Evaluation of possible intramolecular [4+2] cycloaddition routes for assembling the central tetracyclic core of the potent marine antiinflammatory agent mangicol A

Article abstract of DOI:10.1016/j.tet.2005.11.096

A plan for enantioselective construction of the mangicol A framework by means of intramolecular Diels-Alder cycloaddition is outlined. First to be assembled is the enantiopure cyclopentenecarboxylic acid 16. Of the several approaches targeting the 1,3-die

Full text of DOI:10.1016/j.tet.2005.11.096

Tetrahedron 62 (2006) 5178–5194
Evaluation of possible intramolecular [4+2] cycloaddition routes
for assembling the central tetracyclic core of the potent marine
antiinflammatory agent mangicol A
*
Stefan Pichlmair, Manuel de Lera Ruiz, Kallol Basu and Leo A. Paquette
The Evans Chemical Laboratories, The Ohio State University, Columbus, OH 43210, United States
Received 6 October 2005; revised 1 November 2005; accepted 3 November 2005
Available online 31 March 2006
Abstract—A plan for enantioselective construction of the mangicol A framework by means of intramolecular Diels–Alder cycloaddition is out-
lined. First to be assembled is the enantiopure cyclopentenecarboxylic acid 16. Of the several approaches targeting the 1,3-diene component 56,
only that involving palladium-catalyzed enyne cyclization proved successful. Following the coupling of 16 to 56, we were unable to bring about
any detectable level of (4p+2p) cycloaddition. Activation of the diene by incorporation of an OSiEt3 substituent on a terminal sp2-hybridized
center likewise proved unsuccessful. Further facilitation was sought in the form of cyclopentenonecarboxylate 66. However, thermal activation,
Lewis acid catalysis, and high-pressure conditions proved ineffective and did not lead to C–C bond formation. These studies serve to underscore
the extent to which steric complications can complicate matters and the extent to which they must be skirted to arrive at the title compound.
Ó 2006 Elsevier Ltd. All rights reserved.
25
24
13
1. Introduction
Me
Me
Me
Me
11
2
10
8
Two reports emanating from the Fenical group in 19981 and
20002 described the isolation, structural elucidation, biologi-
cal properties, and biosynthesis of a new class of spirotetra-
cyclic sesterterpenoids named mangicols A–G (1–7). The
highlycomplexcarbon frameworkofthesefascinatingmetab-
olites isgenerated bya marinefungusbelieved tobeFusarium
heterosporum, which was collected from driftwood discov-
ered in a mangrove habitat at Sweetings Cay in the Bahamas.
Also identified were the neomangicols 8–10 whose potent cy-
totoxic and antibiotic activity profiles differentiate them from
1–7. Mangicol A (1) has shownvery significant antiinflamma-
toryactivityinthephorbolmyristateacetate(PMA)mouseear
edema assay.3 On the basis of its medicinal potential, 1 has
come to be regarded as an attractive target for total synthesis.4
6
15
1
7
16
H
H
OH
R1
Me
22Me
OH
Me
OH
Me
OH
3
HO
HO
Me
23
21
R2
19
Me
OH
20
OH
OH
1, Mangicol A
2, Mangicol B: R1 = H, R2 = OH
3, Mangicol C: R1 = H, R2 = H
Me
R1
Me
Me
Me
H
H
Me
Me
O
Me
HO
O
Me
OH
Me
OH
Any plan for the de novo elaboration of 1 must take into ac-
count its intertwined rings and 11 stereogenic centers, sev-
eral of which are quaternary in nature. The biogenetic
proposal that has been advanced2 is of little value in suggest-
ing an avenue by which to attack this challenging problem.
To us, the presence of a central six-membered ring suggested
the possible utilization of a protocol based upon an intra-
molecular (4+2) reaction.
OH
Me
R2
4, Mangicol D: R1 = OH, R2 = H
5, Mangicol E: R1 = H, R2 = OH
6, Mangicol F: R1 = H, R2 = H
7, Mangicol G
Me
Me
Me
Me
H
H
H
H
Me
OH
Me
Me
HO
HO
OH
Keywords: Mangicols; Pd-catalyzed enyne cyclization; Intramolecular aldol
cyclizations; Chiral nonracemic substituted cyclopentadienones; Enantio-
selective diene synthesis.
* Corresponding author. Tel.: +1 614 292 2520; fax: +1 614 292 1685;
e-mail: paquette.1@osu.edu
R
Me
OH
Me
OH
OH
OH
8, R = Cl
9, R = Br
10
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.096

S. Pichlmair et al. / Tetrahedron 62 (2006) 5178–5194
5179
This type of cycloaddition is recognized to be amenable
to catalysis by enzymes known collectively as Diels–
Alderases,5 and to play a useful role in select biosynthetic
applications.6 In this light, the source of our inspiration
converges nicely with the general theme of this Sympo-
sium-in-Print.
2). The action of sodium borohydride on 19 gave rise to two
diastereomeric alcohols, which converged to the identical
cyclohexenecarboxylic acid 20 by mesylate-mediated elim-
ination with subsequent saponification.13 Treatment of 20
with lithium aluminum hydride furnished the primary carbi-
nol that was protected as the tert-butyldiphenylsilyl ether 21.
At this point, the stage was set for a ring cleavage-reclosure
sequence14 involving ozonolysis to the dialdehyde and p-tol-
uenesulfonic acid-promoted intramolecular aldolization. As
a result of the substitution plan, only that reaction channel
leading to 22 is operative (81% for the two steps). Oxidation
of 22 to 16 was readily and efficiently accomplished with
sodium chlorite.15
2. Synthetic analysis
From the outset, it was envisioned that the final diastereo-
selective addition of an organometallic intermediate gener-
ated from iodide 11 to aldehyde 127 would result in
eventual arrival at the target molecule (Scheme 1).
O
O
1. NaBH4, MeOH
2. MsCl, Et3N, CH2Cl2
PLE,
KH2PO4
Me
Me
Me
Me
Me
CO2Et
OTIPS
3. KOH, H2O, MeOH
(60% over 3 steps)
CO2Et
pH 8
+
MOMO
1
O
OTIPS
I
18
19
OR1
Me
H
Me
Me
Me
1. LiAlH4, THF (98%)
12
11
OTBDPS
CO2H
2. TBDPSCl, imid, DMF, 50 °C
(91%)
O
O
Me
Me
20
21
Me
H
Me
NaClO2, NaH2PO4,
Me
CHO
OPMB
OPMB
H
1. O3, MeOH:CH2Cl2 (1:1);
PPh3
Me
Me
Me
Me
TBDPSO
TBDPSO
16
t-BuOH:H2O (1:1)
2. p-TsOH, PhH, 65 °C
(81% over 2 steps)
13
Me
OTBDPS
14
(94%)
OR1
O
22
O
CO2H
Scheme 2.
+
OR2
2.2. Exploration of a possible enantioselective route to
a diene of type 17
OMOM
TBDPSO
H
Me
Me
TBDPSO
R3O
OBn
This phase of our investigation began with the generation
from commercially available 1,8-octanediol (23) of its
monobenzoylated derivative. The latter was subjected to
Swern oxidation and homologated to produce a,b-unsatu-
rated aldehyde 24 via an improved Mannich reaction16
(Scheme 3). The reduction of 24 with sodium borohydride
gave rise to the primary carbinol, which was sequentially
transformed via the mesylate and bromide into allylic iodide
25. The Finkelstein displacement step17 was performed im-
mediately prior to the utilization of 25 in subsequent chem-
ical maneuvers.
15
16
17
Scheme 1.
The framework of 11 was to be made available by samarium
diiodide-promoted cleavage of the cyclobutane ring in 138
followed by a Shapiro reaction.9 A key feature of this reduc-
tive step is its capability for unveiling the C(23) methyl
group in its proper configuration. Cyclobutane 13 was to
stem from an intramolecular photochemical (2+2) cycload-
dition involving the terminal alkene and a,b-unsaturated ke-
tone subunits resident in 14.10,11 It was further conjectured
that 14 would be accessible by suitable chemical modifica-
tion of 15, the construction of which was to be realized by
thermally induced or Lewis acid-catalyzed cycloaddition in-
volving the ester to be formed from 16 and 17 or activated
forms thereof. As will be seen, provision was made for the
anticipated need that modest structural variations might be
necessary at this stage. Should the cyclization proceed as re-
quired, the lactone bridge was to serve the role of progenitor
to the two cis-related angular methyl groups positioned at
C(9) and C(12).
Next to be explored was the enantioselective alkylation of
the sodium enolate derived from 2618 with 25. In this in-
stance, C–C bond formation proceeded very smoothly,
thus allowing direct reductive cleavage of the chiral oxazo-
lidinone with sodium borohydride in methanol. The config-
uration depicted for alcohol 27 formed in this two-step
sequence (de>95%) is founded on extensive prior prece-
dent.19 Esterification of the unmasked hydroxyl group in
27 with pivaloyl chloride afforded 28 (93%). With this inter-
mediate in hand, its ozonolytic conversion to a keto aldehyde
and ensuing acid-promoted aldol cyclization to generate
cyclohexenone 29 were accomplished without event.
2.1. Construction of (+)-cyclopentenecarboxylic acid 16
Pig liver esterase-mediated kinetic resolution of the racemic
keto ester 18 made available the desired S-enantiomeric 19
at the 91% ee level as determined by chiral HPLC12 (Scheme
Reduction of enone 29 under Luche conditions20 gave rise to
the equatorial alcohol21 as the only detectable product
(Scheme 4), where protection as the PMB ether was affected

5180
S. Pichlmair et al. / Tetrahedron 62 (2006) 5178–5194
by way of trichloroacetimidate technology.22 Aldehyde 31
1. BzCl, NEt3,
(DMAP), 0°C
CH2Cl2 (60%)
rt
was in turn produced by careful ozonolysis followed directly
by aldol ring closure in the presence of piperidine and acetic
acid.14 The primary alcohol obtained from 31 by boro-
hydride reduction reacted smoothly with tert-butyldimethyl-
silyl chloride and imidazole to furnish the quadruply
functionalized (ꢀ)-cyclopentene 32. When stirred with po-
tassium carbonate in methanol at rt, this intermediate was ef-
ficiently debenzoylated, thus allowing replacement with an
MEM protecting group at that site as in 33. Subsequent re-
moval of the pivaloyl ester with DIBAL-H resulted in forma-
tion of the key building block 34 whose role was to be
coupled to 16. The utilization of EDC23 was quickly found
to be well suited to the generation of ester 35. In line with
expectation, the OTBS group in 35 could subsequently be
cleaved selectively without incurring unwanted side reac-
tions.24 This step lent itself to the uncomplicated generation
of alcohol 36 (92%), whose hydroxyl group proved quite
amenable to activation as the bromide 37 as well as other
derivatives.
H
BzO
HO
OH
5
6
2. Swern oxidation (90%)
3. CH2O, Me2NH•HCl, 110 °C
(74%)
O
23
24
1. NaBH4, MeOH (97%)
2. MsCl, NEt3, CH2Cl2
I
BzO
3. LiBr, THF
(81% over 2 steps)
4. NaI, acetone (90%)
5
25
Ph
Me
1. NaHMDS, THF, -78 °C
then 25
O
N
2. NaBH4, MeOH
(60% over 2 steps)
O
O
26
PivCl, Py,
CH2Cl2
OH
OPiv
(93%)
BzO
BzO
5
5
Quite unexpectedly, all attempts to accomplish the conver-
sion of 37 into diene 38 were to no avail. Recovery of un-
changed starting material or complete decomposition25
was the alternative encountered. In an effort to bypass this
complication, 36 was treated with 2,4-dinitrobenzenesul-
fenyl chloride in the expectation that 39 so formed would un-
dergo [1,3] sigmatropic shift to generate the sulfoxide that
would, in turn, experience elimination.26 However, the
27
28
OBz
1. O3, CH2Cl2/MeOH (1:1)
-78 °C; PPh3
2. p-TsOH, PhH, reflux
(65% over 2 steps)
OPiv
O
29
Scheme 3.
O
TBSO
1. NaBH4, MeOH
(100%)
1. NaBH4, MeOH
CeCl3 (91%)
OBz
1. O3, Ph3P
OPiv
OPiv
29
2. PMBIm, TfOH,
Et2O (80%)
2. AcOH, piperidine
(80% over 2 steps)
2. TBSCl, imid
(94%)
OPiv
OPMB
OBz
OPMB
OBz
PMBO
TBSO
30
31
32
TBSO
O
1. K2CO3, MeOH
(94%)
16
OPiv
DIBAL-H
OH EDC, DMAP
O
OPMB
2. MEMCl, i-Pr2NEt,
CH2Cl2 (93%)
CH2Cl2
(87%)
CH2Cl2, rt
(70%)
OPMB
OPMB
OMEM
TBDPSO
Me
OMEM
OMEM
OTBS
33
34
35
O
CSA, 0 °C
O
MeOH:CH2Cl2 (1:1)
1. MsCl, Et3N, CH2Cl2, 0 °C
OPMB
TBDPSO
(92%)
2. LiBr, THF, rt
(86% over 2 steps)
Me
OMEM
OH
36
O
O
O
O
OPMB
OPMB
TBDPSO
TBDPSO
Me
Br
OMEM
OMEM
Me
37
38
Scheme 4.

S. Pichlmair et al. / Tetrahedron 62 (2006) 5178–5194
5181
intended sequential transformation did not occur and no
allylic alcohol was detected.27
Application of Ireland–Claisen conditions34 to 48 resulted in
smooth conversion to the silyl ether, direct hydrolysis of
which with 8 N lithium hydroxide in THF and ensuing expo-
sure to methyl iodide and potassium carbonate gave rise to
49 in 73% yield over the three steps. Advantage was next
taken of the ease of conversion of 49 to aldehyde 50. The
subsequent hurdle was the enantioselective 1,2-addition of
5-benzyloxy-1-pentyne30 to 50. Unfortunately, the standard
conditions reported by Carreira et al.35 proved inapplicable
to our system. Attempts to bring about effective scale-up
of the reaction (to a maximum of 1.8 g) furnished only
a 1:1 mixture of diastereomers.
O
O
OPMB
TBDPSO
OMEM
Me
O
S
O2N
NO2
39
O
O
OPMB
To overcome this problem, the mixture of alcohols was
oxidized to 51 by means of activated manganese dioxide.
At this juncture, recourse was made to the R-CBS reagent,36
whose reactivity potential could be commandeered to de-
liver the R alcohol quantitatively with a de¼88%.
OMEM
TBDPSO
Me
40
HO
We also undertook exploration of the conversion of 36 to the
rearranged allylic alcohol 40 via a three-step sequence in-
volving Sharpless epoxidation,28 treatment of the resulting
epoxy alcohol with triphenylphosphine, imidazole, and
Formation of the MOM ether 53 allowed ozonolytic cleav-
age of the olefinic bond to be performed. Since the resulting
aldehyde is prone to b-elimination, the Wittig olefination
with methylenetriphenylphosphorane must be performed
under controlled conditions. A particularly attractive option
iodine,29 and finally warming to 40 C in water. While this
ꢁ
conversion proceeded satisfactorily, 40 resisted xanthate for-
mation at every turn,27 thereby thwarting its eliminative
transformation into 38. At this point, the decision was
made to undertake an alternate approach to subunit 17.
ꢁ
is to conduct the ozonolysis in hexane at ꢀ78 C, to stir with
triphenylphosphine at rt for 2 h, and to introduce the
Ph3P]CH2 reagent in ether without further delay.
2.3. Implementation of alternative palladium-mediated
diene construction
The availability of 54 led us to explore the possibility for pal-
ladium-catalyzed cycloisomerization.37 Under conditions
recommended for comparable applications38,39 (Table 1),
three catalysts were examined in a move to achieve optimi-
zation. Unsatisfactory conversion was observed in the first
three runs. Recourse instead of palladium(II) acetate in com-
bination with N,N-bis(benzylidene)ethylenedimine (55) as
the ligand in 1,2-dichloroethane solution did prove effective
(E:Z¼4:1). The minimum temperature to realize complete
The observations detailed above led us to entertain a series of
retrosynthetic disconnections within 17 that would involve
somewhat less complex intermediates (Scheme 5). More
specifically, the applicability of an appropriate transition
metal-mediated cycloisomerization as a direct route from
41 to 17 could constitute a more straightforward route to
its generation. Success here would open up the possibility
that precursor compounds such as 42 and 4330 might also
contribute to greater expediency. To this end, lactone 44,
readily available in two steps from ascorbic acid,31 was
used to define the absolute configuration of 45 via an estab-
lished one-pot procedure32 (Scheme 6). The ester was re-
duced with DIBAL-H and the carbinol so formed was
protected as the tert-butyldiphenylsilyl ether. Although at-
tempts to hydrolyze the acetonide in 46 chemoselectively
with methanolic HCl caused concomitant desilylation, diol
47 could be secured in 90% yield following treatment with
80% acetic acid at rt. Continued success was realized with
site-specific introduction of a second OTBDPS group as
long as coupling to the silyl chloride was performed in
ꢁ
conversion was 60 C. Subsequent treatment with TBAF
generated 56 without incident.
This result made possible the opportunity to esterify 56 with
16, thereby generating 57, the substrate desired for valida-
tion of its Type II Diels–Alder reactivity40 (Scheme 7). We
next sought to transform 57 into 58 by purely thermal means
ꢁ
(e.g., toluene, 220 C, 7 h) or under milder Lewis acid-cata-
lyzed conditions such as with Et2AlCl in CH2Cl2 at rt. Under
no circumstance was conversion into 58 seen. This body of
experiments provided convincing evidence that conditions
for intramolecular cycloaddition within 57 as in 57’ were
not likely to be found. Our attention was consequently di-
rected instead to the incorporation of activated components.
33
ꢁ
THF at ꢀ10 C. Subsequent acetylation delivered 48 in
excellent overall yield.
2.4. Development of routes to a diene and a dienophile
with intent to enhance reactivity
O
OR1
R1O
We hoped to solve the total synthesis problem via the inter-
mediacy of either a substituted cyclopentenone or a 1-silyl-
oxybutadiene derivative. It is widely recognized that
rendering dienophiles more electron-deficient and dienes
more electron-rich contributes in utilitarian fashion because
of decreases in HOMO–LUMO gaps. With the availability
of alcohol 36, it proved an easy matter to achieve oxidation
to the aldehyde level with manganese dioxide as a prelude to
H
42
+
17
OR2
R3O
R3O
41
43
Scheme 5.

