Total synthesis of five thapsigargins: Guaianolide natural products exhibiting sub-nanomolar SERCA inhibition

Article abstract of DOI:10.1002/chem.200700302

Herein we describe the total synthesis of five guaianolide natural products: thapsigargin. thapsivillosin C, thapsivillosin F, trilobolide and nortrilobolide. Prodrug derivatives of thapsigargin have shown selective in vivo cytotoxicity against prostate tumours and the need for further investigation of this phenomenon highlights the importance of these total syntheses. The first absolute stereochemical assignment of thapsivillosin C is also delineated.

Full text of DOI:10.1002/chem.200700302

DOI: 10.1002/chem.200700302
Total Synthesis of Five Thapsigargins: Guaianolide Natural Products
Exhibiting Sub-Nanomolar SERCA Inhibition
Stephen P. Andrews, Matthew Ball, Frank Wierschem, Ed Cleator, Steven Oliver,
Klemens Hçgenauer, Oliver Simic, Alessandra Antonello, Udo Hünger,
Martin D. Smith, and Steven V. Ley*[a]
Abstract: Herein we describe the total synthesis of five guaianolide natural prod-
ucts: thapsigargin, thapsivillosin C, thapsivillosin F, trilobolide and nortrilobolide.
Keywords:
natural products · sesquiterpene ·
thapsigargin · total synthesis
guaianolide
·
Prodrug derivatives of thapsigargin have shown selective in vivo cytotoxicity
against prostate tumours and the need for further investigation of this phenomen-
on highlights the importance of these total syntheses. The first absolute stereo-
chemical assignment of thapsivillosin C is also delineated.
Table 1. The 17 known thapsigargins.
Introduction
The Thapsigargins: Thapsigargin (1) is the most prominent
and intensely studied member of the family of 17 structural-
ly-related sesquiterpenones isolated from Thapsia, which are
collectively termed the thapsigargins. All are densely oxy-
genated 6,12-guaianolides (Figure 1) differing only in the
Name
R1
R2
1
2
3
4
5
6
7
8
thapsigargin
trilobolide
O-Oct
H
H
But
(S)-2-MeBut
But
Sen
2-MeBut
But
nortrilobolide
thapsivillosin F
thapsivillosin C
thapsigargicin
thapsitranstagin
thapsivillosning AO-A
thapsivillosin B
thapsivillosin D
thapsivillosin E
thapsivillosin G
thapsivillosin H
thapsivillosin I
thapsivillosin J
thapsivillosin L
thapsivillosin K
H
O-Oct
O-Hex
O-iVal
Sen
O-Ang
O-6-MeOct
O-6-MeOct
O-6-MeHep
O-Ang or -Sen
O-Ang
2-MeBut
Figure 1. Structures of 6,12- and 8,12-guaianolides, respectively.
9
2-MeBut
Sen
2-MeBut
2-MeBut
Ang or Sen
But
But
But
2-MeBut
10
11
12
13
14
15
16
17
acyl groups appended to O-2 or O-8, with the exception of
trilobolide (2), nortrilobolide (3) and thapsivillosin F (4)
(the trilobolide series) which are not oxygenated at C-2
(Table 1).[1,2]
O-iVal
O-But
O-Sen
The first isolated thapsigargin was trilobolide (2), from
Laser trilobum in 1968,[3] and it remains the only member of
Abbreviations: But=butanoyl, Sen=senecioyl, Ang=angeloyl, Hex=
hexanoyl, Hep=heptanoyl, Oct=octanoyl, iVal =isovaleroyl.
[a] Dr. S. P. Andrews, Dr. M. Ball, Dr. F. Wierschem, Dr. E. Cleator,
Dr. S. Oliver, Dr. K. Hçgenauer, Dr. O. Simic, Dr. A. Antonello,
Dr. U. Hünger, Dr. M. D. Smith, Prof. Dr. S. V. Ley
University Chemical Laboratory, Lensifield Road
Cambridge, CB21EW (UK)
the family to have been discovered in a plant outside the
Thapsia genus.[1a] Degradation of trilobolide and identifica-
tion of the (S)-2-methylbutanoyl side chain allowed the first
absolute stereochemical assignment of its crystal structure,[4]
and these findings were used to aid the first correct stereo-
Fax : (+44)1223-336442
E-mail: svl1000@cam.ac.uk
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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FULL PAPER
chemical assignment of thapsigargin,[5,6] isolated from Thap-
sia garganica L. in 1978.[7,8]
of it every year, elevating the need for an efficient route to
the natural products and related analogues.[25]
Owing to the extensive medicinal uses of Thapsia prepa-
rations, which have been recorded as far back as the time of
Hippocrates (ca. 400 BC),[9] the isolation of thapsigargin
prompted immediate investigation into the origins of its bio-
logical activity. Initially, thapsigargin was found to be a his-
tamine liberator,[7,10] but the subsequent discovery of its
potent inhibitory action on sarco/endoplasmic reticulum AT-
Pases (SERCAs),[11,12] earned it widespread and increasing
recognition as a powerful molecular tool for studying cell
physiology.[13]
Thapsigargin is a sub-nanomolar inhibitor of molecular
Ca2+ pumps, SERCA.[14] When applied to intact cells, thap-
sigargin can severely alter cellular Ca2+ levels,[15] leading to
disrupted cell growth and function,[16] and in many cases to
programmed cell death.[17,18] Recently, prodrug derivatives
have shown potential as treatments for prostate cancer by
exploiting this mechanism, and with the continual emer-
gence of new analogues and a growing understanding of the
SAR of the natural product, a viable drug candidate appears
increasingly attainable.[19–23]
Coupling the peptide residue His-Ser-Ser-Lys-Leu-Gln to
an amine linker attached to thapsigargin at O-8 generated
18 (Figure 2), which when used to treat mice with xenograft
tumours, was cytotoxic specifically to prostate tumours,
whilst having no observed effect on renal carcinomas.[24]
Compound 18 is cell impermeant and stable in mouse and
human blood plasma, but is cleaved extracellularly by pros-
tate-specific antigen (PSA, found in the vicinity of prostate
tumours). The enzyme recognises and cleaves the peptide
sequence, delivering a cell permeable, cytotoxic thapsigargin
derivative to the site of action.
Despite the wealth of biologically-related publications on
the thapsigargins, the synthetic community has been slow to
respond.[26] The intriguing structural complexity of the thap-
sigargins first attracted our attention some years ago, and
we have previously published communications describing
the total synthesis of the trilobolide series;[27] thapsigargin
itself;[28] designed unnatural analogues,[23b] including those
which exhibit sub-picomolar inhibition of SERCA;[23a] as
well as a review in which we described our early synthetic
strategies.[29] In this full paper, we detail how our current
route may facilitate efficient access to all 17 of the known
thapsigargins, as well as a range of unnatural analogues
which have been used for SAR studies. We delineate five
total syntheses, including the previously unpublished total
synthesis and absolute stereochemical assignment of thapsi-
villosin C (5);[30] and demonstrate how degradation studies
of a natural sample of thapsigargin helped resolve critical
end-game stereochemical issues.
Synthetic plan: We have previously disclosed some of our
early attempts to prepare the guaianolide skeleton of thapsi-
gargin, and the iterations that led to our current route.[29]
One of the major benefits of this route is the inherent sub-
strate control that governs each newly established stereo-
genic centre, and this has allowed us to obtain thapsigargin
as a single diastereomer in 42 synthetic steps from (S)-car-
vone (25) (average yield of 88.6% per step). Furthermore,
these reactions can reliably be conducted on multi-gram
scale and exhibit consistently high yields and selectivities
without the need for extensive chromatographic purification
between steps.
Prostate cancer is the most frequently diagnosed cancer in
men, accounting for more than 25% of new male cancer di-
agnoses in the UK (population ca. 61 million). The lifetime
risk of being diagnosed with prostate cancer for men in the
UK is 1 in 14, but currently, no method for the treatment of
androgen-independent primary or metastatic prostate can-
cers exists.[19] In 2005, more than 30000 men were diagnosed
with the disease and more than 10000 die as a direct result
The polycyclic thapsigargins incorporate dense arrays of
oxygenated stereocentres and up to four different ester
functionalities. We anticipated that the late-stage C-2 oxida-
tion of a suitable precursor, such as 19, and sequential in-
stallation of the esters would impart a degree of flexibility
to the route that would provide access to all 17 of the
known thapsigargins, including trilobolide, nortrilobolide
and thapsivillosin F, which do not carry oxygenation at C-2
(Scheme 1). Of further significance is the observation that
we can tailor our approach to allow acylation at O-8 as the
last step of the synthesis, allowing efficient access to prodrug
conjugates for the treatment of prostate cancer.
Another key disconnection came from the recognition
that the C-7/11 anti diol could be installed via the well-es-
tablished syn osmylation reaction.[31] By performing a dihy-
droxylation/translactonisation protocol on a suitable precur-
sor, such as 8,12-guaianolide 20, the syn diol would be trans-
lated into the requisite anti C-7/11 diol with concomitant
formation of the correct 6,12-guaianolide geometry. It was
thought that the butenolide 20 could be derived from a bicy-
clic intermediate such as 21, a molecule which later proved
to be an important common intermediate for our analogue
projects.[23] It was envisaged that ketone 21 would be avail-
able from enol ether 22 via ring-closing metathesis[32] and di-
Figure 2. Hexapeptide side chain of 18 is recognised and cleaved by a
protease, releasing a cell-permeable, cytotoxic thapsigargin derivative.
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S. V. Ley et al.
Scheme 1. Retrosynthesis of thapsigargin.
hydroxylation.[31] The enantiomer of cyclopentane 23 has
previously been prepared in four steps from (R)-carvone,[33]
and was used in the total synthesis of cladantholide and es-
tafiatin.[34] Commercially-available (S)-carvone was there-
fore an ideal starting point for the generation of 23 via a Fa-
vorskii[35] ring-contraction of 24.
vorskii rearrangement: treatment of 28 with sodium methox-
ide at 08C effected a stereo- and regioselective rearrange-
ment, affording one cyclopentane geometry (30) (but as a
mixture of epimeric acetals), whereas, treatment of the anal-
ogous tert-butyldiphenylsilyl ether 29 with the same reaction
conditions afforded 73% of the desired cyclopentane 32.[38]
With the functionalised cyclopentane motif 30 in hand, the
more robust tert-butyldiphenylsilyl protecting group was in-
troduced via a two-step process, affording 32 as a single dia-
stereomer (dr >19:1). This opening sequence of reactions
has been used effectively on scales in excess of 100 g of (S)-
carvone to efficiently generate large quantities of synthetic
intermediates.
Based on previous work in our group, we were confident
that the correct C-6 stereochemistry of the natural product
could later be controlled by Felkin–Anh addition of a suita-
ble nucleophile to a C-6 aldehyde,[39] so we now turned our
attention to installing the C-10 stereocentre (Scheme 3). Re-
duction of methyl ester 32 and protection of the resultant
primary hydroxyl as a para-methoxybenzyl ether[40] afforded
34 which was smoothly converted to ketone 35 by oxidative
cleavage with osmium tetroxide and sodium periodate.[41]
Dropwise addition of allylmagnesium bromide to the ketone
at ꢀ788C afforded the desired C-10 (S)-configured homoal-
lylic alcohol 36s as the major product, but with a relatively
low diastereomeric ratio of 3.5:1. Preliminary attempts to
form 36s via an enantioselective allylation reaction proved
fruitless, but further optimisation of the Grignard reaction
allowed the selectivity of the process to increase to 11:1 in
favour of the desired product (Table 2).[42]
Results and Discussion
Synthesis and elaboration of cyclopentane fragment 32: The
opening sequence of reactions leading to common inter-
mediate 21 began with commercially-available (S)-carvone
and used a Favorskii ring-contraction to deliver a functional-
ised cyclopentane unit 32 as a single diastereomer (dr
>19:1).[33] Thus, stereoselective epoxidation[36] of enone 25
and acid-mediated opening of the resulting oxirane[37] af-
forded chlorohydrin 27 as a single diastereoisomer (dr
>19:1, Scheme 2). Protection of the chlorohydrin as a tetra-
hydropyranyl acetal 28 was pivotal to the success of the Fa-
After further screening of reaction conditions, it was
found that on a small scale (100 mg of ketone), pre-mixing
ketone 35 with titanium(IV) isopropoxide in 1,2-dimethoxy-
ethane, and then addition of allylmagnesium bromide, gen-
erated an 11:1 diastereomeric mixture of C-10 alcohols in
preference for the desired Felkin–Anh product 36s; howev-
er, on larger scales this ratio dropped to 6:1. By pre-mixing
the ketone with MgBr2·Et2O in 1,2-dimethoxyethane before
addition of the Grignard reagent, it was found that a consis-
Scheme 2. Generation of cyclopentane fragment 32. a) H2O2, MeOH,
NaOH, RT, 3 h; b) TFA, THF, LiCl, 08C, 90 min, 98% over two steps; c)
2,3-dihydropyran, PPTS, CH2Cl2, RT, 17 h, 84%; d) NaOMe, MeOH,
Et2O, 0 8C, 1 h; e) MeOH, PPTS, 508C, 15 h; f) TBDPSCl, imidazole,
DMAP, DMF, RT, 16 h, 84% over three steps (TFA=trifluoroacetic
acid, THF=tetrahydrofuran, PPTS=pyridinium para-toluenesulfonate,
TBDPS=tert-butyldiphenylsilyl, THP=tetrahydropyran-2-yl).
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Natural Products
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Scheme 3. Formation of aldehyde 39. a) LiAlH4, THF, 08C, 1 h, then RT, 1 h, 99%; b) NaH, PMBCl, DMF, RT, 15 h, 82%; c) OsO4, NMO, Me2CO,
H2O, RT, 4.5 h, then NaIO4, 08C, 30 min, 92%; d) MgBr2·Et2O, DME, allylmagnesium bromide, ꢀ788C, 2 h, (dr 8:1); e) MOMCl, Hünigꢁs base, DMAP,
CH2Cl2, RT, 3 d, 84% over two steps; f) DDQ, pH 7 buffer, RT, 30 min, then column chromatography, 75% 38s (dr >24:1); g) DMP, NaHCO3, CH2Cl2,
RT, 1 h (PMB=para-methoxylbenzyl, DMF=N,N-dimethylformamide, NMO=N-methylmorpholine-N-oxide, DME=1,2-dimethoxyethane, MOM=me-
thoxylmethyl, DMAP=4-N,N-dimethylaminopyridine, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone).
Table 2. Allylation of 35.
component. Removal of the
methoxymethyl acetal from
38s afforded diol 40s which
was oxidised[46] to lactone 41s
(Scheme 4; the corresponding
lactone 41r was also made in
the same fashion). Comparison
of the NOE data for the two
lactones clearly demonstrated
that the major product from
the allylation of ketone 35 ex-
hibited the desired C-10 ste-
reochemistry.
With the successful forma-
tion of aldehyde 39, we were
now in a position to investigate
the addition of nucleophiles to
this substrate. Unfortunately,
Reagent(s)
Solvent
T [8C]
Yield [%]
dr (36s/36r)
AllylMgBr
AllylMgBr
AllylMgBr
AllylMgCl
AllylMgBr
AllylMgBr
AllylMgBr
AllylMgBr, MgBr2·Et2O
AllylMgBr, MgBr2·Et2O
PhMe
Et2O
THF
THF
THF
DME
DME
THF
DME
DME
DME
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ100
ꢀ78
ꢀ100
ꢀ78
ꢀ78
ꢀ78
ꢀ78
99
98
99
82
89
99
93
99
1.5:1
1.8:1
3:1
3.5:1
3.5:1
7:1
7:1
5:1
99
8:1[a]
11:1[b]
6:1[c]
AllylMgBr, Ti
AllylMgBr, Ti
A
quantitative
quantitative
ACHTREUNG
[a] Irrespective of scale. [b] 100 mg reaction scale w.r.t. ketone. [c] 1.9 g scale w.r.t. ketone.
tent ratio of C-10 alcohols could be achieved at 8:1 (S/R),
regardless of scale.
one relatively large batch of the aldehyde (ca. 20 g) was
found to decompose on storage at 08C, affording 42 as the
When compared to the reaction with titanium(IV) iso-
propoxide, this procedure also had the added advantage that
the metal salts generated on work-up were more easily re-
moved at the end of the reaction, thus column chromatogra-
phy could be avoided at this stage. Nonetheless, separation
of the C-10 isomers was not trivial, and they were carried
through the next two steps as a mixture. Protection of the
alcohols as methoxymethyl acetals,[43] and oxidative cleavage
of the benzylic ethers at pH 7[44] afforded a mixture of C-10
isomers (38s and 38r). The C-10 diastereomers were separa-
ble by flash column chromatography at this stage, and oxi-
dation[45] of the desired isomer 38s to the requisite C-6 alde-
hyde was now possible.
Scheme 4. Synthesis of lactones 41s and 41r (R=TBDPS). a) PPTS,
MeOH, RT, 34%; b) cat. TPAP, NMO, 4 Š molecular sieves, CH2Cl2, RT,
76%; c) PPTS, MeOH, RT, 32%; d) cat. TPAP, NMO, 4 Š molecular
sieves, CH2Cl2, RT, 92% (TPAP=tetra-n-propylammonium perruthen-
ate).
Following the successful separation of the two C-10 epi-
mers, we were able to set about determining whether we
had correctly assigned the stereochemistry of the major
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S. V. Ley et al.
major decomposition product (Scheme 5). It was felt that
we may be able to recover this material, but before attempt-
ing to regenerate the aldehyde from 42, it was necessary to
check the integrity of the C-10 stereocentre through the de-
Scheme 6. Formation of bicyclic intermediate 49. a) Ethyl vinyl ether,
tBuLi, THF, ꢀ788C, 90 min; b) TESCl, imidazole, DMAP, DMF, RT,
19 h, 86% over three steps from alcohol 38s; c) Grubbs’ second genera-
tion catalyst, CH2Cl2, reflux, 21 h, 88%; d) AD-mix a, NaHCO3,
MeSO2NH2, tBuOH, H2O, RT, 15 h, 96%; e) TBAF, THF, 08C, 20 min
(TES=triethylsilyl).
Scheme 5. Regeneration of alcohol 38s from decomposition product 42.
a) decomposition of 42 at 08C; b) AcOH, THF, H2O, 35 8C, 3 d, 62%; c)
cat. TPAP, NMO, 4 Š molecular sieves, CH2Cl2, 87%; d) NaBH4, MeOH,
RT, 18 h, 75 %; e) Ac2O, DMAP, pyridine, CH2Cl2, RT, 16 h; f) MOMCl,
Hünigꢁs base, DMAP, CH2Cl2, RT, 5 d; g) NaOMe, MeOH, 99% over
three steps.
(16:1) without the use of chiral reagents, at this point we
could opt to use Sharpless’ asymmetric dihydroxylation con-
ditions[50] to improve this ratio further. Treatment of enol
ether 48 with AD mix-a led to the desired hydroxy ketone
49 as the only detectable isomer [dr >19:1; treatment of 48
with AD mix-b gave a product ratio of 1.3:1 (S/R at C-8)].
The relative stereochemistry of 49 was unambiguously deter-
mined by removal of the TES group, affording crystalline
derivative 50, which was subjected to X-ray analysis.[51]
composition. To this end, a sample of 42 was hydrolysed to
43, and the lactol was oxidised to known lactone 41s.[46]
Thus, the integrity of the C-10 stereocentre had been re-
tained through the decomposition of 42, and we were able
to set about salvaging this batch of material.
Lactol 43 was reduced with sodium borohydride affording
diol 40s; temporary protection of the primary hydroxyl as
the corresponding acetate allowed selective formation of a
methoxymethyl acetal at the more hindered tertiary alcohol.
Transesterification of the acetate then afforded alcohol 38s,
the synthetic precursor of the aldehyde which had decom-
posed. This series of reactions ultimately regenerated over
10 g of the desired alcohol 38s, and provided intermediates
which were converted into simple analogues for SAR stud-
ies.
Guaianolide formation: Butenolide 51 was prepared in two
steps from a-hydroxy ketone 49 via a tethered Horner–
Wadsworth–Emmons reaction (Scheme 7).[52] However, di-
hydroxylation of 51 proved difficult, presumably due to a
combination of steric and electronic factors. To address this
issue, the butenolide was reduced and differentially protect-
ed, affording 54. The desired dihydroxylation reaction of the
ring opened derivative 54 could be achieved; osmylation of
54 was slow, possibly due to steric hindrance from the neigh-
bouring bulky silyl group, but the reaction proceeded with
excellent facial selectivity and delivered the desired tetrol
product 55 as the only detectable isomer (dr >19:1) after
removal of the acetate and TES groups.
Synthesis of bicyclic intermediate 49: Addition of a solution
of aldehyde 39 to the lithium anion of ethyl vinyl ether at
ꢀ788C occurred as predicted, with Felkin–Anh control, to
deliver the desired alcohol 46 as the major product (dr
>19:1). Formation of the corresponding triethylsilyl ether
provided the required metathesis precursor 47, and continu-
al dropwise addition of Grubbs’ second generation cata-
lyst[47] to the diene in refluxing dichloromethane generated
enol ether 48 in a pleasing 88% isolated yield (Scheme 6).
Osmylation of 48 under Upjohn conditions[48] afforded a
12:1 mixture of a-hydroxy ketones, in favour of the desired
C-8 (S)-diastereomer, and this ratio could be improved to
16:1 using Sharpless’ biphasic conditions[49] with potassium
ferricyanide and catalytic osmium tetroxide.
TPAP oxidation[46] of tetrol 55, led exclusively to the de-
sired 6,12-guaianolide system 56, with the C-7/8/11 stereo
triad bearing the correct stereochemistry of the natural
products. In a one-pot reaction sequence, the methoxymeth-
yl acetals were then hydrolysed under acidic conditions in
wet acetone and after 48 h, molecular sieves were added to
the reaction mixture to drive the formation of the isopropy-
lidene ketal 57.
The remaining key steps of the total synthesis of thapsi-
gargin would involve the introduction of the C-4/5 alkene,
stereoselective C-2 oxidation and regioselective installation
of the four different esters. It was anticipated that the C-2
oxygen of thapsigargin could be installed using a Rubottom
oxidation.[53] To that end, the O-3 hydroxyl was unmasked
It is worthy of mention that although we could obtain the
desired product 49 with a respectable diastereomeric ratio
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Natural Products
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Scheme 7. Generation of 6,12-guaianolide 19. a) EDCI, HO2CCH(Me)P(O)(OEt)2, CH2Cl2, RT, 3 h, 81%; b) NaH, reflux, 15 min; c) LiBH4, THF,
G
reflux, 40 h; d) Ac2O, DMAP, 2,6-lutidine, CH2Cl2, RT, 3 h; e) MOMCl, Hünigꢁs base, DMAP, CH2Cl2, RT, 18 h, 60% over four steps; f) OsO4, quinucli-
dine, K2CO3, MeSO2NH2, K3Fe(CN)6, tBuOH, H2O, RT, 17 d; g) K2CO3, MeOH, RT, 85% over two steps; h) 10 mol% TPAP, 40 equiv NMO, 4 Š molec-
ular sieves, MeCN, RT, 74%; i) Amberlyst 15, wet Me2CO, 2,2-dimethoxypropane, RT, then 4 Š molecular sieves, 95%; j) TBAF, THF, RT; k) Dess–
Martin periodinane, NaHCO3, CH2Cl2, RT, 91% over two steps (EDCI=1-ethyl-3-(3’-dimethylaminopropyl)carbodiimide, TBAF=tetrabutylammonium
fluoride).
under standard conditions, and oxidised to the correspond-
not harbour oxygenation at C-2. Reduction of 62 with
sodium borohydride afforded the desired alcohol 63, which
is the fully oxygenated guaianolide skeleton required for the
total synthesis of the trilobolide series.
ing ketone 19 with Dess–Martin periodinane.[45]
Enone formation part I—Total synthesis of the trilobolide
series: Enolisation of the ketone 19 was found to occur at
the less hindered (C-2) position with trimethylsilyl chloride
and triethylamine at 1208C, affording silyl enol ether 59
(Scheme 8). Oxidation with dimethyldioxirane occurred ex-
clusively from the exo face to give the desired C-2 alcohol
61 (dr >19:1). It was found that treatment of 61 with trime-
thylsilyl chloride and triethylamine generated the corre-
sponding silyl enol ether at C-4. Unexpectedly, treatment of
this compound with phenylselenium bromide caused a cata-
lytic reaction which resulted in loss of the newly installed C-
2 oxygen, and formation of the desired enone functionality
(62).[54] This “undesired” C-2 deoxygenation reaction had in-
advertently provided a route to the trilobolide series, as tri-
lobolide (2), nortrilobolide (3) and thapsivillosin F (4), do
Esterification of 63 under Yamaguchi conditions,[55,56] and
removal of the trimethylsilyl groups afforded 65 (Scheme 9).
The diol was then selectively acetylated at O-10, and the
acetonide removed to give the final precursor to the trilobo-
lide series. Selective acylation at the more reactive (secon-
dary) hydroxyl of 67 with (S)-2-methylbutyric anhydride, bu-
tyric anhydride or senecioic anhydride completed the first
total syntheses of trilobolide (2), nortrilobolide (3) and
thapsivillosin F (4), respectively.
Enone formation part II—O-2 MOM strategy: To address
the issue of C-2 deoxygenation of 61, the free alcohol was
converted to the corresponding octanoate 68, as required
for the total synthesis of thapsigargin (Scheme 10), but un-
fortunately, installation of the
C-4 selenide could not be ach-
ieved on this substrate.
Alternatively, O-2 could be
masked as a methoxymethyl
acetal (69, Scheme 11).[43] For-
mation of the C-4 selenide of
this substrate was possible via
the silyl enol ether without loss
of the C-2 oxygen, but an epi-
meric mixture of selenides 70
and 71 (87:13) was obtained.
Once oxidised, the selenoxide
derived from epimer 70 may
undergo syn elimination with
Scheme 8. Enone formation, part I. a) TMSCl, Et3N, DMF, 1308C, 43 h; b) DMDO, Me2CO, CH2Cl2, ꢀ788C
for 30 min, then RT for 40 min, 87% over two steps; c) TMSCl, Et3N, DMF, 1508C, 90%; d) PhSeBr, CH2Cl2,
08C to RT, 94%; e) NaBH4, MeOH, 08C, 86%, dr 4:1 (R/S at C-3) (TMS=trimethylsilyl, DMDO=dimethyl-
dioxirane).
the desired C-5 proton to
afford enone 73, or it may
eliminate with a proton from
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S. V. Ley et al.
the facial selectivity of the re-
duction with sodium borohy-
dride appeared to be very
high, as only one C-3 alcohol
could be detected (dr >19:1).
Having successfully generated
the desired C-3 stereochemis-
try of 63 by a similar means en
route to trilobolide (see enone
formation part I, above), we
postulated that once again the
hydride had been delivered
from the exo face of the ring
system, and continued to the
next step in the hope that we
would be able to confirm the
stereochemical course of this
reduction at a later stage.
Scheme 9. Total synthesis of the trilobolides a) Angelic acid, Et3N, 2,4,6-trichlorobenzoyl chloride, PhMe,
808C, 76%; b) TBAF, THF, RT, 98%; c) isopropenyl acetate, PS-pTsOH, CH2Cl2, RT, 68%; d) HCl, MeOH,
408C; e) senecioic anhydride, DMAP, CH2Cl2, RT, 60% over two steps; f) (S)-2-methylbutyric anhydride,
DMAP, CH2Cl2, RT, 78% over two steps; g) butyric anhydride, DMAP, CH2Cl2, RT, 72% over two steps
(PS=polymer supported, pTsOH=para-toluensulfonic acid).
As such, removal of the silyl
ethers formed during the sele-
nation sequence, and angeloy-
lation under Yamaguchi conditions[55,56] proceeded in moder-
ate yield, but at this stage, we were still unable to confirm
the C-3 stereochemistry. It was not until later that we
showed by direct comparison with a derivative of a natural
source of thapsigargin that we had formed the undesired
epimer 74 in the reduction reaction, and that we had now
formed the undesired C-3 angelate epimer 75 (see degrada-
tion and selective transformations of thapsigargin, below).
Although unaware of the incorrect stereogenicity at the
time of conducting this work, cleavage of the methoxymeth-
yl acetal from 75 could not be satisfactorily achieved and we
were, in any case, forced to re-evaluate the strategy.[57]
At this stage, we decided to use a 2-(trimethylsilyl)ethoxy-
methyl (SEM) acetal at O-2.[58] It was envisaged that this
group should show similar behaviour to the methoxymethyl
congener in terms of its installation and the local effects it
exerts on the substrates bearing it, but should be more
Scheme 10. C-2 octanoate installation. a) Octanoic anhydride, DMAP,
CH2Cl2, 90 min, RT, 94%.
the neighbouring methyl group, producing the exocyclic
enone 72. However, the same ratio of selenides (70/71
87:13) is expressed in the ratio of enones generated (72/73),
suggesting that 70 leads solely to the desired endocyclic
enone.
At the time of performing the reduction of 73 to afford
the corresponding allylic alcohol, we were unable to con-
vincingly assign the new stereogenic centre at C-3; however,
Scheme 11. Enone formation, part II. a) MOMCl, Hünigꢁs base, CH2Cl2, RT, 18 h, 88%; b) NaHMDS, THF, ꢀ78 to ꢀ208C then TMSCl at ꢀ788C; c)
PhSeCl, CH2Cl2, ꢀ788C, 2 h; d) O3, ꢀ788C, 2 min then diisopropylamine, ꢀ788C to RT, 37% 73 over three steps; e) NaBH4, THF, RT, 19 h, 99% (dr
>19:1); f) TBAF, THF, 08C to RT, 35 min; g) 2,4,6-trichlorobenzoyl chloride, Et3N, PhMe, angelic acid, 758C, 2 d, 48% over two steps (HMDS=bis(tri-
methylsilyl)amide).
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FULL PAPER
easily removed when required. At the same time as initiat-
ing the SEM route, we began a degradation study in which
we used a natural sample of thapsigargin in an attempt to
intercept the synthetic route and conclusively determine the
C-3 stereochemistry of derivatives such as 75.
Degradation and selective transformations of thapsigargin:
Some simple derivatives of thapsigargin have previously
been obtained via degradation of the natural product.[1a] For
example, the O-8/11 acetonide derivative (78) of thapsigar-
gin has previously been reported, as has the selective remov-
al of some of thapsigarginꢁs esters. From the outset of this
investigation, it was anticipated that further development of
such transformations would allow access to 77, and ultimate-
ly to compounds resembling our most advanced synthetic in-
termediates, such as 76 (Scheme 12). This would allow a
conclusive assessment of the stereochemistry of our synthet-
ic route by direct comparison with a natural product deriva-
Scheme 13. Known transformations of thapsigargin. a) Et3N, MeOH, RT,
7 h, 99%;[8] b) Et3N, MeOH, 758C 48 h, 47% 79 + 48% 80;[59] c) 2,2-di-
methoxypropane, Me2CO, pTsOH, RT, 3 h (yield not reported).[6]
ture (Scheme 14). When 78 was treated with sodium meth-
oxide it was found that the O-2 octanoyl and O-10 acetyl
groups were cleaved, but unfortunately, the O-3 angelate
ester was also transesterified under these conditions, afford-
ing the tetrol 81 in 81% isolated yield.
Pleasingly, it was found that the desired acetonide 77
could be formed from 80 by treatment of the pentol with
2,2-dimethoxypropane under acidic conditions, and that the
acetonide could readily be selectively mono-alkylated with
MOMCl[43] or SEMCl[58] affording 82 or 83, respectively. At
this stage, the direct comparison of 82 and 75 was possible,
and this provided the first indication that we had not ach-
ieved the desired C-3 stereochemistry during the reduction
of enone 73.[61]
Scheme 12. Proposed degradation of thapsigargin.
tive, and may provide key advanced intermediates to test
the viability of later steps on the new SEM route.
Christensen showed that methanolysis of thapsigargin (1)
in the presence of triethylamine could give O-8-debutanoyl
thapsigargin (79),[8] and this
Enone formation part III—O-2 SEM Strategy: As anticipat-
ed, the SEM route proceeded similarly to the analogous O-2
MOM route, but an improved one-pot selenation procedure
was developed, avoiding the need to isolate the unstable in-
was successfully converted to
acetonide 78 (Scheme 13).[6] If
the transesterification reaction
was performed for prolonged
reaction times at elevated tem-
perature, the O-2 and O-10
esters were also removed, af-
fording 80.[59]
We used the latter condi-
tions in an attempt to remove
the O-2 and O-10 esters from
78,[60] but when the acetonide
was treated with triethylamine
in methanol the reaction was
sluggish at 758C; after 8 h, the
temperature was increased to
Scheme 14. Selective transformation of thapsigargin derivatives. a) Et3N, MeOH, 758C, 8 h, then 958C, 24 h,
11%; b) NaOMe, MeOH, RT, 6 h, 81%; c) pTsOH, Me2CO, 2,2-dimethoxypropane, RT, 20 min, 67%; d)
MOMCl, Hünigꢁs base, DMAP, CH2Cl2, RT, 90 min, 27%; e) SEMCl, Hünigꢁs base, DMAP, CH2Cl2, RT, 48 h,
71% (SEM=2-(trimethylsilyl)ethoxymethyl).
958C but only 11% of the de-
sired triol 77 was isolated after
a further 24 h at this tempera-
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5695

