
a
colorless oil. [a]D20 =À2.66 (c=1.2, CH2Cl2). 1H NMR
(400 MHz, CDCl3): d=7.25 (d, J=8.5 Hz, 2H), 6.86 (d, J=8.5 Hz, 2H),
5.15 (t, J=7.3 Hz, 1H), 4.51 (d, J=11.6 Hz, 1H), 4.44 (d, J=11.6 Hz,
1H), 3.80 (s, 3H), 3.69–3.65 (m, 1H), 3.47–3,44 (m, 1H), 3.44 (dd, J=
11.9, 6.1 Hz, 1H), 3.34 (dd, J=9.7, 6.7 Hz, 1H), 2.31–2.23 (m, 1H), 2.12–
1.93 (m, 3H), 1.67 (s, 3H), 1.61–1.54 (m, 1H), 1.42–1.28 (m, 3H), 1.12 (d,
J=6.32 Hz, 3H), 1.08–1.00 (m, 1H), 0.89 (s, 9H), 0.86 (s, 9H), 0.86 (d,
J=6.7 Hz, 3H), 0.03 (s, 6H), 0.00 (s, 3H), À0.02 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=159.1, 136.5, 131.3, 129.1, 122.3, 113.8, 77.0, 74.4,
70.6, 68.4, 55.3, 35.8, 33.2, 32.3, 29.9, 25.9, 25.8, 25.5, 23.5, 18.1, 16.7, 14.1,
À4.5, À4.6 À5.3 ppm; IR (film): n˜ =2856, 1513, 1472, 1249, 1249,
1093 cmÀ1
521.3482, found: 521.3489.
;
HRMS (ESI): m/z: [MÀC4H9]+ calcd for C29H53O4Si2:
ACHTUNGTRENNUNG(3S,4S,6S)-3-[(S)-5-(tert-Butyldimethylsilanyloxy)-4-methylpentyl]-4-hy-
droxy-6-[(S)-1-(4-methoxybenzyloxy)ethyl]-3-methyltetrahydropyran-2-
one (33): To b-hydroxyl lactone 32 (350 mg, 0.65 mmol) in ethyl acetate
(6 mL) was added PtO2 (12 mg, 0.07 mmol) and the resulting suspension
was stirred under an atmosphere of hydrogen. After 1.5 h the reaction
mixture was filtered through Celite and the filtrate was evaporated to
yield 33 (350 mg; quant.) as a colorless oil. Separation by column chro-
matography (hexane/ethyl acetate=10:1) yielded diastereoisomer 33
(245 mg; 70%). [a]2D0 =24 (c=0.4, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d=7.26 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 4.63 (d, J=11.6 Hz,
1H), 4.42 (d, J=11.6 Hz, 1H), 4.39 (m, 1H), 3.86 (ddd, J=6.9, 6.7,
4.3 Hz, 1H), 3.80 (s, 3H), 3.56 (ddd, J=12.6, 6.4, 3.2 Hz, 1H), 3.42 (dd,
J=9.8, 5.8 Hz, 1H), 3.34 (dd, J=9.8, 6.6 Hz, 1H), 2.83 (d, J=6.4 Hz,
1H), 2.14 (ddd, J=14.1, 6.7, 4,2 Hz, 1H), 2.01 (dt, J=14.2, 7.6 Hz, 1H),
1.75–1.67 (m, 2H), 1.59 (m, 1H), 1.33–1.28 (m, 2H), 1.31 (d, J=6.4 Hz,
3H), 1.25 (s, 3H), 1.05 (m, 1H), 0,84 (d, J=6.8 Hz, 3H), 0.88 (s, 9H),
0.03 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=175.3, 159.4, 129.7,
129.5, 113.9, 78.1, 74.9, 70.8, 70.7, 68.4, 55.3, 47.0, 35.6, 33.7, 33.1, 28.6,
25.9, 21.1, 18.3, 16.7, 14.6, À5.4 ppm; IR (film): n˜ = 2953, 1732, 1514,
1463, 1250, 1092 cmÀ1; HRMS (ESI): m/z: [M]+ calcd for C28H48O6Si:
508.3220, found:508.3224.
(Z)-(2S,3S,10S)-3,11-Bis-(tert-butyldimethylsilanyloxy)-6,10-dimethylun-
dec-5-en-2-ol (36): To a stirred solution of triprotected triol 35 (85 mg,
0.14 mmol) in DCM (2 mL) with water (0.5 mL) was added DDQ
(37 mg, 0.16 mmol) in small portions and the mixture was stirred vigo-
rously for 20 min. The reaction was quenched with saturated NaHCO3 so-
lution, the organic layer separated and the aqueous solution extracted
with DCM. The combined organic solutions were dried over MgSO4, the
solvent was evaporated, and the residue was purified by column chroma-
tography (hexane/ethyl acetate=20:1) to yield 36 (63 mg; 98%). [a]D20
=
11.8 (c=1.05, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=5.13 (t, J=
7.2 Hz, 1H), 3.66–3.58 (m, 1H), 3.42 (m, 1H), 3.43 (dd, J=9.7, 5.9 Hz,
1H), 3.36 (dd, J=9.8, 6.6 Hz, 1H), 2,34–2,27 (m, 1H), 2.17 (d, J=6.6 Hz,
1H), 2.17–2.11 (m, 1H), 2,05–1.95 (m, 2H), 1.68 (d, J=1.0 Hz, 3H),
1.62–1.54 (m, 1H), 1.45–1,27 (m, 3H), 1.12 (d, J=6.3 Hz, 3H), 1.08–1.01
(m, 1H), 0.91 (s, 9H), 0.89 (s, 9H), 0.87 (d, J=6.8 Hz, 3H), 0.09 (s, 3H),
0.08 (s, 3H), 0.03 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=137.7,
120.3, 76.7, 68.7, 68.3, 35.7, 33.2, 32.4, 32.2, 25.9, 25.8, 25.4, 23.5, 19.9,
18.1, 16.7, À4.1, À4.7, À5.3 ppm; IR (film): n˜ = 2929, 2857, 1472, 1256,
1094 cmÀ1; HRMS (ESI): m/z: [M]+ calcd for C25H54O3Si2: 458.3612,
found: 458.3618.
(Z)-(2S,3S,10S)-11-(tert-Butyldimethylsilanyloxy)-2-(4-methoxybenzyl-
ACHTUNGTRENNUNGoxy)-6,10-dimethylundec-5-en-3-ol (34): Alcohol 33 (50 mg, 0.1 mmol)
(Z)-(3S,10S)-3,11-Bis-(tert-butyldimethylsilanyloxy)-6,10-dimethylundec-
5-en-2-one (37): To a stirred solution of alcohol 36 (40 mg, 0.087 mmol)
in DCM (2 mL) was added DMP (74 mg, 0.17 mmol) and the suspension
was stirred for 1.5 h. The reaction was quenched with saturated NaHCO3
solution, the organic layer was separated, and the aqueous layer was ex-
tracted with DCM. The combined organic solutions were dried over
MgSO4, the solvent was evaporated, and the residue was purified by
column chromatography (hexane/ethyl acetate=20:1) to yield ketone 37
was dissolved in Et2O (3 mL), Et3N (0.30 mL) was added at 08C, and the
mixture was stirred for 15 min. Methanesulfonyl chloride (9 mL,
0.11 mmol) was added and stirring was continued. After 1.5 h the reac-
tion mixture was quenched with brine, the organic layer separated, and
the aqueous layer was extracted with Et2O. The combined organic layers
were dried over MgSO4 and the solvent was evaporated. This yielded
80 mg of the crude mesylate which was used without further purification.
To a stirred solution of the crude mesylate (70 mg, 0.1 mmol) in methanol
(3 mL) at 08C was added 1m KOH (0.2 mL, 0.2 mmol) and the solution
was stirred for 2 h. The reaction was quenched with saturated NH4Cl so-
lution, the organic layer separated, and the aqueous layer extracted with
DCM. The combined organic layers were dried over MgSO4 and the sol-
vent was evaporated. Purification by column chromatography (hexane/
ethyl acetate=15:1) yielded 34 (42 mg; 91%) as a colorless oil. [a]2D0 =20
(c=1.9, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.26 (d, J=8.8 Hz,
2H), 6.88 (d, J=8.8 Hz, 2H), 5.21 (t, J=7.1 Hz, 1H), 4.59 (d, J=11.1 Hz,
1H), 4.38 (d, J=11.1 Hz, 1H), 3.80 (s, 3H), 3.46–3.40 (m, 3H), 3.35 (dd,
J=9.8, 6.6 Hz, 1H), 2.47 (d, J=3.5 Hz, 1H), 2.28–2.21 (m, 1H), 2.19–2.11
(m, 1H), 2.00 (t, J=7.9 Hz, 2H), 1.70 (d, J=1.0 Hz, 3H), 1.61–1.53 (m,
1H), 1.45–1.31 (m, 3H), 1.18 (d, J=5.8 Hz, 3H), 1.08–1.01 (m, 1H), 0.90
(s, 9H), 0.86 (d, J=6.8 Hz, 3H), 0.03 ppm (s, 6H); 13C NMR (100 MHz,
CDCl3): d=159.3, 137.9, 130.5, 129.3, 120.5, 113.9, 77.3, 75.1, 70.7, 68.3,
55.3, 35.7, 33.1, 32.2, 25.9, 25.3, 23.5, 18.3, 16.7, 15.7, À5.3 ppm; IR (film):
1
(39 mg; quant.). H NMR (400 MHz, CDCl3): d=5.11 (t, J=7.3 Hz, 1H),
3.97 (dd, J=6.8, 5.6 Hz, 1H), 3.43 (dd, J=9.8, 5.8 Hz, 1H), 3.35 (dd, J=
9.7, 6.4 Hz, 1H), 2.38–2.22 (m, 2H), 2.15 (s, 3H), 2.04–1.91 (m, 2H), 1.68
(d, J=1.0 Hz, 3H), 1.61–1.53 (m, 1H), 1.39–1.27 (m, 3H), 1.08–1.00 (m,
1H), 0.91 (s, 9H), 0.89 (s, 9H), 0.86 (d, J=6.6 Hz, 3H), 0.05 (s, 3H), 0.04
(s, 3H), 0.03 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=212.0, 138.6,
119.0, 79.2, 68.3, 35.7, 33.4, 33.1, 32.2, 25.9, 25.7, 25.4, 25.3, 23.5, 16.7,
14.1, À4.9, À5.0, À5.3 ; HRMS (ESI): m/z: [M]+ calcd for C25H52O3Si2:
456.3455, found: 456.3461.
4-[(1E,5Z)-(3S,10S)-3,11-Bis-(tert-butyldimethylsilanyloxy)-2,6,10-trime-
thylundeca-1,5-dienyl]-2-methylthiazole (38): To a stirred solution of (2-
methyl-thiazol-4-yl)methyltributylphosphonium
chloride
(115 mg,
0.33 mmol) in THF (1 mL) at 08C was added nBuLi (130 mL, 2.5m in
hexane, 0.33 mmol) to form a bright red solution, which was stirred for
1 h. The mixture was cooled to À788C and ketone 37 (15 mg,
0.033 mmol) in THF (0.50 mmol) was added. The cooling bath was re-
moved and the mixture stirred at 608C for 1.5 h. After cooling down to
room temperature, the reaction was quenched with saturated NH4Cl so-
lution, the organic layer separated and the aqueous layer was extracted
with Et2O. The combined organic solutions were dried over MgSO4 and
the solvent was evaporated. The crude product was purified by column
chromatography (hexane/ethyl acetate=20:1) to yield northern fragment
38 (17 mg; 93%). [a]D20 =2.1 (c=0.7, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=6.91 (s, 1H), 6.45 (s, 1H), 5.13 (t, J=6.8 Hz, 1H), 4.08 (t, J=
6.4 Hz, 1H), 3.44 (dd, J=9.8, 5.8 Hz, 1H), 3.34 (dd, J=9.8, 6.6 Hz, 1H),
2.71 (s, 3H), 2.29–2.20 (m, 2H), 2.05–1.94 (m, 2H), 2.00 (d, J=1.3 Hz,
n˜ = 2929, 1726, 1514, 1249, 1180, 1093 cmÀ1
; HRMS (ESI): m/z:
[MÀC4H9]+ calcd for C23H39O4Si: 407.2617, found: 407.2610.
1-[(Z)-(1S,2S,9S)-2,10-Bis-(tert-butyldimethylsilanyloxy)-1,5,9-trimethyl-
dec-4-enyloxymethyl]-4-methoxybenzene (35): To a stirred solution of al-
cohol 34 (150 mg, 0.32 mmol) in DCM (4 mL) was added 2,6-lutidine
(58 mL, 0.48 mmol) and TBSOTf (92 mL, 0.38 mmol). After 1 h the reac-
tion was quenched with saturated NH4Cl solution and extracted with
DCM. The combined organic solutions were dried over MgSO4 and the
solvent was evaporated. Purification by column chromatography
496
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 485 – 506

Synthesis of (Z)-Trisubstituted Olefins
FULL PAPER
3H), 1.66 (d, J=1.3 Hz, 3H), 1.61–1.53 (m, 1H), 1.45–1.28 (m, 3H),
1.08–1.00 (m, 1H), 0.89 (s, 18H), 0.86 (d, J=6.6 Hz, 3H), 0.05 (s, 3H),
0.03 (s, 6H), 0.00 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=164.3,
153.3, 142.6, 136.9, 121.4, 118.7, 114.9, 79.1, 68.4, 35.8, 35.3, 33.2, 32.3,
25.9, 25.8, 25.4, 23.5, 19.2, 16.7, 13.9, À4.6, À4.9, À5.3 ppm; IR (film): n˜ =
152.1, 137.3, 119.9, 116.7, 80.6, 70.4, 68.2, 47.1, 38.7, 35.5, 33.5, 31.4, 25.9,
21.4, 19.2, 19.1, 18.3, 16.6, 14.4, À5.4 ppm; IR (film): n˜ = 2952, 1710,
1250, 1086 cmÀ1 HRMS (ESI): m/z: [M]+ calcd for C25H43O4NSSi:
;
481.2682, found: 481.2669.
AHCTUNGTRENGN(UN 3S,4S,6S)-3-[(S)-5-(tert-Butyl-dimethylsilanyloxy)-4-methylpentyl]-4-hy-
2929, 1472, 1257, 1090 cmÀ1
;
HRMS (ESI): m/z: [M]+ calcd for
droxy-3-methyl-6-[(E)-1-methyl-2-(2-methylthiazol-4-yl)vinyl]tetrahydro-
pyran-2-one (10): Dess–Martin-periodinane (229 mg, 0.54 mmol) was
added portionwise to a suspension of alcohol 56 (90 mg, 0.18 mmol) and
NaHCO3 (45 mg, 0.54 mmol) in DCM (3 mL) at 08C under argon. After
4 h water was added, the layers were separated and the aqueous layer
was extracted with DCM. The combined DCM phases were dried over
MgSO4 and the solvent was evaporated. Column chromatography
(hexane/ethyl acetate=3:1) yielded the ketone (85 mg; 94%) as colorless
oil. [a]2D0 =À23.4 (c=1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.04
(s, 1H), 6.61 (s, 1H), 4.97 (dd, J=11.9, 2.3 Hz, 1H), 3.37 (dd, J=9.8,
6.0 Hz, 1H), 3.33 (dd, J=9.8, 6.0 Hz, 1H), 2.83 (dd, J=16.3, 2.7 Hz, 1H),
2.75–2.68 (m, 1H), 2.71 (s, 3H), 2.17 (d, J=1.0 Hz, 3H), 2.01–1.81 (m,
2H), 1.57–1.49 (m, 1H), 1.46 (s, 1H), 1.40–1.17 (m, 3H), 1.07–1.00 (m,
1H), 0.88 (s, 9H), 0.81 (d, J=6.84 Hz, 3H), 0.02 ppm (s, 6H); 13C NMR
(100 MHz, CDCl3): d=206.6, 173.6, 165.1, 151.7, 134.2, 122.0, 117.7, 78.2,
68.2, 56.4, 44.2, 38.4, 35.3, 33.3, 25.9, 23.6, 22.9, 19.3, 18.3, 16.5, 13.9,
À5.4 ppm; IR (film): n˜ = 2928, 1751, 1718, 1257, 1140, 1093 cmÀ1. HRMS
(ESI): m/z: [MÀC4H9]+ calcd for C21H32O4NSSi: 422.1821, found:
422.1833. Sodium borohydride (13 mg, 0.3 mmol) was added to the keto
lactone (150 mg, 0.3 mmol) in methanol (4 mL) at À788C. After 5 h
brine was added, the mixture was warmed to room temperature and ex-
tracted with DCM. The combined DCM layers were dried over MgSO4
and the solvent was evaporated. Column chromatography (hexane/ethyl
C30H57O2Si2NS: 551.3849, found: 551.3635.
