Norrisolide: Total synthesis and related studies

Article abstract of DOI:10.1002/chem.200500513

A stereoselective synthesis of (+)-norrisolide is presented. This natural product belongs to a family of marine spongiane diterpenes the structure of which is characterized by a fused γ-lactone-γ-lactol ring system attached to a bicyclic hydrophobic core.

Full text of DOI:10.1002/chem.200500513

FULL PAPER
DOI: 10.1002/chem.200500513
Norrisolide: Total Synthesis and Related Studies
Thomas P. Brady, Sun Hee Kim, Ke Wen, Charles Kim, and Emmanuel A. Theodorakis*[a]
Abstract: A stereoselective synthesis of
(+)-norrisolide is presented. This natu-
ral product belongs to a family of
marine spongiane diterpenes the struc-
ture of which is characterized by a
fused g-lactone–g-lactol ring system at-
tached to a bicyclic hydrophobic core.
Our studies led to the development of
a expedient synthesis of such g-lac-
tone–g-lactol motifs based on ring ex-
pansion of a fused cyclopropyl ester.
Highlights of the synthetic strategy
toward norrisolide include the coupling
of the two bicyclic systems by con-
ꢀ
structing a sterically demanding C9
C10 bond and the installation of the
C19 oxygen at the last step of the syn-
thesis via a Baeyer–Villiger oxidation.
Keywords: natural
oxidation synthetic methods
terpenoids · total synthesis
products
·
·
·
Introduction
scopic and crystallographic studies established that norriso-
lide belongs to a family of rearranged spongiane diter-
penes[5,6] that also includes macfarlandin C (2),[7] dendrillo-
lide A (3),[8] shahamin K (4)[9] and chromodorolide A (5)[10]
(Figure 1). The biological profile of these family members
includes antifungal, antimicrobial, antifeedant, antiviral and
antitumor properties as well as PLA2 inhibition.[11] The
structural diversity of these compounds is proposed to origi-
nate from the spongiane skeleton (6) following a series of
ring oxidations and skeletal rearrangements. In the case of
1, 2 and 3, such a process produces an unusual motif high-
lighted by a fused g-lactone–g-lactol ring system attached to
a hydrophobic core. The degree of oxygenation and pattern
of functionalities encountered in this side chain confer to
Nudibranchs (nudibranchia) are a class of shell-less, brightly
collored sea slugs that comprise one of the largest groups of
marine molluscs with over 3000 species described to-date.[1]
Their name, a combination of the Latin word nudus (naked)
and the Greek word branchia (gills), appropriately describes
their shell-less, seemingly vulnerable appearance. To avoid
their natural predators, these marine animals have devel-
oped an alternative “chemical shell”, consisting of toxic and
antifeedant substances that are concentrated in their skin.[2]
Further studies indicated that these metabolites are acquired
from the nudibranchꢀs dietary habits that include generally
praying on sponges and bryozoans. With or without further
chemical modifications, these metabolites are stored in the
animalꢀs dorsal mantle and excreted when the animal is in
danger, thus protecting it from its natural predators.
As a part of a program on molluscan chemical defenses,
Faulkner and co-workers isolated norrisolide (1) from the
skin extracts of the nudibranch Chromodoris norrisi.[3] Sub-
sequent studies led to the isolation of 1 from the marine
sponges Dendrilla sp. and Dysidea sp., providing additional
evidence of the feeding patterns of this animal.[4] Spectro-
[a]T. P. Brady, Dr. S. H. Kim, Dr. K. Wen, Dr. C. Kim,
Prof. Dr. E. A. Theodorakis
Department of Chemistry and Biochemistry
University of California at San Diego
9500 Gilman Drive, La Jolla, CA 92093-0358 (USA)
Fax : (+1)858-822-0386
E-mail: etheodor@chem.ucsd.edu
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Figure 1. Representative structures of rearranged spongiane diterpenes.
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these molecules a high degree of chemical reactivity, the
biological significance of which remains largely unex-
plored.[12]
to be advantageous during scale-up. This approach is high-
lighted in Scheme 2 and began with an asymmetric Robin-
son annulation of enone 11 with diketone 12.[18] Use of d-
CSA and l-phenylalanine during this reaction led to an
The combination of interesting structural features and un-
explored biological profile of 1 prompted us to develop a
stereocontrolled approach to this natural product.[13] Herein
we present a full account of our studies toward this goal,
culminating in an expedient and stereoselective synthesis of
(+)-norrisolide.[14] These studies establish the absolute ster-
eochemistry of this natural product and pave the way for a
more precise study of its structure–activity relationship.[15]
Results and Discussion
Retrosynthetic analysis and strategic bond disconnections:
The retrosynthetic analysis toward norrisolide (1) is shown
in Scheme 1. To avoid any issues related to the reactivity
and fragility of the of the g-lactone–g-lactol ring system, we
Scheme 2. a) 1.5 equiv Et3N, EtOAc, 258C, 12 h, 89%; b) 0.6 equiv d-
CSA, 0.8 equiv l-Phe, acetonitrile, 25 ! 708C, 5 d, 60% (after recrystal-
lization); c) 0.33 equiv NaBH4, EtOH, ꢀ258C, 0.5 h, 99%; d) 2.5 equiv
imidazole, 2.0 equiv TBDPSCl, 0.1 equiv DMAP, DMF, 258C, 4 h, 77%;
e) 2.0 equiv tBuOK, DMF, 0 ! 258C, 1 h, then 2.0 equiv MeI, 08C, 1 h,
66% f) 1.2 equiv NaBH4, MeOH, 08C, 1 h, 100%; g) 1.2 equiv nBuLi,
08C, 0.5 h, 10 equiv CS2, 2 h, then 3.0 equiv MeI, THF, 0.5 h, 95%; h)
2.5 equiv nBu3SnH, 0.1 equiv AIBN, toluene, 1208C, 0.5 h, 86%; i)
3.0 equiv BH3·THF, THF, 08C, 12 h, then 20 equiv 3m NaOH (aq),
20 equiv H2O2, 258C, 12 h, 78% (56% of trans and 24% of cis); j)
1.2 equiv nBuLi, 08C, 0.5 h, 10 equiv CS2, 2 h, then 3.0 equiv MeI, THF,
08C, 0.5 h; k) 2.5 equiv nBu3SnH, 0.1 equiv AIBN, toluene, 1208C, 0.5 h,
92% (over 2 steps); l) 3.0 equiv TBAF, THF, 608C, 8 h, 99 %; m)
4.5 equiv PCC, Celite, CH2Cl2, 258C, 1 h, 92%; n) 30 equiv N2H4·H2O,
5.0 equiv Et3N, EtOH, reflux, 5 h, 99%; o) I2 (until N2 evolution ceased),
10 equiv DBU, THF, 258C, 0.25 h, 62%.
Scheme 1. Strategic bond disconnections of 1 (PG, X indicate protecting
groups).
chose to adjust its oxygenation pattern during the last steps
of the synthesis. This analysis led us to consider compound 7
as an appropriate synthetic precursor of 1. In the forward di-
rection, we envisioned that 7 could lead to 1 via a sequence
of reactions that include olefination of the C10 carbonyl
group and oxidation at the C14 and C19 centers. The latter
functionalization could be achieved via a Baeyer–Villiger
oxidation that was projected to install the C19 oxygen in a
regio- and stereoselective manner.[16] Compound 7 could be
formed by connecting fragments 8 and 9 representing the
side chain and the core of norrisolide. The trans-fused hy-
drindane motif of 9 could be traced to enantiomerically en-
riched ketone (+)-10. The synthesis of norrisolide based on
these considerations is presented in the following schemes.
enantioselective synthesis of the desired ketone (+)-13,
which, after one recrystallization, was isolated in 60% yield
and greater than 95% ee. Selective reduction of the more
reactive C9 carbonyl group, followed by silylation of the re-
sulting alcohol afforded compound 15 (76% yield over two
steps). Treatment of 15 with tBuOK produced the extended
enolate that upon methylation gave rise to ketone 16 in
66% yield.[19] Reduction of the C4 carbonyl group of 16, fol-
lowed by a Barton–McCombie radical deoxygenation of the
resulting alcohol, produced alkene 19 in 82% yield (over
three steps).[20] Several methods were examined for the con-
version of alkene 19 to the trans-fused bicycle 20. All hydro-
genation conditions produced a mixture of cis (major prod-
uct) and trans bicycles which were difficult to separate by
Synthesis of the hydrindane core fragment of norrisolide:
An enantioselective synthesis of ketone 10 has been previ-
ously reported by Paquette starting from the well known
Wieland–Miescher enone.[17] In the course of our studies we
developed an alternative route to ketone 10 which proved
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FULL PAPER
using standard chromatographic techniques. We found, how-
ever, that hydroxylation of 19 (BH3·THF/H2O2) afforded the
trans-bicycle 20 as the major isomer in 56% yield (trans/cis
2.3:1). The diastereomeric outcome of this hydroxylation
was found to be dependant upon the size of the C9 silyl
ether, and in the case of the bulky TBDPS group it pro-
duced the best ratio of trans to cis isomers that were easily
separated by column chromatography. Radical deoxygena-
tion of alcohol 20, followed by deprotection of the C9 silyl
ether and oxidation of the resulting alcohol, produced
ketone 10 in 84% yield (over four steps). Treatment of 10
with hydrazine produced hydrazone 24 that upon reaction
with I2/Et3N/DBU produced vinyl iodide 25 in 61% yield
(over two steps).[21] The trans junction of the bicyclic scaf-
fold of 25 was unambiguously determined by a single-crystal
X-ray diffraction analysis of hydrazone 24.[22]
Synthesis of the side chain motif of norrisolide: Having de-
veloped an efficient synthesis of the core fragment of norri-
solide, we turned our attention to the synthesis of the bicy-
clic side chain motif of 1. At the onset of our investigation,
we chose to pursue this synthesis by creating the fused g-lac-
tone ring from ring expansion of an appropriately substitut-
ed cyclopropyl ester (see conversion of 31 to 34, Scheme 3).
It is well established that the strained three-membered ring
of cyclopropanes can lead, upon activation, to a variety of
ring cleavage and ring expansion reactions.[23] Based on this,
we expected that the presence of both electron withdrawing
and electron donating substituents at vicinal positions of the
cyclopropyl ring of 31 would allow the cleavage of the
anomeric bond to occur under mild acidic conditions.[24] This
approach appeared advantageous since compound 31 could
be constructed by a substrate-directed cyclopropanation of a
chiral dihydrofuran, such as 30, the stereochemistry of
which could be traced to d-mannose (26). In this manner,
the chirality inherent in 26 could be translated to the desired
stereochemistry of all stereocenters of the side chain of 1.
Scheme 3 highlights these efforts.[14a]
Scheme 3. a) 0.1m d-mannose in acetone, 0.2 equiv I2, 258C, 2 h, 85%;
b) 0.6 equiv DMAP, 1.2 equiv TsCl, 1.0 equiv Et3N, CH2Cl2, 258C, 2 h,
60%; c) 3.0 equiv naphthalene, 10 equiv Na, THF, 0 ! 258C, 10 min,
80%; d) 1.2 equiv BnBr, 1.2 equiv NaH, 0.5 equiv nBu4N+Iꢀ, 08C to
258C, 2 h, 90%; e) 0.01 equiv Rh2(OAc)4, 1.1 equiv N2CHCO2Et (0.1m in
CH2Cl2, syringe pump addition), CH2Cl2, 258C, 14 h, 45%; f) EtOH,
0.8m H2SO4, 258C, 48 h, 78%; g) 3.0 equiv NaIO4, THF/H2O 1:1, 20 min,
258C; h) 1.0 equiv TiCl4, 3.0 equiv Ti(OiPr)4, THF, 08C; 4.0 equiv MeLi,
1 h, 0 ! 258C, 1 h, 63% (2 steps); i) 4.0 equiv (COCl)2, 5.0 equiv DMSO,
ꢀ788C, 0.5 h, CH2Cl2; Et3N, ꢀ408C, 10 min, 79%; j) 6.0 equiv MeSO3H
in CH2Cl2, ꢀ5 ! 08C, 12 h, 67%; k) urea/hydrogen peroxide, trifluoro-
acetic anhydride, 40 min, 08C, CH2Cl2, 258C, 2 h, 69%.
amounts of byproducts arising from dimerization of ethyl di-
azoacetate. Best results were obtained upon syringe pump
addition of ethyl diazoacetate (0.1m in CH2Cl2) into a con-
centrated mixture of 30 (2m in CH2Cl2) and rhodium acetate
at 258C, producing cyclopropyl ester 31 in 45% yield. In
this case we observed the formation of two diasteromers at
the C13 center (4:1 in favor of the exo adduct), which were
both subjected to the next reaction.
Treatment of 31 with a dilute ethanolic solution of H2SO4
induced acetonide deprotection and concomitant opening of
the cyclopropyl ring leading to compound 32 in 78% yield
(Scheme 3).[29] Conversion of 32 to 33 was accomplished via
a sequence of three steps that included: a) oxidative cleav-
age of the 1,2-diol of 32 (NaIO4); b) methylation of the re-
sulting aldehyde using MeTi(OiPr)4;[30] and Swern oxidation
of the resulting alcohol (51% yield over three steps). It is
worth mentioning that the titanium-induced methylation
proceeded with excellent chemoselectivity (no interference
with the ester functionality) and diastereoselectivity (about
10:1 mixture of isomers at the C21 center, presumably aris-
ing from a chelation-controlled addition). Formation of the
bicyclic system 34 was achieved under acidic conditions. Al-
though a variety of Brçnsted acids and Lewis acids could
effect this transformation, we found that best yields were
obtained by using methanesulfonic acid, which at 08C pro-
duced compound 34 as a single isomer in 67% yield.[31]
Conversion of d-mannose (26) to the known bisacetonide
27 was accomplished by a modification of the reported pro-
cedure in which I2 was used as the catalyst (instead of
H2SO4).[25] This modification led to isolation of 27 in 85%
yield after
a
simple filtration and recrystallization
(Scheme 3). Treatment of 27 with TsCl and Et3N afforded
glycosyl chloride 28, which upon slow addition to a stirring
mixture of sodium naphthalenide in THF gave rise to glycal
29 (48%, over two steps).[26] Compound 29 was labile upon
standing and was immediately benzylated to produce benzyl
ether 30 in 90% yield. Rhodium acetate-catalyzed cyclopro-
panation of 30 produced ester 31 as a single isomer at the
C12 center.[27,28] As expected, the bulky acetonide group at
C19 in conjunction with the benzyl ether group at C11 were
able to direct this sterically demanding cyclopropanation
from the a-face of the dihydrofuran ring. During optimiza-
tion attempts we found that the yield of cyclopropanation
depended upon the reagent concentration; for example
under dilute conditions we observed formation of increased
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E. A. Theodorakis et al.
With bicyclic lactone 34 in hand, we decided to test the
crucial Baeyer–Villiger oxidation in order to install the C19
oxygen (Scheme 3). Both mCPBA/NaOH and urea/hydro-
gen peroxide in combination with trifluoroacetic anhydride
produced the desired structure 35. This conversion was
cleaner using the urea-hydrogen peroxide conditions, lead-
ing to formation of 35 in 69% yield. As predicted, a single
isomer was obtained during this oxidation having the de-
sired stereochemistry at the C19 center, as established by a
combination of spectroscopic techniques (COSY and NOE
experiments).
Encouraged by the positive results of the Baeyer–Villiger
oxidation, we sought to optimize further the above strategy.
One of its main drawbacks was the rather cumbersome and
multistep sequence developed for the conversion of cyclo-
propyl ester 31 to lactone 34. The problem with this conver-
sion was due to the presence of the labile acetonide, that un-
derwent deprotection under the acidic conditions employed
(H2SO4 in EtOH). To circumvent this problem we per-
formed this reaction using MeSO3H in acetone. Under the
modified conditions, we were able to suppress entirely the
acetonide deprotection and achieve conversion of cyclo-
propyl ester 31 to lactone 36 in one step and 77% yield
(Scheme 4).[14c] The stereochemistry of 36 was established
that are summarized here: a) we found that the Baeyer–Vil-
liger oxidation was reliable and could be used during the
last steps of the norrisolide synthesis (conversion of 34 to
35); b) we established that an appropriately substituted di-
hydrofuran could be converted to the desired g-lactone–g-
lactol motif (conversion of 30 to 34) and we developed a
one-pot ring expansion protocol (conversion of 31 to 36);
and c) we found that homologation of the C11 carbonyl
group was problematic, at least in the presence bicycles 31
and 37, indicating that this one carbon extension had to be
performed prior to the formation of the bicyclic system.
These conclusions paved the way for the development of a
second generation strategy toward norrisolide.
Synthesis of fragment 47: Evaluation of the above informa-
tion led us to consider butenolide 39 as a synthetic precursor
of the norrisolide side chain (Scheme 5). We envisioned that
this compound would be suitable for the one carbon exten-
sion at the C11 center and it could also be converted to a di-
hydrofuran (such as 47), a presumed substrate for the key
cyclopropanation reaction. Reduction of this plan to prac-
tice is shown in Scheme 5.
Enantiomerically pure butenolide 39 was prepared from
d-mannitol (38) as described in the literature.[32] Reaction of
39 with vinyl magnesium bromide in the presence of catalyt-
ic copper(i) bromide produced adduct 40 in 85% yield.[33]
This 1,4-addition proceeded exclusively anti to the bulky
TBDPS silyl ether, setting the desired stereochemistry at
C11. DIBAL-H reduction of lactone 40, followed by an
acid-catalyzed protection of the resulting lactol, produced
methyl acetal 41 as an unseparable mixture of anomers.[34]
Osmium-catalyzed dihydroxylation of 41 afforded, after oxi-
dative cleavage of the resulting diol, aldehyde 42, which was
immediately subjected to coupling with 43.
Kishi–Nozaki coupling[35] of freshly prepared vinyl triflate
43 with aldehyde 42 followed by Dess–Martin periodinane
(DMP) oxidation of the resulting alcohol, produced enone
44 in 52% yield over two steps (Scheme 5). Hydrogenation
Scheme 4. a) MeSO3H/acetone 1:10, 258C, 12 h, 77%; b) 10% Pd(OH)2,
H2, CH2Cl2, 258C, 24 h, 82%; c) 1.2 equiv DMP, 258C, 12 h, 93%.