5182
S. Pichlmair et al. / Tetrahedron 62 (2006) 5178–5194
Me
O
Me
OTBDPS
OTBDPS
CO2Me
O
1. NaIO4, H2O
2. K2CO3,
1. DIBAL-H, THF (95%)
2. TBDPSCl, DMF
80% AcOH,
HO
O
O
O
O
O
O
OH
rt, 4 h (95%)
Me
H
Me
Me
Me
imid (100%)
O
P
O
45
47
46
HO
OH
MeO
OMe
44
OMe
(40%)
1. TBDPSCl, imid
THF, -10 °C (82%)
1. KHMDS, TBSCl,
THF, -78 °C, then rt
1. DIBAL-H, 0 °C,
THF (95%)
OTBDPS
OTBDPS
CO2Me
OTBDPS
OAc
OTBDPS
OTBDPS
OTBDPS
2. Ac2O, Py, DCM
(1 : 3), DMAP (92%)
2. Swern oxidation
(95%)
2. 8 N LiOH, THF
3. MeI, K2CO3, DMF
(73% over 3 steps)
H
O
48
49
50
OTBDPS
OTBDPS
OTBDPS
OR
OTBDPS
1. n-BuLi, HC C(CH2)3OBn,
THF, -78 °C (74%)
1. (R)-CBS, BH3, THF,
THF (100% de = 88%)
1. O3, -78 °C, hexane
then Ph3P, 2 h, rt
O
2. MOMCl, N(i-Pr)2Et,
DCM, rt (92%)
2. MnO2, DCM (95%)
2. Ph3PCH2, hexane
(85% over 2 steps)
BnO
BnO
52, R = H
53, R = MOM
51
OTBDPS
OMOM
OH
N
N
55
1. Pd(OAc)2, 55, ClC2H4Cl,
OMOM
OBn
60 °C, separation of E/Z
isomers (32%)
2. TBAF, THF (86%)
BnO
54
56
Scheme 6.
O-silylation as in 60 (Scheme 8). At this point, it quickly be-
came apparent that the hurdle of engaging 60 in intermolec-
ular cycloaddition was not to be surmounted. All attempts to
achieve cyclization under basic, acidic, purely thermal, or
high-pressure conditions failed to come to fruition.41 Simply
stated, 60 proved to be too sensitive for our purposes. When
intermolecular variants designed to avoid the incorporation
of a lactone bridge were also found to lead to decomposi-
tion,42 dienophile activation was pursued.
After adjustment of the substitution plan about the quater-
nary carbon as in 64, sequential allylic oxidation44 and a-io-
dination45 followed to provide 65. Finally, the carbomethoxy
group was incorporated in palladium-catalyzed carbonyla-
tion.46 The diactivated dienophile 66 was isolated in 61%
yield.
The recalcitrance of 66 to function as a dienophile in
intermolecular Diels–Alder reactions involving 67 soon
became apparent. Decomposition and/or polymerization
were clearly operative under conditions involving either
purely thermal conditions (e.g., toluene, sealed tube,
To arrive at the levorotatory keto ester 62, the racemic cyclo-
pentanonecarboxylate 61 was kinetically resolved by appli-
cation of Brown’s (ꢀ)-DIPCl methodology43 (Scheme 9).
Cyclopentene 63 was subsequently generated by mesylate-
mediated dehydration.
47
ꢁ
160 C), catalysis by select Lewis acids (e.g., AlBr3/
48
ꢁ
AlMe3, ꢀ10 to 0 C), or high-pressure conditions (e.g.,
CH2Cl2, rt).49
Table 1. Conditions employed for the Pd(II)-catalyzed cycloismerization of 54
Run
Catalyst
Ligand
Additive
Solvent
Time, h
Temperature, ꢁC
% Conversion
E/Z ratio
1
2
3
4
5
Pd2(dba)3 CHCl3
$
Ph3P
Ph3P
—
55
55
HOAc
HOAc
—
—
—
Benzene
Benzene
ClCH2CH2Cl
Benzene
ClCH2CH2Cl
48
24
48
22
22
60
90
60
63
63
30
40
0
100
100
—
—
—
2:1
3–4:1
Pd2(dba)3 CHCl3
$
Pd[P(o-tol)3]2(OAc)2
Pd(OAc)2
Pd(OAc)2

S. Pichlmair et al. / Tetrahedron 62 (2006) 5178–5194
5183
O
OH
in intermolecular (4+2) cycloadditions is a checkered one. In
general, this compound class performs poorly and as a result
has not been made recourse to with a great deal of frequency.
The presence of a 2-methyl group as in 68 has no apparent
deleterious consequences50 relative to the parent system.51
In contrast, exceptionally low reactivity has been noted for
6952 and 70.53 Their complete failure to react has been attrib-
uted to the effective shielding brought on by the quaternary
nature of C-4. The significant transition state destabilizing
effect operative in these substrates can be offset to some de-
gree by the proper positioning of a carbomethoxy group as in
71.47,53 Seemingly more advantageous yet is the acetylcy-
clopentene motif present in 72 and 73,48 and esters of similar
type.54
O
CO2H
+
DCC, DMAP,
DCM (90%)
OMOM
Me
OTBDPS
OMOM
OBn
Me
OTBDPS
OBn
56
16
57
O
O
O
O
Me
OTBDPS
H
Me
OMOM
OBn
OTBDPS
OMOM
OBn
O
O
O
R
Me
Me
Me
57'
58
Me
Me
R
Scheme 7.
69, R = H
70, R = CH3
71, R = COOMe
68
72, R = H
73 =
SiMe3
O
O
O
O
OPMB
MnO2
36
CH2Cl2
(85%)
Although intramolecular Diels–Alder cycloadditions have
long been recognized to offer heightened reactivity advan-
tages stemming from favorable entropic contributions,55
these effects were not apparent in transition states typified
by 570. In contrast, Uemura and co-workers found 74 and
76 to cyclize efficiently in refluxing toluene with formation
of the mangicol core (Scheme 10).4 An added bonus was the
co-discovery of a remarkable interrelationship between
stereoselectivity and the configuration of the secondary
hydroxyl group. Both possible endo avenues of approach are
clearly subject to subtle nonbonded steric interactions. Not
withstanding, the kinetic advantages associated with the pre-
formation of a 12-membered cyclic trienone framework are
notable and promising.
OMEM
Me
H
TBDPSO
59
O
TESOTf,
Et3N, CH2Cl2
O
OPMB
TESO
Me
-78 °C
0 °C
OMEM
(64%)
60
TBDPSO
Scheme 8.
1. MsCl, Et3N (71%)
2. DBU, DMF (84%)
(-)-DlPCl, DEA
(72%; 92% ee)
O
OH
Me
EtO2C
EtO2C
Me
61
62
OBn
Me
BnO
Me
H
H
1. LiAlH4 (91%)
1. CrO3, 3,5-DMP (41%)
2. I2, py (97%)
9
toluene
9
15
Me
H
Me
2. TBDPSCl,
im (89%)
15
reflux, 12 h
Me
EtO2C
O
O
Me
3S
Me
3
Me
TBDPSO
63
64
HO
OH
75
O
O
74
O
(quant)
I
OMe
CO, Pd2(dba)3, Et3N
Ph3P, MeOH (61%)
OBn
Me
BnO
Me BnO
+
15
Me
H
H
H
9
Me
65
Me
toluene
reflux, 12 h
9
9
15
H
H
TBDPSO
TBDPSO
Me
15
Me
O
O
Me
3
66
3
H
OPiv
O
3R
Me
Me
TBSO
Me
HO
HO
OH
76
77 (42%)
78 (42%)
OPMB
Scheme 10.
67
Scheme 9.
The studies that have been detailed above serve to under-
score the sorts of steric complications that may beset intra-
molecular cycloaddition reactions. These complexities
obviously need to be avoided, and we hope to report on
one or more alternative synthetic routes to mangicol A in
the near future.
3. Overview
The history dealing with the participation of substituted 2-
cyclopentenones and other electron-deficient cyclopentenes

5184
S. Pichlmair et al. / Tetrahedron 62 (2006) 5178–5194
4. Experimental
4.3. tert-Butyl-((S)-1-methylcyclohex-2-enylmethoxy)
diphenylsilane (21)
4.1. (S)-1-Methyl-2-oxo-cyclohexanecarboxylic acid
ethyl ester (19)
ꢁ
To a cold (0 C) suspension of LiAlH4 (1.25 g, 32.86 mmol)
in dry THF (40 mL) was added a solution of 20 (2.0 g,
14.29 mmol) in dry THF (40 mL) via an addition funnel. Af-
ter the addition was complete, the cold bath was removed
and the reaction mixture was stirred at rt for 14 h, cooled
To a rapidly stirred solution of racemic 18 (10.4 g, 0.06 mol)
in KH2PO4 buffer (250 mL, 0.1 M) was added pig liver es-
terase (0.17 g, 20,000 Units) at pH 8.0 and rt. The mixture
was stirred for 24 h while the pH was maintained at 8.0 by
pH stat-controlled addition of 1.0 N aqueous NaOH solu-
tion, and extracted with CH2Cl2 (2ꢂ800 mL). The combined
organic phases were dried and evaporated to give a residue
that was purified by column chromatography on silica gel
(elution with 10:1 hexane–ethyl acetate) to give 3.16 g
(61%) of 19 as a colorless liquid; IR (neat, cmꢀ1) 1714,
1260, 1158; 1H NMR (300 MHz, CDCl3) d 4.24–4.15
(m, 2H), 2.55–2.45 (m, 3H), 2.04–2.02 (m, 1H), 1.75–1.64
(m, 3H), 1.51–1.44 (1H), 1.29 (s, 3H), 1.26 (t, J¼7.1 Hz,
3H); 13C NMR (75 MHz, CDCl3) d 206.7, 172.2, 60.4,
56.3, 39.9, 37.5, 26.9, 22.0, 20.5, 13.4; HRMS ES m/z
ꢁ
to 0 C, carefully quenched with 1 N NaOH solutiꢁon
(1.25 mL) followed by H2O (3.75 mL), and stirred at 0 C
for 1 h during which time a white precipitate formed. The
precipitate was filtered off and washed with Et2O
(100 mL). The filtrate was concentrated under vacuum to
leave a light yellow residue that was purified by column
chromatography on silica gel (elution with 5:1 hexane–ethyl
acetate) to give 1.77 g (98%) of the primary alcohol as a col-
orless oil; IR (neat, cmꢀ1) 3355; 1H NMR (300 MHz,
CDCl3) d 5.90–5.78 (m, 1H), 5.41–5.37 (m, 1H), 3.43–
3.30 (m, 2H), 2.00–1.95 (m, 2H), 1.71–1.60 (m, 2H),
1.40–1.27 (m, 2H), 0.96 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 133.0, 128.1, 70.8, 36.7, 31.5, 25.0, 24.1, 18.8;
25
(M+Na)+ calcd 207.0992, obsd 207.1000; ½aꢃD +109.0 (c
25
1.0, CHCl3).
½aꢃD +8.5 (c 1.0, CHCl3).
4.2. (S)-1-Methylcyclohex-2-enecarboxylic acid ethyl
ester (20)
To a solution of the above alcohol (1.77 g, 14.05 mmol)
in dry DMF (7 mL) were added TBDPSCl (4.63 g,
16.86 mmol) and imidazole (2.87 g, 42.15 mmol). The
ꢁ
ꢁ
Toa cold(ꢀ78 C)suspensionofNaBH4 (1.23 g, 32.6 mmol)
mixture was heated to 50 C for 2 h before being cooled
in anhydrous MeOH (30 mL) was added dropwise a solution
of 19 (5.0 g, 27.2 mmol) in ꢁthe same solvent (50 mL). The
mixture was stirred at ꢀ78 C for 2 h, quenched with 10%
aqueous HCl solution (50 mL), warmed to rt, and stirred
for 15 min. This solution was extracted with CH2Cl2
(3ꢂ100 mL), and the combined organic phases were dried
and evaporated to give a mixture of diastereomeric hydroxy
esters.
to rt and diluted with H2O (100 mL). The aqueous layer
was extracted with Et2O (5ꢂ100 mL), and the organic
layers were combined, dried, and evaporated to leave a res-
idue that was purified by column chromatography on silica
gel (elution with 40:1 hexane–ethyl acetate) to obtain
4.65 g (91%) of 21 as a colorless oil; IR (neat, cmꢀ1
)
1470, 1361; 1H NMR (250 MHz, CDCl3) d 7.70–7.66
(m, 4H), 7.46–7.27 (m, 6H), 5.71–5.64 (m, 1H), 5.46–
5.31 (m, 1H), 3.44–3.33 (m, 2H), 1.97–1.70 (m, 2H),
1.70–1.53 (m, 3H), 1.41–1.33 (m, 1H), 1.08–1.05 (s,
12H); 13C NMR (75 MHz, CDCl3) d 135.7 (4C), 134.0
(2C), 133.8, 129.5 (2C), 127.6 (4C), 127.1, 71.5, 37.2,
31.9, 26.9 (3C), 25.4, 24.8, 19.5, 19.0; HRMS ES m/z
ꢁ
To a cold (0 C) solution of the above material in dry
CH2Cl2 (100 mL) was added Et3N (5.49 g, 54.3 mmol)
and MsCl (6.22 g, 54.3ꢁmmol) in sequence. The cloudy solu-
tion was stirred at 0 C for 1.5 h before being quenched
with 10% aqueous HCl (50 mL) and diluted with H2O
(100 mL). The separated aqueous layer was extracted with
CH2Cl2 (3ꢂ50 mL). The combined organic layers were
dried and concentrated to give a mixture of mesylates as
yellow oil.
25
(M+Na)+ calcd 387.2115, obsd 387.2092; ½aꢃD ꢀ28.2 (c
1.4, CHCl3).
4.4. (S)-3-(tert-Butyldiphenylsilanyloxymethyl)-3-methyl-
cyclopent-1-enecarbaldehyde (22)
ꢁ
To a solution of the mesylate mixture from above in MeOH
(200 mL) and H2O (25 mL) was added KOꢁH (10.67 g,
190.19 mmol). The mixture was heated to 60 C for 16 h,
cooled to rt, evaporated under vacuum, and acidified to pH
1 by careful addition of 1 N HCl solution. The aqueous layer
was extracted with CH2Cl2 (4ꢂ100 mL). The combined
organic phases were dried and evaporated to leave a residue
that was purified by column chromatography on silica gel
(elution with 5:1 hexane–ethyl acetate) to give 2.28 g
(60% over three steps) of 20 as a colorless liquid; IR (neat,
cmꢀ1) 1697, 1296, 1188; 1H NMR (250 MHz, CDCl3)
d 5.85–5.67 (m, 2H), 2.20–2.14 (m, 1H), 2.05–1.98
(m, 2H), 1.70–1.66 (m, 2H), 1.53–1.48 (m, 1H), 1.32–1.24
(m, 3H); 13C NMR (75 MHz, CDCl3) d 183.7, 130.0,
128.3, 42.8, 32.6, 26.1, 24.6, 19.4; HRMS ES m/z
Ozone was passed through a cold (ꢀ78 C) solution of 21
(4.0 g, 10.98 mmol) in a 1:1 mixture of CH2Cl2 and
MeOH (130 mL each). After the reaction was over, PPh3
(3.17 g, 12.09 mmol) was added and the mixture was stirred
at rt for 4 h. The solvent was evaporated under vacuum; the
residue was further evaporated with benzene (250 mL), and
redissolved in benzene (250 mL). To this solution was added
p-TꢁsOH (0.63 g, 3.29 mmol) and the mixture was heated to
65 C for 20 h. The solvent was removed and the residue
was purified by column chromatography on silica gel (elu-
tion with 5:1 hexane–ethyl acetate) to give 3.36 g (81%
over two steps) of 22 as a colorless oil; IR (neat, cmꢀ1
)
1
1681, 1105; H NMR (250 MHz, CDCl3) d 9.75 (s, 1H),
7.71–7.63 (m, 4H), 7.48–7.36 (m, 6H), 6.90–6.61 (m, 1H),
3.55 (s, 2H), 2.58–2.52 (m, 2H), 2.02–1.94 (m, 1H), 1.73–
1.59 (m, 1H), 1.17 (s, 3H), 1.07 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 190.4, 158.5, 146.3, 135.7 (4C), 133.5
25
(M+Na)+ calcd 140.0832, obsd 140.0824; ½aꢃD ꢀ100.9 (c
1.2, CHCl3).