(E)-(2S,3R)-2-[(S)-5-(tert-Butyldimethylsilanyloxy)-4-methylpentyl]-3-hy-
droxy-2,6-dimethyl-7-(2-methylthiazol-4-yl)-5-oxo-hept-6-enoic
acid
methyl ester (53): LiHMDS (0.66 mL, 1m in THF, 0.66 mmol) was added
to methyl ketone 52 (120 mg, 0.66 mmol) in THF (8 mL) at À788C under
argon. After 1 h a solution of aldehyde 50 (219 mg, 0.66 mmol) premixed
with MgBr2·Et2O (342 mg, 1.32 mmol) in THF (6 mL) at 08C for 1 h was
slowly added by using a canula. After 3.5 h a saturated NH4Cl solution
was added and the aqueous phase was extracted with DCM. The com-
bined organic layers were dried over MgSO4 and the solvent was re-
moved under reduced pressure. Column chromatography (hexane/ethyl
acetate=3:1) yielded the aldol adduct 53 (312 mg; 92%) as a colorless
oil. [a]2D0 =26.15 (c=1.3, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.51
(s, 1H), 7.38 (s, 1H), 4.34–4.30 (m, 1H), 3.69 (s, 3H), 3.42 (dd, J=9.9,
5.8 Hz, 1H), 3.35 (dd, J=9.9, 6.6 Hz, 1H), 3.33 (d, J=3.5 Hz, 1H), 2.92–
2.89 (m, 2H), 2.75 (s, 3H), 2.23 (d, J=1.00 Hz, 3H), 1.84–1.77 (m, 1H),
1.60–1.50 (m, 2H), 1.42–1.32 (m, 2H), 1.23–1.17 (m, 1H), 1.20 (s, 3H),
1.08–1.02 (m, 1H), 0.89 (s, 9H), 0.85 (d, J=6.6 Hz, 3H), 0.03 ppm (s,
6H); 13C NMR (100 MHz, CDCl3): d=202.6, 176.3, 165.5, 151.6, 137.2,
131.2, 121.9, 71.6, 68.3, 51.7, 50.4, 39.8, 36.9, 35.5, 33.5, 25.9, 21.9, 19.3,
18.4, 16.6, 16.5, 13.2, À5.4 ppm; IR (film): n˜ = 3436, 2953, 1722, 1652,
1628, 1250, 1087 cmÀ1. HRMS (ESI): m/z: [M]+ calcd for C26H45O5NSSi:
511.2788, found: 511.2776.
acetate=1:1) yielded lactone 10 (140 mg, 93%) as a colorless oil. [a]D20
=
À11.45 (c=2, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.00 (s, 1H),
6.55 (s, 1H), 4.75 (dd, J=11.3, 4.1 Hz, 1H), 4.02 (dd, J=11.3, 4.1 Hz,
1H), 3.42 (dd, J=9.7, 5.9 Hz, 1H), 3.36 (dd, J=9.7, 6.4 Hz, 1H), 2.71 (s,
(E)-(2S,3R,5R)-2-[(S)-5-(tert-Butyldimethylsilanyloxy)-4-methylpentyl]-
3,5-dihydroxy-2,6-dimethyl-7-(2-methylthiazol-4-yl)-hept-6-enoic
acid
methyl ester (55): To a solution of 53 (950 mg, 1.90 mmol) in THF
(20 mL) at À108C under argon was added catecholborane (0.99 mL,
9.5 mmol) and stirred for 5 h. A saturated solution of potassium-sodium-
tartrate was added and the mixture was stirred for 1 h. The layers were
separated and the aqueous layer was extracted with DCM. The combined
organic layers were dried over MgSO4 and the solvent was removed
under reduced pressure. Column chromatography (hexane/ethyl ace-
tate=1:1) yielded dihydroxy ester 55 (835 mg; 88%) as a colorless oil.
[a]2D0 =À0.4 (c=0.5, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=6.97 (s,
1H), 6.60 (s, 1H), 4.40 (dd, J=9.2, 2.9 Hz, 1H), 4.02 (dd, J=9.9, 1.6 Hz,
1H), 3.68 (s, 3H), 3.41 (dd, J=9.9, 5.8 Hz, 1H), 3.34 (dd, J=9.7, 6.4 Hz,
1H), 2.75 (s, 3H), 2.01 (d, J=1.0 Hz, 3H), 1.80–1.66 (m, 2H), 1.63–1.52
(m, 2H), 1.50–1.43 (m, 1H), 1.39–1.20 (m, 3H), 1.15 (s, 3H), 1.07–0.97
(m, 1H), 0.88 (s, 9H), 0.84 (d, J=6.6 Hz, 3H), 0.03 ppm (s, 6H);
13C NMR (100 MHz, CDCl3): d=176.9, 165.3, 151.8, 142.8, 118.1, 115.7,
78.3, 76.3, 68.4, 51.8, 50.9, 36.9, 36.1, 35.5, 33.6, 25.9, 22.0, 18.8, 18.4, 16.9,
16.6, 14.4, À5.4 ppm; IR (film): n˜ = 2952, 1731, 1090, 837 cmÀ1; HRMS
(ESI): m/z: [M]+ calcd for C26H47O5NSSi: 513.2945, found: 513.2936.
3H), 2.27–2.18 (m, 1H) 2.10 (d, J=1.0 Hz, 3H), 2.13–2.06ACTHNUTRGENUG(N m, 1H), 1.75–
1.55 (m, 3H), 1.48–1.26 (m, 3H), 1.37 (s, 3H), 1.11–1.01 (m, 1H), 0.88 (s,
9H), 0.86 (d, J=6.8 Hz, 3H), 0.03 ppm (s, 6H); 13C NMR (100 MHz,
CDCl3): d=175.3, 165.0, 152.0, 136.5, 120.6, 116.9, 81.2, 72.5, 68.3, 47.7,
35.6, 33.7, 33.0, 32.7, 25.9, 21.8, 20.9, 19.2, 18.3, 16.6, 14.0, À5.4 ppm; IR
(film): n˜ = 3420, 2954, 1727, 1250, 1127, 1078 cmÀ1; HRMS (ESI): m/z:
[M]+ calcd for C25H43O4NSSi: 481.2682, found: 481.2676.
AHCTUNGTRENGN(UN 1E,5Z)-(3S,10S)-11-(tert-Butyldimethylsilanyloxy)-2,6,10-trimethyl-1-(2-
methylthiazol-4-yl)-undeca-1,5-dien-3-ol (7): To a solution of b-hydroxy
lactone 10 (25 mg, 0.05 mmol) in 10:1 Et2O/Et3N (1 mL) at 08C under
argon was added MsCl (6 mL, 0.07 mmol). After 1.5 h brine was added
and the aqueous layer was extracted with Et2O. The combined ethereal
layers were dried over MgSO4 and the solvent was removed under re-
duced pressure. The residue was taken up in THF (1 mL) and LiOH
(0.15 mL, 1m in water, 0.15 mmol) was added at 08C. After 1 h TLC
showed completion of the reaction, and a saturated NH4Cl solution was
added, the layers were separated and the aqueous phase was extracted
with DCM. The combined organic layers were dried over MgSO4 and the
solvent was evaporated. Column chromatography (hexane/ethyl acetate=
3:1) yielded di-olefin 7 (17.5 mg; 81%) as a colorless oil. [a]2D0 =À8.2 (c=
0.5, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=6.94 (s, 1H), 6.56 (s, 1H),
5.16 (t, J=7.1 Hz, 1H), 4.14 (t, J=6.3 Hz, 1H), 3.43 (dd, J=9.5, 5.4 Hz,
1H), 3.35 (dd, J=9.8, 6.6 Hz, 1H), 2.71 (s, 3H), 2.35 (t, J=6.6 Hz, 2H),
2.05 (d, J=1.3 Hz, 3H), 2.03 (t, J=6.9 Hz, 2H), 1.71 (d, J=1.3 Hz, 3H),
1.62–1.54 (m, 1H), 1.44–1.31 (m, 3H), 1.10–1.01 (m, 1H), 0.89 (s, 9H),
0.86 (d, J=6.8 Hz, 3H), 0.02 ppm (s, 6H); 13C NMR (100 MHz, CDCl3):
d=164.5, 152.9, 141.7, 139.5, 120.1, 118.8, 115.4, 77.2, 68.3, 65.8, 35.7,
34.1, 33.1, 32.3, 26.0, 25.5, 19.2, 18.4, 16.7, 15.2, 14.5, À5.3 ppm; IR (film):
n˜ = 3390, 2955, 2928, 1256, 1093 cmÀ1; HRMS (ESI): m/z: [M]+ calcd for
C24H43O2NSSi: 437.2784, found: 437.2779.
ACHTUNGTRENNUNG(3S,4R,6S)-3-[(S)-5-(tert-Butyldimethylsilanyloxy)-4-methylpentyl]-4-hy-
droxy-3-methyl-6-[(E)-1-methyl-2-(2-methylthiazol-4-yl)-vinyl]tetrahy-
dropyran-2-one (56): LiOH (2.4 mL, 1m in water, 2.4 mmol) was added
to ester 55 (400 mg, 0.78 mmol) in THF (10 mL) at 08C and the mixture
was stirred vigorously for 4 h. Brine was added and the aqueous layer
was acidified with 1n HCl and extracted with DCM. The combined or-
ganic layers were dried over MgSO4 and the solvent was evaporated. The
residue was dissolved in DCM (8 mL) and EDC·HCl (227 mg,
1.17 mmol) and DMAP (190 mg, 1.56 mmol) were added. After 4 h brine
was added and the aqueous layer was extracted with DCM. The com-
bined DCM phases were dried over MgSO4 and the solvent was evapo-
rated. Column chromatography yielded lactone 56 (350 mg; 94%) as a
colorless oil. [a]2D0 =À0.54 (c=1.4, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d=6.99 (s, 1H), 6.56 (s, 1H), 5.21 (dd, J=10.9, 3.9 Hz, 1H), 4.01 (dd, J=
4.5, 2.0 Hz, 1H), 3.40 (dd, J=9.9, 6.2 Hz, 1H), 3.36 (dd, J=9.9, 6.2 Hz,
1H), 2.73 (s, 3H), 2.27 (ddd, J=14.1, 11.1, 2.0 Hz, 1H) 2.11 (d, J=
0.9 Hz, 3H), 2.04 (dt, J=14.3, 4.5 Hz, 1H), 1.68–1.50 (m, 3H), 1.43–1.25
(m, 3H), 1.34 (s, 3H), 1.09–0.99 (m, 1H), 0.88 (s, 9H), 0.84 (d, J=6.6 Hz,
3H), 0,02 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=176.1, 165.0,
4-[(1E,5Z)-(3S,10S)-3,11-Bis-(tert-butyldimethylsilanyloxy)-2,6,10-trime-
thylundeca-1,5-dienyl]-2-methylthiazole (38): To a stirred solution of al-
cohol 13 (15 mg, 0.034 mmol) in DCM (1 mL) was added 2,6-lutidine
(9 mL, 0.051 mmol) and TBSOTf (10 mL, 0.041 mmol). After 1 h the reac-
tion was quenched with saturated NH4Cl solution and extracted with
DCM. The combined organic extracts were dried over MgSO4 and the
Chem. Eur. J. 2010, 16, 485 – 506
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
497

J. Mulzer and K. Prantz
solvent was evaporated. Purification by column chromatography
(hexane/ethyl acetate=20:1) yielded 38 (16 mg; 85%) as a colorless oil.
The experimental data were identical with the literature data. [a]2D0 =3.5
(c=1.1, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=6.91 (s, 1H), 6.45 (s,
1H), 5.13 (t, J=7.1 Hz, 1H), 4.08 (t, J=6.7 Hz, 1H), 3.44 (dd, J=9.7,
5.8 Hz, 1H), 3.34 (dd, J=9.7, 6.7 Hz, 1H), 2.71 (s, 3H), 2.30–2.20 (m,
2H), 2.04–1.95 (m, 2H), 2.00 (d, J=1.2 Hz, 3H), 1.66 (d, J=1.2 Hz, 3H),
1.61–1.53 (m, 1H), 1.43–1.28 (m, 3H), 1.08–1.00 (m, 1H), 0.89 (s, 18H),
0.86 (d, J=6.56 Hz, 3H), 0.05 (s, 3H), 0.03 (s, 6H), 0.00 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=164.3, 153.3, 142.6, 136.9, 121.4, 118.7,
114.9, 79.1, 68.4, 35.8, 35.3, 33.2, 32.3, 25.9, 25.8, 25.4, 23.5, 19.2, 18.4,
18.2, 16.7, 13.9, À4.6, À4.9, À5.3 ppm; IR (film): n˜ =2955, 2929, 1471,
1256, 1091 cmÀ1; HRMS (ESI): m/z: [M]+ calcd for C30H57O2Si2NS:
551.3849, found: 551.3635.
16.6, 15.4, À5.4 ppm; IR (film): n˜ = 3400, 2952, 2989, 1731, 1256,
1091 cmÀ1; HRMS (ESI): m/z: [M]+ calcd for C26H47O5NSSi: 513.2944,
found: 513.2953.
AHCTUNGTRENGN(UN 3S,4R,6R)-3-[(S)-5-(tert-Butyldimethylsilanyloxy)-4-methylpentyl]-4-hy-
droxy-3-methyl-6-[(E)-1-methyl-2-(2-methylthiazol-4-yl)vinyl]tetrahydro-
pyran-2-one (63): LiOH (1.5 mL, 1m in water, 1.5 mmol) was added to
ester 62 (240 mg, 0.47 mmol) in THF (5 mL) at 08C and vigorously
stirred for 4 h. Brine was added, the aqueous layer was acidified with 1n
HCl and was extracted with DCM. The combined organic layers were
dried over MgSO4 and the solvent was evaporated. The residue was
taken up in DCM (5 mL) and EDC·HCl (136 mg, 0.7 mmol) and DMAP
(116 mg, 0.94 mmol) were added. After 3 h, brine was added and the
aqueous layer was extracted with DCM, the combined DCM phases were
dried over MgSO4 and the solvent was evaporated. Column chromatogra-
phy (hexane/ethyl acetate=1:1) yielded lactone 63 (192 mg; 85%) as col-
orless oil. [a]2D0 =À6.6 (c=2, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=
7.00 (s, 1H), 6.56 (s, 1H), 4.74 (dd, J=9.6, 5.8 Hz, 1H), 4.20 (dd, J=8.5,
6.9 Hz, 1H), 3.42 (dd, J=9.8, 6.2 Hz, 1H), 3.38 (dd, J=9.8, 6.2 Hz, 1H),
2.71 (s, 3H), 2.16–2.09 (m, 2H), 2.10 (d, J=1.0 Hz, 3H), 1.85 (ddd, J=
13.7, 11.1, 4.9 Hz, 1H), 1 63 (ddd, J=13.8, 11.1, 5.5 Hz, 1H), 1.59–1.54
(m, 1H), 1.45–1.26 (m, 3H), 1.29 (s, 3H), 1.26–1.17 (m, 1H), 0.89 (s, 9H),
0.86 (d, J=6.8 Hz, 3H), 0.04 ppm (s, 6H); 13C NMR (100 MHz, CDCl3):
d=176.0, 165.0, 152.1, 136.4, 120.8, 116.9, 81.0, 68.4, 67.8, 48.7, 36.3, 35.7,
33.6, 33.3, 25.9, 22.3, 19.2, 16.7, 14.1, À5.4 ppm; IR (film): n˜ = 2953, 2928,
ACHTUNGTRENNUNG(1E,5E)-(3S,10S)-11-(tert-Butyldimethylsilanyloxy)-2,6,10-trimethyl-1-(2-
methylthiazol-4-yl)-undeca-1,5-dien-3-ol (60) and (3S,4S)-3-[(S)-5-(tert-
butyldimethylsilanyloxy)-4-methylpentyl]-4-[(E)-(S)-2-hydroxy-3-methyl-
4-(2-methylthiazol-4-yl)-but-3-enyl]-3-methyloxetan-2-one (61): To a so-
lution of b-hydroxy lactone 56 (25 mg, 0.05 mmol) in 10:1 Et2O/Et3N
(1 mL) at 08C under argon was added MsCl (6 mL, 0.07 mmol). After
1.5 h brine was added and the aqueous layer was extracted with Et2O.
The combined ethereal layers were dried over MgSO4 and the solvent
was removed under reduced pressure. The residue was taken up in THF
(1 mL) and LiOH (0.15 mL, 1m in water, 0.15 mmol) was added at 08C.
After 2 h TLC showed completion of the reaction and a saturated NH4Cl
solution was added, the layers were separated and the aqueous phase
was extracted with DCM. The combined organic layers were dried over
MgSO4 and the solvent was evaporated. Column chromatography
(hexane/ethyl acetate=5:1) yielded di-olefin 60 (8 mg; (38%) and b-lac-
tone 61 (12 mg; 52%). 60: [a]2D0 =À9.06 (c=0.85, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=6.94 (s, 1H), 6.56 (s, 1H), 5.17 (t, J=7.2 Hz, 1H),
4.16 (t, J=6.3 Hz, 1H), 3.42 (dd, J=9.7, 5.9 Hz, 1H), 3.34 (dd, J=9.7,
6.1 Hz, 1H), 2.71 (s, 3H), 2.36 (t, J=6.8 Hz, 2H), 2.06 (d, J=1.3 Hz,
3H), 2.00 (t, J=7.3 Hz, 2H), 1.78 (d, J=3.3 Hz, 1H), 1.64 (s, 3H), 1.60–
1.53 (m, 1H), 1.46–1.30 (m, 3H), 1.06–1.00 (m, 1H), 0.89 (s, 9H), 0.85 (d,
J=6.8 Hz, 3H), 0.03 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=
164.6, 153.0, 141.7, 139.4, 119.5, 118.9, 115.4, 77.2, 68.4, 40.2, 35.7, 34.4,
32.9, 26.0, 25.4, 19.2, 18.3, 16.7, 16.2, 14.5, À5.3 ppm; IR (film): n˜ =2954,
2856, 1712, 1250, 1087 cmÀ1
C25H43O4NSSi: 481.2682, found: 481.2671.
