Studies of neodolastanes - Synthesis of the tricyclic core of the trichoaurantianolides

Article abstract of DOI:10.1139/v2012-088

Studies toward the synthesis of trichoaurantianolide C (5) are described. Stille cross-coupling reactions of (E)-and (Z)-β-stannyl-α,β- unsaturated esters with allylic acetate 32 provide for the stereocontrolled formation of nonconjugated 2,5-diene-1-ols. Studies of the asymmetric Sharpless epoxidation are utilized to establish diastereofacial selectivity for the preparation of a crucial C₂ tertiary allylic alcohol for subsequent esterification and ring-closing metathesis. SmI₂ reductive cyclization of the key butenolide precursor 49 led to formation of the central seven-membered ring of the tricyclic core of the natural product.

Full text of DOI:10.1139/v2012-088

21
Studies of neodolastanes — Synthesis of the
tricyclic core of the trichoaurantianolides
David R. Williams and Joseph R. Pinchman
Abstract: Studies toward the synthesis of trichoaurantianolide C (5) are described. Stille cross-coupling reactions of
(E)- and (Z)-␤-stannyl-␣,␤-unsaturated esters with allylic acetate 32 provide for the stereocontrolled formation of nonconjugated
2,5-diene-1-ols. Studies of the asymmetric Sharpless epoxidation are utilized to establish diastereofacial selectivity for the
preparation of a crucial C2 tertiary allylic alcohol for subsequent esterification and ring-closing metathesis. SmI2 reductive
cyclization of the key butenolide precursor 49 led to formation of the central seven-membered ring of the tricyclic core of the
natural product.
Key words: ␲-allyl Stille cross-coupling, reductive cyclization, stereoselective synthesis.
Résumé : On décrit une série d’études réalisées dans le but de faire la synthèse du trichoaurantianolide C (5). Des réactions de
couplages croisés de Stille entre des esters (E)- et (Z)-␤-stannyl-␣,␤-insaturés et l’acétate allylique 32 conduisent a la formation
`
stéréocontrôlée de 2,5-dién-1-ols non conjugués. On a utilisé les méthodes d’époxydation asymétrique de Sharpless pour
déterminer la sélectivité diastéréofaciale pour la préparation d’un alcool allylique tertiaire en C2 crucial pour l’estérification
subséquente et la réaction de métathèse qui permet d’effectuer la fermeture du cycle. La cyclisation réductrice a l’aide de SmI
`
2
du précurseur buténolide clé 49 conduit cycle central a sept chaînons de la partie tricyclique fondamentale du produit naturel.
`
Mots-clés : couplage croisé ␲-allylique de Stille, cyclisation réductrice, synthèse stéréosélective.
[Traduit par la Rédaction]
3 may also give rise to interesting transannular events.7 In fact,
the 3,7-dolabelladienes are key precursors to the dolastanes,8 a
class of 5–7–6 tricyclic marine terpenes, as illustrated in
dolatriol (4), as well as the fusicoccanes of fungi origin that
feature the 5–8–5 carbocyclic skeleton.9 Similarly, the initia-
tion of a transannular reaction in the neodolabellene series (3)
yields the corresponding family of neodolastanes, and the first
examples of these diterpenes were independently discovered
by Vidari and co-workers10 and Steglich and co-workers.11
Thus, trichoaurantianolides A–D (trichoaurantianolide C (5))
were isolated from a Tricholoma species, a large genus of
gilled mushrooms. In these structures, the anticipated 5–7–6
tricyclic neodolastane core is otherwise disguised by subse-
quent oxidations of the cyclohexenyl ring, which is reorga-
nized with the fusion of a butyrolactone and the unsaturated
tetrahydrofuranyl system featured in 5. Extensive NMR stud-
ies have established the relative stereochemistry and structural
connectivity of the trichoaurantianolides, and Steglich and
co-workers11 assigned the absolute configuration of trichoau-
rantianolide B by X-ray crystallographic analysis. Subsequently,
Sterner and co-workers12 reported the isolation of lepistol (6) and
its corresponding aldehyde, which are deoxygenated C8 deriva-
tives of 5. In 2003, Ohta and co-workers13 further described the
characterization of tricholomalides A, B, and C (tricholomalide
A, 7), and these studies concluded that the absolute configuration
Introduction
Natural products of the dolabellane and dolastane families
have been studied as significant targets for synthesis because
they present a number of interesting structural features as well
as an impressive array of biological activities.1 These metab-
olites share a common biogenetic pathway from geranylgera-
nyl pyrophosphate via the dolabellane cation 1 (Fig. 1), which
may give rise to 3,7-dolabelladienes (2) by elimination or
capture by water. In 1976, Ireland et al.2 first described the
isolation of the dolabellanes as secondary metabolites of the
sea hare Dolabella californica, and the first synthesis was
described in 1993.3,4 Since these initial reports, approximately
150 examples have been discovered from marine and terres-
trial sources.5 A stereospecific backbone migration of substitu-
ents in the dolabellane cation 1 results in the neodolabellanes,
as exemplified by ␤-neodolabellenol (3).6 The neodolabellanes
have been exclusively found in various species of coral. On the
other hand, it is apparent that the dolabellanes and many
related derivatives are available in the biosphere as examples
of the d- or l-enantiomeric series based on an initial species-
specific cyclization. This can be a challenging issue for natural
product isolation because of problems resulting from the sea-
water filtration of feeding organisms, cohabitation, and sym-
biotic fungi. The [9.3.0] cyclotetradecane framework of 2 and
Received 22 June 2012. Accepted 1 September 2012. Published at www.nrcresearchpress.com/cjc on 20 December 2012.
D.R. Williams and J.R. Pinchman. Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana,
47405-7102, USA.
Corresponding author: David R. Williams (e-mail: williamd@indiana.edu).
This article is part of a Special Issue dedicated to Professor Derrick Clive in celebration of his many contributions to organic chemistry.
Can. J. Chem. 91: 21–37 (2013)
doi:10.1139/v2012-088
Published by NRC Research Press

22
Can. J. Chem. Vol. 91, 2013
Fig. 1. Representative dolabellane and dolastane diterpenes.
H3C
CH3
OH
H
10
CH3
H
H
HO
H
CH3
OH
H
H3C
H3C
12
14
7
1
CH3
3
6
2
CH3
CH3
CH3
CH3
CH3
HO
4
H3C
CH3
CH3
OH
1 (Dolabellane cation)
2 (3,7-Dolabelladiene-18-ol)
3 (β-Neodolabellenol)
4 (Dolatriol)
OH
O
O
O
O
H
H
O
O
O
HO
H3C
O
O
H3C
HO
CH3
CH3
7 (Tricholomalide A)
CH3
H3C
CH3
CH3
CH3
CH3
6 (Lepistol)
O
CH3
O
CH3
5 (Trichoaurantianolide C)
is opposite to that assigned for the trichoaurantianolides based on
studies of circular dichromism. In 2009, Danishefsky and co-
workers14 reported a structure revision and total synthesis for
racemic tricholomalides A and B. In addition, examples of the
guanacastepene family have subsequently characterized these
diterpenes as 5–7–6 representatives of the neodolastane family.
The guanacastepenes have been the subject of a number of
synthesis studies.15
The preparation of the enantioenriched cyclopentene pre-
cursors is summarized in Scheme 2. We have previously
described the synthesis of racemic cyclopentenone 13 begin-
ning with 2-methyl-2-cyclopenten-1-one via cuprate conjugate
addition, enolate alkylation with allyl bromide, and oxidative
cleavage followed by selective reduction.16 The Corey–
Bakshi–Shibata (CBS) reduction17 of ketone 13 has been used
to effect a resolution by generating equal amounts of the
diastereomeric alcohols 14 and 15 (diastereomeric ratio (dr)
1:1). The diastereomers are readily separated by flash chro-
matography on a multigram scale, and the oxidation of alcohol
Results and discussion
Trichoaurantianolide C (5) exhibits a novel neodolastane
skeleton in which the cyclohexane precursor of these metab-
olites is oxidatively cleaved and transformed into the cis-fused
lactone and a bridging tetrahydrofuran containing C2, C3, and
C4 of the original carbocycle. We sought to address the chal-
lenging aspects presented by seven contiguous stereogenic
carbon centers in 5 with a retrosynthetic plan (Scheme 1)
designed to simplify the required tasks. We have focused our
attention on the tricyclic lactone 9 as a key intermediate, which
displays the trans orientation of methyl substituents at C7 and
C10. This rationale suggests that a reductive cyclization of the
butenolide 10 would achieve our objective via the diastere-
oselective formation of the seven-membered ring. In principle,
our goal for an enantiocontrolled synthesis would be met
by a convergent approach that provides a stereocontrolled
alkylation of a suitably rendered nonracemic cyclopentene 11
with the substituted butenolide 12. Indeed, the latter discon-
nection is seen as a critical barrier for success of the overall plan
because of the need to establish the appropriate chirality at C2 of
10. To circumvent this problem, our studies have explored two
strategies to satisfy this stereochemical requirement. Firstly, the
C2 chirality may be directly incorporated into 10 by an alkylation
leading to C1–C11 bond formation. This approach would mask
the butenolide of 12 as an enantiopure synthon that contains an
additional carbon (C1) as well as the desired C2 stereochemistry.
Alternatively, we have reasoned that the allylic C1–C2 bond of 10
could readily be formed if this operation were to precede instal-
lation of the C2 chirality. The latter alternative suggests a reagent-
controlled reaction for accessing the desired C2 configuration in
the butenolide 10.
14 provided the nonracemic ketone (–)-13 ([α]2D0 –57.6 (c
2.04, CHCl3)) for further chemistry. Hydrazone formation is
followed by radical decomposition of 16 with iodine in the
presence of tetramethylguanidine (TMG) to yield the alkenyl
iodide 17,18 and halogen–metal exchange readily produced
high yields of ethyl ester 18 for reduction to the nonracemic
allylic alcohol 19.
With ample quantities of the cyclopentene components in
hand, our studies examined a strategy for formation of the C1–C11
bond of the intermediate lactone 20 (Fig. 2). We rationalized that
a direct alkylation by nucleophilic displacement of the hin-
dered unreactive bromide of 21 would be problematic. This
difficulty may be overcome by the reaction of the epoxide 22
with an appropriate alkenylmetal species (23) to yield the
desired 20 via facile lactonization. However, plans for the
straightforward preparation of nonracemic 21 or 22 were not
apparent. This concept can be extended to the racemic six-membered
lactone 24, which may be prepared with excellent enantioselectivity.
Nucleophilic opening of the terminal oxirane of 24 and internal
transesterification would produce lactone 20.
To test this idea, initial efforts provided the racemic epoxide 24
in three steps from the known keto-alcohol 2519 via nucleophilic
epoxidation and esterification to yield the ketophosphonate 26
for ring closure by an internal Horner–Wadsworth–Emmons
olefination using the LiCl/DBU (1,8-diazabicyclo[5.4.0]undec-
7-ene) protocol.20 However, our subsequent experiments
leading to the formation of a higher order cuprate from the
alkenyl iodide 17 proved to be capricious. In these efforts, the
novel triene 28 was characterized as the product of SN2= opening
Published by NRC Research Press

Williams and Pinchman
23
Scheme 1. Retrosynthetic analysis.
4
R
R
O
O
O
3
H
O
O
O
1
5
12
O
11
10
2
13
14
2
O
O
10
7
6
7
8
H3C
CH3
CH3
CH3
H3C
H3C
CH3
CH3
CH3
CH3
OH
OH
OH
CH3
CH3
9 (R = functionalized alkyl)
5
8 (R = alkyl)
X
R
1
12
11
1
O
R
2
O
2
O
10
O
H3C
CH3
CH3
CH3
CH3
CH3
O
CH3
CH3
H
O
H
12 (R = functionalized alkyl)
10 (R = functionalized alkyl)
11 (X = leaving group)
Scheme 2. Preparation of enantioenriched cyclopentenes.
HO
HO
O
(+)-CBS, BH3•SMe2
THF; 40 °C (85%)
+
CH3
CH3
H3C
CH3
H3C
CH3
H3C
14
CH3
CH3
(dr 1:1)
TBSO
TBSO
TBSO
( )-13
15
TPAP; NMO
(95%)
(–)-13
H2NNH2; Et3N
EtOH (96%)
H2N
N
I
R
1) n-BuLi; THF
I2; THF
TMG (68%)
EtO2CCl (99%)
CH3
H3C
16
CH3
H3C
17
CH3
H3C
2) DIBAL
CH3
CH3
CH3
CH2Cl2 at –78 °C
(80%)
TBSO
TBSO
TBSO
18 R = COOEt
19 R = CH2OH
of the epoxide 24 (15%–20% yields). The reduced alkene of 17
and unreacted enone 24 were substantially recovered. To circum-
vent this issue, the saturated lactone 27 was also prepared by
hydrogenation with Wilkinson’s catalyst at elevated hydrogen
pressure (50 bar; 1 bar ϭ 100 kPa). Unfortunately, the terminal
epoxide 27 proved to be completely unreactive with various
cuprates derived from the metalation of iodide 17.
Concomitantly, our plans for C1–C2 bond formation began
to show promise for subsequent introduction of C2 chirality in
20. As summarized in Scheme 3, the conjugate addition of
tri-n-butylstannyl cuprate with alkynyl ethyl ester 29 affords
the (Z)-␣,␤-unsaturated product 30 in an excellent yield with
high stereoselectivity when these reactions are quenched after
warming to 22 °C. On the other hand, the (E)-product 31,
resulting from syn addition of the cuprate reagent, is obtained
by the inclusion of anhydrous methanol for a kinetic quench
at –78 °C.21 In this fashion, the individual Z- and E-isomers 30
and 31, respectively, have been examined in studies of ␲-allyl
Stille cross-coupling reactions15h,22 with the allylic acetate 32,
which is available from the nonracemic alcohol 19 (Scheme 2).
Gratifyingly, the Stille cross-coupling processes demonstrated
O
n-BuLi,
LiCuCN(2-Th),
–78 °C, then
I
O
TBSO
CH3
CH3
O
H3C
H3C
H3C
CH3
28
O
CH3
24
TBSO
H3C
17
O
Published by NRC Research Press