S. Pichlmair et al. / Tetrahedron 62 (2006) 5178–5194
5185
(2C), 129.7 (2C), 127.7 (4C), 70.4, 52.6, 33.4, 27.6, 26.8
(3C), 22.7, 19.3; HRMS ES m/z (M+Na)+ calcd 401.1907,
25.6; HRMS ES m/z (M+Na)+ calcd 283.1305, obsd
283.1306.
25
obsd 401.1900; ½aꢃD ꢀ40.4 (c 0.6, CHCl3).
4.7. Benzoic acid 7-iodomethyloct-7-enyl ester (25)
4.5. (S)-3-(tert-Butyldiphenylsilanyloxymethyl)-3-methyl-
cyclopent-1-enecarboxylic acid (16)
ꢁ
To a cold (ꢀ20 C), stirred solution of 24 (31.7 g,
115.8 mmol) in anhydrous MeOH (250 mL) was added
NaBH4 (4.4 g, 115.8 mꢁmol) in portions. The resulting mix-
ture was stirred at ꢀ20 C for 30 min before being quenched
with 10% HCl solution (200 mL). The mixture was extracted
with CH2Cl2 (4ꢂ300 mL). The combined organic layers
were dried and evaporated to leave a residue that was purified
by column chromatography (elution with 4:1 petroleum
ether–ethyl acetate) to afford 31.0 g (91%) of the alcohol
To a stirred mixture of 22 (3.0 g, 7.94 mmol) and 2-methyl-
2-butene (5.57 g, 79.4 mmol) in t-BuOH (20 mL) was added
an aqueous solution of NaClO2 (2.87 g, 31.8 mmol) and
NaH2PO4 (3.29 g, 23.8 mmol) in H2O (20 mL). The result-
ing solution was stirred at rt overnight before it was
quenched with 10% HCl solution to reach pH 5.0. The aque-
ous layer was extracted with EtOAc (5ꢂ50 mL), and
the combined organic phases were dried and evaporated
to leave a residue that was purified by column chromato-
graphy on silica gel (elution with 5:1 hexane–ethyl acetate)
to afford 2.94 g (94%) of 16 as a colorless liquid; IR
(neat, cmꢀ1) 2858, 1684, 1280; 1H NMR (300 MHz,
CDCl3) d 7.67–7.63 (m, 4H), 7.46–7.35 (m, 6H), 6.73–
6.71 (m, 1H), 3.53–3.46 (m, 2H), 2.64–2.58 (m, 2H),
2.05–1.96 (m, 1H), 1.71–1.61 (m, 1H), 1.15 (s, 3H), 1.06
(s, 9H); 13C NMR (75 MHz, CDCl3) d 170.6, 152.1, 135.6
(4C), 135.1, 133.5 (2C), 129.6 (2C), 127.6 (4C), 70.4,
52.5, 33.7, 30.3, 26.8 (3C), 22.7, 19.3; HRMS ES m/z
as a colorless oil; IR (neat, cmꢀ1) 3422, 1720, 1118; H
1
NMR (300 MHz, CDCl3) d 8.07–8.03 (m, 2H), 7.57–7.54
(m, 1H), 7.48–7.42 (m, 2H), 5.02 (s, 1H), 4.88 (s, 1H),
4.33 (t, J¼6.6 Hz, 2H), 4.08 (d, J¼5.8 Hz, 2H), 2.12–2.06
(m, 2H), 1.81–1.76 (m, 2H), 1.54–1.40 (m, 6H); 13C NMR
(75 MHz, CDCl3) d 166.4, 148.7, 132.5, 130.0, 129.2 (2C),
128.0 (2C), 108.5, 65.1, 64.7, 32.5, 28.7, 28.3, 27.2, 25.5;
HRMS ES m/z (M+Na)+ calcd 285.1461, obsd 285.1473.
ꢁ
To a cold (ꢀ78 C), stirred solution of the above alcohol
(14.7 g, 53.15 mmol) in dry CH2Cl2 (150 mL) was added
Et3N (10.8 g, 106.3 mmol) followed by MsCl (12.2 g,
106.3 mmol) under N2. The resulting solution was slowly
25
(M+Na)+ calcd 417.1856, obsd 417.1876; ½aꢃD +18.3 (c
1.3, CHCl3).
ꢁ
ꢁ
warmed to 0 C and stirred at 0 C for 1.5 h before being
quenched with 10% HCl (100 mL). The separated aqueous
layer was extracted with CH2Cl2 (4ꢂ100 mL). The com-
bined organic layers were dried and evaporated to leave a
residue that was dissolved in dry THF (100 mL) and treated
4.6. Benzoic acid 7-formyl-oct-7-enyl ester (24)
ꢁ
To a cold (ꢀ78 C), stirred solution of oxalyl chloride
ꢁ
(48.2 g, 0.38 mol) in dry CH2Cl2 (400 mL) was added a solu-
tion of DMSO (44.5 g, 0.57 mol) in dry CH2Cl2 (300 mL)
under N2. After 30 min of stirring, a solution of the mono-
benzoate of 1,8-octanediol (48.0 g, 0.19 moꢁl) in dry
CH2Cl2 (300 mL) was added over 30 min at ꢀ78 C. The re-
with anhydrous LiBr (9.2 g, 106.2 mmol) at 0 C. The mix-
ture was stirred at rt for 2 h before it was filtered through
a pad of silica gel. The solid residue was washed with
Et2O (4ꢂ100 mL) and the combined filtrates were evapo-
rated under vacuum to afford a yellow residue, which was
purified by column chromatography on silica gel (elution
with 40:1 hexane–ethyl acetate) to furnish 14.60 g (81%
over two steps) of the allylic bromide as a light yellow oil;
ꢁ
sulting cloudy solution was stirred at ꢀ78 C for 1 h before
Et3N (96.0 g, 0.95 mol) was introduced. The cold baꢁth was
removed and the mixture was allowed to warm to 0 C be-
fore being quenched with a saturated solution of NH4Cl
(500 mL). The separated aqueous phase was extracted with
CH2Cl2 (3ꢂ500 mL). The organic layers were combined,
dried, and evaporated to leave a yellow residue that was pu-
rified by column chromatography on silica gel (elution with
5:1 petroleum ether–ethyl acetate) to afford 42.4 g (90%) of
the saturated aldehyde as a colorless oil.
IR (neat, cmꢀ1) 1721, 1451, 1275; H NMR (300 MHz,
1
CDCl3) d 8.07–8.03 (m, 2H), 7.59–7.53 (m, 1H), 7.47–
7.41 (m, 2H), 5.16 (s, 1H), 4.96 (s, 1H), 4.32 (t,
J¼6.64 Hz, 2H), 3.97 (s, 2H), 2.25–2.20 (m, 2H), 1.83–
1.74 (m, 2H), 1.56–1.35 (m, 6H); 13C NMR (75 MHz,
CDCl3) d 166.4, 145.3, 132.6 (2C), 130.3, 129.4, 128.2
(2C), 114.8, 64.8, 36.7, 33.0, 28.7, 28.5, 27.0, 25.7.
A
Et2NH HCl (5.6 g, 68.2 mmol), and CH2O (5.53 mL of
37% aqueous solution, 68.2 mmol) was heated to 110 C
mixture of above aldehyde (13.0 g, 52.4 mmol),
$
To a stirred solution of the above product (10.0 g,
30.8 mmol) in acetone (50 mL) was added NaI (6.92 g,
46.15 mmol) at rt. The resulting cloudy solution was stirred
in the dark for 24 h before being quenched with H2O
(50 mL). The resulting solution was extracted with Et2O
(3ꢂ100 mL). The combined organic layers were evaporated
under vacuum to give 11.0 g of crude 25 as an orange oil; IR
(neat, cmꢀ1) 1716, 1451, 1271; 1H NMR (250 MHz, CDCl3)
d 8.08–8.04 (m, 2H), 7.57–7.54 (m, 1H), 7.48–7.42 (m, 2H),
5.24 (s, 1H), 4.92 (s, 1H), 4.34 (t, J¼6.61 Hz, 2H), 3.94 (s,
2H), 2.27–2.24 (m, 2H), 1.80–1.78 (m, 2H), 1.55–1.43 (m,
6H); 13C NMR (75 MHz, CDCl3) d 166.0, 145.9, 132.4
(2C), 130.1, 129.1, 128.0 (2C), 113.1, 64.6, 33.5, 28.5,
28.3, 26.8, 25.5; HRMS ES m/z (M+Na)+ calcd 395.0478,
obsd 395.0475.
ꢁ
for 16 h, cooled to rt, diluted with H2O (200 mL), and ex-
tracted with CH2Cl2 (4ꢂ200 mL). The organic layers were
combined, dried, and evaporated to leave a yellow residue
that was purified by column chromatography on silica gel
(elution with 10:1 petroleum ether–ethyl acetate) to yield
10.6 g (74%) of 24 as colorless oil; IR (neat, cmꢀ1) 1718,
1
1692, 1117; H NMR (300 MHz, CDCl3) d 9.53 (s, 1H),
8.05–8.02 (m, 2H), 7.58–7.53 (m, 1H), 7.46–7.41 (m, 2H),
6.25 (s, 1H), 5.99 (s, 1H), 4.33–4.29 (m, 2H), 2.28–2.23
(m, 2H), 1.79–1.72 (m, 2H), 1.51–1.35 (m, 6H); 13C NMR
(75 MHz, CDCl3) d 194.4, 166.3, 149.9, 133.8, 132.6,
130.2, 129.3 (2C), 128.1 (2C), 64.7, 28.7, 28.4, 27.5, 27.4,

5186
S. Pichlmair et al. / Tetrahedron 62 (2006) 5178–5194
4.8. Benzoic acid (R)-9-hydroxymethyl-7-methylenedo-
dec-11-enyl ester (27)
(20 mL each). After the reaction was complete, PPh3
(3.17 g, 12.09 mmol) was added and the mixture was stirred
at rt for 6 h. The solvent was evaporated under vacuum, the
residue was further evaporated with benzene (60 mL), and
redissolved in benzene (60 mL). To this solution was added
p-TꢁsOH (0.20 g, 1.04 mmol) and the mixture was heated to
65 C for 15 h. The solvent was removed and the residue
was purified by column chromatography on silica gel (elu-
tion with 5:1 hexane–Et2O) to afford 0.52 g (65% over two
steps) of 29 as a colorless oil; IR (neat, cmꢀ1) 1720, 1674,
ꢁ
To a cold (ꢀ78 C), stirred solution of 26 (1.8 g, 6.95 mmol)
in dry THF (24 mL) was added NaHMDS (7.3 mL of 1.0 M
solution in THF, 7.3 mmol) slowly over 5 min under N2. Af-
ter 45 min of stirring at this temperature, a solution of 25
(1.27 g, 3.42 mmol) in THF (12 mL) was introduced. The re-
ꢁ
sulting mixture was stirred for 5 h at ꢀ78 C before being
quenched with saturated NH4Cl solution (30 mL). The mix-
ture was allowed to warm to rt, stirred for an additional
10 min, and diluted with H2O (50 mL). The separated aque-
ous layer was extracted with CH2Cl2 (3ꢂ30 mL) and the
combined organic layers were dried and evaporated to leave
a residue thatꢁwas dissolved in anhydrous MeOH (90 mL).
To a cold (0 C) flask of this solution was added NaBH4
(1.3 g, 34.4 mmol) in portions and the resulting solution
1
1480; H NMR (300 MHz, CDCl3) d 8.06–8.03 (m, 2H),
7.59–7.53 (m, 1H), 7.47–7.42 (m, 2H), 6.70–6.68 (m, 1H),
4.32 (t, J¼6.6 Hz, 2H), 4.03–4.00 (m, 2H), 2.60–2.53 (m,
1H), 2.46–2.39 (m, 2H), 2.28–2.18 (m, 4H), 1.81–1.77 (m,
2H), 1.48–1.43 (m, 4H), 1.22 (s, 9H); 13C NMR (75 MHz,
CDCl3) d 198.0, 178.2, 166.6, 143.2, 139.7, 132.8 (2C),
130.5, 129.5 (2C), 128.3, 66.9, 64.9, 41.2, 38.8, 34.9, 29.2,
28.8, 28.5, 28.2, 27.2 (3C), 25.7; HRMS ES m/z (M+Na)+
ꢁ
was allowed to stir at 0 C overnight prior to quenching
20
with saturated NH4Cl solution (100 mL) followed by H2O
(100 mL). The mixture was extracted with CH2Cl2
(4ꢂ200 mL) and the combined organic layers were dried
and evaporated to yield a residue that was purified by column
chromatography on silica gel (elution with 5:1 hexane–ethyl
acetate) to afford 0.68 g (60% over two steps) of 27 as a col-
orless oil; IR (neat, cmꢀ1) 3424, 1721, 1641, 1176; 1H NMR
(250 MHz, CDCl3) d 8.07–8.03 (m, 2H), 7.56–7.52 (m, 1H),
7.47–7.27 (m, 2H), 5.84–5.77 (m, 1H), 5.10–5.01 (m, 2H),
4.80–4.77 (m, 2H), 4.32 (t, J¼6.6 Hz, 2H), 3.55 (d,
J¼5.3 Hz, 2H), 2.13–2.00 (m, 6H), 1.84–1.75 (m, 3H),
1.50–1.37 (m, 6H); 13C NMR (75 MHz, CDCl3) d 166.7,
148.1, 136.8, 132.8, 130.4, 129.5 (2C), 128.3 (2C), 116.4,
110.9, 65.5, 65.0, 38.14, 38.10, 35.7, 35.4, 28.9, 28.6,
27.4, 25.9; HRMS ES m/z (M+Na)+ calcd 353.2087, obsd
calcd 423.2142, obsd 423.2112; ½aꢃD ꢀ3.0 (c 1.2, CHCl3).
4.11. Benzoic acid 5-[(4R,6R)-4-(2,2-dimethylpropionyl-
oxy methyl)-6-(5-methoxybenzyloxy) cyclohex-1-enyl]-
pentyl ester (30)
To a mixture of 29 (1.0 g, 2.5 mmol) and CeCl3 7H2O
$
(1.4 g, 3.8 mmol) in anhydrous MeOH (20 mL) was added
NaBH4 (0.12 g, 3.0 mmol) in portions at 0 C. After being
ꢁ
stirred at 0 C for 1 h, the reaction mixture was quenched
ꢁ
with saturated NH4Cl solution (40 mL). The aqueous layer
was extracted with CH2Cl2 (3ꢂ40 mL). The combined or-
ganic layers were dried and evaporated to leave a residue
that was purified by column chromatography on silica gel
(elution with 5:1 petroleum ether–ethyl acetate) to afford
0.93 g (92%) of the allylic alcohol as a colorless oil; IR
(neat, cmꢀ1) 3503, 1721, 1480; 1H NMR (300 MHz,
CDCl3) d 8.07ꢀ8.03 (m, 2H), 7.59–7.53 (m, 1H), 7.48–
7.42 (m, 2H), 5.49–5.46 (m, 1H), 4.36–4.28 (m, 3H), 3.97
(d, J¼6.0 Hz, 2H), 2.30–2.28 (m, 1H), 2.16–2.00 (m, 5H),
1.82–1.78 (m, 3H), 1.49–1.31 (m, 4H), 1.21 (s, 9H); 13C
NMR (75 MHz, CDCl3) d 177.6, 165.8, 139.5, 131.9 (2C),
130.2, 128.6 (2C), 127.4, 121.5, 67.5, 67.2, 64.1, 38.0,
35.4, 32.1, 31.5, 27.8, 27.7, 26.5, 26.3 (3C), 24.9; HRMS
20
353.2061; ½aꢃD +0.3 (c 1.0, CHCl3).
4.9. Benzoic acid (R)-9-(2,2-dimethylpropionyloxy-
methyl)-7-methylenedodec-11-enyl ester (28)
ꢁ
To a cold (0 C), stirred solution of 27 (1.7 g, 5.15 mmol) in
dry CH2Cl2 (30 mL) was added pyridine (1.2 g, 15.5 mmol)
followed by PivCl (1.24 g, 10.3 mmol). The mixture was
stirred at rt overnight prior to quenching with 10% HCl
(30 mL). The separated aqueous layer was extracted with
CH2Cl2 (3ꢂ30 mL). The combined organic layers were dried
andevaporatedtoobtaina residuethat waspurifiedbycolumn
chromatography on silica gel (elution with 20:1 hexane–ethyl
acetate) to provide 1.98 g (93%) of 28 as a colorless oil; IR
(neat, cmꢀ1) 1724, 1641, 1160; 1H NMR (300 MHz,
CDCl3) d 8.06–8.03 (m, 2H), 7.58–7.53 (m, 1H), 7.46–7.41
(m, 2H), 5.82–5.70 (m, 1H), 5.06–4.99 (m, 2H), 4.77 (d,
J¼15.5 Hz, 2H), 4.32 (t, J¼6.62 Hz, 2H), 3.99–3.91 (m,
2H), 2.13–1.94 (m, 7H), 1.80–1.73 (m, 2H), 1.55–1.33 (m,
6H), 1.21 (s, 9H); 13C NMR (75 MHz, CDCl3) d 178.2,
166.4, 146.8, 135.8, 132.6 (2C), 131.3, 129.4 (2C), 128.2,
116.7, 111.3, 65.8, 64.8, 38.9, 37.6, 35.4, 35.3, 35.2, 28.8,
28.6, 27.4, 27.1 (3C), 25.8; HRMS ES m/z (M+Na)+ calcd
20
ES m/z (M+Na)+ calcd 425.2298, obsd 425.2285; ½aꢃD
ꢀ24.1 (c 1.1, CHCl3).
ꢁ
To a cold (0 C), stirred mixture of the above alcohol
(2.15 g, 5.35 mmol) and p-methoxybenzyl trichloroacetimi-
date (2.27 g, 8.02 mmol) in dry Et2O (72 mL) was added
TfOH (0.16 mL, 0.16 mmol). The resulting mixture was
stirred at rt for 5 h prior to quenching with a saturated
NaHCO3 solution (20 mL) followed by H2O (100 mL).
The separated aqueous layer was extracted with Et2O
(3ꢂ50 mL), the combined organic layers were dried and
evaporated, and the residue was purified by column chroma-
tography on silica gel (elution with 10:1 petroleum ether–
ethyl acetate) to afford 2.23 g (80%) of 30 as a colorless
oil; IR (neat, cmꢀ1) 1721, 1612, 1160; 1H NMR
(250 MHz, CDCl3) d 8.07–8.03 (m, 2H), 7.57–7.53 (m,
1H), 7.47–7.41 (m, 2H), 7.29–7.25 (m, 2H), 6.89–6.85 (m,
2H), 5.52–5.49 (m, 1H), 4.59 (d, J¼11.3 Hz, 1H), 4.40 (d,
J¼11.3 Hz, 1H), 4.38–4.29 (m, 2H), 4.03–3.98 (m, 3H),
3.79 (s, 3H), 2.30–1.76 (m, 8H), 1.49–1.36 (m, 5H), 1.21
(s, 9H); 13C NMR (75 MHz, CDCl3) d 178.5, 166.6, 159.0,
20
437.2662, obsd 437.2681; ½aꢃD ꢀ3.0 (c 1.2, CHCl3).
4.10. Benzoic acid 5-[(R)-4-(2,2-dimethylpropionyloxy
methyl)-6-oxocyclohex-1-enyl]-pentyl ester (29)
ꢁ
(0.82 g, 1.99 mmol) in a 1:1 mixture of CH2Cl2/MeOH
Ozone was passed through a cold (ꢀ78 C) solution of 28