S. V. Ley et al.
Scheme 15. Enone formation, part III. a) SEMCl, Hünigꢁs base, CH2Cl2, RT, 18 h, 92%; b) LiHMDS, THF, ꢀ78 to ꢀ158C, 2 h, then PhSeCl in THF,
ꢀ908C, 30 min; c) O3 then diisopropylamine, ꢀ788C, 60% over two steps; d) NaBH4, MeOH, RT, 20 h, dr >95:5; e) TBAF, 08C to RT, 2 h; f) 2,4,6-tri-
chlorobenzoyl chloride, Et3N, PhMe, angelic acid, 758C, 2 d, 50% over three steps (Note: the angeloylation reaction was later found to work more effi-
ciently by pre-forming and isolating the mixed anhydride, see below).
termediate silyl enol ether (Scheme 15). The new procedure
still generated a mixture of C-4 selenides, and as before, the
ratio of enone products (88/87 80:20) was the same as the
ratio of these epimeric selenides.
Clearly, selenoxide 86 can only perform a syn elimination
with a proton from the methyl group leading to the exocy-
clic enone 87. One possible ex-
radative route, and it was thought that the molecules dif-
fered only by their relative configuration at C-3. In order to
show this was the difference and link the two routes togeth-
er, we attempted to generate enone 94 from our natural
source of thapsigargin (Scheme 16). If we could remove the
angelate ester from 83 and oxidise the resulting secondary
planation for the observed re-
luctance of selenoxide 85 to
eliminate with a proton from
the C-4 methyl group may be
derived from the predicted
major conformation of this
molecule. It may reasonably
be assumed that the preferred
conformation of the selenoxide
is one in which the dipole of
ꢀ
the Se O bond opposes that
of the neighbouring carbonyl
group (i.e., 85 as drawn in
Scheme 15).[62] This intrinsical-
ly places the proton at C-5
within close proximity to the
selenoxide oxygen, favouring
elimination from this site. Of
course, this picture is some-
what simplified, as it does not
Scheme 16. Selective removal of angelate esters. a) 1) KMnO4, BnEt3NCl, PhMe, H2O, 7 h, RT; 2) MeOH, pyr-
idine, H2O, reflux, 7 h, 46% for 1 to 92; b) 1) O3, CH2Cl2 ꢀ788C for 2 min then PS-triphenylphosphine, RT,
18 h, 2) MeOH, pyridine, H2O, reflux 2 h 15 min, 53% for 1 to 92; c) Dess–Martin periodinane, pyridine,
CH2Cl2, RT, 2 h, 77% for 92 to 93.
take into account the configuration of the selenium atom,
which can potentially exist as two stereoisomeric forms with
different conformational preferences.
alcohol 91, the product enone should match with the syn-
thetic enone (88 after removal of its TMS groups).
As with the analogous O-2 MOM derivative (73,
Scheme 11), enone 88 was found to react with sodium boro-
hydride with good facial selectivity, but the C-3 stereochem-
istry could not be determined at this stage. After removal of
the trimethylsilyl groups and angeloylation under Yamagu-
chi conditions,[55,56] comparison of product 90 with degrada-
tion product 83 was possible. The NMR spectra of 90 from
the synthetic route did not match those of 83 from the deg-
Towards enone 94 from thapsigargin—Selective angelate
cleavage: It has been shown that the angelate ester of thap-
sigargin can be selectively removed by first oxidising with
potassium permanganate to the corresponding pyruvate, and
then hydrolysing the crude product with aqueous pyridine,[59]
but application of these conditions to degradation product
83 resulted in decomposition (Scheme 16). Whilst investigat-
ing milder procedures for the removal of angelate esters,
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FULL PAPER
thapsigargin was treated for a
limited time with ozone. It was
found that selective ozonolysis
of the angelate in the presence
of the C-4 olefin was possible,
as proved by hydrolysis of the
product to afford known alco-
hol 92. However, when this
two-step ozonolysis procedure
Scheme 17. Formation of angelate 83 via the synthetic route. a) Zn
(EDTAwork-up), 80%; b) 96, PhMe, NaHCO3, 808C, 2 d, 52%.
ACHTREUNG
was performed on angelate 83, decomposition was again ob-
served and none of the desired C-3 alcohol 91 could be iso-
lated.
(Scheme 17). For previous substrates, our favoured angeloy-
lation conditions had been to pre-mix angelic acid and 2,4,6-
trichlorobenzoyl chloride with triethylamine in toluene to
make the corresponding mixed anhydride 96 in situ and
then treat the resulting mixture with a solution of the alco-
hol to be acylated.[56] However, when these conditions were
applied to 91, they resulted in the partial loss of SEM and
bis-angeloylation at O-2/3.[65] By pre-forming and isolating
anhydride 96, and using a pure sample of this to treat the al-
cohol under mildly basic conditions, the desired angelate
ester 83 could be isolated in 52% yield.[66]
Compiling the results from all of the C-3 ketone reduc-
tions, we can make some generalisations. It appears that for
the trilobolide precursor 62, which bears no C-2 substituent,
the most significant stereocontrolling factor during the
ketone reduction, is the C-1 ring junction—sodium borohy-
dride approaches the ketone predominantly from the least
hindered (exo) face to afford the desired alcohol (63,
Scheme 8) as the major product. However, for ketones 73
and 88, sodium borohydride approaches predominantly
from the endo face, as the bulky C-2 substituent now blocks
the exo line of approach. However, by using a chelating
metal in the source of the hydride, as with zinc borohydride,
the oxygen rich C-2 protecting group can be used to deliver
hydride from the desired (exo) face.[63]
It was anticipated that an alternative route to 94 may be
achieved from thapsigargin by changing the order of steps.
First, oxidising 92 to the corresponding ketone 93, then re-
moving the remaining esters and introducing the O-8/11 ace-
tonide and O-2 SEM groups. Oxidation of 92 to enone 93
was possible with Dess–Martin periodinane (Scheme 16).[45]
However, attempts to remove the esters from 93 by treat-
ment with sodium methoxide in methanol or triethylamine
in methanol, caused decomposition and the formation of
multiple products in each case.
Stereoselective enone reduction: Further studies on the syn-
thetic route revealed that the observed facial selectivity of
the reduction of 88 with sodium borohydride could be over-
turned by performing the reaction with freshly prepared
zinc borohydride (Table 3).[63,64]
Table 3. Reduction of enone 88.
Total synthesis of thapsigargin and thapsivillosin C: Fully
aware of the facile isomerisation that angelate esters under-
go to their tiglate counterparts,[67] we were gratified to find
that treatment of 83 with n-butane thiol and MgBr2·Et2O[68]
effected clean removal of the O-2 SEM group with no ob-
served substrate decomposition or angelate scrambling
(Scheme 18). Selective acylation of the secondary C-2 alco-
hol 77 was possible with octanoic anhydride, affording 97.
However, it is important to note that esterification at this
point should be possible with a range of acylating agents, al-
lowing installation of any of the other C-2 ester moieties
found in the thapsigargins (Table 1), or indeed a number of
other functionalities that may be desirable for the genera-
tion of unnatural analogues.
Reaction conditions
dr (95/89), comments
NaBH4, THF, RT
NaBH4, MeOH, RT
<5:95
<5:95
CeCl3·7H2O, MeOH, RT then NaBH4, ꢀ788C <5:95
LiBH4, THF, ꢀ308C
<5:95
<5:95
L-Selectride, THF, Et2O
Zn
A
work-up
62:38, decomposition on
work-up
62:38, decomposition on
work-up
88:12, 90% isolated yield
(R=H)
Zn
up)
A
PS-Zn
A
Zn
A
(EDTAwork-up)
It has been shown that acetylation at O-7 is relatively
slow.[1a] Indeed, it was possible to acetylate 97 selectively at
O-10 with neat isopropenyl acetate and a catalytic amount
of para-toluenesulfonic acid, affording 78 in quantitative iso-
lated yield. Solvolysis of 78 with acidic methanol at 458C
generated the free C-8 hydroxyl derivative 79 in 83% yield.
Esterification of 79 with butyric anhydride or (S)-2-methyl-
butyric anhydride afforded thapsigargin (1) in 91% isolated
Decomposition of 95 frequently occurred during the
work-up of reactions with zinc borohydride, and its isolation
proved troublesome. After extensive investigation it was
found that the addition of TBAF at the end of a reaction,
and the use of a tetrasodium EDTAwork-up procedure, al-
lowed 91 to be isolated cleanly in 80% yield from 88
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5697

S. V. Ley et al.
Scheme 18. Total synthesis of thapsigargin and thapsivillosin C. a) nBuSH, MgBr2·Et2O, K2CO3, Et2O, 30 min, RT, 84%; b) octanoic anhydride, DMAP,
CH2Cl2, RT, 1 h, 86%; c) isopropenyl acetate, pTsOH, RT, 2 h, quantitative; d) HCl, MeOH, 458C, 45 min, 83%; e) butyric anhydride, DMAP, CH2Cl2,
RT, 1 h, 91%; f) (S)-2-methylbutyric anhydride, DMAP, CH2Cl2, RT, 3 h 30 min, 92%.
vents used were of reagent grade and were distilled before use: tetrahy-
drofuran and diethyl ether over calcium hydride and lithium aluminium
hydride; dichloromethane, toluene, methanol and acetonitrile over calci-
um hydride. Petroleum ether (PE) refers to the fraction of petroleum
ether that was distilled between 40 and 608C; anhydrous N,N-dimethyl-
formamide and acetone were sourced commercially and used as supplied.
yield or thapsivillosin C (5) in 92% isolated yield, respec-
tively. By performing the esterification at O-8 as the last
step, we have the ability to access the natural products bear-
ing different acyl groups at this position, as well as unnatural
analogues (including prodrug 18), simply by using different
acylating agents.
Until now, the stereochemistry of the methylbutanoyl side
chain of thapsivillosin C was thought to be (S) (as was
shown to be the case for trilobolide), but this had not been
proven.[4] Comparison of our synthetic sample of thapsivillo-
sin C with an authentic sample of the natural product has
confirmed the (S)-configuration of the methylbutanoyl side
chain.[69]
Flash column chromatography was performed with Merck 60 Kieselgel
(230–400 mesh). Thin-layer chromatography (TLC) was performed with
Merck 60 F254 silica gel plates and viewed under UV radiation (254 nm)
or by staining with acidic aqueous ammonium molybdate(IV) and heat-
ing as necessary. All 1H NMR spectra were recorded on a Bruker DPX-
400 operating at 400 MHz; Bruker Avance 500 with dual cryoprobe, op-
erating at 500 MHz; Bruker DRX-600, operating at 600 MHz; or Bruker
DRX-700, operating at 700 MHz, as stated with each experiment. Sam-
ples were either dissolved in CDCl3 and the residual protic solvent cali-
brated to 7.27 ppm or in CD3OD and the residual solvent calibrated to
3.31 ppm (as stated). Signals are quoted in ppm to the nearest 0.01 ppm
and multiplicities (J) are recorded in Hertz (Hz). 13C NMR spectra were
recorded on Bruker DPX-400 operating at 100 MHz; Bruker Avance 500
with dual cryoprobe operating at 125 MHz; Bruker DRX-600 operating
at 150 MHz; or Bruker DRX-700, operating at 175 MHz (as stated).
Samples were either dissolved in CDCl3 and the solvent calibrated to
77.0 ppm or in CD3OD and the residual solvent calibrated to 49.0 ppm
(as stated). Signals are quoted in ppm to the nearest 0.1 ppm. COSY,
HMQC, HMBC and DEPT experiments were used to aid the assignment
of NMR signals.
Conclusion
We have developed an efficient substrate-controlled synthet-
ic route which may facilitate access to all 17 of the thapsi-
gargins, as well as unnatural analogues. To illustrate this
tenet, we have successfully completed the first total synthe-
ses of five of the natural products: thapsigargin (1), trilobo-
lide (2), nortrilobolide (3), thapsivillosin F (4) and thapsivil-
losin C (5). Thapsigargin, an important and prolific biologi-
cal tool, and a promising lead in the development of a treat-
ment for prostate cancer, was prepared in 42 synthetic steps
in 0.61% overall yield (88.6% average yield per step). We
have also delineated the first absolute stereochemical assign-
ment of thapsivillosin C.
High-resolution mass spectrometry was conducted using a Kratos Con-
cept spectrometer or Waters Micromass LCT Premier spectrometer using
EI or ESI ionisation techniques. Optical rotations were recorded on a
Perkin-Elmer 343 digital polarimeter at 258C, path length 10 cm using a
sodium lamp (589 nm) as the light source, reported in 10ꢀ1 degcm2 gꢀ1
(concentration, c in g per 100 mL). Infrared spectra of sample films were
recorded by a Perkin-Elmer Spectrum One spectrometer equipped with
an attenuated total reflectance sampler and signals are quoted in cmꢀ1
.
Melting points are uncorrected and were measured with Reichert hot-
stage apparatus using BDH microscopic slides.
Experimental procedures towards guaianolide 61
Epoxide 26: Hydrogen peroxide solution (97.0 mL, 1.00 mol, 35% v/v in
H2O) was steadily added to a solution of (S)-carvone (25) (50.0 g,
333 mmol) in methanol (400 mL) at 08C over a period of 10 min. Aque-
ous sodium hydroxide solution (83.0 mL, 166 mmol, 2.0m) was then
added over a period of 30 min, such that the reaction temperature did
not exceed 308C. The mixture was cooled to 08C, stirred for 30 min, then
warmed to RT and stirred for 3 h. The reaction was diluted with water
(400 mL) and quenched by the gradual addition of sodium sulfite (126 g,
1.00 mol) over 3 h, maintaining the internal temperature below 358C.
Experimental Section
All non-aqueous reactions were performed in oven-dried (2008C) glass-
ware under an argon atmosphere; synthetic intermediates were dried in
vacuo before use. All reagents were obtained from commercial sources
and used as supplied unless otherwise stated. Molecular sieves were
dried at 2008C before use, and Amberlyst-15 resin washed thoroughly
with methanol and dichloromethane then dried in vacuo before use. Sol-
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The mixture was extracted with CH2Cl2 (3”300 mL) and the combined
organics washed with brine (400 mL), dried (MgSO4) and evaporated
under reduced pressure. The crude oil was used without further purifica-
tion. [a]D = ꢀ79.0 (c = 1.00, CHCl3); H NMR (400 MHz, CDCl3): d =
Alcohol 31: PPTS (1.00 g, 3.98 mmol) was added to a solution of acetals
30 (45.2 g, 160 mmol) in methanol (600 mL) and the resulting mixture
stirred at 508C for 15 h. The mixture was concentrated to ca. 50 mL
under reduced pressure, quenched with saturated NaHCO3 solution
(200 mL) and further diluted with water (100 mL). The mixture was then
extracted with Et2O (3”400 mL) and the combined organic phases
washed with brine (200 mL), dried (MgSO4) and evaporated under re-
duced pressure. The crude oil showed traces of pyridine in its 1H NMR
spectrum but was used without further purification. [a]D = +4.20 (c =
1.20, CHCl3); 1H NMR (400 MHz, CDCl3): d = 4.80 (apparent t, J=
1.5 Hz, 1H), 4.71 (s, 1H), 4.27 (dd, J=4.3, 4.3 Hz, 1H), 3.61 (s, 3H), 3.25
(ddd, J=10.2, 7.0, 6.5 Hz, 1H), 2.84 (dd, J=10.2, 8.8 Hz, 1H), 2.50 (m,
1H), 2.06 (ddd, J=13.5, 10.8, 4.3 Hz, 1H), 1.85 (ddd, J=13.5, 7.0, 1.0 Hz,
1H), 1.74 (s, 3H), 1.08 (d, J=7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d = 174.9, 145.3, 111.5, 75.1, 53.2, 51.3, 46.7, 42.5, 39.4, 22.5, 13.6; IR
(film): nmax = 3490 (br OH), 2958 (C-H), 2924 (C-H), 2878 (C-H), 1731
(C=O), 1647 cmꢀ1 (w C=C); ESI+ MS: m/z: calcd for C11H19O3:
199.1334; found: 199.1328 [M+H]+.
1
4.72 (s, 1H), 4.66 (s, 1H), 3.38 (d, J=2.0 Hz, 1H), 2.64 (m, 1H), 2.50 (m,
1H), 2.30 (m, 1H), 1.96 (ddd, J=13.4, 11.6, 2.6 Hz, 1H), 1.85 (ddd, J=
14.8, 12.1, 1.0 Hz, 1H), 1.63 (s, 3H), 1.34 (d, J=3.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d = 205.2, 146.2, 110.3, 61.2, 58.6, 41.6, 34.9, 28.5,
20.4, 15.1; IR (film): nmax = 2977 (C-H), 2935 (C-H), 2851 (C-H), 1709
(C=O), 1649 cmꢀ1 (w C=C); ESI+ MS: m/z: calcd for C10H15O2:
167.1072; found: 167.1069 [M+H]+.
Chlorohydrin 27: Epoxide 26 was split into two approximately equal
batches and treated in parallel for ease of handling. TFA(34.4 mL,
447 mmol) was added dropwise to a mixture of epoxide 26 (24.8 g,
149 mmol) and LiCl (66.0 g, 1.55 mol) in THF (1.00 L) at 08C over
15 min. The mixture was stirred at 08C for 90 min and quenched by the
gradual addition of aqueous NaHCO3 solution (500 mL, 450 mmol) at
08C over a period of 1 h. The mixture was stirred at RT overnight and ex-
tracted with Et2O (3”200 mL). The combined extracts were washed with
brine (2”150 mL), dried over MgSO4 and concentrated in vacuo, leaving
TBDPS-ether 32: Imidazole (11.1 g, 163 mmol), TBDPSCl (42.5 mL,
163 mmol) and DMAP (1.95 g, 16.0 mmol) were added to a solution of
impure alcohol 31 (33.1 g) in DMF (110 mL) and stirred at RT overnight.
The mixture was then poured into aqueous LiCl solution (450 mL, 10%
w/w) and extracted with Et2O (3”500 mL). The combined extracts were
washed with brine (400 mL), dried (MgSO4), concentrated in vacuo and
purified by column chromatography (silica gel, neat PE gradually increas-
ing to 5% Et2O in PE) to afford the silyl ether as a colourless oil (61.2 g,
84% over three steps from chloroketone 28). [a]D = +29.6 (c = 1.00,
CHCl3); 1H NMR (400 MHz, CDCl3): d = 7.67 (m, 4H), 7.42–7.38 (m,
6H), 4.72 (s, 1H), 4.61 (s, 1H), 4.32 (m, 1H), 3.59 (s, 3H), 3.27 (m, 1H),
2.95 (dd, J=10.1, 9.6 Hz, 1H), 2.36 (m, 1H), 1.68 (ddd, J=13.5, 10.4,
3.9 Hz, 1H), 1.67 (s, 3H), 1.64 (m, 1H), 1.09 (s, 9H), 1.02 (d, J=6.9 Hz,
3H); 13C NMR (100 MHz, CDCl3): d = 174.9, 145.5, 136.0, 135.9, 134.7,
134.0, 129.6, 127.5, 111.5, 76.8, 53.7, 51.2, 46.4, 43.4, 39.6, 27.1, 22.3, 19.5,
14.5; IR (film): nmax = 2929 (C-H), 2856 (C-H), 1730 (C=O), 1646 cmꢀ1
(w C=C); ESI+ MS: m/z: calcd for C27H37O3Si: 437.2512; found:
437.2506 [M+H]+.
a
cloudy oil. The two batches were combined, poured into water
(600 mL) and extracted with Et2O (3”300 mL). The combined organic
phases were washed with brine (200 mL), dried (MgSO4) and evaporated
under reduced pressure. The crude yellow oil (66.1 g, 98% over two
steps) was analytically pure and used without further purification. [a]D
=
ꢀ47.3 (c = 1.00, CHCl3); 1H NMR (400 MHz, CDCl3): d = 4.79 (m,
2H), 4.24 (dd, J=3.2, 2.8 Hz, 1H), 3.02 (dd, J=13.7, 13.0 Hz, 1H), 2.82
(m, 1H), 2.42 (m, 2H), 2.06 (brs, 1H), 1.88 (m, 1H), 1.77 (s, 3H), 1.65 (s,
3H); 13C NMR (100 MHz, CDCl3): d = 204.5, 146.5, 110.6, 77.0, 68.0,
41.1, 39.0, 32.9, 22.1, 20.3; IR (film): nmax = 3447 (br OH), 2938 (C-H),
2688 (C-H), 1721 (C=O), 1646 cmꢀ1 (w C=C); ESI+ MS: m/z: calcd for
C10H15O2ClNa: 225.0658; found: 225.0650 [M+Na]+.
THP acetals 28: PPTS (532 mg, 211 mmol) was added at RT to a stirred
solution of chlorohydrin 27 (42.8 g, 211 mmol) and dihydropyran
(67.8 mL, 744 mmol) in CH2Cl2 (250 mL). After 17 h, the reaction was
quenched by adding half saturated NaHCO3 solution (600 mL). The reac-
tion mixture was extracted with Et2O (3”300 mL). The combined organ-
ic layers were dried (MgSO4) and concentrated under reduced pressure.
The crude product was purified by flash chromatography (Et2O/PE 5:95)
to give THP ethers 28 (50.9 g, 84%; 1:1 mixture of epimers at the acetal
carbon) as a colourless oil. [a]D = ꢀ88.0 (c = 1.00, CHCl3); 1H NMR
(400 MHz, CDCl3): d = 4.80 (m, 4H), 4.71 (m, 2H), 4.24 (m, 1H), 4.11
(m, 1H), 3.80 (m, 2H), 3.53 (m, 2H), 3.00 (m, 2H), 2.86 (m, 1H), 2.60
(m, 1H), 2.38 (m, 4H), 2.04 (m, 2H), 1.8–1.5 (m, 24H); 13C NMR
(100 MHz, CDCl3): d = 204.2, 146.9, 110.4, 101.7, 83.9, 67.8, 62.5, 41.1,
39.6, 32.1, 30.6, 27.6, 25.3, 22.7, 20.4, 19.1; IR (film): nmax = 2941 (C-H),
2871 (C-H), 1726 (C=O), 1646 cmꢀ1 (w C=C); ESI+ MS: m/z: calcd for
C15H23O3ClNa: 309.1233; found: 309.1229 [M+Na]+.
Alcohol 33: LiAlH4 (121 mL, 121 mmol, 1.0m in THF) was added over
20 min at 08C to a stirred solution of methyl ester 32 (52.7 g, 121 mmol)
in anhydrous THF (250 mL). The reaction was kept at 08C for 1 h, then
allowed to come to RT and stirred for another hour. After that time, the
reaction was quenched by slowly adding a saturated solution of Ro-
chelleꢁs salt (70 mL), followed by water (200 mL). After stirring for 15 h,
the reaction mixture was extracted with Et2O (3”400 mL). The com-
bined organic layers were dried (MgSO4) and the solvent was removed
under reduced pressure. The crude product was filtered through a short
plug of silica gel, eluting with Et2O to give alcohol 33 (48.8 g, 99%) as a
clear, colourless oil. [a]D
= +15.5 (c =
1.22, CHCl3); 1H NMR
(400 MHz, CDCl3): d = 7.67 (m, 4H), 7.42–7.38 (m, 6H), 4.84 (s, 1H),
4.72 (s, 1H), 4.30 (m, 1H), 3.51 (m, 2H), 3.12 (m, 1H), 2.10 (m, 1H),
1.89 (m, 1H), 1.82 (m, 2H), 1.63 (s, 3H), 1.09 (s, 9H), 1.03 (d, J=7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3): d = 147.6, 136.0, 135.9, 134.7, 134.4,
129.9, 127.4, 110.8, 76.4, 53.7, 48.9, 44.8, 42.3, 39.0, 27.1, 22.8, 19.5, 14.9;
IR (film): nmax = 3402 (br OH), 2962 (C-H), 2931 (C-H), 1646 cmꢀ1 (w
C=C); ESI+ MS: m/z: calcd for C26H40NO2Si: 426.2823; found: 426.2826
[M+NH4]+.
Methyl esters 30: Freshly prepared sodium methoxide solution (250 mL,
250 mmol, 1.0m in methanol) was added dropwise at 08C via cannula to
a solution of chloroketones 28 (48.1 g, 168 mmol) in Et2O (700 mL). The
mixture was stirred at 08C for 1 h, quenched with saturated ammonium
chloride solution (300 mL) and diluted with water (100 mL). The mixture
was stirred at RT for 1 h and extracted with Et2O (3”400 mL). The com-
bined organics were washed with brine (300 mL), dried over MgSO4 and
concentrated in vacuo. The crude oil was obtained as a 1:1 mixture of
epimers at the acetal carbon, and was used without further purification.
PMB-ether 34: NaH (2.2 g, 54.2 mmol, 60% dispersion in mineral oil)
was added at 08C in two portions over 2 min to a solution of alcohol 33
(17.7 g, 43.1 mmol) in DMF (100 mL). After stirring for 1 h at RT, a solu-
tion of para-methoxybenzyl chloride (6.8 mL, 50.0 mmol) in DMF
(10 mL) was added. Stirring was continued for 15 h, the reaction mixture
quenched with water (50 mL) and diluted with Et2O. The aqueous layer
was extracted with Et2O (3”100 mL), the combined organic layers were
dried with MgSO4 and the solvent removed under reduced pressure. The
product was purified by flash chromatography (PE/Et2O 35:1) to yield 34
(18.8 g, 82%) as a colourless oil. [a]D = +7.48 (c = 1.08, CHCl3); 1H
NMR (400 MHz, CDCl3): d = 7.67 (m, 4H), 7.42–7.38 (m, 6H), 7.21 (d,
J=6.7 Hz, 2H), 6.84 (d, J=6.7 Hz, 2H), 4.74 (apparent t, J=1.4 Hz,
1H), 4.53 (s, 1H), 4.36 (d, J=11.4 Hz, 1H), 4.30 (d, J=11.4 Hz, 1H),
1
[a]D = +14.0 (c = 1.00, CHCl3); H NMR (400 MHz, CDCl3): d = 4.80
(m, 2H), 4.7–4.6 (m, 4H), 4.24 (m, 1H), 4.13 (m, 1H), 3.88 (m, 2H), 3.60
(s, 6H), 3.30 (m, 2H), 3.20 (ddd, J=9.3, 9.3, 9.2 Hz, 1H), 3.04 (ddd, J=
10.2, 9.5, 7.1 Hz, 1H), 2.83 (m, 2H), 2.56 (m, 2H), 2.02 (dd, J=8.9,
3.0 Hz, 2H), 1.90 (m, 2H), 1.74 (s, 6H), 1.70–1.50 (m, 12H), 1.13 (d, J=
7.0 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): d =
175.1, 145.4, 111.3, 100.5, 81.8, 62.9, 53.6, 51.2, 46.8, 42.3, 38.2, 31.1, 25.6,
22.5, 19.9, 14.1; IR (film): nmax = 2957 (C-H), 2929 (C-H), 2851 (C-H),
1727 (C=O), 1646 cmꢀ1 (w C=C); ESI+ MS: m/z: calcd for C16H27O4:
283.1909; found: 283.1901 [M+H]+.
Chem. Eur. J. 2007, 13, 5688 – 5712
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5699