24
Can. J. Chem. Vol. 91, 2013
Fig. 2. Initial considerations for C1–C11 bond formation in 20.
M
M
OR
1
CH3
CH3
H3C
OR
O
RO
O
CH3
CH3
1
TBSO
TBSO
O
H3C
2
11
EtOOC
O
Br
2
23 (M = metal)
23 (M = metal)
1
2
O
H3C
CH3
CH3
CH3
CH3
CH3
21
TBSO
22
20
1) 30% H2O2/H2O
Triton B
O
O
O
O
O
LiCl; CH3CN
DBU
RhCl(PPh3)3
P(OEt)2
O
O
THF (78%)
O
O
H3C
OH
2
O
O
H2 (50 bar)
(92%)
H3C
H3C
2)
H3C
P(OEt)2
(89%)
O
HO
O
O
1
25
N,N'-diisopropylcarbodiimide
DMAP; CH2Cl2
26
24
27
(85%)
Scheme 3. Preparation of (E)- and (Z)-epoxy alcohols.
AcO
BnO
X
Y
32
1) n-Bu3SnH; n-BuLi
COOEt
CuCN; THF; –78 °C
CH3
H3C
CH3
SnBu3
Y
quench at 22 °C
TBSO
BnO
2) n-Bu3SnH; n-BuLi
CuCN; THF
Pd(PPh3)4
LiCl; CuCl
DMSO; 50 °C
X
OBn
CH3
CH3
30 (X = H; Y = COOEt) (86%)
31 (X = COOEt; Y = H) (59%)
MeOH quench
at –78 °C
TBSO
29
H3C
33 (X = H; Y = COOEt) (85%)
34 (X = COOEt; Y = H) (67%)
OH
BnO
H
BnO
O
O
OH
1) DIBAL–H
–78 °C to –15 °C
(82%)
H
2) Sharpless Epoxidation
(see Table 1)
CH3
H3C
CH3
CH3
H3C
36 (75%)
CH3
TBSO
TBSO
35 (70%)
high stereocontrol in both cases and provided good yields of the
individual isomers, (E)-33 (85%) and (Z)-34 (67%). Our plan to
establish C2 chirality by means of a chemoselective asymmetric
epoxidation is facilitated by the convenient reduction of 33 and
34 to their corresponding (E)- and (Z)-allylic alcohols. Indeed, a
site selective oxidation of the nonconjugated 2,5-diene-1-ols was
readily achieved under the conditions of the asymmetric Sharp-
less epoxidation with tert-butyl hydroperoxide.23 However, sur-
prisingly poor diastereofacial selectivity was observed for
epoxidations for the (E)-allylic alcohol leading to 35 (Table 1,
entries 1–4). A change to (ϩ)-diisopropyl-L-tartrate (L-DIPT)
and a decrease in catalyst loading offered minimal improve-
ments favoring 35 (dr 65:35; Table 1, entry 4). The absence
of a clear facial preference and the inability to separate the
diastereomeric products also prevents a confident assign-
ment of stereochemistry at this point. By comparison, the
corresponding (Z)-allylic alcohol produced a selective ep-
oxidation to yield 36 (dr 92:8; Table 1, entry 5) using
D-DIPT.
The assignments of epoxide stereochemistry in these
experiments are clarified by subsequent transformations
leading to the tricyclic core of trichoaurantianolide C. Prog-
ress toward this goal independently utilized inseparable
oxiranes (Table 1, entries 3 and 5) for the reaction sequence
Published by NRC Research Press

Williams and Pinchman
25
Table 1. Conditions for asymmetric Sharpless epoxidation.
the substrate, the influence of a proton source, and the presence of
certain additives. For example, methanol forms a complex with
SmI2, whereas tert-butyl alcohol does not lead to complexation.31
Procter and co-workers32 found that changing the proton
source from methanol to tert-butyl alcohol may produce dif-
ferent cyclization pathways. Inorganic salts, such as LiCl and
NiI2, and cosolvents, including hexamethylphosphoramide
(HMPA), N-methyl-2-pyrrolidinone (NMP), and 1,3-dimethyl-3,
4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), have effectively
increased the oxidation potential of the reduction.33,34
Allylic
alcohol
Tartrate
(equiv)
Ti(O-i-Pr)4
(equiv)
Epoxide
(dr)
Entry
1
2
3
4
5
(E)
(E)
(E)
(E)
(Z)
L-DET (1.6)
L-DET (0.26)
L-DIPT (1.3)
L-DIPT (0.12)
D-DIPT (0.6)
0.6
0.2
1.0
0.1
0.5
45:55
55:45
60:40
65:35
92:8
As summarized in Scheme 5, aldehyde 49 is readily pre-
pared from alcohol 43 (Dess–Martin periodinane, CH2Cl2,
92% yield). However, the initial attempts for SmI2 cycliza-
tions in dry tetrahydrofuran (THF) containing methanol (2.2
equiv led only to recovered starting material. When HMPA is
included as a cosolvent (THF/HMPA, 10:1 by volume), sig-
nificant amounts of the desired products 50a and 50b (dr
85:15) are obtained (30% yield), accompanied by an equal
quantity of the uncyclized reduced butyrolactone 51 as a
mixture of diastereomers.
illustrated in Scheme 4 to yield the desired butenolides. Thus,
the conversion to the epoxy bromides 37 is followed by the
addition of n-butyllithium at low temperature to give a mixture
of C2 tertiary alcohols, 38. Acylation of the hindered alkoxide
with freshly distilled acryloyl chloride affords esters 39 (70%
yield, 81% based on recovered starting material (brsm)), and
this material is immediately submitted for ring-closing metath-
esis (RCM).24 A survey of RCM catalysts and conditions
revealed that the Grubbs II catalyst25 is extremely effective
and provides nearly quantitative yields of the five-
membered lactone 40. To install the remaining methyl
substituent at C7, we utilized a two-step procedure for facile
conjugate addition with dimethylcuprate in ether at –25 °C
(86%) followed by ␣-selenation of the enolate and oxida-
tive elimination using metachloroperbenzoic acid. After
deprotection, the diastereomers 43 and 44 were successfully
separated and fully characterized. Butenolide 43 was char-
acterized as the major product stemming from the asym-
metric Sharpless epoxidation, and this substance was
advanced for our studies of reductive cyclization.
Our efforts for the formation of the central seven-membered
ring of trichoaurantianolide C focused on the use of samar-
ium diiodide, which has been widely utilized for intramo-
lecular reductive ketyl-enone/enoate coupling reactions of
five- and six-membered systems.26,27 There are relatively
few studies that feature intramolecular reductive coupling
reactions to yield seven- and eight-membered examples.
In this regard, Arimotoand co-workers28 described high
stereoselectivity for the reductive cyclization of 45 to give
the tricyclic ketone 46.29 However, Tori and co-workers30
reported approximately equal amounts of all four diaste-
reomers of 48 in the SmI2 reduction of the unrestricted
enone 47.
We were somewhat surprised that the aldehyde had sur-
vived these conditions, and subsequently we investigated SmI2
reductions in the absence of a proton source. At 0 °C, an
excess of SmI2 (6 equiv) is required for consumption of the
starting material, and a rapid conversion to the desired 50a and
50b is apparent by thin-layer chromatography (TLC). How-
ever, various quenching procedures lead to a crude mixture
that contains substantial amounts of side products. These ex-
periments produced approximately 50% yields of the desired
cycloheptanes 50a and 50b (dr 1:1) after careful chromatog-
raphy. When tert-butyl alcohol is introduced as a proton
source, in addition to the use of HMPA, these reactions pro-
duce fewer side products and the yield of the reductive cycl-
ization is increased to 63% with a modest preference for the
formation of ␤-alcohol 50a (dr 65:35). The desired reaction
proceeds via the initial formation of the ketyl radical 52,
arising from a one-electron reduction of the ␣,␤-unsaturated
lactone. Introduction of a second electron at the aldehyde site
may lead to a diradical species for C–C bond formation by
radical cyclization. Alternatively, further reduction of 52
would produce a dianion as a two-electron reduction, which
could account for competing cyclization to provide the diaste-
reomeric alcohols 50a and 50b or protonation to give the
byproduct 51. The tethered arrangement of 52 provides an
energetically favored conformational bias for facial selectiv-
ity. Thus, the arrangement of 7,10-anti-dimethyl substituents
in the products 50a and 50b is enforced by the substantial
steric requirements leading to the cis-fused butyrolactones.
The diastereomers were separated and characterized with 2D
NMR spectroscopic analysis. Significantly, the 2D-NOESY
analysis identifies key correlations between the C7 methyl and
C2 methylene substituents (refers to natural product number-
ing; see Scheme 1) to support the assignment of the cis-fused
lactone. The stereochemistry of the C8 alcohol is established
by 2D NOESY correlations between the C8 hydrogen and the
OH
H3C
H3C
H
SmI2 (20 equiv)
CHO
THF; tBuOH
0 °C (86%)
H
H
H
O
TBSO
O
TBSO
45
46
O
O
SmI2 (3 equiv)
H
HMPA (12 equiv)
C
10 methyl as well as the ␣-hydrogen at C1. The minor isomer
H
THF; 22 °C
(78%)
H3C
50b shows the expected correlations of the ␤ hydrogen at C8
with the C2 and C7 alkyl groups. Oxidation of a mixture of
these diastereomers yielded ketone 53 as a crystalline solid,
and X-ray crystallographic studies unambiguously confirmed
the stereochemistry of the tricyclic system (Fig. 3).35 This
CH3
O
HO
48
47
A number of variables are key factors that can affect the
outcome of these SmI2 cyclizations, including the geometry of
Published by NRC Research Press

26
Can. J. Chem. Vol. 91, 2013
Scheme 4. Formation of butyrolactones 43 and 44.
X
BnO
O
OBn
OBn
1) CBr4; imidazole
PPh3; CH2Cl2
(88%)
iPrMgCl (1.0 equiv); THF;
then acryloyl chloride
HO
O
O
2) n-BuLi;
(81%)
CH3
CH3
CH3
H3C
CH3
CH3
CH3
THF at –90 °C
(87%)
TBSO
TBSO
TBSO
H3C
H3C
39
38
35/36 X = OH
37 X = Br
1) Me2CuLi;
Et2O at –25 °C
(86%)
OBn
OBn
OBn
1) Grubbs II catalyst
O
O
O
(0.1 equiv)
O
O
O
2) LDA; THF;
PhSeBr at –78 °C
(88%)
3) then MCPBA; CH2Cl2;
–78 °C to 22 °C
2) toluene; 70 °C
(99%)
H3C
H3C
RO
H
CH3 CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
RO
TBSO
aq. HF;
CH3CN
(91%)
41 R = TBS
43 R = H
aq. HF;
CH3CN
(91%)
42 R = TBS
44 R = H
40
(75%, 2 steps)
Scheme 5. Formation of the tricyclic core of trichoaurantianolide D.
OBn
OBn
OBn
O
O
O
SmI2
O
O
O
+
THF:HMPA
(10:1 by volume)
MeOH (2.2 equiv)
H3C
H3C
H CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
HO
CH3
O
H
O
H
49
50ab
51
OBn
DMP; NaHCO3
CH2Cl2 (77%)
O
O
OBn
1
H3C
8
CH3
CH3
O
CH3
2
54
O
7
10
S
H3C
CH3
CH3
CH3
1)
2) n-Bu3SnH
N
N
N
O
N
AIBN
53
THF; 80 °C
BnO
O
OBn
OBn
O
O
O
SmI2
H
O
2
2
+
O
H
CH3
CH3
8
8
H3C
HO
H3C
CH3
CH3
CH3
CH3
CH3
HO
O
CH3
52
50a
50b
result also confirms the absolute stereochemistry of the major
lactone diastereoisomer 50a as the desired C2 configuration,
which is produced in the Sharpless epoxidation affording
epoxy alcohol 36 (dr 92:8). The parent ring system conserved
within this family of neodolastanes also was characterized by
Barton–McCombie deoxygenation of alcohol 50b, yielding
the tricyclic lactone 54 as featured in lepistol and related
natural products.
Published by NRC Research Press