AHCTUNGTRENGN(UN 3S,4S,6R)-3-[(S)-5-(tert-Butyldimethylsilanyloxy)-4-methylpentyl]-4-hy-
;
HRMS (ESI): m/z: [M]+ calcd for
droxy-3-methyl-6-[(E)-1-methyl-2-(2-methylthiazol-4-yl)vinyl]tetrahydro-
pyran-2-one (64): Dess–Martin periodinane (178 mg, 0.42 mmol) was
added portionwise to a suspension of alcohol 63 (70 mg, 0.14 mmol) and
NaHCO3 (35 mg, 0.42 mmol) in DCM (2 mL) at 08C under argon. After
4 h, water was added, layers were separated, and the aqueous layer was
extracted with DCM. The combined DCM phases were dried over
MgSO4 and the solvent was evaporated. Column chromatography
(hexane/ethyl acetate=3:1) yielded the ketone (66 mg; 94%) as a color-
less oil. [a]2D0 =6.89 (c=1.2, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=
7.03 (s, 1H), 6.60 (s, 1H), 5.01 (dd, J=11.1, 3.0 Hz, 1H), 3.41–3.34 (m,
2H), 2.87 (dd, J=16.2, 11.1 Hz, 1H), 2.77 (dd, J=16.2, 3.3 Hz, 1H), 2.72
(s, 3H), 2,17 (d, J=1.3 Hz, 3H), 1.99 (ddd, J=13.2, 11.9, 4.5 Hz, 1H),
1.73 (ddd, J=12.9, 12.9, 3.7 Hz, 1H), 1.60–1.52 (m, 2H), 1.42 (s, 1H),
1.43–1.17 (m, 3H), 1.10–1.02 (m, 1H), 0.89 (s, 9H), 0.84 (d, J=6.8 Hz,
3H), 0.03 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=205.9, 173.7,
165.1, 151.8, 134.4, 121.9, 117.8, 78.0, 68.1, 57.0, 42.2, 37.6, 35.4, 33.1, 26.0,
22.7, 22.1, 19.3, 18.3, 16.6, 14.0, À5.4 ppm; IR (film): n˜ = 2953, 2928,
1749, 1716, 1256, 1090 cmÀ1; HRMS (ESI): m/z: [MÀCH3]+ calcd for
2928, 1471, 1255, 1092 cmÀ1
;
HRMS (ESI): m/z: [M]+ calcd for
C24H43O2NSSi: 437.2784, found: 437.2785. 61: [a]2D0 =À25.9 (c=1.35,
1
CH2Cl2); H NMR (400 MHz, CDCl3): d=6.96 (s, 1H), 6.06 (s, 1H), 4.66
(dd, J=9.3, 3.3 Hz, 1H), 4.36 (dt, J=8.9, 3.3 Hz, 1H), 3.43–3.36 (m, 2H),
2.71 (s, 3H), 2.07 (d, J=3.3 Hz, 1H), 2.06 (d, J=1.0 Hz, 3H), 2.00–1.86
(m, 2H), 1.74–1.67 (m, 2H), 1.62–1.56 (m, 2H), 1.49–1.34 (m, 3H), 1.26
(s, 3H), 1.14–1.05 (m, 1H), 0.89 (s, 9H), 0.86 (d, J=6.8 Hz, 3H),
0.03 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=175.0, 164.8, 152.5,
141.5, 119.0, 116.1, 78.4, 73.6, 68.2, 57.4, 36.4, 36.1, 35.6, 33.3, 25.9, 21.7,
19.2, 18.3, 16.6, 14.8, 14.4, À5.4 ppm; IR (film): n˜ =2954, 2528, 1820,
1094 cmÀ1; HRMS (ESI): m/z: [M]+ calcd for C25H43O42NSSi: 481.2682,
found: 481.2672.
C24H38O4NSSi
: 464.2281, found: 464.2279 . Sodium boron hydride
(1.5 mg, 0.041 mmol) was added to the keto lactone (20 mg, 0.041 mmol)
in methanol (1 mL) at À788C. After 4 h, brine was added, the mixture
was warmed to room temperature, and the aqueous phase was extracted
with DCM. The combined DCM layers were dried over MgSO4 and the
solvent was evaporated. Column chromatography (hexane/ethyl acetate=
1:1) yielded lactone 64 (18 mg; 90%) as a colorless oil. [a]2D0 3.8 (c=1.1,
CH2Cl2). 1H NMR (400 MHz, CDCl3): d=6.99 (s, 1H), 6.58 (s, 1H), 5.23
(dd, J=11.6, 3.8 Hz, 1H), 4.02 (dd, J=4.0, 2.0 Hz, 1H), 3.47–3.36 (m,
2H), 2.72 (s, 3H), 2.24 (ddd, J=14.0, 11.4, 2.2 Hz, 1H), 2.10 (d, J=
0.8 Hz, 3H), 2.02 (ddd, J=14.0, 4.6, 3.8 Hz, 1H), 1.68–1.51 (m, 3H),
1.41–1.24 (m, 3H), 1.34 (s, 3H), 1.08–1.01 (m, 1H), 0.89 (s, 9H), 0.87 (d,
J=6.4 Hz, 3H), 0.05 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=
176.6, 165.0, 152.5, 136.8, 120.1, 116.7, 80.6, 70.5, 68.3, 47.2, 38.8, 35.6,
33.7, 31.4, 25.8, 21.6, 20.2, 19.1, 18.7, 16.9, 14.2, À5.3 ppm; IR (film): n˜ =
(E)-(2S,3R,5R)-2-[(S)-5-(tert-Butyldimethylsilanyloxy)-4-methylpentyl]-
3,5-dihydroxy-2,6-dimethyl-7-(2-methylthiazol-4-yl)-hept-6-enoic
acid
methyl ester (62): To a solution of tetramethylammonium triacetoxybor-
on hydride (1.06 g, 3.88 mmol) in acetonitrile (7 mL) and acetic acid
(5 mL) at À308C was slowly added a solution of 53 (260 mg, 0.48 mmol)
in acetonitrile (5 mL). After the mixture had been stirred for 9 h, a satu-
rated solution of NaHCO3 and solid NaHCO3 was added very carefully
till gas evolution ceased. The aqueous layer was extracted with DCM,
the combined organic layers were dried over MgSO4, and the solvent was
removed under reduced pressure. Column chromatography (hexane/ethyl
acetate=1:1) yielded dihydroxy ester 62 (242 mg; 97%) as colorless oil.
[a]2D0 =14.6 (c=0.5, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=6.93 (s,
1H), 6.67 (s, 1H), 4.45 (dd, J=6.4, 2.9 Hz, 1H), 4.00 (dd, J=10.2, 1.1 Hz,
1H), 3.67 (s, 3H), 3.40 (dd, J=9.7, 5.9 Hz, 1H), 3.34 (dd, J=9.7, 6.3 Hz,
1H), 2.70 (s, 3H), 1.99 (d, J=0.8 Hz, 3H), 1.81–1.63 (m, 3H), 1.60–1.52
(m, 1H), 1.46–1.37 (m, 1H), 1.36–1.23 (m, 2H), 1.15 (s, 3H), 1.16–0.98
(m, 2H), 0.88 (s, 9H), 0.83 (d, J=6.6 Hz, 3H), 0.02 ppm (s, 6H);
13C NMR (100mHz, CDCl3): d=177.1, 164.6, 153.0, 141.9, 118.0, 115.4,
74.4, 73.0, 68.3, 51.8, 50.6, 36.0, 35.8, 35.5, 33.6, 25.9, 21.9, 19.2, 18.4, 17.3,
3400, 2928, 1712, 1462, 1251, 1182, 1088 cmÀ1
; HRMS (ESI): m/z:
[MÀC4H9]+ calcd for C21H34O4NSSi: 424.1978, found: 424.1985.
AHCTUNGTERG(NNUN 1E,5E)-(3R,10S)-11-(tert-Butyldimethylsilanyloxy)-2,6,10-trimethyl-1-
(2-methylthiazol-4-yl)-undeca-1,5-dien-3-ol (65): To a solution of b-hy-
droxy lactone 63 (25 mg, 0.05 mmol) in 10:1 Et2O:Et3N (1 mL) at 08C
under argon was added MsCl (6 mL, 0.075 mmol). After 2 h, brine was
added and the aqueous layer was extracted with Et2O. The combined
ethereal layers were dried over MgSO4 and the solvent was removed
498
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 485 – 506

Synthesis of (Z)-Trisubstituted Olefins
FULL PAPER
under reduced pressure. The residue was taken up in THF (1 mL), and
LiOH (0.15 mL, 1m in water, 0.15 mmol) was added at 08C. After 2 h,
TLC showed completion of the reaction and a saturated NH4Cl solution
was added, the layers were separated, and the aqueous phase was extract-
ed with DCM. The combined organic layers were dried over MgSO4 and
the solvent was evaporated. Column chromatography (hexane/ethyl ace-
tate=3:1) yielded the di-olefin 65 (14 mg; 64%). [a]2D0 =5.1 (c=1.0,
CH2Cl2). 1H NMR (400 MHz, CDCl3): d=6.94 (s, 1H), 6.56 (s, 1H), 5.17
(t, J=7.3 Hz, 1H), 4.16 (t, J=6.3 Hz, 1H), 3.42 (dd, J=9.7, 5.9 Hz, 1H),
3.34 (dd, J=9.7, 6.7 Hz, 1H), 2.71 (s, 3H), 2.36 (t, J=6.8 Hz, 2H), 2.06
(s, 3H), 1.99 (t, J=6.8 Hz, 2H), 1.64 (s, 3H), 1.61–1.53 (m, 1H), 1.46–
1.23 (m, 3H), 1.06–0.96 (m, 1H), 0.89 (s, 9H), 0.85 (d, J=6.6 Hz, 3H),
0.03 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=164.7, 153.0, 141.7,
139.3, 119.5, 118.9, 115.4, 77.2, 68.4, 40.2, 35.7, 34.4, 32.8, 29.7, 26.0, 25.4,
19.2, 16.7, 16.3, 14.4, À5.3 ppm; IR (film): n˜ = 2928, 2357, 1255,
1091 cmÀ1; HRMS (ESI): m/z: [M]+ calcd for C24H43O2NSSi: 437.2784,
found: 437.2776.
CDCl3): d=176.8, 168.4, 152.9, 141.3, 120.1, 115.4, 78.3, 73.6, 68.4, 51.7,
50.9, 40.5, 39.0, 36.5, 35.5, 33.5, 25.9, 22.0, 19.2, 18.1, 16.5, 13.6, 12.5, À0.4,
À5.4 ppm; IR (film): n˜ = 2948, 2865, 1734, 1465, 1256, 1088 cmÀ1; HRMS
(ESI): m/z: [M]+ calcd for C25H43O4NSSi2: 481.2682, found: 481.2688.
(E)-(2S,3R,5S)-2-[(S)-5-(tert-Butyldimethylsilanyloxy)-4-methylpentyl]-3-
methanesulfonyloxy-2,6-dimethyl-7-(2-methylthiazol-4-yl)-5-triisopropyl-
silanyloxy-hept-6-enoic acid methyl ester (69): To alcohol 68 (95 mg,
0.14 mmol) in 10:1 Et2O:Et3N (3 mL) at room temperature was added
mesyl chloride (38 mL, 0.42 mmol) and the reaction was stirred for 2 h.
Brine was added, the layers were separated and the aqueous layer ex-
tracted with Et2O. The ethereal layers were dried over MgSO4 and sol-
vent was evaporated. Column chromatography (hexane/ethyl acetate=
5:1) yielded 69 (100 mg; 96%) as a colorless oil. [a]2D0 =14.27 (c=0.55,
1
CH2Cl2); H NMR (400 MHz, CDCl3): d=6.97 (s, 1H), 6.63 (s, 1H), 4.84
(t, J=8.8 Hz, 1H), 4.59 (dd, J=10.7, 3.7 Hz, 1H), 3.61 (s, 3H), 3.38 (dd,
J=9.7, 5.9 Hz, 1H), 3.31 (dd, J=9.8, 6.3 Hz, 1H), 3.05 (s, 3H), 2.71
(s,3H), 2.03–1.94 (m, 1H), 1.98 (d, J=1.0 Hz, 3H), 1.84–1.74 (m, 2H),
1.56–1.48 (m, 2H), 1.46–1.23 (m, 3H), 1.17 (s, 3H), 1.05 (s, 21H), 1.07–
0.97 (m, 1H), 0.87 (s, 9H), 0.81 (d, J=6.6 Hz, 3H), 0.01 ppm (s, 6H);
13C NMR (100 MHz, CDCl3): d=175.4, 164.2, 153.8, 144.9, 138.8, 121.9,
116.2, 83.3, 79.9, 75.2, 68.4, 63.1, 52.1, 51.5, 36.7, 35.6, 33.4, 32.8, 25.9,
19.4, 18.1, 16.7, 15.9, 12.2, À5.4 ppm; IR (film): n˜ = 2951, 2865, 1736,
ACHTUNGTRENNUNG(1E,5Z)-(3R,10S)-11-(tert-Butyldimethylsilanyloxy)-2,6,10-trimethyl-1-(2-
methylthiazol-4-yl)-undeca-1,5-dien-3-ol (67) and (3S,4R)-3-[(S)-5-(tert-
Butyldimethylsilanyloxy)-4-methylpentyl]-4-[(E)-(R)-2-hydroxy-3-
methyl-4-(2-methylthiazol-4-yl)-but-3-enyl]-3-methyloxetan-2-one
(66):
To a solution of b-hydroxy lactone 64 (18 mg, 0.035 mmol) in 10:1
Et2O:Et3N (1 mL) at 08C under argon was added MsCl (4 mL,
0.05 mmol). After 1.5 h, brine was added and the aqueous layer was ex-
tracted with Et2O. The combined ethereal layers were dried over MgSO4
and the solvent was removed under reduced pressure. The residue was
taken up in THF (1 mL) and LiOH (0.15 mL, 1m in water, 0.15 mmol)
was added at room temperature. After 2.5 h, TLC showed completion of
the reaction and a saturated NH4Cl solution was added, the layers were
separated and the aqueous phase was extracted with DCM. The com-
bined organic layers were dried over MgSO4 and the solvent was evapo-
rated. Column chromatography (hexane/ethyl acetate=5:1) yielded di-
olefin 67 (8 mg; 52%) and b-lactone 66 (6 mg; 36%). 67: [a]2D0 1.73 (c=
1340, 1174 cmÀ1
C36H69O7NS2Si2Na: 770.3952, found: 770.3968.
Methanesulfonic acid (1R,2S,6S)-7-(tert-butyldimethylsilanyloxy)-2-
;
HRMS (ESI): m/z: [M+Na]+ calcd for
formyl-2,6-dimethyl-1-[(E)-(S)-3-methyl-4-(2-methylthiazol-4-yl)-2-triiso-
propylsilanyloxybut-3-enyl]heptyl ester (70): To ester 69 (90 mg,
0.12 mmol) in toluene (2 mL) at À788C was slowly added DIBALH
(0.1 mL, 1.5m in toluene, 0.14 mmol). After the reaction mixure had been
stirred for 3 h, the reaction mixture was quenched by the addition of
methanol, potassium sodium tartrate solution was added and stirring was
continued for 2 h. The layers were separated and the aqueous layer was
extracted with DCM, the combined organic layers were dried over
MgSO4 and the solvent was evaporated. Column chromatography
(hexane : ethyl acetate=10:1) yielded the alcohol (75 mg; 87%) as a col-
1
0.75, CH2Cl2); H NMR (400 MHz, CDCl3): d=6.94 (s, 1H), 6.56 (s, 1H),
5.17 (t, J=7.2 Hz, 1H), 4.14 (dt, J=6.6, 2.7 Hz, 1H), 3.43 (dd, J=9.8,
5.8 Hz, 1H), 3.36 (dd, J=9.8, 6.5 Hz, 1H), 2.71 (s, 3H), 2.35 (t, J=
6.9 Hz, 2H), 2.05 (d, J=1.3 Hz, 3H), 2.09–1.97 (m, 2H), 1.71 (d, J=
1.0 Hz, 1H), 1.61–1.53 (m, 1H), 1.46–1.26 (m, 3H), 1.09–1.00 (m, 1H),
0.89 (s, 9H), 0.86 (d, J=6.6 Hz, 3H), 0.03 ppm (s, 6H); 13C NMR
(100 MHz, CDCl3): d=172.5, 164.6, 153.0, 141.7, 139.5, 120.15, 118.9,
115.4, 77.3, 68.3, 40.2, 35.7, 34.1, 33.1, 32.3, 26.0, 25.4, 23.6, 22.7, 19.2,
18.3, 16.7, 14.5, À5.3 ppm; IR (film): n˜ = 2955, 2929, 1472, 1256,
1093 cmÀ1; HRMS (ESI): m/z: [M]+ calcd for C24H43O2NSSi: 437.2784,
1
orless oil. [a]2D0 =20.17 (c=1.2, CH2Cl2); H NMR (400 MHz, CDCl3): d=
6.94 (s, 1H), 6.64 (s, 1H), 4.70 (d, J=7.6 Hz, 1H), 4.66 (dd, J=10.3,
3.8 Hz, 1H), 3.57 (d, J=11.9 Hz, 1H), 3.42 (dd, J=9.8, 6.0 Hz, 1H), 3.34
(dd, J=9.8, 6.4 Hz, 1H), 3.33 (d, J=12.6 Hz, 1H), 3.07 (s, 3H), 2.70 (s,
3H), 2.07 (m, 1H), 2.02 (s, 3H), 1.91 (ddd, J=15.4, 8.7, 3.9 Hz, 1H), 1.56
(m, 1H), 1.40–1.19 (m, 5H), 1.07 (s, 3H), 1.05 (s, 21H), 0.99 (m, 1H),
0.89 (s, 9H), 0.84 (d, J=6.8 Hz, 3H), 0.03 ppm (s, 6H); 13C NMR
(100 MHz, CDCl3): d=164.4, 152.9, 139.3, 121.9, 116.1, 83.9, 75.4, 68.3,
66.5, 42.4, 38.6, 37.4, 35.6, 34.3, 32.8, 25.9, 20.7, 19.4, 19.2, 18.1, 18.0, 16.6,
12.2, À5.4 ppm; IR (film): n˜ = 3368, 2944, 2893, 2865, 1464, 1334, 1171,
1083, 1062 cmÀ1; HRMS (ESI): m/z: [M]+ calcd for C35H69O6NS2Si2:
719.4105, found: 719.4112. Dess–Martin periodinane (87 mg, 0.21 mmol)
was added portionwise to a suspension of the alcohol (50 mg, 0.07 mmol)
and NaHCO3 (52 mg, 0.63 mmol) in DCM (3 mL) at 08C under argon.
