Studies toward the enantioselective syntheses of oxylipins: Total synthesis and structure revision of solandelactone E

Article abstract of DOI:10.1021/jo701739v

(Chemical Equation Presented) An efficient and general entry to unsaturated cyclopropane- and lactone-containing oxylipins of marine origin has been designed and applied to the first enantioselective total synthesis of solandelactone E. The synthesis, whi

Full text of DOI:10.1021/jo701739v

Studies toward the Enantioselective Syntheses of Oxylipins: Total
Synthesis and Structure Revision of Solandelactone E
Jennifer E. Davoren, Christian Harcken, and Stephen F. Martin*
Department of Chemistry and Biochemistry, The UniVersity of Texas, Austin, Texas 78712
sfmartin@mail.utexas.edu
ReceiVed August 10, 2007
An efficient and general entry to unsaturated cyclopropane- and lactone-containing oxylipins of marine
origin has been designed and applied to the first enantioselective total synthesis of solandelactone E. The
synthesis, which proceeds in a total of 23 steps from commercially available materials, features a
diastereoselective acetal-directed cyclopropanation of an electron-deficient diene, a regioselective Sharpless
enantioselective dihydroxylation, and a stereoselective [2,3]-sigmatropic rearrangement of a selenoxide
to effect a 1,3-transposition of an allylic alcohol. Comparison of spectral data for the synthetic
solandelactone, thus prepared, with data in the literature led to a revision of the original structural
assignments of the C(11)-epimeric solandelactones.
1. Introduction
The solandelactones A-H (1-8) comprise a family of novel
oxygenated fatty acids that were first isolated from the marine
invertebrate Solanderia secunda off the Korean coast in 1996.1
There are two primary subfamilies of solandelactones that vary
with respect to the absolute stereochemistry of the hydroxyl-
bearing carbon atom at C(11). Namely, compounds 1-4 have
the S-configuration at C(11), whereas 5-8 possess the R-
configuration (Figure 1). The solandelactones also vary in the
degree of unsaturation in their lactone rings and their pendant
side chains. There are a number of marine oxylipins that are
related to the solandelactones, including halicholactone (9) and
neohalicholactone (10)2 and constanolactones A and B (11 and
12).3 These oxylipins differ from the solandelactones in that
they have two fewer carbon atoms, opposite absolute configura-
tions at various stereocenters, and either larger or smaller lactone
rings.
Members of the oxylipin family exhibit an array of useful
biological activities. For example, halicholactone (9) displays
FIGURE 1. Cyclopropane containing marine oxylipins.
weak inhibitory activity against 5-lipoxygenase. Although the
solandelactones are not known to share this property, solan-
delactones C, D, and G do show biological activity as inhibitors
of farnesyl transferase,1 an enzyme responsible for the expres-
sion of ras proteins that are found in many types of cancer cells.4
(1) Seo, Y.; Cho, K. W.; Rho, J.-R.; Shin, J.; Kwon, B.-M.; Bok, S.-H.;
Song, J.-I. Tetrahedron 1996, 52, 10583-10596.
(2) (a) Niwa, H.; Wakamatsu, K.; Yamada, K. Tetrahedron Lett. 1989,
30, 4543-4546. (b) Kigoshi, H.; Niwa, H.; Yamada, K.; Stout, T. J.; Clardy,
J. Tetrahedron Lett. 1991, 32, 2427-2428. (c) Proteau, P. J.; Rossi, J. V.;
Gerwick, W. H. J. Nat. Prod. 1994, 57, 1717-1719.
(3) (a) Nagle, D. G.; Gerwick, W. H. Tetrahedron Lett. 1990, 31, 2995-
2998. (b) Nagle, D. G.; Gerwick, W. H. J. Org. Chem. 1994, 59, 7227-
7237.
(4) Lee, S.-H.; Kim, M.-J.; Bok, S. H.; Lee, H.; Kwon, B.-M.; Shin, J.;
Seo, Y. J. Org. Chem. 1998, 63, 7111-7113.
10.1021/jo701739v CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/19/2007
J. Org. Chem. 2008, 73, 391-402
391