Williams and Pinchman
27
Fig. 3. ORTEP of ketone 53.
visualized under UV light and (or) staining with ethanolic
p-anisaldehyde, potassium permanganate, or phosphomolybdic
acid. Flash chromatography was performed using Merck silica
gel 60 (Kiesegel 60) (EM Science; 230–400 mesh, American
Society for Testing and Materials (ASTM)) or similar products
from Whatman Scientific or Sorbent Technologies, and pressure
was obtained using an airline bleed.
All reagents and solvents were reagent grade and used as
received unless noted otherwise. Bulk-grade hexanes and ethyl
acetate (EtOAc) for chromatography were distilled before use.
Diethyl ether (Et2O) and tetrahydrofuran (THF) were obtained
anhydrous by degassing with argon and then passing through
activated alumina columns under pressure to remove water and
oxygen.36 Methylene chloride (CH2Cl2), N,N-diisopropylamine
(DIPEA), and triethylamine (Et3N) were distilled from CaH2
under dry air immediately before use. HMPA was stored over
CaH2 and distilled under high vacuum.
Unless otherwise noted, all reactions were conducted in
flame-dried glassware under an atmosphere of argon. All non-
volatile samples were pumped to a constant weight under high
vacuum (0.1–0.2 mm Hg; 1 mm Hg ϭ 133.3224 Pa) at
ambient temperature following removal of solvents by rotary
evaporation.
Conclusions
In summary, we have devised an enantioselective pathway
for the synthesis of neodolastane metabolites as exemplified
by trichoaurantianolide C. Our studies have described an efficient
␲-allyl Stille cross-coupling reaction, and we have resolved some
unanticipated problems stemming from the asymmetric Sharpless
epoxidations of our nonracemic E- and Z-2,5-diene-1-ols.
Samarium-mediated reductive cyclizations have provided the tri-
cyclic core of the neodolastane natural products as confirmed by
characterization of the 5–7–5 tricyclic ketone 53. These efforts
provide a basis to further our investigations toward the trichoau-
rantianolide natural products.
((2R,3R)-2-(2-(tert-Butyldimethylsilyloxy)ethyl)-3-isopropyl-2-
methylcyclopenty-lidene)hydrazine (16)
To a solution of (–)-13 (1.23 g, 4.1 mmol), EtOH (50 mL),
and Et3N (13.8 mL, 98.7 mmol) was added an 85% aqueous
hydrazine solution (9.92 mL, 271 mmol) and the reaction
mixture was heated to reflux. After 68 h, the reaction mixture
was cooled to room temperature (rt) and was partitioned
between CH2Cl2 (200 mL) and H2O (100 mL). The organic
layer was extracted, the aqueous layer was extracted with
CH2Cl2 (1 ϫ 200 mL), and the organic layers were combined,
washed with brine (60 mL), dried over Na2SO4, and concen-
trated in vacuo to provide a yellow oil. The crude product was
purified via flash chromatography (hexanes/EtOAc, 4:1 ¡ 3:2),
providing the hydrazone 16 (1.230 g, 96%) as a clear sligh-
tly yellow oil. Hydrazone 16 is characterized as follows:
Experimental
General
Optical rotations were obtained on a PerkinElmer 241 polar-
imeter at 589 nm (sodium D line) using a 10 cm path length and
a 1.0 mL volume. Concentrations (c) are given in g/100 mL.
Infrared (FT-IR) spectra were recorded on a Nicolet Avatar 360
spectrometer and are reported in wavenumbers (cm–1). Proton
nuclear magnetic resonance (1H NMR) spectra were measured on
a Varian VXR-400 (400 MHz), Varian INOVA-500 (500 MHz),
or Varian INOVA-400 (400 MHz) instrument. Carbon nuclear
magnetic resonance (13C NMR) spectra were measured on an
INOVA-400 (101 MHz), VXR-400 (101 MHz), or INOVA-500
[α]2D3 –29.9 (c 1.65, CHCl3). Rf ϭ 0.22 (30% EtOAc in
hexanes). IR (neat, cm–1): 3380, 3220, 2970, 2860, 1740,
1520, 1396, 1370, 1260, 1090, 840, 780. 1H NMR (400 MHz,
CDCl3) ␦: 4.80 (br s, 2H), 3.68–3.53 (m, 2H), 2.36–2.28 (m,
1H), 2.05–1.90 (m, 3H), 1.83–1.60 (m, 3H), 1.50–1.38 (m,
1H), 1.01 (d, J ϭ 6.6 Hz, 3H), 0.98 (s, 3H), 0.87 (s, 9H), 0.86
(d, J ϭ 6.6 Hz, 3H), 0.03 (s, 3H), 0.02, (s, 3H). 13C NMR
(101 MHz, CDCl3) ␦: 165.8, 60.2, 50.7, 46.8, 41.9, 28.6, 26.0,
24.9, 24.6, 22.8, 21.2, 21.1, 18.3, –5.2, –5.3. MS (CI, NH3)
m/e (relative intensity): 313 (1), 255 (13), 241 (8), 154 (29),
149 (24), 123 (10), 111 (100), 107 (12), 85 (25), 55 (10).
HR-MS m/e calcd for C12H25OS [M ϩ 1]ϩ: 313.2677; found:
313.2666.
(125 MHz) spectrometer. H NMR and 13C NMR spectra were
1
acquired as solutions in CDCl3 and are reported in parts per
million (ppm) downfield (␦) from tetramethylsilane using resid-
ual chloroform (CHCl3) as an internal standard set to ␦ 7.26 and
77.00 ppm, respectively. Proton NMR data are reported in the
following form: ␦ (multiplicity, coupling constants, number of
protons). Mass spectral data (low-resolution mass spectrometry
(LR-MS) and high-resolution (HR)-MS) were recorded on a
Waters LCT Classic electrospray time-of-flight analyzer with an
Agilent 1100 capillary high-performance liquid chromatography
(HPLC) inlet, a Sciex API III electrospray quadropole with direct
infusion inlet, or a Finnigan MAT-95 by use of chemical ioniza-
tion (CI) or electron impact (EI). Analytical HPLC was per-
formed using a Waters 600E HPLC on a Supelco Ascentis Si
5 ␮m (25 cm ϫ 4.6 mm) column. Preparative HPLC was per-
formed using a Waters LC2000 HPLC on a Supelco Ascentis Si
5 ␮m (25 cm ϫ 21.2 mm) column. HPLC purifications used
either a hexanes/EtOAc or hexanes/i-PrOH isocratic gradient,
with ultraviolet (UV) detection at ␭ ϭ 254 nm using a Waters 796
PDA.
tert-Butyl(2-((1R,5R)-2-iodo-5-isopropyl-1-methylcyclopent-2-
enyl)ethoxy)dimethylsilane (17)
To a 100 mL round-bottom flask was added I2 (1.41 g,
5.57 mmol) and THF (20 mL). A solution of 1,1,3,3-
tetramethylguanidine (1.81 mL, 14.4 mmol) in THF (20 mL)
was added dropwise to the flask over 5 min. The reaction was
stirred for 10 min at which point hydrazone 16 (300 mg,
0.960 mmol) in THF (2 mL) was added dropwise. The reaction
mixture was stirred for 30 min, Et2O (120 mL) was added, and
Analytical TLC was performed using glass-backed 0.25 mm
thickness silica gel 60 (F254) plates (EM Science), which were
Published by NRC Research Press

28
Can. J. Chem. Vol. 91, 2013
the reaction mixture was washed with saturated aqueous
CuSO4 (2 ϫ 60 mL). The aqueous layer was extracted with
Et2O (30 mL), and the combined organic layers were washed
with saturated aqueous Na2SO3 (2 ϫ 40 mL), brine (30 mL),
dried over Na2SO4, and concentrated in vacuo to provide a
yellow oil. The crude product was purified via flash chroma-
tography (hexanes/EtOAc, 15:1) to provide 17 (268 mg, 68%)
as a clear colorless oil. Rf ϭ 0.55 (10% EtOAc in hexanes). IR
(neat, cm–1): 3060, 2980, 1620, 1470, 1390, 1370, 1295, 1260,
vacuo to provide a clear colorless oil. The product was purified
by flash chromatography (hexanes/EtOAc, 10:1) to provide
((4R,5R)-5-(2-(tert-butyldimethylsilyloxy)ethyl)-4-isopropyl-
5-methylcyclopent-1-enyl)methanol (19) (108 mg, 80%) as a
clear colorless oil. [α]D23 –3.5 (c 2.28, CHCl3). Rf ϭ 0.19 (10%
EtOAc in hexanes). IR (neat, cm–1): 3381, 2955, 1472, 1254,
835. 1H NMR (400 MHz, CDCl3) ␦: 5.54 (d, J ϭ 1.1 Hz, 1H),
4.11 (d, J ϭ 4.3 Hz, 2H), 3.75–3.58 (m, 2H), 2.77 (t, J ϭ
5.1 Hz, 1H), 2.36–2.28 (m, 1H), 2.00–1.90 (m, 2H), 1.85 (q,
J ϭ 8.1 Hz, 1H), 1.78–1.65 (m, 2H), 0.97 (d, J ϭ 6.4 Hz, 3H),
0.96 (s, 3H), 0.89 (d, J ϭ 6.4 Hz, 3H), 0.88 (s, 9H), 0.05 (s,
3H), 0.04 (s, 3H). 13C NMR (101 MHz, CDCl3) ␦: 150.9,
124.9, 60.6, 59.7, 51.0, 48.8, 40.4, 34.8, 29.2, 25.9, 22.6, 22.4,
20.7, 18.3, Ϫ5.5. MS (CI, CH4) m/e (relative intensity): 137
(100), 163 (71), 237 (14), 312 (2). HR-MS m/e calcd for
C18H36O2Si (Mϩ): 312.24846; found: 312.24899. Anal.
calcd for C18H36O2Si: C 69.17, H 11.61; found: C 68.93, H
11.63.
1
1090, 1030, 1005, 980, 930, 900, 840, 810, 740. H NMR
(400 MHz, CDCl3) ␦: 6.08–6.05 (m, 1H), 3.68–3.53 (m, 2H),
2.40–2.30 (m, 1H), 2.03–1.93 (m, 2H), 1.80–1.65 (m, 3H),
1.03 (d, J ϭ 6.5 Hz, 3H), 0.89 (s, 9H), 0.88 (d, J ϭ 6.8 Hz,
3H), 0.87 (s, 3H), 0.06 (s, 3H), 0.06 (s, 3H). 13C NMR
(101 MHz, CDCl3) ␦: 137.7, 111.4, 60.0, 52.4, 46.9, 41.6,
37.8, 29.7, 26.0, 22.4, 21.9, 20.5, 18.2, –5.1, –5.2. MS (CI,
NH3) m/e (relative intensity): 351 (17), 184 (8), 149 (36), 123
(56), 121 (19), 107 (44), 93 (42), 83 (47), 49 (100). HR-MS
m/e calcd for C17H33IOSi [M ϩ H]ϩ: 409.1424; found:
409.1448.
((4R,5R)-5-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-4-
isopropyl-5-methylcyclopent-1-en-1-yl)methyl acetate (32)
A solution of ((4R,5R)-5-(2-(tert-butyldimethylsilyloxy)
ethyl)-4-isopropyl-5-methylcyclopent-1-enyl)methanol (19;
1.82 g, 5.83 mmol) in CH2Cl2 (29 mL) was cooled to 0 °C and
treated with 4-dimethylaminopyridine (1 crystal), pyridine
(3.76 mL, 46.6 mmol), and acetic anhydride (1.66 mL,
17.5 mmol). The cooling bath was removed and the reaction
was allowed to warm to rt. After 45 min, the reaction was
quenched with saturated aqueous NaHCO3 (20 mL). The or-
ganic layer was separated and the aqueous layer was washed
with CH2Cl2 (3 ϫ 30 mL). The combined extracts were
washed with brine, dried over Na2SO4, filtered, and isolated in
vacuo to provide a clear colorless oil. The product was purified
by flash column chromatography (hexanes/EtOAc, 20:1) to
(4R,5R)-Ethyl 5-(2-(tert-butyldimethylsilyloxy)ethyl)-4-
isopropyl-5-methylcyclopent-1-ene-1-carboxylate (18)
To a solution of 17 (337 mg, 0.825 mmol) in Et2O (3.5 mL)
at –78 °C was added n-BuLi (2.5 mol/L in hexanes, 396 ␮L,
0.99 mmol) dropwise. After 30 min, ethyl chloroformate
(316 ␮L, 3.3 mmol) was added dropwise, and the reaction was
allowed to slowly warm to room temperature. After 12 h, Et2O
(6 mL) was added to the reaction mixture followed by the
addition of saturated aqueous NaHCO3 (3 mL). The layers
were separated and the aqueous layer was extracted with Et2O
(3 mL). The organic layers were combined, washed with H2O
(6 mL), brine (5 mL), dried over MgSO4, and concentrated in
vacuo to provide a clear colorless oil. The crude oil was
purified by flash chromatography (hexanes/EtOAc, 10:1) to
provide (4R,5R)-ethyl 5-(2-(tert-butyldimethylsilyloxy)ethyl)-4-
isopropyl-5-methylcyclopent-1-ene-1-carboxylate (18; 290 mg,
provide 1.83 g (90%) of 32 as a clear colorless oil. [α]2D0 –11.8
(c 6.81, CHCl3). Rf ϭ 0.65 (hexanes/EtOAc, 2:1). IR (film, cm–1):
2956, 2930, 2857, 1746, 1473, 1365, 1228, 1092, 1040, 939, 836. 1H
NMR (400 MHz, CDCl3) ␦: 5.62 (bs, 1H), 4.62–4.51 (m, 2H),
3.69 (ddd, J ϭ 10.1, 8.5, 6.1 Hz, 1H), 3.55 (ddd, J ϭ 10.1, 8.8,
5.6 Hz, 1H), 2.35–2.25 (m, 1H), 2.07 (s, 3H), 2.00–1.92 (m,
1H), 1.85–1.65 (m, 4H), 1.00 (d, J ϭ 6.5 Hz, 3H), 0.97 (s, 3H),
0.88 (s, 9H), 0.87 (d, J ϭ 6.5 Hz, 3H), 0.03 (s, 6H). 13C NMR
(101 MHz, CDCl3) ␦: 170.8, 145.3, 127.4, 61.3, 60.4, 51.4,
49.3, 40.8, 34.7, 29.2, 26.0, 22.5, 22.3, 21.0, 20.4, 18.3, –5.3
(2C). HR-MS-ESI calcd for C20H38O3SiNa [M ϩ Naϩ]:
377.2488; found: 344.2473.
99%) as a clear colorless oil. [α]2D2 –8.2 (c 0.45, CHCl3). Rf ϭ
0.55 (hexanes/EtOAc, 10:1). IR (film, cm–1): 2957, 1715, 1627,
1471 1368, 1236, 1096, 835, 775. 1H NMR (300 MHz, CDCl3)
␦: 6.69–6.67 (m, 1H), 4.16 (q, J ϭ 7.1 Hz, 2H), 3.66–3.45 (m,
2H), 2.48–2.36 (m, 1H), 2.24 (ddd, J ϭ 14.2, 8.4, 5.9 Hz, 1H),
2.09–1.96 (m, 2H), 1.85–1.69 (m, 2H), 1.28 (t, J ϭ 7.1 Hz, 3H),
1.12 (s, 3H), 1.03 (d, J ϭ 6.5 Hz, 3H), 0.89 (d, J ϭ 6.5 Hz, 3H),
0.86 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H). 13C NMR (75 MHz,
CDCl3) ␦: 165.3, 143.0, 142.6, 61.2, 60.1, 51.4, 49.5, 40.4, 35.4,
29.4, 26.4, 23.2, 22.7, 20.8, 18.7, 14.6, –4.94 (2C). HR-MS-ESI
calcd for C20H38O3SiNa [M ϩ Naϩ]: 377.2488; found:
377.2481.
1-(2-(Hydroxymethyl)oxiran-2-yl)ethanone
To a solution of 25 (1.13 g, 11.3 mmol) in THF (40 mL) at
0 °C was added H2O2 (30% wt in H2O, 5.13 g, 45.2 mmol)
dropwise over 6 min, followed by benzyltrimethylammonium
hydroxide (Triton B; 40% wt in MeOH, 473 mg, 1.13 mmol).
The reaction mixture was stirred for 80 min and quenched
slowly with solid Na2S2O3 (16.24 g, 102.75 mmol; noted
extensive gas evolution). After being quenched, the reaction
mixture was brought to ambient temperature, CH2Cl2
(70 mL) was added, and the solution was dried over
Na2SO4. The solids were filtered, and the filtrate was
washed with CH2Cl2 (50 mL) and EtOAc (50 mL). Removal
of the solvent in vacuo provided a slightly yellow oil.
Purification of the crude material via flash chromatography
(hexanes/EtOAc, 1:1) afforded 1-(2-(hydroxymethyl)oxiran-
((4R,5R)-5-(2-(tert-Butyldimethylsilyloxy)ethyl)-4-
isopropyl-5-methylcyclopent-1-enyl)methanol (19)
To a solution of (4R,5R)-ethyl 5-(2-(tert-butyldimethylsilyloxy)
ethyl)-4-isopropyl-5-methylcyclopent-1-ene-1-carboxylate
(153 mg, 0.43 mmol) in CH2Cl2 (2.4 mL) at –78 °C was added
diisobutylaluminum hydride (1.0 mol/L in hexanes, 1.08 mL,
1.08 mmol) dropwise. After 45 min at –78 °C, the reaction
temperature was allowed to warm to –10 °C over 3 h and then
was quenched with 4 mL of saturated aqueous sodium potas-
sium tartrate (4 mL) and stirred overnight. The reaction mix-
ture was extracted with CH2Cl2 (2 ϫ 4 mL) and the combined
organic layers were dried over MgSO4 and concentrated in
Published by NRC Research Press