S. V. Ley et al.
4.28 (m, 1H), 3.80 (s, 3H), 3.29 (dd, J=9.3, 6.5 Hz, 1H), 3.15 (dd, J=9.3,
7.0 Hz, 1H), 3.07 (dd, J=9.0, 8.9 Hz, 1H), 2.18 (dddd, J=9.0, 7.0, 6.8,
6.5 Hz, 1H), 1.84 (m, 1H), 1.73 (s, 3H), 1.62 (dd, J=8.9, 3.3 Hz, 2H),
1.08 (s, 9H), 1.07 (d, J=7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d =
159.0, 146.1, 136.0, 136.0, 135.0, 134.5, 130.9, 129.5, 129.0, 127.5, 127.4,
113.7, 110.1, 76.2, 72.7, 71.6, 55.3, 46.3, 44.8, 43.5, 39.1, 27.1, 23.9, 19.5,
15.4; IR (film): nmax = 2932 (C-H), 2857 (C-H), 1612 (w C=C), 1590 cmꢀ1
(Ar); ESI+ MS: m/z: calcd for C34H48NO3Si: 546.3404; found: 546.3400
[M+NH4]+.
MgSO4 and concentrated in vacuo. The orange oil was purified by
column chromatography (silica gel, PE/Et2O 19:1) to afford as pale
yellow oil, an 8:1 (S/R) mixture of the C-10 epimers (36.8 g, 84% over
two steps). Major diastereomer (37s): [a]D = ꢀ7.60 (c = 0.75, CHCl3);
1H NMR (400 MHz, CDCl3): d = 7.67 (m, 4H), 7.42–7.38 (m, 6H), 7.16
(d, J=6.7 Hz, 2H), 6.81 (d, J=6.7 Hz, 2H), 5.73 (dddd, J=17.6, 10.6, 7.6,
7.2 Hz, 1H), 5.12 (d, J=10.6 Hz, 1H), 4.99 (d, J=17.6 Hz, 1H), 4.63 (d,
J=7.2 Hz, 1H), 4.54 (d, J=7.2 Hz, 1H), 4.37 (m, 1H, and d, J=11.8 Hz,
2H), 4.30 (d, J=11.8 Hz, 1H), 3.79 (s, 3H), 3.65 (dd, J=10.0, 4.8 Hz,
1H), 3.23 (s, 3H), 3.10 (dd, J=10.0, 10.0 Hz, 1H), 2.45 (ddd, J=11.2, 8.0,
7.9 Hz, 1H), 2.33 (dd, J=13.8, 7.2 Hz, 1H), 2.24 (m, 1H), 2.15 (dd, J=
13.8, 7.6 Hz, 1H), 2.04 (m, 1H), 1.79 (ddd, J=13.1, 11.4, 7.2 Hz, 1H),
1.58 (m, 1H), 1.22 (s, 3H), 1.09 (s, 9H), 1.08 (d, J=6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3): d = 159.0, 135.9, 134.9, 134.5, 131.0, 129.4,
128.9, 127.5, 127.4, 117.6, 113.7, 91.0, 78.8, 74.4, 72.5, 71.5, 55.5, 55.3, 47.0,
45.6, 44.4, 42.3, 33.9, 27.1, 21.6, 19.4, 15.6; IR (film): nmax = 2931 (C-H),
2857 (C-H), 1621 (w C=C), 1513 cmꢀ1 (w Ar); ESI+ MS: m/z: calcd for
C38H56O5NSi: 634.3928; found: 634.3923 [M+NH4]+.
Ketone 35: OsO4 (2.5% solution in tBuOH, 25.8 mL, 2.54 mmol) was
added to a stirred solution of PMB-ether 34 (67.1 g, 127 mmol) and N-
methylmorpholine N-oxide (17.9 g, 152 mmol) in acetone/H2O (420 mL,
3:1). After OsO4 addition the reaction became immediately dark brown.
The reaction mixture was stirred for 2 h at RT. After that time, the ho-
mogeneous orange mixture was cooled to 08C and NaIO4 (81.5 g,
380 mmol) was added in two portions. After stirring vigorously for
30 min, the reaction was allowed to warm up to RT. To maintain effective
stirring, acetone (150 mL) and water (150 mL) were added. After stirring
overnight, the reaction was quenched by adding a saturated NaS2O3 solu-
tion (100 mL) and water (100 mL). The suspension was filtered through a
Buchner funnel and extracted with Et2O (3”350 mL). The combined or-
ganic layers were dried (MgSO4) and the solvent was evaporated under
reduced pressure. The crude product was purified by filitration through a
pad of silica gel (PE/Et2O 3:1) to give ketone 35 (61.7 g, 92%) as a pale
Alcohols 38s and 38r:
Procedure A: ACH 2Cl2 solution (300 mL) of the PMB-ethers 37s and
37r (36.5 g, 59.3 mmol) was treated with phosphate buffer solution (pH 7,
45 mL) and DDQ (27.5 g, 119 mmol). The solution immediately turned
red and was stirred at RT for 30 min, then quenched by stirring with satu-
rated NaHCO3 solution (600 mL) for 30 min. The mixture was diluted
with water (2.5 L) and extracted with CH2Cl2 (3”600 mL). The combined
extracts were washed with brine (300 mL), dried over MgSO4 and con-
centrated in vacuo. The crude product was combined with a smaller
batch and purified by repeated chromatography to separate C-10 epimers
(silica gel, eluting with PE/EtOAc 8:1). The isomerically-pure primary al-
cohol (>24:1 S/R at C-10) was obtained as a colourless oil (23.6 g, 75%;
based on theoretical maximum yield from the 8:1 mixture of isomeric
PMB ethers).
yellow oil. [a]D
= +51.1 (c =
1.10, CHCl3); 1H NMR (400 MHz,
CDCl3): d = 7.67 (m, 4H), 7.42–7.38 (m, 6H), 7.21 (d, J=6.7 Hz, 2H),
6.87 (d, J=6.7 Hz, 2H), 4.29 (m, 3H), 3.80 (s, 3H), 3.42 (m, 2H), 3.21
(dd, J=9.5, 9.4 Hz, 1H), 2.46 (dddd, J=9.7, 9.6, 9.4, 4.2 Hz, 1H), 2.12 (s,
3H), 1.75 (ddd, J=13.5, 9.3, 4.2 Hz, 1H), 1.67 (m, 1H), 1.61 (ddd, J=
13.5, 7.8, 1.5 Hz, 1H), 1.07 (s, 9H), 0.98 (d, J=6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d = 212.1, 160.1, 135.9, 135.8, 134.8, 134.0, 130.2,
129.5, 129.5, 127.5, 113.7, 76.7, 72.9, 70.3, 55.2, 49.7, 47.5, 42.7, 37.9, 32.5,
27.1, 19.5, 14.1; IR (film): nmax = 2932 (C-H), 2857 (C-H), 1705 (C=O),
1612 (Ar), 1513 cmꢀ1 (Ar); ESI+ MS: m/z: calcd for C33H42O4SiNa:
553.2750; found: 553.2758 [M+Na]+.
Procedure B: Amethanolic solution (10 mL) of the crude primary ace-
tate 45 (combined from different batches, assume 12.0 mmol) was treated
with sodium methoxide solution (50.0 mL, 25.0 mmol, 0.5m in methanol)
at RT for 16 h. The reaction was then quenched with saturated NaHCO3
solution, diluted with water (100 mL) and extracted with Et2O (3”
150 mL). The combined extracts were washed with brine (200 mL), dried
(MgSO4) and evaporated under reduced pressure. The crude brown oil
was purified by column chromatography (silica gel, Et2O/PE 2:3) to
afford 38s, 6.22 g, 99% over three steps.
Compound 38s: [a]D = +35.6 (c = 1.85, CHCl3); 1H NMR (400 MHz,
CDCl3): d = 7.67 (m, 4H), 7.42–7.38 (m, 6H), 5.67 (dddd, J=16.9, 11.0,
7.5, 7.3 Hz, 1H), 5.01 (d, J=16.9 Hz, 1H), 4.99 (d, 1H, J=11.0 Hz, 1H),
4.79 (d, J=7.2 Hz, 1H), 4.70 (d, J=7.2 Hz, 1H), 4.41 (ddd, J=5.2, 5.2,
1.8 Hz, 1H), 3.81 (ddd, J=11.9, 4.5, 3.3 Hz, 1H), 3.62 (dd, J=4.5, 4.5 Hz,
1H), 3.45 (ddd, J=11.9, 5.0, 4.5 Hz, 1H), 3.34 (s, 3H), 2.52 (ddd, J=13.4,
7.5, 6.0 Hz, 1H), 2.41 (dd, J=13.5, 7.3 Hz, 1H), 2.20 (dd, J=13.5, 7.5 Hz,
1H), 2.06 (m, 1H), 1.85 (m, 1H), 1.66 (ddd, J=12.7, 12.7, 5.2 Hz, 1H),
1.53 (ddd, J=12.7, 7.1, 1.8 Hz, 1H), 1.38 (s, 3H), 1.09 (s, 9H), 1.02 (d,
J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d = 135.9, 134.9, 134.4,
133.8, 129.5, 127.4, 127.4, 117.4, 90.9, 80.3, 74.9, 63.1, 55.8, 48.6, 46.3, 44.1,
42.5, 36.0, 27.1, 22.5, 19.4, 15.1; IR (film): nmax = 3465 (br OH), 2931 (C-
H), 2889 (C-H), 1639 (w C=C), 1590 cmꢀ1 (w Ar); ESI+ MS: m/z: calcd
for C30H48O4NSi: 514.3353; found: 514.3350 [M+NH4]+.
Compound 38r: 1H NMR (400 MHz, CDCl3): d = 7.67 (m, 4H), 7.42–
7.38 (m, 6H), 5.80 (dddd, J=17.6, 10.1, 7.5, 7.3 Hz, 1H), 5.11 (d, J=
17.6 Hz, 1H), 5.09 (d, J=10.1 Hz, 1H), 4.73 (s, 2H), 4.33 (m, 1H), 3.82
(m, 2H), 3.53 (m, 1H), 3.34 (s, 3H), 2.57 (m, 2H), 2.45 (dd, J=13.7,
7.3 Hz, 1H), 2.01 (m, 1H), 1.96 (m, 1H), 1.51 (m, 1H), 1.48 (m, 1H),
1.15 (s, 3H), 1.09 (s, 9H), 1.07 (d, J=7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d = 135.9, 135.8, 135.1, 134.3, 133.9, 129.5, 129.5, 127.4, 118.0,
91.2, 81.0, 75.1, 63.1, 55.9, 48.3, 45.9, 43.8, 42.6, 36.2, 27.1, 22.9, 19.5, 14.9;
ESI+ MS: m/z: calcd for C30H48O4NSi: 514.3353; found: 514.3351
[M+NH4]+.
Homoallylic alcohols 36s and 36r: Asolution of ketone 35 (36.3 g,
68.4 mmol) in THF (150 mL) was treated with MgBr2·Et2O (35.3 g,
137 mmol) for 1 h at RT, then diluted with 1,2-dimethoxyethane (1.0 L)
and cooled to ꢀ788C. Allylmagnesiumbromide solution (103 mL,
103 mmol, 1.0m in Et2O) was added dropwise over 40 min and the reac-
tion stirred for a further 2 h at ꢀ788C. The reaction was then warmed to
RT and quenched by stirring with saturated ammonium chloride solution
(1.0 L) overnight. The crude mixture was further diluted with water
(200 mL) to aid solubility, and extracted with Et2O (3”500 mL). The
combined extracts were washed with brine (500 mL), dried over MgSO4
and evaporated under reduced pressure to afford the crude homoallylic
alcohols as an 8:1 (S/R) mixture of C-10 epimers, used without further
purification. Major diastereomer (36s): [a]D = +25.7 (c = 1.45, CHCl3);
1H NMR (400 MHz, CDCl3): d = 7.67 (m, 4H), 7.42–7.38 (m, 6H), 7.16
(d, J=6.8 Hz, 2H), 6.83 (d, J=6.8 Hz, 2H), 5.79 (dddd, J=16.9, 10.2, 6.8,
6.7 Hz, 1H), 5.01 (d, J=10.2 Hz, 1H), 4.81 (d, J=16.9 Hz, 1H), 4.42 (d,
J=11.3 Hz, 1H), 4.35 (d, J=11.3 Hz, 1H), 4.29 (ddd, J=5.2, 5.2, 1.6 Hz,
1H), 3.79 (s, 3H), 3.55 (dd, J=10.1, 3.7 Hz, 1H), 3.48 (dd, J=10.1,
6.8 Hz, 1H), 2.45 (ddd, J=8.6, 7.9, 3.8 Hz, 1H), 2.08 (m, 3H), 1.81 (m,
1H), 1.70 (ddd, J=11.9, 8.0, 7.9 Hz, 1H), 1.58 (ddd, J=13.1, 7.5, 1.6 Hz,
1H), 1.21 (s, 3H), 1.07 (s, 9H), 0.98 (d, J=7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d = 158.7, 135.9, 135.0, 134.8, 134.4, 129.5, 129.5,
129.4, 129.2, 127.5, 117.2, 113.9, 74.9, 73.0, 72.6, 70.6, 55.2, 47.2, 46.3, 46.3,
42.9, 35.3, 27.1, 26.9, 19.4, 14.9; IR (film): nmax = 3422 (br OH), 2930 (C-
H), 2857 (C-H), 1621 (w Ar), 1514 cmꢀ1 (w Ar); ESI+ MS: m/z: calcd
for C36H52O4N: 590.3666; found: 590.3663 [M+NH4]+.
MOM acetals 37s and 37r: A CH2Cl2 (300 mL) solution of the crude ter-
tiary alcohols 36s and 36r (assume 71.4 mmol, crude from two batches)
was treated with Hünigꢁs base (124 mL, 714 mmol), MOMCl (36.3 mL,
478 mmol) and DMAP (867 mg, 7.14 mmol) at RT over a weekend. The
resulting orange solution was quenched with half-saturated ammonium
chloride solution (600 mL) and extracted with CH2Cl2 (3”500 mL). The
combined organic extracts were washed with brine (500 mL), dried over
Aldehyde 39: Pyridine (33.9 mL, 419 mmol) was added at RT before por-
tionwise addition of Dess–Martin periodinane (28.4 g, 67.0 mmol) to a so-
lution of alcohol 38s (20.8 g, 41.9 mmol) in CH2Cl2 (200 mL). After stir-
5700
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Chem. Eur. J. 2007, 13, 5688 – 5712

Natural Products
FULL PAPER
ring for 1 h at RT, the reaction was quenched by the addition of saturated
aqueous sodium thiosulfite solution (100 mL) and saturated aqueous
NaHCO3 solution (100 mL). The separated aqueous phase was extracted
with ethyl acetate (3”80 mL), and the combined organics washed with
saturated aqueous sodium thiosulfite solution (100 mL), dried (MgSO4)
and concentrated under reduced pressure to afford the title compound 39
(dddd, J=17.0, 10.2, 7.5, 7.0 Hz, 1H), 5.08 (d, J=10.2 Hz, 1H), 5.02 (d,
J=17.0 Hz, 1H), 4.27 (dd, J=8.1, 4.1 Hz, 1H), 2.86 (m, 2H), 2.28 (m,
2H), 2.10 (dd, J=14.1, 7.5 Hz, 1H), 1.65 (ddd, J=13.4, 10.7, 0.8 Hz, 1H),
1.43 (ddd, J=13.4, 8.8, 4.3 Hz, 1H), 1.31 (s, 3H), 1.20 (d, J=7.0 Hz, 3H),
1.09 (s, 9H); 13C NMR (100 MHz, CDCl3): d = 175.5, 135.8, 135.7, 134.3,
133.4, 132.2, 129.7, 127.6, 127.5, 119.1, 85.0, 76.6, 51.4, 47.2, 43.6, 41.2,
35.1, 27.0, 19.3, 15.1; IR (film): nmax = 2963 (C-H), 2932 (C-H), 2858 (C-
H), 1764 (C=O), 1642 (w C=C), 1588 cmꢀ1 (w Ar); ESI+ MS: m/z: calcd
for C28H37O3: 449.2512; found: 449.2513 [M+H]+.
which was used in the next step without further purification. [a]D
=
+5.60 (c = 1.00, CHCl3); 1H NMR (400 MHz, CDCl3): d = 9.60 (d, J=
5.5 Hz, 1H), 7.67 (m, 4H), 7.42–7.38 (m, 6H), 5.62 (dddd, J=17.0, 10.0,
7.5, 7.2 Hz, 1H), 5.00 (m, 2H), 4.70 (d, J=7.3 Hz, 1H), 4.54 (d, J=
7.3 Hz, 1H), 4.43 (m, 1H), 3.28 (s, 3H), 2.78 (m, 1H), 2.53 (ddd, J=9.4,
6.0, 5.5 Hz, 1H), 2.38 (dd, J=13.5, 7.2 Hz, 1H), 2.26 (m, 1H), 2.13 (dd,
J=13.5, 7.5 Hz, 1H), 1.83 (ddd, J=12.3, 12.3, 4.5 Hz, 1H), 1.70 (ddd, J=
12.3, 7.0, 1.4 Hz, 1H), 1.30 (s, 3H), 1.09 (s, 9H), 1.01 (d, J=7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3): d = 204.0, 135.9, 135.8, 134.4, 133.9, 133.7,
129.7, 129.6, 127.5, 127.4, 118.1, 90.8, 79.1, 76.1, 59.0, 55.6, 51.1, 44.0, 40.9,
35.9, 27.1, 22.4, 19.4, 14.3; IR (film): nmax = 2932 (C-H), 2857 (C-H),
1710 (C=O), 1639 (w C=C), 1589 cmꢀ1 (w Ar); ESI+ MS: m/z: calcd for
C30H42O4SiNa: 517.2750; found: 517.2753 [M+Na]+.
Diol 40s: NaBH4 (1.26 g, 33.0 mmol) was added portionwise to a stirring
solution of lactol 43 (4.97 g, 11.0 mmol) in methanol (70 mL). After stir-
ring at RT for 18 h, the mixture was added dropwise to ammonium chlo-
ride solution (200 mL) and extracted with Et2O (3”200 mL). The com-
bined organics were washed with brine (200 mL), dried (MgSO4) and
evaporated under reduced pressure. Column chromatography (silica gel,
Et2O/PE 3:7) afforded the diol as a colourless gum (3.70 g, 75%). [a]D
=
+36.1 (c = 0.71, CHCl3); 1H NMR (400 MHz, CDCl3): d = 7.66 (m,
4H), 7.42 (m, 2H), 7.37 (m, 4H), 5.79 (dddd, J=17.4, 10.1, 7.6, 7.5 Hz,
1H), 5.13 (d, J=10.1 Hz, 1H), 5.07 (d, J=17.4 Hz, 1H), 4.34 (m, 1H),
3.80 (dd, J=12.0, 2.6 Hz, 1H), 3.50 (dd, J=12.0, 5.8 Hz, 1H), 2.48 (ddd,
1H, J=12.3, 7.7, 7.7 Hz, 1H), 2.10 (m, 2H), 1.97–1.92 (m, 2H), 1.62
(ddd, J=12.9, 12.5 5.2 Hz, 1H), 1.56 (ddd, J=12.9, 7.7, 1.5 Hz, 1H), 1.45
(s, 3H), 1.09 (s, 9H), 1.05 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d = 135.9, 135.8, 134.9, 134.2, 133.7, 129.5, 127.4, 127.4, 119.1,
75.0, 73.5, 62.8, 48.5, 47.0, 46.6, 42.4, 35.7, 27.1, 26.6, 19.4, 14.9; IR (film):
nmax =3272 (br OH), 2931 (C-H), 1640 cmꢀ1 (w C=C); ESI+ MS: m/z:
calcd for C28H40O3SiNa: 475.2639; found: 475.2659 [M+Na]+.
Decomposition product 42: When aldehyde 39 was left at 08C, it decom-
posed in less than one week. The crude oil was a complex mixture, from
which the major component (the title compound) was separated by
column chromatography of a small sample (silica gel, neat PE ramped
gradually to 40% Et2O/PE) to afford an analytically pure sample for
characterisation purposes. [a]D = ꢀ4.39 (c = 0.775, CHCl3); 1H NMR
(400 MHz, CDCl3): d = 7.67 (m, 4H), 7.42 (m, 2H), 7.37 (m, 4H), 5.62
(dddd, J=17.3, 10.8, 7.2, 7.2 Hz, 1H), 5.01 (d, J=10.8 Hz, 1H), 4.97–4.94
(m, 2H), 4.86 (d, J=6.5 Hz, 1H), 4.54 (d, J=6.5 Hz, 1H), 4.25 (dd, J=
7.0, 3.7 Hz, 1H), 3.38 (s, 3H), 2.74 (m, 1H), 2.64 (dd, J=8.3, 7.6 Hz,
1H), 2.23 (dd, J=13.8, 7.2 Hz, 1H), 2.08 (dd, J=13.8, 7.2 Hz, 1H), 1.77
(m, 1H), 1.60–1.56 (ddd, J=13.3, 8.1, 2.9 Hz, 1H), 1.47–1.44 (ddd, J=
13.3, 9.1, 4.1 Hz, 1H), 1.31 (s, 3H), 1.09 (s, 9H), 1.06 (d, J=7.1 Hz, 3H);
Acetate 44: Astirring solution of diol 40s (5.42 g, 12.0 mmol from sever-
al batches), DMAP (150 mg, 1.2 mmol) and pyridine (5.82 mL,
72.0 mmol) in CH2Cl2 (10 mL) was treated with acetic anhydride
(5.42 mL, 47.9 mmol) and stirred at RT for 16 h. The reaction was
quenched with ammonium chloride solution (400 mL) and extracted with
Et2O (3”150 mL). The combined extracts were washed with brine
(400 mL), dried (MgSO4) and concentrated in vacuo to afford the acetate
which was used without further purification. [a]D = +8.33 (c = 0.18,
CHCl3); 1H NMR (400 MHz, CDCl3): d = 7.66 (m, 4H), 7.41 (m, 2H),
7.37 (m, 4H), 5.78 (dddd, J=17.2, 10.2, 7.5, 7.2 Hz, 1H), 5.10 (d, J=
10.2 Hz, 1H), 5.04 (d, J=17.2 Hz, 1H), 4.38–4.35 (m, 2H), 3.85 (dd, J=
11.5, 9.2 Hz, 1H), 2.44 (ddd, J=12.1, 7.7, 7.7 Hz, 1H), 2.10–2.05 (m, 3H),
1.99 (s, 3H), 1.95 (m, 1H), 1.68 (m, 1H), 1.59 (m, 1H), 1.28 (s, 3H), 1.08
13C NMR (100 MHz, CDCl3): d
= 135.9, 135.8, 134.7, 134.3, 134.0,
129.58, 129.57, 127.53, 127.50, 117.5, 106.7, 93.1, 85.8, 78.2, 57.9, 55.5,
50.3, 44.9, 42.7, 35.3, 27.9, 27.0, 19.4, 14.6; IR (film): nmax = 2930 (C-H),
2858 (C-H), 1641 (w C=C), 1589 cmꢀ1 (w Ar); ESI+ MS: m/z: calcd for
C30H42O4SiNa: 517.2750; found: 517.2761 [M+Na]+.
Hemiacetal 43: The crude acetal 42 (8.0 g, 16.2 mmol) was stirred in a
mixture of acetic acid, THF and water (30:30:8, 68 mL) at 358C for 4 d.
The reaction was then cooled and added dropwise to NaHCO3 solution
(600 mL). The resulting mixture was extracted with Et2O (3”200 mL),
the combined extracts washed with brine (200 mL), dried (MgSO4) and
evaporated under reduced pressure. Column chromatography (silica gel,
(s, 9H), 1.04 (d, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d
=
170.8, 135.8, 135.7, 134.6, 134.2, 133.8, 129.6, 129.5, 127.51, 127.48, 118.7,
74.2, 72.7, 66.0, 47.3, 46.7, 45.7, 42.8, 34.4, 27.0, 25.8, 21.0, 19.3, 15.6; IR
(film): nmax = 3478 (br OH), 2931 (C-H), 2859 (C-H), 1738 (C=O), 1639
(w C=C), 1590 cmꢀ1 (w Ar); ESI+ MS: m/z: calcd for C30H42O4SiNa:
517.2750; found: 517.2750 [M+Na]+.
Et2O/PE 1:4) afforded the diol as a colourless gum (4.56 g, 62%). [a]D
=
+6.56 (c = 1.22, CHCl3); 1H NMR (400 MHz, CDCl3): d = 7.67 (m,
4H), 7.42 (m, 2H), 7.37 (m, 4H), 5.64 (dddd, J=17.1, 10.1, 7.3, 7.1 Hz,
1H), 5.12 (s, 1H), 5.02 (d, J=10.1 Hz, 1H), 4.99 (d, J=17.1 Hz, 1H),
4.21 (dd, J=7.2, 3.8 Hz, 1H), 2.75 (ddd, J=8.8, 8.7, 8.7 Hz, 1H), 2.58
(dd, J=7.7, 7.6 Hz, 1H), 2.46 (s, 1H), 2.18 (dd, J=13.8, 7.3 Hz, 1H), 2.03
(dd, J=13.8, 7.1 Hz, 1H), 1.75 (m, 1H), 1.58–1.54 (m, 4H), 1.45 (m, 1H),
1.09–1.08 (m, 12H) [no observed NOE interactions between H-1 and =
MOM acetal 45: MOMCl (6.02 mL, 79.2 mmol) was added to a stirring
solution of alcohol 44 (assume 12.0 mmol), DMAP (150 mg, 1.2 mmol)
and Hünigꢁs base (21.0 mL, 120 mmol) in CH2Cl2 (50 mL). The mixture
was stirred at RT for 5 d then quenched with ammonium chloride solu-
tion (300 mL), diluted with water (100 mL) and extracted with CH2Cl2
(3”150 mL). The combined extracts were washed with brine (250 mL),
dried (MgSO4) and evaporated under reduced pressure. Column chroma-
tography (silica gel, Et2O/PE 1:4) afforded the MOM ether as a colour-
less oil. [a]D = ꢀ5.67 (c = 0.635, CHCl3); 1H NMR (400 MHz, CDCl3):
d = 7.66 (m, 4H), 7.41 (m, 2H), 5.70 (dddd, J=17.3, 9.9, 7.6, 7.2 Hz,
1H), 5.01 (d, J=17.3 Hz, 1H), 5.00 (d, J=9.9 Hz, 1H), 4.71 (d, J=
7.3 Hz, 1H), 4.59 (d, J=7.3 Hz, 1H), 4.38 (m, 2H), 4.37 (m, 4H), 3.75
(dd, J=11.1, 10.8 Hz, 1H), 3.29 (s, 3H), 2.47 (ddd, J=11.6, 7.7, 7.6 Hz,
1H), 2.36 (dd, J=13.6, 7.2 Hz, 1H), 2.16 (dd, J=13.6, 7.6 Hz, 1H), 1.97
(s, 3H), 1.96 (m, 2H), 1.82 (ddd, J=12.9, 11.8, 6.5 Hz, 1H), 1.59 (ddd,
J=12.9, 7.8, 2.8 Hz, 1H), 1.27 (s, 3H), 1.08 (s, 9H), 1.01 (d, J=7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3): d = 171.1, 135.8, 134.6, 134.3, 134.2,
129.5, 129.4, 127.5, 127.4, 117.7, 90.6, 78.5, 74.2, 66.5, 55.6, 45.8, 45.6, 44.4,
42.7, 33.9, 27.0, 21.7, 21.0, 19.3, 15.7; IR (film): nmax = 2963 (C-H), 2932
(C-H), 1737 (acetate C=O), 1639 (w C=C), 1588 cmꢀ1 (w Ar); ESI+ MS:
m/z: calcd for C32H46O5SiNa: 561.3012; found: 561.3008 [M+Na]+.
C(H)CH2 or C
tween H-1 and H-5 (3.5% enhancement), and H-1 and C
(4% enhancement)]; 13C NMR (100 MHz, CDCl3): d
135.9, 135.8,
ACHTREUNG
AHCTREUNG
=
134.2, 134.0, 129.6, 127.5, 127.5, 117.7, 104.8, 85.8, 78.0, 58.8, 50.9, 44.6,
42.8, 35.2, 28.8, 27.0, 19.4, 14.6; IR (film): nmax = 3260–3505 (br OH),
2932 (C-H), 2858 (C-H), 1639 (w C=C), 1588 cmꢀ1 (w Ar); ESI+ MS:
calcd for C28H39O3Si: 451.1002; found: 451.0999 [M+H]+.
Lactone 41s: TPAP (3.2 mg, 9.2 mmol) was added to a mixture of NMO
(32.3 mg, 276 mmol), lactol 43 (83 mg, 184 mmol) and 4 Š MS in CH2Cl2
(400 mL). The resulting black mixture was stirred at RT for 18 h then di-
luted with CH2Cl2 (20 mL) and washed with saturated Na2SO3 solution
(20 mL). The separated aqueous phase was back-extracted with CH2Cl2
(20 mL) and the combined organic phases washed with brine (20 mL),
CuSO4 solution (20 mL), dried (MgSO4) and evaporated under reduced
pressure. Column chromatography (silica gel, Et2O/PE 1:9) afforded the
lactone (72 mg, 87%). [a]D
(400 MHz, CDCl3): d = 7.67 (m, 4H), 7.44 (m, 2H), 7.38 (m, 4H), 5.56
= +12.8 (c =
1.34, CHCl3); 1H NMR
Chem. Eur. J. 2007, 13, 5688 – 5712
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5701