S. Pichlmair et al. / Tetrahedron 62 (2006) 5178–5194
5187
139.2, 132.8, 130.7, 130.4, 129.5 (2C), 129.2 (2C), 128.3
(2C), 123.0, 113.7, (2C), 74.4, 70.1, 68.2, 65.0, 55.2, 38.8,
32.73, 32.70, 31.5, 28.6, 28.5, 27.4, 27.2 (3C), 25.8;
HRMS ES m/z (M+Na)+ calcd 545.2874, obsd 545.2842;
½aꢃD ꢀ34.8 (c 0.8, CHCl3).
4.89 mmol) followed by TBSCl (0.37 g, 2.44 mmol). The
mixture was stirred at rt for 1 h before it was quenched
with H2O (20 mL). The separated aqueous layer was ex-
tracted with CH2Cl2 (3ꢂ15 mL). The organic layers were
combined, dried, and evaporated to leave a residue that
was purified by column chromatography on silica gel (elu-
tion with 15:1 petroleum ether–ethyl acetate) to afford
1.0 g (94%) of 32 as a colorless oil; IR (neat, cmꢀ1) 1713,
20
4.12. Benzoic acid 5-[(3S,5R)-3-(2,2-dimethylpropionyl-
oxy methyl)-2-formyl-5-(4-methoxybenzyloxy)cyclo-
pent-1-enyl]pentyl ester (31)
1
1613, 1169; H NMR (300 MHz, CDCl3) d 8.09–8.03 (m,
2H), 7.57–7.53 (m, 1H), 7.47–7.41 (m, 2H), 7.27–7.24 (m,
2H), 6.88–6.85 (m, 2H), 4.53 (d, J¼11.6 Hz, 1H), 4.38–
4.27 (m, 6 H), 4.16 (d, J¼12.5 Hz, 1H), 4.08–3.91 (m,
1H), 3.79 (s, 3 H), 3.02–3.95 (m, 1H), 2.29–2.12 (m, 3 H),
1.78–1.70 (m, 2H), 1.64–1.55 (m, 1H), 1.48–1.39 (m, 4H),
1.19 (s, 9H), 0.88 (s, 9 H), 0.07–0.03 (m, 6 H); 13C NMR
(75 MHz, CDCl3) d 178.4, 166.5, 159.0, 140.5, 138.2,
132.7 (2C), 130.9, 130.4, 129.4, 129.2 (2C), 128.2 (2C),
113.6 (2C), 83.8, 70.4, 66.6, 64.6, 58.1, 54.9, 43.5, 38.6,
32.6, 28.4, 27.6, 27.0 (3C), 25.9, 25.7 (3C), 25.6, 18.0,
ꢀ5.6 (2C); HRMS ES m/z (M+Na)+ calcd 675.3688, obsd
To a stirred solution of 30 (1.3 g, 2.49 mmol) in a 1:1 mix-
ture of CH2Cl2/MeOH (30 mL each) was passed O3 at
ꢁ
ꢀ78 C. After reaction was complete, PPh3 (0.72 g,
2.74 mmol) was added and the resulting mixture was stirred
at rt for 4 h. Solvent was evaporated under vacuum, the resi-
due was further evaporated with Et2O (75 mL), and redis-
solved in Et2O (75 mL). To this solution was added
piperidine (78 mg, 0.92 mmol) and the resulting mixture
was stirred at rt before HOAc (97 mg, 1.62 mmol) was
added. The mixture was heated to reflux for 20 h, the solvent
was removed under vacuum, and the residue was purified by
column chromatography on silica gel (elution with 5:1 pe-
troleum ether–ether) to afford 1.06 g (80%) of 31 as a color-
20
675.3660; ½aꢃD ꢀ17.4 (c 0.06, CHCl3).
4.14. 2,2-Dimethylpropionic acid (1S,4R)-2-(tert-butyl-
dimethylsilanyloxymethyl)-4-(4-methoxybenzyloxy)-3-
[5-(2-methoxyethoxymethoxy) pentyl]cyclopent-2-enyl-
methyl ester (33)
1
less liquid; IR (neat, cmꢀ1) 1719, 1671, 1611; H NMR
(250 MHz, CDCl3) d 10.04 (s, 1H), 8.06–8.02 (m, 2H),
7.57–7.54 (m, 1H), 7.48–7.42 (m, 2H), 7.28–7.24 (m, 2H),
6.90–6.86 (m, 2H), 4.60 (d, J¼11.5 Hz, 1H), 4.51–4.48
(m, 1H), 4.42–4.29 (m, 4 H), 4.20–4.13 (m, 1H), 3.79 (s,
3H), 3.20–3.12 (m, 1H), 2.79–2.54 (m, 2H), 2.35–2.21 (m,
1H), 1.76–1.45 (m, 7H), 1.18 (s, 9H); 13C NMR (75 MHz,
CDCl3) d 188.7, 178.3, 166.5, 165.1, 137.7, 132.9, 130.3,
129.9, 129.54 (2C), 129.50 (2C), 128.3 (2C), 113.8 (2C),
82.7, 71.4, 65.5, 64.5, 55.2, 41.4, 38.8, 32.2, 28.4, 28.1,
27.1 (3C), 26.0, 25.8; HRMS ES m/z (M+Na)+ calcd
To a stirred solution of 32 (1.0 g, 1.53 mmol) in anhydrous
MeOH (60 mL) was added K2CO3 (1.06 g, 7.65 mmol).
The mixture was stirred at rt overnight before it was
quenched with saturated NH4Cl solution (30 mL). The mix-
ture was extracted with EtOAc (4ꢂ40 mL). The combined
organic layers were dried and evaporated to leave a residue
that was purified by column chromatography on silica gel
(elution with 2:1 petroleum ether–ethyl acetate) to afford
0.78 g (94%) of the primary alcohol as a colorless oil; IR
(neat, cmꢀ1) 3443, 1731, 1613; 1H NMR (300 MHz,
CDCl3) d 7.28–7.23 (m, 2H), 6.89–6.84 (m, 2H), 4.53 (d,
J¼11.5 Hz, 1H), 4.43–4.26 (m, 4H), 4.15 (d, J¼12.4 Hz,
1H), 4.05–3.80 (m, 1H), 3.80 (s, 3 H), 3.62–3.57 (m, 2H),
2.99–2.95 (m, 1H), 2.30–2.20 (m, 1H), 2.15–2.11 (m, 2H),
1.64–1.50 (m, 3H), 1.37–1.18 (m, 13H), 0.88 (s, 9H),
0.06–0.03 (m, 6H); 13C NMR (75 MHz, CDCl3) d 178.4,
159.0, 140.6, 138.1, 130.9, 129.2 (2C), 113.6 (2C), 83.8,
70.5, 66.7, 62.6, 58.2, 55.1, 43.5, 38.7, 32.7, 32.5, 27.8,
27.1 (3C), 26.0, 25.76 (3C), 25.70, 18.1, ꢀ5.5 (2C);
HRMS ES m/z (M+Na)+ calcd 571.3425, obsd 571.3434;
20
559.2666, obsd 559.2646; ½aꢃD +7.1 (c 0.7, CHCl3).
4.13. Benzoic acid 5-[(3S,5R)-2-(tert-butyldimethylsila-
nyloxy methyl)-3-(2,2-dimethylpropionyloxymethyl)-5-
(4-methoxybenzyloxy)cyclopent-1-enyl]pentyl ester (32)
ꢁ
To a cold (0 C), stirred solution of 31 (0.49 g, 0.91 mmol) in
anhydrous MeOH (25 mL) was added NaBH4 (70 mg,
1.85 mmol) in portions. The resulting mixture was stirred
ꢁ
at 0 C for 20 min prior to quenching with saturated
NH4Cl solution (30 mL), and extracted with CH2Cl2
(4ꢂ50 mL). The organic layers were combined, dried, and
evaporated to leave a residue that was purified by column
chromatography on silica gel (elution with 4:1 petroleum
ether–ethyl acetate) to afford 0.49 g (100%) of the allylic al-
cohol as a colorless oil; IR (neat, cmꢀ1) 3475, 1722, 1612; 1H
NMR (300 MHz, CDCl3) d 8.06–8.03 (m, 2H), 7.59–7.54
(m, 1H), 7.47–7.42 (m, 2H), 7.27–7.23 (m, 2H), 6.89–6.84
(m, 2H), 4.54 (d, J¼11.4 Hz, 1H), 4.44–4.11 (m, 8H), 3.79
(s, 3H), 3.00–2.95 (m, 1H), 2.33–2.18 (m, 3H), 1.77–1.72
(m, 3 H), 1.47–1.42 (m, 4H), 1.21 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 178.2, 166.3, 158.8, 141.8, 138.0,
132.5 (2C), 130.5, 130.1, 129.2 (2C), 128.9 (2C), 128.0
(2C), 113.4, 83.3, 70.4, 66.7, 64.5, 57.0, 54.8, 43.2, 38.5,
32.5, 28.2, 27.5, 26.8 (3C), 25.6; HRMS ES m/z (M+Na)+
20
½aꢃD ꢀ21.3 (c 0.08, CHCl3).
To a stirred solution of the above alcohol (1.29 g,
2.35 mmol) in dry CH2Cl2 (7 mL) was added i-Pr2NEt
(0.91 g, 7.05 mmol) followed by MEMCl (0.59 g,
ꢁ
4.70 mmol) at 0 C under N2. The resultant solution was
stirred at rt for 18 h before it was quenched with 10% HCl
(10 mL). The separated aqueous phase was extracted with
CH2Cl2 (2ꢂ10 mL). The combined organic layers were
dried and evaporated to provide a residue, which was puri-
fied by column chromatography on silica gel (elution with
5:1 petroleum ether–ether) to afford 1.39 g (93%) of 33 as
a colorless oil; IR (neat, cmꢀ1) 1726, 1612, 1251; 1H
NMR (300 MHz, CDCl3) d 7.29–7.27 (m, 2H), 6.94–6.90
(m, 2H), 4.76 (s, 2H), 4.60–4.56 (m, 1H), 4.49–4.31 (m,
4H), 4.23–4.19 (m, 1H), 4.10–4.04 (m, 1H), 3.86 (s, 3H),
20
calcd 561.2823, obsd 561.2800; ½aꢃD ꢀ20.0 (c 0.1, CHCl3).
To a stirred solution of above alcohol (0.88 g, 1.63 mmol)
in dry CH2Cl2 (15 mL) was added imidazole (0.33 g,