Williams and Pinchman
29
2-yl)ethanone (912 mg, 78%) as a clear colorless oil. Rf ϭ
0.43 (hexanes/EtOAc, 1:3). IR (film, cm–1): 3445, 2929, 1666,
1362, 1222, 1045. 1H NMR (400 MHz, CDCl3) ␦: 4.00 (d, A of
AB, JAB ϭ 12.7 Hz, 1H), 3.89 (d, B of AB, JAB ϭ 12.7 Hz,
1H), 3.08 (d, A of AB, JAB ϭ 5.0 Hz, 1H), 3.03 (d, B of AB,
was added dropwise. The reaction was stirred for 10 min
at –78 °C, placed in a 0 °C ice bath for 10 min, then cooled
back to –78 °C. A solution of the racemic epoxide 24 (67 mg,
0.478 mmol) in THF (2 mL) was cooled to –78 °C and was
cannulated into the cuprate solution. The reaction was main-
tained at –50 °C for 1 h, and then was warmed to rt and was
stirred overnight. The reaction was quenched with 50% satu-
rated aqueous NH4Cl with stirring for 15 min. The organic
layer was separated and the aqueous layer was washed with
EtOAc (3 ϫ 4 mL). The organic layers were combined, dried
over Na2SO4, filtered, and concentrated in vacuo to provide an
oil. Purification via flash chromatography (hexanes/EtOAc,
4:1) provided triene 28 (30 mg, 15%) as a white solid. Rf ϭ
0.48 (hexanes/EtOAc, 4:1). IR (film, cm–1): 2974, 2949, 2855,
1702, 1471, 1389, 1276, 1091, 836. 1H NMR (300 MHz,
CDCl3) ␦: 5.54 (t, J ϭ 2.4 Hz, 1H), 5.43(s, 1H), 5.36 (s, 1H),
4.82 (s, 2H), 3.71–3.57 (m, 2H), 2.49–2.40 (m, 1H), 2.25–2.16
(m, 1H), 2.04 (s, 3H), 1.97–1.76 (m, 2H), 1.67 (t, J ϭ 7.4 Hz,
2H), 1.01–0.99 (m, 6H), 0.94 (d, J ϭ 6.5 Hz, 3H), 0.87 (s,
9H), 0.02 (s, 6H). 13C NMR (101 MHz, CDCl3) ␦: 163.7,
147.1, 144.8, 138.0, 131.5, 127.2, 115.4, 69.6, 60.4, 53.0, 52.8,
42.9, 33.9, 28.7, 26.0, 23.1, 20.9, 19.5, 18.3, 16.9, –5.2.
HR-MS-CI calcd for C24H41O3Si [M ϩ Hϩ]: 405.2819;
found: 405.2811.
J
AB ϭ 5.0 Hz, 1H), 2.08 (s, 3H). 13C NMR (75 MHz, CDCl3)
␦: 207.7, 61.6, 61.2, 48.9, 23.8. HR-MS-CI calcd for C5H9O3
[M ϩ Hϩ]: 117.0546; found: 117.0549.
(2-Acetyloxiran-2-yl)methyl 2-(diethoxyphosphoryl)
acetate (26)
To a solution of 1-(2-(hydroxymethyl)oxiran-2-yl)ethanone
(864 mg, 7.44 mmol) in CH2Cl2 (20 mL) at 0 °C was added
4-dimethylaminopyridine (DMAP; 45.4 mg, 0.372 mmol) fol-
lowed by 2-diethylphosphonoacetic acid (1.44 mL, 8.93 mmol)
and N,N=-diisopropylcarbodiimide (1.44 mL, 9.67 mmol). The
reaction mixture was warmed to room temperature and stirred
overnight. The insoluble materials were filtered from the reaction
mixture and the reaction mixture was concentrated in vacuo. Et2O
(60 mL) was added to the crude reaction mixture, insoluble
materials were filtered, and the reaction mixture was concentrated
in vacuo. This procedure was repeated three times to afford a
yellow oil. Purification by flash chromatography (hexanes/
EtOAc, 1:5) provided 26 (1.85 g, 85%) as a clear oil. Rf ϭ 0.18
(hexanes/EtOAc, 1:3). IR (film, cm–1): 2986, 2934, 1744, 1716,
1269, 1119, 1026, 972. 1H NMR (400 MHz, CDCl3) ␦: 4.80 (d,
A of AB, JAB ϭ 12.4 Hz, 1H), 4.32 (d, B of AB, JAB ϭ 12.4 Hz,
1H), 4.16 (m, 4H), 3.15 (d, A of AB, JAB ϭ 4.9 Hz, 1H), 3.02 (d,
B of AB, JAB ϭ 4.9 Hz, 1H), 3.00 (s, 1H), 2.94 (s, 1H), 2.09 (s,
3H), 1.35 (m, 6H). 13C NMR (75 MHz, CDCl3) ␦: 218.3, 165.2
(d, JCP ϭ 6.2 Hz), 62.8 (d, JCP ϭ 6.3 Hz), 62.5, 60.0, 48.8, 34.1
(d, JCP ϭ 134.0 Hz), 23.7, 16.3 (d, JCPϭ 6.2 Hz). HR-MS-ESI
calcd for C11H19O7Na [M ϩ Naϩ]: 317.0766; found: 317.0758.
4-Methyl-1-oxaspiro[2.5]octan-6-one (27)
To a solution of 24 (79 mg, 0.056 mmol) in benzene
(1.7 mL) was added (PPh3)2RhCl (10 mg, 0.011 mmol). The
reaction flask was put in a reaction bomb, charged with 50 bar
H2, and reacted over 18 h at rt. After purging the reaction flask
with argon, the solvent was removed in vacuo and the crude
product was purified via flash column chromatography
(hexanes/EtOAc, 1:1) to afford 74 mg (92%) of 27 as a clear
yellow oil as a 60:40 mixture of inseparable diastereomers. Rf ϭ
0.44 (hexanes/EtOAc, 1:3). IR (thin film, cm–1): 2973, 2942,
1741, 1460, 1420, 1379, 1354, 1274, 1185, 1153, 1047.
1H NMR (400 MHz, CDCl3) ␦: 4.57 (d, J ϭ 12.7 Hz, 0.4H),
4.53 (d, J ϭ 12.5 Hz, 0.6H), 4.08 (d, J ϭ 12.5 Hz, 0.6H), 4.07
(d, J ϭ 12.7 Hz, 0.4H), 2.97–2.90 (m, 1.37H), 2.81–2.68 (m,
1.70H), 2.55–2.42 (m, 1.61H), 2.10–2.01 (m, 0.47H), 1.14 (d,
J ϭ 7.1 Hz, 1.15H), 0.91 (m, 1.84H). 13C NMR (126 MHz,
CDCl3) ␦: 169.9, 169.8, 72.9, 71.2, 57.6, 56.3, 49.6, 49.2,
36.4, 36.3, 31.4, 28.3, 16.8, 13.5. GC-HR-MS calcd for
C7H11O3 [M ϩ Hϩ]: 143.0703; found: 143.0707.
8-Methyl-1,5-dioxaspiro[2.5]oct-7-en-6-one (24)
To a solution of 26 (430 mg, 1.46 mmol) in acetonitrile
(60 mL) at 0 °C was added LiCl (74.2 mg, 1.75 mmol)
followed by dropwise addition of DBU (221.4 ␮L, 1.46 mmol).
The white suspension was stirred for 1 h, allowed to warm to rt,
and was quenched with a 50% saturated NH4Cl solution (50 mL).
The aqueous layer was then extracted with CH2Cl2 (3 ϫ
25 mL) and the combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo to afford a red oil.
The crude product was purified via flash chromatography
(hexanes/EtOAc, 1:1) to provide racemic 24 (181 mg, 89%) as
a white solid. Rf ϭ 0.50 (hexanes/EtOAc, 1:3). IR (film, cm–1):
3064, 2991, 1731, 1639, 1446, 1398, 1270, 1231, 1151, 1104,
1061, 941, 855. 1H NMR (400 MHz, CDCl3) ␦: 6.09 (m, 1H),
4.39 (d, A of AB, JAB ϭ 12.2 Hz, 1H), 4.27 (d, B of AB, JAB ϭ
12.2 Hz, 1H), 3.15 (d, A of AB, JAB ϭ 4.4 Hz, 1H), 3.01 (d, B
of AB, JAB ϭ 4.4 Hz, 1H), 1.81 (d, J ϭ 1.0 Hz, 3H). 13C NMR
(100 MHz, CDCl3) ␦: 162.8, 154.3, 122.0, 69.8, 53.2, 51.1, 15.7.
HR-MS-CI calcd for C7H9O3 [M ϩ Hϩ]: 141.0546; found:
141.0546.
(Z)-Ethyl 4-(benzyloxy)-3-(tributylstannyl)but-2-enoate (30)
A suspension of CuCN (1.36 g, 15.2 mmol) in THF (52 mL)
was cooled to –78 °C and treated with n-BuLi (2.5 mol/L in
hexanes, 12.2 mL, 30.4 mmol) dropwise. The resulting yellow
heterogeneous solution was warmed to 0 °C and stirred for
30 min. The suspension became a clear yellow solution. The
solution was then cooled to –78 °C and treated with neat
n-Bu3SnH (8.85 g, 30.4 mmol) dropwise over 10 min with a
noted color change to a dark yellow solution with H2 evolu-
tion. After 10 min, ethyl ester 29 (3.01 g, 13.8 mmol) in THF
(6 mL) was added dropwise and the reaction turned a dark red
color. After 10 min, the reaction mixture was quenched by
cannulation into a 90% saturated aqueous NH4Cl / 10%
NH4OH solution (200 mL). After 45 min, the layers were
separated and the aqueous layer was washed with Et2O (3 ϫ
100 mL). The combined organic extracts were washed with
brine, dried over Na2SO4, filtered, and concentrated in vacuo
3-((4R,5R)-5-(2-(tert-Butyldimethylsilyloxy)ethyl)-4-
isopropyl-5-methylcyclopent-1-enyl)-5-methylene-5,
6-dihydro-2H-pyran-2-one (28)
To a solution of iodide 17 (143 mg, 0.348 mmol) in THF
(1.5 mL) at –78 °C was added n-BuLi (2.5 mol/L in hexanes,
167 ␮L, 0.418 mmol) dropwise. After 30 min, a solution of
LiCuCN(2-Th) (0.25 mol/L in THF, 1.50 mL, 0.375 mmol)
Published by NRC Research Press