S. V. Ley et al.
Allylic alcohol 46: Asolution of tert-butyllithium (123 mL, 1.7m in pen-
tane, 209 mmol) was added at ꢀ788C via canula over 15 min to a solution
of ethyl vinyl ether (40.1 mL, 418 mmol) in THF (300 mL). After a fur-
ther 15 min, the resulting solution was warmed to 08C before stirring for
10 min. After cooling to ꢀ788C, a solution of the crude residue of alde-
hyde 39 in THF (75 mL) was added via canula over 20 min, before stir-
ring for 1.5 h at ꢀ788C. After allowing to warm to RT over 40 min, the
reaction mixture was allowed to warm to RT and stirred for a further
1.5 h. Half saturated aqueous NaHCO3 solution (250 mL) was added and
the aqueous phase extracted with ether (4”100 mL). The combined or-
ganics phases were dried (MgSO4) and concentrated under reduced pres-
sure to afford the crude title compound 46 which was used in the next
step without further purification. [a]D = +19.7 (c = 1.10, CHCl3); 1H
NMR (400 MHz, CDCl3): d = 7.67 (m, 4H), 7.42–7.38 (m, 6H), 5.67
(dddd, J=17.2, 10.2, 7.6, 7.2 Hz, 1H), 5.01 (d, J=17.2 Hz, 1H), 4.92 (d,
J=10.2 Hz, 1H), 4.81 (d, J=7.4 Hz, 1H), 4.68 (d, J=7.4 Hz, 1H), 4.47
(m, 2H), 4.18 (s, 1H), 3.98 (m, 2H), 3.72–3.67 (m, 2H), 3.31 (s, 3H), 2.57
(m, 1H), 2.41 (dd, J=13.5, 7.6 Hz, 1H), 2.21 (m, 2H), 2.08 (m, 1H), 1.71
(ddd, J=13.0, 9.1, 5.1 Hz, 1H), 1.55 (m, 1H), 1.43 (s, 3H), 1.26 (t, J=
7.0 Hz, 3H), 1.08 (s, 9H), 0.85 (d, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d = 162.5, 136.0, 136.0, 135.0, 134.5, 133.8, 129.4, 127.4, 118.1,
90.9, 80.4, 80.1, 75.2, 70.5, 62.3, 55.9, 48.3, 46.2, 44.9, 38.4, 36.3, 27.2, 21.8,
19.5, 15.3, 14.5; IR (film): nmax = 3474 (br OH), 2857 (C-H), 1662 cmꢀ1
(w C=C); ESI+ MS: m/z: calcd for C34H50O5SiNa: 589.3325; found:
589.3328 [M+Na]+.
(100 MHz, CDCl3): d = 158.6 (C-7), 136.0 (o-Ph), 135.9 (o-Ph), 135.0
(ipso-Ph), 134.4 (ipso-Ph), 129.4 (p-Ph), 127.4 (m-Ph), 127.4 (m-Ph), 92.2
(C-8), 90.3 (OCH2O), 78.4 (C-10), 74.7 (C-3), 72.9 (C-6), 62.1
(OCH2CH3), 55.1 (OCH3), 52.5 (C-5), 47.6 (C-1), 39.30 (C-4), 38.8 (C-2),
32.3 (C-9), 27.1 (C
A
ACHTREUNG
14.3 (C-15), 6.9 (Si
C
ACHTREUNG
a-Hydroxy ketone 49: Solid NaHCO3 (4.38 g, 52.1 mmol) was added at
RT to a solution of AD mix-a (24.3 g) in tert-butanol and water 1:1
(210 mL). The resulting solution was added to the neat enol ether 48
(11.4 g, 17.4 mmol) before addition of methanesulfonamide (1.65 g,
17.4 mmol) and stirred at RT for 15 h. The reaction was quenched by the
addition of sodium sulfite (7.50 g), with stirring for 1 h before addition of
a half-saturated aqueous NaHCO3 solution (200 mL) and ethyl acetate
(200 mL). The separated aqueous phase was extracted with ethyl acetate
(3”100 mL) and the combined organics dried (MgSO4), concentrated
under reduced pressure and purified by filtration through a short plug of
silica gel (Et2O/PE 1:5 ! 1:1) to afford the title compound as a white
amorphous solid (10.7 g, 96%). [a]D = +42.9 (c = 1.72, CHCl3); 1H
NMR (400 MHz, CDCl3): d = 7.67 (m, 4H; o-Ph), 7.42–7.38 (m, 6H; m-
and p-Ph), 4.97 (ddd, 8.1, 6.1, 5.7 Hz, 1H; H-8), 4.89 (d, J=7.6 Hz, 1H;
OCH2O), 4.78 (d, J=7.6 Hz, 1H; OCH2O), 4.25 (d, J=3.9 Hz, 1H; H-6),
4.14 (m, 1H; H-3), 3.33 (s, 3H; OCH3), 3.10 (d, J=5.7 Hz, 1H; OH),
2.90 (m, 1H; H-1), 2.34 (dd, J=14.2, 6.1 Hz, 1H; H-9), 2.19 (ddd, J=
10.7, 9.4, 3.9 Hz, 1H; H-5), 1.64 (m, 1H; H-4), 1.56 (dd, J=14.2, 8.1 Hz,
1H; H-9), 1.47 (ddd, J=13.6, 7.3, 1.8 Hz, 1H; H-2), 1.27 (m, 4H; H-2, H-
TES-ether 47: Imidazole (8.55 g, 126 mmol), TESCl (9.84 mL, 58.6 mmol)
and catalytic DMAP were added to a solution of the crude residue of al-
cohol 46 in DMF (77 mL) and the reaction was stirred at RT for 19 h.
Half-saturated aqueous NaHCO3 solution and 10% w/v aqueous lithium
chloride solution (150 mL) were then added and the separated aqueous
phase was extracted with ether (4”80 mL). The combined organic phases
were dried (MgSO4), concentrated under reduced pressure and purified
by flash chromatography on basic alumina doped with triethylamine
(Et2O/PE 1:20 + 1% NEt3) to afford the title compound as a colourless
oil (24.4 g, 86% over three steps from alcohol 38s). [a]D = ꢀ7.50 (c =
1.00, CHCl3); 1H NMR (400 MHz, CDCl3): d = 7.67 (m, 4H), 7.42–7.38
(m, 6H), 5.82 (dddd, J=17.1, 10.1, 7.8, 7.0 Hz, 1H), 5.07 (d, J=10.1 Hz,
1H), 5.05 (d, J=17.1 Hz, 1H), 4.82 (d, J=7.5 Hz, 1H), 4.64 (d, J=
7.5 Hz, 1H), 4.55 (m, 2H), 3.98 (s, 1H), 3.83 (s, 1H), 3.65–3.62 (m, 2H),
3.31 (s, 3H), 2.56 (m, 1H), 2.49 (dd, J=13.6, 7.0 Hz, 1H), 2.40 (m, 1H),
2.25 (dd, J=13.6, 7.8 Hz, 1H), 2.00 (ddd, J=13.0, 12.9, 8.0 Hz, 1H), 1.82
(d, J=6.6 Hz, 1H), 1.44 (m, 1H), 1.29 (s, 3H), 1.23 (t, J=7.0 Hz, 3H),
1.09 (s, 9H), 0.95 (d, J=7.0 Hz, 3H), 0.79 (m, 9H), 0.43 (m, 6H); 13C
NMR (100 MHz, CDCl3): d = 166.2, 135.9, 135.8, 135.4, 134.9, 129.2,
127.4, 127.3, 117.3, 90.6, 80.0, 79.1, 75.1, 71.8, 62.4, 55.1, 53.3, 45.7, 44.4,
37.8, 35.3, 27.1, 22.3, 19.4, 17.0, 14.4, 6.9, 5.1; IR (film): nmax = 2954 (C-
H), 2987 (C-H), 1662 cmꢀ1 (w C=C); ESI+ MS: calcd for
C40H64O5Si2Na: 703.4190; found: 703.4183 [M+Na]+.
14), 1.09 (d, J=7.0 Hz, 3H; H-15), 1.06 (s, 9H; C
ACHTREUNG
7.8 Hz, 9H; Si(CH2CH3)3), 0.61 (q, J=7.8 Hz, 6H; Si
A
ACHTREUNG
(100 MHz, CDCl3): d = 213.5 (C-7), 135.9 (o-Ph), 135.8 (o-Ph), 134.7
(ipso-Ph), 133.8 (ipso-Ph), 129.6 (p-Ph), 127.6 (m-Ph), 127.5 (m-Ph), 90.8
(OCH2O), 78.4 (C-6), 78.2 (C-10), 74.8 (C-3), 69.9 (C-8), 55.4 (OCH3),
51.0 (C-5), 46.4 (C-1), 42.1 (C-4), 41.4 (C-9), 38.3 (C-2), 31.2 (C-14), 27.1
(C
A
G
N
N
1710 cmꢀ1 (C=O); ESI+ MS: m/z: calcd for C36H56O6Si2Na: 663.3513;
found: [M+Na]+ 663.3513.
Butenolide
51:
2-(Diethoxyphosphoryl)propionic
acid
(5.27 g,
25.07 mmol) and EDCI (10.37 g, 54.09 mmol) were added at RT to a so-
lution of ketoalcohol 49 (11.48 g, 17.91 mmol) in CH2Cl2 (210 mL). The
reaction mixture was stirred for 3 h before addition of saturated aqueous
NaHCO3 solution (100 mL), separation of the phases, extraction of the
aqueous with CH2Cl2 (2”60 mL) and drying the combined organics
(MgSO4). Purification by flash chromatography (ethyl acetate/PE 1:1
then 2:1) afforded the title compounds as a colourless oil (12.08 g, 81%;
1:1 mixture of diastereoisomers). To a solution of this ketophosphonate
(12.08 g, 14.50 mmol) in THF (620 mL) was added NaH (617 mg of a 60
wt% dispersion in mineral oil, 15.43 mmol) at RT. After 5 min, the reac-
tion mixture was heated to reflux (828C external temperature) for
15 min, after which time a colourless to yellow colour change was appar-
ent. Cooling to RT, addition of saturated aqueous NaHCO3/water 1:1
(400 mL), separation of the phases, extraction of the aqueous with
CH2Cl2 (3”150 mL), drying the combined organics (MgSO4) and concen-
tration under reduced pressure afforded the crude residue of the title
compound which was used without further purification. [a]D = +50.5 (c
= 1.54, CHCl3); 1H NMR (600 MHz, CDCl3): d = 7.65–7.64 (m, 4H; o-
Ph), 7.43–7.42 (m, 2H; p-Ph), 7.41–7.33 (m, 4H; m-Ph), 5.40–5.38 (m,
1H; H-8), 4.98 (d, J=7.6 Hz, 1H; OCH2O), 4.72 (d, J=2.4 Hz, 1H; H-
6), 4.60 (d, J=7.6 Hz, 1H; OCH2O), 4.11–4.08 (m, 1H; H-3), 3.39 (s, 3H;
OCH3), 3.07–3.06 (m, 1H; H-1), 2.37 (dd, J=13.8, 5.7 Hz, 1H; H-9),
2.34–2.30 (m, 1H; H-5), 1.75 (s, 3H; H-13), 1.45 (dd, J=13.0, 7.0 Hz,
1H; H-2), 1.33–1.26 (m, 1H; H-9), 1.25–1.24 (m, 1H; H-4), 1.13–1.12 (d,
Enol ether 48: Asolution of diene 47 (17.0 g, 24.9 mmol) in CH2Cl2
(750 mL) was degassed with a stream of dry argon at RT for 1 h. Grubbs’
second generation catalyst (529 mg, 0.62 mmol) was added before heating
to reflux. Whilst stirring under reflux, a second portion of Grubbs’ 2nd
generation catalyst (529 mg, 0.62 mmol) as a solution in CH2Cl2 (20 mL)
was added through a glass side arm (positioned between flask and con-
denser) via syringe pump over 14 h. After a total of 21 h at reflux, the re-
action mixture was cooled to RT, concentrated under reduced pressure
and purified by flash chromatography on basic alumina doped with trie-
thylamine (Et2O/PE 1:30 + 1% NEt3 followed by 1:5, Et2O/PE + 1%
NEt3) to afford the title compound as colourless oil (14.3 g, 88%). [a]D
= +14.0 (c = 0.10, CHCl3); 1H NMR (400 MHz, CDCl3): d = 7.67 (m,
4H; o-Ph), 7.42–7.38 (m, 6H; m-, p-Ph), 4.67 (d, J=7.5 Hz, 1H;
OCH2O), 4.63 (d, J=7.5 Hz, 1H; OCH2O), 4.41 (dd, J=6.4, 6.3 Hz, 1H;
H-8), 4.33 (ddd, J=7.2, 7.1, 4.7 Hz, 1H; H-3), 4.07 (dd, J=6.0, 1.0 Hz,
1H; H-6), 3.57 (q, J=7.0 Hz, 2H; OCH2CH3), 3.26 (s, 3H; OCH3), 2.80
(dd, J=13.8, 6.3 Hz, 1H; H-9), 2.72 (m, 1H; H-1), 2.19 (ddd J=10.5, 6.4,
6.0 Hz, 1H; H-5), 1.93 (dd, J=13.8, 6.4 Hz, 1H; H-9), 1.82 (m, 2H; H-2,
H-4), 1.55 (m, 1H; H-2), 1.24 (t, J=7.0 Hz, 3H; OCH2CH3), 1.08 (s, 9H;
J=6.6 Hz, 3H; H-15), 1.08 (s, 9H; C(CH3)3), 1.05 (s, 3H; H-14), 0.95 (t,
N
J=8.0 Hz, 9H; SiCH2CH3), 0.60–0.52 (m, 6H; SiCH2); 13C NMR
(150 MHz, CDCl3): d = 174.2 (C-12), 163.4 (C-7), 135.9 (o-Ph), 135.8 (o-
Ph), 134.6 (ipso-Ph), 133.7 (ipso-Ph), 129.7 (p-Ph), 129.7 (p-Ph), 127.6
(m-Ph), 127.6 (m-Ph), 123.2 (C-11), 91.6 (CH2OCH3), 78.6 (C-8), 75.2 (C-
3), 67.9 (C-6), 55.3 (CH2OCH3), 51.5 (C-5), 44.5 (C-1), 44.2 (C-4), 40.8
(C-9), 39.0 (C-2), 29.3 (C-11), 27.1 (C-20), 19.5 (C-19), 14.5 (C-15), 9.0
C(CH3)3), 1.01 (d, J=7.0 Hz, 3H; H-15), 0.92 (s, 3H; H-14), 0.88 (t, J=
G
7.8 Hz, 9H; Si
N
N
5702
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 5688 – 5712

Natural Products
FULL PAPER
(C-13), 6.7 (SiCH2CH3), 4.5 (SiCH2CH3); IR (film): nmax = 2955, 2877,
1757, 1458, 1427, 1191, 1144, 1102, 1076, 1035, 1005, 918, 821, 741,
701 cmꢀ1; ESI+ MS: m/z: calcd for C39H58O6SiNa: 701.3670; found:
701.3693 [M+Na].
to a solution of the crude alcohol 53 in CH2Cl2 (180 mL). After stirring
for 18 h, a half-saturated aqueous ammonium chloride solution (300 mL)
was added and stirring continued for 15 min. Separation of the phases,
extraction of the aqueous with CH2Cl2 (3”80 mL), drying the combined
organics (MgSO4), concentration under reduced pressure and purification
by flash chromatography (Et2O/PE 1:10 ! 1:1) afforded the title com-
pound as a colourless oil (6.69 g, 60% yield over 4 steps from ketoalco-
hol 49. [a]D = ꢀ79.4 (c = 0.175, CHCl3); 1H NMR (600 MHz, CDCl3):
d = 7.68–7.63 (m, 4H; o-Ph), 7.43–7.32 (m, 6H; p-Ph, m-Ph), 4.72 (d,
J=12.0 Hz, 1H; H-12), 4.67–4.55 (m, 5H; OCH2O, H-8, H-12), 4.35 (d,
J=7.0 Hz, 1H; OCH2O), 4.25–4.21 (m, 1H; H-3), 4.02 (d, J=11.0 Hz,
1H; H-6), 3.32 (s, 3H; OCH3), 3.31 (s, 3H; OCH3), 2.80 (dt, J=14.0,
8.0 Hz, 1H; H-1), 2.25–2.18 (m, 1H; H-4), 2.11–2.05 (m, 1H; H-5), 2.04
(s, 3H; CH3C=O), 1.99–1.93 (m, 1H; H-9), 1.95 (s, 3H; H-13), 1.63 (dd,
J=14.0, 9.0 Hz, 1H; H-9), 1.44 (dd, J=14.0, 6.0 Hz, 1H; H-2), 1.29 (dt,
J=12.0, 6.0 Hz, 1H; H-2), 1.17 (d, J=7.0 Hz, 3H; H-15), 1.07 (s, 9H; C-
Diol 52: Asolution of lithium borohydride (140 mL of a 2.0 m solution in
THF, 280 mmol) was added over 30min via cannula at RT to the crude
residue of butenolide 51 in THF (200 mL). The resulting solution was
heated to reflux (848C external temperature) for 40 h, after which time
TLC analysis of the reaction (ethyl acetate/PE 1:2) showed consumption
of the starting lactone to product diol but also a quantity of the inter-
mediate lactol. Addition of further lithium borohydride solution (40 mL
of a 2.0m solution in THF, 80 mmol) and heating under reflux for 24 h
completed the reaction by TLC. The reaction mixture was carefully
poured into a 1:1 mixture of saturated aqueous ammonium chloride solu-
tion and ice before stirring for 20 min. Separation of the phases, extrac-
tion of the aqueous with ether (3”150 mL), drying the combined organ-
ics (MgSO4) and concentration under reduced pressure afforded the
crude title compound as a white foam which was used without purifica-
tion in the subsequent step. [a]D =+26.6 (c = 1.22, CHCl3); 1H NMR
(600 MHz, CDCl3): d = 7.66–7.65 (m, 4H; o-Ph), 7.41–7.40 (m, 2H; p-
Ph), 7.39–7.33 (m, 4H; m-Ph), 4.81 (t, J=8.3 Hz, 1H; H-8), 4.65 (d, J=
6.6 Hz, 1H; OCH2O), 4.62 (d, J=6.6 Hz, 1H; OCH2O), 4.33 (d, J=
11.1 Hz, 1H; H-12), 4.26–4.24 (m, 1H; H-3), 4.04 (d, J=11.2 Hz, 1H; H-
6), 3.73 (d, J=11.1 Hz, 1H; H-12), 3.33 (s, 3H; OCH3), 2.80–2.77 (m,
1H; H-1), 2.41 (brs, 1H; OH), 2.27–2.25 (m, 1H; H-4), 2.04–2.00 (m,
6H; H-5, H-9, H-13), 1.59 (brs, 1H; OH), 1.57 (dd, J=14.3, 5.2 Hz, 1H;
H-9), 1.41–1.39 (m, 1H; H-2), 1.30–1.25 (m, 1H; H-2), 1.17 (d, J=7.1 Hz,
A
(m, 6H; SiCH2CH3); 13C NMR (150 MHz, CDCl3): d = 171.1 (C=O),
138.7 (C-7), 135.9 (o-Ph), 135.9 (o-Ph), 135.0 (ipso-Ph), 134.2 (ipso-Ph),
131.0 (C-11), 129.5 (p-Ph), 129.5 (p-Ph), 127.5 (m-Ph), 127.5 (m-Ph), 92.4
(O-8-CH2OCH3), 90.9 (O-10-CH2OCH3), 78.6 (C-10), 74.1 (C-3), 70.5 (C-
6), 68.1 (C-8), 65.4 (C-12), 55.4 (O-8-CH2OCH3), 55.1 (O-10-CH2OCH3),
53.3 (C-5), 44.8 (C-1), 43.2 (C-4), 38.6 (C-9), 38.0 (C-2), 28.9 (C-14), 27.1
(C
N
N
(SiCH2CH3), 4.7 (SiCH2CH3); IR (film): nmax = 2955 (C-H), 2933 (C-H),
1740 (C=O), 1725 cmꢀ1 (C=O); ESI+ MS: m/z: calcd for C43H68O8Si2Na:
791.4350; found: 791.4385 [M+Na]+.
Tetrol 55: To the commercially available solution of osmium tetroxide
(4.70 mL of a 2.5% solution in tert-butanol) and water (13.7 mL) was
added further solid osmium tetroxide (100 mg, 391 mmol), quinuclidine
(968 mg, 8.70 mmol), potassium carbonate (3.65 g, 26.10 mmol), potassi-
um hexacyanoferrate (8.57 g, 26.10 mmol) and methane sulfonamide
(2.49 g, 26.10 mmol) with vigorous stirring at RT. Olefin 54 (6.70 g,
8.70 mmol) in tert-butanol (9.0 mL) was added before continuing vigo-
rous stirring for 10 d (flask wrapped in foil to exclude light). After this
time, sodium sulfite (6.10 g) was added and the reaction mixture stirred
for 1 h. Addition of water (25 mL), separation of the phases, extraction
of the aqueous with Et2O (6”60 mL), drying the combined organics
(MgSO4) and concentration under reduced pressure afforded a crude res-
idue in which the reaction was judged to be incomplete by TLC. Subject-
ing the crude mixture to exactly the same olefination conditions as de-
scribed above for 7 d, followed by the same workup procedure, afforded
the crude title compound as a dark amber oil which was used without fur-
ther purification. To a solution of the crude residue of the diol in metha-
nol (400 mL) was added solid potassium carbonate (10.90 g, 78.90 mmol).
After vigorous stirring for 1 h, the reaction mixture was poured into a 1:1
mixture of saturated aqueous NaHCO3 solution and water. Separation of
the phases, extraction of the aqueous with CH2Cl2 (4”80 mL), drying the
combined organic layers (MgSO4), concentrating under reduced pressure
and purification by flash chromatography (ethyl acetate/PE 3:2) afforded
the title compound as a pale yellow oil (4.78 g, 85% over two steps from
olefin 54). Rf =0.56 (ethyl acetate); [a]D = +1.7 (c = 1.18, CHCl3); 1H
NMR (600 MHz, CDCl3): d = 7.68–7.62 (m, 4H; o-Ph), 7.45–7.32 (m,
6H; m-Ph, m-Ph), 4.97 (s, 1H; 7-OH), 4.79 (d, J=3 Hz, 1H; OCH2O),
4.67–4.56 (m, 3H; OCH2O), 4.36–4.31 (m, 1H; H-3), 4.19–4.06 (m, 4H;
6-OH, H-8, H-12), 3.77 (dd, J=10, 3 Hz, 1H; H-6), 3.48–3.42 (m, 1H; H-
12), 3.37 (s, 3H; OCH3), 3.34 (s, 3H; OCH3), 3.12–3.06 (m, 1H; 12-OH),
2.81–2.75 (m, 1H; H-1), 2.61–2.54 (m, 1H; H-4), 2.10–2.05 (m, 1H; H-5),
1.95 (dd, J=16, 8 Hz, 1H; H-9), 1.82 (d, J=16 Hz, 1H; H-9), 1.56–1.46
(m, 2H; H-2), 1.31 (s, 3H; H-13), 1.12 (d, J=7 Hz, 3H; H-15), 1.07 (s,
3H; H-15), 1.07 (s, 9H; C(CH3)3), 1.02 (s, 3H; H-14), 0.86 (t, J=8.0 Hz,
G
9H; SiCH2CH3), 0.51–0.48 (m, 6H; SiCH2); 13C NMR (150 MHz,
CDCl3): d = 141.4 (C-11), 135.9 (o-Ph), 135.8 (o-Ph), 134.9 (ipso-Ph),
134.1 (ipso-Ph), 133.8 (C-7), 129.6 (p-Ph), 129.5 (p-Ph), 127.5 (m-Ph),
127.5 (m-Ph), 90.1 (CH2OCH3), 79.3 (C-10), 74.0 (C-3), 69.8 (C-6), 66.0
(C-8), 64.6 (C-12), 55.7 (CH2OCH3), 53.3 (C-5), 44.7 (C-1), 43.1 (C-4),
39.2 (C-9), 37.9 (C-2), 28.5 (C-14), 27.1 (C(CH)3), 19.4 (C(CH)3), 16.6 (C-
15), 7.0 (SiCH2CH3), 4.8 (SiCH2CH3); IR (film): nmax = 3366 (br), 2932,
2875, 1457, 1427, 1373, 1191, 1105, 1065, 1005, 928, 856, 820, 740,
701 cmꢀ1; ESI+ MS: m/z: calcd for C39H62O6SiNa: 705.3983; found:
705.4001 [M+Na]+.
Acetate 53: 2,6-Lutidine (4.90 mL, 41.97 mmol), acetic anhydride
(1.58 mL, 16.75 mmol) and DMAP (60 mg) was added at RT to a solu-
tion of the crude diol 52 in CH2Cl2 (160 mL). After stirring for 3 h, a
half-saturated aqueous ammonium chloride solution (200 mL) was added
before separation of the phases and extraction of the aqueous with Et2O
(3”80 mL). The combined organics were dried (MgSO4), then concentra-
tion under reduced pressure and filtration through a short plug of silica
gel (Et2O/PE 1:5) afforded the title compound, contaminated with ca.
15% 2,6-lutidine. The crude material was carried through the subsequent
step without the need for further purification. 1H NMR (600 MHz,
CDCl3): d = 7.68–7.63 (m, 4H; o-Ph), 7.43–7.32 (m, 6H; m-Ph, p-Ph),
5.37 (d, J=11.0 Hz, 1H; H-12), 4.88–4.83 (m, 1H; H-8), 4.60 (d, J=
7.0 Hz, 1H; OCH2O), 4.51 (d, J=7.0 Hz, 1H; OCH2O), 4.25–4.21 (m,
1H; H-3), 4.05 (d, J=12.0 Hz, 1H; H-6), 3.97 (d, J=11.0 Hz, 1H; H-12),
3.28 (s, 3H; OCH3), 2.77 (s, 1H; 8-OH), 2.73 (dt, J=13.0, 7.0 Hz, 1H; H-
1), 2.31–2.24 (m, 1H; H-4), 2.02–1.96 (m, 2H; H-5, H-9), 2.02 (s, 3H;
CH3C=O), 1.94 (s, 3H; H-13), 1.58 (dd, J=14.0, 9.0 Hz, 1H; H-9), 1.45–
1.39 (m, 1H; H-2), 1.29 (dt, J=13.0, 6.0 Hz, 1H; H-2), 1.15 (d, J=7.0 Hz,
3H; H-15), 1.07 (s, 9H; C(CH3)3), 1.00 (s, 3H; H-14), 0.83 (t, J=8.0 Hz,
E
9H; SiCH2CH3), 0.46 (dq, J=8.0, 3.0 Hz, 6H; SiCH2CH3); 13C NMR
(150 MHz, CDCl3): d = 171.9 (C=O), 144.0 (C-7), 135.9 (o-Ph), 135.9 (o-
Ph), 134.9 (C-11), 134.2 (ipso-Ph), 129.5 (p-Ph), 129.5 (p-Ph), 127.5 (m-
Ph), 90.7 (CH2OCH3), 78.5 (C-10), 74.0 (C-3), 69.8 (C-6), 66.5 (C-12),
65.4 (C-8), 55.3 (CH2OCH3), 53.1 (C-5), 45.2 (C-1), 42.8 (C-4), 38.3 (C-
H-14 Hz, 12H; C
(CH3)3); 13C NMR (150 MHz, CDCl3): d = 135.8 (o-
A
Ph), 135.8 (o-Ph), 134.9 (ipso-Ph), 134.1 (ipso-Ph), 129.5 (p-Ph), 129.5 (p-
Ph), 127.5 (m-Ph), 127.5 (m-Ph), 95.9 (O-8-CH2OCH3), 90.5 (O-10-
CH2OCH3), 80.4 (C-7), 78.7 (C-8), 78.6 (C-10), 78.2 (C-11), 73.2 (C-3),
71.5 (C-6), 69.2 (C-12), 56.3 (OCH3), 55.7 (OCH3), 48.8 (C-5), 45.5 (C-1),
9), 37.8 (C-2), 28.7 (C-14), 27.1 (C(CH3)3), 21.1 (C=OCH3), 19.4 (C-
N
(CH3)3), 18.3 (C-13), 16.5 (C-15), 7.0 (SiCH2CH3), 4.6 (SiCH2CH3); IR
(film): nmax = 3410 (br OH), 2956 (C-H), 1725 cmꢀ1 (C=O); ESI+ MS:
m/z: calcd for C41H64O7Si2Na: 747.4088; found: 747.4094 [M+Na]+.
41.5 (C-4), 40.2 (C-9), 37.0 (C-2), 27.0 (C(CH3)3), 25.9 (C-14), 22.5 (C-
R
13), 19.4 (C(CH3)3), 16.3 (C-15); IR (film): nmax = 2955 (C-H), 2933 (C-
N
MOM acetal 54: Diisopropylethylamine (19.10 mL, 109.91 mmol),
MOMCl (8.30 mL, 109.91 mmol) and DMAP (60 mg) were added at RT
H), 1740 (C=O), 1725 cmꢀ1 (C=O); ESI+ MS: m/z: calcd for
C35H54O9SiNa: 669.3435; found: 669.3444 [M+Na]+.
Chem. Eur. J. 2007, 13, 5688 – 5712
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5703