After 2 h, water was added, layers were separated and the aqueous layer
was extracted with DCM. The combined DCM phases were dried over
MgSO4 and the solvent was evaporated. Column chromatography
(hexane/ethyl acetate=3:1) yielded aldehyde 70 (47 mg; 94%) as color-
less oil. [a]2D0 =23.58 (c=0.95, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=
9.46 (s, 1H), 6.98 (s, 1H), 6.65 (s, 1H), 4.78 (dd, J=5.8, 4.5 Hz, 1H), 4.62
(dd, J=7.8, 6.3 Hz, 1H), 3.37 (dd, J=9.9, 6.2 Hz, 1H), 3.32 (dd, J=9.7,
6.2 Hz, 1H), 3.03 (s, 3H), 2.70 (s, 3H), 2.02 (s,3H), 1.95 (dd, J=6.8,
5.6 Hz, 2H), 1.71 (dq, J=12.9, 4.6 Hz, 1H), 1.52 (m, 1H), 1.46–1.32 (m,
4H), 1.27–1.14 (m, 2H), 1.08 (s, 3H), 1.04 (s, 21H), 0.88 (s, 9H), 0.80 (d,
J=6.8 Hz, 3H), 0.02 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=
203.2, 164.3, 153.0, 138.6, 122.4, 116.5, 81.6, 75.2, 68.2, 53.5, 38.9, 37.9,
35.5, 33.8, 32.4, 25.9, 21.2, 19.3, 18.1, 17.9, 16.6, 16.0, 12.5, 12.2, À5.4 ppm;
IR (film): n˜ =2945, 2865, 1731, 1463, 1339, 1174, 1085, 1064 cmÀ1; HRMS
(ESI): m/z: [M]+ calcd for C35H67O6NS2Si2: 717.3948, found: 717.3943.
found: 437.2783. 66: [a] 20 =14.4 (c=0.5, CH2Cl2); 1H NMR (400 MHz,
D
CDCl3): d=6.96 (s, 1H), 6.00 (s, 1H), 4.57 (dd, J=8.5, 4.4 Hz, 1H), 4.37
(dd, J=8.5, 4.4 Hz, 1H), 3.41 (dd, J=9.9, 5.9 Hz, 1H), 3.37 (dd, J=9.7,
6.2 Hz, 1H), 2.71 (s, 3H), 2.07 (s, 3H), 2.00–1.94 (m, 2H), 1.76–1.54 (m,
3H), 1.49–1.25 (m, 3H), 1.43 (s, 3H), 1.12–1.04 (m, 1H), 0.88 (s, 9H),
0.86 (d, J=6.8 Hz, 3H), 0.03 ppm (s, 6H); 13C NMR (100 MHz, CDCl3):
d=174.8, 164.9, 152.5, 141.4, 119.0, 116.1, 80.7, 73.7, 56.8, 35.9, 35.5, 33.6,
25.9, 21.5, 19.6, 19.1, 18.3, 16.6, 14.4, À5.4 ppm; IR (film): n˜ = 2953, 1820,
1175, 1093 cmÀ1 HRMS (ESI): m/z: [M]+ calcd for C25H43O4NSSi:
.
481.2682, found: 481.2688.
(E)-(2S,3R,5S)-2-[(S)-5-(tert-Butyldimethylsilanyloxy)-4-methylpentyl]-3-
hydroxy-2,6-dimethyl-7-(2-methylthiazol-4-yl)-5-triisopropylsilanyloxy-
hept-6-enoic acid methyl ester (68): To a stirred solution of dihydroxy
ester 53 (110 mg, 0.22 mmol) in DCM (4 mL) was added 2,6-lutidine
(58 mL, 0.48 mmol) and TIPSOTf (68 mL, 0.24 mmol). After 1.5 h, the re-
action was quenched with saturated NH4Cl solution and the aqueous
layer was extracted with DCM. The combined organic solutions were
dried over MgSO4 and the solvent was evaporated. Purification by
column chromatography (hexane/ethyl acetate=10:1) yielded 68
1
(125 mg; 85%) as a colorless oil. [a]2D0 =À0.22 (c=0.9, CH2Cl2); H NMR
(400 MHz, CDCl3): d=6.95 (s, 1H), 6.52 (s, 1H), 4.55 (t, J=6.8 Hz, 1H),
3.79 (dd, J=9.7, 3.9 Hz, 1H), 3.65 (s, 3H), 3.39 (dd, J=9.6, 5.8 Hz, 1H),
3,32 (dd, J=9.6, 6.4 Hz, 1H), 2.75 (d, J=3.7 Hz, 1H), 2.71 (s, 3H), 1.99
(d, J=1.0 Hz, 3H), 1.78–1.66 (m, 2H), 1.61–1.50 (m, 2H), 1.48–1.40 (m,
1H), 1.36–1.21 (m, 3H), 1.12 (s, 3H), 1.06 (s, 21H), 1.07–0.97 (m, 1H),
0.88 (s, 9H), 0.82 (d, J=6.6 Hz, 3H), 0.02 (s, 6H); 13C NMR (100 MHz,
4-[(1E,5E)-(3S,10S)-11-(tert-Butyldimethylsilanyloxy)-2,6,10-trimethyl-3-
triisopropylsilanyloxyundeca-1,5-dienyl]-2-methylthiazole (71): To alde-
hyde 70 (25 mg, 0.035 mmol) in THF (1 mL) was added LiOH (0.1 mL,
1m in water, 0.1 mmol) at 08C. After 6 h, a saturated NH4Cl solution was
Chem. Eur. J. 2010, 16, 485 – 506
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
499

J. Mulzer and K. Prantz
added, the layers were separated and the aqueous layer was extracted
with DCM. The combined organic layers were dried over MgSO4 and the
solvent was evaporated. Column chromatography (hexane/ethyl acetate=
10:1) yielded olefin 71 (17 mg; 82%) as a colorless oil. [a]2D0 =8.12 (c=
(50 mL) was added dropwise. Stirring was continued for 1 h and then the
mixture was cooled to À788C and a solution of (S)-2-(tert-butyldimethyl-
silanyloxymethyl)-2,6-dimethyl-hept-5-enal (75) (11.38 g, 40 mmol) in di-
ethyl ether (70 mL) was added over 25 min. After the addition was com-
plete the reaction was kept at À788C for 3 h, then it was warmed to 08C
for 15 min and pH 7 buffer solution (500 mL), methanol (100 mL), and
H2O2 (50 mL, 30% aqueous) were added. After the mixture had been
stirred for 1.5 h at room temperature, it was extracted with DCM, the
combined organic layers were dried over MgSO4, and the solvent was
evaporated. The crude aldol product was purified by column chromatog-
raphy (hexane/ethyl acetate=50:1 to 10:1) to yield 77 (14.30 g; 75%) as
a pale yellow oil. At smaller scales (5 mmol) was the yield quantitative.
[a]2D0 =16.23 (c=1.4, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.21 (d,
J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.07 (bt, J=7.1 Hz, 1H), 4.43
(d, J=11.4 Hz, 1H), 4.39 (d, J=11.4 Hz, 1H), 3.98 (d, J=8.1 Hz, 1H
(OH)), 3.80 (s, 3H), 3.62–3.55 (m, 3H), 3.44–3.37 (m, 2H), 3.09–3.00 (m,
2H), 1.97–1.88 (m, 2H), 1.67 (s, 3H), 1.59 (s, 3H), 1.45–1.37 (m, 1H),
1.26–1.18 (m, 1H), 1.21 (d, J=7.1 Hz, 3H), 1.07 (d, J=7.3 Hz, 3H), 0.89
(s, 9H), 0.77 (s, 3H), 0.06 (s, 3H), 0.05 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=219.0, 159.2, 131.3, 130.1, 129.2, 124.9, 113.8, 79.9, 73.0, 72.0,
67.9, 55.3, 47.5, 45.5, 42.5, 35.0, 25.9, 22.1, 18.2, 16.7, 13.6, À5.6 ppm; IR
(film): n˜ = 3474, 2931, 1696, 1613, 1514, 1463, 1249, 1092 cmÀ1; HRMS
(ESI): m/z: [M+Na]+ calcd for C30H52O5SiNa: 543.3482, found: 543.3476.
1
0.85, CH2Cl2); H NMR (600 MHz, CDCl3): d=6.90 (s, 1H), 6.43 (s, 1H),
5.09 (t, J=7.2 Hz, 1H), 4.24 (t, J=6.6 Hz, 1H), 3.40 (dd, J=9.8, 6.0 Hz,
1H), 3.30 (dd, J=9.8, 6.8 Hz, 1H), 2.70 (s, 3H), 2.38–2.34 (m, 1H), 2.33–
2.28 (m, 1H), 2.00 (d, J=1.1 Hz, 3H), 1.94–1.88 (m, 2H), 1.57 (s, 3H),
1.52 (m, 1H), 1.39–1.35 (m, 1H), 1.32–1.25 (m, 3H), 1.06 (s, 11H), 1.04
(s, 10H), 1.00–0.95 (m, 1H), 0.88 (s, 9H), 0.81 (d, J=6.8 Hz, 3H),
0.02 ppm (s, 6H); 13C NMR (150 MHz, CDCl3): d=164.1, 153.2, 142.2,
136.8, 120.2, 119.1, 114.7, 78.8, 68.4, 40.2, 35.7, 35.6, 32.9, 29.7, 25.9, 25.4,
19.2, 18.3, 18.1, 18.0, 16.7, 16.2, 12.4, À5.3 ppm; IR (film): n˜ = 2928, 2864,
1463, 1255, 1091, 1064 cmÀ1
.
HRMS (ESI): m/z: [M]+ calcd for
C33H63O2NSSi2: 593.4118, found: 593.4125.
Benzoic acid (Z)-(1S,8S)-9-(tert-butyldimethylsilanyloxy)-4,8-dimethyl-1-
[(E)-1-methyl-2-(2-methylthiazol-4-yl)vinyl]non-3-enyl ester (72a): To a
solution of b-hydroxy lactone 57 (30 mg, 0.06 mmol) in 10:1 Et2O: Et3N
(1.5 mL) at 08C under argon was added MsCl (17 mL, 0.09 mmol). After
1 h, brine was added and the aqueous layer was extracted with Et2O. The
combined ethereal layers were dried over MgSO4 and the solvent was re-
moved under reduced pressure. The residue was taken up in THF (1 mL)
and PhLi (0.18 mL, 1m in dibutyl ether, 0.18 mmol) was added at À788C
under argon. After 3 h, a saturated NH4Cl solution was added, the layers
were separated and the aqueous layer was extracted with DCM. The
combined organic layers were dried over MgSO4 and the solvent was
evaporated. Column chromatography (hexane/ethyl acetate=3:1) yielded
72a (14 mg; 43%) and free alcohol 7 (5 mg; 19%). [a]2D0 =5.2 (c=0.25,
CH2Cl2); 1H NMR (600 MHz, CDCl3): d=8.07 (m, 2H), 7.55 (m, 1H),
7.44 (m, 2H), 6.95 (s, 1H), 6.60 (s, 1H), 5.47 (t, J=6.8 Hz, 1H), 5.15 (t,
J=6.6 Hz, 1H), 3.43 (dd, J=9.6, 5.8 Hz, 1H), 3.34 (dd, J=9.6, 6.6 Hz,
1H), 2.70 (s, 3H), 2.64–2.59 (m, 1H), 2.54–2.50 (m, 1H), 2.15 (d, J=
1.5 Hz, 3H), 2.07–1.98 (m, 2H), 1.66 (d, J=1.1 Hz, 3H), 1.56 (m, 1H),
1.42–1.24 (m, 3H), 1.07–1.02 (m, 1H), 0.88 (s, 9H), 0.85 (d, J=6.8 Hz,
3H), 0.03 ppm (s, 6H); 13C NMR (150 MHz, CDCl3): d=165.7, 164.5,
152.6, 138.6, 137.6, 132.8, 130.6, 129.7, 128.3, 120.6, 119.3, 116.2, 79.6,
68.3, 35.8, 33.1, 32.3, 31.8, 25.9, 25.4, 23.5, 22.6, 19.2, 16.7, 14.9, À5.3 ppm;
IR (film): n˜ =2955, 2360, 2343, 1718, 1654, 1458, 1271 cmÀ1; HRMS
(ESI): m/z: [M]+ calcd for C31H47O3SiNS: 541.3046, found: 541.3055.
(2S,3S,4R,5R,6S)-6-(tert-Butyldimethylsilanyloxymethyl)-1-(4-methoxy-
benzyloxy)-2,4,6,10-tetramethylundec-9-ene-3,5-diol (79): To a solution of
tetramethylammonium triacetoxyboron hydride (17.07 g, 102.9 mmol) in
1:1 acetonitrile: acetic acid (120 mL) at À308C was slowly added a solu-
tion of 78 (6.70 g, 12.86 mmol) in acetonitrile (30 mL). After the reaction
had been stirred for 7 h, the reaction was kept in the freezer (À258C) for
96 h, then a saturated solution of NaHCO3 and solid NaHCO3 was added
very carefully until the gas evolution ceased. The aqueous layer was ex-
tracted with DCM, the combined organic layers were dried over MgSO4
and the solvent was removed under reduced pressure. Column chroma-
tography (hexane/ethyl acetate=1:1) yielded dihydroxy ester 79 (4.30 g,
64%) and the precursor 78 (2.01 g, 30%). [a]2D0 =10.72 (c=0.97, CH2Cl2);
1H NMR (600 MHz, CDCl3): d=7.25 (d, J=8.7 Hz, 2H), 6.86 (d, J=
8.7 Hz, 2H), 5.07 (bt, J=7.0 Hz, 1H), 4.46 (d, J=11.3 Hz, 1H), 4.43 (d,
J=11.3 Hz, 1H), 3.86 (d, J=9.8 Hz, 1H), 3.80 (s, 3H), 3.65–3.60 (m,
2H), 3.57 (m, 1H), 3.49–3.40 (m, 2H), 1.98–1.87 (m, 4H), 1.68 (s, 3H),
1.60 (s, 3H), 1.45–1.40 (m, 1H), 1.33–1.25 (m, 1H), 1.04 (d, J=7.0 Hz,
3H), 0.90 (s, 3H), 0.89 (s, 9H), 0.86 (d, J=6.8 Hz, 3H), 0.06 (s, 3H),
0.05 ppm (s, 3H); 13C NMR (150 MHz, CDCl3): d=159.0, 131.3, 130.5,
129.2, 124.7, 113.7, 82.4, 74.8, 74.3, 70.2, 55.2, 41.7, 36.3, 35.5, 25.8, 22.0,
18.0, 17.7, 13.8, 13.4, À5.7, À5.8 ppm; IR (film): n˜ = 3447, 2930, 2856,
1513, 1406, 1249, 1094 cmÀ1; HRMS (ESI): m/z: [M+Na]+ calcd for
C30H54O5SiNa: 545.3638, found: 545.3632; [a]D À2.98 (c=1.5, CH2Cl2).
Acetic acid (Z)-(1S,8S)-9-(tert-butyldimethylsilanyloxy)-4,8-dimethyl-1-
[(E)-1-methyl-2-(2-methylthiazol-4-yl)vinyl]non-3-enyl ester (72b): To a
solution of b-hydroxy lactone 57 (18 mg, 0.036 mmol) in 10:1 Et2O:NEt3
(1 mL) at 08C under argon was added MsCl (4 mL, 0.052 mmol). After
1 h, brine was added and the aqueous layer was extracted with Et2O. The
combined ethereal layers were dried over MgSO4 and the solvent was re-
moved under reduced pressure. The residue was taken up in THF (1 mL)
and MeLi (36 mL, 1.6m in diethyl ether, 0.054 mmol) was added at
À788C. After 5 h, a saturated NH4Cl solution was added, layers were
separated and the aqueous layer was extracted with DCM. The combined
organic layers were dried over MgSO4 and the solvent was evaporated.
Column chromatography (hexane/ethyl acetate=3:1) yielded 72b (4 mg;
23%) and free alcohol 7 (8 mg; 51%). [a]2D0 =À12 (c=0.1, CH2Cl2);
1H NMR (400 MHz, CDCl3): d=6.94 (s, 1H), 6.51 (s, 1H), 5.23 (t, J=
6.8 Hz, 1H), 5.07 (t, J=6.8 Hz, 1H), 3.44 (dd, J=9.8, 6.0 Hz, 1H), 3.35
(dd, J=9.6, 6.6 Hz, 1H), 2.70 (s, 3H), 2.49–2.34 (m, 2H), 2.08 (d, J=
1.2 Hz, 3H), 2.06 (s, 3H), 2.00 (t, J=7.0 Hz, 2H), 1.67 (d, J=1.2 Hz,
3H), 1.57 (m, 1H), 1.42–1.32 (m, 3H), 1.05 (m, 1H), 0.89 (s, 9H), 0.86
(d, J=6.5 Hz, 3H), 0.03 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=
170.2, 164.5, 152.7, 138.5, 137.6, 120.5, 119.3, 116.1, 78.9, 68.3, 35.7, 33.1,
32.3, 31.7, 29.7, 25.9, 25.4, 23.5, 21.2, 19.2, 18.3, 16.7, 14.9, À5.3 ppm; IR
(film): n˜ = 2929, 1508, 1458, 1238; HRMS (ESI): m/z: [M]+ calcd for
C26H45O3SiNS: 479.2889, found: 479.2899.
tert-Butyl-((S)-2-{(4R,5R,6S)-6-[(S)-2-(4-methoxybenzyloxy)-1-methyl-
ethyl]-2,2,5-trimethyl-[1,3]dioxan-4-yl}-2,6-dimethylhept-5-enyloxy)dime-
thylsilane (83): To a stirred solution of 79 (2.50 g, 4.75 mmol) in DCM
(50 mL) at room temperature under argon was added 2,2-dimethoxypro-
pane (2.25 mL, 14.25 mmol) followed by CSA (110 mg, 0.47 mmol). After
2 h, brine was added and the aqueous layer was extracted with DCM, the
combined DCM layers were dried over MgSO4 and the solvent was re-
moved under reduced pressure. Column chromatography (hexane/ethyl
acetate=10:1) yielded acetonide 83 (2.30 g, 86%) as a colorless oil.