30
Can. J. Chem. Vol. 91, 2013
to provide a brown oil. The crude product was purified by flash
column chromatography (petroleum ether / Et2O, 99:1) to pro-
vide 30 (6.00 g, 86%) as a clear colorless oil. Rf ϭ 0.55
(hexanes/EtOAc, 10:1). IR (film, cm–1): 2955, 2870, 1702,
1604, 1456, 1307, 1194. 1H NMR (400 MHz, CDCl3) ␦:
7.36–7.26 (m, 5H), 6.75 (t, J ϭ 2.1 Hz, JSn–H ϭ 52 Hz, 1H),
4.56 (s, 2H), 4.31 (m, 2H), 4.20 (q, J ϭ 7.1 Hz, 2H), 1.51–1.27
(m, 15H), 1.08–0.84 (m, 15H). 13C NMR (101 MHz, CDCl3)
␦: 168.2, 168.0, 138.2, 128.4, 127.6, 127.5, 126.3, 75.5, 72.5,
60.3, 29.2, 27.4, 14.3, 13.7, 10.9. HR-MS-ESI calcd for
C25H42O3SnNa [M ϩ Naϩ]: 533.2054; found: 533.2073.
oil. The crude product was purified by flash column chromatog-
raphy (hexanes/EtOAc, 30:1) to afford 33 (594.2 mg, 85%) as a
clear colorless oil. [α]2D0 –21.5 (c 0.69, CHCl3). Rf ϭ 0.68
(hexanes/EtOAc, 4:1). IR (film, cm–1): 2955, 2856, 1718, 1659,
1
1472, 1255, 1178, 1095, 836. H NMR (500 MHz, CDCl3) ␦:
7.37–7.28 (m, 5H), 6.16 (bs, 1H), 5.14 (bs, 1H), 4.54 (ABq,
⌬␯AB ϭ 9.6 Hz, JAB ϭ 12 Hz, 2H), 4.16 (d, J ϭ 7 Hz, 2H), 4.00
(dq, J ϭ 15.1, 1.5 Hz, 2H), 3.72 (td, J ϭ 9.7, 6.4, 1H), 3.56 (td,
J ϭ 9.9, 4.9 Hz, 1H), 3.20 (dd, J ϭ 15.7, 2.1 Hz, 1H), 3.11 (d,
J ϭ 15.7, 1H), 2.26–2.19 (m, 1H), 1.89–1.64 (m, 5H), 1.27
(t, J ϭ 7.1 Hz, 3H), 1.00 (d, J ϭ 7.7 Hz, 3H), 0.93 (s, 3H), 0.89
(s, 9H), 0.86 (d, J ϭ 6.5 Hz, 3H), 0.05 (s, 6H). 13C NMR
(126 MHz, CDCl3) ␦: 166.1, 155.6, 147.0, 137.9, 128.4, 127.7,
127.6, 122.6, 116.5, 72.6, 72.5, 60.5, 59.7, 51.2, 49.9, 40.7, 34.5,
29.3, 27.3, 26.0, 22.6, 22.3, 19.9, 14.3, –5.2 (2C). HR-MS-ESI
calcd for C31H50O4SiNa [M ϩ Naϩ]: 537.3376; found:
537.3365.
(E)-Ethyl 4-(benzyloxy)-3-(tributylstannyl)but-2-enoate (31)
A suspension of CuCN (88 mg, 1 mmol) in THF (3 mL) was
cooled to –78 °C and treated with n-BuLi (2.1 mol/L in
hexanes, 1.05 mL, 2.2 mmol) dropwise. The resulting yellow
heterogeneous solution was warmed by removal of the cold
bath until the reaction mixture became a clear yellow solution.
The solution was then cooled to –78 °C and treated with neat
n-Bu3SnH (640 mg, 2.2 mmol) dropwise with a noted color
change to a dark yellow solution with H2 evolution. After
15 min, a solution of ester 29 (328 mg, 1 mmol) in THF
(2 mL) and MeOH (202 ␮L, 5 mmol) was added dropwise and
the reaction turned a dark red color. After 15 min, the reaction
mixture was quenched by the addition of a 90% saturated
aqueous NH4Cl / 10% NH4OH solution (10 mL) at –78 °C and
warmed to rt. After 1 h, Et2O (15 mL) was added and the
phases were separated. The aqueous layer was washed with
Et2O (2 ϫ 15 mL) and the combined organic extracts were
washed with brine, dried over Na2SO4, filtered, and concen-
trated in vacuo to provide a clear colorless oil. The crude
product was purified by flash column chromatography (petro-
leum ether / Et2O, 97:3) to provide 31 (302 mg, 59%) as a
clear colorless oil. Rf ϭ 0.50 (hexanes/EtOAc, 10:1). IR (film,
cm–1): 3032, 2957, 2854, 1709, 1606, 1456, 1344, 1179, 1093,
(Z)-Ethyl 4-(benzyloxy)-3-(((4R,5R)-5-(2-((tert-
butyldimethylsilyl)oxy)ethyl)-4-isopropyl-5-methylcyclopent-
1-en-1-yl)methyl)but-2-enoate (34)
To a small flask, LiCl (19.3 mg, 0.457 mmol) was added
and flame-dried under a stream of argon. Upon cooling,
Pd(PPh3)4 (8.8 mg, 7.6 ␮mol) and CuCl (38 mg, 0.38 mmol)
were added to the flask. After flushing the reaction flask with
argon for several minutes, a solution of allylic acetate 32
(27 mg, 0.076 mmol) in DMSO (0.7 mL) was added followed
by vinyl stannane 31 (54.2 mg, 0.107 mmol) in DMSO
(0.8 mL). The resulting reaction mixture was degassed (3ϫ)
by the freeze–pump–thaw method. The reaction was stirred for
1 h at rt and then heated to 50 °C for 13 h. After cooling to rt,
the reaction was transferred to a separatory funnel and water
(20 mL) and Et2O (20 mL) were added. The organic layer was
separated and then the aqueous layer was washed with Et2O
(2 ϫ 20 mL). The combined organic layers were washed with
brine (10 mL), dried over Na2SO4, filtered, and concentrated
in vacuo to provide a brown oil. The crude product was
purified by flash column chromatography (Et2O / petroleum
ether, 3:97) to afford 34 (29.0 mg, 67%) in about 90% purity
(as judged by evidence in the 1H NMR spectrum with approx-
imately 5%–10% of an inseparable side product) as a clear
colorless oil. Rf ϭ 0.67 (hexanes/EtOAc, 4:1). IR (film, cm–1):
2956, 2928, 2856, 1716, 1643, 1497, 1463, 1374, 1255, 1215,
1146, 1093. 1H NMR (300 MHz, CDCl3) ␦: 7.35–7.26 (m, 5H),
1
864. H NMR (400 MHz, CDCl3) ␦: 7.33–7.26 (m, 5H), 5.90
(t, J ϭ 2.6 Hz, JSn–H ϭ 31.2 Hz, 1H), 4.71 (m, 2H), 4.54 (s,
2H), 4.13 (q, J ϭ 7.1 Hz, 2H), 1.52–1.20 (m, 15H), 0.95–0.78
(m, 15H). 13C NMR (101 MHz, CDCl3) ␦: 176.0, 164.4,
138.1, 128.2, 128.1, 127.6, 124.0, 74.4, 73.0, 59.8, 29.1, 29.0,
27.3, 14.3, 13.7, 10.9. HR-MS-ESI calcd for C25H42O3SnNa
[M ϩ Naϩ]: 533.2054; found: 533.2048.
(E)-Ethyl 4-(benzyloxy)-3-(((4R,5R)-5-(2-((tert-
butyldimethylsilyl)oxy)ethyl)-4-isopropyl-5-methylcyclopent-1-
en-1-yl)methyl)but-2-enoate (33)
5.81 (s, 1H), 5.23 (s, 1H), 4.63 (ABq, ⌬␯ ϭ 49 Hz, JAB
ϭ
AB
13.6 Hz, 2H), 4.50 (ABq, ⌬␯AB ϭ 6 Hz, JAB ϭ 12 Hz, 2H), 4.14
(q, J ϭ 7.1 Hz, 2H), 3.73–3.61 (m, 1H), 3.50 (td, J ϭ 9.7, 5.2 Hz,
1H), 2.90 (ABq, ⌬␯AB ϭ 29 Hz, JAB ϭ 15.8, 2H), 2.28–2.22 (m,
1H), 1.94–1.59 (m, 5H), 1.27 (t, J ϭ 7.1 Hz, 3H), 1.01 (d, J ϭ
5.8 Hz, 3H), 0.89–0.83 (m, 15H), 0.03 (s, 6H). 13C NMR
(126 MHz, CDCl3) ␦: 166.0, 157.7, 147.3, 138.3, 128.3, 127.7,
127.5, 124.6, 119.3, 72.6, 67.4, 60.5, 59.9, 51.1, 50.1, 40.7, 34.6,
32.6, 29.3, 26.0, 22.6, 22.3, 20.0, 18.3, 14.3, –5.2 (2C). HR-MS-
ESI calcd for C31H50O4SiNa [M ϩ Naϩ]: 537.3376; found:
537.3358. This material was used without the need for additional
purification.
To a 100 mL round-bottom flask, LiCl (345 mg, 8.14 mmol)
was added and was flame-dried under a stream of argon. Upon
cooling, Pd(PPh3)4 (157 mg, 0.136 mmol) and CuCl (671 mg,
6.78 mmol) were added to the flask. After flushing the flask
with argon for several minutes, a solution of allylic acetate 32
(481 mg, 1.36 mmol) in dimethyl sulfoxide (DMSO; 13.6 mL)
was added followed by the vinyl stannane 30 (967 mg,
1.90 mmol) in DMSO (13.6 mL). The resulting reaction mix-
ture was degassed (3ϫ) by the freeze–pump–thaw method.
The reaction was stirred for 1 h, and then heated to 50 °C for
13 h. After cooling to rt, the reaction was transferred to a
separatory funnel and water (200 mL) and Et2O (60 mL) were
added. The organic layer was separated and then the aqueous
layer was extracted with Et2O (3 ϫ 60 mL). The combined
organic layers were washed with brine (40 mL), dried over
Na2SO4, filtered, and concentrated in vacuo to provide a brown
(E)-4-(Benzyloxy)-3-(((4R,5R)-5-(2-((tert-
butyldimethylsilyl)oxy)ethyl)-4-isopropyl-5-methylcyclopent-1-
en-1-yl)methyl)but-2-en-1-ol
A solution of 33 (156.4 mg, 0.304 mmol) in CH2Cl2 (6.2 mL) was
cooled to –78 °C and treated with diisobutylaluminium hydride
Published by NRC Research Press

Williams and Pinchman
31
(DIBAL-H; 760 ␮L, 1 mol/L in hexanes, 0.760 mmol). After 1 h
at –78 °C, additional DIBAL-H was added (304 ␮L, 1 mol/L in
hexanes, 0.304 mmol). After 30 min, the reaction was warmed
to –15 °C over 1.5 h and then quenched with saturated aqueous
Rochelle’s salt (6 mL). The reaction was warmed to rt and stirred
for 2 h after which the layers were separated. The aqueous layer
was washed with CH2Cl2 (3 ϫ 10 mL), and the organic layers
were combined. The organic layer was washed with brine (5 mL),
dried with Na2SO4, filtered, and concentrated in vacuo to provide
a yellow oil. The crude product was purified by flash column
chromatography (hexanes/EtOAc, 10:1) to afford the expected
(E)-allylic alcohol (132.4 mg, 92%) as a clear colorless oil. Rf ϭ
2.33–2.18 (m, 1H), 1.96–1.66 (m, 5H), 1.60 (ddd, J ϭ 14.1, 8.9,
4.9, 1H), 1.01 (d, J ϭ 5.9 Hz, 3H), 0.93 (m, 15H), 0.03 (s, 6H).
13C NMR (101 MHz, CDCl3) ␦: 146.4, 138.0, 128.3, 127.6,
123.8, 73.3, 71.4, 62.7, 61.0, 60.4, 59.5 50.7, 50.1, 40.4, 34.9,
29.3, 27.1, 26.0, 22.5, 22.3, 19.5, 18.3, –5.2, –5.3. HR-MS-ESI
calcd for C29H48O4SiNa [M ϩ Naϩ]: 511.3220; found:
511.3200. Data for the sample of the minor diastereomer of 35:
Rf ϭ 0.20 (hexanes/EtOAc, 4:1). 1H NMR (400 MHz) ␦: 7.34–
7.28 (m, 5H), 5.37 (s, 1H), 4.55 (ABq, ⌬␯ ϭ 8 Hz, JAB
ϭ
12.1 Hz, 2H), 3.79–3.73 (m, 1H), 3.72 (d,AJBϭ 11.3 Hz, 1H),
3.68–3.58 (m, 2H), 3.52 (d, J ϭ 11.3 Hz, 1H), 3.48–3.43 (m,
1H), 3.31 (dd, J ϭ 6.8, 4.6 Hz, 1H), 2.59–2.54 (m, 1H), 2.32–
2.24 (m, 1H), 1.95–1.51 m, 6H), 1.00 (d, J ϭ 6.4 Hz, 3H),
0.89–0.84 (m, 15H), 0.02 (s, 6H). 13C NMR (101 MHz, CDCl3)
␦: 146.6, 137.9, 128.4, 127.6, 127.6, 123.2, 73.4, 71.6, 62.7, 61.1,
60.3, 59.2, 50.7, 50.1, 40.6, 34.7, 29.2, 27.2, 26.0, 22.6, 22.1,
19.8, 18.3, –5.2 (2C). HR-MS-ESI calcd for C29H48O4SiNa
[M ϩ Naϩ]: 511.3220; found: 511.3203.
0.26 (hexanes/EtOAc, 4:1). [α]2D0 –19.7 (c 3.10, CHCl3). IR
1
(film, cm–1): 3384, 2954, 2929, 1471, 1255, 1094, 1006. H
NMR (400 MHz, CDCl3) ␦: 7.34–7.26 (m, 5H), 5.85 (t, J ϭ
6.8 Hz, 1H), 5.20 (s, 1H), 4.49 (ABq, ⌬␯ ϭ 17 Hz, JAB
ϭ
AB
11.9 Hz, 2H), 4.23–4.10 (m, 1H), 3.92 (ABq, ⌬␯ ϭ 32 Hz,
J
AB ϭ 12.2 Hz, 2H), 3.70 (td, J ϭ 9.7, 6.5 Hz, 1H),A3B.45 (td, J ϭ
10.0, 4.7 Hz, 1H), 2.70 (ABq, ⌬␯ ϭ 23 Hz, JAB ϭ 16.5 Hz,
AB
(Z)-4-(Benzyloxy)-3-(((4R,5R)-5-(2-((tert-butyldimethylsilyl)
oxy)ethyl)-4-isopropyl-5-methylcyclopent-1-en-1-yl)methyl)
but-2-en-1-ol
2H), 2.25–2.19 (m, 1H), 1.89–1.53 (m, 5H), 1.01 (d, J ϭ 5.9 Hz,
3H), 0.91 (s, 3H), 0.89 (s, 9H), 0.87 (d, J ϭ 5.9 Hz, 3H), 0.05 (s,
6H). 13C NMR (75 MHz, CDCl3) ␦: 147.8, 138.3, 137.3, 128.3,
127.6, 127.5, 127.4, 123.6, 73.4, 72.2, 60.7, 59.2, 51.4, 49.8, 40.5,
24.5, 29.4, 26.0, 25.9, 22.6, 22.3, 19.9, 18.4, –5.2 (2C). HR-MS-
ESI calcd for C29H48O3SiNa [M ϩ Naϩ]: 495.3270; found:
495.3274.
A solution of 34 (378 mg, 0.73 mmol) in CH2Cl2 (15 mL)
was cooled to –78 °C and treated with DIBAL-H (1.84 mL,
1 mol/L in hexanes, 1.84 mmol). After 2.5 h at –78 °C, the
reaction was quenched with saturated aqueous Rochelle’s salt
(20 mL). The reaction was warmed to rt and stirred overnight,
after which the layers were separated. The aqueous layer was
washed with CH2Cl2 (3 ϫ 15 mL), and the organic layers were
combined. The organic layer was washed with brine (5 mL),
dried with Na2SO4, filtered, and concentrated in vacuo to
provide a yellow oil. The crude product was purified by flash
column chromatography (Et2O / petroleum ether, 1:1) to pro-
vide the expected (Z)-allylic alcohol from 34 (283 mg, 82%) in
approximately 85% purity as a clear colorless oil (approxi-
mately 10%–15% of an inseparable alkane side product was
((2S,3S)-3-(Benzyloxymethyl)-3-(((4R,5R)-5-(2-(tert-
butyldimethylsilyloxy)ethyl)-4-isopropyl-5-methylcyclopent-
1-enyl)methyl)oxiran-2-yl)methanol (35)
A heterogeneous solution of L-DIPT (152 mg, 0.65 mmol),
CH2Cl2 (8 mL), and 4 Å powdered molecular sieves (95 mg)
was cooled to –20 °C and treated with Ti(O-i-Pr)4 (148 ␮L,
0.5 mmol) dropwise. After 30 min, t-BuOOH (559 ␮L,
3.6 mol/L in toluene, 1.64 mmol) was added dropwise. After
an additional 30 min, the starting (E)-allylic alcohol from ester
33 was added as a solution (473 mg, 1 mmol) in CH2Cl2
(5 mL) via syringe followed by a CH2Cl2 (5 mL) syringe
wash. The reaction was allowed to stir for 20 h at –20 °C and
was quenched with a 30% aqueous NaOH solution saturated
with NaCl (740 ␮L) followed by H2O (2 mL). The reaction
was warmed to rt and stirred for 40 min. The mixture was then
filtered through Celite, and the filtrate was washed with H2O
(10 mL) and CH2Cl2 (10 mL). The organic layer was then
separated and the aqueous layer was washed with CH2Cl2 (3 ϫ
10 mL). The organic layers were combined, washed with
brine, dried over MgSO4, filtered, and concentrated in vacuo to
provide a cloudy yellow oil containing a 65:35 mixture of
epoxy alcohol diastereomers (Table 1, entry 4). The product was
purified by flash column chromatography (hexanes/EtOAc,
5:1) to provide small amounts of the major diastereomer
(10 mg), the minor diastereomer epoxide (2 mg), and com-
bined mixed fractions (331 mg, 70% overall yield) as a 65:35
mixture of epoxy alcohol diastereomers 35. Data for the sam-
1
estimated by H NMR spectra). Rf ϭ 0.26 (hexanes/EtOAc,
4:1). IR (film, cm–1): 3422, 3031, 2955, 2857, 1472, 1364,
1
1255, 1091, 1005. H NMR (400 MHz, CDCl3) ␦: 7.37–7.27
(m, 5H), 5.78 (t, J ϭ 7.1 Hz, 1H), 5.22 (s, 1H), 4.49 (ABq,
⌬␯ ϭ 12 Hz, JAB ϭ 12 Hz, 2H), 4.20–4.10 (m, 2H), 4.00
AB
(ABq, ⌬␯AB ϭ 27 Hz, JAB ϭ 11.1 Hz, 2H), 3.68 (td, J ϭ 9.8,
6.4 Hz, 1H), 3.43 (td, J ϭ 10.1, 4.8, 1H), 2.73 (ABq, ⌬␯AB ϭ
30 Hz, JAB ϭ 16.0 Hz, 2H), 2.25–2.20 (m, 1H), 2.13–2.10 (m,
1H), 1.89–1.63 (m, 5H), 1.00 (d, J ϭ 5.9 Hz, 3H), 0.90–0.85
(m, 15H), 0.04 (s, 6H). 13C NMR (101 MHz, CDCl3) ␦: 147.9,
138.1, 137.9, 130.6, 128.4, 127.8, 127.7, 124.6, 72.5, 67.2,
60.7, 58.7, 51.1, 49.9, 40.5, 34.6, 34.2, 29.3, 26.0, 22.6, 22.4,
20.1, 18.3, –5.1, –5.2. HR-MS-ESI calcd for C29H48O3SiNa
[M ϩ Naϩ]: 495.3270; found: 495.3275. This material was
utilized without the need for additional purification.
((2R,3S)-3-((Benzyloxy)methyl)-3-(((4R,5R)-5-(2-((tert-
butyldimethylsilyl)oxy)ethyl)-4-isopropyl-5-methylcyclopent-1-
en-1-yl)methyl)oxiran-2-yl)methanol (36)
A heterogeneous solution of D-DIPT (30 mg, 0.127 mmol),
CH2Cl2 (1 mL), and 4 Å powdered molecular sieves (100 mg)
was cooled to –25 °C and treated with Ti(O-i-Pr)4 (31.3 ␮L,
0.106 mmol) dropwise. The mixture was stirred for 30 min,
followed by the addition of t-BuOOH (90 ␮L, 3.58 mol/L in
toluene, 0.317 mmol). After an additional 30 min, a solution of
the (Z)-allylic alcohol (100 mg, 0.212 mmol) in CH2Cl2
ple of the major epoxide diastereomer of 35: [α]2D0 –26.2 (c
0.69, CHCl3). Rf ϭ 0.24 (hexanes/EtOAc, 4:1). IR (film, cm–1):
3439, 2955, 2866, 1472, 1363, 1256, 1098. 1H NMR (400 MHz)
␦: 7.35–7.26 (m, 5H), 5.33 (s, 1H), 4.53 (ABq, ⌬␯AB ϭ 19 Hz,
JAB ϭ 12.0 Hz, 2H), 3.84–3.78 (m, 1H), 3.77 (d, J ϭ 11.2 Hz, 1H),
3.71–3.62 (m, 2H), 3.43–3.38 (m, 1H), 3.39 (d, J ϭ 11.3 Hz, 1H),
3.27 (dd, J ϭ 6.5, 4.7 Hz, 1H), 2.61 (d, J ϭ 17.3 Hz, 1H),
Published by NRC Research Press