ꢀ
of the C8 C9 double bond proceeded exclusively from the
unambiguously by a single-crystal X-ray diffraction analysis,
thus also confirming the outcome of the cyclopropanation
sequence.[22]
more accessible a-face of the bicyclic core to form ketone
45 in 92% yield. Standard olefination procedures (Wittig
and Tebbe)[36] failed to convert 45 into 46, presumably due
to the steric hindrance of the C10 carbonyl group. We found
however, that this reaction could be achieved by a modified
Peterson olefination procedure (TMSCH2Li; KH reflux),[37]
which produced alkene 45 in 72% yield (over two steps).
Treatment of methyl acetal 46 with phenyl selenol in the
presence of BF3·Et2O produced, after oxidation, enol ether
47 thus setting the stage for the crucial cyclopropanation re-
action. Much to our disappointment, however, in sharp con-
trast to the conversion of 30 to 31 (Scheme 3), this reaction
proved to be problematic. Both rhodium- and copper-cata-
lyzed cyclopropanation procedures were tested but resulted
in very low conversion of the starting material and low
yields of complex product mixtures. The differences in the
reactivity profiles between 30 and 47 could be due to the
stereochemistry of the C11 and C19 centers. In the case of
Reductive debenzylation of 36 produced, after oxidation
of the resulting alcohol, ketone 37 in 76% yield (over two
steps). Unfortunately, all efforts to homologate this carbonyl
group met with failure. Only low yields were obtained with
a variety of Wittig ylids, while, under harsh conditions, sub-
stantial amounts of decomposition were observed. We hy-
pothesized that the steric hindrance imposed by the bicyclic
motif of 37 together with the reactivity of the lactone func-
tionality were responsible for the side products obtained
during these reactions. We also attempted to homologate
the C11 center in compound 31 but this was similarly prob-
lematic, suggesting that a different strategy may be needed
for the synthesis of norrisolide.
Despite the disappointing outcome, the strategy presented
in Schemes 3 and 4 allowed us to draw several conclusions
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Norrisolide
FULL PAPER
alkene. These findings led to our successful campaign
toward the synthesis of norrisolide.
Total synthesis of norrisolide: Re-evaluation of the above
results led us to install the functionalities at the C11 and
C12 centers early in the synthesis. Since these substituents
needed to be syn to each other, we decided to start our
strategy with a Diels–Alder reaction between butenolide 39
and butadiene (48).[38] Under AlCl3 catalysis this reaction
proceeded exclusively from the opposite face of the bulky
TBDPS group and afforded 49 in 85% yield as a single en-
antiomer (Scheme 6).[39] Reduction of the C20 lactone of 49
(DIBAL-H) produced, after oxidative cleavage of the
double bond (OsO4, NMO; Pb(OAc)4), lactol 50 in 63%
yield as a 1:1 mixture of isomers at the C14 center. Further
treatment of 50 with MeOH in the presence of acid cataly-
sis,[40] afforded the isomeric methyl ethers 51 that were
easily separable by standard chromatographic techniques.
After separation, both C14 anomers of 51 were employed
toward the synthesis of norrisolide. Unambiguous stereo-
chemical assignment for these isomers was established at a
later stage via a crystal structure of anomer 56b (see
Scheme 6 for X-ray of 56b). Aldehyde 51 was then convert-
ed to selenide 54, via intermediates 52 and 53, that, after ox-
idation (NaIO4) and elimination, produced alkene 55 (61%
overall yield from 51).[41] Dihydroxylation of compound 55
(OsO4, NMO), followed by oxidative cleavage of the result-
ing diol, gave rise to aldehyde 56 (94% yield over two
steps). As mentioned above, the C14b anomer of aldehyde
56 was crystalline and a single-crystal X-ray diffraction anal-
ysis confirmed the relative and absolute stereochemistry of
all chiral centers.[22]
Guided by our previous results, we attempted the Kishi–
Nozaki coupling between aldehyde 56 and vinyl triflate 43.
Unfortunately, this reaction produced the coupled product
in less than 10% yield, accompanied by substantial amounts
of the reduced trans-hydrindane. Suspecting that the re-
duced reactivity of aldehyde 56 was due to the steric hin-
drance of its concave bicyclic motif, we decided to alter the
size of the vinyl nucleophile. With this in mind, we attempt-
ed this coupling using a vinyl lithium as the corresponding
nucleophile. As shown in Scheme 2, ketone 10 could be
easily converted to vinyl iodide 25 that, upon treatment with
tBuli and quenching of the anion with aldehyde 56, afforded
the desired coupling product 57. The resulting allylic alcohol
was then oxidized to enone 58 by using Dess–Martin period-
inane (71% yield, over two steps, Scheme 6). Compound 58
Scheme 5. a) 0.01 equiv SnCl2, 2,2-dimethoxypropane/DME 2:3, reflux,
4 h, 78%; b) 2.0 equiv NaIO4, saturated aqueous NaHCO3/CH2Cl2 1:20,
08C, 2 h, 73%; c) 1.5 equiv Ph3P=CHCO2Me, MeOH, 08C, 16 h, 70%; d)
conc. H2SO4/MeOH 1:100, 258C, 1 h, 90%; e) 1.2 equiv TBDPSCl,
5.0 equiv NH4NO3, DMF, 258C, 12 h, 92%; f) 1.1 equiv CH2=CHMgBr,
10% CuBr·Me2S, THF, ꢀ788C, 15 min then 39, 45 min, 85%; g)
1.05 equiv DIBAL-H CH2Cl2, ꢀ788C, 30 min, 99%; h) cat. HCl (~1%),
MeOH, 258C, 1 h, 88%; i) 2.5% OsO4, 1.1 equiv NMO, 0.1 mL pyridine,
acetone/H2O 95:5, 12 h, 97%; j) 1.1 equiv Pb(OAc)4, CH2Cl2, 258C, 0.5 h,
92%; k) 5.0 equiv CrCl2, 0.05 equiv NiCl2, DMF, 258C, 6 h, 53%; l)
DMP, CH2Cl, 258C, 12 h, 99%; m) 10% Pd/C, H2, MeOH, 258C, 12 h,
92%; n) 3 equiv TMSMeLi, THF, 0 ! 258C, 1 h, 81%; o) 10 equiv KH,
THF, reflux, 2 h, 89%; p) 1.5 equiv PhSeH, BF3·Et2O, CH2Cl2, 08C, 0.5 h,
90%; q) 1.8 equiv Et3N, 2.3 equiv tBuOOH, 0.3 equiv Ti(OiPr)4, CH2Cl2,
08C, 45 min, 67%; r) 1.1 equiv NaHMDS, 1.1 equiv PhNTf2, THF,
ꢀ788C, 4 h, 85%.
dihydrofuran 30 these substituents are syn to each other and
both shield the b-face of the dihydrofuran directing the cy-
clopropanation from the a-face. In the case of 47 these sub-
stituents are anti hindering substantially both faces of the
enol ether. The presence of an additional alkene in 47 could
also interfere and complicate the results of this cyclopropa-
nation.
ꢀ
was hydrogenated across the C8 C9 bond, exclusively from
the a-face of the hydrindane core, producing ketone 59 in
85% yield. Interestingly, treatment of the C14a anomer of
58 under the same reaction conditions led to inversion of
configuration at the C14 center and isolation of 59b as the
major adduct.
The above studies led us to conclude that the C12 stereo-
center should be functionalized prior to constructing the
ꢀ
C9 C10 bond. Such a functionality should be able to with-
stand strong nucleophilic conditions that are required for
the installation of the alkene at the C10 center. In the other
As expected, ketone 59 did not convert to alkene 60
under the standard Wittig conditions. Moreover, the previ-
ously explored Peterson olefination reaction was also inef-
fective, resulting in complete recovery of the starting materi-
ꢀ
hand, we were able to construct C9 C10 bond and found
also conditions that led to the formation of the terminal
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E. A. Theodorakis et al.
Scheme 6. a) 0.33 equiv AlCl3, CH2Cl2, 608C, 6 d, 85%; b) 1.2 equiv DIBAL-H, CH2Cl2, ꢀ788C, 0.5 h, 98%; c) 0.01 equiv OsO4, 1.1 equiv NMO, 3 drops
pyridine, acetone/H2O 10:1, 258C, 8 h; d) 1.2 equiv Pb(OAc)4, CH2Cl2, 08C, 0.5 h, 64% (over 2 steps); e) 1.2 equiv MeOH, Amberlyst 15, 3 Š MS, Et2O,
258C, 10 h, 77% (51a/51b 1:1); f) 1.5 equiv NaBH4, MeOH, 258C, 0.5 h; g) 2.2 equiv imid, 1.1 equiv PPh3, 1.2 equiv I2, THF, 258C, 0.5 h, 93% (over 2
steps); h) 0.55 equiv (PhSe)2, 1.5 equiv NaBH4, EtOH, 258C, 0.5 h, 92%; i) 1.6 equiv NaIO4, MeOH/H2O 5:2, 258C, 1 h, then Et3N/PhH 1:1, reflux, 0.5 h,
78%; j) 0.05 equiv OsO4, 1.1 equiv NMO, 3 drops pyridine, acetone/H2O 10:1, 258C, 10 h; k) 1.2 equiv Pb(OAc)4, CH2Cl2, 08C, 0.5 h, 94% (over 2
steps); l) 1.5 equiv 25, 3.0 equiv tBuLi, THF, ꢀ78 to ꢀ408C, 0.5 h, then 56, THF, ꢀ788C, 1 h, 75%; m) 8.0 equiv DMP, CH2Cl2, 258C, 10 h, 95%; n) 10%
Pd/C, H2, MeOH, 258C, 10 h, 85%; o) 5.0 equiv MeLi, THF/DME 1:3, 08C, 0.5 h, 75%; p) 10.0 equiv SOCl2, 20.0 equiv pyridine, CH2Cl2, 08C, 0.5 h,
85%; q) 2.0 equiv TBAF, THF, 258C, 8 h, 99%; r) 3.0 equiv IBX, MeCN, 808C, 2 h, 96%; s) 10.0 equiv MeMgBr, THF, 08C, 0.5 h, 72%; t) 2.5 equiv
DMP, CH2Cl2, 258C, 6 h, 94%; u) 10 equiv CrO3, AcOH/H2O 2:1, 258C, 6 h, 80%; v) 2.5 equiv mCPBA, 2.5 equiv NaHCO3, CH2Cl2, 08C, 4 h, 60%.
al. Neither increased temperature nor excess of reagent
could overcome the sluggish reactivity of the severely hin-
dered carbonyl group of 59. However, this ketone could be
reduced to the corresponding alcohol with NaBH4, suggest-
ing that it was not completely inert. After substantial experi-
mentation we found that excess MeLi in the presence of 1,2-
dimethoxyethane was sufficiently reactive to methylate
ketone 59, affording the corresponding tertiary alcohol in
good yield (75%). The latter compound underwent smooth
elimination when exposed to 10 equivalents of thionyl chlo-
ride in the presence of excess pyridine, to afford terminal
alkene 60 as the sole product (85% yield).[42] Fluoride-in-
duced deprotection of the silyl ether and oxidation of the re-
sulting alcohol 61, furnished aldehyde 62 in 93% combined
yield. This compound was rather labile and was treated im-
an authentic sample. Moreover, both samples exhibited dex-
rotatory optical rotation and identical biological activity.
Conclusion
In conclusion, we present herein our studies toward the syn-
thesis of norrisolide (1), a marine diterpene with an uncom-
mon chemical structure and unexplored biological proper-
ties. The compact and sterically cumbersome structure of 1
led to several unsuccessful reactions and several modifica-
tions of the overall synthetic strategy. Nonetheless, explora-
tion of each strategy led to conclusions that were critical to
the design of the successful strategy. Moreover, novel ap-
proaches for the synthesis of the uncommon g-lactone–g-
lactol motif of 1 were developed. The synthetic approach is
stereoselective and allows construction of analogues of 1
that could be used to evaluate the biological mode of action
of this natural product.
mediately after
a short filtration with excess methyl
Grignard producing, after oxidation of the ensuing alcohol,
ketone 63 (68% yield, over two steps). Treatment of 63 with
CrO3 in aqueous acetic acid produced lactone 64 in 80%
yield. Finally, Baeyer–Villiger oxidation of 64 with mCPBA
in the presence of NaHCO3 led to insertion of the oxygen
between the C19 and C21 centers with complete retention
of configuration, producing norrisolide (1) in 60% yield.
The spectra of the final product were identical with that of
Experimental Section
General techniques: All reagents were commercially obtained (Aldrich,
Acros) at highest commercial quality and used without further purifica-
7180
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ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 7175 – 7190

Norrisolide
FULL PAPER
tion except where noted. Air- and moisture-sensitive liquids and solutions
were transferred via syringe or stainless steel cannula. Organic solutions
were concentrated by rotary evaporation below 458C at approximately
20 mmHg. All non-aqueous reactions were carried out under anhydrous
conditions using flame-dried glassware within an argon atmosphere in
dry, freshly distilled solvents, unless otherwise noted. Tetrahydrofuran
(THF), diethyl ether (Et2O), dichloromethane (CH2Cl2), toluene
(PhCH3) and benzene (PhH) were purified by passage through a bed of
activated alumina. N,N-Diisopropylethylamine (DIPEA), diisopropyla-
mine, pyridine, triethylamine (TEA) and boron trifluoride etherate were
distilled from calcium hydride prior to use. Dimethylsulfoxide (DMSO)
and dimethylformamide (DMF) were distilled from calcium hydride
under reduced pressure (20 mmHg) and stored over 4 Š molecular
sieves until needed. Yields refer to chromatographically and spectroscop-
ically (1H NMR, 13C NMR) homogeneous materials, unless otherwise
stated. Reactions were monitored by thin-layer chromatography (TLC)
carried out on 0.25 mm E. Merck silica gel plates (60F-254) with UV
light as the visualizing agent and 10% ethanolic phosphomolybdic acid
(PMA) or p-anisaldehyde solution and heat as developing agents. E.
Merck silica gel (60, particle size 0.040–0.063 mm) was used for flash
chromatography. Preparative thin-layer chromatography separations
were carried out on 0.25 or 0.50 mm E. Merck silica gel plates (60F-254).
NMR spectra were recorded on Varian Mercury 400 and/or Unity
500 MHz instruments and calibrated using the residual undeuterated sol-
vent as an internal reference. The following abbreviations were used to
explain the multiplicities: s=singlet, d=doublet, t=triplet, q=quartet,
m=multiplet, br=broad. IR spectra were recorded on a Nicolet 320
Avatar FT-IR spectrometer and values are reported in cmꢀ1 units. Optical
rotations were recorded on a Jasco P-1010 polarimeter and values are re-
ported as follows: [a]Tl (c: g per 100 mL, solvent). High resolution mass
spectra (HRMS) were recorded on a VG 7070 HS mass spectrometer
under chemical ionization (CI) conditions or on a VG ZAB-ZSE mass
spectrometer under fast atom bombardment (FAB) conditions. X-ray
data were recorded on a Bruker SMART APEX 3kW Sealed Tube X-ray
diffraction system.
9H); 13C NMR (100 MHz, CDCl3): d = 198.8, 167.6, 135.9, 135.8, 134.8,
129.6, 127.7, 127.6, 127.5, 81.6, 45.7, 34.0, 33.4, 29.7, 27.0, 19.3, 15.8, 10.5;
HRMS: m/z: calcd for C27H34O2Si: 441.2211, found 441.2201 [M+Na]+.
Ketone 16: Ketone 15 (20 g, 47.7 mmol) was dissolved in DMF (80 mL)
under an argon atmosphere and cooled to 08C by means of an ice bath.
Potassium tert-butoxide (10.6 g, 95 mmol) was added to the mixture and
it was stirred at 08C for 15 min. The ice bath was removed and the mix-
ture was stirred for an additional 45 min. The mixture was again cooled
to 08C and iodomethane (13.4 g, 95 mmol) was added to the reaction
over a five-minute period and the ice bath was removed. The reaction
was stirred for 1 h, diluted with Et2O (350 mL) and washed with aqueous
saturated ammonium chloride (400 mL). The aqueous phase was extract-
ed Et2O (2”200 mL) and the combined organic phases were dried over
magnesium sulfate, concentrated on the rotary evaporator, and subjected
to silica gel chromatography (100% hexanes) to yield 16 (13.6 g, 66%)
and starting material 15 (5 g, 25%). Rf =0.7 (50% Et2O in hexanes);
[a]2D5 = ꢀ10.6 (c=2.0, CH2Cl2); 1H NMR (400 MHz, CDCl3): d = 7.71–
7.68 (m, 4H), 7.46–7.36 (m, 6H), 5.28 (dd, J=3.6, 1.6 Hz, 1H), 3.96 (dd,
J=9.2, 7.6 Hz, 1H), 2.53–2.45 (m, 1H), 2.33 (dd, J=14.8, 8.8 Hz, 1H),
2.17–2.05 (m, 2H), 1.78–1.72 (m, 1H), 1.51–1.44 (m, 1H), 1.32 (s, 3H),
1.25 (s, 3H), 1.14 (s, 3H), 1.12 (s, 9H); 13C NMR (100 MHz, CDCl3): d =
214.9, 153.6, 135.7, 134.2, 133.6, 129.6, 129.5, 127.5, 127.3, 119.8, 81.8,
48.4, 47.1, 37.7, 35.1, 33.5, 28.1, 27.1, 23.7, 19.5, 18.2; IR (film): nmax
=
3070, 2964, 2931, 2857, 1714, 1460, 1427, 1112, 1039, 820, 702 cmꢀ1
;
HRMS: m/z: calcd for C28H36O2Si: 455.2383, found: 455.2368 [M+Na]+.