5188
S. Pichlmair et al. / Tetrahedron 62 (2006) 5178–5194
3.79–3.73 (m, 2H), 3.64–3.45 (m, 4H), 3.45 (s, 3H), 3.11–
2.94 (m, 1H), 2.35–2.25 (m, 1H), 2.20–2.16 (m, 2H),
1.70–1.60 (m, 3H), 1.49–1.27 (m, 4H), 1.24 (s, 9H), 0.93
(s, 9 H), 0.12–0.08 (m, 6H); 13C NMR (75 MHz, CDCl3)
d 178.4, 159.0, 140.6, 138.1, 131.0, 129.1 (2C), 113.6
(2C), 95.4, 83.9, 71.7, 70.5, 67.8, 66.8, 66.6, 58.9, 58.2,
55.2, 43.6, 38.7, 32.8, 29.5, 28.1, 27.2 (3C), 26.3, 26.1,
25.8 (3C), 18.2, ꢀ5.4, ꢀ5.5; HRMS ES m/z (M+Na)+ calcd
(75 MHz, CDCl3) d 165.3, 158.9, 148.9, 140.7, 138.3,
135.7, 135.6 (4C), 133.5, 133.4, 130.8, 129.52, 129.49,
129.1 (2C), 127.5 (4C), 113.6 (2C), 95.3, 83.7, 71.7, 70.4,
67.7, 67.1, 66.5, 58.9, 58.2, 55.1, 52.1, 43.6, 33.7, 32.8,
30.6, 30.2, 29.5, 27.9, 26.7 (3C), 26.3, 26.1, 25.8 (3C),
22.7, 19.2, 18.1, ꢀ5.5 (2C); HRMS ES m/z (M+Na)+ calcd
951.5233, obsd 951.5210.
20
659.3949, obsd 659.3914; ½aꢃD ꢀ15.1 (c 1.7, CHCl3).
4.17. (S)-3-(tert-Butyldiphenylsilanyloxy)-3-methylcy-
clopent-1-enecarboxylic acid (1S,4R)-2-hydroxymethyl-
4-(4-methoxybenzyloxy)-3-[5-(2-methoxyethoxy-
methoxy)pentyl]cyclopent-2-enylmethyl ester (36)
4.15. (S)-3-(tert-Butyldiphenylsilanyloxymethyl)-3-
methylcyclopent-1-enecarboxylic acid (1S,4R)-2-(tert-
dimethylsilanyloxymethyl)-4-(4-methoxybenzyloxy)-3-
[5-(2-methoxyethoxymethoxy)pentyl]cyclopent-2-enyl-
methyl ester (34)
To a stirred solution of 35 (0.57 g, 0.61 mmol) in a 1:1 mix-
ꢁ
ture of CH2Cl2/MeOH (10 mL each) at 0 C was aꢁdded CSA
(0.14 g, 0.61 mmol). The mixture was stirred at 0 C for 1 h,
quenched with saturated NaHCO3 solution (20 mL), and ex-
tracted with CH2Cl2 (3ꢂ20 mL). The organic layers were
combined, dried, and evaporated to leave a residue, purifica-
tion of which by chromatography on silica gel (elution with
1:1 petroleum ether–ether) afforded 0.46 g (92%) of 36 as
a colorless oil; IR (neat, cmꢀ1) 3482, 1714, 1613; 1H
NMR (300 MHz, CDCl3) d 7.65–7.61 (m, 4H), 7.44–7.34
(m, 6H), 7.26–7.23 (m, 2H), 6.91–6.83 (m, 2H), 6.60–6.59
(m, 1H), 4.70 (s, 2H), 4.55–4.51 (m, 1H), 4.41–4.16 (m,
6H), 3.79 (s, 3H), 3.70–3.66 (m, 2H), 3.57–3.48 (m, 6H),
3.39 (s, 3H), 3.08–2.92 (m, 1H), 2.61–2.56 (m, 2H), 2.27–
2.26 (m, 1H), 2.20–2.15 (m, 2H), 2.00–1.96 (m, 1H),
1.66–1.55 (m, 4H), 1.44–1.26 (m, 3H), 1.26 (s, 3H), 1.06
(s, 9H); 13C NMR (75 MHz, CDCl3) d 165.3, 159.1, 149.5,
142.3, 138.6 (2C), 135.5 (2C), 133.5, 130.8, 129.5 (4C),
129.2 (4C), 127.6 (2C), 113.7 (2C), 95.4, 83.4, 71.8, 70.6,
70.4, 67.7, 67.3, 66.7, 58.9, 57.7, 55.2, 52.2, 43.5, 33.7,
32.8, 30.6, 29.6, 27.7, 26.8 (3C), 26.0, 25.7, 22.7, 19.3
(2C); HRMS ES m/z (M+Na)+ calcd 837.4368, obsd
To a stirred solution of 33 (0.62 g, 0.97 mmol) in dry CH2Cl2
(10 mL) was added DIBAL-ꢁH (2.43 mL of 1.0 M solution in
hexane, 2.43 mmol) at ꢀ78 C under N2. The resultant solu-
ꢁ
ꢁ
tion was stirred at ꢀ78 C for 0.5 h and at 0 C for 1 h
before it was quenched with a saturated solution of
potassium sodium tartrate (10 mL). The resultant cloudy so-
lution was stirred at rt overnight, diluted with water (20 mL),
and extracted with CH2Cl2 (3ꢂ15 mL). The combined or-
ganic layers were dried, and evaporated to provide a residue
that was purified by column chromatography on silica gel
(elution with 2:1 petroleum ether–ethyl acetate) to furnish
0.42 g (78%) of 34 as a colorless oil; IR (neat, cmꢀ1
)
3457, 1612, 1514, 1249; 1H NMR (300 MHz, CDCl3)
d 7.28–7.23 (m, 2H), 6.91–6.84 (m, 2H), 4.71 (s, 2H),
4.58–4.53 (m, 1H), 4.39–4.29 (m, 3H), 4.15–4.11 (m, 1H),
3.80 (s, 3H), 3.74–3.66 (m, 2H), 3.57–3.48 (m, 6H), 3.40
(s, 3H), 2.82–2.68 (m, 1H), 2.27–2.09 (m, 3H), 1.61–1.50
(m, 3H), 1.43–1.29 (m, 4H), 0.88 (s, 9H), 0.09 (s, 6H); 13C
NMR (75 MHz, CDCl3) d 159.8, 141.7, 138.7, 130.5,
129.3 (2C), 113.6 (2C), 95.4, 82.9, 71.7, 70.6, 67.7, 66.6,
64.5, 58.9, 58.5, 55.2, 47.6, 32.5, 29.5, 28.0, 26.3, 26.0,
25.8 (3C), 18.2, ꢀ5.4, ꢀ5.5; HRMS ES m/z (M+Na)+ calcd
20
837.4348; ½aꢃD ꢀ24.5 (c 1.08, CHCl3).
4.18. (S)-3-(tert-Butyldiphenylsilanyloxymethyl)-3-
methylcyclopent-1-ene carboxylic acid (1S,4R)-2-bromo-
methyl-4-(4-methoxybenzyloxy)-3-[5-(2-methoxyethoxy-
methoxy)pentyl]cyclopent-2-enyl methyl ester (37)
20
575.3375, obsd 575.3362; ½aꢃD ꢀ31.5 (c 0.72, CHCl3).
4.16. (S)-3-(tert-Butyldiphenylsilanyloxymethyl)-3-
methylcyclopent-1-ene carboxylic acid (1S,4R)-2-(tert-
butyldimethylsilanyloxymethyl)-4-(4-methoxybenzyl-
oxy)-3-[5-(2-methoxyethoxymethoxy)pentyl]cyclopent-
2-enyl methyl ester (35)
To a solution of 36 (30 mg, 0.036 mmol) in dry CH2Cl2
(1 mL) was added freshly distilled Et3N (0.01 mL,
0.074 mmol) followed by MsCl (6 mL, 0.074 mmol) at
ꢁ
ꢁ
0 C under N2. The mixture was stirred at 0 C for 30 min
and quenched with 1 N HCl (2 mL) followed by H2O
(1 mL). The separated aqueous phase was washed with
CH2Cl2 (2ꢂ5 mL). The combined CH2Cl2 layers were dried
and concentrated under vacuum to provide the allyl mesylate
as yellowish oil.
To a mixture of alcohol 34 (0.25 g, 0.46 mmol), 1-[3-(di-
methylamino)propyl]-3-ethylcarbodiimide hydrochloride
(0.26 g, 1.38 mmol), and DMAP (0.06 g, 0.46 mmol) in
dry CH2Cl2 (5 mL) was added a solution of 34 (0.18 g,
0.46 mmol) in dry CH2Cl2 (3 mL) via cannula. The resulting
mixture was stirred at rt for 24 h, freed of solvent, and sub-
jected to column chromatography on silica gel (elution with
5:1 petroleum ether–ethyl acetate) to give 0.30 g (70%) of 35
as a colorless oil; IR (neat, cmꢀ1) 1714, 1613, 1514, 1251;
1H NMR (300 MHz, CDCl3) d 7.66–7.63 (m, 4H), 7.44–
7.34 (m, 6H), 7.26–7.22 (m, 2H), 6.89–6.84 (m, 2H), 6.57
(s, 1H), 4.71 (s, 2H), 4.55–4.16 (m, 6H), 4.08–4.02 (m,
1H), 3.80 (s, 3H), 3.71–3.68 (m, 2H), 3.58–3.47 (m, 6H),
3.40 (s, 3H), 3.09–2.98 (m, 1H), 2.61–2.56 (m, 2H), 2.28–
2.23 (m, 1H), 2.14–2.11 (m, 2H), 1.99–1.95 (m, 1H),
1.69–1.54 (m, 4H), 1.34–1.26 (m, 4H), 1.12 (s, 3H), 1.05
(s, 9H), 0.88 (s, 9H), 0.05–0.04 (m, 6H); 13C NMR
The above material was dissolved in dry THF (2 mL) and an-
hydrous LiBr (5 mg, 0.06 mmol) was added at rt. The mix-
ture was stirred at rt for 1.5 h and filtered through a pad of
silica gel, where the pad was further washed with ether
(50 mL). The filtrate was concentrated under vacuum to af-
ford a yellowish oil, which was purified by chromatography
on silica gel (elution with 3:1 petroleum ether–ethyl acetate)
to furnish 27 mg (86%) of 37 as a colorless liquid; IR
1
(neat, cmꢀ1) 1711, 1658, 1513, 1249; H NMR (300 MHz,
CDCl3) d 7.66–7.61 (m, 4H), 7.45–7.34 (m, 6H), 7.27–
7.23 (m, 2H), 6.89–6.84 (m, 2H), 6.63–6.62 (m, 1H), 4.71

S. Pichlmair et al. / Tetrahedron 62 (2006) 5178–5194
5189
(s, 2H), 4.55–4.51 (m, 1H), 4.43–4.34 (m, 2H), 4.27–4.14
(m, 3 H), 4.05–4.02 (m, 1H), 3.80 (s, 3H), 3.71–3.68 (m,
2H), 3.58–3.48 (m, 6H), 3.39 (s, 3H), 3.15–3.08 (m, 1H),
2.63–2.57 (m, 2H), 2.37–2.33 (m, 1H), 2.21–2.18 (m, 2H),
2.04–1.95 (m, 1H), 1.68–1.54 (m, 4H), 1.40–1.32 (m, 4H),
1.12 (s, 3H), 1.05 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 165.3, 159.2, 149.8, 146.1, 135.7 (2C), 135.6, 133.6
(2C), 130.6, 129.6 (4C), 129.3 (4C), 127.6 (2C), 113.8
(2C), 95.5, 82.9, 71.8, 70.8, 70.5, 67.8, 66.7, 66.6, 59.0,
55.3, 52.3, 42.7, 38.9, 33.7, 32.5, 30.7, 29.7, 27.7, 26.9
(3C), 26.8, 26.4, 26.2, 22.8, 19.4; HRMS ES m/z (M+Na)+
The alcohol from above (20.02 g, 33.7 mmol) was dissolved
in a mixture of pyridine–CH2Cl2¼1:4 (375 mL) and cooled
ꢁ
to 0 C. DMAP (411 mg, 3.37 mmol) was introduced fol-
lowed by acetic anhydride (31.6 mL, 0.34 mmol) in dropwise
fashion. The mixture was allowed to warm to rt, stirred over-
night, and freed of solvent. The residue was purified by col-
umn chromatography on silica gel (gradient elution with
hexane–ethyl acetate 50:1 to 25:1) to give 19.7 g (92%) of
48 as a colorless oil; IR (neat, cmꢀ1) 1738, 1472, 1369; 1H
NMR (300 MHz, CDCl3) d 7.78–7.63 (m, 8H), 7.50–7.32
(m, 12H), 5.87–5.81 (m, 2H), 5.52 (dd, J¼4.2 Hz, 1H),
4.23 (s, 2H), 3.82–3.68 (m, 2H), 2.09 (s, 3H), 1.08 (s,
18H); 13C NMR (75 MHz, CDCl3) d 170.2, 135.7, 135.6,
135.5, 135.3, 133.5, 127.74, 127.71, 124.6, 74.6, 65.6, 63.5,
26.94, 26.87, 21.2, 19.3, 19.1; HRMS ES m/z (M+Na)+ calcd
20
calcd 899.3524, obsd 899.3547; ½aꢃD ꢀ47.0 (c 0.83, CHCl3).
4.19. (E)-(R)-5-(tert-Butyldiphenylsilanyloxy)pent-3-
ene-1,2-diol (47)
20
659.2983, obsd 659.2948; ½aꢃD ꢀ8.3 (c 1.34, CHCl3).
A solution of 46 (3.86 g, 1.8 mmol) in 170 mL of 80%
ꢁ
HOAc at 0 C was allowed to warm to rt, stirred for 12 h,
4.21. (E)-(S)-6-(tert-Butyldiphenylsilanyloxy)-3-(tert-di-
phenylsilanyloxymethyl)hex-4-enoic acid methyl ester
(49)
poured into a slurry of 200 g of NaHCO3 suspended in 1 L
of water, and extracted with ether (4ꢂ150 mL). The com-
bined organic phases were dried and evaporated to leave
a residue that was purified by chromatography on silica
gel (hexane–ethyl acetate 2:1) to give 47 as a colorless oil
(2.78 g, 84%); IR (neat, cmꢀ1) 3416, 1472, 1427; 1H
NMR (300 MHz, CDCl3) d 7.22–7.13 (m, 4H), 7.50–7.32
(m, 6H), 5.57 (dt, J¼10.2, 2.2 Hz, 1H), 5.23 (dd, J¼10.2,
6.3 Hz, 1H), 4.32–4.20 (m, 3H), 3.63 (dd, J¼9.4, 1.8 Hz,
1H), 3.47 (dd, J¼8.1, 10.3 Hz, 1H), 2.95–2.15 (bm, 1H),
1.07 (s, 9 H); 13C NMR (75 MHz, CDCl3) d 135.5, 132.3,
131.8, 129.7, 128.2, 127.7, 72.6, 67.1, 63.7, 26.8, 18.5;
HRMS ES m/z (M+Na)+ calcd 379.1700, obsd 379.1713;
The above acetate (4.00 g, 6.28 mmol) dissolved in 80 mL of
dry THF was treated with TBDMSCl (3.92 g, 25.1 mmol)
ꢁ
and cooled to ꢀ78 C. KHMDS (28.5 mL, 18.8 mmol) was
ꢁ
introduced and the mixture was kept for 3 h at ꢀ78 C, al-
lowed to warm to rt overnight prior to quenching with a mix-
ture of saturated NaCl solution (200 mL) and 1 N HCl
(40 mL). The aqueous phase was extracted with ether (3ꢂ
60 mL), and the combined organic phases were filtered and
freed of solvent to give a mixture of ester and the correspond-
ing carboxylic acid. To obtain pure acid, the crude product
was dissolved in 80 mL of THF and 4 N LiOH (20 mL)
20
½aꢃD ꢀ7.0 (c 3.46, CHCl3).
ꢁ
ꢁ
was added at 0 C. After 1 h or stirring at 0 C, the TBS ester
was cleaved quantitatively to the carboxylic acid and the re-
action was stopped by acidification with 1 N HCl (160 mL)
and extraction with ether (3ꢂ60 mL) and CH2Cl2 (3ꢂ
60 mL). The combined organic phases were dried, filtered,
and distilled to give almost pure carboxylic acid. The acid
was further purified by column chromatography on silica
gel (gradient elution with ethyl acetate–hexane 1:10 to 1:7)
4.20. Acetic acid (E)-(R)-4-(tert-butyldiphenylsilanyl-
oxy)-1-(tert-butyldiphenylsilanyloxymethyl)-but-2-enyl
ester (48)
Diol 47 (10.7 g, 41.2 mmol) was dissolved in dry THF
(80 mL) ꢁcontaining imidazole (3.65 g, 53.6 mmol), cooled
to ꢀ15 C, and treated with a solution of TBDPSCl
(9.51 mL, 37.1 mmol) in 10 mL of dry THF via syringe
to give 3.98 g (100%) of colorless oil; IR (neat, cmꢀ1
)
pump over 2.5 h. Stirring was continued at ꢀ15 C for an-
2856, 1710, 1471; 1H NMR (300 MHz, CDCl3) d 7.77–7.58
(m, 8H), 7.47–7.28 (m, 12H), 5.62–5.58 (m, 2H), 4.12 (s,
2H), 3.65 (dd, J¼9.7, 4.6 Hz, 1H), 3.51 (dd, J¼9.7, 6.9 Hz,
1H), 2.86–2.73 (m, 1H), 2.72 (dd, J¼15.4, 5.9 Hz, 1H),
2.37 (dd, J¼15.5, 7.6 Hz, 1H), 1.04 (s, 9 H), 1.03 (s, 9H);
13C NMR (75 MHz, CDCl3) d 173.8, 135.6, 135.5, 133.7,
133.5, 130.8, 129.7, 129.6, 129.4, 127.7, 127.6, 66.5, 64.2,
40.9, 36.2, 26.8, 19.8, 19.3, 19.2; HRMS ES m/z (M+Na)+
calcd 659.2984, obsd 659.3016; ½aꢃ2D0 +5.3 (c 0.87, CHCl3).
ꢁ
other 2 h and a second portion of TBDPSCl (0.76 mL,
2.96 mmol) was added slowly at the same temperature within
30 min. The reaction mixturewas stirred for another hour and
a third portionꢁof TBDPSCl (0.76 mL, 2.96 mmol) was intro-
duced at ꢀ15 C, quenched an hour later with saturated am-
monium chloride solution (50 mL), and extracted with ether
(4ꢂ80 mL). The combined organic layers were dried and
evaporated to dryness to give a colorless oil, which was puri-
fied by chromatography on silica gel (gradient elution with
hexane–ethyl acetate 25:1 to 7:1) to give 20.02 g (82%) of
The carboxylic acid (4.49 g, 7.06 mL) was dissolved in
44 mL of dry DMF and methyl iodide (5.27 mL,
84.7 mmol) was added. The reaction was started by the ad-
dition of dry K2CO3 (5.85 g, 42.3 mmol). The mixture was
stirred at rt for 1.5 h and stopped by the addition of hexane
(100 mL) and water (300 mL). The aqueous phase was ex-
tracted with hexane (4ꢂ100 mL), dried, and evaporated to
afford a crude oil that was purified by chromatography on
silica gel (hexane–ethyl acetate 25:1) to afford 3.33 g
(73%) of 49 as a colorless oil; IR (neat, cmꢀ1) 1730, 1428,
pure alcohol in the form of a colorless oil; IR (neat, cmꢀ1
)
1
3420, 1472, 1427; H NMR (300 MHz, CDCl3) d 7.77–
7.60 (m, 8H), 7.50–7.28 (m, 12H), 5.83 (dt, J¼18.1,
2.5 Hz, 1H), 5.70 (dd, J¼18.1, 8.4 Hz, 1H), 4.30–4.10 (m,
1H), 4.18 (d, J¼5.8 Hz, 2H), 3.66 (dd, J¼8.2, 5.6 Hz, 1H),
3.53 (dd, J¼8.2, 5.9 Hz, 1H), 2.65–2.54 (m, 1H), 1.08 (s, 9
H), 1.04 (s, 9H); 13C NMR (75 MHz, CDCl3) d 135.54,
135.48, 134.8, 133.5, 133.1, 133.0, 131.4, 129.8, 129.6,
129.5, 127.79, 127.78, 127.63, 127.60, 72.3 (d), 67.8, 63.7,
26.83, 26.79, 19.2, 18.9 (s); HRMS ES m/z (M+Na)+ calcd
1
1112; H NMR (300 MHz, CDCl3) d 7.72–7.60 (m, 8H),
7.49–7.29 (m, 12H), 5.62 (s, 1H), 5.61 (d, J¼0.5 Hz, 1H),
20
617.2878, obsd 617.2861; ½aꢃD +0.6 (c 1.33, CHCl3).