32
Can. J. Chem. Vol. 91, 2013
(500 ␮L) was added via syringe followed by a CH2Cl2
(500 ␮L) syringe wash. The reaction was warmed to –18 °C
and stirred for 17 h. The reaction was quenched at –20 °C via
the addition of a 30% aqueous NaOH solution saturated with
NaCl (400 ␮L). The reaction was warmed to rt and CH2Cl2
(1 mL) and H2O (1 mL) were added, and the mixture was
vigorously stirred for 1 h. The aqueous phase was washed with
CH2Cl2 (2 ϫ 2 mL), and the combined organic extracts were
washed with brine (5 mL), dried over MgSO4, filtered, and
concentrated in vacuo to provide clear colorless oil. The prod-
uct was purified by flash column chromatography (hexanes/
EtOAc, 20:1) to provide epoxide 36 (75 mg, 75%) as a 92:8
(4 mL) and warmed to rt. Water (30 mL) and CH2Cl2 were
added to the reaction mixture, the organic layer was separated,
and the aqueous layer was washed with CH2Cl2 (2 ϫ 50 mL).
The combined organic layers were washed with brine, dried
over Na2SO4, and concentrated in vacuo to provide a clear
yellow oil. Purification by flash column chromatography
(hexanes/EtOAc, 15:1) provided the alcohols 38 (482 mg,
87%) as a 58:42 mixture of inseparable diastereomers as a
clear colorless oil originating from the Sharpless epoxidation
(Table 1, entry 3). This mixture of diastereomers was character-
1
ized as follows: Rf ϭ 0.32 (hexanes/EtOAc, 10:1). H NMR
(400 MHz, CDCl3) ␦: 7.37–7.26 (m, 5H), 5.95 (dd, J ϭ 17.3,
10.8 Hz, 0.42H), 5.92 (dd, J ϭ 17.3, 10.8 Hz, 0.58 H), 5.62 (s,
1H), 5.40 (dd, J ϭ 17.4, 1.3 Hz, 0.58 H), 5.35 (dd, J ϭ 17.4,
1.2 Hz, 0.42H), 5.19 (dd, J ϭ 10.6, 1.4 Hz, 0.58H), 5.18 (dd, J ϭ
10.8, 1.2 Hz, 0.42H), 4.61–4.54 (m, 2H), 3.66 (td, J ϭ 9.7,
6.2 Hz, 1H), 3.50–3.39 (m, 3H), 2.55 (s, 0.58H), 2.49 (s, 0.42H),
2.36–2.09 (m, 3H), 1.93–1.89 (m, 1H), 1.82–1.58 (m, 4H), 1.01–
1.00 (m, 3H), 0.88–0.84 (m, 15H), 0.04 (6H). 13C NMR
(101 MHz, CDCl3) ␦: 144.6, 144.4, 142.2, 141.9, 138.1, 138.0,
128.4, 127.6 (3C), 125.0, 124.9, 114.3, 114.2, 77.0, 76.8, 74.8
(2C), 73.5, 60.5 (2C), 50.6, 50.5, 50.3 (2C), 40.7, 35.0 (2C), 34.4,
34.3, 29.3, 29.2, 26.0, 22.7, 22.3, 22.2, 19.9, –5.2 (4C). HR-MS-
ESI calcd for C29H48O3SiNa [M ϩ Naϩ]: 495.3270; found:
495.3290. In a similar fashion, the mixture of 36 (Table 1, entry
5) gave rise to an enriched sample of 38 (dr 91:9).
mixture of inseparable diastereomers. [α]2D0 ϩ2.0 (c 0.45,
CHCl3). Rf ϭ 0.46 (hexanes/EtOAc, 2:1). Data for the major
diastereomer 36: IR (film, cm–1): 3431, 2955, 2929, 2856,
1
1454, 1255, 1091. H NMR (400 MHz, CDCl3) ␦: 7.37–7.30
(m, 5H), 5.43 (s, 1H), 4.7 (ABq, ⌬␯
ϭ 12 Hz, JAB ϭ
12.0 Hz, 2H), 3.92–3.82 (m, 2H), A3B.73–3.57 (m, 4H),
3.49–3.38 (m, 2H), 3.09 (t, J ϭ 6.2 Hz, 1H), 2.29 (ABq, ⌬␯AB ϭ
80 Hz, JAB ϭ 16.4 Hz, 2H), 2.29–2.26 (m, 2H), 1.95–1.89 (m, 1H),
1.83–1.59 (m, 4H), 1.01 (d, J ϭ 6.0 Hz, 3H), 0.88–0.87 (m, 15H),
0.04 (s, 6H). 13C NMR (101 MHz, CDCl3) ␦: 145.4, 137.4, 128.5,
127.9, 127.8, 125.2, 73.6, 70.0, 61.6 (2C), 61.3, 60.5, 50.7, 49.8,
40.4, 34.9, 32.4, 29.3, 26.0, 22.6, 22.3, 19.7, 18.3, –5.2 (2C).
HR-MS-ESI calcd for C29H48O4SiNa [M ϩ Naϩ]: 511.3220; found:
511.3212.
(2-((1R,5R)-2-(((2S,3R)-2-(Benzyloxymethyl)-3-
(bromomethyl)oxiran-2-yl)methyl)-5-isopropyl-1-
1-(Benzyloxy)-2-(((4R,5R)-5-(2-(tert-butyldimethylsilyloxy)
ethyl)-4-isopropyl-5-methylcyclopent-1-enyl)methyl)but-3-
en-2-yl acrylate (39)
methylcyclopent-2-enyl)ethoxy)(tert-butyl)dimethylsilane (37)
To a solution of the epoxide 35 (322.6 mg, 0.68 mmol) in
CH2Cl2 (14 mL) at 0 °C was added imidazole (278 mg,
4.08 mmol) and PPh3 (677 mg, 2.04 mmol), and this was
followed by the addition of CBr4 (677 mg, 2.04 mmol). The
reaction was protected from light and was stirred for 2 h at
which time the solvent was removed in vacuo to provide a
white solid. The crude product was immediately purified by
flash column chromatography (hexanes/EtOAc, 20:1) afford-
ing bromides 37 (330 mg, 88%) as a 55:45 ratio of inseparable
diastereomers as a clear yellow oil starting from the mixture of
epoxy alcohols (Table 1, entry 3). Similarly, the epoxide 36
was transformed to the corresponding mixture of bromides (dr
90:10). The crude epoxy bromides were characterized as fol-
A solution of alcohol 38 (240 mg, 0.51 mmol) in THF
(5.1 mL) was treated by the dropwise addition of isopro-
pylmagnesium chloride (1.68 mol/L in Et2O, 332 ␮L,
0.558 mmol), and the mixture was stirred for 30 min. Then,
freshly distilled acryloyl chloride (248 ␮L, 3.05 mmol) was
added dropwise and the colorless solution turned a yellow
color. The reaction was stirred for an additional 16 h at rt and
was then cooled to 0 °C and quenched with saturated aqueous
NaHCO3 (10 mL). After warming to rt, CH2Cl2 (10 mL) and
water (10 mL) were added and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (2 ϫ 15 mL) and the
combined organic extracts were washed with brine (10 mL),
dried over Na2SO4, filtered, and concentrated in vacuo to
provide a clear yellow oil. Purification by flash column chro-
matography (hexanes/EtOAc, 30:1) provided the ester 39
(187 mg, 70%, 81% brsm) as a 58:42 mixture of inseparable
diastereomers and recovered allyl alcohol 38 (34 mg, 11%).
The mixture of diastereomers was characterized as follows:
Rf ϭ 0.45 (hexanes/EtOAc, 10:1). 1H NMR (400 MHz,
CDCl3) ␦: 7.34–7.26 (m, 5H), 6.37–6.31 (m, 1H), 6.14–6.00
(m, 2H), 5.80–5.77 (m, 1H), 5.45 (bs, 1H), 5.31–5.20 (m, 2H),
4.54–4.53 (m, 2H), 3.93–3.82 (m, 2H), 3.67–3.61 (m, 1H),
3.51–3.41 (m, 1H), 2.83–2.77 (m, 1H), 2.54–2.49 (m, 0.40H),
2.43 (d, J ϭ 16.9 Hz, 0.60H), 2.25–2.19 (m, 1H), 1.89–1.55
(m, 5H), 0.99 (d, J ϭ 5.9 Hz, 3H), 0.89–0.88 (m, 9H),
0.85–0.83 (m, 6H), 0.03–0.02 (m, 6H). HR-MS-ESI calcd for
C32H50O4SiNa [M ϩ Naϩ]: 549.3376; found: 549.3386. Sim-
ilarly, the alcohol 38 (Table 1, entry 5) led to the desired ester
39 as a 92:8 ratio of C2 diastereomers.
1
lows: Rf ϭ 0.68 (hexanes/EtOAc, 4:1). H NMR (300 MHz,
CDCl3) ␦: 7.37–7.27 (m, 5H), 5.41–5.39 (m 1H), 4.59–4.48
(m, 2H), 3.72–3.28 (m, 7H), 2.54–2.46 (m, 1H), 2.32–2.24 (m,
1H), 2.05–1.55 (m, 6H), 1.00 (d, J ϭ 6.0 Hz, 3H), 0.89–0.86
(m, 15H), 0.03 (m, 6H). HR-MS-ESI calcd for C29H47O3BrSiNa
[M ϩ Naϩ]: 573.2376; found: 573.2490. The bromides were not
stored and were immediately used in the subsequent reaction.
Comparable results were obtained by using the epoxy alcohol 36.
(R)-1-(Benzyloxy)-2-(((4R,5R)-5-(2-(tert-butyldimethylsilyloxy)
ethyl)-4-isopropyl-5-methylcyclopent-1-enyl)methyl)but-3-
en-2-ol (38)
A solution of diastereomeric bromides 37 (646 mg,
117 mmol) in THF (20 mL) was cooled to –95 °C in a
hexanes/N2(l) bath and treated with n-BuLi (703 ␮L,
2.50 mol/L in hexanes, 1.76 mmol) dropwise. The reaction
was stirred for 25 min with a cooling bath temperature no
higher than –85 °C and then allowed to warm to –78 °C at
which point the reaction was quenched with a pH 7 buffer
Published by NRC Research Press