1
[a]2D0 =6.9 (c=0.86, CH2Cl2); H NMR (400 MHz, CDCl3): d=7.25 (d, J=
8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 5.08 (bt, J=6.6 Hz, 1H), 4.45–4.38
(m, 2H), 3.80 (s, 3H), 3.56 (dd, J=8.8, 3.0 Hz, 1H), 3.48 (dd, J=10.4,
2.8 Hz, 1H), 3.46 (d, J=9.4 Hz, 1H), 3.40–3.32 (m, 3H), 1.99–1.89 (m,
3H), 1.84–1.76 (m, 1H), 1.68 (s, 3H), 1.60 (s, 3H), 1.36–1.18 (m, 2H),
1.29 (s, 3H), 1.22 (s, 3H), 0.92 (d, J=6.6 Hz, 3H), 0.88 (s, 12H), 0.80 (s,
3H), 0.03 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=159.0, 131.1,
129.1, 125.3, 113.7, 99.9, 76.9, 72.8, 72.5, 70.5, 65.2, 55.3, 41.9, 33.8, 32.7,
32.0, 25.9, 23.5, 22.0, 18.2, 17.6, 16.1, 13.4, 13.3, À5.5, À5.6 ppm; IR
(film): n˜ = 2932, 1614, 1513, 1458, 1376, 1248, 1098 cmÀ1; HRMS (ESI):
m/z: [M]+ calcd for C33H58O5Si: 562.4054, found: 562.4049.
(2S,4S,5R,6S)-6-(tert-Butyldimethylsilanyloxymethyl)-5-hydroxy-1-(4-me-
thoxybenzyloxy)-2,4,6,10-tetramethylundec-9-en-3-one (78): To a solution
of chlorodicyclohexylborane (55 mL, 1m in hexane, 54.6 mmol) in diethyl
ether (200 mL) at 08C under argon atmosphere was added triethylamine
(8 mL, 58.2 mmol). After 15 min, a solution of (R)-1-(4-methoxy-benzy-
loxy)-2-methyl-pentan-3-one (77) (8.60 g, 36.4 mmol) in diethyl ether
(S)-2-{(4R,5R,6S)-6-[(S)-2-(4-Methoxybenzyloxy)-1-methylethyl]-2,2,5-
trimethyl-[1,3]dioxan-4-yl}-2,6-dimethyl-hept-5-en-1-ol (82): To a stirred
500
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 485 – 506

Synthesis of (Z)-Trisubstituted Olefins
FULL PAPER
solution of silyl ether 83 (1.20 g, 2.07 mmol) in acetonitrile (8 mL) and
pyridine (3 mL) in a plastic vessel was added HF·py (2 mL, 70%) and
the mixture was then stirred overnight. HF·py (1 mL, 70%) was added
and stirred for another 5 h, the reaction was quenched by addition of sa-
turated NaHCO3 solution and DCM was added. The aqueous layer was
extracted with DCM, and the combined organic layers were dried over
MgSO4 and the solvent was removed under reduced pressure. Column
chromatography (hexane/ethyl acetate=5:1) yielded free alcohol 82
2H), 2.07–1.97 (m, 3H), 1.69–1.59 (m, 1H), 1.66 (s, 3H), 1.58 (s, 3H),
1.31 (s, 3H), 1.08 (d, J=7.1 Hz, 3H), 0.96 ppm (d, J=7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=176.1, 159.3, 131.7, 129.9, 129.6, 124.3,
113.7, 81.3, 76.0, 72.9, 71.6, 55.2, 46.5, 34.4, 34.1, 33.8, 25.8, 25.6, 22.8,
15.9, 8.8 ppm; IR (film): n˜ = 3435, 2968, 1706, 1513, 1248, 1102 cmÀ1
;
HRMS (ESI): m/z: [M]+ calcd for C24H36O5: 404.2563, found: 404.2559.
(Z)-(2S,3R,4S)-1-(4-Methoxybenzyloxy)-2,4,6,10-tetramethylundeca-5,9-
dien-3-ol (86): To lactone 12 (450 mg, 1.05 mmol) in 1:1 DCM:pyridine
(10 mL) at room temperature under argon atmosphere was added metha-
nesulfonyl chloride (0.25 mL, 3.15 mmol) and DMAP (136 mg,
1.05 mmol). After 3 h, brine was added, the layers were separated and
the aqueous layer extracted with DCM. The combined organic phases
were dried over MgSO4 and the solvent was evaporated. The residue was
dissolved in THF (10 mL) and LiOH (3.15 mL, 1m in water, 3.15 mmol)
was added. After 2 h, the reaction was quenched with saturated NH4Cl
solution and the aqueous layer was extracted with DCM. The combined
organic layers were dried over MgSO4 and the solvent was evaporated.
Column chromatography (hexane/ethyl acetate=3:1) yielded olefin 86
(900 mg; 97%) as
a
colorless oil. [a]2D0 =10.72 (c=0.97, CH2Cl2);
1H NMR (400 MHz, CDCl3): d=7.25 (d, J=8.6 Hz, 2H), 6.87 (d, J=
8.6 Hz, 2H), 5.11 (bt, J=6.9 Hz, 1H), 4.41 (s, 2H), 3.80 (s, 3H), 3.72 (dd,
J=11.4, 3.8 Hz, 1H), 3.59 (dd, J=10.7, 3.4 Hz, 1H), 3.53 (dd, J=8.7,
2.9 Hz, 1H), 3.39–3.32 (m, 3H), 2.01–1.94 (m, 3H), 1.86–1.79 (m, 1H),
1.69 (s, 3H), 1.61 (s, 3H), 1.53–1.38 (m, 2H), 1.33 (s, 3H), 1.27 (s, 3H),
0.95 (d, J=6.8 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H), 0.81 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=159.0, 131.4, 130.9, 129.2, 124.7, 113.7,
100.6, 81.9, 72.9, 72.1, 70.6, 68.6, 55.3, 40.8, 34.8, 33.7, 32.5, 25.7, 23.2,
21.9, 17.0, 13.4, 13.2 ppm; IR (film): n˜ = 3509, 2967, 2933, 1513, 1377,
1247, 1085, 1038 cmÀ1; HRMS (ESI): m/z: [M]+ calcd for C27H44O5:
448.3189, found: 448.3192.
(333 mg, 88%). [a] 20 =18.42 (c=1.14, CH2Cl2); 1H NMR (400 MHz,
D
CDCl3): d=7.23 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 5.10 (m,
2H), 4.46–4.39 (m, 2H), 3.80 (s, 3H), 3.59 (dd, J=9.1, 4.0 Hz, 1H), 3.41
(dd, J=9.1, 6.3 Hz, 1H), 3.30–3.23 (m, 1H+1H (OH)), 2.53–2.44 (m,
1H), 2.08–1.94 (m, 4H), 1.93–1.86 (m, 2H), 1.68 (s, 6H), 1.61 (s, 3H),
0.96 ppm (d, J=6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=159.3,
134.0, 129.9, 129.3, 129.1, 124.3, 113.8, 80.4, 74.5, 73.2, 55.3, 35.7, 35.6,
32.2, 26.6, 25.7, 23.4, 22.6, 15.4, 14.8 ppm; IR (film): n˜ = 3503, 2930, 1513,
1248, 1083, 1037 cmÀ1; HRMS (ESI): m/z: [M]+ calcd for C23H36O3:
360.2664, found: 360.2671.
(R)-2-{(4R,5R,6S)-6-[(S)-2-(4-Methoxybenzyloxy)-1-methylethyl]-2,2,5-
trimethyl-[1,3]dioxan-4-yl}-2,6-dimethyl-hept-5-enoic acid (84): To a solu-
tion of alcohol 83 (2.1 g, 4.68 mmol) in ethyl acetate (40 mL) was added
IBX (2.62 g, 9.35 mmol). The mixture was heated under reflux for 2 h,
then the white precipitate was filtered off and the solvent was removed
under reduced pressure. Column chromatography (hexane/ethyl ace-
tate=10:1) yielded the aldehyde (1.78 g; 86%) as colorless oil. [a]D20
=
4.56 (c=1.36, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=9.54 (s, 1H),
7.24 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 5,03 (tt, J=7.0, 1.3 Hz,
1H), 4.40 (s, 2H), 3.80 (s, 3H), 3.54–3.49 (m, 3H), 3.36 (dd, J=8.7,
6.2 Hz, 1H), 1.98–1.85 (m, 2H), 1.83–1.71 (m, 2H), 1.67 (s, 3H), 1.64–
1.46 (m, 2H), 1.57 (s, 3H), 1.31 (s, 3H), 1.22 (s, 3H), 1.06 (s, 3H), 0.94
(d, J=6.6 Hz, 3H), 0.91 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=206.1, 159.0, 132.3, 130.9, 129.2, 123.7, 113.7, 100.5, 78.3, 72.9,
72.0, 70.1, 55.3, 53.3, 33.6, 32.8, 32.6, 25.7, 25.3, 23.2, 22.2, 17.7, 13.6, 13.2,
13.0 ppm; IR (film): n˜ = 2969, 2935, 1726, 1515, 1456, 1378, 1247, 1096,
1037 cmÀ1; HRMS (ESI): m/z: [M]+ calcd for C27H42O5: 446.3032, found:
446.3028. To a solution of the aldehyde (1.65 g, 3.69 mmol) in tert-butyl
alcohol (25 mL) with 2-methyl-2-butene (5 mL) was added dropwise a so-
lution of NaClO2 (4 950 mg, 55 mmol) and NaH2PO4 (4.95 g) in water
(15 mL). After 3 h, 0.01n NaOH was added and the aqueous layer was
extracted with diethyl ether, 1n HCl was added until pH 2 was reached
and the aqueous layer was extracted with DCM. The organic layers were
dried over MgSO4 and the solvent was removed under reduced pressure.
Column chromatography (hexane/ethyl acetate=1:1) yielded acid 84
(1.71 g; quant.). [a]D20 =14.26 (c=1.36, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=7.24 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 5.06 (bt, J=
6.9 Hz, 1H), 4.41 (s, 2H), 3.80 (s, 3H), 3.56 (dd, J=10.7, 3.4 Hz, 1H),
3.49 (dd, J=8.6, 2.8 Hz, 1H), 3.48 (d, J=6.1 Hz, 1H), 3.37 (dd, J=8.6,
6.1 Hz, 1H), 2.08–1.96 (m, 3H), 1.89–1.70 (m, 1H), 1.67 (s, 3H), 1.59 (s,
3H), 1.48–1.38 (m, 2H), 1.34 (s, 3H), 1.30 (s, 3H), 1.19 (s, 3H), 0.97 (d,
J=6.6 Hz, 3H), 0.91 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=178.4, 159.0, 132.4, 130.9, 129.1, 123.4, 113.7, 101.5, 79.1, 72.9,
71.9, 70.6, 55.3, 50.8, 35.9, 33.9, 33.6, 25.6, 25.2, 23.3, 22.7, 17.6, 16.5, 13.6,
13.2, 13.0 ppm; IR (film): n˜ = 2981, 2935, 1701, 1513, 1226 cmÀ1; HRMS
(ESI): m/z: [M+Na]+ calcd for C27H42O6Na: 485.2879, found: 485.2896.
tert-Butyl-{(Z)-(1R,2S)-1-[(S)-2-(4-methoxybenzyloxy)-1-methylethyl]-
2,4,8-trimethylnona-3,7-dienyloxy}dimethylsilane (87): To a stirred solu-
tion of alcohol 86 (240 mg, 0.65 mmol) in DCM (6 mL) was added 2,6-lu-
tidine (120 mL, 0.98 mmol) and TBSOTf (160 mL, 0.72 mmol). After 1 h,
the reaction was quenched with saturated NH4Cl solution and extracted
with DCM. The combined organic solutions were dried over MgSO4 and
the solvent was evaporated. Purification by column chromatography
(hexane/ethyl acetate=10:1) yielded protected diol 87 (320 mg; quant.)
as a colorless oil. [a]D20 =6.64 (c=1.28, CH2Cl2). 1H NMR (400 MHz,
CDCl3): d=7.24 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.10 (t, J=
6.1 Hz, 1H), 4.98 (d, J=9.8 Hz, 1H), 4.39 (s, 2H), 3.80 (s, 3H), 3.51 (dd,
J=9.1, 4.8 Hz, 1H), 3.39 (t, J=5.3 Hz, 1H), 3.20 (t, J=8.7 Hz, 1H),
2.59–2.50 (m, 1H), 2.12–1.91 (m, 5H), 1.68 (s, 3H), 1.65 (s, 3H), 1.60 (s,
3H), 0.96 (d, J=6.8 Hz, 3H), 0.89 (d, J=6.1 Hz, 3H), 0.89 (s, 9H),
0.02 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=159.0, 133.3, 131.5,
130.2, 129.1, 124.1, 113.7, 78.6, 72.7, 72.6, 55.3, 38.5, 35.5, 32.2, 26.6, 26.1,
25.7, 23.3, 18.4, 17.6, 16.9, 14.8, À3.8, À3.9 ppm; IR (film): n˜ =2957, 2929,
1462, 1249, 1083, 1040 cmÀ1
;
HRMS (ESI): m/z: [M]+ calcd for
C29H50O3Si: 474.3529, found: 474.3532.
tert-Butyl-{(Z)-(1R,2S)-6-dimethyloxiranyl-1-[(S)-2-(4-methoxybenzyl-
AHCTUNGTERGoNNUN xy)-1-methylethyl]-2,4-dimethylhex-3-enyloxy}dimethylsilane (88): To a
stirred solution of 87 (320 mg, 0.65 mmol) in DCM (7 mL) at À208C
NaOAc (60 mg, 0.68 mmol) and mCPBA (168 mg, 80wt%, 0.68 mmol)
was added. The mixture was warmed to 08C over 2 h and saturated
NaHCO3 solution was added. The organic layer was separated and the
aqueous layer was extracted with DCM. The combined organic layers
were dried over MgSO4 and the solvent was evaporated. Column chro-
matography (hexane/ethyl acetate=10:1) yielded epoxide 88 (293 mg,
92%) as a 1:1 mixture of diastereoisomers. 1H NMR (400 MHz, CDCl3):
d=7.24 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 5.03 (d, J=9.8 Hz,
1H), 4.39 (s, 2H), 3.80 (s, 3H), 3.51 (dd, J=8.8, 4.8 Hz, 1H), 3.40 (t, J=
5.4 Hz, 1H), 3.21 (t, J=8.6 Hz, 1H), 2.68 (t, J=6.2 Hz, 1H) or 2.67 (t,
J=6.2 Hz, 1H), 2.60–2.54 (m, 1H), 2.30–2.16 (m, 2H), 2.10–1.93 (m,
3H), 1.66 (s, 3H), 1.64–1.53 (m, 3H), 1.30 (s, 3H), 1.26 (s, 3H), 0.96 (d,
J=6.8 Hz, 3H), 0.90 (d, J=6.9 Hz, 3H), 0.89 (s, 9H), 0.03 (s, 3H), 0.02
(s, 3H). 13C NMR (100 MHz, CDCl3): d=159.0, 132.5, 130.9, 130.8/130.7,
129.1/129.0, 113.7, 78.6, 72.6, 72.5/72.4, 64.1/64.0, 58.3/58.2, 55.3, 38.4,
36.5/36.4, 35.6/35.5, 28.8, 27.6/27.5, 26.2, 24.9/24.8, 23.3, 18.7/18.6, 18.4,
17.0/16.9, 14.9/14.8, À3.8, À3.9 ppm; IR (film): n˜ = 2952, 1612, 1513,
(3R,4R,5S,6S)-4-Hydroxy-6-[(S)-2-(4-methoxybenzyloxy)-1-methylethyl]-
3,5-dimethyl-3-(4-methylpent-3-enyl)tetrahydropyran-2-one (12): To
a
stirred solution of acid 84 (1.66 mg, 3.5 mmol) in DCM (35 mL) at room
temperature under argon was added CSA (783 mg, 3.5 mmol) and the
mixture was stirred for 6 h. Brine was added and the aqueous layer was
extracted with DCM. The combined organic layers were dried over
MgSO4 and the solvent was evaporated. Column chromatography
(hexane/ethyl acetate=3:1) yielded lactone 12 (1.175 g, 83%) as a color-
1
less oil. [a]2D0 =À23.5 (c=0.92, CH2Cl2); H NMR (400 MHz, CDCl3): d=
7.23 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.01 (bt, J=7.2 Hz,
1H), 4.45 (d, J=11.4 Hz, 1H), 4.36 (d, J=11.4 Hz, 1H), 4.18 (dd, J=7.7,
4.4 Hz, 1H), 3.79 (s, 3H), 3.73 (d, J=4.0 Hz, 1H), 3.62 (dd, J=8.8,
6.1 Hz, 1H), 3.60 (m, 1H), 3.49 (dd, J=8.9, 4.7 Hz, 1H), 2.42–2.29 (m,
Chem. Eur. J. 2010, 16, 485 – 506
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
501

J. Mulzer and K. Prantz
1458, 1376, 1248, 1037 cmÀ1. HRMS (ESI): m/z: [MÀC4H9]+ calcd for
(400 MHz, CHCl3): d=7.23 (d, J=8.6 Hz, 2H), 7.05 (s, 3H), 6.85 (d, J=
8.6 Hz, 2H), 5.09 (d, J=9.6 Hz, 1H), 4.41 (d, J=11.4 Hz, 1H), 4.37 (d,
J=11.4 Hz, 1H), 3.78 (s, 3H), 3.51 (dd, J=9.1, 5.1 Hz, 1H), 3.42 (t, J=
5.1 Hz, 1H), 3.21 (dd, J=8.9, 8.2 Hz, 1H), 2.68–2.55 (m, 4H), 2.44–2.36
(m, 1H), 2.12 (s, 6H), 2.02–1.95 (m, 1H), 1.64 (d, J=1.2 Hz, 3H), 0.97
(d, J=6.8 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H), 0.89 (s, 9H), 0.04 (s, 3H),
0.03 ppm (s, 3H); 13C NMR (100 MHz, CHCl3): d=171.0, 159.0, 148.2,
131.8, 131.3, 131.0, 129.1, 128.6, 125.8, 113.7, 78.6, 72.6, 72.5, 55.3, 38.4,
35.7, 32.6, 27.5, 26.2, 23.0, 18.4, 16.9, 16.3, 14.9, À3.8, À3.9 ppm; IR
(film): n˜ = 2928, 1757, 1249 cmÀ1; HRMS (ESI): m/z: [MÀC4H9]+ calcd
for C30H43O5Si: 511.2880, found: 511.2875.