5190
S. Pichlmair et al. / Tetrahedron 62 (2006) 5178–5194
ꢁ
4.13 (s, 2H), 3.63 (s, 3H), 3.68–3.53 (m, 1H), 3.53 (dd,
J¼9.5, 6.6 Hz, 1H), 2.69 (dd, J¼9.5, 5.8 Hz, 1H), 2.27
(dd, J¼15.2, 8.4 Hz, 1H), 1.08 (s, 9 H), 1.06 (s, 9 H); 13C
NMR (75 MHz, CDCl3) d 173.1, 135.6, 135.5, 133.8,
133.6, 130.7, 129.7, 129.6, 127.7, 127.6, 66.5, 643, 51.5,
41.3, 36.4, 26.9, 26.8, 19.3, 19.2; HRMS ES m/z (M+Na)+
45.2 mmol, 1.6 N in hexane) was added at ꢀ65 C. The
ꢁ
mixture was warmed to ꢀ40 C and stirred at that tempera-
ꢁ
ture for 1 h and returned to ꢀ78 C. At this point, 50
(12.48 g, 20.1 mmol) was added via cannula as a solution
in dry THF (50 mL), the temperature was raised slowly to
ꢁ
ꢀ40 C within 1 h, saturated NH4Cl solution was added
20
calcd 673.3140, obsd 673.3101; ½aꢃD +4.8 (c 3.38, CHCl3).
and the product was extracted into ether (3ꢂ150 mL). The
combined organic layers were dried and evaporated to leave
a residue that was purified by flash chromatography on silica
gel (gradient elution with hexane–ethyl acetate 25:1 to 10:1)
to yield 14.15 g (87%) of the alcohol as a 1:1 mixture of di-
astereomers.
4.22. (E)-(S)-6-(tert-Butyldiphenylsilanyloxy)-3-(tert-
butyldiphenylsilanyloxymethyl)hex-4-enal (50)
A solutiꢁon of 49 (2.09 g, 3.21 mmol) in dry THF was cooled
to ꢀ78 C and treated with DIBAL-H (9.64 mL, 9.64 mmꢁol,
1 M in hexane). The reaction mixture was stirred at ꢀ78 C
The above alcohol mixture (94.3 mg, 0.119 mmol) was dis-
solved in CH2Cl2 (2.2 mL) and activated MnO2 (104 mg,
1.19 mmol) was added. The reaction mixture was stirred
for 15 h, treated with fresh MnO2 (208 mg, 2.38 mmol),
stirred for an additional 4 h, filtered through Celite, and pu-
rified by chromatography on silica gel (gradient elution with
hexane–ethyl acetate 25:1 to 10:1) to afford 89.6 mg (95%)
ꢁ
for 10 min, warmed to 0 C, and stirred for an additional
40 min in ice and 30 min at rt. Then 2 mL of methanol
was added to quench and the resulting mixture was stirred
for 10 min at rt prior to the introduction of saturated KNa-
tartrate solution (60 mL) and ether (60 mL). Stirring was
continued until the mixture was clear (2–4 h). The mixture
was extracted with ether (4ꢂ50 mL), dried, and freed of sol-
vents. The crude product was purified by chromatography on
silica gel (hexane–ethyl acetate 7:1) to furnish the alcohol as
a colorless oil (1.91 g, 95%); IR (neat, cmꢀ1) 3440, 1644,
of pure 51; IR (neat, cmꢀ1) 1673, 1472, 1428; H NMR
1
(300 MHz, CDCl3) d 7.77–7.60 (m, 10H), 7.52–7.25 (m,
14H), 5.67–5.57 (m, 2H), 4.53 (s, 2H), 4.18 (d, J¼1.5 Hz,
2H), 3.67 (dd, J¼10.1, 5.3 Hz, 1H), 3.59 (t, J¼5.8 Hz,
2H), 3.52–3.50 (m, 1H), 3.10–2.97 (m, 1H), 2.90 (dd,
J¼15.9, 5.8 Hz, 1H), 2.57 (dd, J¼15.9, 7.8 Hz, 1H), 2.53
(t, J¼7.0 Hz, 2H), 1.90 (q, J¼7.0 Hz, 2H), 1.10 (s, 9H),
1.09 (s, 9H); 13C NMR (75 MHz, CDCl3) d 138.3, 135.7,
135.6, 133.74, 133.71, 133.5, 130.9, 129.7, 129.6, 129.4,
128.4, 127.74, 127.71, 127.67, 93.6, 81.4, 73.1, 68.4, 66.5,
64.3, 46.4, 40.7, 28.1, 26.9, 19.32, 19.26, 16.0; HRMS ES
1
1471; H NMR (300 MHz, CDCl3) d 7.76–7.60 (m, 8H),
7.50–7.29 (m, 12H), 5.62–5.53 (m, 2H), 4.20–4.12 (m,
2H), 3.75–3.52 (m, 4H), 2.47–2.33 (m, 1H), 2.10–1.88 (dt,
J¼19.8, 6.8 Hz, 1H), 1.61 (dt, J¼22.0, 6.0 Hz, 1H), 1.08
(s, 9H), 1.06 (s, 1H); 13C NMR (75 MHz, CDCl3) d 135.7,
135.5, 133.8, 133.6, 131.4, 130.4, 129.7, 129.6, 127.7,
127.6, 67.6, 64.4, 61.2, 42.4, 34.8, 26.99, 26.86, 19.3,
19.2; HRMS ES m/z (M+Na)+ calcd 645.3191, obsd
20
m/z (M+Na)+ calcd 815.3922, obsd 815.3908; ½aꢃD +5.0 (c
20
645.3161; ½aꢃD +2.9 (c 1.13, CHCl3).
4.21, CHCl3).
Oxalyl chloride (70.1 mL, 0.83 mmol) waꢁs dissolved in dry
CH2Cl2 (5 mL) and cooled to ꢀ78 C. Dry DMSO
(117.5 mL, 1.66 mmol) was slowly added and after 1 h the
above alcohol (258 mg, 0.41 mmol) dissolved in dry
CH2Cl2 (5 mL) was introduced. The reaction mixture was
4.24. [(E)-(4S,6S)-11-Benzyloxy-4-(tert-butyldiphenyl-
siloxy)-6-methoxymethoxyundec-2-en-7-ynyloxy-tert-
butyldiphenylsilane (53)
Ketone 51 (112 mg, 0.14 mmol) was dissolved in dry THF
(2.7 mL) and the CBS reagent (0.4 mL, 0.4 M solution in
THF, 0.16 mmol) ꢁwas added. The reaction mixture was
cooled to ꢀ78 C, treated with borane ꢁ(0.71 mL,
0.71 mmol, 1 M in THF), warmed to ꢀ40 C within
15 min and kept at that temperature for an hour. When reac-
tion was found to be complete (TLC analysis), MeOH
(0.7 mL) was added and stirring was continued for another
10 min. After the addition of saturated NH4Cl solution, the
mixture was extracted with ether (3ꢂ5 mL), and the com-
bined organic layers were dried and evaporated to dryness.
The residue was purified by flash chromatography on silica
gel (hexane–ethyl acetate 10:1) to give 112 mg (100%) of
52 as a colorless oil; IR (neat, cmꢀ1) 3433, 1472, 1428; 1H
NMR (300 MHz, CDCl3) d 7.55–7.54 (m, 10H), 7.46–7.21
(m, 14H), 5.67–5.46 (m, 2H), 4.50 (s, 2H), 4.38–4.28 (m,
1H), 4.14 (d, J¼4.0 Hz, 2H), 3.48–3.10 (m, 4 H), 2.62–
2.47 (m, 1H), 2.35 (dt, J¼1.6, 7.0 Hz, 2H), 2.12–1.98 (m,
1H), 1.96–1.80 (m, 1H), 1.81 (q, J¼6.8 Hz, 2H), 1.75–
1.63 (m, 1H), 1.05 (s, 9H), 1.04 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 138.5, 135.7, 135.6, 133.7, 133.6,
131.1, 131.0, 129.7, 128.4, 127.72, 127.69, 127.6, 84.5,
82.0, 68.8, 67.6, 64.4, 60.8, 41.8, 40.6, 28.9, 26.93, 26.91,
19.3, 15.7; HRMS ES m/z (M+Na)+ calcd 817.4079, obsd
ꢁ
stirred for 15 min at ꢀ78 C, triethylamine (349 mL,
2.49 mmol) was added, and the reaction mixture was warmed
to 0 C, stirred for 30 min, and quenched with saturated
ꢁ
NH4Clsolution(10 mL).Theproductwasextractedintoether
(3ꢂ15 mL) and the combined organic phases were dried,
evaporated to dryness, and quickly filtered through silica
(hexane–ethyl acetate 7:1) to give pure 50 (259 mg, 100%);
1
IR (neat, cmꢀ1) 1727, 1427, 1112; H NMR (300 MHz,
CDCl3) d 9.72 (t, J¼2.25 Hz, 1H), 7.69–7.56 (m, 8H),
7.47–7.28 (m, 12H), 5.58 (d, J¼3.9 Hz, 2H), 4.13 (s, 2H),
3.64 (dd, J¼5.02, 7.5 Hz, 1H), 3.49 (dd, J¼7.5, 9.9 Hz,
1H), 2.33–2.96 (m, 1H), 2.66 (ddd, J¼16.5, 6.1, 2.2 Hz,
1H), 2.43 (ddd, J¼16.5, 7.7, 2.2 Hz, 1H), 1.04 (s, 9H), 1.03
(s, 9H); 13C NMR (75 MHz, CDCl3) d 202.3, 135.6, 135.5,
133.7, 131.1, 129.7, 129.6, 129.2, 127.7, 127.6, 66.8, 64.1,
45.7, 39.6, 26.8, 19.22, 19.19; HRMS ES m/z (M+Na)+ calcd
643.3034, obsd 643.3030; ½aꢃ2D0 +1.6 (c 0.57, CHCl3).
4.23. (E)-(S)-11-Benzyloxy-1-(tert-butyldiphenylsilanyl-
oxy)-4-(tert-butyldiphenylsilanyloxymethyl)undec-2-en-
7-yn-6-one (51)
Benzyloxy-1-pentyne (7.88 g, 45.2 mmol) was dissolved in
200 mL of dry THF (200 mL) and n-BuLi (28.3 mL,
20
817.4060; ½aꢃD +2.5 (c 6.51, CHCl3).

S. Pichlmair et al. / Tetrahedron 62 (2006) 5178–5194
5191
This enantiomerically enriched alcohol (2.45 g, 3.09 mmol)
0.08 mmol) and N,N-bis-(benzylidene)ethylenediamine
ꢁ
was dissolved in CH2Cl2 (50 mL) and Hunig’s base
¨
(2.64 mL, 15.4 mmol) was added. The mixture was cooled
(55) (18.3 mg, 0.08 mmol) and stirred at 60 C for three
days until all starting material was consumed. The solvent
was removed to leave a residue (E:Z¼3.5:1) from which it
was possible to separate the major part of the desired E-iso-
mer 56 (72.5 mg, 31%) from the E:Z mixture (63.7 mg,
32%) (silica gel, gradient elution from 25:5 hexane–ethyl
acetate; IR (neat, cmꢀ1) 1468, 1427, 1112; 1H NMR
(300 MHz, CDCl3) d 7.80–7.60 (m, 5H), 7.51–7.26 (m,
10H), 6.04 (t, J¼7.5 Hz, 1H), 5.45 (s, 1H), 4.81 (s, 2H),
4.72 (d, J¼6.9 Hz, 1H), 4.56 (d, J¼6.9 Hz, 1H), 4.52 (s,
2H), 3.85–3.68 (m, 2H), 3.51 (t, J¼6.3 Hz, 2H), 3.36 (s,
3H), 2.90–2.74 (m, 1H), 2.52–2.24 (m, 2H), 2.14–2.00 (m,
1H), 1.99–1.58 (m, 3 H), 1.09 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 148.6, 140.9, 135.6, 134.1, 129.5, 128.4, 127.64,
127.61, 127.55, 127.48, 104.0, 94.4, 75.6, 72.9, 69.8, 68.1,
55.6, 45.7, 32.9, 29.7, 26.9, 26.0, 19.3; HRMS ES m/z
ꢁ
to 0 C, treated with MOMCl (1.16 mL, 15.4 mmol), stirred
for 8.5 h, and quenched with saturated NH4Cl solution
(30 mL). The aqueous layer was extracted with CH2Cl2
(3ꢂ30 mL), the combined organic layers were dried, and
evaporated to give a crude product that was purified by chro-
matography on silica gel (gradient elution with hexane–ethyl
acetate 25:1 to 10:1) to afford 2.48 g (96%) of 53; IR (neat,
cmꢀ1) 1472, 1428, 1112; 1H NMR (300 MHz, CDCl3)
d 7.83–7.67 (m, 10H), 7.50–7.26 (m, 14H), 5.73–5.62 (m,
2H), 5.00 (d, J¼6.7 Hz, 1H), 4.62 (d, J¼6.7 Hz, 1H), 4.54
(s, 2H), 4.50–4.38 (m, 1H), 4.25 (s, 2H), 3.72–3.58 (m, 4
H), 3.38 (s, 3H), 2.54–2.58 (m, 1H), 2.5–2.37 (m, 2H),
2.18–2.04 (m, 1H), 1.87 (q, J¼6.7 Hz, 2H), 1.78–1.55 (m,
1H), 1.14 (s, 18 H); 13C NMR (75 MHz, CDCl3) d 138.5,
135.7, 133.8, 131.1, 129.6, 128.4, 127.68, 127.65, 127.58,
94.0, 85.4, 79.4, 73.0, 68.9, 65.4, 64.5, 63.9, 55.8, 41.4,
35.6, 28.9, 26.9, 19.4, 19.3, 15.8; HRMS ES m/z (M+Na)+
calcd 861.4341, obsd 861.4389; ½aꢃ2D0 +36.9 (c 4.39, CHCl3).
20
(M+Na)+ calcd 593.3058, obsd 593.3080; ½aꢃD ꢀ32.0 (c
3.63, CHCl3).
The above material (66.9 mg, 0.12 mmol) was dissolved in
dry THF (3.9 mL) and TBAF (123 mL, 1 M in THF,
0.12 mmol) was added. The reaction mixture was stirred at
rt for 4 h and diluted with water (5 mL) and ether (2 mL).
The mixture was extracted with ether (3ꢂ4 mL) and the
combined organic layers were dried and evaporated. The
residue was purified by chromatography on silica gel (gradi-
ent elution with hexane–ethyl acetate 10:1 to 2:1) to give
34 mg (88%) of pure 56; IR (neat, cmꢀ1) 3428, 1453,
4.25. ((2S,4R)-9-Benzyloxy-4-methoxymethoxy-2-vinyl-
non-5-ynyloxy)-tert-butyldiphenylsilane (54)
Enyne 53 (500 mg, 0.596 mmol) was dissolved in hexane
(34 mL) and ozone was bubbled through the solution at
ꢁ
for 15 more minutes, treated with a solution of PPh3
(469 mg, 1.79 mmol) in ether (1 mL), and stirred at 0 C
ꢀ78 C for 15 min. The solution was purged with oxygen
1
ꢁ
1147; H NMR (300 MHz, CDCl3) d 7.42–7.18 (m, 5 H),
for 3.5 h at rt. Simultaneously, methylenetriphenylphosphor-
ane was prepared in a separate flask by adding n-BuLi
(2.98 mL, 4.17 mol, 1.4 N solution in hexane) to a suspen-
sion of PPh3CH+3Brꢀ (2.34 g, 6.56 mmol) in ether
6.07 (dt, J¼7.2, 1.0 Hz, 1H), 5.41 (d, J¼1.8 Hz, 1H), 4.91
(d, J¼1.3 Hz, 1H), 4.72 (d, J¼5.4 Hz, 1H), 4.63 (dd,
J¼18.2, 6.9 Hz, 2H), 4.50 (s, 3H), 3.70 (d, J¼6.3 Hz, 2H),
3.37 (s, 3H), 2.76–2.88 (m, 1H), 2.53–2.22 (m, 2H), 2.01
(ddd, J¼18.9, 14.4, 5.3 Hz, 1H), 1.94–1.63 (m, 3 H); 13C
NMR (75 MHz, CDCl3) d 148.5, 140.3, 138.5, 128.4,
128.2, 127.6, 127.5, 127.4, 104.3, 94.3, 75.1, 72.9,
69.7, 66.3, 55.8, 45.3, 33.9, 29.6, 26.1; HRMS ES m/z
ꢁ
(9.8 mL). The suspension was stirred at 0 C for 4 h and
then added to the phosphorane over a period of 10 min at
ꢁ
0 C. Stirring was continued overnight and the reaction mix-
ture was allowed to warm to rt, quenched with saturated
NH4Cl solution (30 mL), and extracted with ether
(4ꢂ20 mL) and CH2Cl2 (1ꢂ20 mL). The combined organic
layers were dried and freed of solvent prior to chromato-
graphy on silica gel (gradient elution with pure hexane to
hexane–ethyl acetate 3:1) to afford 291 mg (85%) of 54;
20
(M+Na)+ calcd 355.1880, obsd 355.1861; ½aꢃD ꢀ20.6 (c
1.81, CHCl3).
4.27. (S)-3-(tert-Butyldiphenylsilanyloxymethyl)-3-
methylcyclopent-1-enecarboxylic acid (1S,4R)-3-[4-
benzyloxybut-(Z)-ylidene]-4-methoxymethoxy-2-
methylenecyclopentyl methyl ester (57)
1
IR (neat, cmꢀ1) 1468, 1527, 1112; H NMR (300 MHz,
CDCl3) d 7.80–7.67 (m, 5H), 7.50–7.25 (m, 10H), 5.84–
5.78 (m, 1H), 5.64 (s, 1H), 5.00 (d, J¼9.7 Hz, 1H), 4.90
(d, J¼6.8 Hz, 1H), 4.58 (d, J¼6.8 Hz, 1H), 4.52 (s, 2H),
4.44–4.34 (m, 1H), 3.13 (d, J¼5.6 Hz, 2H), 3.57 (t,
J¼6.2 Hz, 2H), 3.38 (s, 3H), 2.64–2.50 (m, 1H), 2.36 (t,
J¼7.0 Hz, 2H), 2.05 (ddd, J¼9.3, 4.6, 4.6 Hz, 1H), 1.82
(q, J¼6.5 Hz, 2H), 1.72 (ddd, J¼9.3, 4.6, 4.6 Hz, 1H),
1.08 (s, 9H); 13C NMR (75 MHz, CDCl3) d 139.3, 138.5,
135.70, 135.67, 135.5, 134.8, 133.8, 129.7, 129.6, 128.4,
127.7, 127.63, 127.58, 116.5, 94.0, 85.4, 79.3, 73.0, 68.8,
67.3, 63.9, 55.8, 42.8, 37.9, 28.9, 26.9, 19.3, 15.6; HRMS
Diene 56 (7.3 mg, 0.014 mmol) was dissolved in dry CH2Cl2
(1.8 mL) and carboxylic acid 16 (28.3 mg, 0.072 mmol) and
DMAP (20.5 mg, 0.168 mmol) were added. Finally DCC
(34.7 mg, 0.168 mmol) was added and the reaction mixture
was stirred for three days. The reaction was arrested by the
addition of water (5 mL) and extraction with CH2Cl2
(3ꢂ5 mL). The combined organic layers were dried and
evaporated to leave a residue that was purified by flash chro-
matography on silica gel (gradient elution with hexane–ethyl
acetate 25:1 to 10:1) to give 9.2 mg (90%) of 57 as a colorless
oil; IR (neat, cmꢀ1) 1715, 1646, 1456; 1H NMR (400 MHz,
CDCl3) d 7.71–7.61 (m, 4H), 7.47–7.25 (m, 11H), 6.62 (t,
J¼2.0 Hz, 1H), 6.08 (t, J¼7.6 Hz, 1H), 5.91 (d, J¼1.6 Hz,
1H), 5.40 (d, J¼1.6 Hz, 1H), 4.75–4.69 (m, 1H), 4.65 (s,
2H), 4.52 (s, 2H), 4.31 (dd, J¼10.4, 7.2 Hz, 1H), 4.36 (dd,
J¼10.2, 8.4 Hz, 1H), 3.53–3.47 (m, 4H), 3.37 (s, 3H),
3.00–2.90 (m, 1H), 2.68–2.58 (m, 4H), 2.97–2.25 (m, 2H),
20
ES m/z (M+Na)+ calcd 593.3058, obsd 593.3070; ½aꢃD
+53.4 (c 0.99, CHCl3).
4.26. {(1S,4R)-3-[4-Benzyloxybut-(Z)-ylidene]-4-methoxy-
methoxy-2-methylenecyclopentyl}methanol (56)
A solution of 54 (221 mg, 0.39 mmol) in deoxygenated
dichloroethane was treated with Pd(OAc)2 (17.4 mg,