Alcohol 17: Ketone 16 (49 g, 113 mmol) was dissolved in methanol
(250 mL) and cooled to 08C. Sodium borohydride (1.5 g, 37.6 mmol) was
added in four portions. The reaction was stirred at 08C for 20 min then
diluted with Et2O followed by careful addition of aqueous saturated am-
monium chloride (350 mL). The aqueous phase was extracted with Et2O
(3”200 mL), dried over magnesium sulfate, filtered and concentrated on
the rotary evaporator to yield analytically pure alcohol (48 g, 98%). Rf =
0.3 (50% Et2O in hexanes); [a]2D5 = ꢀ31.9 (c=1.6, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d = 7.68–7.66 (m, 4H), 7.42–7.36 (m, 6H), 5.18 (dd,
J=3.2, 1.2 Hz, 1H), 3.82 (dd, J=9.2, 7.2 Hz, 1H), 3.16 (dd, J=11.6,
3.6 Hz, 1H), 2.17 (dd, J=14.4, 8.8 Hz, 1H), 1.96 (dd, J=14.8, 7.2 Hz,
1H), 1.77–1.68 (m, 2H), 1.63–1.57 (m, 1H), 1.20 (s, 3H), 1.07 (s, 9H),
1.06 (s, 3H), 1.06–1.02 (m, 1H), 1.02 (s, 3H); 13C NMR (100 MHz,
CDCl3): d = 155.4, 136.0, 135.9, 134.7, 134.0, 129.6, 129.5, 127.5, 127.4,
118.6, 84.3, 47.4, 39.4, 37.9, 37.0, 27.8, 27.0, 25.5, 21.5, 19.4, 17.9; IR
(film): nmax = 3393, 3069, 3050, 2962, 2932, 2856, 1468, 1427, 1112, 1037,
820, 702 cmꢀ1; HRMS: calcd for C28H38O2Si: 457.2540, found: 457.2561
[M+Na]+.
Enone 13: Enone 13 was prepared as described in ref. [19b]. [a]2D5 = +
285.1 (c=2.1, CH2Cl2); 1H NMR (400 MHz, CDCl3): d = 2.94–2.71 (m,
3H), 2.59–2.35 (m, 3H), 2.05 (dd, J=13.6, 5.2 Hz, 1H), 1.82 (dt, J=13.6,
6.0 Hz, 1H), 1.76 (s, 3H), 1.27 (s, 3H); 13C NMR (100 MHz, CDCl3): d =
217.2, 197.5, 162.2, 129.6, 48.9, 35.5, 32.8, 28.9, 24.6, 21.3, 10.9.
Alcohol 14: Sodium borohydride (5.4 g, 135 mmol) was added, in four
portions to enone 13 (48 g, 263 mmol) in methanol (125 mL) cooled to
08C, and the reaction was stirred for 30 min. The reaction was quenched
by
a dropwise addition of saturated aqueous ammonium chloride
Xanthate 18:
A solution of alcohol 17 (8.68 g, 20 mmol) in THF
(500 mL). The mixture was extracted with Et2O (3”200 mL). The com-
bined organic layers were dried over magnesium sulfate, filtered and con-
centrated under vacuum to afford analytically pure alcohol 14 (47 g,
97%). Rf =0.2 (100% Et2O); [a]2D5 = +55.2 (c=1.3, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d = 3.82 (dd, J=10.4, 7.6 Hz, 1H), 2.59–2.51 (m,
2H), 2.44–2.37 (m, 2H), 2.15–2.03 (m, 2H), 1.85–1.75 (m, 2H), 1.64 (s,
3H), 1.10 (s, 3H); 13C NMR (100 MHz, CDCl3): d = 198.8, 167.8, 129.0,
81.0, 45.0, 33.9, 33.3, 29.5, 25.6, 15.2, 10.7; IR (film): nmax = 3411, 2925,
1642, 1448, 1418, 1376, 1330, 1099, 1022 cmꢀ1; HRMS: m/z: calcd for
C11H16O2: 203.1049, found: 203.1051 [M+Na]+.
(200 mL) under an argon atmosphere was cooled to 08C by means of an
ice bath. n-Butyllithium (16 mL, 40 mmol, 2.5m in hexanes) was added
dropwise and the solution was stirred for 45 min at 08C followed by the
slow addition of carbon disulfide (4.6 mL, 100 mmol). The solution was
stirred for 90 min and iodomethane (7 mL, 120 mmol) was slowly added
to the reaction mixture and stirring was continued for an additional
90 min at 08C. The reaction was diluted with Et2O and quenched with sa-
turated ammonium chloride. The aqueous phase was extracted with Et2O
(3”100 mL), dried over magnesium sulfate and concentrated on the
rotary evaporator. The residue was purified by silica gel chromatography
(5% Et2O in hexanes) to yield xanthate 18 (10.1 g, 95%), as an orange
oil. Rf =0.9 (100% hexanes); [a]2D5 = ꢀ15.4 (c=3.50, CHCl3); 1H NMR
Enone 15: Imidazole (18.4 g, 270 mmol), DMAP (3.3 g, 27 mmol) and
TBDPS chloride (72.6 g, 265 mmol) were added sequentially to a solution
of alcohol 14 (47 g, 261 mmol) in anhydrous DMF (200 mL) cooled to
08C. The ice bath was removed and the mixture was stirred at 358C for
12 h under an argon atmosphere. The mixture was diluted with Et2O
(250 mL) and water (300 mL). The aqueous phase was extracted with
Et2O (3”300 mL) and the combined organic phases were dried over
magnesium sulfate. The solvent was concentrated on the rotary evapora-
tor and the residue was purified using silica gel chromatography (5%
Et2O in hexanes) to yield protected alcohol 15 (84 g, 77%). Rf =0.7
(400 MHz, CDCl3): d
= 7.68–7.65 (m, 4H), 7.40–7.38 (m, 6H), 5.24
ꢀ5.20 (m, 2H), 3.87 (dd, J=9.2, 7.6 Hz, 1H), 2.54 (s, 3H), 2.17 (dd, J=
14.8, 9.2 Hz, 1H), 1.96 (dd, J=15.2, 7.6 Hz, 1H), 1.91–1.84 (m, 2H), 1.77
(dt, J=13.2, 3.2 Hz, 1H), 1.26 (s, 3H), 1.20 (s, 3H), 1.20–1.09 (m, 1H),
1.08 (s, 9H), 1.02 (s, 3H); 13C NMR (100 MHz, CDCl3): d = 154.0, 135.9,
135.8, 134.6, 133.8, 129.7, 129.5, 127.6, 127.4, 119.6, 89.4, 84.1, 47.3, 39.3,
37.8, 36.4, 27.0, 25.5, 23.6, 23.3, 19.4, 18.7, 18.0; IR (film): nmax = 3070,
2964, 2931, 2856, 1233, 1215, 1112, 1063, 1041 cmꢀ1; HRMS: m/z: calcd
for C30H40O2S2Si: 547.2137, found 547.2119 [M+Na]+.
(40% Et2O in hexanes); [a]D25
(400 MHz, CDCl3): d = 7.72–7.66 (m, 4H), 7.40–7.38 (m, 6H), 3.74 (dd,
J=7.2, 10.4 Hz, 1H), 2.58–2.19 (m, 6H), 1.97 (ddd, J=1.6, 5.2, 12.8 Hz,
1H), 1.91–1.69 (m, 3H), 1.57 (s, 3H), 1.46 (dt, J=5.2, 14 Hz, 1H), 1.08 (s,
=
ꢀ40.2 (c=2.77, CH2Cl2); 1H NMR
Alkene 19: Tributyl tin hydride (17.5 g, 60 mL) and AIBN (0.5 g,
3 mmol) was added to a solution of xanthate 18 (10.1 g, 19 mmol) in tolu-
ene (100 mL). The mixture was rapidly brought to reflux by immersing
Chem. Eur. J. 2005, 11, 7175 – 7190
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7181

E. A. Theodorakis et al.
into a silicon oil bath preheated to 1508C and heated under reflux for
20 min. The reaction was cooled to room temperature and the solvent re-
moved on the rotary evaporator. The residue was purified by silica gel
chromatography (100% hexanes) to yield 19 (6.6 g, 86%) as a clear oil.
1H NMR (400 MHz, CDCl3): d = 7.82 (dd, J=7.6, 2.0 Hz, 4H), 7.53–7.44
(m, 6H), 5.21 (dd, J=3.2, 1.6 Hz, 1H), 3.99 (dd, J=9.2, 8.0 Hz, 1H), 2.25
(dd, J=14.8, 9.2 Hz, 1H), 2.04 (dd, J=14.4, 7.2 Hz, 1H), 1.91–1.87 (m,
1H), 1.82 (dt, J=13.6, 3.6 Hz, 1H), 1.57–1.46 (m, 2H), 1.33 (s, 3H), 1.22
(s, 9H), 1.22–1.12 (m, 1H), 1.18 (s, 3H), 1.10 (s, 3H), 1.06–0.98 (m, 1H);
13C NMR (100 MHz, CDCl3): d = 155.8, 135.9, 135.8, 134.7, 134.0, 129.4,
129.3, 127.3 (2), 116.1, 84.6, 47.6, 40.6, 39.7, 36.9, 34.0, 30.5, 28.8, 27.2,
19.6, 19.3, 18.1; HRMS: m/z: calcd for C28H38OSi: 441.2590, found
441.2568 [M+Na]+.
aqueous phase was extracted with Et2O (3”100 mL), dried over magnesi-
um sulfate and concentrated on the rotary evaporator. The residue was
purified by silica gel chromatography (5% Et2O in hexanes) to yield silyl
ether 22 (22.1 g, 100%) as an orange oil. Rf =0.9 (100% hexanes); [a]D25
=
+4.6 (c=1.10, CH2Cl2); 1H NMR (400 MHz, CDCl3): d = 7.73–7.70
(m, 4H), 7.47–7.38 (m, 6H), 3.58 (t, J=7.6 Hz, 1H), 1.75–1.33 (m, 8H),
1.12 (s, 9H), 1.00 (s, 3H), 0.99–0.85 (m, 2H), 0.89 (s, 3H), 0.78 (s, 3H),
0.77–0.70 (m, 1H); 13C NMR (100 MHz, CDCl3): d = 135.9, 135.8, 134.8,
134.2, 129.3, 129.2, 127.2 (2), 83.0, 52.3, 43.6, 41.7, 37.8, 33.1, 32.7, 29.9,
27.2, 20.8, 20.4, 19.7, 19.5, 12.5; IR (film): nmax = 3070, 2954, 2928, 2859,
1111, 702 cmꢀ1
; HRMS: m/z: calcd for C28H40OSi: 443.2746, found
443.2761 [M+Na]+.
Alcohol 23: Compound 22 (15 g, 35.7 mmol) was dissolved in THF
(100 mL) at 258C and treated with TBAF (100 mL, 100 mmol, 1m in
THF). The mixture was stirred for 8 h, concentrated on the rotary evapo-
rator and purified by silica gel chromatography to afford alcohol 23
Alcohol 20: Alkene 19 (21 g, 50 mmol) was dissolved in anhydrous THF
(250 mL). The solution was cooled to 08C and borane/dimethyl sulfide
complex (6 mL, 60 mmol, 10m in THF) was added and the ice bath re-
moved. The solution was stirred for 5 h at which time the temperature
was increased to 308C and the reaction was stirred for 12 h. The reaction
was cooled to 08C and treated with a mixture of 30% aqueous H2O2/3m
NaOH solution (1 L, 1:1), slowly added maintaining the reaction temper-
ature below 358C. The solution was removed from the ice bath and stir-
red for 6 h at 258C. The reaction was judged complete by the disappear-
ance of the borane adduct (by TLC analysis) and the formation of com-
pound 20 (Rf =0.65, 50% Et2O in hexanes) together with the cis-fused
isomer (Rf =0.70, 50% Et2O in hexanes). The reaction was quenched by
the careful addition of saturated sodium thiosulfate at 08C, maintaining
the internal temperature below 308C. The solution was stirred for 12 h
after which time it was diluted with Et2O and the aqueous phase was ex-
tracted with Et2O (3”100 mL). The combined organic phases were
washed with brine, dried over magnesium sulfate and concentrated to
give an oily residue that was purified using silica gel chromatography
(100% hexanes ! 50% Et2O in hexanes) to yield the cis isomer (4.4 g)
and 20 (12.7 g, 78%, 2.28:1 trans/cis). Rf =0.65 (50% Et2O in hexanes);
(6.4 g, 99%). Rf =0.3 (50% Et2O in hexanes); [a]D25
= +11.8 (c=6,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d = 3.53 (m, 1H), 2.01 (m, 1H),
1.71–1.30 (m, 6H), 1.06–0.87 (m, 3H), 0.87 (s, 3H), 0.82 (s, 3H), 0.81 (s,
3H); 13C NMR (100 MHz, CDCl3): d = 82.5, 53.1, 42.7, 41.6, 37.3, 33.0,
32.7, 29.4, 20.7, 20.1, 19.5, 11.7; IR (film): nmax = 3044, 2923, 2867, 2844,
1459, 1383, 1104, 1064, 1020, 702 cmꢀ1
; HRMS: m/z: calcd for
C12H22ONa: 205.1568, found 205.1572 [M+Na]+.
Ketone 10: Alcohol 23 (6.4 g, 35.1 mmol) was dissolved in CH2Cl2
(200 mL). Celite (20 g) followed by PCC (19.7 g, 93 mmol) were added
and the heterogeneous mixture was stirred for 12 h at 258C. The reaction
mixture was filtered through Celite and concentrated to a residue on the
rotary evaporator. The residue was purified by silica gel chromatography
(5% Et2O in hexanes) to afford ketone 10 (5.8 g, 92%). Rf =0.6 (50%
Et2O in hexanes); [a]D25
=
+107.0 (c=3.80, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d = 2.40 (dd, J=19.2, 8.8 Hz, 1H), 2.09–1.99 (m,
1H), 1.91–1.84 (m, 1H), 1.73–1.56 (m, 4H), 1.47 (dt, J=13.6, 3.2 Hz,
1H), 1.30–1.03 (m, 3H), 0.94 (s, 3H), 0.92 (s, 6H); 13C NMR (100 MHz,
CDCl3): d = 221.3, 54.1, 48.1, 41.3, 35.4, 34.0, 32.4, 32.1, 21.5, 19.2, 19.1,
15.8; IR (film): nmax = 1739, 1474, 1459, 1369, 1120, 1020 cmꢀ1; HRMS:
m/z: calcd for C12H20ONa: 203.1412, found 203.1431 [M+Na]+.
1
[a]2D5 = +26.3 (c=2.52, CHCl3); H NMR (400 MHz, CDCl3): d = 7.72–
7.69 (m, 4H), 7.47–7.38 (m, 6H), 4.21 (dt, J=10.0, 3.2 Hz, 1H), 3.83 (t,
J=8.8 Hz, 1H), 2.06 (dt, J=14.0, 9.2 Hz, 1H), 1.69–1.16 (m, 6H), 1.12 (s,
9H), 1.01 (s, 3H), 1.00 (s, 3H), 0.99 (s, 3H), 0.92 (d, J=10.0 Hz, 1H),
0.79 (dt, J=12.8, 3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d = 135.8,
135.7, 134.0, 129.6, 129.5, 127.4, 80.1, 70.6, 45.4, 42.3, 42.0, 38.0, 33.9, 33.2,
27.1, 21.8, 19.5, 19.4, 14.3; IR (film): nmax = 3390, 3071, 3049, 2928, 2858,
Hydrazone 24: Ketone 10 (503 mg, 2.7 mmol) was dissolved in ethanol
(10 mL) and treated with hydrazine monohydrate (4.2 mL, 86.5 mmol)
and triethylamine (2.2 mL, 15.8 mmol). The reaction was stirred at reflux
for 12 h. The reaction was cooled to 258C and the solvent removed
under vacuum. The residue was taken up in ethyl acetate and was
washed with water to neutrality, the combined organic phases were dried
1112, 703 cmꢀ1
; HRMS: m/z: calcd for C28H40O2Si: 459.2695, found
459.2701 [M+Na]+.
1
over sodium sulfate and concentrated on the rotary evaporator. H NMR
Xanthate 21: A solution of alcohol 20 (18 g, 41 mmol) in THF (350 mL)
under an argon atmosphere was cooled to 08C and treated with n-butyl-
lithium (34 mL, 85 mmol, 2.5m in hexanes), added dropwise over 45 min,
followed by a slow addition of carbon disulfide (15.2 g, 200 mmol). After
stirring for 90 min, iodomethane (19 mL, 300 mmol) was slowly added
and the reaction was stirred for an additional 90 min at 08C. The reaction
was diluted with Et2O and quenched with saturated ammonium chloride.
The aqueous phase was extracted with Et2O (3”100 mL), dried over
magnesium sulfate and concentrated on the rotary evaporator. The resi-
due was purified by silica gel chromatography (5% Et2O in hexanes) to
yield xanthate 21 (22.1 g, 100%) as an orange oil. Rf =0.3 (50% Et2O in
hexanes); [a]2D5 = +9.4 (c=1.9, CH2Cl2); 1H NMR (400 MHz, CDCl3): d
= 7.68–7.62 (m, 4H), 7.46–7.35 (m, 6H), 5.81 (dt, J=9.6, 2.8 Hz, 1H),
3.76 (t, J=8.8 Hz, 1H), 2.49 (s, 3H), 2.23 (dt, J=14.4, 9.2 Hz, 1H), 1.63–
1.51 (m, 4H), 1.44–1.36 (m, 3H), 1.07 (s, 9H), 1.03 (s, 3H), 0.95 (s, 3H),
0.81 (s, 3H), 0.74–0.68 (m, 1H); 13C NMR (100 MHz, CDCl3): d = 135.8,
135.7, 134.1, 133.7, 129.5, 127.4, 82.8, 80.1, 56.2, 44.8, 41.7, 38.7, 37.8, 33.3,
33.0, 27.1, 21.9, 19.5, 19.4, 19.0; IR (film): nmax = 3070, 2954, 2927, 2857,
(400 MHz, CDCl3): d = 4.65 (brs, 2H), 2.21–2.02 (m, 2H), 1.77–1.70 (m,
2H), 1.59–1.37 (m, 4H), 1.22–1.01 (m, 3H), 0.88 (s, 3H), 0.83 (s, 6H).
This compound was recrystallized from ethanol/H2O and the structure
was confirmed by X-ray analysis.
Vilyl iodide 25: Crude hydrazone 24 (524 mg, 2.7 mmol) was dissolved in
Et2O (100 mL) and treated with DBU (4.1 g, 27 mmol). Iodine, dissolved
in Et2O, was added dropwise to the stirring solution until a light brown
color persists (observed nitrogen evolution). Excess saturated sodium thi-
osulfate was added and the mixture was stirred vigorously for 10 min.
The aqueous phase was extracted with Et2O (3”50 mL) and washed with
brine. The organic phases were collected, dried over sodium sulfate, and
the solvent removed on the rotary evaporator. The residue was purified
on silica gel with 100% hexane to yield vinyl iodide 25 (510 mg, 62%).