S. V. Ley et al.
Lactone 56: NMO (14.41 g, 123 mmol) was suspended in acetonitrile
(38 mL) before addition of 4 Š molecular sieves (14.11 g), TPAP (95 mg,
270 mmol) and stirring for 30 min. The starting tetraol 55 (1.59 g,
2.46 mmol) was dissolved in acetonitrile (38 mL) and added dropwise via
cannula, to the original mixture. After stirring for a further 1.5 h, the re-
action mixture was concentrated to dryness under reduced pressure
before re-dissolving the crude mixture in ethyl acetate and filtering
through a short plug of silica gel (ethyl acetate) to remove TPAP residues
and afford the pure title compound as a white foam (1.17 g, 74%). Rf =
0.58 (ethyl acetate/PE 2:1); [a]D = +8.0 (c = 2.25, CHCl3); 1H NMR
(600 MHz, CDCl3): d = 7.68–7.61 (m, 4H; o-Ph), 7.45–7.33 (m, 6H; m-
Ph, p-Ph), 5.21 (s, 1H; 11-OH), 4.87 (s, 1H; 7-OH), 4.85 (d, J=7 Hz,
1H; OCH2O), 4.74–4.68 (m, 3H; OCH2O), 4.57 (d, J=11 Hz, 1H; H-6),
4.45–4.40 (m, 1H; H-3), 4.20 (dd, J=10, 6 Hz, 1H; H-8), 3.41 (s, 3H;
OCH3), 3.38 (s, 3H; OCH3), 2.86–2.79 (m, 1H; H-1), 2.51–2.44 (m, 1H;
H-4), 2.20–2.11 (m, 2H; H-5, H-9), 1.72 (dd, J=14, 11 Hz, 1H; H-9),
1.55–1.48 (m, 1H; H-2), 1.46 (s, 3H; H-13), 1.38 (dd, J=13, 6 Hz, 1H; H-
2), 1.20 (d, J=7 Hz, 3H; H-15), 1.17 (s, 3H; H-14), 1.08 (s, 9H; C-
by Dess–Martin periodinane (1.81 g, 4.27 mmol). Stirring was continued
for 90 min before addition of
a 1:1 mixture of saturated aqueous
NaHCO3 solution and saturated aqueous sodium thiosulfate solution
(80 mL) and CH2Cl2 (80 mL). The phases were separated and the aque-
ous phase extracted with CH2Cl2 (3”50 mL), the combined organics
washed with the afore-mentioned 1:1 solution (80 mL), dried (MgSO4),
concentrated under reduced pressure and purified by column chromatog-
raphy (ethyl acetate/PE 1:1 ! 2:1) to afford the title compound 19 as a
white foam (810 mg, 91% over 2 steps from TBDPS-ether 57). [a]D
=
+0.41 (c = 1.75, CHCl3); 1H NMR (600 MHz, CDCl3): d = 4.61 (d, J=
11.7 Hz, 1H; H-6), 4.22 (m, 1H; H-8), 2.76 (m, 1H; H-4), 2.70 (m, 1H;
H-1), 2.60 (m, 1H; H-5), 2.47 (dd, J=15.8, 8.5 Hz, 1H; H-9), 2.34 (dd,
J=18.2, 7.7 Hz, 1H; H-2), 2.22 (m, 1H, H-2), 1.73 (dd, J=15.8, 5.4 Hz,
1H; H-9), 1.51, 1.49 (2”s, 3H; H-13, C
(CH3)
(CH3)), 1.21 (d, J=7.7 Hz, 3H; H-15); 13C NMR (150 MHz,
CDCl3): d = 218.8 (C-3), 174.6 (C-12), 98.9 (C(CH3)2), 79.9 (C-6), 79.4
(C-11), 74.2 (C-10), 72.3 (C-7), 66.5 (C-8), 47.4 (C-4), 46.8 (C-1), 42.9 (C-
5), 39.9 (C-2), 39.9 (C-9), 30.4 (C(CH3)(CH3)), 30.4 (C-14), 23.6 (C-13),
18.3 (C(CH3)
A
G
C
A
ACHTREUNG
AHCTREUNG
A
ACHTREUNG
A
A
G
(br OH), 2973 (C-H), 2941 (C-H), 1767 (lactone C=O), 1734 cmꢀ1
(ketone C=O); accurate mass analysis was performed, but the parent ion
could not be found.
134.8 (ipso-Ph), 133.6 (ipso-Ph), 129.7 (p-Ph), 129.6 (p-Ph), 127.7 (m-Ph),
127.5 (m-Ph), 97.1 (O-8-CH2OCH3), 91.1 (O-10-CH2OCH3), 82.8 (C-6),
81.3 (C-8), 80.0, 79.8, 78.3 (C-7, C-10, C-11), 73.4 (C-3), 56.8 (O-8-
CH2OCH3), 56.2 (O-10-CH2OCH3), 46.9 (C-1), 45.0 (C-5), 43.7 (C-4),
a-Hydroxy ketone 61: To a solution of ketone 19 (311 mg, 0.88 mmol) in
DMF (9.8 mL) at RT was added triethylamine (60 mL) and TMSCl
before heating to reflux (1308C external temperature) for 43 h. The re-
sulting mixture was carefully poured into a mixture of saturated aqueous
NaHCO3 solution and ice (200 mL, 1:1). Extraction with ethyl acetate
(4”100 mL), drying (MgSO4), concentration under reduced pressure and
purification by brief filtration through a pad of silica gel (Et2O/PE 1:10)
afforded the silyl enol ether which was used immediately in the next step
without further purification. To a solution of TMS enol ether (651 mg,
derived from 1.26 mmol ketone 19) in CH2Cl2 (9 mL) at ꢀ788C was
added a freshly prepared solution of DMDO (60 mL, 1.50 mmol, 0.025m)
dropwise before continuing at ꢀ788C for 30 min. The resulting solution
was warmed to RT before stirring for a further 40 min. Saturated aque-
ous ammonium chloride solution (7.5 mL) was added and the reaction
vigorously stirred to complete hydrolysis of the intermediate silyl enol
ether (15 h). Partitioning between further saturated aqueous ammonium
chloride solution (100 mL) and CH2Cl2 (100 mL), separation of the
phases, extraction of the aqueous with CH2Cl2 (3”40 mL), drying the
combined organics (MgSO4), concentration under reduced pressure and
purification of the resulting residue by flash chromatography (ethyl ace-
tate/PE 1:10 then 1:5, ethyl acetate/PE) afforded the title compound as a
white foam (567 mg, 87% over two steps from ketone 19). [a]D =+7.5 (c
= 1.08, CHCl3); 1H NMR (600 MHz, CDCl3): d = 5.19 (d, J=10.3 Hz,
1H; H-6), 4.40 (s, 1H; H-2), 4.15 (m, 1H; H-8), 2.57 (m, 1H; H-4), 2.44
(m, 1H; H-1), 2.40 (d, J=1.86, 1H; OH), 2.25 (m, 2H; H-5, H-9), 2.17
39.7 (C-9), 38.0 (C-2), 27.5 (C-14), 27.0 (C
A
G
(C-13), 16.0 (C-15); IR (film): nmax = 3419, 2924, 2853, 1789, 1459, 1110,
1014 cmꢀ1; ESI+ MS: m/z: calcd for C47H80O7SiNa: 665.312; found:
665.3110 [M+Na]+.
Acetonide 57: Amberlyst 15 (1.90 g) and 2,2-dimethoxypropane
(3.50 mL) were added at RT to a rapidly stirred solution of bis-MOM
diol 56 (2.23 g, 3.47 mmol) in acetone (53 mL). After stirring for 48 h,
4 Š molecular sieves (1.47 g) were added and vigorous stirring continued
for a further 48 h. Filtration through celite with copious ethyl acetate
washings, concentration under reduced pressure followed by filtration of
the residue through a short plug of silica gel (Et2O/PE 1:2 then 1:1) first
afforded the title compound as a colourless oil (1.77 g). Switching to pure
ethyl acetate afforded the crude residue of the intermediate tetraol (1.0 g
of a cloudy gel). This was subjected without further purification, to the
same 4 day transacetalisation as described above in acetone (15 mL),
using Amberlyst 15 (0.48 g), 2,2-dimethoxypropane (1.00 mL) and after
48 h, 4 Š molecular sieves (0.50 g). This afforded an additional quantity
of clean title compound after purification as above (0.19 g). (The total
yield after one “recycle” was therefore 1.96 g, 95%.) Rf =0.34 (ethyl ace-
tate/PE 1:2); [a]D = +4.0 (c
=
0.250, CHCl3); 1H NMR (600 MHz,
CDCl3): d = 7.61–7.59 (m, 4H; o-Ph), 7.39–7.28 (m, 6H; m-Ph, p-Ph),
4.32–4.30 (m, 2H; H-3, H-6), 4.05 (t, J=5.2 Hz, 1H; H-8), 3.71 (s, 1H;
OH), 2.55–2.50 (m, 2H; OH, H-1), 2.41–2.11 (m, 3H; H-4, H-5, H-9),
1.49–1.40 (m, 1H; H-9), 1.39–1.36 (m, 2H; H-2), 1.39 (s, 3H; H-13), 1.23,
1.19 (2”s, 6H; (CH3)2C), 1.17 (d, J=7.1 Hz, 1H; H-15), 1.16 (s, 3H; H-
(dd, J=3.2, 14.7; H-9), 1.57 (s, 3H; H-13), 1.54, 1.53 (2”s, 6H; C
(CH3)), 1.34 (d, J=6.6 Hz; H-15), 1.24 (s, 3H; H-14), 0.22, 0.17 (2”s,
18H; Si
(CH3)3); 13C NMR (150 MHz, CDCl3): d = 216.7 (C-3), 173.2 (C-
12), 112.0 (C(CH3)(CH3)), 99.9 (C-13), 82.6 (C-6), 79.1, 78.0 (C-7, C-10),
74.9 (C-2), 66.2 (C-8), 53.7 (C-1), 46.2 (C-4), 45.2 (C-9), 41.7 (C-5), 30.4
(C-15), 26.6 (C(CH3)(CH3)), 23.4 (C-13), 17.9 (C(CH3)(CH3)), 13.7 (C-
14), 2.7 (Si
A
14), 1.07 (s, 9H; C
(CH3)3); 13C NMR (150 MHz, CDCl3): d = 174.8 (C-
E
AHCTREUNG
12), 135.9 (o-Ph), 135.8 (o-Ph), 134.7 (ipso-Ph), 133.6 (ipso-Ph), 129.7 (p-
Ph), 129.6 (p-Ph), 127.6 (m-Ph), 127.5 (m-Ph), 98.3 (OCO), 82.2 (C-11),
78.9 (C-7), 74.8 (C-3), 73.8 (C-10), 69.7 (C-6), 67.0 (C-8), 53.7 (C-5), 49.6
AHCTREUNG
A
ACHTREUNG
(C-9), 44.5 (C-4), 43.7 (C-1), 38.5 (C-2), 30.4 (C
27.1 (C(CH3)3), 23.6 (C-13), 19.4 (C(CH3)(CH3)), 18.9 (C
(C-15); IR (film): nmax
G
ACHTREUNG
A
G
A
ACHTREUNG
A
N
G
ACHTREUNG
A
=
3390 (br OH), 3200 (br OH), 2933 (C-H),
1035, 821, 701 cmꢀ1; ESI+ MS: m/z: calcd for C24H42O8Si2Na: 537.2316;
found: 537.2328 [M+Na]+.
1764 cmꢀ1 (C=O); ESI+ MS: m/z: calcd for; C34H46O7Si1Na: 617.2911;
found: 617.2928 [M+Na]+.
Experimental procedures towards the trilobolide series (2, 3 and 4) from
61
Ketone 19: Asolution of TBAF (80 mL, 1.0 m in THF, 85 mmol) was
added to neat TBDPS-ether 57 (1.49 g, 2.51 mmol) at RT. After stirring
the resulting solution for 4 d, 4 Š molecular sieves (1.20 g) were added
and vigorous stirring applied for a further 4 d. Filtration through Celite
(washing with ethyl acetate), partitioning between water (80 mL) and
ethyl acetate (80 mL), separation of the phases, extensive extraction of
the aqueous with ethyl acetate (5”60 mL), drying the combined organics
(MgSO4), concentration under reduced pressure and filtration through a
short plug of silica gel (ethyl acetate) afforded the title compound
(883 mg) which was used immediately in the next step without further
purification. Rf =0.26 (ethyl acetate). To a solution of triol 58 in CH2Cl2
(52 mL) at RT was added solid NaHCO3 (720 mg, 8.57 mmol) followed
Enone 62: Asolution of ketone 61 (150 mg, 0.256 mmol) in DMF (4 mL)
in a three-neck round bottom flask fitted with reflux condenser, was
treated with triethylamine (4 mL, 28.7 mmol) and TMSCl (3 mL,
23.6 mmol). The mixture was heated to reflux (1258C) for 48 h, then
cooled to RT and quenched into half-saturated aqueous NaHCO3 solu-
tion (50 mL). The aqueous mixture was extracted with ethyl acetate (4”
50 mL) and the combined organic extracts were dried with MgSO4 and
evaporated to dryness. The residue was purified by column chromatogra-
phy (silica gel, PE/ethyl acetate 5:1) to obtain the TMS enol ether as an
off-white foam (152 mg, 90%). Rf =0.46 (PE/Et2O 5:2). The TMS enol
5704
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 5688 – 5712

Natural Products
FULL PAPER
ether (38 mg, 58 mmol) in CH2Cl2 at 08C was treated with a solution of
PhSeBr (1.38 mg, 5.8 mmol) in CH2Cl2 (5 mL). The mixture was warmed
to 108C over 2 h, after which the reaction was complete by TLC. The
mixture was treated with saturated aqueous NaHCO3 (3 mL), water
(3 mL) and extracted into CH2Cl2 (3”10 mL). The combined extracts
were dried (MgSO4) and evaporated to dryness. The residue was purified
by column chromatography (silica gel, PE/Et2O 5:1) to give the enone as
2925, 1775, 1687, 1455, 1383 cmꢀ1
; ESI+ MS: m/z: calcd for
C23H32O8SiNa: 459.1995; found: 459.1996 [M+Na]+.
Acetate 66: Isopropenyl acetate (100 mL, 909 mmol) in CH2Cl2 (300 mL)
was treated with Amberlyst 15 resin (PS-pTsOH, 10 mg) and 4 Š molec-
ular sieves (powdered, 10 mg) and aged for 1 h at RT. The angelate-diol
65 (14 mg, 32 mmol) in CH2Cl2 (300 mL) was then added to the resin sus-
pension and the mixture was aged with gentle shaking for 16 h. The resin
was removed by filtration and washed with CH2Cl2 (1 mL). The com-
bined filtrates were evaporated to dryness and the residue was purified
by column chromatography (silica gel, PE/EtOAc 2:1) to give a clear oil
(10 mg, 68%). Rf =0.39 (PE/EtOAc 1:1); 1H NMR (600 MHz, CDCl3): d
= 6.10 (apparent qd, J=7.2, 1.2 Hz, 1H; =CHCH3), 5.85 (d, J=2.1 Hz,
1H; H-6), 5.57 (apparent t, J=6.8 Hz, 1H; H-3), 4.27 (m, 1H; H-8), 3.96
(m, 1H; H-1), 2.93 (dd, J=14.8, 4.6 Hz, 1H; H-9), 2.57 (ddd, J = 13.6,
7.6, 6.0 Hz, 1H; H-2), 2.43 (m, 2H; H-9, OH), 2.02 (apparent dd, J=7.2,
1.3 Hz; =CHCH3), 1.95 (s, 3H; C(O)CH3), 1.93 (s, 3H; H-15), 1.92 (d,
a clear colourless oil (27 mg, 94%). Rf =0.26 (PE/Et2O 5:2); [a]D
=
ꢀ86.6 (c = 1.3, CHCl3); 1H NMR (700 MHz, CDCl3): d = 5.98 (s, 1H;
H-6), 4.21 (apparent t, J=3.5 Hz, 1H; H-8), 3.44 (brm, 1H; H-1), 2.46
(m, 2H; H-2), 2.33 (dd, J=14.5, 4.1 Hz, 1H; H-9), 2.14 (dd, J=14.5,
3.0 Hz, 1H; H-9), 1.98 (s, 3H; H-15), 1.60 (s, 3H; H-13), 1.58 (s, 3H; C-
A
N
G
N
A
N
=
A
ACHTREUNG
A
G
A
ACHTREUNG
J=1.3 Hz, 3H; C(O)CCH3), 1.57 (s, 3H; H-13), 1.54 (s, 3H; C
A
(CH3)3); IR (film): nmax = 2957, 1798, 1709,
A
C
A
ACHTREUNG
(150 MHz, CDCl3): d = 172.8 (C-12), 170.4 (C(O)CH3), 167.7 (C=O an-
geloyl), 141.3 (=CHCH3), 138.5 (C-5), 129.3 (C-4), 127.8 (C(O)CCH3),
Allylic alcohol 63: Enone 62 (27 mg, 54 mmol) in MeOH at 08C was
treated with solid NaBH4 (22 mg, 580 mmol) added in a single portion.
The mixture was aged for 1 h at 08C then treated with saturated aqueous
NaHCO3 (5 mL), water (5 mL) and extracted into CH2Cl2 (4”15 mL).
Combined extracts were dried (MgSO4) and evaporated to dryness. The
residue was purified by column chromatography (silica gel, PE/Et2O 2:1)
to give the allylic alcohol as a clear oil (22 mg, 86%). Rf =0.22 (PE/Et2O
100.9 (C
76.1 (C-7), 66.1 (C-8), 51.6 (C-1), 38.3 (C-9), 33.2 (C-2), 30.5 (C
(CH3)), 23.6 (C(CH3)(CH3)), 22.4 (C(O)CH3), 20.7 (C-14, C(O)CCH3),
15.9, 15.8 (C-13, =CHCH3), 12.6 (C-15); IR (film): nmax = 3424, 2932,
1794, 1730, 1371, 1244 cmꢀ1; [a]D = ꢀ43 (c = 0.18, CHCl3); accurate
mass analysis could not find the parent ion.
A
ACHTREUNG
ACHTREUNG
A
G
ACHTREUNG
Trilobolide (2): Asolution of the acetonide 66 (6 mg, 13 mmol) in MeOH
(1 mL) was treated with 3n HCl (75 mL) and heated at 408C until the re-
action was complete by TLC (approximately 2 h). After cooling to RT,
the reaction was quenched with half-saturated NaHCO3 solution (1 mL)
and extracted with CH2Cl2 (3”5 mL). The organics were dried (MgSO4)
and evaporated to dryness. The triol was dissolved in dry CH2Cl2
(0.5 mL) and treated with DMAP (2 mg) and (S)-2-methylbutyric anhy-
dride (20 mL, 96 mmol, in 0.5 mL of CH2Cl2). The solution was stirred at
RT until the triol was fully consumed (as observed by TLC, approximate-
ly 1 h) then 3n HCl (0.5 mL) was added. The mixture was stirred for fur-
ther 25 min, diluted with water (1 mL) and extracted with CH2Cl2 (3”
5 mL). The organics were dried (MgSO4) and evaporated and the residue
was purified by column chromatography (silica gel, PE/ethyl acetate 2:1)
to obtain trilobolide as a clear oil (5 mg, 78% yield, 2 steps). Rf =0.23
1
1:1); [a]D =ꢀ64.0 (c = 0.630, CHCl3); H NMR (600 MHz, CDCl3): d =
5.81 (d, J=1.9 Hz, 1H; H-6), 4.45 (s, 1H; H-3), 4.11 (apparent t, J=
3.5 Hz; H-8), 2.99 (brm, 1H; H-1), 2.43 (m, 1H; H-2), 2.21 (dd, J=14.4,
3.9 Hz, 1H; H-9), 2.04 (dd, J=14.4, 3.2 Hz, 1H; H-9), 1.98 (s, 3H; H-15),
1.53 (s, 3H; H-13), 1.52 (s, 3H; C
(CH3)), 1.20 (s, 3H; H-14), 0.12 (s, 9H; Si
13C NMR (150 MHz, CDCl3): d = 173.3 (C-12), 142.7 (C-4), 129.2 (C-5),
100.1 ((C(CH3)(CH3)), 80.0 (C-7), 79.5 (C-6), 79.2 (C-11), 77.7 (C-3), 76.9
(C-10), 67.2 (C-8), 55.0 (C-1), 45.2 (C-9), 36.7 (C-2), 30.5 ((C(CH3)-
(CH3)), 23.5 ((C(CH3)(CH3)), 23.2 (C-14), 17.1 (C-13), 12.2 (C-15), 2.8,
2.7 (Si ;
(CH3)3); IR (film): nmax = 3431, 2953, 1792, 1372, 1251, 1191 cmꢀ1
A
G
A
A
N
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
A
N
ACHTREUNG
U
ESI+ MS: m/z: calcd for C24H42O7Si2Na: 521.2367; found: 521.2372
[M+Na]+.
Angelate ester 64: Angelic acid (50 mg, 50 mmol), 2,4,6-trichlorobenzoyl
chloride (79 mL, 51 mmol) and triethylamine (70 mL, 51 mmol) were mixed
in toluene (200 mL) at RT for 2 h. The mixture became cloudy and vis-
cous and was then treated with allylic alcohol 63 (22 mg, 44 mmol) in tol-
uene (200 mL) and was heated to 808C for 4 h. Saturated aqueous
NaHCO3 (3 mL) and water (3 mL) were added and the mixture was ex-
tracted into CH2Cl2 (3”10 mL). The combined extracts were dried
(MgSO4) and evaporated to dryness. The residue was purified by column
chromatography (silica gel, PE/Et2O 1:1) to give the angelate as a clear
oil (19 mg, 76%). Rf =0.14 (PE/Et2O 1:1). The bis-TMS angelate (19 mg,
33 mmol) in THF (500 mL) was treated with TBAF (1m in THF, 165 mL,
165 mmol) at RT and aged for 3 h. The mixture was partitioned between
half-saturated aqueous NaHCO3 (5 mL) and CH2Cl2 (5 mL) and the
aqueous phase was extracted with CH2Cl2 (2”10 mL). The combined or-
ganics were dried (MgSO4), evaporated and purified by column chroma-
tography (silica gel, PE/EtOAc 1:1) to give a clear oil (14 mg, 98%). Rf =
(PE/ethyl acetate 2:1); [a]D
=
ꢀ20 (c
=
0.16, CHCl3); 1H NMR
(700 MHz, CDCl3): d = 6.14 (m, 1H; =CHCH3), 5.73 (brs, 1H; H-6),
5.64 (m, 2H; H-3 H-8), 4.28 (brm, 1H; H-1), 3.07 (dd, J=14.8, 3.4 Hz,
1H; H-9), 2.62 (ddd, J=14.7, 8.5, 8.5 Hz, 1H; H-2), 2.38 (m, 1H; C-
AHCTREUNG
AHCTREUNG
AHCTREUNG
NMR (175 MHz, CDCl3): d = 175.2 (C-12), 174.8 (C=O 2-methylbutano-
yl), 170.4 (C=O acetyl), 167.6 (C=O angeloyl), 144.4 (C-4), 138.6
(C(O)C=C), 130.5 (C-5), 127.7 (C(O)C=), 85.1 (C-10), 79.4 (C-3), 78.9,
78.6 (C-7, C-11), 77.4 (C-6), 66.5 (C-8), 51.3 (C-1), 41.4 (C(O)CHCH3),
38.6 (C-9), 32.3 (C-2), 26.2 (CH2CH3), 22.4 (C=OCH3), 22.0 (C-14), 20.7
(C(O)CCH3), 16.4, 16.3 (C(O)CHCH3, =CHCH3), 15.9 (C-13), 13.2 (C-
15), 11.6 (CH2CH3); IR (film): nmax = 3442, 2923, 1790, 1734, 1713, 1459,
1381, 1239 cmꢀ1
found: 545.2361 [M+Na]+.
; ESI+ MS: m/z: calcd for C27H38NaO10: 545.2363;
0.16 (PE/EtOAc 1:1); [a]D
=
ꢀ0.825 (c
=
1.2, CHCl3); 1H NMR
Nortrilobolide (3): Prepared using the same procedure as described for
trilobolide above, using butyric anhydride for the final acylation (3 mg,
72% over 2 steps). [a]D = ꢀ43 (c = 0.18, CHCl3); 1H NMR (600 MHz,
CDCl3): d = 6.12 (q, J=7.2 Hz, 1H; =CHCH3), 5.71 (s, 1H; H-6), 5.61
(m, 2H; H-3, H-8), 4.21 (brm, 1H; H-1), 3.01 (dd, J=14.8, 3.2 Hz, 1H;
H-9), 2.61 (m, 1H; H-2), 2.32 (dd, J=14.8, 4.0 Hz, 1H; H-9), 2.28 (m,
2H; C(O)CH2CH2), 2.02 (m, 3H; =CHCH3), 1.97 (s, 3H; C(O)CH3), 1.92
(s, 6H; H-15, C(O)CCH3), 1.67 (m, 3H; H-2, C(O)CH2CH2), 1.51 (s, 3H;
H-13), 1.26 (s, 3H; H-14), 0.86 (m, 3H; CH2CH3); 13C NMR (150 MHz,
(600 MHz, CDCl3): d = 6.12 (m, 1H; =CHCH3), 5.86 (s, 1H; H-6), 5.45
(brm, 1H; H-3), 4.12 (brm, 1H; H-8), 3.42 (s, 1H; OH), 3.32 (brm, 1H;
H-1), 2.67 (ddd, J=13.1, 7.4, 6.3 Hz, 1H; H-2), 2.29 (dd, J=14.5, 3.7 Hz,
1H; H-9), 2.07 (dd, J=14.5, 3.7 Hz, 1H; H-9), 1.99 (d, J=7.3 Hz, 3H; =
CHCH3), 1.92 (s, 3H; H-15), 1.90 (s, 3H; C(O)CCH3), 1.59 (m, 1H; H-
2), 1.56 (s, 3H; H-13), 1.54 (s, 3H; C
(CH3)), 1.20 (s, 3H; H-14); 13C NMR (150 MHz, CDCl3): d = 173.0 (C-
12), 168.3 (C=O angeloyl), 140.2 (=CHCH3), 138.9 (C-5), 130.4 (C-4),
127.7 (C=CHCH3), 100.7 ((C(CH3)(CH3)), 79.9 (C-3), 79.2 (C-11), 78.8
(C-6), 76.0 (C-7), 73.6 (C-10), 66.1 (C-8), 54.1 (C-1), 45.0 (C-9), 33.3 (C-
2), 30.5 ((C(CH3)(CH3)), 23.6 ((C(CH3)(CH3)), 22.5 (C-14), 20.6
(C(O)CCH3), 15.9 (C-13, =CHCH3), 12.5 (C-15); IR (film): nmax = 3420,
A
(CH3)), 1.42 (s, 3H; C
A
ACHTREUNG
A
ACHTREUNG
CDCl3): d
= 175.0 (C-12), 172.3 (C=O 2-methylbutanoyl), 170.4 (C=
A
N
G
N
OCH3), 167.6 (C=O angeloyl), 144.2 (C-4), 138.4 (C(O)C=C), 130.6 (C-
5), 127.8 (C(O)C=), 85.2 (C-10), 79.4 (C-3), 78.8, 78.6 (C-7, C-11), 77.4
Chem. Eur. J. 2007, 13, 5688 – 5712
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5705