C25H41O4Si: 433.2774, found: 433.2768.
(Z)-(6S,7R,8S)-7-(tert-Butyldimethylsilanyloxy)-9-(4-methoxybenzyl
ACHTUNGTNERoNUNG xy)-
4,6,8-trimethyl-non-4-enal (89): To stirred solution of epoxide 88
a
(190 mg, 0.38 mmol) in diethyl ether (3 mL) at 08C was added dropwise
a solution of HIO4·2H2O (97 mg, 0.42 mmol) in THF (2 mL). The mix-
ture was stirred for 2.5 h and then a saturated NaHCO3 solution was
added. The organic layer was separated and the aqueous layer was ex-
tracted with DCM. The combined organic layers were dried over MgSO4
and the solvent was evaporated. Column chromatography (hexane/ethyl
acetate=10:1) yielded aldehyde 89 (155 mg; 90%) as colorless oil.
[a]2D0 =2.2 (c=1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3): d=9.70 (t, J=
1.6 Hz, 1H), 7.24 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 5.03 (d, J=
9.8 Hz, 1H), 4.39 (s, 2H), 3.80 (s, 3H), 3.50 (dd, J=9.1, 5.1 Hz, 1H), 3.39
(dd, J=6.1, 4.3 Hz, 1H), 3.20 (dd, J=9.2, 7.8 Hz, 1H), 2.60–2.53 (m,
1H), 2.47–2.33 (m, 2H), 2.26–2.17 (m, 1H), 2.01–1.93 (m, 1H), 1.63 (s,
3H), 0.96 (d, J=7.1 Hz, 3H), 0.90 (d, J=5.3 Hz, 3H), 0.89 (s, 9H), 0.03
(s, 6H); 13C NMR (100 MHz, CDCl3): d=202.1, 159.0, 132.5, 131.4, 131.4,
130.7, 129.1, 113.7, 78.7, 72.7, 72.4, 55.3, 42.2, 38.3, 35.8, 28.8, 27.5, 26.2,
24.4, 23.1, 18.4, 17.3, 15.1, À3.8, À3.9 ppm; IR (film): n˜ = 2958, 2930,
2856, 1725, 1513, 1249, 1089, 1037 cmÀ1; HRMS (ESI): m/z: [MÀC4H9]+
calcd for C22H35O4Si: 391.2305, found: 391.2308.
(Z)-(6S,7R,8S)-N-[7-(tert-Butyldimethylsilanyloxy)-9-(4-methoxybenzyl-
AHCTUNGTREGoNNUN xy)-4,6,8-trimethylnon-4-enoyl]-(1’R)-bornan-2’,10’-sultam (93): To a
stirred solution of crude acid 90 (60 mg, 0.13 mmol), DMAP (16 mg,
0.13 mmol) and (1R)-camphore-2,10-sultam (29 mg, 0.13 mmol) in DCM
(2 mL) under argon at room temperature was slowly added DIC (23 mL.
0.14 mmol). The mixture was stirred for 2 h, brine was added, and the
layers were separated. The aqueous layer was extracted with DCM and
the combined organic phases were dried over MgSO4 and the solvent was
evaporated. Purification by column chromatography (hexane/ethyl ace-
tate=3:1) yielded N-acyl sultam 93 (83 mg; 96%). [a]2D0 =34.95 (c=1.58,
CH2Cl2); 1H NMR (400 MHz, CHCl3): d=7.25 (d, J=8.8 Hz, 2H), 6.86
(d, J=8.8 Hz, 2H), 5,03 (d, J=9.3 Hz, 1H), 4.39 (s, 2H), 3.85 (dd, J=7.6,
5.5 Hz, 1H), 3.80 (s, 3H), 3.51 (dd, J=9.3, 5.1 Hz, 1H), 3.48 (d, J=
13.9 Hz, 1H), 3.41 (d, J=13.4 Hz, 1H), 3.39 (t, J=5.3 Hz, 1H), 3.19 (t,
J=8.7 Hz, 1H), 2.82–2.69 (m, 2H), 2.64–2.55 (m, 1H), 2.53–2.46 (m,
1H), 2.32–2.20 (m, 1H), 2.15–2.02 (m, 2H), 1.99–1.84 (m, 4H), 1.65 (d,
J=1.3 Hz, 3H), 1.43–1.25 (m, 3H), 1.15 (s, 3H), 0.97 (s, 3H), 0.96 (d, J=
7.1 Hz, 3H), 0.89 (d, J=6.8 Hz, 3H), 0.88 (s, 9H), 0.01 ppm (s, 6H);
13C NMR (100 MHz, CHCl3): d=171.5, 159.0, 131.3, 131.1, 129.1, 113.7,
78.5, 72.6, 72.5, 65.2, 55.3, 52.9, 48.4, 47.7, 44.7, 38.6, 38.5, 35.4, 34.0, 32.9,
26.9, 26.5, 26.2, 23.0, 20.9, 19.9, 18.4, 16.8, 14.7, À3.8, À3.9 ppm; IR
(film): n˜ = 2958, 2855, 1698, 1513, 1461, 1332, 1248, 1212, 1171, 1133,
1085 cmÀ1. HRMS (ESI): m/z: [M+Na]+ calcd for C36H59O6SNSiNa:
684.3730, found: 684.3736.
(Z)-(6S,7R,8S)-7-(tert-Butyldimethylsilanyloxy)-9-(4-methoxybenzyloxy)-
4,6,8-trimethylnon-4-enoic acid (90): To
a solution of aldehyde 87
(155 mg, 0.34 mmol) in tert-butyl alcohol (3 mL) with 2-methyl-2-butene
(0.5 mL) was added dropwise a solution of NaClO2 (465 mg, 5.2 mmol)
and NaH2PO4 (465 mg) in water (2 mL). After 3 h, 0.01n NaOH was
added and the aqueous layer was extracted with diethyl ether. 1n HCl
was added until pH 2 was reached and the aqueous layer was extracted
with DCM. The organic layers were dried over MgSO4 and the solvent
was removed under reduced pressure to give the crude acid 90 (160 mg),
which was directly used for the following reaction. 1H NMR (400 MHz,
C6D6): d=7.27 (d, J=8.6 Hz, 2H), 6.82 (d, J=8.6 Hz, 2H), 5.11 (d, J=
10.1 Hz, 1H), 4.40 (d, J=2.0 Hz, 2H), 3.60 (dd, J=9.1, 5.3 Hz, 1H), 3.53
(dd, J=6.3, 4.3 Hz, 1H), 3.33 (s, 3H), 3.32 (m, 1H), 2.81–2.72 (m, 1H),
2.37–2.20 (m, 4H), 2.18–2.11 (m, 1H), 1.53 (d, J=1.3 Hz, 3H), 1.08 (d,
J=7.1 Hz, 3H), 1.04 (d, J=6.6 Hz, 3H), 1.01 (s, 9H), 0.10 ppm (s, 6H);
13C NMR (100 MHz, C6D6): d=179.1, 159.7, 132.1, 131.8, 131.2, 129.6,
114.1, 79.1, 73.0, 72.6, 54.8, 39.0, 36.0, 32.7, 27.6, 26.4, 22.9, 18.7, 17.5,
15.4, À3.6, À3.7 ppm.
(Z)-(2S,6S,7R,8S)-N-[7-(tert-Butyldimethylsilanyloxy)-9-(4-methoxyben-
zyloxy)-2,4,6,8-tetramethylnon-4-enoyl]-(1’R)-bornan-2’,10’-sultam (94):
To N-acyl sultam 93 (35 mg, 0.05 mmol) in THF (1 mL) at À788C was
slowly added NaHMDS (55 mL, 1m in THF, 0.055 mmol) and the solution
was stirred for 1 h. MeI (9 mL, 0.1 mmol) was added and stirring was con-
tinued for 1.5 h. The reaction was quenched by the addition of a saturat-
ed NH4Cl solution and the layers were separated. The aqueous layer was
extracted with DCM and the combined organic phases were dried over
MgSO4 and the solvent was evaporated. Purification by column chroma-
tography (hexane/ethyl acetate=5:1) yielded a-methylated N-acyl sultam
94 (30 mg; 89%). [a]2D0 =55.3 (c=1.00, CH2Cl2); 1H NMR (400 MHz,
CHCl3): d=7.25 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.09 (d, J=
9.9 Hz, 1H), 4.39 (d, J=1.8 Hz, 2H), 3.87 (t, J=6.3 Hz, 1H), 3.80 (s,
3H), 3.49 (dd, J=14.8, 9.7 Hz, 1H), 3.49 (d, J=13.6 Hz, 1H), 3.42 (d, J=
13.6 Hz, 1H), 3.40 (t, J=5.2 Hz, 1H), 3.19 (t, J=8.7 Hz, 1H), 2.65–2.56
(m, 1H), 2.40 (dd, J=13.5, 9.5 Hz, 1H), 2.23 (dd, J=13.2, 4.8 Hz, 1H),
2.08–1.93 (m, 3H), 1.91–1.79 (m, 3H), 1.64 (s, 3H), 1.44–1.23 (m, 3H),
1.16 (s, 3H), 1.12 (d, J=6.8 Hz, 3H), 0.97 (s, 3H), 0.96 (d, J=6.8 Hz,
3H), 0.90 (d, J=7.1 Hz, 3H), 0.88 (s, 9H), 0.02 (s, 3H), 0.01 ppm (s,
3H); 13C NMR (100 MHz, CHCl3): d=176.0, 159.0, 132.8, 131.1, 130.2,
129.1, 113.7, 78.5, 72.7, 72.5, 65.2, 55.3, 53.2, 48.3, 47.7, 44.6, 38.6, 38.4,
37.9, 35.5, 34.2, 32.9, 29.5, 26.4, 26.2, 23.0, 20.9, 19.9, 18.4, 17.8, 16.9, 14.7,
À3.8, À3.9 ppm; IR (film): n˜ = 2959, 1696, 1513, 1332, 1248, 1132,
1036 cmÀ1; HRMS (ESI): m/z: [M+Na]+ calcd for C37H61O6SNSiNa:
698.3887, found: 698.3902.
(Z)-(6S,7R,8S)-7-(tert-Butyldimethylsilyloxy)-9-(4-methoxybenzyloxy)-
4,6,8-trimethylnon-4-enoic acid methyl ester (9): Crude acid 90 (10 mg,
0.022 mmol) in methanol (1 mL) was treated with diazomethane (0.5 mL,
ca. 0.1m in Et2O) until the solution remained yellow. Acetic acid was
added to quench excess diazomethane until the solution was colorless.
The solvent was removed under educed pressure and purification by
column chromatography (hexane/ethyl acetate=10:1) yielded methyl
1
ester 9 (11 mg; quant.). [a]D20 =2.20 (c=0.5, CH2Cl2); H NMR (400 MHz,
CHCl3): d=7.24 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 5.02 (d, J=
9.8 Hz, 1H), 4.39 (s, 2H), 3.80 (s, 3H), 3.66 (s, 3H), 3.50 (dd, J=9.1,
4.8 Hz, 1H), 3.39 (dd, J=5.9, 4.7 Hz, 1H), 3.20 (t, J=8.6 Hz, 1H), 2.61–
2.52 (m, 1H), 2.43–2.33 (m, 3H), 2.29–2.20 (m, 1H), 2.02–1.93 (m, 1H),
1.64 (d, J=1.3 Hz, 3H), 0.96 (d, J=6.8 Hz, 3H), 0,89 (d, J=6.1 Hz, 3H),
0.89 (s, 9H), 0.02 ppm (s, 6H); 13C NMR (100 MHz, CHCl3): d=173.7,
159.0, 131.5, 131,4, 131.0, 129.2, 113.7, 78.6, 72.6, 72.5, 55.3, 51.5, 38.4,
35.7, 32.7, 27.4, 26.1, 22.9, 18.4, 17.2, 14.9, À3.8, À3.9 ppm; IR (film): n˜ =
2957, 1741, 1513, 1249, 1087, 1038 cmÀ1; HRMS (ESI): m/z: [M]+ calcd
for C27H46O5Si: 478.3115, found: 478.3107.
(Z)-(6S,7R,8S)-7-(tert-Butyldimethylsilanyloxy)-9-(4-methoxybenzyloxy)-
4,6,8-trimethylnon-4-enoic acid 2,6-dimethylphenyl ester (91): To acid 90
(5 mg, 0.01 mmol) in DCM (1 mL) at room temperature under argon was
added 2,6-dimethylphenol (2 mg, 0.015 mmol) followed by DMAP
(1.5 mg, 0.011 mmol) and DIC (2 mL, 0.011 mmol) and the mixture was
stirred for 18 h. Brine was added and the organic layer was separated.
The aqueous layer was extracted with DCM and the combined organic
phases were dried over MgSO4 and the solvent was evaporated. Purifica-
tion by column chromatography (hexane/ethyl acetate=20:1) yielded ar-
omatic ester 91 (6 mg; 99%). [a]2D0 =10.4 (c=0.25, CH2Cl2); 1H NMR
(Z)-(2S,6S,7R,8S)-7-(tert-Butyldimethylsilanyloxy)-9-(4-methoxybenzyl-
AHCTUNGERTGoNNUN xy)-2,4,6,8-tetramethylnon-4-enal (95): To N-acyl sultam 94 (65 mg,
0.092 mmol) in DCM (2 mL) at À1008C was slowly added DIBALH
(62 mL, 1.5m in toluene, 0.92 mmol) and the mixture was stirred for 1 h.
A second equivalent of DIBALH (62 mL, 1.5m in toluene, 0.92 mmol)
was added and stirring was continued for 1 h, after which time the tem-
perature reached À658C. The reaction was quenched by the addition of a
small amount of methanol, and potassium sodium tartrate was added and
502
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 485 – 506

Synthesis of (Z)-Trisubstituted Olefins
FULL PAPER
stirred vigorously at room temperature for 2 h. The layers were separated
and the aqueous layer was extracted with DCM. The combined organic
phases were dried over MgSO4 and the solvent was evaporated. Purifica-
tion by column chromatography (hexane/ethyl acetate=10:1) yielded al-
dehyde 95 (40 mg; 94%). [a]2D0 =3.92 (c=1.30, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=9.61 (d, J=1.5 Hz, 1H), 7.24 (d, J=8.8 Hz, 2H),
6.87 (d, J=8.8 Hz, 2H), 5.12 (d, J=10.6 Hz, 1H), 4.39 (s, 2H), 3.80 (s,
3H), 3.48 (dd, J=9.1, 5.0 Hz, 1H), 3.38 (dd, J=5.8, 4.8 Hz, 1H), 3.19
(dd, J=8.8, 8.1 Hz, 1H), 2.57–2.43 (m, 2H), 2.22 (dd, J=13.9, 5.8 Hz,
1H), 2.16 (dd, J=13.8, 9.6 Hz, 1H), 2.26–2.17 (m, 1H), 2.00–1.88 (m,
1H), 1.63 (d, J=1.2 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H), 0.94 (d, J=6.8 Hz,
3H), 0.90 (d, J=6.8 Hz, 3H), 0.89 (s, 9H), 0.03 ppm (s, 6H); 13C NMR
(100 MHz, CDCl3): d=204.5, 158.6, 134.0, 133.0, 130.9, 129.3, 113.8, 78.5,
72.7, 72.4, 57.6, 55.2, 44.5, 38.4, 35.7, 32.6, 26.8, 23.3, 17.1, 14.9, 13.0, À4.1,
À4.2 ppm; IR (film): n˜ = 2958, 2930, 2856, 1727, 1513, 1472, 1462, 1249,
1091, 1037 cmÀ1; HRMS (ESI): m/z: [M]+ calcd for C27H46O4Si: 462.3165,
found: 462.3171.
38.7, 37.7, 36.5, 35.5, 26.1, 25.7, 23.1, 18.4, 17.0, 14.5, 14.4, 14.0, À3.5,
À3.8, À4.0 ppm; IR (film): n˜ =2930, 1784, 1698, 1514, 1463, 1385, 1249,
1040 cmÀ1 HRMS (ESI): m/z: [M+Na]+ calcd for C46H75NO7Si2Na:
.
832.4980, found: 832.4987.