Rf =0.9 (100% hexanes); [a]D25
=
ꢀ5.93 (c=4.85, CH2Cl2); 1H NMR
(400 MHz, C6D6): d = 5.97 (t, J=2.4 Hz, 1H), 1.83–1.73 (m, 2H), 1.53–
1.39 (m, 4H), 1.28–1.24 (m, 2H), 1.09–1.02 (m, 1H), 0.94–0.87 (m, 2H),
0.79 (s, 3H), 0.77 (s, 3H), 0.75 (s, 3H); 13C NMR (100 MHz, C6D6): d =
137.1, 114.4, 58.0, 50.5, 41.5, 37.3, 33.2, 32.6, 31.3, 21.4, 20.3, 17.4; IR
1461, 1233, 1201, 1113, 1052, 702 cmꢀ1
; HRMS: m/z: calcd for
C30H42O2S2Si: 549.2293, found 549.2289 [M+Na]+.
(film): nmax
HRMS: m/z: calcd for C12H19I: 291.0569, found 291.0551 [M+H]+.
= ;
2997, 2928, 2863, 1457, 1373, 987, 847, 803, 680 cmꢀ1
Silyl ether 22: Xanthate 21 (22 g, 41 mmol) was dissolved in toluene
(175 mL). Tributyl tin hydride (35 g, 120 mmol) and AIBN (0.7 g,
4 mmol) were added and the mixture was rapidly brought to reflux by
immersing it in a pre-heated silicon oil bath and reflux continued for
20 min. The reaction was cooled to room temperature and diluted with
Et2O and quenched with saturated aqueous ammonium chloride. The
Acetonide 27: Iodine (14.21 g, 0.056 mol) was added to a suspension of
d-mannose (26) (50 g, 0.28 mol) in acetone (2.5 L) and the mixture was
stirred for 2 h at 258C. The reaction mixture was quenched at 08C with
sodium thiosulfate and sodium bicarbonate and the organic residues ex-
tracted with chloroform. After washing with sodium bicarbonate (3”
7182
www.chemeurj.org
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 7175 – 7190

Norrisolide
FULL PAPER
200 mL), the organic layer was dried over MgSO4, concentrated and re-
crystallized from acetone/hexane to produce 27 (60 g, 0.24 mol, 85%) as
a colorless solid. Rf =0.33 (silica gel, 50% Et2O in hexanes); 1H NMR
(400 MHz, CDCl3): d = 5.38 (d, J=2.4 Hz, 1H), 4.81 (dd, J=3.6, 6 Hz,
1H), 4.62 (d, J=6.0 Hz, 1H), 4.40 (m, 1H), 4.18 (dd, J=3.6, 7.2 Hz, 1H),
4.06 (m, 2H), 2.57 (brs, 1H), 1.46 (s, 3H), 1.45 (s, 3H), 1.38 (s, 3H), 1.32
(s, 3H); 13C NMR (100 MHz, CDCl3): d = 112.4, 108.9, 100.9, 85.3, 79.9,
79.5, 73.2, 66.3, 26.7, 25.8, 25.1, 24.4.
3H), 1.36 (s, 3H), 1.24 (t, J=6.8, 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d = 170.6, 137.5, 128.2, 127.6, 127.5, 108.6, 81.9, 78.8, 72.7, 72.1,
66.5, 64.9, 60.7, 28.5, 26.7, 25.4, 21.4, 14.3; IR (film): nmax = 2984, 2935,
1715, 1268, 1187, 1097 cmꢀ1
; HRMS: m/z: calcd for C20H26O6Na:
385.1627, found 385.1623 [M+Na]+.
Diol 32: A solution of cyclopropyl ester 31 (2.5 g, 6.90 mmol) in EtOH
(75 mL) was treated with sulfuric acid (1.0 mL) and the reaction was stir-
red vigorously for 24 h. The reaction was quenched with triethylamine
and concentrated under reduced pressure. The mixture was taken up
again in ethyl acetate and washed with brine (1”100 mL). The com-
pound was dried over magnesium sulfate, filtered and concentrated in
vacuo. Silica gel column chromatography (0–60% ethyl acetate in hex-
anes) yielded diol 32 (1.98 g, 78%, 5.78 mmol) as a clear foam. Rf =0.2
(80% Et2O in hexanes); 1H NMR (CDCl3, 400 MHz): d = 7.30–7.25 (m,
5H), 4.78 (d, J=5.6 Hz, 1H), 4.55 (d, J=5.6 Hz, 1H), 4.38 (d, J=3.4 Hz,
1H), 4.25 (d, J=3.6 Hz, 1H), 4.22–4.12 (m, 5H), 3.91 (brs, 1H), 3.88–
3.58 (m, 6H), 2.8 (brs, 1H), 2.38 (m, 1H), 1.85 (m, 1H), 1.26–1.18 (m,
6H); 13C NMR (CDCl3, 100 MHz): d = 171.01, 138.30, 128.07, 127.76,
127.35, 125.45, 108.84, 87.32, 80.15, 79.15, 71.15, 69.78, 64.52, 62.15, 60.71,
28.85, 22.15, 19.05, 16.17.
Chloride 28: A solution of compound 27 (20 g, 0.077mol) in dry methyl-
ene chloride (200 mL) was treated sequentially with DMAP (5.64 g,
0.046 mol), tosyl chloride (16.32 g, 0.092 mol) and triethylamine
(10.7 mL, 0.077 mol). The reaction mixture was stirred at 258C until TLC
showed completion of reaction (approx. 2 h) at which time the solution
was washed with aqueous copper sulfate, sodium bicarbonate and ex-
tracted with Et2O. The organic layer was extracted with sodium chloride
(3”200 mL), dried over MgSO4, concentrated and purified by chroma-
tography (silica gel, 10–50% Et2O in hexanes) to afford 10 (13.5 g,
46.2 mmol, 60%) as a viscous, amber-colored oil. Rf =0.80 (50% Et2O in
hexanes); 1H NMR (400 MHz, CDCl3): d = 6.07 (s, 1H), 4.96 (d, J=
5.6 Hz, 1H), 4.89 (m, 1H), 4.44 (m, 1H), 4.21 (dd, J=3.6, 11.2 Hz, 1H),
4.10 (dd, J=6.0, 8.8 Hz, 1H), 4.02 (dd, J=4.4, 8.8 Hz, 1H), 1.47 (s, 3H),
1.46 (s, 3H), 1.39 (s, 3H), 1.33 (s, 3H); 13C NMR (100 MHz, CDCl3): d =
113.2, 109.4, 97.5, 89.1, 82.3, 78.5, 72.3, 66.7, 27.0, 25.9, 25.2, 24.7.
Ketone 34: A solution of diol 32 (0.126 g, 0.33 mmol) in 1:1 mixture of
THF and water (5 mL each) was treated at 258C with sodium periodate
(0.211 g, 0.989 mmol) for 30 min. The reaction turned cloudy after some
time and was quenched, when TLC showed completion of reaction, with
sodium thiosulfate and sodium bicarbonate. The reaction was extracted
with ethyl acetate (3”30 mL), dried over magnesium sulfate and concen-
trated under reduced pressure and dried under high vacuum. The residue
was treated with THF (5 mL) and MeTi(OiPr)3 (5 mL, 5 mmol, 0.5m) at
08C. The reaction was brought up to 258C after 30 min and stirred for
another 3 h. Afterwards, the reaction was quenched with aqueous ammo-
nium chloride, extracted with ethyl acetate (3”30 mL) and dried with
magnesium sulfate. After concentration, the compound (0.080 g,
0.31 mmol) was run through a quick silica gel column and subjected to
Dess–Martin periodinane oxidation conditions. The reaction took 1 h to
go to completion at which time it was quenched with sodium thiosulate
and sodium bicarbonate. After extraction with ethyl acetate (3”25 mL)
the organic solution was dried over magnesium sulfate and concentrated
in vacuo. Column chromatography gave 33 (0.060 g, 0.165 mmol) as a
light yellow oil that was subjected to the next step. A solution of ester 33
(0.929 g, 2.64 mmol) in dry CH2Cl2 (90 mL) was cooled to ꢀ208C and
treated under argon with methanesulfonic acid (1 mL, 6 equiv) added
dropwise via syringe. The temperature of the reaction mixture was al-
lowed to rise to ꢀ58C where it was stirred for 6 h. During this time the
reaction mixture changed from a light yellow to a dark brown color. At
the end of 6 h, the dry-ice bath was exchanged for an ice-water bath and
allowed to stir for another 6 h. Upon completion of the reaction (TLC
test, the cyclized product is distinctly more polar than the starting materi-
al) the reaction was quenched with a mixture of triethylamine and
sodium bicarbonate and extracted with Et2O. The organic layer was
washed with sodium bicarbonate (3”50 mL), dried over MgSO4 and con-
centrated. The resulting crude solid was purified by chromatography
(silica gel, 30–80% Et2O in hexanes) to afford ketone 34 (0.491 g,
1.76 mmol, 67%) as a light yellow solid. Rf =0.40 (80% Et2O in hex-
anes); [a]2D5 = ꢀ53.5 (c=0.85, CH2Cl2); 1H NMR (400 MHz, CDCl3): d
= 7.34 (t, J=7.2, 10 Hz, 3H), 7.23 (d, J=6.4 Hz, 2H), 6.33 (d, J=5.6 Hz,
1H), 4.54 (m, 2H), 4.46 (d, J=11.6 Hz, 1H), 4.15 (d, J=4 Hz, 1H), 3.23
(q, J=5.6, 6.0 Hz, 1H), 2.84 (dd, J=19.2, 11.6 Hz, 1H), 2.33 (dd, J=5.2,
Benzyl ether 30: Napthalene (4.8 g, 37.5 mmol) was dissolved in THF
(200 mL) under an argon atmosphere. Sodium (2.9 g, 125 mmol) was
added over a period of 45 min and the solution was stirred at ambient
temperature until a deep green color was observed. Chloride 28 (3.5 g,
12.5 mmol) dissolved in THF (100 mL) was added to the naphthalene/
sodium mixture over a period of 4 h, taking care that the green color per-
sisted through the entire addition. The reaction was judged complete by
consumption of the starting material (TLC) and the solution was careful-
ly filtered through a plug of Celite. The solution was diluted with Et2O
(300 mL) and washed with water (300 mL) and by brine (300 mL). The
organic phase was dried over magnesium sulfate and the solvent was re-
moved on the rotary evaporator. The residue was purified by flash chro-
matography (Rf =0.3; 70% Et2O in hexanes) and the semi pure glycal 29
was taken to the next step directly. A solution of glycal 29 (2.0 g,
10 mmol) in THF (5 mL) at 08C was treated under argon with sodium
hydride (283 mg, 12 mmol), benzyl bromide (2.02 g, 12 mmol), and tetra-
butyl ammonium iodide (0.198 g, 0.54 mmol). The reaction mixture was
allowed to warm up to 258C and stirred for 2 h at which time the TLC
showed disappearance of the starting material. The reaction was
quenched with brine and extracted with Et2O. The organic layer was
washed with brine (3”50 mL), dried over MgSO4, and concentrated. The
residue was purified by flash chromatography (silica gel, 5–30% Et2O in
hexanes) to produce compound 30 (2.5 g, 9 mmol, 90%) as a viscous,
bright-yellow oil. Rf =0.65 (30% Et2O in hexanes); [a]2D5 = ꢀ103.4 (c=
1
1.0, CH2Cl2); H NMR (400 MHz, CDCl3): d = 7.32 (m, 5H), 6.62 (d, J=
2.4 Hz, 1H), 5.29 (t, J=2.8 Hz, 1H), 4.66 (m, 1H), 4.55 (m, 3H), 4.44
(dd, J=4.4, 5.2 Hz, 1H), 4.12 (m, 1H), 3.99 (m, 1H), 1.47 (s, 3H), 1.40 (s,
3H); 13C NMR (100 MHz, CDCl3): d = 150.3, 138.2, 128.1, 127.4, 127.3,
108.5, 101.7, 83.9, 79.1, 73.0, 70.9, 65.9, 26.6, 25.3; IR (film): nmax = 2978,
2925, 1606, 1064.
Cyclopropyl ester 31: Benzyl ether 30 (7.75 g, 0.028 mol) was dissolved in
CH2Cl2 (30 mL) and a catalytic amount of rhodium acetate (0.023 g,
0.01 equiv) was added to give a blue-green colored solution. As the solu-
tion was being stirred, ethyl diazoacetate (3.52 g, 0.031 mol), dissolved in
CH2Cl2 (40 mL) was added via syringe pump over a period of 14 h. The
reaction was carried out at 258C and open to the atmosphere. After the
completion of addition, the mixture was allowed to stir for another 3 h
and then concentrated to reveal a blue, viscous oil. After silica gel sepa-
ration the two isomeric cyclopropyl esters (3.7 g, 0.013 mmol, 45%) (4:1
ratio at the C13 center) were isolated together and were taken forward
to the remaining steps. Major isomer: Rf =0.75 (50% Et2O in hexanes);
[a]2D5 = ꢀ4.95 (c=0.93, CH2Cl2); 1H NMR (400 MHz, CDCl3): d = 7.35
(m, 5H), 4.71 (d, J=11.6 Hz, 1H), 4.59 (d, J=12 Hz, 1H), 4.35 (m, 2H),
4.18 (d, J=4.8 Hz, 1H), 4.07 (m, 3H), 3.95 (dd, J=6.0, 8.4 Hz, 1H), 3.68
(m, 1H), 2.34 (t, J=4.4, 4.8 Hz, 1H), 1.89 (d, J=2.8 Hz, 1H), 1.40 (s,
18.8 Hz, 1H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3): d
= 204.8,
173.5, 136.2, 128.5, 128.2, 127.6, 107.4, 85.4, 85.1, 72.2, 44.3, 31.1, 28.4; IR
(film): nmax = 3634, 3528, 2918, 2861, 1780, 1731 cmꢀ1; HRMS: m/z: calcd
for C15H16O5Cs: 409.0049, found: 409.0055 [M+Cs]+.
Lactone 35: A suspension of urea/30% hydrogen peroxide (0.447 g,
4.75 mmol) in dry CH2Cl2 (20 mL) was cooled to 08C and treated with
trifluoroacetic anhydride (0.336 mL, 2.38 mmol) added dropwise over a
5-min period. The reaction mixture was brought up to 258C, allowed to
stir for 30 min and added via cannula to a solution of ketone 34 (0.164 g,
0.594 mmol) in dry CH2Cl2 (5 mL). After stirring at 258C for 2 h (com-
pletion by TLC), the reaction was quenched with sodium thiosulfate and
Chem. Eur. J. 2005, 11, 7175 – 7190
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7183

E. A. Theodorakis et al.
sodium bicarbonate at 08C and stirred for 0.5 h. The organic layer was di-
luted with Et2O and washed with sodium bicarbonate (3”20 mL). The
organic layer was collected, dried over MgSO4, concentrated and purified
(silica gel, 20–60% Et2O in hexanes) to afford compound 35 (0.12 g,
69%) as a white powdery solid. Rf =0.30 (70% Et2O in hexanes); [a]D25
(100 MHz, CDCl3): d = 154.0, 135.5, 135.4, 132.7, 132.4, 129.9, 127.8,
122.6, 83.2, 63.2, 26.6, 19.1.
Lactone 40: Copper bromide/dimethyl sulfide complex (3.5 g, 10.2 mmol)
was dissolved in THF (20 mL) under an argon atmosphere and cooled to
ꢀ788C (dry ice/acetone). Vinylmagnesium bromide (11 mL, 11 mmol, 1m
in THF) was added via syringe and the solution was stirred at ꢀ788C for
15 min. Butenolide 39 (2.9 g, 8.2 mmol) dissolved in THF (20 mL) was
added to the stirring solution via syringe. When the addition was com-
plete the dry ice bath was replaced with an ice water bath and the solu-
tion was stirred for 1 h. The solution was diluted with Et2O (75 mL) and
saturated aqueous ammonium chloride (150 mL). The aqueous phase was
extracted with Et2O (3”75 mL). The combined organic phases were
dried over magnesium sulfate and concentrated on the rotary evaporator.
The residue was purified on silica gel (40% Et2O in hexanes) to afford
1
= +68.1 (c=0.7, CH2Cl2); H NMR (400 MHz, CDCl3): d = 7.35 (t, J=
7.2, 9.2 Hz, 3H), 7.30 (d, J=7.6 Hz, 2H), 6.45 (d, J=4.0 Hz, 1H), 6.04
(d, J=6.0 Hz, 1H), 4.63 (d, J=11.6 Hz, 1H), 4.49 (d, J=11.6 Hz, 1H),
3.88 (qr, J=4 Hz, 1H), 3.10 (m, 1H), 2.79 (dd, J=9.2, 18.8 Hz, 1H), 2.48
(dd, J=1.6, 18.8 Hz, 1H), 2.12 (s, 3H); 13C NMR (100 MHz, CDCl3): d =
172.7, 169.2, 136.5, 128.6, 128.4, 127.8, 105.3, 95.1, 81.9, 73.5, 41.7, 33.2,
21.1; IR (film): nmax = 2919, 2854, 1788, 1745, 1374, 1235, 1138 cmꢀ1
;
HRMS: m/z: calcd for C15H16O6Na: 315.0845, found: 315.0859 [M+Na]+.