S. V. Ley et al.
(C-6), 66.4 (C-8), 51.3 (C-1), 38.6 (C-9), 36.5 (C(O)CH2), 32.3 (C-2), 22.7
(C(O)CH3), 22.4 (C(O)CH2CH2), 21.8 (C(O)CH3), 20.6 (C(O)CCH3),
18.0 (C-14), 16.4 (=CHCH3), 15.8 (C-13), 13.7 (CH2CH3), 13.1 (C-15); IR
(film): nmax = 3447, 2923, 2853, 1789, 1712, 1458, 1370 cmꢀ1; ESI+ MS:
m/z: calcd for C26H36NaO10: 531.2206; found: 531.220 [M+Na]+.
10.0 Hz; H-5), 2.38 (m, 1H; H-4), 2.37 (dd, J=14.7, 3.9 Hz, 1H; H-9),
2.37 (dd, J=14.7, 3.2 Hz, 1H; H-9), 1.57 (s, 3H; H-13), 1.54, 1.53 (2”s,
6H; C
0.22, 0.17 (2”s, 18H; Si
(C-3), 173.2 (C-12), 127.8 (C-11), 100.3 (C
A
ACHTREUNG
AHCTREUNG
A
ACHTREUNG
83.7 (C-6), 79.7 (C-2), 79.4, 77.3 (C-10, C-7), 66.2 (C-8), 55.5 (OCH3),
53.7 (C-1), 48.1 (C-4), 46.0 (C-9), 42.8 (C-5), 30.4 (C-15), 23.4 (C-13),
Thapsivillosin F (4): Asolution of acetonide 66 (30 mg, 62.7 mmol) in
MeOH (3.5 mL) was treated with 4 drops (200 mL) of 3n HCl and
heated at 408C for 2 h. After cooling down to RT, the reaction was
quenched with 2 mL of half-saturated NaHCO3 solution and extracted
with CH2Cl2 (4”10 mL). The organics were dried (brine, MgSO4), then
evaporated. The obtained triol was dissolved, at RT in dry CH2Cl2
(2 mL), then catalytic DMAP and senecioic anhydride (11.4 mg,
62.7 mmol, in 0.5 mL of CH2Cl2) were added and the solution was stirred
at RT for 2.5 h. 3n HCl (0.2 mL) was added and the mixture was stirred
for further 20 min before being diluted with water (3 mL)and extracted
with CH2Cl2 (4”10 mL). The organics were dried (brine, MgSO4) and
evaporated the residue was purified by chromatography (PE/ethyl ace-
tate 2:1 then 1:1) to obtain a white solid (18 mg, 60% over 2 steps). [a]D
17.7 (C
C
(CH3)), 16.2 (C
U
N
N
;
ESI+ MS: m/z: calcd for C24H42O8Si2Na: 581.2578; found: 581.2575
[M+Na]+.
Alcohol 74: Asolution of NaHMDS (0.38 mL of a 1.0 m solution in THF,
0.38 mmol) was added dropwise at ꢀ788C to a solution of ketone 69
(41 mg, 0.073 mmol) in THF (8 mL). The resulting solution was stirred at
ꢀ788C for 30 min before warming to ꢀ208C and stirring for 1 h. After
re-cooling to ꢀ788C, TMSCl (49 mL, 0.38 mmol) was added before stir-
ring at ꢀ788C for 30 min, followed by warming to RT. The reaction mix-
ture was then partitioned between saturated aqueous ammonium chlo-
ride solution (12 mL) and Et2O (12 mL), the phases separated, the aque-
ous extracted with Et2O (2”10 mL), the combined organics washed with
saturated aqueous ammonium chloride solution (10 mL), dried (MgSO4)
and concentrated in vacuo to afford the intermediate TMS enol ether as
a pale yellow oil which was immediately dissolved in CH2Cl2 (5.8 mL)
and cooled to ꢀ788C. In a separate flask, phenylselenyl chloride (108 mg,
0.562 mmol) was dissolved in CH2Cl2 (4.0 mL) and cooled to ꢀ788C
before being added to the TMS enol ether solution via cannula. After
stirring at ꢀ788C for 2 h, saturated aqueous sodium thiosulfate solution
was added and the reaction mixture was warmed to RT and partitioned
between saturated aqueous NaHCO3 solution (15 mL) and CH2Cl2
(10 mL). Separation of the phases, extraction of the aqueous with CH2Cl2
(3”10 mL), drying (MgSO4), concentration in vacuo and filtration
through a short plug of silica gel (ethyl acetate/PE 1:40 then 1:4) afforded
the crude mixture of 70 and 71 (87:13 ratio by 1H NMR) which were
used directly without further purification. Astream of oxygen was bub-
bled through a solution of an 83:17 mixture of selenides 70 and 71 (de-
rived from 0.073 mmol of ketone 69) in CH2Cl2 (10 mL) at ꢀ788C before
a stream of ozone was bubbled through until a deep blue colour was ob-
served (2 min). Oxygen was again applied until no blue colour remained
(2 min). After addition of diisopropylamine (0.6 mL) the reaction mix-
ture was allowed to warm to RT and stirred for a further 30 min. Addi-
tion of saturated aqueous NaHCO3 solution (15 mL), separation of the
phases, extraction of the aqueous with Et2O (3”10 mL), drying the com-
bined organics (MgSO4), concentration under reduced pressure and pu-
rification by flash chromatography (ethyl acetate/PE 1:20 then 1:13) af-
forded the title compound as a colourless foam (31 mg, 37% yield of 73
1
= ꢀ35 (c = 0.1, CHCl3); H NMR (600 MHz, CDCl3): d = 6.10 (dq, J=
7, 2 Hz, 1H; =CHCH3), 5.72 (d, J=1, 1H; H-6), 5.62 (t, J=1 Hz, 1H; =
CHCO2), 5.59 (m, 2H; H-3, H-8), 4.35 (brs, 1H; H-1), 3.10 (dd, J=14.5,
3.5 Hz, 1H; H-9), 2.55 (m, 1H; H-2), 2.22 (dd, J=14.5, 3.5 Hz, 1H; H-9),
2.17 (d, J=1 Hz, 3H; =CH3CH3), 2.01 (dd, J = 7, 2 Hz, 3H; =CHCH3),
1.96 (s, 3H; C(O)CCH3), 1.90 (m, 9H; C-15, C(O)CH3, =CH3CH3), 1.65
(m, 1H; H-2), 1.50 (s, 3H; H-13), 1.31 (s, 3H; H-14); 13C NMR
(150 MHz, CDCl3): d = 175.2 (C-12), 170.8 (C(O)CH3), 167.7 (C=O an-
geloyl), 165.15 (C=O senecioyl), 159.6 (=CCH3CH3), 144.0 (C-5), 138.3
(C-3), 78.9 (C-11), 78.8 (C-7), 77.5 (C-6), 66.4 (C-8), 50.9 (c-1), 38.4 (c-9),
32.1 (C-2), 27.5 (=CH3CH3), 22.3 (C(O)CH3), 22.0 (C-14), 20.6
(C(O)CCH3), 20.4 (=CH3CH3), 16.4 (C-13), 15.8 (=CHCH3), 13.0 (C-15);
IR (film): nmax = 3429 (br OH), 2927 (C-H), 1770 (C=O), 1706 (C=O),
1648 cmꢀ1 (C=C); ESI+ MS: m/z: calcd for C27H36NaO10: 543.2206;
found: 543.2145 [M+Na]+.
Experimental procedures towards MOM derivative 75 from 61
Octanoate 68: DMAP (71.2 mL, 0.584 mmol) and octanoic anhydride
(115.6 mg in 1.2 mL CH2Cl2) were added at RT to a solution of alcohol
61 (40 mg, 0.078 mmol) in CH2Cl2 (2.4 mL). The reaction mixture was
stirred for 90 min and quenched by adding a saturated NH4Cl solution
(5 mL). The aqueous layer was extracted with Et2O (4”10 mL). The
combined organic layers were dried (MgSO4) and the solvent was re-
moved under reduced pressure. The crude product was submitted to flash
chromatography (EtOAc/PE 1:20) to obtain 68 (47 mg, 94%) as a colour-
1
less oil. [a]D = +8.7 (c = 1.1, CHCl3); H NMR (700 MHz, CDCl3): d =
5.19 (d, J=10.6 Hz, 1H; H-6), 5.07–5.06 (m, 1H; H-2), 4.13–4.12 (m, 1H;
H-8), 2.66–2.56 (m, 1H; H-1), 2.51–2.47 (m, 2H; H-4 H-5), 2.35–2.30 (m,
2H; CH2 octanoyl), 2.22 (dd, J=14.6, 3.9 Hz, 1H; H-9), 2.13 (dd, J=
14.6, 3.9 Hz, 1H; H-9), 1.63–1.59 (m, 2H; CH2 octanoyl), 1.56 (s, 3H;
CH3), 1.53 (s, 3H; CH3), 1.41 (s, 3H; CH3), 1.39 (s, 3H; CH3), 1.33 (s,
3H; CH3), 1.32–1.25 (m, 8H; CH2 octanoyl), 0.88–0.86 (m, 3H; CH3 oc-
tanoyl), 0.20, 0.14 (2”s, 18H; TMS); 13C NMR (125 MHz, CDCl3): d =
over
3 steps from ketone 69). To a solution of enone 73 (7 mg,
0.013 mmol) in THF (1.5 mL) at RT was added sodium borohydride
(2 mg, 0.083 mmol) before stirring at RT for 17 h. After this time, TLC
analysis showed that the reaction was incomplete and so a second portion
of sodium borohydride (2 mg, 0.083) was added before stirring for 2 h.
Addition of saturated aqueous ammonium chloride solution (2 mL) and
Et2O (1 mL), stirring for 15 min, partitioning between further saturated
aqueous ammonium chloride solution (10 mL) and Et2O (10 mL), separa-
tion of the phases, extraction of the aqueous with Et2O (3”5 mL), drying
(MgSO4) concentration in vacuo and purification by flash chromatogra-
phy (1:30 then 2:3, ethyl acetate/petrol) afforded the title compound 74
as a colourless foam (7 mg, 99%). [a]D =ꢀ66.1 (c = 0.31, CHCl3); 1H
NMR (400 MHz, CDCl3): d = 5.68 (m, 1H; H-6), 4.83 (d, J=6.0 Hz,
1H; OCH2O), 4.63 (d, J = 6.0 Hz, 1H; OCH2O), 4.36 (m, 1H; H-3),
4.23 (dd, J=6.9, 3.9 Hz, 1H; H-2), 4.12 (m, 1H; H-8), 3.43 (s, 1H;
OCH3), 3.28 (m, 1H; H-1), 3.02 (d, J=5.5 Hz, 1H; OH), 2.28 (dd, J=
14.5, 4.1 Hz, 1H; H-9), 2.07 (dd, J=14.5, 3.1 Hz, 1H; H-9), 1.98 (s, 3H;
212.2 (C-3), 173.0 (C-12), 172.5 (CO octanoyl), 99.9 (C
N
N
(C-6), 79.9, 79.1, 77.6 (C-7, C-10, C-11.), 77.0 (C-2), 66.1 (C-8), 52.3 (C-
1), 47.7 (C-4), 45.1 (C-9), 42.0 (C-5), 33.7 (CH2 octanoyl), 31.5 (CH2 octa-
noyl), 30.3 (C
26.0 (C-15), 24.8 (CH2 octanoyl), 23.4 (C-17), 22.5 (CH2 octanoyl), 17.9
(C(CH3)(CH3)), 14.0 (CH3 octanoyl), 13.9 (C-11), 2.6 (TMS); IR (film):
A
N
A
ACHTREUNG
nmax = 2955, 1793, 1761, 1734, 1372, 1284, 1253, 1193, 1155, 1127, 1111,
1033, 988, 868 cmꢀ1; accurate mass analysis could not find the parent ion.
MOM acetal 69: Alcohol 61 (88 mg, 0.17 mmol) was dissolved in CH2Cl2
(1.8 mL) and treated with MOMCl (65 mL, 850 mmol), and Hünigꢁs base
(300 mL, 1.70 mmol) at RT for 12 h with stirring. The solution was the
quenched by the addition of saturated NaHCO3 solution, and the sepa-
rated organic phase washed with water, dried (MgSO4) and evaporated
under reduced pressure. Column chromatography (silica gel, PE/EtOAc
5:1) afforded the title compound (86 mg, 88%). [a]D = +7.5 (c = 1.08,
H-15), 1.54 (s, 3H; C
(CH3)(CH3)), 1.10 (s, 3H, 14-H), 0.22 (s, 9H; Si
(CH3)3); 13C NMR (150 MHz, CDCl3): d = 173.4 (C-12), 142.3 (C-4),
127.1 (C-5), 100.4 (C(CH3)2), 96.6 (OCH2O), 79.9 (C-11), 79.8 (C-6), 77.8
(C-3), 77.7 (C-2), 76.9 (C-10), 76.7 (C-7), 67.0 (C-8), 63.5 (C-1), 55.9
(OCH3), 45.3 (C-9), 30.5 (C(CH3)(CH3)), 24.9 (C-14), 23.6 (C-13), 17.1
(C(CH3)(CH3)), 13.8 (C-15), 2.8 (Si(CH3)3), 2.7 (Si(CH3)3); IR (film):
A
ACHTREUNG
A
N
ACHTREUNG
AHCTREUNG
AHCTREUNG
1
CHCl3); H NMR (600 MHz, CDCl3): d = 5.18 (d, J=10.3 Hz, 1H, H-6),
4.68 (dd, J=6.4, 6.4 Hz, 2H; OCH2O), 4.31 (s, 1H; H-2), 4.14 (m, 1H;
H-8), 3.40 (s, 3H; CH3O), 2.56 (d, J=9.8 Hz, 1H; H-1), 2.46 (dd, J=9.9,
A
ACHTREUNG
A
G
A
ACHTREUNG
5706
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 5688 – 5712

Natural Products
FULL PAPER
nmax = 3550 (br OH), 2952 (C-H), 1793 cmꢀ1 (lactone C=O); ESI+ MS:
m/z: calcd for C26H46O9NaSi2: 581.2578; found: 581.2603 [M+Na]+.
(brm, 1H; H-6), 4.26 (m, 2H; H-3, H-8), 4.03 (dd, J = 7.1, 6.3 Hz, 1H;
H-2), 2.99 (m, 1H; H-1), 2.26 (dd, J = 14.8, 4.3 Hz, 1H; H-9), 1.95 (dd,
J = 14.8, 5.1 Hz, 1H; H-9), 1.87 (s, 3H; H-15), 1.53 (s, 3H; C
(CH3)), 1.46 (s, 3H; H-13), 1.37 (s, 3H; C(CH3)(CH3)), 1.23 (s, 3H; H-
14); 13C NMR (150 MHz, CD3OD): d = 173.8 (C-12), 138.3 (C-5), 125.8
(C-4), 100.3 (C(CH3)(CH3)), 82.7 (C-3), 80.8 (C-2), 79.3 (C-6), 79.2 (C-
11), 75.4 (C-7), 73.2 (C-10), 65.9 (C-8), 58.3 (C-1), 44.6 (C-9), 29.4 (C-
(CH3)(CH3)), 22.5 (C-14, C(CH3)(CH3)), 14.9 (C-13), 10.8 (C-15); IR
(film): nmax
C
Angelate ester 75: Asolution of TBAF (0.2 mL of a 1.0 m solution in
THF, 0.1 mmol) was added dropwise at 08C to a solution of alcohol 74
(9.5 mg, 0.017 mmol) in THF (0.7 mL). After warming the reaction mix-
ture to RT, stirring was continued for 35 min before partitioning between
saturated aqueous NaHCO3 solution (10 mL) and ethyl acetate (10 mL).
Separation of the phases, extraction of the aqueous with ethyl acetate
(4”8 mL), drying (MgSO4), concentration in vacuo and filtration through
a short plug of silica gel (ethyl acetate/PE 4:1) afforded the intermediate
triol which was used in the next step without further purification. In a
separate flask, to a solution of angelic acid (90 mg, 0.896 mmol) in tolu-
ene (0.8 mL) at RT was added 2,4,6-trichlorobenzoyl chloride (140 mL,
0.896 mmol) and triethylamine (125 mL, 0.896 mmol). After stirring the
resulting white suspension for 65 min, a solution of crude triols (derived
from 0.017 mmol of alcohol 74) was added via cannula before heating the
reaction mixture to 758C for 48 h. Addition of saturated aqueous
NaHCO3 solution (15 mL) and ethyl acetate (15 mL), separation of the
phases, extraction of the aqueous with ethyl acetate (2”5 mL), drying
(MgSO4), concentration in vacuo and purification by flash chromatogra-
phy afforded the title compound 75 as a colourless oil (4 mg, 48% yield
G
R
ACHTREUNG
N
ACHTREUNG
G
G
G
ACHTREUNG
=
Alcohol 92: Ozone was bubbled through a CH2Cl2 (10 mL) solution of
thapsigargin (1) (20.0 mg, 30.8 mmol) at ꢀ788C for two minutes until the
solution had turned pale blue. The solution was flushed with oxygen for a
further 3 min and treated with pre-washed (methanol then CH2Cl2) poly-
mer-supported triphenylphosphine (140 mg, 168 mmol, 1.2 mmolgꢀ1). The
mixture was gradually warmed to RT, stirred for a further 18 h, then fil-
tered and the resin washed thoroughly with CH2Cl2. Combined filtrates
were evaporated under reduced pressure, dissolved in MeOH (5.0 mL)
and treated with pyridine (400 mL) and water (250 mL). The resulting
mixture was refluxed for 2 h 15 min, cooled, quenched with saturated am-
monium chloride solution (30 mL) and extracted with EtOAc (3”
30 mL). Combined extracts were washed with brine (40 mL), dried
(MgSO4) and concentrated in vacuo. Column chromatography (silica gel,
Et2O/PE 1:1) afforded the C-3 alcohol as a colourless gum (9.3 mg,
53%). NMR spectra in agreement with literature data: 1H NMR
1
over 2 steps from alcohol 74). [a]D = ꢀ37.0 (c = 0.20, CHCl3); H NMR
(500 MHz, CDCl3): d = 6.05 (m, 1H; =CHCH3), 5.77 (m, 1H; H-6), 5.60
(d, J=5.8 Hz, 1H; H-3), 4.75 (d, J=6.6 Hz, 1H; OCH2O), 4.55 (d, J =
6.6 Hz, 1H; OCH2O), 4.32 (dd, J=7.3, 5.9 Hz, 1H; H-2), 4.22 (dd, J=
4.3, 3.1 Hz, 1H; H-8), 3.38 (s, 3H; OCH3), 2.00 (s, 3H; H-15), 1.96 (m,
3H; CH3C=CH), 1.87 (m, 3H; =CHCH3), 1.54 (s, 3H; (C
1.53 (s, 3H; H-13), 1.42 (C(CH3)
(CH3)), 1.25 (s, 3H; H-14); 13C NMR
(125 MHz, CDCl3): d = 172.6 (C-12), 168.0 (C=O angeloyl), 137.7, 137.6
(C-4, =CHCH3), 131.6 (C-5), 127.9 (C=CHCH3), 100.7 (C(CH3)(CH3)),
97.1 (OCH2O), 79.5 (C-11), 78.7 (C-6), 78.0 (C-3), 76.6 (C-7), 76.4 (C-2),
73.2 (C-10), 65.7 (C-8), 59.0 (C-1), 56.5 (OCH3), 45.0 (C-9), 30.4 (C-
C
N
(500 MHz, CDCl3): d = 5.62 (m, 2H; H-6, H-8), 4.87 (dd, J
= 4.7,
U
ACHTREUNG
3.3 Hz, 1H; H-2), 4.39 (m, 1H; H-3), 4.32 (m, 1H; H-1), 3.20 (dd, J =
14.8, 3.4 Hz, 1H; H-9), 2.30 (m, 2H; octanoyl CH2), 2.24 (t, J = 7.5 Hz,
2H; butanoyl CH2), 2.18 (dd, J = 14.8, 3.9 Hz, 1H; H-9), 1.92 (m, 3H;
H-15), 1.88 (s, 3H; CH3C=O), 1.63–1.57 (m, 4H; butanoyl CH2, octanoyl
CH2), 1.45 (s, 3H; H-13), 1.35 (s, 3H; H-14), 1.32–1.25 (m, 8H; 4”octa-
noyl CH2), 0.93 (t, J = 7.4 Hz, 3H; butanoyl CH3), 0.85 (m, 3H; octanoyl
CH3) (3 OH signals not observed); 13C NMR (125 MHz, CDCl3): d =
175.8 (octanoyl C=O), 175.2 (C-12), 172.5 (butanoyl C=O), 170.3
(CH3C=O), 144.3 (C-5), 126.5 (C-4), 84.6 (C-2), 84.6 (C-10), 83.7 (C-3),
78.63, 78.58 (C-7, C-11), 76.5 (C-6), 65.8 (C-8), 55.3 (C-1), 38.1 (C-9),
36.5 (butanoyl CH2C=O), 34.1 (octanoyl CH2C=O), 31.5 (octanoyl CH2),
29.0 (octanoyl CH2), 28.8 (octanoyl CH2), 24.7 (octanoyl CH2), 23.2 (C-
14), 22.6 (octanoyl CH2), 22.5 (CH3C=O), 17.9 (C-18), 16.2 (C-13), 14.0
(octanoyl CH3), 13.67 (butanoyl CH3), 12.8 (C-15); ESI+ MS: m/z: calcd
for C29H44O11Na: 591.2781; found: 591.2801 [M+Na]+.
A
(CH3)), 23.7, 23.6 (C-14, (C
G
N
CCH3), 15.8 (C-13), 14.7 (C-15); IR (film): nmax = 3397 (br OH), 2926
(C-H), 1791 (C=O), 1711 cmꢀ1 (C=O); ESI+ MS: m/z: calcd for
C25H36O10Na: 519.2206; found: 519.2216 [M+Na]+.
Degradation and selective transformations of thapsigargin: procedures
(also, see alternative procedures towards thapsigargin from 61, see
below)
Pentol 80: Triethylamine (950 mL, 6.82 mmol) was added to a solution of
thapsigargin (1) (167 mg, 256 mmol) in methanol (17.0 mL) in a Smith
vial. The vessel was flushed with Ar, sealed and heated (758C) for 48 h
before being quenched by the addition of saturated ammonium chloride
solution (60 mL). The crude mixture was diluted with water (10 mL), ex-
tracted with EtOAc (5”50 mL) and the combined organic layers were
washed with brine (100 mL), dried (MgSO4) and evaporated. Column
chromatography (silica gel, EtOAc/PE 2:3 then EtOAc with 1% AcOH)
afforded firstly the triol 79 (75.2 mg, 51%) then the pentol 80 (50.0 mg,
47%). NMR spectra in agreement with literature data: 1H NMR
(600 MHz, CDCl3): d = 6.16 (brm, 1H; =CHCH3), 5.76 (brs, 1H; H-6),
5.61 (brs, 1H; H-3), 4.29 (dd, J = 4.6, 4.5 Hz, 1H; H-2), 4.24 (dd, J =
3.4, 3.3 Hz, 1H; H-8), 3.35 (brs, 1H; H-1), 2.24 (dd, J = 14.5, 3.3 Hz,
1H; H-9), 2.00 (dd, J = 7.0, 1.3 Hz, 3H; =CHCH3), 1.97 (m, 1H; H-9),
1.92 (brs, 3H; CH3C=CHCH3), 1.79 (s, 3H; H-15), 1.39 (s, 3H; H-13),
1.18 (s, 3H; H-14) (4 OH signals not observed); 13C NMR (150 MHz,
CD3OD): d = 176.0 (C-12), 167.9 (C-16), 137.7 (C-5), 137.1 (C-18), 131.7
(C-4), 127.6 (C-17), 86.3 (C-3), 78.9 (C-6), 78.8 (C-11), 77.7 (C-2), 77.5
(C-7), 72.9 (C-10), 68.6 (C-8), 61.4 (C-1), 48.1 (C-9), 23.3 (C-14), 19.3 (C-
20), 14.9, 14.6 (C-13, C-19), 11.7 (C-15); ESI+ MS: m/z: calcd for
C20H29O9Na: 143.1812; found: 413.1799 [M+H]+.
Enone 93: Triol 92 (9.1 mg, 16 mmol) was dissolved in CH2Cl2 (1.0 mL)
and treated with pyridine (1 drop) and Dess–Martin periodinane (6.8 mg,
16 mmol). The mixture was stirred at RT for 2 h and quenched with
sodium thiosulfate solution (10 mL). The mixture was further diluted
with NaHCO3 solution (10 mL) and extracted with CH2Cl2 (3”20 mL).
The combined extracts were washed with brine (20 mL), dried (MgSO4)
and concentrated in vacuo. Column chromatography (silica gel, Et2O/PE
1:1 increasing to neat Et2O) afforded the ketone as a colourless gum
1
(7.0 mg, 77%). NMR spectra in agreement with literature data: H NMR
(600 MHz, CDCl3): d = 5.84 (s, 1H; H-6), 5.69 (dd, J = 3.5, 3.8 Hz, 1H;
H-8), 5.46 (d, J = 1.0 Hz, 1H; H-2), 4.52 (d, J = 1.0 Hz, 1H; H-1), 3.49
(dd, J = 14.8, 3.5 Hz, 1H; H-9), 2.36–2.29 (m, 5H; H-9, octanoyl CH2C=
O, butanoyl CH2C=O), 2.02 (s, 3H; H-15), 1.96 (s, 3H; CH3C=O), 1.62–
1.57 (m, 4H; butanoyl CH2, octanoyl CH2), 1.53 (s, 3H; H-13), 1.40 (s,
3H; H-14), 1.30–1.27 (m, 8H; 4”octanoyl CH2), 0.96 (t, J = 7.4 Hz, 3H;
butanoyl CH3), 0.88 (m, 3H; octanoyl CH3.); 13C NMR (125 MHz,
CDCl3): d = 201.2 (C-3), 174.0 (C-12), 172.7 (octanoyl C=O), 172.2 (bu-
tanoyl C=O), 170.4 (CH3C=O), 155.7 (C-5), 142.3 (C-4), 83.5 (C-10), 79.0
(C-11), 78.4 (C-6), 77.7 (C-7), 73.0 (C-2), 65.8 (C-8), 51.8 (C-1), 38.7 (C-
9), 36.4 (butanoyl CH2), 33.8 (octanoyl CH2), 31.6 (octanoyl CH2), 29.6
(octanoyl CH2), 28.9 (octanoyl CH2), 24.6 (octanoyl CH2), 22.9 (CH3C=
O), 22.6 (octanoyl CH2), 22.5 (C-14), 17.9 (butanoyl CH2), 16.5 (C-13),
14.0 (octanoyl CH3), 13.6 (butanoyl CH3), 10.2 (C-15); ESI+ MS: m/z:
calcd for C29H42O11Na: 589.2625; found: 589.2638 [M+Na]+.
Tetrol 81: Acetonide 78 (14.0 mg, 22.6 mmol) was treated with sodium
methoxide (1.0 mL, 500 mmol, 0.5m in methanol) at RT for 6 h. The reac-
tion was quenched with saturated ammonium chloride solution (20 mL)
and extracted with EtOAc (3”30 mL). The combined organic layers
were washed with brine (30 mL), dried (MgSO4) and evaporated under
reduced pressure. Column chromatography (silica gel, EtOAc then
EtOAc with 3% AcOH) afforded the tetrol (6.8 mg, 81%). [a]D
=
MOM acetal 82: Asolution of triol 77 (5.4 mg, 11.9 mmol) and Hünigꢁs
base (40 mL, 230 mmol) in CH2Cl2 (800 mL) was treated sequentially with
ꢀ9.57 (c 5.76
=
0.115, CHCl3); 1H NMR (600 MHz, CD3OD): d
=
Chem. Eur. J. 2007, 13, 5688 – 5712
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5707