5192
S. Pichlmair et al. / Tetrahedron 62 (2006) 5178–5194
2.24–1.60 (m, 6H), 1.16 (s, 3H), 1.07 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 171.3, 165.4, 154.0, 149.3, 148.0,
140.2, 139.4, 139.0, 135.6, 133.6 (2C), 129.6, 128.4,
127.6, 127.1, 105.0, 100.0, 99.9, 94.5, 75.5, 72.9, 70.5,
70.2, 69.7, 68.0, 58.8, 55.7, 33.7, 33.0, 31.0, 29.7, 26.9,
26.8, 26.6, 24.6, 22.8, 22.7, 14.1; HRMS ES m/z (M+Na)+
67.8, 66.7, 65.9, 60.4, 59.0, 55.2, 52.2, 39.4, 37.1, 33.8,
29.7, 29.4, 29.3, 26.5, 22.9, 22.7, 22.6, 19.4, 14.2, 14.1,
11.4, 6.5, 4.5; HRMS ES m/z (M+Na)+ calcd 949.5077,
obsd 949.5119; ½aꢃD ꢀ15.7 (c 0.78, CHCl3).
20
4.29. (S)-1-Methylcyclopent-2-enecarboxylic acid ethyl
ester (63)
20
calcd 731.3738, obsd 731.3740; ½aꢃD ꢀ8.9 (c 0.46, CHCl3).
4.28. (S)-3-(tert-Butyldiphenylsilanyloxy)-3-methyl-
cyclopent-1-enecarboxylic acid (1S,4R)-2-formyl-4-(4-
methoxybenzyloxy)-3-[5-(2-methoxyethoxymethoxy)
pentyl]cyclopent-2-enylmethyl ester (59)
Dry triethylamine (237 mL, 1.70 mol) and methanesul-
phonyl chloride (57 mL, 0.74 mol) were added to a stirred
solution (2S)-hydroxy-(1S)-methylcyclopentanecarboxylic
acid ethyl ester (97.45 g, 0.567 mol) in dry CH2Cl2
ꢁ
ꢁ
(1.15 L) at 0 C under N2. The mixture was stirred at 0 C
for 3 h, diluted with CH2Cl2 (800 mL), and washed with
brine (1 L). The aqueous phase was extracted with CH2Cl2
(500 mL), the combined organic layers were dried and freed
of solvent to leave a residue that was purified by chromato-
graphy on silica gel (gradient elution with pure hexane to
hexane–ethyl acetate 3:1) to afford the mesylate (101.1 g,
71%) as a yellow oil; IR (neat, cmꢀ1) 3548, 1725, 1466;
1H NMR (250 MHz, CDCl3) d 5.32–5.23 (m, 1H), 3.80 (q,
J¼7.1Hz, 2H), 3.03 (s, 3 H), 2.32–1.58 (m, 6H), 1.31 (s,
3H), 1.27 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 174.9, 89.3, 60.6, 52.1, 37.5, 34.7, 30.7, 19.8, 17.8, 13.6;
HRMS ES m/z (M+Na)+ calcd 273.0767, obsd 273.0771;
To a solution of 36 (179 mg, 0.19 mmol) in dry CH2Cl2
(17 mL) was added MnO2 (334 mg, 3.84 mmol). After
15 h of stirring at rt, the MnO2 was removed by filtration
over a pad of Celite. The filtrate was evaporated and the res-
idue was purified by flash chromatography on silica gel
(hexane–ethyl acetate 4:1) to give 122 mg (85%) of pure
59 as a colorless oil; IR (neat, cmꢀ1) 1714, 1672, 1250; 1H
NMR (300 MHz, CDCl3) d 9.95 (s, 1H), 7.68–7.59
(m, 4H), 7.47–7.34 (m, 6H), 7.24 (d, J¼11.6 Hz, 2H), 6.86
(d, J¼11.6 Hz, 2H), 6.55 (s, 1H), 4.70 (s, 2H), 4.58 (d,
J¼11.5 Hz, 1H), 4.48 (dd, J¼10.7, 4.3 Hz, 1H), 4.36
(d, J¼11.5 H, 1H), 4.17 (dd, J¼10.7, 7.7 Hz, 1H), 3.79 (s,
3H), 3.70–3.64 (m, 2H), 3.58–3.47 (m, 4H), 3.45 (s, 3H),
3.39 (s, 3H), 3.26–3.14 (m, 1H), 2.74–2.41 (m, 4H), 2.35–
2.22 (m, 1H), 2.01–1.87 (m, 1H), 1.78–1.16 (m, 8H), 1.12
(s, 3H), 1.05 (s, 9H); 13C NMR (75 MHz, CDCl3) d 188.8,
165.3, 159.4, 149.3, 137.9, 135.7, 135.6, 133.6, 133.,
130.0, 129.6, 129.5, 127.6, 113.8, 95.5, 82.8, 71.8, 71.4,
70.5, 67.6, 66.7, 65.8, 59.0, 55.2, 41.5, 33.8, 32.3, 31.9,
30.7, 29.4 (2C), 29.2, 28.4, 26.9, 26.3, 26.0, 22.7 (2C),
19.4, 14.1; HRMS ES m/z (M+Na)+ calcd 835.4212, obsd
20
½aꢃD +46.7 (c 1.4, CHCl3).
1,8-Diazabicyclo[5.4.0]undec-7-ene (91 mL, 0.61 mol) was
added to a solution of the above mesylate (101.1 g,
0.404 mol) in dry DMF (300 mL) at rt under N2. The reac-
ꢁ
tion mixture was heated at 160 C for 12 h, diluted with
ether (800 mL), and washed with water (2ꢂ800 mL). The
combined organic layers were dried and evaporated to leave
a brown oil, which was purified by chromatography on silica
gel (hexane–ethyl acetate 99:1) to afford 63 (35.05 g, 84%)
as a pale yellowish oil; IR (neat, cmꢀ1) 1731, 1464, 1372; 1H
NMR (300 MHz, CDCl3) d 5.78 (dt, J¼5.5, 2.1 Hz, 1H),
5.69 (dt, J¼5.5, 2.0 Hz, 1H), 4.13 (q, J¼7.1 Hz, 2H),
2.51–2.35 (m, 4H), 1.31 (s, 3H), 1.25 (t, J¼7.1 Hz, 3H);
13C NMR (75 MHz, CDCl3) d 176.2, 134.8, 131.0,
89.3, 59.9, 55.1, 34.6, 31.3, 24.2, 13.7; HRMS ES m/z
20
835.4236; ½aꢃD ꢀ0.77 (c 4.81, CHCl3).
4.28.1. (S)-3-(tert-Butyldiphenylsilanyloxy)-3-methyl-
cyclopent-1-enecarboxylic Acid (1S,4R)-2-[1-(tert-butyl-
dimethylsilanyloxy)-meth-(E)-ylidene]-4-(4-methoxy-
benzyloxy)-3-[5-(2-methoxyethoxymethoxy)pent-(Z)-yli-
dene]cyclopentylmethyl ester (60). A solution of 59
(21.2 mg, 0.026 mmol) and triethylamine (40 mL,
20
(M+Na)+ calcd 177.0886, obsd 177.0885; ½aꢃD ꢀ78.5 (c
ꢁ
0.29 mmol) in dry CH2Cl2 (1 mL) was cooled to ꢀ78 C
1.1, CHCl3).
and triethylsilyl triflate (22 mL, 0.098 mmol) was added.
The reaction mixture was warmed to 0 C and kept at that
ꢁ
4.30. tert-Butylmethyl-((S)-1-methylcyclopent-2-enyl-
methoxy) phenylsilane (64)
temperature for 1 h. The reaction mixture was diluted with
CH2Cl2 (2 mL) and evaporated, and the residue was purified
by flash chromatography (hexane–ethyl acetate 10:1) to give
15.5 mg (64%) of 60 as a colorless oil; IR (neat, cmꢀ1) 1716,
Lithium aluminum hydride (11.2 g, 0.295 mol) was added
portion wise over a period of 2 h to a stirred solution of 63
(35.05 g, 0.227 mol) in dry ether (450ꢁmL) at rt. The mixture
was stirred for 30 min, cooled to 0 C, treated with 1.0 N
NaOH solution until the mixture turned white, and extracted
with CH2Cl2 (3ꢂ1 L). The combined organic phases were
dried and freed of solvent. The residue was chromato-
graphed on silica gel (hexane–ethyl acetate 5:1) to give the
primary carbinol (23.25 g, 91%) as a pale yellow oil; IR
(neat, cmꢀ1) 3370, 1457, 1379; 1H NMR (250 MHz,
CDCl3) d 5.81 (dt, J¼5.6, 2.3 Hz, 1H), 5.46 (dt, J¼5.6,
2.2 Hz, 1H), 3.50–3.31 (m, 2H), 2.45–2.33 (m, 2H), 2.00–
1.87 (m, 1H), 1.65–1.49 (m, 1H), 1.06 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 136.6, 131.0 69.9, 50.8, 33.3, 31.7,
23.0; HRMS ES molecular ion too fleeting for accurate
1
1652, 1457; H NMR (400 MHz, CDCl3) d 7.71–7.62 (m,
4H), 7.48–7.34 (m, 6H), 7.26 (d, J¼8.4 Hz, 2H), 6.86 (d,
J¼8.4 Hz, 2H), 6.82 (s, 1H), 6.60 (s, 1H), 5.67 (t,
J¼7.6 Hz, 1H), 4.73 (s, 2H), 4.64 (dd, J¼10.4, 4.8 Hz,
1H), 4.50 (d, J¼10.8 Hz, 1H), 4.43–4.51 (m, 1H), 4.11 (t,
J¼10.4 Hz, 1H), 3.80 (s, 3 H), 3.72–3.67 (m, 2H), 3.61–
3.47 (m, 4H), 3.42 (s, 3H), 3.32–3.11 (m, 1H), 2.68–2.49
(m, 2H), 2.31 (d, J¼20.8 Hz, 1H), 2.23–2.07 (m, 2H),
2.03–1.93 (q, J¼7.6 Hz, 1H), 1.75–1.20 (m, 9H), 1.17 (s,
3H), 1.07 (s, 9H), 1.00 (t, J¼6.5 Hz, 6H), 0.70 (q,
J¼6.5 Hz, 9H); 13C NMR (75 MHz, CDCl3) d 165.4,
159.0, 139.5, 136.1, 135.7, 135.6, 134.2, 133.7, 133.6,
130.8, 129.6, 129.5, 129.1, 127.7, 127.6, 126.0, 125.8,
123.8, 121.4, 120.2, 113.7, 95.5, 78.6, 71.8, 70.6, 69.7,
20
mass measurement; ½aꢃD ꢀ32.0 (c 1.3, CHCl3).