Lactone 36: 10% methanesulfonic acid solution (1.0 mL) in acetone at
258C was added to a solution of the cyclopropyl ester 31 (0.44 mmol) in
acetone (1 mL). The reaction mixture was stirred overnight, quenched by
triethylamine (0.26 mL) in an ice bath and then stirred for 30 min. The
solution was concentrated in vacuo and purified by column chromatogra-
phy (20 ! 60% Et2O in petroleum ether) to give the g-lactone 36 as a
(3.5 g, 85%). Rf =0.4 (50% Et2O in hexanes); [a]D25
= +38.3 (c=2.3,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d = 7.69–7.66 (m, 4H), 7.24–7.37
(m, 6H), 5.76 (m, 1H), 5.14 (s, 1H), 5.09 (d, J=17.6 Hz, 1H), 4.26 (m,
J=3.2 Hz, 1H), 3.93 (dd, J=2.8, 11.6 Hz, 1H), 3.73 (dd, J=3.2, 11.6 Hz,
1H), 3.21 (m, J=7.6 Hz, 1H), 2.83 (dd, J=9.2, 17.6 Hz, 1H), 2.45 (dd,
J=8.4, 17.6 Hz, 1H), 1.07 (s, 9H); 13C NMR (100 MHz, CDCl3): d =
175.9, 136.4, 135.6, 135.5, 132.9, 132.5, 129.9, 127.8, 117.4, 84.5, 63.3, 40.7,
35.0, 26.7, 19.2; HRMS: m/z: calcd for C23H28O3SiNa: 403.1706, found:
403.1729 [M+Na]+.
white powdery solid. [a]D25
=
ꢀ21.7 (c=1.68, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d = 7.37–7.31 (m, 5H), 6.16 (d, J=5.6 Hz, 1H), 4.63
(d, J=1.6 Hz, 2H), 4.43 (q, J=7.6 Hz, 1H), 4.14 (dd, J=8.8, 6.0 Hz, 1H),
4.02–3.99 (m, 2H), 3.91 (d, J=2.8 Hz, 1H), 3.22–3.19 (m, 1H), 2.84 (dd,
J=18.8, 11.6 Hz, 1H), 2.35 (dd, J=18.8, 5.2 Hz, 1H), 1.42 (s, 3H), 1.38
Alkene 41: Lactone 40 (2.2 g, 5.8 mmol) was dissolved in CH2Cl2 (75 mL)
and cooled to ꢀ788C (dry ice/acetone). DIBAL (5.9 mL, 5.9 mmol, 1m in
CH2Cl2), was added dropwise over 5 min, and the solution was stirred for
30 min. Methanol (10 mL) was added and the dry ice bath was removed.
Stirring was continued as the reaction warmed to 258C (30 min). Saturat-
ed aqueous ammonium chloride (100 mL) was added and the mixture
was stirred for an additional 30 min then filtered through Celite. The
aqueous phase was extracted with CH2Cl2 (3”75 mL). The combined or-
ganic phases were dried over sodium sulfate. The solvent was removed
on the rotary evaporator and the residue was thoroughly dried under
high vacuum for 12 h to give analytically pure product (2.2 g) which was
carried directly to the next step. The crude lactol was dissolved in metha-
nol (30 mL). In a separate vial four drops of diphenyldichlorosilane was
added to methanol (3 mL). The acidic methanol solution was added to
the lactol solution and the reaction mixture was stirred at 258C. The re-
action, judged complete after 30 min (TLC), was quenched with pyridine
(0.5 mL), concentrated on the rotary evaporator, and purified by silica
gel chromatography (15% Et2O in hexanes) to afford the protected
lactol as a mixture of anomers (2.0 g). Rf =0.8 (50% Et2O in hexanes);
1H NMR (400 MHz, CDCl3): d = 7.73–7.71 (m, 8H), 7.42–7.39 (m, 12H),
5.90–5.67 (m, 2H), 5.09–4.95 (m, 6H), 3.91–3.70 (m, 6H), 3.99 (s, 3H),
3.90 (s, 3H), 2.96 (m, 1H), 2.72 (m, J=8.4 Hz, 1H), 2.37 (m, 1H), 2.09
(dd, J=12.4, 16 Hz, 1H), 1.88 (dt, J=4.8, 12 Hz, 1H), 1.76 (dq, J=2.4,
(s, 3H); 13C NMR (100 MHz, CDCl3): d
= 174.4, 137.3, 128.5, 128.0,
127.6, 109.3, 107.2, 83.4, 81.9, 72.1, 67.2, 45.0, 31.4, 26.8, 25.4; HRMS: m/
z: calcd for C18H22O6Na: 357.1314, found 357.1330 [M+Na]+.
Ketone 37: Benzyl alcohol 36 (200 mg, 0.6 mmol) was dissolved in THF
(10 mL), treated with activated 10% Pd(OH)2 (25 mg) and stirred under
an atmosphere of hydrogen for 24 h. The solution was filtered through a
plug of celite, concentrated on the rotary evaporator and the residue was
applied to silica gel chromatography (60% Et2O in hexanes) to afford of
the corresponding alcohol 37a (120 mg, 82%). Rf =0.3 (50% Et2O in
hexanes); [a]2D5 = ꢀ20 (c=0.66, CH2Cl2); 1H NMR (500 MHz, CDCl3): d
= 6.20 (d, J=6 Hz, 1H), 4.32 (m, 1H), 4.25 (m, 1H), 4.20 (m, 1H), 3.98
(m, 1H), 3.95 (dd, J=2.8, 8 Hz, 1H), 3.17 (m, J=5.6 Hz, 1H), 2.90 (dd,
J=11.6, 19.2 Hz, 1H), 2.46 (d, J=3.2 Hz, 1H), 2.42 (d, J=5.2 Hz, 1H),
1.42 (s, 3H), 1.36 (s, 3H); 13C NMR (125 MHz, CDCl3): d = 174.4, 109.8,
107.5, 82.2, 76.7, 73.0, 67.7, 47.3, 31.5, 26.9, 25.1; HRMS: m/z: calcd for
C11H16O6Na: 267.0845, found: 267.0865 [M+Na]+. A solution of alcohol
37a (120 mg, 0.5 mmol) in CH2Cl2 (25 mL) was treated with DMP
(266 mg, 0.6 mmol) at 258C for 12 h. The solution was diluted with satu-
rated aqueous sodium thiosulfate (20 mL) and saturated sodium hydro-
gen carbonate (20 mL) and stirred vigorously until the biphasic mixture
was visibly clear. The aqueous phase was extracted with CH2Cl2 (3”
20 mL). The combined organic phases were dried over sodium sulfate
and concentrated on the rotary evaporator. The residue was purified on
silica gel (50% Et2O in hexanes) to yield ketone 37 (107 mg, 93%). Rf =
6.8 Hz, 1H), 1.08 (s, 18H); 13C NMR (100 MHz, CDCl3): d
= 139.2,
138.2, 135.7, 135.6, 135.5, 134.8, 133.6, 133.5, 130.4, 129.6, 127.9, 127.6,
116.1, 115.5, 105.2, 104.9, 85.1, 83.0, 65.9, 64.3, 54.9, 54.4, 50.9, 44.2, 43.4,
39.8, 26.8, 19.3; HRMS: m/z: calcd for C24H32O3SiNa: 419.2019, found:
419.2039 [M+Na]+.
0.5 (50% Et2O in hexanes); [a]D25
=
+76 (c=0.61, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d = 6.43 (d, J=5.6 Hz, 1H), 4.43 (m 1H), 4.24 (s,
1H), 4.09 (m, 2H), 3.28 (m, 1H), 2.88 (m, 2H), 1.35 (s, 3H), 1.33 (s,
3H); 13C NMR (100 MHz, CDCl3): d = 209.5, 171.9, 110.5, 104.8, 79.2,
75.5, 64.2, 46.7, 31.4, 25.9, 25.2; HRMS: m/z: calcd for C11H16O6Na:
265.0688, found: 265.0691 [M+Na]+.
Aldehyde 42: Compound 41 (2.0 g, 5.1 mmol) was dissolved in wet ace-
tone (50 mL) and treated with osmium tetroxide (75 mg, 0.3 mmol), fol-
lowed by NMO (620 mg, 5.3 mmol) and pyridine (0.1 mL). The reaction
was stirred for 12 h at 258C. The mixture was concentrated and filtered
through a plug of silica gel (100% Et2O). Et2O was removed on the
rotary evaporator and the residue was dissolved in CH2Cl2 (25 mL) and
treated with lead tetraacetate (2.4 g, 5.2 mmol). The reaction mixture was
stirred for 15 min at 258C and quenched with excess ethylene glycol, the
solvent was removed on the rotary evaporator and the residue was ap-
plied to silica gel chromatography (40% Et2O in hexanes) to yield alde-
hyde 42 as a mixture of anomers (1.8 g, 89%). Rf =0.4 (50% Et2O in
hexanes); 1H NMR (400 MHz, CDCl3): d = 9.73 (s, 1H), 9.67 (s, 1H),
7.67–7.63 (m, 8H), 7.44–7.35 (m, 12H), 5.07 (dd, J=3.2, 5.6 Hz, 1H),
5.10 (d, J=4.8 Hz, 1H), 4.44 (q, J=4.4 Hz, 1H), 4.31 (m, 1H), 3.85 (dd,
J=10.4, 5.2 Hz, 1H), 3.77 (d, J=4 Hz, 2H), 3.66 (dd, J=9.6, 7.6 Hz,
1H), 3.29 (s, 3H), 3.25 (m, 1H), 3.23 (s, 3H), 2.95 (m, 1H), 2.26 (m, 3H),
2.85 (dd, J=12.8, 8.0 Hz, 1H), 1.05 (s, 18H); 13C NMR (100 MHz,
Butenolide 39: Hydroxymethyl butenolide (3.0 g, 26.3 mmol) and ammo-
nium nitrate (6.4 g, 80.0 mmol) were dissolved in DMF (100 mL) under
an atmosphere of argon and cooled to 08C. TBDPSCl (7.4 g, 27.0 mmol)
was added and the reaction was stirred 30 min, the ice bath was then re-
moved and the reaction stirred for an additional 12 h. The mixture was
diluted with Et2O (150 mL) and washed with H2O (300 mL). The aque-
ous phase was extracted with Et2O (3”50 mL) and the combined organic
phases were dried over magnesium sulfate and concentrated on the
rotary evaporator. The crude residue was purified on silica gel (20%
Et2O in hexanes) to yield compound 39 (8.8 g, 95%). Rf =0.8 (50% Et2O
in hexanes); [a]D25
=
ꢀ80.7 (c=3.95, CDCl3); 1H NMR (400 MHz,
CDCl3): d = 7.66–7.64 (m, 4H), 7.46–7.39 (m, 7H), 6.18 (dd, J=6.0,
2.0 Hz, 1H), 5.08 (m, 1H), 3.91–3.89 (m, 2H), 1.05 (s, 9H); 13C NMR
7184
www.chemeurj.org
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 7175 – 7190

Norrisolide
FULL PAPER
CDCl3): d = 201.8, 200.2, 135.6, 135.5, 129.8, 127.7, 105.2, 105.0, 80.1,
78.2, 66.5, 65.2, 54.7, 53.2, 51.7, 34.2, 33.8, 26.8, 19.2; HRMS: m/z: calcd
for C23H30O4SiNa: 421.1811, found: 421.1835 [M+Na]+.
105.2, 84.0, 81.3, 66.8, 65.1, 65.0, 64.7, 58.6, 54.6, 52.7, 52.3, 45.1, 45.0,
41.2, 41.1, 39.9, 36.5, 36.0, 33.4, 33.3, 26.9, 26.8, 22.1, 21.7, 20.8, 20.6, 20.5,
19.8, 19.3, 15.3, 15.1; HRMS: calcd for C35H50O4SiNa: 585.3370, found:
585.3368 [M+Na]+.
Triflate 43: Ketone 10 (620 mg, 3.4 mmol) was dissolved in anhydrous
THF (30 mL) and cooled to ꢀ788C (dry ice/acetone) under an argon at-
mosphere. NaHMDS (3.7 mL, 3.7 mmol, 1m in THF) was added by sy-
ringe and the mixture was stirred for 30 min at ꢀ788C. Tf2NPh (920 mg,
3.7 mmol) dissolved in THF (15 mL) was added to the enolate by syringe.
The reaction was stirred for 15 min at which time the dry ice/acetone
bath was replaced with an ice-water bath. Stirring was continued for 2 h
at 08C. The reaction was diluted with Et2O (100 mL) and quenched with
saturated aqueous ammonium chloride. The aqueous phase was extracted
with Et2O (3”75 mL) and the combined organic phases were dried over
magnesium sulfate. The solvent was removed on the rotary evaporator
and the residue was purified on silica gel (5% Et2O in hexanes) to afford
triflate 43 (2.9 g, 85%). [a]2D5 = (c=4.85, CH2Cl2); 1H NMR (400 MHz,
C6D6): d = 5.29 (m, 1H), 1.67–1.62 (m, 2H), 1.46–1.43 (m, 1H), 1.37–
1.25 (m, 3H), 1.22–1.13 (m, 1H), 0.83–0.79 (m, 2H), 0.81 (s, 3H), 0.69 (s,
3H), 0.63 (s, 3H); 13C NMR (100 MHz, C6D6): d = 158.9, 114.6, 57.0,
Alkene 46: A solution of ketone 45 (150 mg, 0.27 mmol) in THF (15 mL)
was cooled to 08C and treated with trimethylsilylmethyllithium (0.9 mL,
0.9 mmol, 1m in pentane) for 30 min. The solution was diluted with Et2O
(50 mL) and the organic phase was washed with saturated ammonium
chloride (100 mL). The aqueous phase was back extracted with Et2O (2”
50 mL). The organic phase was dried over magnesium sulfate and con-
centrated on the rotary evaporator. The crude material was thoroughly
dried on the high vacuum and dissolved in THF (25 mL). KH (116 mg,
2.9 mmol) was added and the solution was heated under reflux for
30 min. The solution was diluted with Et2O (50 mL) and washed with
water (100 mL). The aqueous phase was back extracted with Et2O (2”
50 mL). The combined organic layers were dried over magnesium sulfate
and concentrated on the rotary evaporator. The residue was purified on
silica gel (100% hexanes) to give alkene 46 as a mixture of anomers
(110 mg, 72%, two steps). Rf =0.8 (30% Et2O in hexanes); 1H NMR
(400 MHz, CDCl3): d = 7.71–7.65 (m, 8H), 7.42–7.38 (m, 12H), 5.07–
4.96 (m, 3H), 4.89 (s, 1H), 3.95–3.58 58 (m, 8H), 3.42 (s, 3H), 3.31 (s,
3H), 3.13 (q, J=8 Hz, 1H), 2.89–2.80 (m, 1H), 2.29–1.73 (m, 6H), 1.65–
0.77 (m, 22H), 1.08 (s, 9H), 1.07 (s, 9H), 0.86 (s, 6H), 0.84 (s, 9H), 0.61(s,
3H); 13C NMR (100 MHz, CDCl3): d = 148.2, 135.6, 133.7, 129.6, 127.6,
119.8, 112.3, 110.4, 105.2, 88.6, 83.9, 66.9, 65.8, 58.8, 58.5, 57.9, 54.6, 54.4,
45.4, 45.2, 41.5, 40.9, 40.5, 38.3, 38.5, 36.7, 33.3, 33.2, 30.3, 25.3, 24.9, 21.3,
21.1, 20.5, 20.2, 19.3, 19.2, 18.5, 13.9, 12.5; IR (film): nmax = 2930, 2857,
1470, 1363, 1109, 1046, 703 cmꢀ1; HRMS: m/z: calcd for C36H52O3SiNa:
593.3578, found: 593.3568 [M+Na]+.
45.4, 41.1, 33.3, 32.6, 32.0, 30.4, 26.7, 21.0, 19.5, 17.0; IR (film): nmax
=
2997, 2928, 2863, 1457, 1373, 987, 847, 803, 680 cmꢀ1; HRMS: m/z: calcd
for C13H19F3O3S: 313.1085, found: 313.1004 [M+H]+.
Enone 44: Chromium(ii) chloride (640 mg, 5.2 mmol) and nickel(ii) chlo-
ride (3 mg) were dissolved in anhydrous DMF (10 mL) under an argon
atmosphere. The heterogenous solution was sonicated for 15 min and stir-
red for an additional 15 min. Aldehyde 42 (460 mg, 1.2 mmol) dissolved
in DMF (5 mL) was added to the chromium/nickel/DMF mixture and
stirred for 10 min. Vinyl triflate 43 (420 mg, 1.4 mmol) dissolved in DMF
(5 mL) was added to the reaction via syringe and the solution was stirred
for 6 h. The reaction was quenched with Et2O (75 mL). The solution was
filtered through Celite and the celite was washed with additional portions
of Et2O. The combined organic phases were washed with saturated
sodium hydrogen carbonate (100 mL), dried over magnesium sulfate and
concentrated on the rotary evaporator. The residue was dissolved in
CH2Cl2 (50 mL) and treated with DMP (850 mg, 2 mmol), and the mix-
ture was stirred for 4 h. The reaction was quenched with saturated
sodium thiosulfate (75 mL) and saturated sodium hydrogen carbonate
(50 mL) and the mixture was vigorously stirred until visibly clear. The so-
lution was extracted with CH2Cl2 (3”75 mL). The combined organic
phases were dried over sodium sulfate, concentrated on the rotary evapo-
rator and purified on silica gel (20% Et2O in hexanes) to afford the a,b-
unsaturated ketone 44 as a mixture of anomers (355 mg, 52%, two
Alkene 47: Alkene 46 (425 mg, 1.1 mmol) was dissolved in CH2Cl2
(10 mL) and cooled to 08C. Phenyl selenol (235 mg, 1.15 mmol) was
added followed by BF3·Et2O (~0.1 mL) and stirred for 15 min. The reac-
tion was quenched with pyridine (0.2 mL) and diluted with CH2Cl2
(20 mL). The organic phase was washed with saturated sodium hydrogen
carbonate. The aqueous phase was back extracted with CH2Cl2 (2”
20 mL) and the combined organic layers were dried over sodium sulfate.
The solvent was removed on the rotary evaporator and the residue fil-
tered through a short plug of silica gel with hexane to afford the crude
phenyl selenide as a mixture of anomers (530 mg, 90%). The product
was taken directly to the next step without further purification. 47a: Rf =
0.8 (40% Et2O in hexanes); 1H NMR (400 MHz, CDCl3): d = 7.72–7.70
(m, 8H), 7.63–7.60 (m, 12H), 7.42–7.37 (m, 6H), 7.37–7.26 (m, 4H),
5.96–5.91 (m, 2H), 5.15(s, 1H), 5.07 (s, 1H), 4.94 (s, 1H), 4.90 (s, 1H),
4.00–3.66 (m, 6H), 2.79–2.68 (m, 2H), 2.48–2.90 (m, 2H), 2.10–1.99 (m,
4H), 1.69–0.95 (m, 22H), 1.07 (s, 18H), 0.85 (s, 12H), 0.62 (s, 6H).