(Z)-(2R,3R,4S,8S,9R,10S)-3,9-Bis-(tert-butyldimethylsilanyloxy)-11-(4-
methoxybenzyloxy)-2,4,6,8,10-pentamethyl-undec-6-en-1-ol (110): To 109
(18 mg, 0.022 mmol) in diethyl ether (0.5 mL) with methanol (10 mL) at
08C was slowly added LiBH4 (12 mL, 2m in THF, 0. 024 mmol). After
1.5 h, the reaction was quenched by the addition of brine and the layers
were separated. The aqueous layer was extracted with DCM and the
combined organic layers were dried over MgSO4. After evaporation of
the solvent, purification by column chromatography (hexane/ethyl ace-
tate=5:1) yielded 110 (12 mg; 86%). [a]2D0 =1.81 (c=0.55, CH2Cl2);
1H NMR (400 MHz, CDCl3): d=7.24 (d, J=8.8 Hz, 2H), 6.86 (d, J=
8.8 Hz, 2H), 5.02 (d, J=10.0 Hz, 1H), 4.40 (d, J=11.5 Hz, 1H), 4.36 (d,
J=11.5 Hz, 1H), 3.80 (s, 3H), 3.60 (m, 2H), 3.49–3.43 (m, 2H), 3.38 (dd,
J=6.2, 4.6 Hz, 1H), 3.21 (t, J=8.8 Hz, 1H), 2.51 (m, 1H), 2.16 (t, J=
12.0 Hz, 1H), 1.99–1.88 (m, 2H), 1.83 (m, 1H), 1.77 (m, 1H), 1.59 (s,
3H), 0.94 (d, J=7.0 Hz, 3H), 0.91 (d, J=6.5 Hz, 3H), 0.92 (s, 9H), 0.89
(s, 9H), 0.88 (d, J=8.1 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H), 0.09 (s, 3H),
0.08 (s, 3H), 0.03 (s, 3H), 0.02 ppm (s, 3H); 13C NMR (100 MHz, CDCl3):
d=159.0, 131.9, 131.5, 131.1, 129.1, 113.7, 78.5, 77.8, 72.6, 72.5, 66.4, 55.3,
39.4, 38.5, 36.6, 35.6, 34.5, 26.1, 26.0, 23.1, 18.4, 18.3, 17.0, 15.0, 14.8, 12.3,
À3.8, À3.9, À4.1 ppm; IR (film): n˜ = 2929, 2856, 1613, 1513, 1462, 1250,
(S)-4-Benzyl-3-[(Z)-(2S,3R,4S,8S,9R,10S)-9-(tert-butyldimethylsilanyl-
ACHTUNGTRENNUNGoxy)-3-hydroxy-11-(4-methoxybenzyloxy)-2,4,6,8,10-pentamethylundec-6-
enoyl]oxazolidin-2-one (108): To a stirred solution of acyloxazolidinone
107 (17 mg, 0.071 mmol) in DCM (0.7 mL) at À788C under argon was
slowly added dibutylboron triflate (74 mL, 1m in DCM, 0.074 mmol) fol-
lowed by triethylamine (12 mL, 0.081 mmol) and stirring was continued
for 10 min. The reaction mixture was warmed to 08C for 1 h and then re-
cooled to À788C. Aldehyde 95 (29 mg, 0.062 mmol) in DCM (0.5 mL)
was added dropwise. After 1 h the reaction mixture was warmed to 08C
and stirred for 1.5 h. A pH 7 buffer solution (2 mL), methanol (1 mL),
and H2O2 (0.1 mL, 30% aqueous) were added and the mixture was
stirred for 1 h at room temperature. Layers were separated and the aque-
ous layer was extracted with DCM, the combined organic layers were
dried over MgSO4, and the solvent was evaporated. The crude aldol
product was purified by column chromatography (hexane/ethyl acetate=
5:1 to 3:1) to yield aldol adduct 108 (28 mg; 65%) and aldehyde 95
(10 mg; 34%). [a]2D0 =32.2 (c=0.45, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=7.36–7.28 (m, 4H), 7.24–7.19 (m, 3H), 6.86 (d, J=8.5 Hz,
2H), 5.05 (d, J=10.0 Hz, 1H), 4.67 (ddt, J=9.5, 6.9, 3.43 Hz, 1H), 4.44
(d, J=11.5 Hz, 1H), 4.38 (d, J=11.5 Hz, 1H), 4.18 (m, 2H), 3,94 (m,
1H), 3.80 (s, 3H), 3.65 (dd, J=10.0, 5.0 Hz, 1H), 3.58 (dd, J=9.3, 4.7 Hz,
1H), 3.35 (dd, J=6.6, 3.6 Hz, 1H), 3.24 (dd, J=13.3, 3.3 Hz, 1H), 3.20–
3.16 (m, 2H), 2.77 (dd, J=13.3, 9.5 Hz, 1H), 2.64 (dt, J=9.9, 6.7 Hz,
1H), 2.10 (dd, J=13.3, 6.7 Hz, 1H), 1.98–1.86 (m, 2H), 1.77 (m, 1H),
1.63 (d, J=1.0 Hz, 3H), 1.20 (d, J=6.7 Hz, 3H), 0.94 (d, J=7.0 Hz, 3H),
0.89 (d, J=6.2 Hz, 3H), 0.88 (s, 9H), 0.88 (d, J=6.3 Hz, 3H), 0.04 (s,
3H), 0.02 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=177.0, 159.1,
152.8, 135.1, 132.0, 131.8, 130.7, 129.4, 128.9, 127.4, 113.7, 79.1, 74.0, 72.7,
72.5, 65.9, 55.3, 55.1, 40.5, 38.2, 37.7, 35.9, 35.8, 33.4, 29.2, 26.2, 23.1, 18.4,
17.3, 15.6, 14.4, 12.7, À3.7, À3.8 ppm; IR (film): n˜ = 2928, 1781, 1701,
1512, 1458, 1388, 1248, 1080 cmÀ1; HRMS (ESI): m/z: [M]+ calcd for
C40H61NO7Si: 695.4217, found: 695.4225.
1039 cmÀ1
;
HRMS (ESI): m/z: [M+Na]+ calcd for C36H68O5Si2Na:
636.4605, found: 636.4598.
(Z)-(3S,4S,5R,6R,7S,11S,12R,13S)-6,12-Bis-(tert-butyldimethylsilanyl-
AHCTUNGTERGoNNUN xy)-14-(4-methoxybenzyloxy)-3,5,7,9,11,13-hexamethyltetradeca-1,9-
dien-4-ol (111): To alcohol 110 (10 mg, 0.015 mmol) in DMSO (0.5 mL)
at room temperature under argon was added IBX (9 mg, 0.031 mmol)
and the mixture was stirred for 2 h. Water and diethyl ether were added
and the phases were separated. The aqueous layer was extracted with di-
ethyl ether and the combined ethereal layers were dried over MgSO4.
After evaporation of the solvent the crude aldehyde was used without
further purification. To (E)-(R,R)-crotyl boronate (0.5 mL, 0.3m in tolu-
ene, 0.15 mmol) at À788C was very slowly added the aldehyde (9 mg,
0.015 mmol) in toluene (0.5 mL). The mixture was kept at À788C over-
night and then 1n NaOH was added and the mixture was stirred for
45 min at 08C. The layers were separated and the aqueous layer was ex-
tracted with DCM. The combined organic layers were dried over MgSO4
and the solvent was removed under reduced pressure. Purification by
column chromatography (hexane/ethyl acetate=10:1) yielded olefin 111
(9 mg; 87%) as a single diastereoisomer. [a]2D0 =12 (c=0.4, CH2Cl2);
1H NMR (400 MHz, CDCl3): d=7.24 (d, J=8.6 Hz, 2H), 6.86 (d, J=
8.6 Hz, 2H), 5.79–5.69 (m, 1H), 5.15–5.09 (m, 2H), 5.02 (d, J=10.1 Hz,
1H), 4.40 (d, J=11.6 Hz, 1H), 4.36 (d, J=11.6 Hz, 1H), 3.80 (s, 3H),
3.64 (dd, J=5.6, 3.3 Hz, 1H), 3.48 (dd, J=9.1, 4.5 Hz, 1H), 3.39 (dd, J=
5.7, 5.1 Hz, 1H), 3.31 (dt, J=7.3, 3.7 Hz, 1H), 3.21 (t, J=8.8 Hz, 1H),
2.52 (m, 1H), 2.29 (dd, J=14.6, 7.5 Hz, 1H), 2.22 (t, J=12.1 Hz, 1H),
1.99–1.87 (m, 2H), 1.83–1.77 (m, 2H), 1.60 (s, 3H), 0.99 (d, J=6.8 Hz,
3H), 0.95 (d, J=7.3 Hz, 3H), 0.93 (d, J=7.0 Hz, 3H), 0.92 (s, 9H), 0.89
(s, 9H), 0.89 (d, J=8.1 Hz, 3H), 0.75 (d, J=6.8 Hz, 3H), 0.09 (s, 6H),
0.03 (s, 3H), 0.02 ppm (s, 3H); 13C NMR (150 MHz, CDCl3): d=159.1,
141.3, 132.1, 131.4, 131.0, 129.1, 116.4, 113.7, 78.8, 78.5, 75.8, 72.6, 72.5,
55.3, 42.4, 38.6, 37.9, 36.2, 35.6, 35.1, 26.2, 26.1, 23.2, 18.5, 18.4, 16.9, 16.7,
14.6, 13.5, 9.4, À3.3, À3.7, À3.9 ppm; IR (film): n˜ = 2958, 2930, 2856,
1514, 1463, 1250, 1079, 1040 cmÀ1; HRMS (ESI): m/z: [M]+ calcd for
C40H74O5Si2: 690.5075 , found: 690.5081.
(S)-4-Benzyl-3-[(Z)-(2S,3R,4S,8S,9R,10S)-3,9-bis-(tert-butyldimethylsila-
nyloxy)-11-(4-methoxybenzyloxy)-2,4,6,8,10-pentamethylundec-6-enoyl]-
ACHTUNGTRENNUNGoxazolidin-2-one (109): To a stirred solution of alcohol 108 (14 mg,
0.019 mmol) in DCM (1 mL) was added 2,6-lutidine (4 mL, 0.029 mmol)
and TBSOTf (5 mL, 0.023 mmol). After 1 h, the reaction was quenched
with saturated NH4Cl solution and extracted with DCM. The combined
organic solutions were dried over MgSO4 and the solvent was evaporat-
ed. Purification by column chromatography (hexane/ethyl acetate=5:1)
yielded 109 (16 mg; quant.) as a colorless oil. [a]2D0 =48 (c=0.6, CH2Cl2);
1H NMR (400 MHz, CDCl3): d=7.35–7.27 (m, 3H), 7.24–7.19 (m, 4H),
6.86 (d, J=8.5 Hz, 2H), 5.02 (d, J=10.0 Hz, 1H), 4.65–4.59 (m, 1H), 4.41
(d, J=11.5 Hz, 1H), 4.36 (d, J=11.8 Hz, 1H), 4.16 (d, J=5.0 Hz, 2H),
3.98 (m, 2H), 3.80 (s, 3H), 3.49 (dd, J=9.2, 4.9 Hz, 1H), 3.37 (dd, J=6.0,
4.9 Hz, 1H), 3.26 (dd, J=13.3, 3.3 Hz, 1H), 3.21 (t, J=8.9 Hz, 1H), 2.75
(dd, J=13.3, 9.5 Hz, 1H), 2.51 (m, 1H), 2.21 (t, J=12.4 Hz, 1H), 1.96
(m, 1H), 1.86 (m, 1H), 1.75 (m, 1H), 1.57 (s, 3H), 1.24 (d, J=6.3 Hz,
3H), 0.95 (d, J=7.0 Hz, 3H), 0.93 (s, 9H), 0.88 (d, J=6.5 Hz, 3H), 0.88
(s, 9H), 0.74 (d, J=6.8 Hz, 3H), 0.09 (s, 3H), 0.06 (s, 3H), 0.01 ppm (s,
6H); 13C NMR (100 MHz, CDCl3): d=176.0, 159.0, 152.8, 135.3, 131.2,
129.5, 129.1, 128.9, 127.4, 113.7, 78.5, 76.9, 72.7, 72.5, 65.9, 55.6, 55.3, 41.6,
(Z)-(2R,3S,4R,5R,6S,10S,11R,12S)-5,11-Bis-(tert-butyldimethylsilanyl-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
5.5m in decane, 0.026 mmol). The reaction mixture was kept overnight at
08C. A saturated Na2S2O3 solution was added and the layers were sepa-
rated. The aqueous phase was extracted with DCM and the combined or-
ganic layers were dried over MgSO4 and the solvent was evaporated.
Column chromatography (hexane/ethyl acetate=5:1) yielded epoxide
112 (8 mg; 87%) as a colorless oil. 1H NMR (400 MHz, CDCl3): d=7.24
Chem. Eur. J. 2010, 16, 485 – 506
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
503

J. Mulzer and K. Prantz
(d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.03 (d, J=10.4 Hz, 1H),
4.40 (d, J=11.6 Hz, 1H), 4.36 (d, J=11.6 Hz, 1H), 3.80 (s, 3H), 3.68 (dd,
J=6.1, 3.0 Hz, 1H), 3.64 (dt, J=8.2, 2.8 Hz, 1H), 3.49 (dd, J=9.1,
4.8 Hz, 1H), 3.40 (t, J=5.6 Hz, 1H), 3.21 (t, J=8.7 Hz, 1H), 2.92 (ddd,
J=7.8, 4.0, 2.8 Hz, 1H), 2.75 (t, J=4.4 Hz, 1H), 2.53 (m, 1H), 2.48 (dd,
J=4.8, 2.7 Hz, 1H), 2.40 (d, J=3.0 Hz, 1H (OH)), 2.27 (t, J=12.2 Hz,
1H), 2.00–1.93 (m, 2H), 1.84–1.78 (m, 2H), 1.62 (s, 3H), 0.97 (d, J=
6.8 Hz, 3H), 0.95 (d, J=6.8 Hz, 3H), 0.92 (s, 9H), 0.89 (s, 12H), 0.86 (d,
J=6.3 Hz, 3H), 0.75 (d, J=6.8 Hz, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.03
(s, 3H), 0.02 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=159.0, 132.1,
131.3, 131.1, 129.1, 113.7, 78.7, 78.5, 77.1, 72.6, 72.5, 55.8, 55.3, 45.1, 4.0,
38.6, 38.2, 36.2, 35.6, 34.9, 26.2, 26.1, 23.2, 18.5, 18.4, 16.9, 14.6, 14.1, 13.3,
12.9, 9,2, À3.3, À3.7, À3.9 ppm; IR (film): n˜ = 2929, 1513, 1462, 1250,
1039 cmÀ1; HRMS (ESI): m/z: [M]+ calcd for C40H74O6Si2: 706.5024,
found: 706.5029.
n˜ = 2929, 1514, 1470, 1242, 830 cmÀ1; HRMS (ESI): m/z: [M]+ calcd for
C47H80O7Si2: 812.5443, found: 812.5449.
(S)-2-tert-Butoxymethyl-3-hydroxy-2-methylpropionic acid methyl ester
(115): To
a solution of (R)-2-tert-butoxymethyl-2-methylmalonic acid
monomethyl ester (114) (1.20 g, 5.5 mmol) in THF (15 mL) at 08C under
an argon atmosphere, was added Et3N (0.84 mL, 6.05 mmol) followed by
methyl chloroformate (0.47 mL, 6.05 mmol). After 10 min at 08C, the re-
action mixture was warmed to room temperature and stirred for 45 min.
The white precipitate was filtered off, washed with Et2O, and concentrat-
ed. To the residue was added MeOH (15 mL) and the mixture was
cooled to 08C. NaBH4 (416 mg, 11 mmol) was added portionwise. After
1 h, the reaction was quenched with a saturated solution of NH4Cl, and
extracted with DCM. The organic extracts were dried over MgSO4 and
the organic solvent was removed under reduced pressure. Column chro-
matography (hexane/ethyl acetate=3:1) gave alcohol 115 (934 mg;
1
83%). [a]2D0 =2.00 (c=1.3, CH2Cl2); H NMR (400 MHz, CDCl3): d=3.80
(Z)-(2S,3S,4R,5R,6S,10S,11R,12S)-5,11-Bis-(tert-butyldimethylsilanyl-
ACHTUNGTRENNUNGoxy)-13-(4-methoxybenzyloxy)-2,4,6,8,10,12-hexamethyltridec-8-ene-1,3-
(dd, J=10.9, 5.4 Hz, 1H), 3.74–3.69 (m, 2H), 3.71 (s, 3H), 3.36 (d, J=
8.6 Hz, 1H), 2.92 (dd, J=7.6, 5.6 Hz, 1H (OH)), 1.16 (s, 9H), 1.15 ppm
(s, 3H); 13C NMR (100 MHz, CDCl3): d=175.8, 73.4, 67.7, 66.4, 51.9,
48.6, 27.5, 18.0, 14.0 ppm; IR (film): n˜ = 3467, 2975, 1732, 1364, 1234,
1197, 1084, 1049 cmÀ1; HRMS (ESI): m/z: [MÀCH3]+ calcd for C9H17O4:
189.1127, found: 189.1129.
diol (113): To epoxide 112 (7 mg, 0.0099 mmol) in Et2O/THF 1/1 (1 mL)
at 08C was added HIO4·2H2O (3 mg, 0.0014 mmol) and the mixture was
stirred for 16 h at 08C. A saturated NaHCO3 solution was added and di-
luted with DCM, the layers were separated, and the aqueous layer was
extracted with DCM. The combined organic layers were dried over
MgSO4 and the solvent was evaporated. The residue was taken up in
methanol (1 mL) and NaBH4 was added at 08C. After 30 min, brine was
added and DCM, the layers were separated and the aqueous layer was
extracted with DCM. The combined organic layers were dried over
MgSO4 and the solvent was evaporated. Column chromatography
(hexane : ethyl acetate=3:1) yielded alcohol 113 (2 mg; 29%, 51%
b.r.s.m.) and epoxide 112 (3 mg). [a]2D0 =4 (c=0.1, CH2Cl2); 1H NMR
(600 MHz, CDCl3): d=7.24 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H),
5.04 (d, J=10.2 Hz, 1H), 4.39 (d, J=11.7 Hz, 1H), 4.37 (d, J=11.7 Hz,
1H), 3.80 (s, 3H), 3.68 (t, J=3.9 Hz, 1H), 3.66 (m, 2H), 3.54 (dd, J=9.4,
0.1 Hz, 1H), 3.49 (dd, J=9.1, 4.5 Hz, 1H), 3.38 (dd, J=6.0, 4.9 Hz, 1H),
3.21 (t, J=8.7 Hz, 1H), 2.53 (m, 1H), 2.20 (t, J=12.3 Hz, 1H), 1.97 (m,
1H), 1.91 (m, 1H), 1.88–1.83 (m, 2H), 1.60 (s, 3H), 0.95 (d, J=6.8 Hz,
6H), 0.91 (d, J=9.5 Hz, 3H), 0.92 (s, 9H), 0.88 (s, 9H), 0.79 (d, J=
6.8 Hz, 3H), 0.76 (d, J=6.8 Hz, 3H), 0.12 (s, 3H), 0.11 (s, 3H), 0.03 (s,
3H), 0.02 ppm (s, 3H); 13C NMR (150 MHz, CDCl3): d=159.8, 131.8,
129.1, 116.1, 113.7, 81.4, 80.4, 78.5, 72.6, 68.8, 55.3, 38.5, 37.6, 37.2, 36.9,
35.7, 35.0, 26.2, 26.1, 23.2, 16.8, 14.8, 14.5, 13.7, 9.8, 8.2, À3.3, À3.8,
À4.6 ppm; IR (film): n˜ = 3325, 2928, 2855, 1513, 1466, 1364, 1248, 1098,
1039 cmÀ1; HRMS (ESI): m/z: [M]+ calcd for C39H74O6Si2: 694.5024,
found: 694.5018.