S. Pichlmair et al. / Tetrahedron 62 (2006) 5178–5194
5193
Imidazole (28.3 g, 0.416 mmol) was added to a solution of
the above alcohol (23.2 g, 0.208 mol) in DMF (100 mL)
at 0 C. After 20 min, tert-butyldiphenylsilyl chloride
4.32. (S)-3-(tert-Butylmethylphenylsilanyloxymethyl)-3-
methyl-5-oxocyclopent-1-enecarboxylic acid methyl
ester (66)
ꢁ
(60 mL, 0.23 mol) was added, and the resulting solution
was stirred for 15 h at rt, diluted with ether (600 mL), and
washed with water (2ꢂ500 mL). The organic layer was
dried and the solvent was removed to leave a residue that
was purified by chromatography on silica gel (hexane) to
give 64 as a colorless foam (64.33 g, 89%); IR (neat,
cmꢀ1) 1656, 1589, 1486; 1H NMR (300 MHz, CDCl3)
d 7.73–7.63 (m, 4H), 7.47–7.32 (m, 6H), 5.70 (dt, J¼5.6,
2.2 Hz, 1H), 5.57 (dt, J¼5.6, 2.1 Hz, 1H), 3.48 (d,
J¼9.4 Hz, 1H), 3.44 (d, J¼9.4 Hz, 1H), 2.40–2.31 (m,
2H), 1.93–1.82 (m, 1H), 1.54–1.48 (m, 1H), 1.12 (s, 3 H),
1.08 (s, 9H); 13C NMR (75 MHz, CDCl3) d 137.8, 135.7,
134.0, 130.2, 129.5, 127.6, 71.3, 51.4, 33.9, 31.8, 26.9,
23.8, 19.4; HRMS ES m/z (M+Na)+ calcd 373.1958, obsd
Triethylamine (31 mL, 0.22 mol) and anhydrous MeOH
(6.0 mL, 0.15 mol) were added to a stirred solution of
65 (35.92 g, 73.3 mmol), Pd2(dba)3 CHCl3 (2.62 g,
2.86 mmol), and Ph3P (3.0 g, 0.01 mol) in dry DMF
(260 mL) at rt under a carbon monoxide atmosphere. The
$
ꢁ
resulting mixture was heated at 70 C for 20 h, cooled to
rt, diluted with ether (1.2 L), and washed with water
(2ꢂ1 L). The organic phase was dried and the solvent was
removed to give a black residue that was purified by chroma-
tography on silica gel (hexane–ethyl acetate 5:1) to afford
66 as a yellow oil (18.98 g, 61%); IR (neat, cmꢀ1) 1755,
1
1727, 1624; H NMR (300 MHz, CDCl3) d 8.07 (s, 1H),
7.67–7.54 (m, 4H), 7.49–7.34 (m, 6H), 3.86 (s, 3H), 3.59
(s, 2H), 2.66 (d, J¼18.5 Hz, 1H), 2.27 (d, J¼18.5 Hz, 1H),
1.23 (s, 3 H), 1.03 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 201.6, 176.7, 162.0, 135.7, 135.4, 132.5, 129.7, 127.6,
69.0, 49.6, 51.7, 46.4, 44.8, 26.5, 21.7, 19.0; HRMS ES
20
373.1967; ½aꢃD ꢀ31.9 (c 1.6, CHCl3).
4.31. (S)-4-(tert-Butylmethylphenylsilanyloxymethyl)-2-
iodo-4-methylcyclopent-2-enone (65)
20
m/z (M+Na)+ calcd 445.1806, obsd 445.1784; ½aꢃD ꢀ38.4
3,5-Dimethylpyrazole (179 g, 1.87 mol) was added to a sus-
pension of chromium(ꢁVI) oxide (189.9 g, 1.899 mol) in dry
CH2Cl2 (1 L) at ꢀ15 C and stirred at this temperature for
20 min prior to the introduction of a solution of 64
(43.67 g, 0.125 mol) in dry CH2Cl2 (200 mL). The mixture
(c 1.0, CHCl3).
Acknowledgment
S.P. is indebted to the Austrian Science Fund (FWF) for the
award of an Erwin Schrodinger postdoctoral fellowship
¨
(project number: J2402).
ꢁ
was stirred for 1 h at ꢀ15 C, filtered through a pad of
SiO2 (ethyl acetate 1:hexane 3), and freed of solvent. The
residue was purified by chromatography on silica gel
(hexane–ethyl acetate 5:1) to afford the enone as a pale
orange oil (18.74 g, 41%); IR (neat, cmꢀ1) 1717, 1589,
1
References and notes
1472; H NMR (250 MHz, CDCl3) d 7.65–7.58 (m, 4H),
7.49–7.32 (m, 7H), 6.12 (d, J¼5.6 Hz, 1H), 3.56 (s, 2H),
2.46 (d, J¼18.4 Hz, 1H), 2.08 (d, J¼18.4 Hz, 1H), 1.21 (s,
3H), 1.05 (s, 9H); 13C NMR (75 MHz, CDCl3) d 209.9,
169.9, 135.4, 133.0, 132.8, 129.6, 127.5, 69.4, 47.2, 45.0,
26.6, 22.3, 19.0; HRMS ES m/z (M+Na)+ calcd 387.1751,
1. Renner, M. K.; Jensen, P. R.; Fenical, W. J. Org. Chem. 1998,
63, 8346.
2. Renner, M. K.; Jensen, P. R.; Fenical, W. J. Org. Chem. 2000,
65, 4843.
3. At 81% in edema levels, 1 compares well with the existing
widely distributed antiinflammatory agent indomethacin
(71% reduction).
4. Araki, K.; Saito, K.; Arimoto, H.; Uemura, D. Angew. Chem.,
Int. Ed. 2004, 43, 81.
5. Reviews: (a) Oikawa, O. Yuki Gosei Kagaku Kyokaishi 2004,
62, 778; (b) Oikawa, O.; Tokiwano, T. Nat. Prod. Rep. 2004,
3, 321; (c) Pohnert, G. ChemBioChem 2003, 4, 713; (d) Stock-
ing, E. M.; Williams, R. M. Angew. Chem., Int. Ed. 2003, 42,
3078; (e) Pohnert, G. ChemBioChem 2001, 2, 873.
6. For examples, see: (a) Tarasow, T. M.; Kellogg, E.; Holley, B.
L.; Nieuwlandt, D.; Tarasow, S. L.; Eaton, B. E. J. Am. Chem.
Soc. 2004, 126, 11843; (b) Huang, X.-H.; van Soest, R.;
Roberge, M.; Andersen, R. Org. Lett. 2004, 6, 75; (c) Stuhl-
mann, F.; Jaeschke, A. J. Am. Chem. Soc. 2002, 124, 3238;
20
obsd 387.1752; ½aꢃD ꢀ55.4 (c 0.8, CHCl3).
To a solution of iodine (41.2 g, 0.162 mol) in dry CH2Cl2
ꢁ
(100 mL) and dry pyridine (80 mL) at 0 C was added via
cannula to a solution of the above ketone (27.54 g,
0.076 mol) in a l:l mixture of dry CH2Cl2 and pyridine
(300 mL). The resulting mixture was stirred for 5 min at
ꢁ
0 C and at rt for 22 hꢁ prior to dilution with H2O
(500 mL) and cooling to 0 C. 2 M HCl was slowly added
until pH 4 was reached, at which point the separated aqueous
layer was extracted with CH2Cl2 (600 mL). The combined
organic phases were washed with saturated sodium thiosul-
phate solution (1 L) and the aqueous phase was extracted
with CH2Cl2. The combined organic phases were dried
and the solvent evaporated to leave a brown oil, which was
purified by chromatography on silica gel (hexane–ethyl
acetate 1:1) to give 65 as a pale yellow oil (35.9 g, 97%);
(d) Seelig, B.; Keiper, S.; Stuhlmann, F.; Jaschke, A. Angew.
Chem., Int. Ed. 2000, 39, 4576.
¨
1
IR (neat, cmꢀ1) 1721, 1578, 1472; H NMR (250 MHz,
7. Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404.
8. (a) Comins, D. L.; Zhang, Y.-M.; Zheng, X. Chem. Commun.
1998, 2509; (b) Maradyn, D. J.; Weedon, A. C. J. Am. Chem.
Soc. 1995, 117, 5359.
9. (a) Shapiro, R. H. Org. React. 1976, 23, 1976; (b) Chamberlin,
A. R.; Bloom, S. H. Org. React. 1990, 39, 1.
10. Review: Crimmins, M. T.; Reinhold, T. L. Org. React. 1993,
44, 297.
CDCl3) d 7.68–7.58 (m, 4H), 7.50–7.32 (m, 6H), 7.37 (s,
1H), 3.55 (s, 2H), 2.62 (d, J¼18.3 Hz, 1H), 2.19 (d,
J¼18.3 Hz, 1H), 1.19 (s, 3H), 1.03 (s, 9 H); 13C NMR
(75 MHz, CDCl3) d 202.6, 174.6, 135.4, 132.6, 129.7,
127.6, 101.7, 68.9, 49.6, 42.1, 26.6, 21.9, 14.0; HRMS ES
20
m/z (M+Na)+ calcd 513.0717, obsd 513.0727; ½aꢃD 55.4 (c
2.6, CHCl3).

5194
S. Pichlmair et al. / Tetrahedron 62 (2006) 5178–5194
11. (a) Bach, T.; Kemmler, M.; Herdtweck, E. J. J. Org. Chem.
2003, 68, 1994; (b) Mattay, J.; Banning, A.; Bischof, E. W.;
Heidbreder, A.; Runsink, J. Chem. Ber. 1992, 125, 2119.
12. Westermann, B.; Scharmann, H. G.; Kortmann, I. Tetrahedron:
Asymmetry 1993, 4, 2119.
13. Torii, S.; Inokuchi, T.; Mizuguchi, K.; Yamazaki, M. J. Org.
Chem. 1979, 44, 2303.
14. Birman, V. B.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124,
2080.
33. At higher temperatures, a significant amount of diprotected
product was isolated.
34. (a) Review: Chai, Y.; Hong, S.; Lindsay, H. A.; McFarland, C.;
McIntosh, M. C. Tetrahedron 2002, 58, 2905; (b) For proce-
dural details, consult Ariza, X.; Garcia, J.; Lopez, M.; Montser-
rat, L. Synlett 2001, 120.
35. (a) Carreira, E. M.; Frantz, D. E.; Fassler, R. J. Am. Chem. Soc.
2000, 122, 1806; (b) Anand, N. K.; Carreira, E. M. J. Am.
Chem. Soc. 2001, 123, 9687.
15. Paquette, L. A.; Duan, M.; Konetzki, I.; Kempmann, C. J. Am.
Chem. Soc. 2002, 124, 4257.
36. Parker, K. A.; Ledeboer, M. W. J. Org. Chem. 1996, 61, 3214;
and references therein.
16. Basu, K.; Richards, J.; Paquette, L. A. Synthesis 2004, 2841.
17. Wang, Z. Tetrahedron Lett. 1989, 30, 6611.
37. (a) Trost, B. M.; Krische, M. J. Synlett 1998, 1; (b) Aubert, C.;
Buisine, O.; Malacria, M. Chem. Rev. 2002, 102, 813; (c) Trost,
B. M. Acc. Chem. Res. 1990, 23, 34.
38. (a) Trost, B. M.; Romero, D. L.; Rise, F. J. Am. Chem. Soc.
1994, 116, 4268; (b) Trost, B. M.; Tanoury, G. J.; Lautens,
M.; Chan, C.; MacPherson, D. T. J. Am. Chem. Soc. 1994,
116, 4255; (c) Trost, B. M.; Chung, J. T. L. J. Am. Chem.
Soc. 1985, 107, 4586; (d) Trost, B. M.; Lee, D. C. J. Org.
Chem. 1989, 54, 2271; (e) Holzapfel, C. W.; Lizel, M.; Toerien,
F. Tetrahedron 1999, 55, 3467.
39. (a) Negishi, E.; Holmes, S. J.; Tour, J. M.; Miller, J. A.; Ceder-
baum, F. E.; Swanson, D. R.; Takahashi, T. J. Am. Chem. Soc.
1989, 111, 3336; (b) Krafft, M. E.; Wilson, A. M.; Dasse, O. A.;
Bonaga, L. V. R.; Cheung, Y. Y.; Fu, Z.; Shao, B.; Scott, I. L.
Tetrahedron Lett. 1998, 39, 5911.
18. Evans, D. A. Aldrichimica Acta 1982, 15, 23.
19. (a) Evans, D. A.; Morrissey, M. M.; Dorow, R. L. J. Am. Chem.
Soc. 1985, 107, 4346; (b) Wang, Z. Tetrahedron Lett. 1989, 30,
6611; (c) Wang, Z. Tetrahedron Lett. 1991, 32, 4631; (d) Arva-
nitis, E.; Motevalli, M.; Wyatt, P. B. Tetrahedron Lett. 1996, 37,
4277; (e) Winkler, J. D.; Holland, J. M.; Kasparek, J.; Axelsen,
P. H. Tetrahedron 1999, 55, 8199; (f) Harmat, N. J. S.; Man-
gani, S.; Perrotta, E.; Giannotti, D.; Nannicini, R.; Altamura,
M. Tetrahedron Lett. 2000, 41, 1261; (g) Wee, A. G. H.; Yu,
Q. J. Org. Chem. 2001, 66, 8935.
20. (a) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226; (b) Gemal,
A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
21. Srikrishna, A.; Hememalini, P. J. Org. Chem. 1990, 55, 4883.
22. Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron
Lett. 1988, 29, 4139.
40. Bear, B. R.; Sparks, S. M.; Shea, K. J. Angew. Chem., Int. Ed.
2001, 40, 820.
23. (a) Hanessian, S.; Ugolini, A.; Dube, D.; Hodges, P. J.; Andre,
C. J. Am. Chem. Soc. 1986, 108, 2776; (b) White, J. D.; Ame-
dio, J. C. J. Org. Chem. 1989, 54, 736.
41. Some representative conditions include: (a) enolate generation
with LiHMDS or NaHMDS. (b) protonolysis with TsOH
in benzene. (c) catalysis with EtAlCl2 or AlCl3/AlMe3 in
ꢁ
24. Paterson, I.; Tudge, M. Angew. Chem., Int. Ed. 2003, 42, 343.
25. Examples of conditions giving rise to decomposition include:
CH2Cl2 at 0 C or below, and the like.
42. Ruiz, M. de L., unpublished observations.
43. Ramadrandran, P. V.; Chen, G.-M.; Brown, H. C. J. Org. Chem.
1996, 61, 88.
44. Wright, J.; Drtina, G. J.; Roberts, R. A.; Paquette, L. A. J. Am.
Chem. Soc. 1988, 110, 5806.
45. Toyama, K.; Iguchi, S.; Sakazaki, H.; Oishi, T.; Hirama, M.
Bull. Chem. Soc. Jpn. 2001, 74, 997.
46. Grinsteiner, T.; Yoshito, K. Tetrahedron Lett. 1994, 35, 8337.
47. Liu, H.-J.; Ulibarri, G.; Browne, E. N. C. Can. J. Chem. 1992,
70, 1545.
ꢁ
DBꢁU, toluene, 80 C; KOt-Bu, ꢁ C6H8, rt; KOtBu, THF,
50 C; LiBr, Li2CO3, HMPA, 100 C. In all cases, a reduction
in temperature returned unchanged 37.
26. (a) Reich, H. J.; Wollowitz, S. J. J. Am. Chem. Soc. 1982, 104,
7051; (b) Wang, T.-Z.; Paquette, L. A. J. Org. Chem. 1986, 51,
5232; (c) Paquette, L. A.; Wang, T.-Z.; Luo, J.; Cottrell, C. E.;
Clough, A. E.; Anderson, L. B. J. Am. Chem. Soc. 1990, 112,
239.
27. Basu, K. unpublished observations.
28. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974; (b) Rossiter, B. E.; Katsuki, T.; Sharpless, K. B. J. Am.
Chem. Soc. 1981, 103, 464; (c) Martin, V. S.; Woodard, S. S.;
Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am.
Chem. Soc. 1981, 103, 6237.
48. Jung, M. E.; Davidov, P. Angew. Chem., Int. Ed. 2002, 41, 4125.
49. Baker, R.; Selwood, D. L.; Swain, C. J.; Webster, N. M. H.
J. Chem. Soc., Perkin Trans. 1 1988, 471.
50. Ireland, R. E.; Thompson, W. J.; Mandel, N. S.; Mandel, G. S.
J. Org. Chem. 1979, 44, 3583.
29. Liu, Z.; Lan, J.; Li, Y. Tetrahedron: Asymmetry 1998, 9, 3755.
30. For R3¼Bn, see: (a) Doubsky, S.; Streinz, L.; Saman, D.; Zed-
nik, J.; Koutek, B. Org. Lett. 2004, 6, 4909; (b) Sato, A.; Kino-
sita, H.; Shinokubo, H.; Oshima, K. Org. Lett. 2004, 6, 2217;
(c) Takami, K.; Mikami, S.; Yorimitsu, H.; Shinokubo, H.; Osh-
ima, K. J. Org. Chem. 2003, 68, 6627; (d) Krafft, M. E.; Hiro-
sawa, C.; Dalal, N.; Ramsey, C.; Stiegman, A. Tetrahedron
Lett. 2001, 42, 7733.
51. For examples: Ichihara, A.; Kimura, R.; Moriyasu, K.; Saka-
mura, S. Tetrahedron Lett. 1977, 49, 4331.
52. (a) Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96,
7807; (b) Jung, M. E.; McCombs, C. A.; Charles, A. Tetra-
hedron Lett. 1976, 34, 2935.
53. Caine, D.; Harrison, C. R.; VanDerveer, D. J. Tetrahedron Lett.
1983, 24, 1353.
54. O’Connor, P. D.; Mander, L. N.; McLachlan, M. M. W. Org.
Lett. 2004, 6, 703.
31. (a) Andrews, J. C.; Crawford, T. C.; Bacon, B. E. J. Org.
Chem. 1981, 46, 2976; (b) Hubschwerlein, C. Synthesis
1986, 962.
55. Roush, W. R. Comprehensive Organic Synthesis, Vol. 5;
Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon:
Oxford, 1992; pp 513–550.
32. Bruckner, R. Tetrahedron Lett. 1988, 29, 5747.
¨