1
steps). Rf =0.7 (50% Et2O in hexanes); H NMR (400 MHz, CDCl3): d =
7.77–7.64 (m, 8H), 7.42–7.37 (m, 12H), 6.94 (brs, 1H), 6.70 (brs, 1H),
5.06(d, J=7.2 Hz, 1H), 5.03 (d, J=4.8 Hz,1H), 4.49 (m, 1H), 4.42 (q, J=
5.6 Hz, 1H), 3.91(m, 1H), 3.77–3.70 (m, 4H), 3.29–3.25 (m, 4H), 3.28 (s,
3H), 2.35–2.03 (m, 8H), 1.75–0.89 (m, 14H), 1.06 (s, 9H), 1.05 (s, 9H),
0.97 (s, 12H), 0.90 (s, 6H); 13C NMR (100 MHz, CDCl3): d = 197.6,
197.0, 155.0, 145.2, 143.8, 135.6, 135.5, 133.3, 131.3, 129.7, 127.6, 105.2,
104.6, 82.4, 79.4, 65.8, 64.2, 59.0, 54.6, 47.4, 46.9, 41.2, 38.3, 35.3, 33.1,
32.7, 29.9, 26.8, 21.0, 19.9, 19.2, 17.6; IR (film): nmax = 3070, 3049, 2930,
2859, 1665, 1587, 1471, 1428, 1365, 1306, 1261, 1205, 1109, 1049, 741,
Phenylselenide 47a (530 mg, 0.77 mmol) was dissolved in CH2Cl2
(10 mL) and cooled to 08C. Triethylamine (202 mg, 2 mmol), tert-butyl
peroxide (0.74 mL, 2 mmol, 2.7m in toluene), and titanium isopropoxide
(340 mg, 1.2 mmol) were added successively to the stirring, cooled solu-
tion. The mixture was stirred for 45 min, diluted with CH2Cl2 (50 mL)
and washed with saturated sodium hydrogen carbonate (100 mL). The
aqueous phase was back extracted twice with CH2Cl2 (50 mL). The com-
bined organic layers were dried over magnesium sulfate and concentrated
on the rotary evaporator. The residue was purified on silica gel (100%
hexanes) to yield enol ether 47 (279 mg, 67%). Rf =0.7 (Et2O/hexanes
2:3); [a]2D5 = +19.4 (c=0.1, CH2Cl2); 1H NMR (400 MHz, CDCl3): d =
7.71–7.68 (m, 4H), 7.42–7.39 (m, 6H), 6.37 (dd, J=2.8, 2.0 Hz, 1H), 5.07
(s, 1H), 4.91 (s, 1H), 4.81 (d, J=2.8 Hz, 1H), 4.22 (dd, J=11.2, 5.2 Hz,
1H), 3.76 (m, 1H), 3.66 (m, 1H), 3.26 (m, 1H), 1.91 (dd, J=10.8, 8.0 Hz,
1H), 1.71–0.97 (m, 15H), 1.07 (s, 9H), 0.85 (s, 6H), 0.64 (s, 3H);
13C NMR (100 MHz, CDCl3): d = 151.4 145.4, 135.6, 133.4, 131.5, 129.7,
129.6, 129.2, 127.7, 111.7, 103.0, 88.8, 66.2, 58.5, 57.2, 50.7, 43.2, 41.4, 39.7,
33.2, 28.8, 25.6, 20.5, 20.0, 19.3, 14.0; IR (film): nmax = 3070, 2928, 2855,
1616, 1471, 1427, 1111, 702 cmꢀ1; HRMS: m/z: calcd for C36H52O3SiNa:
551.3321, found: 551.3379 [M+Na]+.
703 cmꢀ1
; HRMS: m/z: calcd for C35H48O4SiNa: 583.3214, found:
583.3212 [M+Na]+.
Ketone 45: 10% palladium on carbon (20 mg) was added to a solution of
ketone 44 (175 mg, 0.31 mmol) in methanol (50 mL). The flask was evac-
uated and filled with hydrogen by means of a balloon. The heterogeneous
solution was stirred at 258C under an atmosphere of hydrogen for 16 h.
The solution was filtered through a plug of Celite, concentrated and ap-
plied to silica gel chromatography (5% Et2O in hexanes) to afford com-
pound 45 as mixture of anomers (165 mg, 92%). Rf =0.7 (50% Et2O in
1
hexanes); H NMR (500 MHz, CDCl3): d = 7.70–7.66 (m, 8H), 7.44–7.37
(m, 12H), 5.08–5.05 (m, 1H), 5.03 (d, J=6 Hz, 1H), 4.21–4.17 (m, 1H),
4.10 (q, J=5.2 Hz, 1H), 3.86–3.68 (m, 4H), 3.47–3.39 (m, 1H), 3.36 (s,
3H), 3.31–3.25 (m, 1H), 3.26 (s, 3H), 2.63 (t, J=8.8 Hz, 1H), 2.45 (t, J=
8.7 Hz, 1H), 2.33–0.9 (m, 26H), 1.08 (s, 9H), 1.07 (s, 9H), 0.86 (s, 6H),
0.84 (s, 6H), 0.66 (s, 3H), 0.63 (s, 3H); 13C NMR (125 MHz, CDCl3): d =
211.9, 210.5, 135.6, 135.6, 133.3, 133.2, 129.7, 127.8, 127.8, 127.7, 105.7,
Lactone 49: Butenolide 39 (5.0 g, 14.2 mmol) was dissolved in CH2Cl2
(50 mL) in a high pressure tube, aluminum chloride (0.62 g, 4.6 mmol)
and excess butadiene (20 mL) were added and the tube was sealed and
Chem. Eur. J. 2005, 11, 7175 – 7190
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7185

E. A. Theodorakis et al.
heated to 608C for 6 d. The reaction was cooled to ꢀ788C (dry ice/ace-
tone) prior to opening the tube and the solution was filtered through a
short plug of Celite. The solvent was removed on the rotary evaporator
and the residue was purified by silica gel chromatography (25% Et2O in
hexanes) to give compound 49 (4.9 g, 85%). Rf =0.7 (50% Et2O in hex-
anes); [a]2D5 = +19.4 (c=3.40, CH2Cl2); 1H NMR (400 MHz, CDCl3): d
= 7.66–7.64 (m, 4H), 7.41–7.39 (m, 6H), 5.84–5.76 (m, 2H), 4.14 (q, J=
4.0 Hz, 1H), 3.85 (dd, J=11.6, 4.0 Hz, 1H), 3.74 (dd, J=11.2, 3.6 Hz,
1H), 3.00 (td, J=8.8, 4.4 Hz, 1H), 2.72–2.65 (m, 1H), 2.43–2.21 (m, 3H),
1.93–1.86 (m, 1H), 1.04 (s, 9H); 13C NMR (100 MHz, CDCl3): d = 179.5,
135.6, 135.5, 132.8, 129.9, 127.8, 126.4, 125.6, 84.8, 64.2, 37.4, 34.0, 26.7,
25.5, 22.5, 19.1; IR (film): nmax = 3070, 3043, 2932, 2857, 1775, 1112,
hexanes) to afford a-isomer (51a; 3.5 g, 38.5%) and b-isomer (51b; 3.5 g,
38.5%).
Compound 51a: Rf =0.67 (50% Et2O in hexanes); [a]D25
= +61.7 (c=
3.14, CH2Cl2); 1H NMR (400 MHz, CDCl3): d = 9.70 (s, 1H), 7.72–7.68
(m, 4H), 7.43–7.37 (m, 6H), 5.91 (d, J=5.6 Hz, 1H), 4.93 (d, J=5.2 Hz,
1H), 3.92–3.77 (m, 3H), 3.32 (s, 3H), 3.17–3.10 (m, 1H), 2.74 (dd, J=
17.6, 10.4 Hz, 1H), 2.63–2.51 (m, 2H), 1.99–1.92 (m, 1H), 1.72 (dd, J=
14.4, 1.2 Hz, 1H), 1.11 (s, 9H); 13C NMR (100 MHz, CDCl3): d = 200.3,
135.3, 133.0, 129.4, 127.4, 109.9, 103.9, 81.0, 64.4, 54.2, 43.7, 42.9, 36.5,
33.2, 26.8, 19.2; HRMS: m/z: calcd for C26H34O5SiNa: 477.2073, found:
477.2049 [M+Na]+.
Compound 51b: Rf =0.62 (50% Et2O in hexanes); [a]2D5 = ꢀ13.4 (c=
2.51, CH2Cl2); 1H NMR (500 MHz, CDCl3): d = 9.71 (s, 1H), 7.68–7.64
(m, 4H), 7.44–7.37 (m, 6H), 5.79 (d, J=5.0 Hz, 1H), 5.13 (d, J=4.0 Hz,
1H), 3.85–3.82 (m, 1H), 3.77–3.69 (m, 2H), 3.33 (s, 3H), 3.31–3.26 (m,
1H), 2.76–2.71 (m, 1H), 2.53 (dd, J=17.5, 4.5 Hz, 1H), 2.41 (dd, J=17.5,
10.0 Hz, 1H), 1.83–1.72 (m, 2H), 1.06 (s, 9H); 13C NMR (125 MHz,
CDCl3): d = 199.8, 135.6, 135.5, 133.1, 133.0, 129.8, 129.7, 127.7, 108.0,
105.5, 81.1, 63.7, 54.8, 44.0, 41.6, 36.8, 31.6, 26.8, 19.2; HRMS: m/z: calcd
for C26H34O5SiNa: 477.2073, found: 477.2061 [M+Na]+.
704 cmꢀ1
429.1891 [M+Na]+.
Lactol 50: solution of lactone 49 (12.9 g, 31.6 mmol) in CH2Cl2
; HRMS: m/z: calcd for C25H30O3SiNa: 429.1862, found:
A
(150 mL) was treated at ꢀ788C with DIBAL-H (33 mL, 33 mmol, 1m in
toluene), added dropwise over a period of 5 min. After 30 min, the reac-
tion was quenched with methanol (10 mL) and the solution was brought
to ambient temperature over a 45 minute period. Saturated ammonium
chloride (100 mL) was added and the solution was filtered through celite.
The solvent was removed in vacuo to yield analytically pure lactol (4.1 g)
which was carried to the next step directly. 49a: [a]2D5 = ꢀ16.9 (c=1.93,
CH2Cl2); 1H NMR (500 MHz, CDCl3): d = 7.71–7.69 (m, 4H), 7.46–7.39
(m, 6H), 5.73–5.70 (m, 1H), 5.61–5.59 (m, 1H), 5.08 (d, J=5.5 Hz, 1H),
3.86–3.81 (m, 2H), 3.64–3.61 (m, 1H), 3.02 (d, J=6.0 Hz, 1H), 2.73 (q,
J=7.5 Hz, 1H), 2.30–2.16 (m, 3H), 1.84–1.80 (m, 2H), 1.09 (s, 9H);
13C NMR (125 MHz, CDCl3): d = 135.7, 135.6, 133.0, 132.9, 129.8, 127.8,
125.2, 123.9, 103.0, 83.4, 64.5, 41.6, 32.1, 26.9, 23.3, 22.8, 19.2; HRMS: m/
z: calcd for C25H32O3SiNa: 431.2019, found: 431.2030 [M+Na]+.
Alcohol 52a: A solution of aldehyde 51a (3.51 g, 7.72 mmol) in methanol
(50 mL) was treated with sodium borohydride (0.70 g, 18.13 mmol). The
solution was stirred for 20 min then carefully quenched with a few drops
of acetic acid/methanol 1ꢀ:10, diluted with CH2Cl2 (100 mL) and washed
with saturated aqueous NaHCO3 (100 mL). The aqueous phase was ex-
tracted with CH2Cl2 (2”100 mL), dried over magnesium sulfate, concen-
trated, and applied to silica gel chromatography (40% Et2O in hexanes)
to yield the corresponding alcohol (3.5 g, ~100%). [a]D25
2.17, CH2Cl2); 1H NMR (500 MHz, CDCl3): d
7.71–7.69 (m, 4H),
= +64.0 (c=
=
The crude lactol (~31.60 mmol) was dissolved in acetone and water 9:1
(150 mL). Osmium tetroxide (2.5 wt% in tert-butanol, 3.9 g, 0.38 mmol)
and N-methyl morpholine oxide (4.22 g, 36 mmol) were added and the
mixture was stirred for 10 h at 258C. The reaction mixture was quenched
with saturated aqueous sodium thiosulfate (100 mL) and stirred for
30 min. The mixture was extracted with Et2O (3”75 mL). The solution
was dried over sodium sulfate and concentrated to give the crude triol
which was carried forward to the next step without purification. Triol
7.44–7.37 (m, 6H), 5.86 (d, J=5.0 Hz, 1H), 5.00 (d, J=4.5 Hz, 1H), 3.95–
3.88 (m, 2H), 3.74 (dd, J=11.0, 4.0 Hz, 1H), 3.65–3.60 (m, 1H), 3.58–
3.53 (m, 1H), 3.33 (s, 3H), 2.94–2.88 (m, 1H), 2.31–2.24 (m, 1H), 2.05–
1.94 (m, 2H), 1.70–1.56 (m, 3H), 1.07 (s, 9H); 13C NMR (125 MHz,
CDCl3): d = 135.7, 135.6, 133.6, 133.4, 129.6, 127.6, 109.7, 104.9, 81.9,
64.3, 61.5, 54.6, 44.4, 38.4, 32.5, 30.5, 26.8, 19.3; HRMS: m/z: calcd for
C26H36O5SiNa: 479.2230, found: 479.2235 [M+Na]+.
Alcohol 52b was prepared similarly to compound 52a starting from alde-
hyde 51b. [a]2D5 = ꢀ19.9 (c=0.78, CH2Cl2); 1H NMR (500 MHz, CDCl3):
d = 7.70–7.67 (m, 4H), 7.43–7.37 (m, 6H), 5.77 (d, J=5.0 Hz, 1H), 5.14
(brs, 1H), 3.89 (dd, J=11.5, 3.0 Hz, 1H), 3.78–3.59 (m, 4H), 3.34 (s, 3H),
3.13–3.07 (m, 1H), 2.43–2.41 (m, 1H), 1.88 (d, J=9.0 Hz, 2H), 1.65–1.48
(m, 3H), 1.06 (s, 9H); 13C NMR (125 MHz, CDCl3): d = 135.7, 135.6,
133.4, 133.2, 129.7, 127.7, 127.6, 108.0, 105.7, 82.0, 63.8, 61.6, 54.8, 44.2,
39.0, 31.6, 29.8, 26.8, 19.3; HRMS: m/z: calcd for C26H36O5SiNa:
479.2230, found: 479.2239 [M+Na]+.
49b: Rf =0.2 (Et2O); [a]D25
=
+2.86 (c=1.43, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d = 7.70–7.66 (m, 4H), 7.44–7.37 (m, 6H), 5.04 (d,
J=3.6 Hz, 1H), 3.96–3.91 (m, 2H), 3.81 (dd, J=11.2, 3.6 Hz, 1H), 3.67–
3.59 (m, 2H), 3.31 (d, J=4.8 Hz, 1H), 2.71–2.66 (m, 1H), 2.49–2.21 (m,
3H), 2.03–1.85 (m, 2H), 1.55–1.50 (m, 1H), 1.39–1.32 (m, 1H), 1.09 (s,
9H); 13C NMR (100 MHz, CDCl3): d = 135.5, 132.6, 129.8, 129.7, 127.7,
102.3, 81.7, 68.7, 67.9, 65.0, 40.7, 35.0, 30.0, 27.0, 26.9, 26.3, 19.3; HRMS:
m/z: calcd for C25H34O5SiNa: 465.2073, found: 465.2091 [M+Na]+.
The crude triol (~31.6 mmol) was dissolved in CH2Cl2 (250 mL) and
treated with lead tetraacetate (14.2 g, 32 mmol). The reaction was stirred
for 15 min then quenched with excess ethylene glycol. The reaction was
concentrated on the rotary evaporator and thoroughly dried. The residue
was purified on silica gel (50% Et2O in hexanes) to afford compound 50
as mixture of anomers (8.9 g, 64%, four steps). Rf =0.4 (50% Et2O in
hexanes); 1H NMR (400 MHz, CDCl3): d = 9.71 (s, 1H), 9.69 (s, 1H),
7.67–7.63 (m, 8H), 7.44–7.35 (m, 12H), 5.89 (d, J=5.2 Hz, 1H), 5.87 (d,
J=5.2 Hz, 1H), 5.65 (t, J=2.8 Hz, 1H), 5.49 (dd, J=5.2, 2.4 Hz, 1H),
4.09 (dt, J=10.0, 4.0 Hz, 1H), 3.85–3.72 (m, 3H), 3.43 (s, 1H), 3.40–3.36
(m, 1H), 3.27 (s, 1H), 3.21–3.17 (m, 1H), 2.82–2.74 (m, 2H), 2.67–2.49
(m, 3H), 2.44–2.36 (m, 1H), 2.01–1.94 (m, 1H), 1.81–1.69 (m, 3H), 1.30–
1.19 (m, 2H), 1.08 (s, 9H), 1.07 (s, 9H); 13C NMR (100 MHz, CDCl3): d
= 200.5, 199.5, 135.5, 135.4, 133.1, 133.0, 132.9, 129.7, 129.6, 127.6, 127.5,
110.2, 108.1, 99.2, 97.9, 81.2, 64.2, 63.8, 44.3, 43.9, 43.0, 41.7, 36.8, 36.5,
33.7, 32.5, 31.6, 27.0, 26.9, 19.4; HRMS: m/z: calcd for C25H32O5SiNa:
463.1917, found: 463.1929 [M+Na]+.
Iodide 53: Imidazole (1.64 g, 23.9 mmol), triphenyl phosphine (3.14 g,
11.9 mmol) and iodine (3.02 g, 11.9 mmol) were added to a solution of al-
cohol 52a (5 g, 11 mmol) in THF (100 mL) and the mixture was stirred
for 30 min. The reaction was quenched with saturated sodium thiosulfate
and extracted with Et2O (3”100 mL). The combined organic phases were
dried over magnesium sulfate, concentrated and purified on silica gel to
afford iodide 53a (3.02 g, over two steps, 74%). [a]2D5 = +77.3 (c=3.68,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d = 7.70–7.66 (m, 4H), 7.40–7.37
(m, 6H), 5.86 (d, J=5.6 Hz, 1H), 4.98 (d, J=5.2 Hz, 1H), 3.90 (dt, J=
10.4, 3.6 Hz, 1H), 3.81 (dd, J=11.6, 3.2 Hz, 1H), 3.70 (dd, J=11.2,
4.0 Hz, 1H), 3.30 (s, 3H), 3.18–3.12 (m, 1H), 2.99 (q, J=8.0 Hz, 1H),
2.94–2.87 (m, 1H), 2.32–2.24 (m, 1H), 2.06–1.84 (m, 4H), 1.06 (s, 9H);
13C NMR (100 MHz, CDCl3): d = 135.7, 135.6, 133.5, 133.4, 129.7, 129.6,
127.7 (2), 109.7, 104.7, 81.3, 64.3, 54.6, 43.4, 43.3, 32.4, 31.6, 26.9, 19.3, 3.7;
IR (film): nmax
= ;
3070, 2956, 2929, 2857, 1111, 1092, 997, 703 cmꢀ1
HRMS: m/z: calcd for C26H35O4ISi: 567.1427, found: 567.1429 [M+H]+.