S. V. Ley et al.
MOMCl (15 mL, 197 mmol) and catalytic DMAP. The reaction was stirred
at RT for 1.5 h, quenched with saturated ammonium chloride solution
(20 mL) and extracted with CH2Cl2 (3”20 mL). The combined extracts
were washed with brine (50 mL), dried (MgSO4) and evaporated under
reduced pressure. Column chromatography (silica gel, EtOAc/PE 1:9 in-
creasing to 1:1) afforded the title compound as a colourless gum (1.6 mg,
27%). [a]D = ꢀ37.5 (c = 0.080, CHCl3); 1H NMR (600 MHz, CDCl3): d
= 6.14 (apparent q, J = 7.2, 1.3 Hz, 1H; =CHCH3), 5.86 (brs, 1H; H-3),
5.82 (brs, 1H; H-6), 4.79 (d, J = 6.8 Hz, 1H; OCH2O), 4.75 (d, J =
6.8 Hz, 1H; OCH2O), 4.31 (dd, J = 5.3, 5.0 Hz, 1H; H-2), 4.24 (brs, 1H;
H-8), 3.38 (s, H-22), 3.24 (brs, 1H, H-1), 2.22 (dd, J = 14.5, 4.2 Hz, 1H;
H-9), 2.16 (dd, J = 14.5, 3.7 Hz, 1H; H-9), 2.03 (d, J = 7.2 Hz, 3H; =
CHCH3), 1.95 (brs, 3H; C(O)CCH3), 1.85 (s, 3H; H-15), 1.56 (s, 6H; H-
silica gel (ethyl acetate/PE 1:50 then 1:10) afforded the title compounds
(287 mg) as a pale amber foam in an 80:20 mixture of 85 to 86, (contain-
ing 10% by mass of unreacted starting ketone 84, as assessed by
1H NMR). Note: The three component mixture had a common Rf =0.43
(ethyl acetate/PE 1:7). This material was used without purification in the
subsequent step. Astream of oxygen was bubbled through a solution of
selenides 85/86 (287 mg, derived from 0.40 mmol of ketone 84) in CH2Cl2
(35 mL) at ꢀ788C before a stream of ozone was bubbled through until a
deep blue colour was observed (2 min). Oxygen was again applied until
no blue colour remained (2 min). After addition of diisopropylamine
(1.40 mL) the reaction mixture was allowed to warm to RT and stirred
for a further 2.5 h. Addition of saturated aqueous NaHCO3 solution
(30 mL), separation of the phases, extraction of the aqueous with CH2Cl2
(3”20 mL), drying (MgSO4), concentration under reduced pressure and
purification by flash chromatography (ethyl acetate/PE 1:20 then 1:13)
afforded the title compound 88 as a colourless foam (153 mg, 60% over
two steps), This followed the isolation of the clean exo double bonded
compound 87 (26 mg, 10% over two steps) and in addition, a mixed
endo/exo fraction (30 mg, approx. 1:1 ratio, 12% over two steps). Rf =
0.33 (ethyl acetate/PE 1:10); [a]D = ꢀ17.9 (c = 0.35, CHCl3); 1H NMR
(600 MHz, CDCl3): d = 5.96 (s, 1H; H-6)), 5.00, 4.74 (2”d, J=6.0 Hz,
1H; OCH2O), 4.20 (dd, J=3.6, 3.6 Hz, 1H; H-8), 4.17 (d, J=2.0 Hz, 1H;
H-2), 4.06 (m, 1H; SiCH2CHHO), 3.58 (m, 1H; SiCH2CHHO), 3.35 (d,
J=2.0 Hz, 1H; H-1), 2.36 (dd, J=14.6, 3.6 Hz, 1H; H-9), 2.17 (dd, J=
14.6, 3.6 Hz, 1H; H-9), 1.97 (s, 3H; H-15), 1.58 (s, 3H; H-13), 1.54 (s,
13, C
NMR (125 MHz, CDCl3): d = 172.6 (C-12), 167.3 (C(O)C=C), 138.6 (=
CHCH3), 138.5 (C-5), 127.7 (C-4), 127.5 (C(O)C=), 100.8 (C(CH3)2), 96.9
(OCH2O), 84.6 (C-2), 84.0 (C-3), 79.0 (C-11), 78.1 (C-6), 76.2 (C-7), 73.2
(C-10), 65.8 (C-8), 56.1 (C-1, OCH3), 45.3 (C-9), 30.5 (C(CH3)(CH3)),
23.6 (C(CH3)(CH3)), 23.4 (C-14), 20.6 (C(O)CCH3), 15.9 (C-13), 15.8 (=
A
G
(CH3)
N
AHCTREUNG
A
ACHTREUNG
A
ACHTREUNG
CHCH3), 12.5 (C-15); IR (film): nmax = 3394 (br OH), 2924 (C-H), 2845
(C-H), 1793 (lactone C=O), 1713 cmꢀ1 (angelate C=O); ESI+ MS: m/z:
calcd for C25H36O10Na: 519.2230; found: 519.2209 [M+Na]+.
Experimental procedures towards thapsigargin (1) and thapsivillosin C
(5) from 61
SEM acetal 84: To a solution of ketoalcohol 61 (460 mg, 0.89 mmol) in
CH2Cl2 (4.1 mL) at 08C was added diisopropylethyl amine (1.25 mL,
7.15 mmol), followed by SEMCl (0.47 mL, 2.68 mmol). The resulting so-
lution was warmed to RT before addition of catalytic DMAP. After stir-
ring for a further 24 h, the reaction mixture was partitioned between sa-
turated aqueous NaHCO3 solution (100 mL) and ethyl acetate (100 mL),
the phases separated and the aqueous extracted with ethyl acetate (3”
50 mL). The combined organics were dried (MgSO4), concentrated under
reduced pressure and purified by flash chromatography (Et2O/PE 1:9) to
afford the title compound 84 as a white foam (518 mg, 92%). Rf =0.67
3H; C
2H; SiCH2), 0.19 (s, 9H; Si
CH2Si
(CH3)3); 13C NMR (150 MHz, CDCl3): d = 205.5 (C-3), 172.4 (C-
12), 157.6 (C-4), 140.3 (C-5), 100.6 (C(CH3)2), 93.7 (OCH2O), 80.4 (C-
10), 79.4 (C-7), 78.6 (C-6), 76.4 (C-11), 75.3 (C-2), 66.8 (C-8), 65.5
(SiCH2CH2O), 59.3 (C-1), 45.3 (C-9), 30.5 (C(CH3)CH3), 24.5 (C-14),
23.5 (C(CH3)CH3), 18.0 (SiCH2), 17.0 (C-13), 9.8 (C-15), 2.8 (Si(CH3)3),
2.7 (Si
C
ACHTREUNG
G
ACHTREUNG
AHCTREUNG
AHCTREUNG
AHCTREUNG
U
ACHTREUNG
(CH3)3), ꢀ1.4 (CH2Si
(CH3)3); IR (film): nmax = 2956, 1800, 1721,
(ethyl acetate/PE 1:4); [a]D
= +8.2 (c =
1.0, CHCl3); 1H NMR
Zinc borohydride (0.5m in Et2O): To a suspension of granular sodium
borohydride (760 mg, 20.0 mmol) in dry Et2O (10 mL) at 08C (ice bath)
was added a solution of zinc(II) chloride (10 mL of a 1.0m solution in
Et2O, 10 mmol) dropwise. The suspension was then allowed to warm
slowly to RT overnight. After a total of 3 d, stirring was discontinued to
allow the solid sodium chloride to settle. This resulted in a solution of
zinc borohydride over sodium chloride (theoretically 0.5m in Et2O),
which was used directly by syringe-based removal of the supernatant,
taking care to prevent inclusion of solid sodium chloride.
(600 MHz, CDCl3): d = 5.17 (d, J=10.2 Hz, 1H; H-6), 4.68, 4.72 (2”d,
J=6.5 Hz, 1H; OCH2O), 4.31 (s, 1H; H-2), 4.11 (m, 1H; H-8), 3.75 (m,
1H; SiCH2CHHO), 3.58 (m, 1H; SiCH2CHHO), 2.54 (d, J=9.1 Hz, 1H;
H-1), 2.44 (m, 1H; H-5), 2.34 (m, 1H; H-4), 2.23 (dd, J=14.7, 3.9 Hz,
1H; H-9’), 2.09 (dd, J=14.7, 3.1 Hz, 1H; H-9), 1.51, 1.56 (2”s, 3H; C-
ACHTREUNG
AHCTREUNG
A
ACHTREUNG
AHCTREUNG
(C-7), 79.4 (C-10), 77.5 (C-2), 76.6 (C-11), 66.2 (C-8), 65.3 (OCH2CH2Si),
53.6 (C-1), 48.0 (C-4), 46.1 (C-9), 42.8 (C-5), 30.4 (C-15), 26.5 (C-13),
Allylic alcohol 91 and its C-3 epimer: To a solution of enone 88 (90 mg,
0.139 mmol) in dry Et2O (5.7 mL) at ꢀ298C was added a pre-cooled solu-
tion of zinc borohydride (10.0 mL of an 0.5m solution in Et2O,
5.70 mmol) at ꢀ298C via cannula. After stirring the solution at ꢀ298C
for a further 2.5 h, a further quantity of zinc borohydride solution was
added (1.4 mL of an 0.5m solution in Et2O, 0.80 mmol) and stirring con-
tinued for a further 30 min to ensure complete reaction. Asolution of
TBAF (12.8 mL of a 1.0m solution in THF, 12.8 mmol) was then added
and the resulting vigorously stirred solution was warmed to RT. After
30 min at RT, ethyl acetate (85 mL) and an aqueous solution of tetrasodi-
um EDTA(85 mL, 30% w/w) were added and the biphasic system vigo-
rously stirred at RT for 2 h. The phases were separated, the aqueous
phase extracted with ethyl acetate (3”50 mL), the combined organics
dried (Na2SO4) and concentrated to approximately 10 mL. After addition
of petrol (10 mL), the resulting solution was loaded directly onto a silica
column, eluting with petrol, followed by ethyl acetate/PE 1:2 to afford
first the title compound 91 as a colourless oil (56 mg, 80%) [followed by
a quantity of the C-3 epimeric compound (7 mg, 10%) on changing to
ethyl acetate/PE 2:1].
17.9, 23.4 (2”C
A
(CH3)3),
2.7 (2”Si(CH3)3); IR (film): nmax = 2954, 1794, 1747, 1385 1373, 1252,
G
1195, 1146, 1099, 1035, 1021, 1005, 988, 839 cmꢀ1; ESI+ MS: m/z: calcd
for C30H56O9NaSi3: 667.3130; found: 667.3130 [M+Na]+.
Enone 88: Asolution of LiHMDS (2.0 mL of a 1.0 m solution in THF,
2.0 mmol) was added dropwise at ꢀ788C to a solution of ketone 84
(256 mg, 0.40 mmol) in THF (10.0 mL). After a further 5 min at ꢀ788C,
the reaction flask was transferred to a ꢀ128C cooling bath and the result-
ing solution maintained at ꢀ12 to ꢀ138C (cryocool apparatus) for 2 h.
The reaction flask was then transferred to a ꢀ958C cooling bath (Et2O/
N2) and
a
pre-cooled (ꢀ788C) solution of phenylselenyl chloride
(380 mg, 2.00 mmol) in THF (7.5 mL) was added via cannula. The exter-
nal reaction temperature was maintained between ꢀ90 and ꢀ958C for
30 min before allowing to warm to ꢀ788C over 10 min. After transferring
to a ꢀ788C bath (acetone/CO2) the resulting orange solution was stirred
for 2.5 h before addition of pyridine (0.59 mL, 5.96 mmol) and transfer-
ring to an ice bath. After 10 min at 08C, the reaction mixture was
warmed to RT and saturated aqueous NaHCO3 solution (20 mL) was
added. Addition of CH2Cl2 (30 mL), separation of the phases, extraction
of the aqueous with CH2Cl2 (3”15 mL), washing the combined organics
with saturated aqueous NaHCO3 solution (30 mL), drying (MgSO4), con-
centration under reduced pressure and filtration through a short plug of
compound: 91: Rf =0.57 (ethyl acetate/PE 5:1); [a]D = ꢀ5.3 (c = 0.47,
CHCl3); 1H NMR (600 MHz, CDCl3): d = 5.79 (s, 1H; H-6)), 4.82, 4.86
(2”d, J=6.2 Hz, 1H; OCH2O), 4.40 (brm, 1H; H-3), 4.20 (m, 1H; H-8),
3.95 (brs, 1H; OH), 3.88 (m, 1H; SiCH2CHHO), 3.83 (dd, J=15.7,
14.2 Hz, 1H; H-2), 3.57 (m, 1H; SiCH2CHHO), 3.21 (brs, 1H; OH), 3.10
5708
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 5688 – 5712

Natural Products
FULL PAPER
(m, 1H; H-1), 2.18 (dd, J=15.1, 4.2 Hz, 1H; H-9’), 2.10 (dd, J=15.1,
ACHTREUNG
2.9 Hz, 1H; H-9), 1.98 (s, 3H; H-15), 1.54 (s, 6H; C
H-13), 1.25 (s, 3H; H-14), 1.03 (ddd, J=11.5, 11.5, 5.9 Hz, 1H; SiCHH),
0.95 (ddd, J=11.5, 11.5, 5.4 Hz, 1H; SiCHH), 0.03 (s, 9H; SiC(CH3)3);
13C NMR (150 MHz, CDCl3): d = 172.7 (C-12), 140.7 (C-4), 123.8 (C-5),
100.7 (C(CH3)2), 95.6 (OCH2O), 90.9 (C-2), 81.4 (C-3), 78.9 (C-11), 78.6
(C-6), 76.2 (C-10), 73.5 (C-7), 66.5 (OCH2CH2Si), 65.7 (C-8), 56.8 (C-1),
45.1 (C-9), 30.4 (C-13), 23.6 (C(CH3)(CH3)), 23.5 (C-14), 18.0
(OCH2CH2Si), 16.0 (C(CH3) (CH3)3); IR
(CH3)), 12.3 (C-15), ꢀ1.5 (Si
C
(C
76.3 (C-7), 73.2 (C-10), 66.5 (OCH2CH2Si), 65.8 (C-8), 59.0 (C-1), 44.9
(C-9), 30.4 (C(CH3)CH3), 23.8 (C-14), 23.6 (C(CH3)CH3), 20.6 (C(O)C-
(CH3)), 18.1 (SiCH2), 15.9 (=C(H)CH3), 15.8 (C-13), 14.7 (C-15), ꢀ1.5
G
AHCTREUNG
ACHTREUNG
1252, 1229, 1193, 1154, 1110, 1056, 997, 859, 837 cmꢀ1; ESI+ MS: m/z:
calcd for C29H46NaO10Si: 605.2758; found: 605.2759 [M+Na]+.
A
ACHTREUNG
G
G
Angelate ester 83: Procedure A: DMAP (1.0 mg, 8.2 mmol) was added to
a solution of the triol 77 (8.5 mg, 18.8 mmol), SEMCl (4.0 mL, 22.5 mmol)
and Hünigꢁs base (10.0 mL, 56.0 mmol) in CH2Cl2 (1.25 mL). After stirring
at RT for 48 h, the reaction was quenched by the addition of saturated
ammonium chloride solution (20 mL) and extracted with EtOAc (3”
20 mL). The combined organic phases were washed with brine (30 mL),
dried (MgSO4) and concentrated in vacuo. Column chromatography
(silica gel, EtOAc/PE 2:3) afforded the SEM ether as a pale yellow gum
(7.8 mg, 71%).
C-3 epimer of 91: Rf =0.39 (ethyl acetate/PE 5:1); [a]2D5 = ꢀ74.5 (c =
0.35, CHCl3); 1H NMR (600 MHz, CDCl3): d = 5.73 (s, 1H; H-6)), 4.76,
4.83 (2”d, J=6.2 Hz, 1H; OCH2O), 4.29 (d, J=5.4 Hz, 1H; H-2), 4.18
(m, 1H; H-8), 4.12 (m, 1H; H-3), 4.00 (s, 1H; OH), 3.68 (m, 2H;
SiCH2CH2O), 3.40 (m, 1H; H-1), 3.35 (brs, 1H; OH), 3.18 (s, 1H; OH),
2.23 (dd, J=14.9, 4.1 Hz, 1H; H-9’), 2.06 (dd, J=14.9, 2.7 Hz, 1H; H-9),
2.02 (s, 3H; H-15), 1.52, 1.53 (2”s, 3H; C
1.17 (s, 3H; H-14), 0.97 (m, 2H; SiCH2), 0.04 (s, 9H; SiC
NMR (150 MHz, CDCl3): d = 172.9 (C-12), 140.7 (C-4), 128.7 (C-5),
100.6 (C(CH3)2), 95.3 (OCH2O), 79.8 (C-2), 79.2 (C-3), 78.5 (C-11), 77.6
(C-6), 76.1 (C-10), 73.3 (C-7), 66.6 (OCH2CH2Si), 65.7 (C-8), 58.6 (C-1),
45.5 (C-9), 30.5 (C-13), 23.6 (C(CH3)(CH3)), 23.2 (C-14), 16.1
(OCH2CH2Si), 14.7 (C(CH3) (CH3)3); IR
(CH3)), 14.1 (C-15), ꢀ1.5 (Si
(film): nmax
ACHTREUNG
Procedure B: Solid NaHCO3 (55 mg, 0.650 mmol) was added at RT to a
solution of 91 (65 mg, 0.130 mmol) in toluene (0.4 mL). Asolution of
mixed anhydride 24 (120 mg, 0.390 mmol) in toluene (0.5 mL) was added
before heating to 808C for 42 h. Further solid NaHCO3 (33 mg,
0.393 mmol) and solid mixed anhydride 24 (80 mg, 0.260 mmol) were
added before heating to 808C for a further 23 h. Cooling to RT, addition
of saturated aqueous NaHCO3 solution (20 mL) and ethyl acetate
(20 mL), separation of the phases, extraction of the aqueous with ethyl
acetate (3”15 mL), drying the combined organics (MgSO4), concentra-
tion under reduced pressure and flash chromatography (ethyl acetate/PE
1:50, 1:2 then 2:1) afforded the title compound 83 as a colourless oil
(39 mg, 52%) [followed by a quantity of unreacted triol 91 (4 mg, 6%)].
Rf =0.29 (ethyl acetate/PE 1:1); [a]D = ꢀ14.9 (c = 0.30, CHCl3); 1H
NMR (600 MHz, CDCl3): d = 6.14 (m, 1H; =CHCH3)), 5.83 (brm, 1H;
H-3), 5.80 (brm, 1H; H-6), 4.77, 4.82 (2”d, J=6.9 Hz, 1H; OCH2O),
4.30 (dd, J=5.1, 5.1 Hz, 1H; H-2), 4.23 (m, 1H; H-8), 3.70 (m, 1H;
SiCH2CHHO), 3.58 (m, 1H; SiCH2CHHO), 3.44 (brs, 1H; OH), 3.27
(brm, 1H; H-1), 2.22 (dd, J=15.0, 4.4 Hz, 1H; H-9’), 2.12 (dd, J=15.0,
AHCTREUNG
ACHTREUNG
G
ACHTREUNG
G
G
ACHTREUNG
=
3379, 3225, 2947, 1791, 1381, 1250, 1111, 1057, 1016,
860 cmꢀ1; ESI+ MS: m/z: calcd for C24H40O9SiNa: 523.2339; found:
523.2354 [M+Na]+.
Mixed anhydride 96: To a solution of 2,4,6-trichlorobenzoyl chloride
(5.25 mL, 33.60 mmol) in toluene (6.7 mL) at RT was added a pre-mixed
solution of angelic acid (336 mg, 3.36 mmol) and triethylamine (0.47 mL,
3.36 mmol) in toluene (16.0 mL), dropwise over 12 min. The resulting so-
lution was stirred for 3 h 40 min, after which time a fine dispersion of
triethylamine hydrochloride had formed. The mixture was triturated with
dry Et2O (200 mL) to cause precipitation of further triethylamine hydro-
chloride, filtered, and the resulting solution concentrated under reduced
pressure until ca. 10 mL toluene remained. Purification of the reaction
mixture by flash chromatography (ethyl acetate/PE 1:80) afforded the
title compound as a white crystalline solid (480 mg, 48%). M.p. 66–688C;
Rf =0.42 (ethyl acetate/PE 1:20); 1H NMR (600 MHz, CDCl3):d = 7.38
(s, 2H; 2”Ar-H)), 6.43 (m, 1H; =C(H)CH3), 2.08 (m, 3H; =C(H)CH3),
2.7 Hz, 1H; H-9), 2.02 (m, 3H; =C(H)CH3), 1.87 (s, 3H; C(O)C
1.83 (s, 3H; H-15), 1.55 (s, 3H; H-13), 1.42, 1.54 (2”s, 3H; C(CH3)2),
1.22 (s, 3H; H-14), 0.95 (m, 1H; SiCHH), 0.89 (m, 1H; SiCHH), 0.00 (s,
9H; SiC
(CH3)3); 13C NMR (150 MHz, CDCl3): d = 172.7 (C-12), 167.2
(OC(O)), 138.9 (=C(H)CH3), 138.3 (C-5), 128.1 (C-4), 127.5 (C=
C(H)CH3), 100.8 (C(CH3)2), 95.2 (OCH2O), 84.5 (C-2), 84.3 (C-3), 79.1
(C-11), 78.1 (C-6), 76.1 (C-7), 73.2 (C-10), 66.1 (OCH2CH2Si), 65.8 (C-8),
59.9 (C-1), 45.2 (C-9), 30.5 (C(CH3)CH3), 23.6 (C(CH3)CH3), 23.5 (C-14),
20.6 (C(O)CCH3), 17.9 (SiCH2), 15.9 (=C(H)CH3), 15.8 (C-13), 12.5 (C-
A
ACHTREUNG
AHCTREUNG
1.97 (brm, 3H; C(O)C
(CH3)); 13C NMR (150 MHz, CDCl3): d = 160.9
E
AHCTREUNG
(C(O)CCH3), 159.4 (PhC=O), 145.8 (=C(H)CH3), 136.9 (C(O)CCH3),
130.9 (Ar-C), 128.3”2 (2”Ar-C), 125.9 (Ar-C), 20.1 (C(O)CCH3), 16.3
(=C(H)CH3); IR (film): nmax = 1798, 1738, 1637, 1577, 1549, 1436, 1370,
1212, 1071, 857, 820 cmꢀ1 [extensive attempts were made, but mass spec-
tral analysis was not successful for this compound].
A
ACHTREUNG
15), ꢀ1.5 (Si
C
Angelate ester 90: Solid NaHCO3 (12.0 mg, 0.143 mmol) was added at
RT to a solution of the C-3 epimer of 91 (7.0 mg, 0.014 mmol) in toluene
(0.4 mL). Asolution of mixed anhydride 96 (22.0 mg, 0.070 mmol) in tol-
uene (0.5 mL) was added before heating to 808C for 26 h. Further solid
NaHCO3 (12.0 mg, 0.143 mmol) and solid mixed anhydride 96 (22.0 mg,
0.070 mmol) were added before heating to 808C for a further 28 h. Cool-
ing to RT, addition of saturated aqueous NaHCO3 solution (15 mL) and
ethyl acetate (15 mL), separation of the phases, extraction of the aqueous
with ethyl acetate (3”10 mL), drying the combined organics (MgSO4),
concentration under reduced pressure and flash chromatography (ethyl
acetate/PE 1:50 then 1:2) afforded the title compound 90 as a colourless
oil (7.9 mg, 98%). Rf =0.37 (ethyl acetate/PE 1:1); [a]D = ꢀ125.0 (c =
0.24, CHCl3); 1H NMR (600 MHz, CDCl3): d = 6.05 (q, J=7.1 Hz, 1H;
=CHCH3)), 5.77 (brm, 1H; H-6), 5.60 (d, J=5.9 Hz, 1H; H-3), 4.63, 4.76
(d, J=6.6 Hz, each 1H; OCH2O), 4.33 (dd, J=6.9, 5.9 Hz, 1H; H-2),
4.22 (m, 1H; H-8), 3.75–3.90 (brs, 1H; OH), 3.72 (m, 1H; SiCH2CHHO),
3.53 (m, 1H; SiCH2CHHO), 3.40 (brm, 1H; H-1), 2.26 (dd, J=15.2,
4.0 Hz, 1H; H-9’), 2.12 (dd, J=15.2, 2.7 Hz, 1H; H-9), 1.99 (s, 3H; H-
Triol 77: Procedure A: p-Toluenesulfonic acid (15 mg, 87 mmol) was
added to a solution of pentol 80 (25 mg, 606 mmol) in acetone (500 mL)
and 2,2-dimethoxypropane (3.0 mL). After 20 min at RT, the reaction
was quenched with saturated NaHCO3 solution (30 mL), and extracted
with EtOAc (3”30 mL). The combined organic phases were washed with
brine (50 mL), dried (MgSO4) and evaporated under reduced pressure.
Column chromatography (silica gel, EtOAc/PE 1:1 to 4:1) afforded the
acetonide as a colourless gum (18.3 mg, 67%).
Procedure B: Amethanolic solution (1.0 mL) of acetonide 78 (10.9 mg,
17.6 mmol) was treated with triethylamine (50 mL) and stirred at 758C for
8 h. At this point TLC showed only a trace of product formation; the re-
action was heated to 958C and stirred for a further 24 h. There was little
change by TLC: the reaction was cooled, quenched with saturated am-
monium chloride solution (20 mL) and extracted with EtOAc (3”
20 mL). The combined organic extracts were washed with brine (40 mL),
dried over MgSO4 and evaporated under reduced pressure. Column chro-
matography (silica gel, EtOAc/PE 1:1) afforded the triol (1.1 mg, 11%).
15), 1.95 (d, J=7.1 Hz, 3H; =C(H)CH3), 1.89 (s, 3H; C(O)C
(s, 6H; H-13, C(CH3)(CH3)), 1.42 (s, 3H; C(CH3)(CH3)), 1.24 (s, 3H; H-
14), 0.94 (m, 1H; SiCHH), 0.88 (m, 1H; SiCHH), 0.00 (s, 9H; SiC-
A
Procedure C: Solid K2CO3 (398 mg, 2.880 mmol), MgBr2·Et2O (390 mg,
1.509 mmol) and n-butane thiol (160 mL, 1.509 mmol) were added at RT
to a solution of SEM-ether 83 (40 mg, 0.069 mmol) in dry Et2O (7.5 mL).
G
G
G
ACHTREUNG
Chem. Eur. J. 2007, 13, 5688 – 5712
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5709