Williams and Pinchman
33
1
polar diastereomer: Rf ϭ 0.24 (hexanes/EtOAc, 10:1). H NMR
(400 MHz, CDCl3) ␦: 7.36–7.26 (m, 5H), 5.60 (s, 0.5H), 5.43 (s,
0.5H), 4.55–4.45 (m, 2H), 3.74–3.40 (m, 4H), 3.00–2.88 (m, 1H),
2.78–2.71 (m, 1H), 2.33–2.11 (m, 4H), 1.93–1.89 (m, 1H), 1.83–
1.70 (m, 3H), 1.63–1.56 (m, 1H), 1.12–1.08 (m, 3H), 1.00–0.99 (m,
3H), 0.89 (m, 15H), 0.03–0.02 (m, 6H). HR-MS-ESI calcd for
C31H50O4Na [M ϩ Naϩ]: 537.3376; found: 537.4648.
5-(Benzyloxymethyl)-5-(((4R,5R)-5-(2-(tert-
butyldimethylsilyloxy)ethyl)-4-isopropyl-5-
methylcyclopent-1-enyl)methyl)furan-2(5H)-one (40)
To a solution of 39 (163 mg, 0.31 mmol) in toluene
(15.5 mL) at 70 °C was added a solution of Grubbs II cata-
lyst25 (26.2 mg, 30.9 ␮mol) in toluene (3.1 mL) portionwise
(500 ␮L) at hourly intervals via microsyringe. After an addi-
tional 90 min of stirring, the reaction was cooled to rt, and the
solvent was removed in vacuo to provide a brown oil. The
product was purified by flash column chromatography
(hexanes/EtOAc, 20:1) to provide 40 (154 mg, 99%) as a 52:48
mixture of inseparable diastereomeric lactones originating from
the epoxy alcohols (Table 1, entry 3). Similar results from the
epoxide 36 (Table 1, entry 5) led to a 92:8 ratio of lactones 40.
The mixture of diastereomers was characterized as follows:
Rf ϭ 0.28 (hexanes/EtOAc, 4:1). 1H NMR (400 MHz, CDCl3)
␦: 7.50 (d, J ϭ 5.7 Hz, 0.48H), 7.39 (d, J ϭ 5.7 Hz, 0.52H),
7.36–7.26 (m, 5H), 6.10 (d, J ϭ 5.4 Hz, 0.48 H), 6.09 (d, J ϭ
5.6 Hz, 0.52H), 5.54 (s, 0.48H), 5.51 (s, 0.52H), 4.57–4.48 (m,
2H), 3.76 (d, J ϭ 9.7 Hz, 0.48H), 3.73 (d, J ϭ 9.9 Hz, 0.52H),
3.66 (m, 1H), 3.55 (d, J ϭ 9.8 Hz, 0.52H), 3.51 (d, J ϭ 9.9 Hz,
0.48H), 3.45–3.36 (m, 1H), 2.57–2.22 (m, 3H), 1.94–1.85 (m,
1H), 1.84–1.51 (m, 4H), 1.00–0.97 (m, 3H), 0.88–0.83 (m,
15H), 0.03–0.02 (m, 6H). 13C NMR (101 MHz, CDCl3) ␦:
172.4, 172.3, 158.7, 158.0, 142.6, 142.2, 137.4, 128.5, 127.9,
127.7, 127.6, 126.8, 126.6, 122.2, 122.0, 90.0, 89.9, 73.8, 73.0,
72.7, 60.4, 60.3, 50.6, 50.5, 50.2, 41.0, 40.8, 34.9, 34.8, 30.9,
30.8, 29.3, 29.2, 26.0 (2C), 22.7 (2C), 22.2, 22.0, 20.2, 19.8,
18.3, –5.2 (2C), –5.3. LR-MS-ESI calcd for C30H46O4Si [M ϩ
Hϩ]: 499.3; found: 499.2.
A solution of the conjugate addition products (195 mg,
0.379 mmol) in THF (7.6 mL) was cooled to –78 °C and was
then treated with freshly prepared lithium diisopropylamide
(LDA; 1 mol/L in THF, 454 ␮L, 0.454 mmol) by dropwise
addition. After 35 min, phenylselenenyl bromide (224 mg,
0.948 mmol) in THF (500 ␮L) was introduced by syringe.
After 2.5 h, the reaction was quenched with saturated aqueous
NH4Cl (6 mL) at –78 °C and allowed to warm to rt. Water
(6 mL) and Et2O (20 mL) were added and the organic layer
was extracted. The aqueous layer was washed with Et2O (3 ϫ
20 mL), and the combined organic extracts were dried over
Na2SO4, filtered, and concentrated in vacuo to provide a
yellow oil. The product was purified via flash column chro-
matography (hexanes/EtOAc, 20:1) to provide the mixture of
␣-phenylselenolactones (224 mg, 88%) as a mixture of insep-
arable diastereomers. Rf ϭ 0.70 (hexanes/EtOAc, 4:1). LR-MS-ESI
calcd for C37H55O4SeSi [M ϩ Hϩ]: 671.3; found: 671.3.
The mixture of crude ␣-phenylselenolactones was directly
submitted for oxidative elimination. A solution of lactone
diastereomers (97.2 mg, 0.145 mmol) in CH2Cl2 (7.3 mL) was
cooled to –78 °C and was treated with a solution of meta-
chloroperoxybenzoic acid (mCPBA; 27.5 mg, 0.16 mmol) in
CH2Cl2 (0.5 mL) by dropwise addition. After 1 h at –78 °C,
Et3N (30 ␮L, 0.218 mmol) was added and the mixture was
allowed to warm to rt overnight. Water was added to the
reaction, and the organic layer was separated. The aqueous
layer was washed with CH2Cl2 (3 ϫ 6 mL), and the organic
extracts were combined, dried over Na2SO4,, and concentrated
in vacuo to provide a yellow oil. The crude product was
purified by flash column chromatography (hexanes/EtOAc,
20:1) to provide 41 and 42 (55.4 mg, 75%) as an inseparable
mixture of C2 diastereomers (dr 58:42). In the case of samples
that were independently processed from the Sharpless epoxi-
dation leading to 36, the product diastereomers (dr 92:8) could
be separated by careful chromatography. Data for character-
5-(Benzyloxymethyl)-5-(((4R,5R)-5-(2-(tert-
butyldimethylsilyloxy)ethyl)-4-isopropyl-5-
methylcyclopent-1-enyl)methyl)-4-methyldihydrofuran-2(3H)-
one (41)
A hetereogeneous solution of CuI (52.3 mg, 0.28 mmol) in
Et2O (1.4 mL) was cooled to 0 °C and treated with meth-
yllithium (344 ␮L, 1.6 mol/L in Et2O, 0.55 mmol) dropwise.
The turbid brown solution became a clear colorless solution
within 5 min. After stirring for 30 min, the reaction was cooled
to –25 °C, and a solution of 40 (55 mg, 0.11 mmol) in Et2O
(0.5 mL) was introduced by syringe. After 90 min at –20 °C,
the reaction was quenched with saturated aqueous NH4Cl
(2 mL) at –20 °C and stirred for 30 min at rt. H2O (2 mL) and
EtOAc (6 mL) were added to the mixture and the organic layer
was separated. The aqueous layer was washed with EtOAc
(3 ϫ 15 mL) and the combined organic extracts were dried
over Na2SO4 and concentrated in vacuo to provide a yellow
oil. The product was purified by flash column chromatography
(hexanes/EtOAc, 10:1) to provide the expected 3-meth-
yl-butyrolactone (49 mg) as a 58:42 mixture of two diaste-
reomers in an 86% yield as a clear colorless oil. Data
characterizing the less polar conjugate addition product: Rf ϭ
ization of the major product 41: [α]2D0 ϩ2.4 (c 0.83, CHCl3).
Rf ϭ 0.63 (hexanes/EtOAc, 2:1). IR (film, cm–1): 2955, 2859,
1
1759, 1650, 1471, 1364, 1292, 1255, 1094, 954. H NMR
(500 MHz, CDCl3) ␦: 7.36–7.26 (m, 5H), 5.83 (d, J ϭ 1.4 Hz,
1H), 5.48 (s, 1H), 4.53 (ABq, ⌬␯AB ϭ 41 Hz, JAB ϭ 12.1 Hz,
2H), 3.67–3.62 (m, 3H), 3.45 (td, J ϭ 9.8, 5.1 Hz, 1H), 2.52
(dd, J ϭ 16.9, 1.7 Hz, 1H), 2.26–2.21 (m, 1H), 2.17 (d, J ϭ
16.9 Hz, 1H), 2.00 (d, J ϭ 1.4 Hz, 3H), 1.91–1.85 (m, 1H),
1.81–1.74 (m, 1H), 1.72–1.63 (m, 2H), 1.61–1.54 (m, 1H),
0.98 (d, J ϭ 6.0 Hz, 3H), 0.88 (s, 9H), 0.86 (s, 3H), 0.84 (d,
J ϭ 6.0 Hz, 3H), 0.03 (s, 6H). 13C NMR (126 MHz, CDCl3)
␦: 137.5, 128.4, 127.8, 127.6, 126.2, 118.4, 90.4, 73.8, 72.3,
60.3, 50.6, 50.3, 40.8, 34.7, 29.5, 29.1, 26.0, 22.7, 22.0, 20.2,
18.3, 13.9, –5.2 (2C). HR-MS-ESI calcd for C31H48O4SiNa
[M ϩ Naϩ]: 535.3220; found: 535.3247. Data for the complete
characterization of the minor butenolide (S)-5-(benzyloxymethyl)-5-
(((4R,5R)-5-(2-(tert-butyldimethylsilyloxy)ethyl)-4-isopropyl-5-
methylcyclopent-1-enyl)methyl)-4-methylfuran-2(5H)-one (42):
1
0.32 (hexanes/EtOAc, 10:1). H NMR (400 MHz, CDCl3) ␦:
7.36–7.26 (m, 5H), 5.67 (s, 0.68H), 5.60 (0.32H), 4.56–4.42
(m, 2H), 3.68–3.51 (m, 3H), 3.44–3.38 (m, 1H), 2.59–2.47
(m, 3H), 2.35–2.20 (m, 2.68H), 2.05 (d, J ϭ 16.6 Hz, 0.32H),
1.95–1.90 (m, 1H), 1.81–1.68 (m, 3H), 1.60–1.55 (m, 1H),
1.16–1.12 (m, 3H), 1.00–0.99 (m, 3H) 0.88–0.84 (m, 15H),
0.03 (s, 6H). HR-MS-ESI calcd for C31H50O4Na [M ϩ Naϩ]:
537.3376; found: 537.4540. Characterization data for the more
[α]2D0 –22.3 (c 0.16, CHCl3). Rf ϭ 0.62 (hexanes/EtOAc, 2:1). IR
Published by NRC Research Press

34
Can. J. Chem. Vol. 91, 2013
(film, cm–1): 2955, 2859, 1759, 1650, 1471, 1364, 1292, 1255,
1094, 954. H NMR (400 MHz, CDCl3) ␦: 7.35–7.25 (m, 5H),
35.1, 29.9, 29.3, 22.4, 22.2, 20.2, 14.0. HR-MS-ESI calcd for
C25H34O4Na [M ϩ Naϩ]: 421.2355; found: 421.2344.
1
5.83 (s, 1H), 5.52 (s, 1H), 4.51 (ABq, ⌬␯ ϭ 30 Hz, JAB
ϭ
AB
2-((1R,5R)-2-(((R)-2-((Benzyloxy)methyl)-3-methyl-5-oxo-
2,5-dihydrofuran-2-yl)methyl)-5-isopropyl-1-methylcyclopent-
2-en-1-yl)acetaldehyde (49)
12.0 Hz, 2H), 3.67–3.60 (m, 3H), 3.39 (td, J ϭ 9.8, 5.3 Hz, 1H),
2.40 (d, J ϭ 16.6 Hz, 1H), 2.30–2.19 (m, 2H), 2.05 (d, J ϭ
0.9 Hz, 3H), 1.91–1.87 (m, 1H), 1.80–1.74 (m, 1H), 1.71–1.61
(m, 2H), 1.59–1.52 (m, 1H), 0.98 (d, J ϭ 5.9 Hz, 3H), 0.88–0.83
(m, 15H), 0.02 (s, 6H). 13C NMR (101 MHz, CDCl3) ␦: 172.3,
170.2, 141.8, 137.5, 128.4, 127.8, 127.7, 126.0, 118.4, 90.5, 73.8,
72.0, 60.5, 50.7, 50.3, 40.9, 34.9, 29.5, 29.2, 26.0, 22.7, 22.2,
19.9, 18.3, 14.0, –5.2, –5.3. HR-MS-ESI calcd for C31H48O4SiNa
[M ϩ Naϩ]: 535.3220; found: 535.3199.
A solution of alcohol 43 (40.8 mg, 0.102 mmol) in CH2Cl2
(1 mL) was cooled to 0 °C and was treated with NaHCO3
(26 mg, 0.306 mmol) and Dess–Martin periodinane (56.4 mg,
0.133 mmol), and the cold bath was then removed. After 2 h,
the reaction was quenched with a mixture of saturated aqueous
NaHCO3 (2 mL) and saturated aqueous Na2S2O3 (2 mL),
diluted with CH2Cl2 (5 mL), and stirred for 20 min. The
organic layer was separated and the aqueous layer was ex-
tracted with CH2Cl2 (2 ϫ 8 mL). The combined organic
extracts were washed with brine (5 mL), dried over Na2SO4,
filtered, and concentrated in vacuo to provide a clear colorless
oil. The product was purified by flash column chromatography
(hexanes/EtOAc, 4:1) to provide aldehyde 49 (37.3 mg, 92%)
(R)-5-((Benzyloxy)methyl)-5-(((4R,5R)-5-(2-hydroxyethyl)-4-
isopropyl-5-methylcyclopent-1-en-1-yl)methyl)-4-
methylfuran-2(5H)-one (43)
To a solution of 41 and 42 (49.4 mg, 96.3 ␮mol) and
CH3CN (1 mL) in a plastic vial was added aqueous HF
(5.4 ␮L, 52% in H2O, 0.579 mmol) and the mixture was
stirred for 15 min. The reaction was poured into saturated
aqueous NaHCO3 (8 mL) and stirred for 5 min. EtOAc (6 mL)
was added and the layers were separated. The aqueous layer
was washed with EtOAc (2 ϫ 8 mL) and the organic extracts
were combined, washed with brine (10 mL), dried over
Na2SO4, filtered, and concentrated in vacuo to provide a clear
light brown oil. The crude product was purified by flash
column chromatography (hexanes/EtOAc, 1:1) to give 43 and
44 (34.8 mg, 91%) as a mixture of C2 diastereomers (dr 60:40)
as a clear colorless viscous oil. Separation of the C2 diaste-
reomers was by preparative HPLC; 30% EtOAc in hexanes
22 mL/min, loading in 19% CH2Cl2 in hexanes (three runs),
afforded 21.3 mg of 43 (retention time (tR): 32.772 min) and
10.8 mg of 44 (tR: 39.079 min). Analytical data: 30% EtOAc
in hexanes for 43 (tR: 44.215 min), for 44 (tR: 52.065 min).
as a clear colorless oil. [α]2D0 –7.6 (c 0.25, CHCl3). Rf ϭ 0.46
(hexanes/EtOAc, 2:1). IR (film, cm–1): 2958, 2870, 1754,
1717, 1650, 1454, 1291, 1098, 954. 1H NMR (400 MHz,
CDCl3) ␦: 9.71 (dd, J ϭ 3.7, 2.1 Hz, 1H), 7.39–7.22 (m, 5H),
5.83 (d, J ϭ 1.4 Hz, 1H), 5.58 (s, 1H), 4.51 (ABq, ⌬␯
ϭ
AB
25 Hz, JAB ϭ 12.0 Hz, 2H), 3.61 (ABq, ⌬␯
ϭ 25 Hz,
AB
JAB ϭ 10.2 Hz, 2H), 2.61–2.52 (m, 2H), 2.44 (dd, J ϭ 16.0,
2.1 Hz, 1H), 2.37–2.30 (m, 1H), 2.24 (d, J ϭ 17.9 Hz, 1H),
2.16 (d, J ϭ 1.4 Hz, 3H), 2.03–1.95 (m, 1H), 1.80–1.70 (m,
2H), 0.99 (s, 3H), 0.98 (d, J ϭ 6.2 Hz, 3H), 0.86 (d, J ϭ
6.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) ␦: 203.7, 172.1,
170.0, 141.0, 137.3, 128.5, 128.1, 127.9, 127.7, 118.4, 90.1,
73.8, 71.8, 52.8, 51.5, 50.7, 34.7, 29.9, 29.1, 22.8, 21.7, 19.7,
13.9. HR-MS-ESI calcd for C25H32O4Na [M ϩ Naϩ]:
419.2198; found: 419.2183.
Characterization data for 43: [α]2D0 –2.3 (c 1.15, CHCl3). Rf ϭ
0.14 (hexanes/EtOAc, 2:1). IR (film, cm–1): 3418, 2955, 1743,
1648, 1455, 1293, 1100, 957. 1H NMR (400 MHz, CDCl3) ␦:
7.39–7.25 (m, 5H), 5.83 (d, J ϭ 1.4 Hz, 1H), 5.46 (s, 1H), 4.52
(3aS,4R,5aR,6R,9aR)-9a-(Benzyloxymethyl)-4-hydroxy-6-
isopropyl-3a,5a-dimethyl-3a,4,5,5a,6,7,9,9a-
octahydroazuleno[5,6-b]furan-2(3H)-one (50a)
To a solution of freshly prepared SmI2 (9.2 mL, 0.1 mol/L
in THF, 0.918 mmol) at rt was added HMPA (639 ␮L,
3.67 mmol) dropwise. After 2 min, aldehyde 49 (178 mg,
0.449 mmol) in a solution of THF/t-BuOH (46 mL, 100:1 by
volume) was added dropwise over 7 min. The reaction quickly
became a yellow color and an additional amount of SmI2
(1.6 mL, 0.1 mol/L in THF, 0.16 mmol) was added to the
reaction mixture via syringe. After 5 min, the reaction was
quenched by the addition of silica gel (20 mL volume). The
crude reaction mixture was filtered through a plug of silica gel
using ethyl acetate. The organic layer was concentrated in
vacuo to provide a clear yellow oil. The product was purified
by flash column chromatography (hexanes / EtOAc, 4:1) to
provide 50a and 50b (113 mg, 63%) as a 66:34 mixture of C8
diastereomers. These diastereomers were separated by HPLC
using a Supelco Ascentis Si column (hexanes / isopropyl al-
cohol, 98:2) to provide pure 50a (73 mg; tR: 40.2 min) and
pure 50b (36 mg; tR: 33.6 min) as clear colorless oils. Char-
(ABq, ⌬␯ ϭ 32 Hz, JAB ϭ 12.0 Hz, 2H), 3.72–3.61 (m,
AB
1H), 3.65 (ABq, ⌬␯ ϭ 26 Hz, JAB ϭ 10.1 Hz, 2H), 3.54–
AB
3.46 (m, 1H), 2.55 (d, J ϭ 16.6 Hz, 1H), 2.30–2.16 (m, 2H),
2.03 (d, J ϭ 1.4 Hz, 3H), 1.93–1.77 (m, 2H), 1.72–1.59 (m,
2H), 1.49–1.47 (m, 1H), 0.97 (d, J ϭ 4.3 Hz, 3H), 0.87 (s,
3H), 0.84 (d, J ϭ 6.3 Hz, 3H). 13C NMR (101 MHz, CDCl3)
␦: 172.4, 170.1, 142.0, 137.4, 128.5, 127.9, 127.7, 126.7,
118.4, 90.4, 73.8, 72.3, 59.8, 50.6, 50.2, 40.6, 34.8, 29.2, 29.1,
22.6, 21.9, 20.3, 13.9. HR-MS-ESI calcd for C25H34O4Na [M ϩ
Naϩ]: 421.2355; found: 421.2343. Complete characterization of
the minor butenolide (S)-5-((benzyloxy)methyl)-5-(((4R,5R)-
5-(2-hydroxyethyl)-4-isopropyl-5-methylcyclopent-1-en-1-
yl)methyl)-4-methylfuran-2(5H)-one (44): [α]2D0 –34.2 (c 0.70,
CHCl3). Rf ϭ 0.14 (hexanes/EtOAc, 2:1). IR (film, cm–1):
1
3431, 2955, 2868, 1745, 1648, 1454, 1365, 1100. H NMR
(300 MHz, CDCl3) ␦: 7.38–7.26 (m, 5H), 5.83 (s, 1H), 5.52 (s,
acterization data for 50a: [α]2D0 –20.3 (c 1.40, CHCl3). Rf ϭ
0.35 (hexanes/EtOAc, 2:1). IR (film, cm–1): 3479, 2955, 2870,
1771, 1454, 1418, 1236, 1103, 1070 953. 1H NMR (400 MHz,
CDCl3) ␦: 7.36–7.27 (m, 5H), 5.34 (s, 1H), 4.53 (ABq,
1H), 4.52 (ABq, ⌬␯
ϭ 12.0 Hz, JAB ϭ 11.3 Hz, 2H),
AB
3.72–3.50 (m, 4H), 2.52 (d, J ϭ 15.9 Hz, 1H), 2.32–2.25 (m,
1H), 2.21 (d, J ϭ 15.9 Hz, 1H), 2.08 (s, 3H), 1.96–1.55 (m,
5H), 1.00 (d, J ϭ 6.1 Hz, 3H), 0.88–0.87 (m, 6H). 13C NMR
(101 MHz, CDCl3) ␦: 172.5, 171.1, 142.5, 137.4, 128.4, 127.9,
127.6, 127.2, 117.9, 90.2, 73.7, 71.5, 60.2, 50.6, 50.0, 40.7,
⌬␯ ϭ 8 Hz, JAB ϭ 12 Hz, 2H), 4.14–4.08 (m, 1H), 3.63
AB
(ABq, ⌬␯ ϭ 118 Hz, JAB ϭ 10.6 Hz, 2H), 3.11 (d, J ϭ
AB
Published by NRC Research Press