Iodide 53b (1.55 g, over two steps from 7, 70%) was prepared similarly
to compound 53a starting from alcohol 52b. [a]D25
= +2.14 (c=2.70,
Aldehyde 51: Anhydrous methanol (0.98 mL, 24 mmol), followed by of
Amberlyst 15 ion-exchange resin (0.50 g) was added to a solution of alde-
hyde 50 (8.88 g, 20.2 mmol) in anhydrous Et2O (100 mL) containing acti-
vated 3 Š molecular sieves (1.50 g) and the solution was stirred for 10 h.
The reaction mixture was filtered through Celite and concentrated on the
rotary evaporator. The residue was purified on silica gel (15% Et2O in
CH2Cl2); 1H NMR (400 MHz, CDCl3): d = 7.71–7.68 (m, 4H), 7.44–7.37
(m, 6H), 5.79 (d, J=5.2 Hz, 1H), 5.15 (d, J=4.0 Hz, 1H), 3.85 (dd, J=
11.2, 3.6 Hz, 1H), 3.78 (dt, J=9.6, 3.2 Hz, 1H), 3.70 (dd, J=10.8, 3.2 Hz,
1H), 3.35 (s, 3H), 3.26–3.20 (m, 1H), 3.17–3.11 (m, 1H), 3.09–3.02 (m,
1H), 2.53–2.45 (m, 1H), 2.04–1.95 (m, 1H), 1.93–1.83 (m, 2H), 1.82–1.70
7186
www.chemeurj.org
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 7175 – 7190

Norrisolide
FULL PAPER
(m, 1H), 1.07 (s, 9H); 13C NMR (100 MHz, CDCl3): d = 135.5, 135.4,
133.2, 133.0, 129.6, 129.5, 127.6, 127.5, 107.9, 105.6, 81.3, 63.7, 54.8, 43.6,
43.3, 31.2, 31.1, 27.0, 19.4, 3.3; IR (film): nmax = 3067, 2952, 2927, 2851,
1109, 1089, 992, 701 cmꢀ1; HRMS: m/z: calcd for C26H35O4ISi: 567.1427,
found: 567.1439 [M+H]+.
The aqueous phase was extracted with Et2O (3”100 mL). The combined
organic layers were dried over magnesium sulfate and concentrated on
the rotary evaporator to afford the ~2 g of the crude diol which was
dried under high vacuum.
A solution of the crude diol in CH2Cl2
(100 mL) was cooled to 08C and treated with lead(iv) tetraacetate
(2.63 g, 5.64 mmol). The solution was stirred for 30 min at 08C, quenched
with excess ethylene glycol and the organic phase was washed twice with
water (100 mL). The aqueous phase was back extracted with CH2Cl2 (2”
100 mL) and the combined organic phases were dried over magnesium
sulfate and concentrated on the rotary evaporator. The residue was puri-
fied by silica gel chromatography (50% Et2O in hexanes) to yield alde-
Phenyl selenide 54a: Sodium borohydride (0.33 g, 8.6 mmol) was added
to diphenyl selenide (0.89 g, 2.8 mmol) in ethanol (50 mL) under an
argon atmosphere. The mixture was stirred for 20 min at room tempera-
ture. Iodide 53a (3.00 g, 5.30 mmol) in ethanol (50 mL) was added to the
above mixture and the reaction was stirred at 258C for 45 min. The solu-
tion was diluted with Et2O (100 mL) and washed with saturated aqueous
ammonium chloride (100 mL). The aqueous phase was extracted with
Et2O (3”75 mL). The combined organic layers were dried over magnesi-
um sulfate, concentrated and purified on silica gel to afford the corre-
hyde 56a (1.8 g, 92%). [a]D25
=
+62.9 (c=1.33, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d 9.77 (d, J=2.4 Hz, 1H), 7.67–7.63 (m, 4H),
=
7.40–7.38 (m, 6H), 5.93 (d, J=5.2 Hz, 1H), 5.01 (dd, J=4.8, 0.8 Hz, 1H),
4.64–4.60 (m, 1H), 3.88–3.79 (m, 2H), 3.34 (s, 3H), 3.24–3.17 (m, 1H),
3.07–3.01 (m, 1H), 2.14–2.01 (m, 2H), 1.04 (s, 9H); 13C NMR (100 MHz,
CDCl3): d = 201.8, 135.6, 135.5, 133.2, 129.7, 127.7, 110.4, 104.7, 78.5,
64.6, 54.6, 54.5, 43.2, 33.7, 26.8, 19.2; IR (film): nmax = 301, 2931, 2858,
1721, 1112, 998, 704 cmꢀ1; HRMS: m/z: calcd for C25H32O5Si: 441.2097,
found: 441.2071 [M+H]+.
sponding selenide (2.88 g, 91%). [a]D25
= +78.1 (c=4.54, CH2Cl2);
1H NMR (400 MHz, CDCl3): d = 7.67 (m, 4H), 7.37–7.36 (m, 8H), 7.22–
7.20 (m, 3H), 5.84 (d, J=5.6 Hz, 1H), 4.97 (d, J=4.8 Hz, 1H), 3.87 (dt,
J=10.0, 3.6 Hz, 1H), 3.80 (dd, J=11.2, 2.8 Hz, 1H), 3.67 (dd, J=11.2,
4.0 Hz, 1H), 3.29 (s, 3H), 2.91–2.82 (m, 1H), 2.78–2.71 (m, 1H), 2.34–
2.26 (m, 1H), 1.98 (dd, J=11.2, 5.6 Hz, 1H), 1.95 (dd, J=10.4, 5.6 Hz,
1H), 1.84 (dd, J=14.0, 2.0, 1H), 1.76 (q, J=7.6 Hz, 2H), 1.05 (s, 9H);
13C NMR (100 MHz, CDCl3): d = 135.7, 135.6, 133.6, 133.5, 132.7, 129.6
(2), 129.0, 127.6 (2), 126.9, 109.7, 104.8, 81.8, 64.3, 54.5, 43.8, 42.1, 32.3,
27.9, 26.8, 26.1, 19.3; IR (film): nmax = 3070, 2955, 2929, 2857, 1111, 1091,
The above procedure was used for the conversion of alkene 55b to alde-
hyde 56b (1.75 g, 94%); [a]D25
=
ꢀ28.7 (c=4.18, CH2Cl2); 1H NMR
(500 MHz, CDCl3): d = 9.78 (s, 1H), 7.69–7.66 (m, 4H), 7.45–7.38 (m,
6H), 5.86 (d, J=5.0 Hz, 1H), 5.18 (d, J=5.0 Hz, 1H), 4.47–4.44 (m, 1H),
3.91 (dd, J=11.0, 4.0 Hz, 1H), 3.82 (dd, J=11.0, 3.0 Hz, 1H), 3.42–3.35
(m, 2H), 3.35 (s, 3H), 2.04 (ddd, J=13.5, 9.0 Hz, 1H), 1.91–1.86 (m, 1H),
1.06 (s, 9H); 13C NMR (125 MHz, CDCl3): d = 199.2, 135.5, 135.4, 133.0,
132.8, 129.7, 127.7, 127.6, 108.3, 105.9, 77.8, 63.6, 55.2, 54.8, 42.4, 32.9,
26.7, 19.1; HRMS: m/z: calcd for C25H32O5Si: 441.2097, found: 441.2081
[M+H]+.
996, 703 cmꢀ1
.
Isomeric selenide 54b (3.02 g, 95%) was prepared accordingly, starting
1
from 53b. [a]2D5 = +6.92 (c=4.32, CH2Cl2); H NMR (400 MHz, CDCl3):
d = 7.69–7.64 (m, 4H), 7.48–7.35 (m, 8H), 7.24–7.22 (m, 3H), 5.76 (d,
J=5.2 Hz, 1H), 5.11 (dd, J=4.0, 1.6 Hz, 1H), 3.82 (dd, J=10.8, 2.8 Hz,
1H), 3.71–3.63 (m, 2H), 3.34 (s, 3H), 3.12–3.04 (m, 1H), 2.97–2.90 (m,
1H), 2.82–2.75 (m, 1H), 2.51–2.43 (m, 1H), 1.82–1.73 (m, 3H), 1.65–1.56
(m, 1H), 1.04 (s, 9H); 13C NMR (125 MHz, CDCl3): d = 135.6, 135.5,
133.3, 133.1, 132.7, 129.7, 129.6, 129.0, 127.6, 126.9, 108.0, 107.9, 105.6,
Alcohol 57: Vinyl iodide 25 (200 mg, 0.69 mmol) was dissolved in anhy-
drous THF (15 mL), cooled to ꢀ788C (dry ice/acetone) under an argon
atmosphere and treated with tert-butyllithium (0.82 mL, 1.4 mmol, 1.7m
in pentane) and the solution was stirred at ꢀ788C for 30 min. The anion
was brought to 08C for ~1 min and then returned to the ꢀ788C bath and
stirred for an additional 10 min. Aldehyde 56a (200 mg, 0.45 mmol) in
anhydrous THF (3 mL) was added dropwise to the vinyl lithium solution
and the reaction was stirred at ꢀ788C for 30 min. The reaction was
quenched by diluting with Et2O (25 mL) followed by saturated ammoni-
um chloride (100 mL). The aqueous phase was extracted with Et2O (3”
35 mL), the combined organic layers were dried over sodium sulfate, and
concentrated on the rotary evaporator. The residue was purified by silica
gel chromatography (40% Et2O in hexanes) to afford pure allylic alcohol
81.7, 63.5, 54.7, 43.5, 42.3, 31.0, 27.4, 26.7, 25.9, 19.2; IR (film): nmax
3073, 2954, 2927, 2856, 1113, 1090, 997, 703 cmꢀ1
=
.
Alkene 55: Compound 54a (2.88 g, 4.83 mmol) was dissolved in THF/
H2O/MeOH 1:1:2 (150 mL). Sodium periodate (5.24 g, 24.3 mmol) was
added in three portions over a 15 min period. The solution was allowed
to stir until the starting material was consumed (30 min as judged by
TLC), the reaction was diluted with CH2Cl2 (100 mL) and the sodium pe-
riodate quenched with saturated aqueous sodium thiosulfate (100 mL).
The aqueous phase was extracted with CH2Cl2 (2”75 mL). The combined
organic layers were dried over magnesium sulfate, filtered, and concen-
trated on the rotary evaporator to yield alkene product 55a (1.7 g, 82%)
and recovered starting material (0.35 g, 9%) after purification on silica
57a (221 mg, 54%). Rf =0.55 (50% Et2O in hexanes); [a]D25
= +45.5
1
gel (20% Et2O in hexanes). [a]D25
=
+59.4 (c=1.1, CH2Cl2); 1H NMR
(c=3.50, CH2Cl2); H NMR (400 MHz, CDCl3): d = 7.69 (m, 4H), 7.41–
7.38 (m, 6H), 5.85 (d, J=5.6 Hz, 1H), 5.70 (s, 1H), 5.00 (d, J=4.0 Hz,
1H), 4.32–4.29 (m, 2H), 3.94 (dd, J=11.2, 3.6 Hz, 1H), 3.78 (dd, J=10.8,
2.8 Hz, 1H), 3.37 (s, 3H), 2.94–2.89 (m, 1H), 2.69–2.63 (m, 1H), 2.05–
1.98 (m, 4H), 1.75–1.26 (m, 7H), 1.07 (s, 9H), 1.02 (s, 3H), 0.97 (s, 3H),
0.86 (s, 3H); 13C NMR (100 MHz, CDCl3): d = 155.7, 135.7, 135.6, 133.4,
133.2, 129.7, 127.7, 127.6, 125.5, 109.6, 104.5, 80.7, 66.7, 65.8, 60.2, 47.1,
46.2, 44.8, 41.4, 35.2, 33.7, 33.2, 32.8, 28.6, 26.9, 21.4, 19.9, 19.2, 18.2; IR
(film): nmax = 3437, 3070, 3049, 2930, 2857, 1112, 999, 703 cmꢀ1; HRMS:
m/z: calcd for C37H52O5SiNa: 627.3482, found: 627.3491 [M+Na]+.
(400 MHz, CDCl3): d = 7.69–7.68 (m, 4H), 7.38–7.35 (m, 6H), 5.91 (d,
J=5.2 Hz, 1H), 5.81–5.72 (m, 1H), 5.09–5.01 (m, 2H), 4.99 (d, J=5.6 Hz,
1H), 4.10–4.06 (m, 1H), 3.85 (dd, J=11.2, 2.0 Hz, 1H), 3.67 (dd, J=11.6,
4.4 Hz, 1H), 3.33 (s, 3H), 2.97–2.90 (m, 1H), 2.86 (q, J=9.2 Hz, 1H),
2.05 (dd, J=14.0, 2.0 Hz, 1H), 1.99–1.92 (m, 1H), 1.05 (s, 9H); 13C NMR
(100 MHz, CDCl3): d = 135.7, 135.6, 133.7, 133.6, 129.5, 127.6, 118.1,
110.1, 104.8, 81.5, 63.6, 54.5, 46.5, 46.0, 33.2, 26.8, 19.3; IR (film): nmax
3071, 2957, 2930, 2858, 1111, 1093, 997, 704 cmꢀ1
=
.
The above procedure was used for the conversion of selenide 54b to
alkene 55b (1.85 g, 83%). [a]D25
=
ꢀ11.5 (c=1.93, CH2Cl2); 1H NMR
The above procedure was used for the conversion of aldehyde 56b to al-
cohol 57b (201 mg, 51%). [a]2D5 = ꢀ13.7 (c=0.85, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d = 7.69–7.67 (m, 4H), 7.44–7.36 (m, 6H), 5.79 (brs,
1H), 5.71 (d, J=4.0 Hz, 1H), 5.13 (d, J=4.0 Hz, 1H), 4.13–4.06 (m, 2H),
3.93–3.87 (m, 2H), 3.34 (s, 3H), 3.01–2.97 (m, 1H), 2.73 (q, J=6.8 Hz,
1H), 2.43 (d, J=4.4 Hz, 1H), 2.07 (dd, J=8.4, 1.6 Hz, 2H), 1.98–1.92 (m,
1H), 1.76 (dd, J=12.0, 9.5 Hz, 3H), 1.62–1.56 (m, 1H), 1.48–1.42 (m,
1H), 1.26–1.20 (m, 2H), 1.10–1.03 (m, 1H), 1.07 (s, 9H), 1.06 (s, 3H),
0.97 (s, 3H), 0.88 (s, 3H); 13C NMR (100 MHz, CDCl3): d = 155.7, 135.7,
135.6, 133.0, 132.8, 129.8 (2), 127.8, 127.7, 126.7, 107.6, 105.9, 81.8, 67.1,
65.4, 60.2, 54.9, 47.9, 47.2, 45.1, 41.4, 35.2, 33.2, 32.8, 31.9, 28.8, 26.9, 21.4,
19.9, 19.2, 18.5; HRMS: m/z: calcd for C37H52O5SiNa: 627.3482, found:
627.3499 [M+Na]+.
(400 MHz, CDCl3): d = 7.74–7.69 (m, 4H), 7.43–7.37 (m, 6H), 5.85 (d,
J=4.8 Hz, 1H), 5.73–5.64 (m, 1H), 5.18–5.11 (m, 3H), 3.98 (dt, J=6.4,
2.8 Hz, 1H), 3.91 (dd, J=11.2, 2.4 Hz, 1H), 3.70 (dd, J=11.2, 3.6 Hz,
1H), 3.38 (s, 3H), 3.19–3.11 (m, 1H), 3.05 (dd, J=18.0, 8.0 Hz, 1H),
2.03–1.96 (m, 1H), 1.94–1.88 (m, 1H), 1.09 (s, 9H); 13C NMR (100 MHz,
CDCl3): d = 135.5, 135.4, 133.7, 133.4, 133.1, 129.4, 127.5, 127.4, 118.5,
108.1, 105.6, 81.1, 63.1, 54.8, 46.3, 45.7, 32.4, 26.8, 19.4.
Aldehyde 56: Osmium tetroxide (0.51 g, 0.050 mmol), NMO (0.63 g,
5.2 mmol), and catalytic amount of pyridine (three drops) were added to
a
solution of alkene 55a (1.90 g, 4.33 mmol) in acetone/water 10:1
(110 mL). The reaction mixture was stirred for 10 h at room temperature
and then quenched with saturated aqueous sodium thiosulfate (125 mL).
Chem. Eur. J. 2005, 11, 7175 – 7190
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7187

E. A. Theodorakis et al.
Enone 58: DMP reagent (1.8 g, 4.4 mmol) was added to a solution of al-
lylic alcohol 57a (200 mg, 0.33 mmol) in CH2Cl2 (5 mL) and the reaction
was stirred for 1 h. Saturated aqueous sodium thiosulfate (15 mL) and
NaHCO3 (5 mL) were added and the mixture was stirred until the organ-
ic layer was clear (45 min). The aqueous layer was extracted with CH2Cl2
(3”50 mL), dried over sodium sulfate, and concentrated on the rotary
evaporator. The residue was purified on silica gel (30% Et2O in hexanes)
to yield enone 58a (196 mg, 99%). Rf =0.6 (50% Et2O in hexanes); [a]D25
= +58.3 (c=0.30, CH2Cl2); 1H NMR (400 MHz, CDCl3): d = 7.68–7.60
(m, 4H), 7.40–7.34 (m, 6H), 6.72 (m, 1H), 5.90 (d, J=5.6 Hz, 1H), 5.02
(dd, J=5.6, 1.2 Hz, 1H), 4.73 (dt, J=10.0, 2.4 Hz, 1H), 3.95 (dd, J=12.0,
2.4 Hz, 1H), 3.88 (t, J=9.6 Hz, 1H), 3.71 (dd, J=11.6, 3.2 Hz, 1H), 3.35
(s, 3H), 3.16–3.09 (m, 1H), 2.31–2.15 (m, 3H), 2.07–1.99 (m, 1H), 1.79–
1.45 (m, 6H), 1.11 (m, 1H), 1.04 (s, 3H), 1.03 (s, 9H), 0.98 (s, 3H), 0.91
3464 cmꢀ1
;
HRMS: m/z: calcd for C38H56O5SiNa: 643.3795, found:
643.3771 [M+Na]+.