(R)-2-tert-Butoxymethyl-2-methyl-3-oxopropionic acid methyl ester
(116): To a stirred solution of alcohol 115 (3.50 g, 17.13 mmol) in dimeth-
yl sulfoxide (50 mL) was added IBX (9.40 g, 34.26 mmol) and stirring was
continued for 2.5 h. Water and diethyl ether were added and the organic
layer was separated. The aqueous layer was extracted with diethyl ether
and the combined ethereal phases were dried over MgSO4 and the sol-
vent was evaporated. Column chromatography (hexane/ethyl acetate=
5:1) yielded aldehyde 116 (2.80 g; 80%) as a colorless oil. [a]2D0 =0.86
(c=1.4, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=9.79 (s, 1H), 3.80 (d,
J=8.6 Hz, 1H), 3.75 (s, 3H), 3.52 (d, J=8.3 Hz, 1H), 1.30 (s, 3H),
1.14 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=199.8, 171.8, 73.4,
65.0, 58.1, 52.3, 27.2, 15.0 ppm; IR (film): n˜ = 1724, 1455, 1237, 1195,
1087 cmÀ1; HRMS (ESI): m/z: [MÀCH3]+ calcd for C9H15O4: 187.0970,
found: 187.0973.
AHCTUNGTERG(NNUN 2R,3R,4R)-4-((R)-4-Benzyl-2-oxooxazolidine-3-carbonyl)-2-tert-butoxy-
methyl-3-hydroxy-2-methylhexanoic acid methyl ester (117): To a stirred
solution of (R)-4-benzyl-3-butyryl-oxazolidin-2-one (122) (612 mg,
2.47 mmol) in DCM (3 mL) at À788C under argon was slowly added di-
butylboron triflate (3.2 mL, 1m in DCM, 3.2 mmol) followed by triethyla-
mine (0.48 mL, 3.45 mmol) and stirring was continued for 30 min. The re-
action mixture was warmed to 08C for 1 h and then recooled to À788C.
Aldehyde 116 (500 mg, 2.47 mmol) in DCM (1 mL) was added dropwise.
After 30 min the reaction mixture was warmed to 08C and stirred for 3 h.
A pH 7 buffer solution (10 mL), methanol (3 mL), and H2O2 (3 mL, 30%
aqueous) were added and the mixture was stirred for 2 h at room temper-
ature. The layers were separated and the aqueous layer was extracted
with DCM, and the combined organic layers were dried over MgSO4 and
the solvent was evaporated. The crude aldol product was purified by
column chromatography (hexane/ethyl acetate=10:1 to 3:1) to yield 117
(950 mg; 85%) as a pale yellow oil. [a]2D0 =À38.47 (c=1.24, CH2Cl2);
1H NMR (400 MHz, CDCl3): d=7.35–7.21 (m, 5H), 4.60–4.54 (m, 1H),
4.23–4.07 (m, 4H), 3.87 (d, J=9.0 Hz, 1H), 3.77 (d, J=10.3 Hz, 1H), 3.64
(s, 3H), 3.43 (d, J=9.0 Hz, 1H), 3.33 (dd, J=13.2, 3.1 Hz, 1H), 2.68 (dd,
J=13.3, 10.3 Hz, 1H), 1.97–1.83 (m, 2H), 1.39 (s, 3H), 1.19 (s, 9H),
0.98 ppm (t, J=7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=175.7,
174.9, 153.3, 135.6, 129.3, 128.9, 127.3, 76.3, 74.0, 65.9, 65.7, 63.8, 55.9,
52.0, 49.5, 46.4, 38.1, 27.2, 23,4, 19.3, 10.7 ppm; IR (film): n˜ = 2974, 1781,
1718, 1387, 1208, 1072 cmÀ1; HRMS (ESI): m/z: [M+Na]+ calcd for
C24H35O7Na: 472.2311, found: 472.2323.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
in DCM (0.5 mL) was added anisaldehyde dimethyl acetal (1 mL,
0.0056 mmol) and CSA (cat.) at room temperature under argon. The
mixture was stirred for 1.5 h. Brine was added and the mixture was dilut-
ed with DCM. The layers were separated and the aqueous layer was ex-
tracted with DCM. The combined organic layers were dried over MgSO4
and the solvent was removed under reduced pressure. Column chroma-
tography (hexane/ethyl acetate=15:1) yielded acetal 92 (1 mg; 86%) as
a colorless oil. Data were in every aspect identical with the literature
data. [a]2D0 =24 (c=0.05, CHCl3); 1H NMR (600 MHz, CDCl3): d=7.37
(d, J=8.7 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 6.85
(d, J=8.7 Hz, 2H), 5.38 (s, 1H), 5.01 (d, J=10.2 Hz, 1H), 4.39 (d, J=
11.7 Hz, 1H), 4.35 (d, J=11.7 Hz, 1H), 4.10 (dd, J=10.9, 4.5 Hz, 1H),
3.79 (s, 3H), 3.78 (s, 3H), 3.61 (dd, J=7.0, 1.7 Hz, 1H), 3.51 (dd, J=9.8,
1.9 Hz, 1H), 3.48 (t, J=11.1 Hz, 1H), 3.47 (dd, J=9.1, 4.9 Hz, 1H), 3.38
(dd, J=5.8, 4.7 Hz, 1H), 3.19 (t, J=8.9 Hz, 1H), 2.51 (m, 1H), 2.32 (t,
J=12.1 Hz, 1H), 2.05 (m, 1H), 1.99–1.94 (m, 2H), 1.88 (m, 1H), 1.67 (d,
J=11.7 Hz, 1H), 1.55 (s, 3H), 1.01 (d, J=7.2 Hz, 3H), 0.94 (d, J=6.8 Hz,
3H), 0.91 (s, 9H), 0.89 (d, J=6.9 Hz, 3H), 0.88 (s, 9H), 0.74 (d, J=
6.8 Hz, 3H), 0.73 (d, J=6.4 Hz, 3H), 0.03 (s, 3H), 0.018 (s, 3H), 0.014 (s,
3H), 0.012 ppm (s, 3H); 13C NMR (150 MHz, CDCl3): d=159.7, 159.0,
131.9, 131.5, 129.0, 127.3, 113.7, 113.4, 101.0, 83.3, 78.42, 78.40, 73.3, 72.6,
72.5, 55.3, 55.2, 38.7, 38.2, 37.6, 35.6, 33.6, 30.8, 26.2, 26.1, 23.1, 18.43,
18.39, 17.0, 14.6, 12.5, 12.1, 10.9, À3.6, À3.7, À3.8, À3.9 ppm; IR (film):
(2R,3R,4S)-2-tert-Butoxymethyl-3-hydroxy-4-hydroxymethyl-2-methyl-
hexanoic acid methyl ester (118): To aldol adduct 117 (440 mg,
0.98 mmol) in diethyl ether (10 mL) and methanol (20 mL) at 08C was
slowly added LiBH4 (21 mg, 0.98 mmol). After 30 min the reaction was
quenched by the addition of saturated NH4Cl solution and the layers
were separated. The aqueous layer was extracted with DCM and the
combined organic layers were dried over MgSO4. After evaporation of
504
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 485 – 506

Synthesis of (Z)-Trisubstituted Olefins
FULL PAPER
the solvent, the crude diol was purified by column chromatography
J=9.2, 7.2 Hz, 1H), 2.59 (m, 1H), 1.78 (s, 3H), 1.68–1.60 (m, 1H), 1.26–
1.17 (m, 1H), 1.21 (s, 9H), 0.86 ppm (t, J=7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=138.8, 135.2, 129.2, 128.3, 127.5, 127.4, 74.1, 72.9,
61.0, 39.8, 27.6, 25.2, 21.9, 11.6 ppm; IR (film): n˜ = 2970, 1454, 1362,
1197, 1058, 1021 cmÀ1; HRMS (ESI): m/z: [M]+ calcd for C19H30O2:
290.2246, found: 290.2251.
(hexane/ethyl acetate=3:1) to yield 118 (215 mg; 80%) as a colorless oil.
1
[a]2D0 =19.90 (c=0.97, CH2Cl2); H NMR (400 MHz, CDCl3): d=3.99 (dd,
J=8.3, 2.0 Hz, 1H), 3.90 (d, J=8.6 Hz, 1H (OH)), 3.76–3.66 (m, 2H),
3.70 (s, 3H), 3.64 (d, J=8.7 Hz, 1H), 3.54 (d, J=8.7 Hz, 1H), 1.53–1.39
(m, 2H), 1.36–1.27 (m, 1H), 1.23 (s, 3H), 1.14 (s, 9H), 0.94 ppm (t, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=176.9, 77.6, 73.5, 66.6, 64.6,
60.3, 52.0, 49.9, 43.3, 27.2, 18.1, 16.7, 12.1 ppm; IR (film): n˜ = 3435, 3974,
(Z)-(R)-4-Benzyloxymethyl-2-methyl-hex-2-en-1-ol (121): To a solution
of 120 (21 mg, 0.07 mmol) in DCM (1 mL) at room temperature was
added TFA (50 mL) and the mixture was stirred for 16 h. The reaction
mixture was diluted with water and the layers were separated. The aque-
ous layer was extracted with DCM and the combined organic phases
were dried over MgSO4. Purification by column chromatography
(hexane/ethyl acetate=40:1) yielded alcohol 121 (15 mg; 92%) as a col-
orless oil. The experimental data were identical with the literature data.
[a]2D0 =À38.8 (c=0.25, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.36–
7.27 (m, 5H), 5.29 (d, J=10.1 Hz, 1H), 4.94 (d, J=11.9 Hz, 1H), 4.80 (d,
J=12.4 Hz, 1H), 4.48 (s, 2H), 3.38 (dd, J=9.2, 5.9 Hz, 1H), 3.28 (dd, J=
9.2, 6.9 Hz, 1H), 2.57 (m, 1H), 1.81 (d, J=1.5 Hz, 3H), 1.61–1.55 (m,
1H), 1.23–1.16 (m, 1H), 0.84 ppm (t, J=7.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=158.3, 138.5, 134.9, 129.3, 128.3, 127.5, 127.4, 73.5,
73.0, 67.0, 40.4, 24.8, 21.2, 11.5 ppm; IR (film): n˜ = 2963, 2895, 1785,
1454, 1364, 1222, 1167 cmÀ1. HRMS (ESI): m/z: [M]+ calcd for C15H22O2:
234.1620, found: 234.1917.
1728, 1364, 1234, 1197, 1141, 1079, 1046 cmÀ1
; HRMS (ESI): m/z:
[M+Na]+ calcd for C14H28O5Na: 299.1834, found: 299.1832.
(3R,4R,5S)-3-tert-Butoxymethyl-5-ethyl-4-hydroxy-3-methyltetrahydro-
pyran-2-one (11): To a stirred solution of ester 118 (180 mg, 0.65 mmol)
in methanol (8 mL) was added K2CO3 (180 mg, 1.3 mmol) and stirring
was continued for 3 h. The mixture was diluted with water, acidified with
1n HCl, and extracted with DCM. After drying the organic layers over
MgSO4, the solvent was removed to yield lactone 11 (159 mg; quant.) as
white crystals, which was directly used in the following fragmentation.
For analytical purposes a small sample was purified by column chroma-
tography (hexane/ethyl acetate=3:1). [a]2D0 =11.56 (c=1.15, CH2Cl2);
1H NMR (400 MHz, CDCl3): d=4.37 (dd, J=11.49, 4.67 Hz, 1H), 3.88 (t,
J=10.99 Hz, 1H), 3.83 (d, J=8.84 Hz, 1H), 3.67 (d, J=7.83 Hz, 1H
(OH)), 3.56 (d, J=8.59 Hz, 1H), 3.49 (dd, J=9.22, 8.21 Hz, 1H), 2.07–
1.97 (m, 2H), 1.87–1.77 (m, 1H), 1.36 (s, 3H), 1.29–1.20 (m, 1H), 1.19 (s,
9H), 0.97 ppm (t, J=7.45 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
175.2, 77.2, 74.5, 69.1, 66.9, 48.2, 41.6, 27.2, 22.0, 21.6, 11.2 ppm; IR
(film): n˜ = 3503, 2973, 1701, 1364, 1237, 1198, 1147, 1089 cmÀ1; HRMS
(ESI): m/z: [M]+ calcd for C13H24O4: 229.1440, found: 229.1442.
Acknowledgements
Methanesulfonic acid (3R,4R,5S)-3-tert-butoxymethyl-5-ethyl-3-methyl-
2-oxotetrahydropyran-4-yl ester (119): To lactone 11 (160 mg, 0.64 mmol)
in DCM (6 mL) and pyridine (0.6 mL) at room temperature under an
argon atmosphere was added mesyl chloride (99 mL, 1.28 mmol) and
DMAP (cat.). After 1 h, brine was added, the layers were separated, and
the aqueous layer was extracted with DCM. The combined organic
phases were dried over MgSO4 and the solvent was evaporated. Column
chromatography (hexane/ethyl acetate=3:1) yielded mesylate 119
(205 mg; 99%). [a]2D0 =44.58 (c=1.2, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=4.66 (d, J=9.8 Hz, 1H), 4.45 (dd, J=11.6, 5.3 Hz, 1H), 3.88
(t, J=11.2 Hz, 1H), 3.63 (d, J=8.3 Hz, 1H), 3.54 (d, J=8.3 Hz, 1H), 3.11
(s, 3H), 2.88–2.78 (m, 1H), 1.83–1.72 (m, 1H), 1.37 (s, 3H), 1.28–1.18 (m,
1H), 1.16 (s, 9H), 0.96 ppm (t, J=7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=174.0, 85.2, 73.6, 68.6, 66.4, 48.7, 38.8, 38.4, 27.2, 21.9, 21.5,
10.8 ppm; IR (film): n˜ = 2974, 1732, 1339, 1177, 1093 cmÀ1; HRMS (ESI):
m/z: [MÀCH3]+ calcd for C13H23O6S: 307.1215, found: 307.1211.
(Z)-(R)-5-tert-Butoxy-2-ethyl-4-methyl-pent-3-en-1-ol (8): Mesylate 119
(200 mg, 0.6 mmol) was dissolved in dioxane (8 mL) and LiOH (1.8 mL,
1m in water, 1.8 mmol) was added. After 1.5 h the reaction was quenched
with saturated NH4Cl solution and the aqueous layer was extracted with
DCM. The combined organic layers were dried over MgSO4 and the sol-
vent was evaporated. Column chromatography (hexane/ethyl acetate=
5:1) yielded olefin 8 (110 mg; 83%). [a]2D0 =32.66 (c=0.65, CH2Cl2);
1H NMR (400 MHz, CDCl3): d=5.07 (d, J=10.1 Hz, 1H), 3.98 (d, J=
9.3 Hz, 1H), 3.63 (d, J=8.3 Hz, 1H), 3.57 (ddd, J=10.2, 6.7, 3.9 Hz, 1H),
3.21 (t, J=9.8 Hz, 1H), 2.87 (dd, J=7.2, 2.6 Hz, 1H (OH)), 2.47–2.38 (m,
1H), 1.82 (s, 3H),1.42–1.33 (m, 1H), 1.27–1.12 (m, 2H), 1.23 (s, 9H),
0.87 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=136.1,
131.8, 73.6, 65.9, 60.8, 43.0, 27.4, 24.9, 23.2, 11.8 ppm; IR (film): n˜ = 3629,
2970, 1653, 2559, 1056 cmÀ1; HRMS (ESI): m/z: [MÀH]+ calcd for
C12H23O2: 199.1698, found: 199.1703.
K.P. thanks the Ernst Schering Foundation for the award of a doctoral
fellowship.
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(Z)-(R)-5-tert-Butoxy-2-ethyl-4-methylpent-3-enyloxymethyl)benzene
(120): To a stirred solution of alcohol 8 (15 mg, 0.07 mmol) in benzylbro-
mide (0.3 mL) was added tetrabutylammonium iodide (2 mg,
0.007 mmol) and after 10 min silver(I) oxide (32 mg, 0.14 mmol) was
added. After 24 h the mixture was filtered over celite, washed with dieth-
yl ether, and the solvent was evaporated. Purification by column chroma-
tography (hexane/ethyl acetate=40:1) yielded benzyl ether 120 (21 mg;
quant.) as a colorless oil. [a]2D0 =À37.07 (c=0.75, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=7.33 (m, 4H), 7.28 (m, 1H), 5.05 (d, J=9.6 Hz,
1H), 4.49 (s, 2H), 3.88 (s, 2H), 3.36 (dd, J=9.2, 5.9 Hz, 1H), 3.31 (dd,
Chem. Eur. J. 2010, 16, 485 – 506
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
505

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Received: June 9, 2009
Published online: November 26, 2009
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