S. V. Ley et al.
The resulting heterogeneous mixture was vigorously stirred for 30 min.
Partitioning between ethyl acetate (30 mL) and water (30 mL), separa-
tion of the phases, extraction of the aqueous with ethyl acetate (3”
20 mL), drying the combined organics (MgSO4) and purification by flash
chromatography (ethyl acetate/PE 1:1) afforded the title compound 77 as
(25.0 mg, quant.). Rf =0.65 (ethyl acetate/PE 1:1); [a]D = ꢀ33.7 (c 0.41,
CHCl3); 1H NMR (600 MHz, CDCl3): d = 6.09 (m, 1H; =CHCH3), 5.77
(brm, 1H; H-6), 5.73 (brm, 1H; H-3), 5.48 (dd, J=4.6, 4.6 Hz, 1H; H-2),
4.27 (m, 1H; H-8), 3.95 (brm, 1H; H-1), 3.30 (brs, 1H; OH), 2.64 (dd,
J=14.7, 2.7 Hz, 1H; H-9), 2.30 (m, 2H; C(O)CH2 octanoyl), 2.24 (dd,
J=14.7, 4.5 Hz, 1H; H-9), 1.97 (m, 3H; =C(H)CH3), 1.91 (brm, 3H;
C(O)CCH3), 1.87 (s, 6H; H-15, C(O)CH3), 1.59 (m, 2H; C(O)CH2CH2
a white foam (26 mg, 84%). Rf =0.21 (ethyl acetate/PE 4:1); [a]D
=
ꢀ106.0 (c = 0.3, CHCl3); 1H NMR (600 MHz, CDCl3): d = 6.05 (q, J=
7.2 Hz, 1H; =CHCH3), 5.77 (brm, 1H; H-6), 5.37 (brm, 1H; H-3), 4.24
(m, 2H; H-2, H-8), 3.60–3.95 (brs, 1H; OH), 3.26 (brm, 1H; H-1), 2.28
(dd, J=14.9, 4.0 Hz, 1H; H-9), 2.07 (dd, J=14.9, 2.1 Hz, 1H; H-9), 2.03
(d, J=7.2 Hz, 3H; =C(H)CH3), 1.92 (s, 6H; H-15, C(O)CCH3), 1.54 (s,
octanoyl), 1.54 (s, 3H; H-13), 1.53 (s, 3H; C
14), 1.42 (s, 3H; C(CH3)
C
ACHTREUNG
G
A
ACHTREUNG
3H; H-13), 1.53 (s, 3H; C
C
(CH3)), 1.40 (s, 3H; C
G
G
(C
76.0 (C-7), 65.8 (C-8), 57.3 (C-1), 38.0 (C-9), 34.3 (OC(O)CH2 octanoyl),
31.6 (CH2 octanoyl), 30.4 (C(CH3)(CH3)), 29.1 (CH2 octanoyl), 28.9 (CH2
octanoyl), 24.7 (OC(O)CH2CH2 octanoyl), 23.6 (C(CH3)(CH3)), 22.6
A
A
ACHTREUNG
C(H)CH3), 100.7 (C
6), 76.1 (C-7), 73.6 (C-10), 65.8 (C-8), 59.6 (C-1), 44.9 (C-9), 30.5 (C-
(CH3)CH3), 23.6 (C(CH3)CH3), 23.5 (C-14), 20.5 (C(O)CCH3), 16.0 (=
C(H)CH3), 15.9 (C-13), 12.6 (C-15); IR (film): nmax = 3439, 3423, 2994,
2929, 1777, 1697, 1384, 1258, 1231, 1198, 1158, 1134, 1108, 998, 733 cmꢀ1
A
A
ACHTREUNG
(CH2 octanoyl), 21.2 (C-14), 20.5 (C(O)CCH3), 15.8 (=C(H)CH3), 15.7
(C-13), 14.0 (CH3 octanoyl), 12.6 (C-15); IR (film): nmax = 3438, 2930,
2857, 1797, 1775, 1738, 1457, 1441, 1372, 1237, 1188, 1160, 1137, 1101,
1001 cmꢀ1; ESI+ MS: m/z: calcd for C33H48NaO11: 643.3094; found:
643.3096 [M+Na]+.
A
ACHTREUNG
;
ESI+ MS: m/z: calcd for C23H32NaO9: 475.1944; found: 475.1938
[M+Na]+.
O-8 Debutanoyl thapsigargin 79: Procedure A: See the formation of 80
via the degradation of 1 (see above).
Octanoate 97: Asolution of octanoic anhydride (23.0 mg, 0.085 mmol) in
CH2Cl2 (1.0 mL) and catalytic DMAP were added at RT to a solution of
triol 77 (24.6 mg, 0.054 mmol) in CH2Cl2 (3.5 mL). After stirring for 1 h,
further octanoic anhydride (23.0 mg, 0.085 mmol) and catalytic DMAP
were added before stirring for a further 1 h. Addition of saturated aque-
ous ammonium chloride solution (15 mL) and ethyl acetate (15 mL), sep-
aration of the phases, extraction of the aqueous with ethyl acetate (3”
10 mL), drying the combined organics (MgSO4), concentration under re-
duced pressure and purification by flash chromatography (ethyl acetate/
PE 1:4 then 1:1) afforded the title compound 97 as a colourless oil
(27.0 mg, 86%). Rf =0.66 (ethyl acetate/PE 4:1); [a]D = ꢀ16.0 (c = 0.3,
CHCl3); 1H NMR (600 MHz, CDCl3): d = 6.12 (q, J=7.0 Hz, 1H; =
CHCH3), 5.78 (brm, 2H; H-3, H-6), 5.37 (dd, J=4.3, 4.3 Hz, 1H; H-2),
4.23 (brm, 1H; H-8), 3.38 (brm, 1H; H-1), 2.89 (brs, 1H; OH), 2.33 (m,
2H; C(O)CH2 octanoyl), 2.24 (dd, J=15.1, 4.1 Hz, 1H; H-9), 2.02 (dd,
J=15.1, 1.8 Hz, 1H; H-9), 1.97 (d, J=7.0 Hz, 3H; =C(H)CH3), 1.90 (s,
3H; C(O)CCH3), 1.87 (s, 3H; H-15), 1.60 (m, 2H; C(O)CH2CH2 octano-
Procedure B: Triethylamine (50 mL, 359 mmol) was added to a solution of
thapsigargin (1) (11.5 mg, 17.7 mmol) in methanol (1.0 mL). The resulting
mixture was stirred at RT for 6 h 30 min before quenching by the addi-
tion of saturated ammonium chloride solution (20 mL). The crude mix-
ture was extracted with EtOAc (5”15 mL) and the combined organic
layers washed with brine (50 mL), dried (MgSO4) and evaporated.
Column chromatography (silica gel, EtOAc/PE 2:3) afforded the triol as
a white solid (10.2 mg, 99%).
Procedure C: An aqueous solution of HCl (50 mL of a 3n solution) was
added dropwise at RT to
a solution of acetonide 79 (24.0 mg,
0.039 mmol) in dry methanol (1.5 mL). The reaction mixture was heated
to 458C for 45 min before cooling to RT, followed by careful addition of
saturated aqueous NaHCO3 solution (10 mL) and ethyl acetate (10 mL).
Separation of the phases, extraction of the aqueous with ethyl acetate
(3”10 mL), drying the combined organics (MgSO4), concentration under
reduced pressure and purification by flash chromatography (ethyl ace-
tate/PE 1:2 then 1:1) afforded the title compound 79 as a colourless oil
yl), 1.54 (s, 3H; C
(CH3)), 1.24–1.28 (m, 8H; CH3
(t, J=6.8 Hz, 3H; CH3 octanoyl); 13C NMR (150 MHz, CDCl3): d
A
G
U
A
ACHTREUNG
(18.6 mg, 83%). Rf =0.57 (ethyl acetate/PE 2:1); [a]D
=
ꢀ27.3 (c
=
0.31, CHCl3); 1H NMR (600 MHz, CDCl3):
d
=
6.11 (m, 1H; =
174.7 (C-12), 172.8 (C=O octanoyl), 167.4 (OC(O)C=), 139.1 (=
C(H)CH3), 137.6 (C-5), 129.4 (C-4), 127.3 (C=C(H)CH3), 100.9 (C-
CHCH3)), 5.81 (brm, 1H; H-6), 5.70 (brm, 1H; H-3), 5.45 (dd, J=3.5,
3.1 Hz, 1H; H-2), 4.70 (brm, 1H; OH), 4.35 (m, 1H; H-8), 4.20 (brm,
1H; H-1), 4.00 (brm, 1H; OH), 3.25 (brs, 1H; OH), 2.64 (dd, J=14.3,
3.1 Hz, 1H; H-9), 2.58 (m, 2H; C(O)CH2 octanoyl), 2.24 (dd, J=14.3,
2.5 Hz, 1H; H-9), 1.98 (m, 3H; =C(H)CH3), 1.90 (brm, 6H; H-15,
C(O)CH3), 1.84 (s, 3H; C(O)CCH3), 1.59 (m, 2H; C(O)CH2CH2 octano-
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
ACHTREUNG
(C-13), 14.0 (CH3 octanoyl), 12.5 (C-15); IR (film): nmax = 3428, 2928,
2858, 1796, 1778, 1713, 1457, 1381, 1256, 1227, 1151, 1133, 1100, 1043,
996, 845 cmꢀ1; ESI+ MS: m/z: calcd for C31H46NaO10: 601.2989; found:
601.2991 [M+Na]+.
yl), 1.50 (s, 3H; H-13), 1.44 (s, 3H; H-14), 1.23–1.33 (m, 8H; CH3
octanoyl), 0.87 (t, J=6.8 Hz, 3H; CH3 octanoyl); 13C NMR (150 MHz,
CDCl3): d 175.4 (C-12), 172.6 (C=O octanoyl), 171.2 (C(O)CH3),
A
=
167.2 (OC(O)C=), 141.1 (=C(H)CH3), 138.8 (C-5), 130.0 (C-4), 127.4 (C=
C(H)CH3), 85.3 (C-10), 84.1 (C-3), 79.6 (C-11), 79.4 (C-7), 77.9 (C-2),
77.2 (C-6), 68.6 (C-8), 57.5 (C-1), 39.1 (C-9), 34.3 (OC(O)CH2 octanoyl),
31.6 (CH2 octanoyl), 29.1 (CH2 octanoyl), 28.9 (CH2 octanoyl), 24.8
(OC(O)CH2CH2 octanoyl), 22.8 (C-14), 22.7 (C(O)CH3), 22.6 (CH2 octa-
noyl), 20.5 (C(O)CCH3), 16.3 (C-13), 15.8 (=C(H)CH3), 14.0 (CH3 octa-
noyl), 12.8 (C-15); IR (film): nmax = 3401, 2928, 2858, 1790, 1771, 1737,
1710, 1457, 1368, 1238, 1153, 1132, 1114, 1083, 989 cmꢀ1; ESI+ MS: m/z:
calcd for C30H44NaO11: 603.2781; found: 603.2779 [M+Na]+.
Acetonide 78: Procedure A: p-Toluenesulfonic acid (12 mg, 70 mmol) was
added to a stirring solution of triol 79 (28 mg, 482 mmol) in acetone
(400 mL) and 2,2-dimethoxypropane (2.5 mL). After 1 h at RT the reac-
tion was quenched by the addition of NaHCO3 solution (30 mL) and ex-
tracted with EtOAc (3”30 mL). The combined organic phases were
washed with brine (50 mL), dried (MgSO4) and evaporated under re-
duced pressure. Column chromatography (silica gel, Et2O/PE 3:7 increas-
ing to 1:1) afforded the acetonide as a white solid (27.1 mg, 91%).
Procedure B: p-Toluenesulfonic acid monohydrate (22.0 mg, 0.130 mmol)
was added at RT to a solution of diol 97 (23.5 mg, 0.041 mmol) in isopro-
penyl acetate (2.0 mL). After stirring for 1 h 45 min, saturated aqueous
NaHCO3 solution (15 mL) and ethyl acetate (15 mL) were added. The
phases were separated and the aqueous extracted with ethyl acetate (3”
10 mL), the combined organics dried (MgSO4), concentrated under re-
duced pressure and purified by flash chromatography (ethyl acetate/PE
1:10, 1:5 then 3:1) to afford the title compound 78 as a colourless oil
Thapsigargin (1): To a solution of triol 79 (16.2 mg, 0.028 mmol) in
CH2Cl2 (0.1 mL) at RT was added a stock solution of butyric anhydride
(9.1 mL, 0.056 mmol, added as 0.3 mL of a stock solution consisting of
150 mL in 5.0 mL CH2Cl2). After stirring for 75 min, the reaction mixture
was quenched by the addition of saturated aqueous ammonium chloride
solution (15 mL) and ethyl acetate (15 mL). Separation of the phases, ex-
traction of the aqueous with ethyl acetate (3”10 mL), drying the com-
bined organics (MgSO4), concentration under reduced pressure and pu-
5710
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 5688 – 5712

Natural Products
FULL PAPER
rification by flash chromatography (ethyl acetate/PE 1:2) afforded the
title compound as a colourless oil (16.6 mg, 91%) which was identical to
an authentic sample of the natural product by normal spectroscopic anal-
ysis. Rf =0.19 (ethyl acetate/PE 1:2); [a]D = ꢀ42.4 (c = 0.17, CHCl3); an
optical rotation on a sample of the natural product was also measured in
our laboratory: [a]D = ꢀ36.0 (c = 0.15, CHCl3); 1H NMR (600 MHz,
3.4 mg sample in 0.65 mL CDCl3): d = 6.09 (m, 1H; =CHCH3), 5.72
(brm, 1H; H-3), 5.67 (brm, 1H; H-6), 5.62 (m, 1H; H-8), 5.50 (dd, J=
3.3, 3.2 Hz, 1H; H-2), 4.18 (brm, 1H; H-1), 2.96 (dd, J=14.8, 3.2 Hz,
1H; H-9’), 2.53 (brs, 1H; OH), 2.38 (dd, J=14.8, 4.0 Hz, 1H; H-9), 2.25–
2.40 (m, 4H; C(O)CH2 octanoyl, C(O)CH2 butanoyl), 2.00 (m, 3H; =
C(H)CH3), 1.92 (m, 3H; C(O)CCH3), 1.88 (s, 3H; C(O)CH3), 1.87 (s,
3H; H-15), 1.62 (m, 4H; C(O)CH2CH2 octanoyl, C(O)CH2CH2 butano-
This work was supported by an Insight Faraday CASE award (SPA),
EPSRC Research Fellowships (M.B., E.C.),
a Royal Society URF
(M.D.S.), the Deutsche Forschungsgemeinschaft (F.W.), the Wellcome
Trust (S.F.O.), Marie Curie Fellowships (K.H. and O.S.) and a Novartis
Research Fellowship (S.V.L.).
[1] a) For a review of the thapsigargins, including isolation, nomencla-
ture and selective manipulations, see S. B. Christensen, A. Andersen,
U. W. Smitt, D. Deepale, S. Srivastar, Fortschr. Chem. Org. Naturst.
1997, 71, 129; b) the most recently isolated thapsigargin was thapsi-
villosin L: H. Liu, K. G. Jensen, L. M. Tran, M. Chen, L. Zhai, C. E.
Olsen, H. Søhoel, S. R. Denmeade, J. T. Isaacs, S. Brøgger Christen-
sen, Phytochemistry 2006, 67, 2651.
yl), 1.51 (s, 3H; H-13), 1.42 (s, 3H; H-14), 1.25–1.35 (m, 8H; CH3(CH2)4
A
octanoyl), 0.95 (t, J=7.4 Hz, 3H; CH3 butanoyl), 0.87 (t, J=6.8 Hz; CH3
octanoyl); 13C NMR (150 MHz, CDCl3): d = 175.3 (C-12), 172.6”2 (C=
O octanoyl, C=O butanoyl), 170.8 (C(O)CH3), 167.1 (OC(O)C=), 141.8
(C-5), 138.7 (=C(H)CH3), 130.1 (C-4), 127.4 (C=C(H)CH3), 84.6 (C-10),
84.1 (C-3), 78.6”2 (C-7, C-11), 77.7 (C-2), 76.8 (C-6), 66.2 (C-8), 57.5 (C-
1), 38.2 (C-9), 36.5 (OC(O)CH2 butanoyl), 34.2. (OC(O)CH2 octanoyl),
31.6 (CH2 octanoyl), 29.0 (CH2 octanoyl), 28.9 (CH2 octanoyl), 24.8
(OC(O)CH2CH2 octanoyl), 22.9 (C-14), 22.6 (CH2 octanoyl), 22.5
(C(O)CH3), 20.5 (C(O)CCH3), 18.0 (OC(O)CH2CH2 butanoyl), 16.2 (C-
13), 15.8 (=C(H)CH3), 14.0 (CH3 octanoyl), 13.7 (CH3 butanoyl), 12.9 (C-
15); IR (film): nmax = 3435, 2959, 2927, 2858, 1790, 1775, 1741, 1721,
1459, 1369, 1256, 1237, 1161, 1128, 1102, 1043, 1019, 987, 802 cmꢀ1; ESI+
MS: m/z: calcd for C34H50NaO12: 673.3200; found: 673.3188 [M+Na]+.
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[8] Thapsigargin is not crystalline but a crystalline epoxide derivative
was made and initially assigned as the wrong enantiomer. For fur-
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Christophersen, J. Org. Chem. 1982, 47, 649.
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Thapsivillosin C (5): (S)-2-Methyl butyric anhydride (20 mL, 102 mmol)
was added to a solution of O-8-debutanoyl thapsigargin (79) (29 mg,
50.0 mmol) followed by a catalytic amount of DMAP (ca. 1 mg). The re-
sulting mixture was stirred at RT for 3.5 h and then quenched by the ad-
dition of saturated aqueous ammonium chloride solution (20 mL). The
mixture was then extracted with EtOAc (3”20 mL), and the combined
organics washed with brine (50 mL) and dried (MgSO4). The crude resi-
due was purified by flash chromatography (silica gel, Et2O/PE 1:1 then
7:3) to afford thapsivillosin C (5) as a white solid (30.5 mg, 92%). [a]D
=
ꢀ21.9 (c = 1.53, CHCl3); 1H NMR (600 MHz, 1.6 mg in 650 mL CDCl3):
d = 6.11 (apparent qd, J=7.2, 1.0 Hz, 1H; =CH(CH3)), 5.72 (brs, 1H;
G
H-3), 5.65 (brs, 1H; H-6), 5.63 (dd, J=3.7, 3.6 Hz, 1H; H-8), 5.50 (appar-
ent t, J=3.2 Hz, 1H; H-2), 4.23 (brs, 1H; H-1), 2.99 (dd, J=14.8, 3.3 Hz,
1H; H-9), 2.37–2.25 (m, 4H; H-9’, C(O)CH2CH2, C(O)CH
(apparent dd, J=7.2, 1.2 Hz, 3H; =CH(CH3)), 1.93 (s, 3H; C(O)CH3),
1.91 (s, 3H; C(O)CCH3), 1.89 (s, 3H; H-15), 1.72 (m, 1H; C(O)CH-
(CH3)CHH), 1.62 (m, 2H; C(O)CH2CH2), 1.52 (s, 3H; H-13), 1.44 (m,
1H; C(O)CH(CH3)CHH), 1.42 (s, 3H; H-14), 1.35–1.25 (m, 8H; 4”octa-
noyl CH2), 1.85 (d, J=7.4 Hz, 3H; C(O)CH(CH3)), 0.92 (m, 3H;
C(O)CH
(CH3)CH2CH3), 0.88 (m, 3H; octanoyl CH3); 13C NMR
(150 MHz, 30 mg in 650 mL CDCl3): 175.7 (C-12), 175.5
A
AHCTREUNG
[13] Asearch for the keyword “thapsigargin” elicits 11659 hits (February
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ACHTREUNG
ACHTREUNG
AHCTREUNG
ACHTREUNG
d
=
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(C(O)CHCH3), 172.6 (C(O)CH2), 171.0 (C(O)CH3), 167.1 (C(O)CCH3),
141.6 (C-4), 138.6 (=CHCH3), 130.4 (C-5), 127.5 (C=CHCH3), 84.8 (C-
10), 84.2 (C-3), 78.6, 78.5 (C-7, C-11), 77.7 (C-2), 76.9 (C-6), 66.2 (C-8),
57.2 (C-1), 41.4 (C(O)CHCH3), 38.3 (C-9), 34.2 (CH2 octanoyl), 31.6
(CH2 octanoyl), 29.0 (CH2 octanoyl), 29.0 (CH2 octanoyl), 26.1
(C(O)C(H)CH2), 24.8 (CH2 octanoyl), 23.2 (C-14), 22.6, 22.5 (CH2 octa-
noyl, C(O)CH3), 20.5 (C(O)CCH3), 16.2 (C-13), 16.1 (C(O)C(H)CH3),
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15.8
(=CHCH3), 14.0
(CH3 octanoyl),
12.9
(C-15),
11.6
(C(O)CHCH2CH3); IR (film; CHCl3): nmax = 3448 (br OH), 2926 (C-H),
1793 (C=O), 1775 (C=O), 1740 (C=O), 1718 (C=O), 1460, 1369, 1235;
ESI+ MS: m/z: calcd for C35H52NaO12
: 687.3357; found: 687.3359
[M+Na]+.
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Acknowledgements
The authors wish to thank Professor Søren Brøgger Christensen (Depart-
ment of Medicinal Chemistry, University of Copenhagen) for the kind
donation of an authentic sample of thapsigargin and thapsivillosin C.
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Chem. Eur. J. 2007, 13, 5688 – 5712
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5711

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glycol, 1508C; 4) TFA, H2O, THF, RT; 5) HCl, MeOH; for a com-
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[61] We had previously performed X-ray analysis on the O-2 TMS ether
of 61, which revealed that during the Rubottom oxidation of 19, we
had installed the C-2 oxygen with the desired facial selectivity. We
were therefore confident that the discrepancy between 82 and 75
arose from differences in their C-3 stereochemistry. CCDC-635138
(61) contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
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[64] Attempts to invert the C-3 alcohol with direct installation of the an-
gelate ester via a Mitsunobu reaction with angelic acid were unsuc-
cessful. Mitsunobu reactions with p-nitrobenzoic acid were unsuc-
cessful and would also introduce further synthetic steps to the se-
quence.
[65] Further analysis of this particular set of reaction conditions revealed
that considerable quantities of symmetrical angelic anhydride and
2,4,6-trichlorobenzoic anhydride were formed in addition to the de-
sired and more reactive mixed anhydride 96. See ref. [28], and refer-
ences therein for further details.
[66] We believe that this modest yield is again a reflection of the instabil-
ity of this particular C-3 epimer 91; we had not been able to isolate
this compound by removal of the angelate from 83 (Scheme 16), and
had experienced difficulties in obtaining it from the reduction of 88
(Scheme 17). Conversely, treatment of the C-3-(R) epimer (i.e., 89
where R=H, see Table 3) under the same reaction conditions result-
ed in an isolated yield of 98% of the corresponding angelate ester
(i.e., 90 as shown in Scheme 15).
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[69] Both the 1H and 13C NMR spectra of thapsivillosin C were highly
concentration dependent, as was previously found for thapsigargin
(see ref. [7] and Supporting Information for further details). NMR
spectroscopic analysis of thapsivillosin C samples (natural, synthetic
and a 1:1 natural/synthetic mixture) was performed at the same con-
centration for each sample in CDCl3 (see Supporting Information
for spectra). The natural and synthetic samples were identical, as
was the mixed sample which showed the presence of a single com-
pound.
Received: February 22, 2007
Published online: May 16, 2007
5712
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