To a solution of the above alcohol (90 mg, 0.14 mmol) in CH2Cl2 (5 mL)
at 258C was added pyridine (0.3 mL, 2.8 mmol), followed by thionyl chlo-
ride (0.5 mL, 1 mmol, 2m in CH2Cl2). The reaction was stirred for 30 min
then diluted with CH2Cl2 (10 mL), washed with water, extracted with
CH2Cl2 (3”15 mL), dried over sodium sulfate and concentrated on the
rotary evaporator. The residue was purified on silica gel (hexanes/Et2O
95:5) to afford alkene 60 (70 mg, 85%). Rf =0.8 (50% Et2O in hexanes);
[a]2D5
=
+10.25 (c=0.625, CH2Cl2); 1H NMR (400 MHz, CDCl3): d =
7.69 (m, 4H), 7.38–7.36 (m, 6H), 5.82 (d, J=4.0 Hz, 1H), 5.11 (d, J=
4.0 Hz, 1H), 4.98 (s, 1H), 4.73 (s, 1H), 4.04 (d, J=8.4 Hz, 1H), 3.89 (d,
J=9.6 Hz, 1H), 3.67 (dd, J=9.6, 2.8 Hz, 1H), 3.37 (s, 3H), 3.12–3.10 (m,
1H), 2.88 (dd, J=8.8, 6.4 Hz, 1H), 2.03–1.95 (m, 2H), 1.73–0.80 (m,
12H), 1.06 (s, 9H), 0.83 (s, 6H), 0.64 (s, 3H); 13C NMR (100 MHz,
CDCl3): d = 144.4, 135.6, 135.5, 133.5, 133.2, 129.4, 127.4, 113.9, 108.0,
105.4, 81.2, 63.0, 59.5, 58.3, 54.9, 47.2, 44.4, 44.1, 41.7, 39.0, 33.2, 33.1,
26.9, 24.9, 20.6, 19.9, 19.4, 14.1; IR (film): nmax = 3071, 3049, 2929, 2859,
1460, 1428, 1107 cmꢀ1; HRMS: m/z: calcd for C38H54O4SiNa: 625.3683,
found 625.3667 [M+Na]+.
(s, 3H); 13C NMR (100 MHz, CDCl3): d
= 195.7, 155.7, 143.6, 135.6,
135.5, 133.6, 133.4, 131.9, 129.5, 127.6, 109.3, 105.5, 78.3, 63.2, 59.2, 50.4,
47.1, 46.0, 41.2, 35.1, 33.8, 33.1, 32.7, 30.0, 26.8, 21.1, 19.8, 19.4, 17.7;
HRMS: m/z: calcd for C37H50O5Si: 603.3505, found: 603.3520 [M+H]+.
The above procedure was used for the conversion of alcohol 57b to
enone 58b. [a]2D5
=
ꢀ38.1 (c=0.40, CH2Cl2); 1H NMR (400 MHz,
Alcohol 61: A solution of silyl ether 60 (70 mg, 0.12 mmol) in THF
(5 mL) was treated with TBAF (0.2 mL, 0.2 mmol, 1m THF) and stirred
at 258C for 12 h. The solution was concentrated and applied to silica gel
chromatography (Et2O/hexanes 4:1) to afford alcohol 61 (43 mg, 99%).
CDCl3): d = 7.67–7.61 (m, 4H), 7.43–7.32 (m, 6H), 6.77 (dd, J=3.6,
2.0 Hz, 1H), 5.84 (d, J=5.2 Hz, 1H), 5.13 (dd, J=4.0, 0.8 Hz, 1H), 4.48
(dt, J=9.6, 2.8 Hz, 1H), 3.96–3.88 (m, 2H), 3.73–3.69 (m, 1H), 3.34 (s,
3H), 3.30–3.24 (m, 1H), 2.27–2.19 (m, 3H), 1.77–1.43 (m, 6H), 1.26–1.04
(m, 2H), 1.03 (s, 12H), 0.97 (s, 3H), 0.90 (s, 3H); 13C NMR (100 MHz,
CDCl3): d = 195.5, 155.2, 144.1, 135.5, 135.3, 133.3, 133.0, 129.5, 127.5,
107.9, 105.6, 79.1, 78.6, 63.1, 59.2, 55.0, 50.3, 45.4, 41.3, 35.1, 33.2, 32.8 (2),
30.1, 26.9, 21.2, 19.9, 19.4, 17.9; HRMS: m/z: calcd for C37H50O5Si:
603.3505, found: 603.3511 [M+H]+.
Rf =0.2 (50% Et2O in hexanes); [a]D25
= +6.25 (c=1.00, CH2Cl2);
1H NMR (400 MHz, CDCl3): d = 5.78 (d, J=5.2 Hz, 1H), 5.11 (d, J=
4.8 Hz, 1H), 5.05 (s, 1H), 4.84 (s, 1H), 4.10–4.05 (m, 1H), 3.87 (dd, J=
12.0, 2.0 Hz, 1H), 3.55 (dd, J=12.4, 4.0 Hz, 1H), 3.36 (s, 3H), 3.18–3.09
(m, 1H), 2.77 (dd, J=10.8, 8.0 Hz, 1H), 2.08–0.81 (m, 14H), 0.85 (s, 6H),
0.69 (s, 3H); 13C NMR (100 MHz, CDCl3): d = 144.2, 114.1, 107.8, 105.5,
80.2, 61.7, 59.3, 58.1, 55.0, 46.7, 44.7, 44.4, 41.7, 38.9, 33.3 (2), 32.9, 24.5,
20.7, 20.6, 19.8, 14.0; IR (film): nmax = 3462, 1025, 998 cmꢀ1; HRMS: m/
z: calcd for C22H36O4Na: 387.3581, found 387.3599 [M+Na]+.
Ketone 59: Enone 58a (192 mg, 0.32 mmol) in methanol (25 mL) was
treated with 10% activated palladium on carbon (30 mg) and stirred for
16 h under an atmosphere of hydrogen. The solution was filtered through
Celite, concentrated and applied to silica gel chromatography to afford
59a (15 mg, 6%) and anomer 59b (144 mg, 75%).
Aldehyde 62: Alcohol 61 (32 mg, 0.09 mmol) in acetonitrile (5 mL) was
treated with IBX (76 mg, 0.27 mmol) and stirred at reflux for 1 h. The re-
action was cooled to 08C and the solids were removed by filtration and
the filter cake was washed with Et2O (3”10 mL). The solvent was re-
moved on the rotary evaporator and the residue was dried under high
vacuum for 2 h to yield crude aldehyde 62 (30 mg, 91%) which was
found to be unstable on silica gel and therefore carried forward without
purification. 1H NMR (400 MHz, CDCl3): d = 9.55 (dd, J=3.2, 1.6 Hz,
1H), 5.88 (d, J=7.2 Hz, 1H), 5.13–5.08 (m, 3H), 4.38 (dd, J=14.8,
3.2 Hz, 1H), 3.35 (s, 3H), 3.24–3.18 (m, 1H), 2.88 (dd, J=14.8, 10.4 Hz,
1H), 2.06–1.94 (m, 3H), 1.76–0.91 (m, 11H), 0.83 (s, 6H), 0.62 (s, 3H).
Treatment of enone 58b under identical reaction conditions led to isola-
tion of 59b as the sole product isolated in 83% yield. 59a: Rf =0.6 (50%
1
Et2O in hexanes); [a]2D5 = +78.9 (c=1.09, CH2Cl2); H NMR (400 MHz,
CDCl3): d = 7.68–7.63 (m, 4H), 7.41–7.36 (m, 6H), 5.87 (d, J=5.2 Hz,
1H), 5.06 (dd, J=4.8, 2.4 Hz, 1H), 4.56 (dt, J=10.0, 2.4 Hz, 1H), 3.90
(dd, J=11.6, 2.4 Hz, 1H), 3.65 (dd, J=11.6, 3.2 Hz, 1H), 3.52 (dd, J=
10.0, 8.4 Hz, 1H), 3.36 (s, 3H), 3.21–3.14 (m, 1H), 2.34 (t, J=9.6 Hz,
1H), 2.06–1.97 (m, 3H), 1.68–1.12 (m, 10H), 1.05 (s, 9H), 0.86 (s, 3H),
0.85 (s, 3H), 0.75 (s, 3H). 59b: Rf =0.6 (50% Et2O in hexanes); [a]D25
=
1
+18.3 (c=0.63, CH2Cl2); H NMR (400 MHz, CDCl3): d = 7.66–7.61 (m,
4H), 7.39–7.36 (m, 6H), 5.8 (d, J=5.5 Hz, 1H), 5.15 (d, J=4.5 Hz, 1H),
4.33–4.29 (m, 1H), 3.90–3.84 (m, 2H), 3.73 (dd, J=12.5, 3.0 Hz, 1H),
3.34 (s, 3H), 2.66–2.60 (m, 1H), 2.22–2.16 (m, 1H), 1.86 (dd, J=12.0,
7.0 Hz, 1H), 1.78–1.04 (m, 12H), 1.04 (s, 9H), 0.89 (s, 3H), 0.87 (s, 3H),
0.73 (s, 3H); HRMS: m/z: calcd for C37H52O5SiNa: 627.3482, found:
627.3491 [M+Na]+.
Ketone 63: Crude aldehyde 62 (30 mg, 0.88 mmol) in anhydrous THF
(5 mL) was cooled to 08C and treated with methyl magnesium bromide
(0.2 mL, 0.28 mmol, 1.4m, THF/toluene) for 1 h. The reaction was diluted
with Et2O (5 mL) and saturated aqueous ammonium chloride (15 mL),
extracted with Et2O (3”10 mL), dried over magnesium sulfate and con-
centrated on the rotary evaporator. The crude mixture of diastereomers
was oxidized with DMP (424 mg, 1 mmol) in CH2Cl2 at 258C for 4 h. The
reaction was diluted with saturated sodium thiosulfate (10 mL) and
NaHCO3 (10 mL) and the heterogenous mixture was vigorously stirred
until the solution was visibly clear. The aqueous layer was extracted with
CH2Cl2 (3”10 mL), dried over sodium sulfate and concentrated on
rotary evaporator. The residue was purified by silica chromatography to
afford the corresponding ketone (14 mg; 43% overall isolated, three
steps). Rf =0.3 (50% Et2O in hexanes); [a]2D5 = ꢀ4.51 (c=0.52, CH2Cl2);
1H NMR (400 MHz, CDCl3): d = 5.89 (d, J=5.2 Hz, 1H), 5.14 (s, 1H),
5.12 (d, J=4.8 Hz, 1H), 5.06 (s, 1H), 4.40 (d, J=10.4 Hz, 1H), 3.37 (s,
3H), 3.22–3.14 (m, 1H), 2.84 (dd, J=10.4, 8.0 Hz, 1H), 2.21 (s, 3H),
2.06–2.01 (m, 2H), 1.75–0.85 (m, 12H), 0.85 (s, 6H), 0.64 (s, 3H);
13C NMR (100 MHz, CDCl3): d = 206.0, 142.7, 115.5, 108.4, 105.6, 84.0,
59.3, 58.1, 55.1, 50.4, 44.9, 44.4, 41.6, 38.9, 33.3 (2), 33.0, 26.5, 24.6, 20.7,
20.6, 19.8, 13.9; IR (film): nmax = 2923, 1720, 1005 cmꢀ1; HRMS: m/z:
calcd for C23H36O4: 377.2691, found 377.2670 [M+H]+.
Alkene 60: Ketone 59b (125 mg, 0.21 mmol) in DME/THF 3:1 (5 mL)
was cooled to 08C and treated with methyl lithium (1 mL, 1.6 mmol,
1.6m in Et2O). The reaction was stirred for 30 min at 08C then diluted
with Et2O (15 mL), quenched with saturated ammonium chloride solu-
tion and extracted with Et2O (3”15 mL). The solvent was removed on
the rotary evaporator and purified by silica gel chromatography (hex-
anes/Et2O 7:3) to give the corresponding alcohol (98 mg, 75%). 60a:
Rf =0.5 (50% Et2O in hexanes); [a]D25
=
ꢀ14.1 (c=1.0, CH2Cl2);
1H NMR (400 MHz, CDCl3): d = 7.72–7.66 (m, 4H), 7.42–7.37 (m, 6H),
5.74 (d, J=4.4 Hz, 1H), 5.18 (d, J=5.2 Hz, 1H), 4.34 (d, J=8.8 Hz, 1H),
4.00 (d, J=10.4 Hz, 1H), 3.67 (dd, J=11.2, 2.0 Hz, 1H), 3.40 (s, 3H),
3.06–3.03 (m, 1H), 2.77 (dd, J=8.4, 6.4 Hz, 1H), 2.69–2.62 (m, 1H),
2.04–1.99 (m, 2H), 1.85 (t, J=10.0 Hz, 1H), 1.74–1.07 (m, 10H), 1.24 (s,
3H), 1.07 (s, 9H), 1.02 (s, 3H), 0.90 (s, 3H), 0.89 (s, 3H); 13C NMR
(100 MHz, CDCl3): d = 135.5, 135.4, 133.4, 133.0, 129.5 (2), 127.6, 127.5,
107.3, 107.2, 78.3, 65.9, 58.9, 57.9, 55.1, 48.8, 44.7, 44.5, 42.0, 41.2, 33.9,
Lactone 64: A solution of ketone 63 (6 mg, 0.016 mmol) in acetone
33.1, 32.8, 26.9, 25.2, 23.7, 21.0, 20.9, 19.9, 19.4, 16.3; IR (film): nmax
=
(0.2 mL) was treated with a solution of chromic acid (15 mg, 0.15 mmol)
7188
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Chem. Eur. J. 2005, 11, 7175 – 7190

Norrisolide
FULL PAPER
in acetic acid (1.5 mL) with water (0.5 mL), and stirred for 6 h at room
temperature. The solution was diluted with CH2Cl2 (5 mL) and washed
with water (10 mL) followed by aqueous sodium hydrogen carbonate
(10 mL). The organic solvent was dried over sodium sulfate and concen-
trated on the rotary evaporator. The residue was purified on silica gel to
yield the corresponding lactone (4.5 mg, 80%). Rf =0.6 (hexanes/Et2O/
CH2Cl2 1:1:0.02); [a]D25 = +22.4 (c=0.16, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d = 6.22 (d, J=5.6 Hz, 1H), 5.31 (s, 1H), 5.04 (s, 1H), 4.46 (d,
J=10.8 Hz, 1H), 3.32–3.25 (m, 1H), 2.93 (t, J=10.4 Hz, 1H), 2.74 (dd,
J=18.8, 4.0 Hz, 1H), 2.56 (dd, J=19.2, 10.8 Hz, 1H), 2.25 (s, 3H), 2.08
(t, J=9.2 Hz, 1H), 1.72–1.02 (m, 11H), 0.86 (s, 6H), 0.65 (s, 3H);
13C NMR (100 MHz, CDCl3): d = 204.1, 174.2, 142.9, 117.4, 107.3, 85.2,
59.6, 58.1, 49.6, 44.5, 42.2, 41.5, 38.9, 33.3, 33.2, 30.5, 27.0, 24.7, 20.7, 20.6,
19.8, 14.2; IR (film): nmax = 2924, 1788, 1721, 992 cmꢀ1; HRMS: m/z:
calcd for C22H32O4: 361.2378, found 361.2391 [M+H]+.
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(+)-Norrisolide (1): Solid NaHCO3 (84 mg, 0.5 mmol) was added at 08C
to a solution of lactone 64 (4.5 mg, 0.012 mmol) in CH2Cl2 (3 mL) and
the heterogeneous mixture was stirred for 5 min. mCPBA (3.5 mg,
0.020 mmol) dissolved in CH2Cl2 (1 mL) was added to the reaction flask
and the mixture was stirred at 08C for 45 min. The reaction was
quenched by the addition of saturated aqueous sodium thiosulfate
(10 mL) and stirred for an additional 30 min. The mixture was diluted
with saturated aqueous NaHCO3 and extracted with CH2Cl2 (3”5 mL).
The combined organic phases were dried over sodium sulfate and the sol-
vent removed on the rotary evaporator. The compound was purified on
silica gel to yield norrisolde as a white solid (1.5 mg). Rf =0.6 (hexanes/
Et2O 3:7); [a]2D5 = +3.5 (c=0.13, CH2Cl2); 1H NMR (400 MHz, C6D6): d
= 6.63 (dd, J=4.0, 1.6 Hz, 1H), 5.66 (dd, J=6.4, 1.6 Hz, 1H), 4.90 (s,
1H), 4.77 (s, 1H), 2.70 (dd, J=8.8, 3.6 Hz, 1H), 2.40–2.33 (m, 1H), 2.15
(dd, J=18.0, 4.0 Hz, 1H), 1.76 (dd, J=18.4, 10.8 Hz, 1H), 1.58 (s, 3H),
1.45–0.60 (m, 12H), 0.85 (s, 3H), 0.79 (s, 3H), 046 (s, 3H); 13C NMR
(100 MHz, C6D6): d = 173.5, 168.5, 143.4, 116.9, 107.1, 101.8, 58.7, 57.7,
50.0, 45.0, 41.7, 40.5, 38.6, 33.4, 33.3, 30.5, 24.2, 21.2, 20.7, 20.4, 19.9, 14.1;
HRMS: m/z: calcd for C22H32O5: 316.2038, found 316.2051 [MꢀAcOH]+.
Acknowledgements
Financial support from the NIH (CA 086079) is gratefully acknowledged.
We also thank Dr. L. N. Zakharov and Dr. P. Gantzel (UCSD, X-Ray Fa-
cility) for the reported crystallographic studies and Professor D. J. Faulk-
ner (Scripps Institute of Oceanography) for a sample of natural norriso-
lide.
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Received: May 6, 2005
Published online: September 15, 2005
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