Williams and Pinchman
35
18.1 Hz, 1H), 2.64 (d, J ϭ 13.9 Hz, 1H), 2.62 (d, J ϭ 18.1 Hz,
1H), 2.39 (d, J ϭ 14.1 Hz, 1H), 2.29 (ddd, J ϭ 16.2, 7.8,
2.6 Hz, 1H), 1.98–1.84 (m, 3H), 1.76–1.65 (m, 2H), 1.51 (dd,
J ϭ 18.1, 9.5 Hz, 1H), 1.15 (s, 3H), 1.01 (s, 3H), 0.98 (d, J ϭ
6.6 Hz, 3H), 0.89 (d, J ϭ 6.6 Hz, 3H). 13C NMR (126 MHz,
CDCl3) ␦: 176.1, 144.2, 137.7, 128.4, 128.2, 127.6, 127.5,
88.6, 74.0, 73.7, 69.0, 60.4, 49.3, 48.2, 48.0, 42.3, 36.1, 33.4,
29.5, 22.8, 22.7, 20.1, 16.1. HR-MS-ESI calcd for
C25H34O4Na [M ϩ Naϩ]: 421.2355; found: 421.2341.
Complete characterization data for (3aS,4S,5aR,6R,9aR)-9a-
((benzyloxy)methyl)-4-hydroxy-6-isopropyl-3a,5a-dimethyl-
3a,4,5,5a,6,7,9,9a-octahydroazuleno[5,6-b]furan-2(3H)-one
0.031 mmol). The reaction was heated to 80 °C for 16 h. The
reaction was cooled to rt, and the solvent was removed in
vacuo and purified by flash column chromatography (hexanes/
EtOAc, 5:1 ¡ 2:1) to provide the imidazole-1-carbothioate
(3.7 mg, 48%, 71% brsm) as a clear colorless oil, which gave
diagnostic signals upon 1H NMR spectroscopy. Rf ϭ 0.5
(hexanes/EtOAc, 1:1). 1H NMR (500 MHz, CDCl3) ␦: 8.33 (s,
1H), 7.58 (s, 1H), 7.42–7.27 (m, 5H), 7.07 (s, 1H), 5.68 (dd,
J ϭ 8.5, 1.7 Hz, 1H), 5.58 (s, 1H), 4.58 (ABq, ⌬␯AB ϭ 20 Hz,
JAB ϭ 12.0 Hz, 2H), 3.73 (ABq, ⌬␯
ϭ 57 Hz, JAB ϭ
AB
10.8 Hz, 2H), 3.01 (d, J ϭ 13.7 Hz, 1H), 2.90 (d, J ϭ 17.3 Hz,
1H), 2.55 (d, J ϭ 17.3 Hz, 1H), 2.43 (d, J ϭ 13.5 Hz, 1H),
2.37–2.25 (m, 2H), 1.74–1.67 (m, 1H), 1.21 (s, 3H), 0.97 (d,
J ϭ 6.5 Hz, 3H), 0.92 (d, J ϭ 6.2 Hz, 3H), 0.91 (s, 3H).
LR-MS-ESI calcd. for C29H37N2O4S [M ϩ Hϩ]: 509.2; found:
509.3.
(50b): [α]2D0 –1.9 (c 0.7, CHCl3). Rf ϭ 0.35 (hexanes/EtOAc,
2:1). IR (film, cm–1): 3467, 2956, 2869, 1763, 1417, 1238, 1104,
1
1096, 956. H NMR (500 MHz, CDCl3) ␦: 7.36–7.26 (m, 5H),
5.45 (s, 1H), 4.56 (ABq, ⌬␯ ϭ 29 Hz, JAB ϭ 11.8 Hz, 2H),
3.75 (d, J ϭ 10.9 Hz, 1H),A3B.74–3.71 (m, 1H), 3.57 (d, J ϭ
10.8 Hz, 1H), 2.85 (d, J ϭ 13.4 Hz, 1H), 2.76 (d, J ϭ 17.3 Hz,
1H), 2.54 (d, J ϭ 13.3 Hz, 1H), 2.49 (d, J ϭ 17.3 Hz, 1H), 2.29
(ddd, J ϭ 16.0, 7.7, 2.5 Hz, 1H), 2.01–1.89 (m, 3H), 1.81–1.69
(m, 1H), 1.63–1.58 (m, 2H), 1.18 (s, 3H), 1.01 (d, J ϭ 6.5 Hz,
3H), 0.99 (s, 3H), 0.90 (d, J ϭ 6.5 Hz, 3H. 13C NMR (126 MHz,
CDCl3) ␦: 176.0, 144.6, 137.9, 128.4, 127.6, 127.4 (2C), 89.7,
75.3, 73.4, 72.4, 57.1, 49.0, 48.7, 45.1, 40.6, 35.9, 31.6, 29.6,
22.9, 22.8, 21.3, 21.1. HR-MS-ESI calcd for C25H34O4Na [M ϩ
Naϩ]: 421.2355; found: 421.2343.
Additional purification of this crude material was not
undertaken. A solution of the crude intermediate thione
(3.7 mg, 7.2 ␮mol) in toluene (500 ␮L) was directly treated
with n-Bu3SnH (7.8 ␮L, 0.029 mmol) and 2,2=-
azobisisobutyronitrile (AIBN; 1 mg, 6.1 ␮mol) and then heated to
100 °C. After 5 h, the reaction was cooled to ambient tempera-
ture. After 16 h, the reaction was concentrated and purified by
flash column chromatography (hexanes/EtOAc, 5:1) to provide
54 (2 mg, 74%) as a clear colorless oil. Rf ϭ 0.58 (hexanes/
EtOAc, 2:1). 1H NMR (500 MHz, CDCl3) ␦: 7.35–7.26 (m, 5H),
5.47 (s, 1H), 4.56 (ABq, ⌬␯AB ϭ 41.9 Hz, JAB ϭ 12.0 Hz, 2H),
3.62 (ABq, ⌬␯AB ϭ 16.7 Hz, JAB ϭ 10.8 Hz, 2H), 2.89 (d, J ϭ
13.4 Hz, 1H), 2.72 (d, J ϭ 17.3 Hz, 1H), 2.32 (d, J ϭ 17.4 Hz,
1H), 2.32–2.26 (m, 1H), 2.16 (d, J ϭ 13.3 Hz, 1H), 1.94–1.89
(m, 1H), 1.77–1.63 (m, 3H), 1.63–1.42 (m, 3H), 1.08 (s, 3H),
0.96 (d, J ϭ 6.5 Hz, 3H), 0.91 (s, 3H), 0.89 (d, J ϭ 6.6 Hz, 3H).
LR-MS-ESI calcd. for C25H35O3 [M ϩ Hϩ]: 383.3; found: 383.3.
(3aR,5aR,6R,9aR)-9a-((Benzyloxy)methyl)-6-isopropyl-3a,5a-
dimethyl-3,3a,5,5a,6,7,9,9a-octahydroazuleno[5,6-b]
furan-2,4-dione (53)
To a solution containing a mixture of 50a and 50b (4.4 mg,
11 ␮mol) in CH2Cl2 (1 mL) was added NaHCO3 (2.8 mg,
33 ␮mol) and Dess–Martin periodinane (14.6 mg, 14.3 ␮mol).
The reaction was stirred for 50 min and was quenched with a
solution of saturated aqueous NaHCO3 (2 mL) and saturated
aqueous Na2S2O3 (2 mL). After 20 min, the layers were
separated and the aqueous layer was washed with CH2Cl2 (2 ϫ
4 mL). The organic extracts were combined, dried over
Na2SO4, and concentrated in vacuo to provide a clear colorless
oil. Purification via flash chromatography (hexanes/EtOAc,
5:1) provided pure ketone 53 (3.4 mg, 77%) as a white
Supplementary data
Supplementary data are available with the article through
the journal Web site http://nrcresearchpress.com/doi/suppl/
10.1139/v2012-088. CCDC 901299 contains the X-ray data in
CIF format for this manuscript. These data can be obtained,
free of charge, via http://www.ccdc.cam.ac.uk/products/csd/
request (or from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: 44 1223
336033; or e-mail: deposit@ccdc.cam.ac.uk). X-ray crystallo-
graphic data for ketone 53 are available in Molecular Structure
Center Report 09013 (Indiana University Molecular Structure
Center).
crystalline solid (see Supplementary data). [α]2D0 ϩ60.3 (c
1.22, CHCl3). Rf ϭ 0.62 (hexanes/EtOAc, 2:1). IR (film, cm–1):
2960, 2870, 1783, 1697, 1497, 1454, 1378, 1233, 1117, 1068,
957. 1H NMR (500 MHz, CDCl3) ␦: 7.37–7.27 (m, 5H), 5.51 (bs,
1H), 4.55 (ABq, ⌬␯AB ϭ 11 Hz, JAB ϭ 11.7 Hz, 2H), 3.75 (ABq,
⌬␯AB ϭ 53 Hz, JAB ϭ 10.7 Hz, 2H), 3.13 (d, J ϭ 17.8 Hz, 1H),
2.92 (d, J ϭ 11.2 Hz, 1H), 2.76 (d, J ϭ 14.2 Hz, 1H), 2.55 (d,
J ϭ 11.1 Hz, 1H), 2.45 (d, J ϭ 17.8 Hz, 1H), 2.33 (ddd, J ϭ 16.3,
7.9, 2.9 Hz, 1H), 2.22–2.14 (m, 1H), 1.99–1.87 (m, 1H), 1.79–
1.66 (m, 1H), 1.57–1.48 (m, 1H), 1.40 (s, 3H), 0.95 (d, J ϭ
6.6 Hz, 3H), 0.94 (s, 3H), 0.89 (d, J ϭ 6.5 Hz, 3H). 13C NMR
(126 MHz, CDCl3) ␦: 209.0, 174.0, 143.5, 137.4, 129.3, 128.4,
127.8, 127.7, 86.3, 73.9, 72.6, 59.6, 57.2, 52.3, 49.2, 39.8, 35.7,
35.5, 29.4, 22.7, 22.6, 20.5, 19.3, 18.5. HR-MS-ESI calcd for
C25H32O4Na [M ϩ Naϩ]: 419.2198; found: 419.2186.
Acknowledgements
We gratefully acknowledge the National Science Founda-
tion (CHE-1055441) and Indiana University (Faculty Re-
search Support Program) for generous support.
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Published by NRC Research Press

36
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