Davoren et al.
SCHEME 1
FIGURE 2. Controlling the five stereocenters in the oxylipins.
Unfortunately, because the availability of solandelactones from
natural sources is limited, their biological properties have not
been adequately explored.
The challenging structural features of the oxylipins coupled
with the biological activities of some members of this family
have stimulated significant interest in their preparation by total
synthesis. Although the total syntheses of oxylipins 9-12 and
some of their analogues had been reported,5,6 none of the
solandelactones had been synthesized prior to our work in this
area.7,8 Subsequently, White and co-workers completed the
syntheses of solandelactones E and F.9 At the time we initiated
our work, none of the approaches to the oxylipins enabled
complete stereochemical control at all five of the stereogenic
centers resident in these natural products. The various tactics
that had been employed in the prior art to control the stereo-
chemistry at these five centers are summarized in Figure 2.
Protocols for the enantioselective cyclopropanation of an olefin
and for establishing the correct stereochemistry of an allylic
alcohol function distal to the cyclopropane ring were well
established. On the other hand, the most commonly employed
tactic for forming the cyclopropyl carbinyl centers in 13 had
involved nucleophilic additions of organometallic reagents to a
substituted cyclopropane carboxaldehyde, and there was typi-
cally little stereochemical control in these reactions. We
therefore queried how we might develop a general entry to the
oxylipin natural products that would be both stereochemically
and chemically efficient.
that resulted in the first total synthesis of solandelactone E (3)
and a structural revision of members of the solandelactone
family of oxylipins.8
2. Results and Discussion
2.1. First-Generation Approach. In light of the preliminary
analysis depicted in Scheme 1, we envisioned that solandelac-
tones A, C, E, and G (1-4) and solandelactones B, D, F, and
H (5-8) might be synthesized from the common intermediate
16 according to the retrosynthetic format outlined in Scheme
2. The stereochemistry at C(7) and C(14) would be controlled
by stereoselective 1,3-transpositions of the corresponding C(10)
and C(12) alcohols in 16. Formation of the correct stereochem-
istry at C(7) would require prior inversion at C(10), whereas
introducing the stereocenter at C(14) would not. Following these
two sequential transpositions, the carbon atoms in the eight-
membered lactone ring and the olefinic side chain would be
introduced. We envisioned that 16 would be available via two
E-selective Wittig olefinations of the known acetonide 17, which
may be readily prepared from commercially available L-
SCHEME 2
There is an underlying symmetry common to natural products
1-12 that is revealed in the diene triol 14 (Scheme 1).
Surprisingly, none of the previous syntheses of any oxylipin
exploited this structural feature. A compound of general form
14 might be accessible by two stereoselective 1,3-transpositions
of the allylic alcohol functions of the isomeric triol 15, which
might be conveniently derived from a suitable carbohydrate
starting material. We now report the details of our investigations
(5) For syntheses of halicholactone and neohalicholactone, see: (a)
Critcher, D. J.; Connolly, S.; Wills, M. J. Org. Chem. 1997, 62, 6638-
6657. (b) Mohapatra, D. K.; Datta, A. J. Org. Chem. 1998, 63, 642-646.
(c) Baba, Y.; Saha, G.; Nakao, S.; Iwata, C.; Tanaka, T.; Ibuka, T.; Ohishi,
H.; Takemoto, Y. J. Org. Chem. 2001, 66, 81-88. (d) Takahashi, T.;
Watanabe, H.; Kitahara, T. Heterocycles 2002, 58, 99-104. (e) Mohapatra,
D. K.; Durugkar, K. A. ARKIVOC 2004, 146-155.
(6) For syntheses of constanolactones, see: (a) White, J. D.; Jensen, M.
S. J. Am. Chem. Soc. 1995, 117, 6224-6233. (b) Miyaoka, H.; Shigemoto,
T.; Yamada, Y. Heterocycles 1998, 47, 415-428. (c) Silva, C. B.-D.;
Benkouider, A.; Pale, P. Tetrahedron Lett. 2000, 41, 3077-3081. (d) Yu,
J.; Lai, J.-Y.; Ye, J.; Balu, N.; Reddy, L. M.; Duan, W.; Fogel, E. R.;
Capdevila, J. H.; Falck, J. R. Tetrahedron Lett. 2002, 43, 3939-3941. (e)
Pietruszka, J.; Wilhelm, T. Synlett 2003, 1698-1700.
(7) For synthetic studies directed toward the solandelactones, see: (a)
Varadarajan, S.; Mohapatra, D. K.; Datta, A. Tetrahedron Lett. 1998, 39,
1075-1078. (b) Da Silva, C. B.; Pale, P. Tetrahedron: Asymmetry 1998,
9, 3951-3954. (c) Mohapatra, D. K.; Yellol, G. S. ARKIVOC 2003, 21-
33.
(8) For a preliminary account of portions of this work, see: Davoren, J.
E.; Martin, S. F. J. Am. Chem. Soc. 2007, 129, 510-511.
(9) White, J. D.; Martin, W. H. C.; Lincoln, C.; Yang, J. Org. Lett, 2007,
9, 3481-3483.
392 J. Org. Chem., Vol. 73, No. 2, 2008

EnantioselectiVe Syntheses of Oxylipins
SCHEME 3
SCHEME 4
The diol 19 was selectively oxidized using a single equivalent
of Swern reagent at -78 °C to provide the lactol 20 in 65%
yield. The undesired regioisomeric lactol 21, which arose from
oxidation of the secondary allylic alcohol, was also isolated in
approximately 18% yield. When 20 was treated with methyl-
(tributylphosphoranylidene)acetate under the same conditions
employed for the E-selective olefination of 17, the diester 16
was isolated in 80% yield as a mixture (20:1) of E/Z-isomers.
We had thus prepared the key intermediate 16 in four steps
and 37% overall yield from L-arabinose. In accordance with
our expectations, treatment of 16 with Amberlyst 15 in acetone
afforded a separable mixture (20:1) of the isomeric acetonides
18 and 16. When 18 was resubjected to the reaction conditions,
the same mixture of 16 and 18 was obtained, thus confirming
that this ratio is thermodynamically controlled.
The next stage of the synthetic plan required that the first of
two 1,3-chirality transfer reactions be performed. Toward this
goal, 16 was converted into its mesylate 22 (Scheme 4). We
had originally envisioned that 22 would undergo highly stereo-
selective SN2′ displacement with a (diethylamino)diphenylsilyl
organometallic derivative to give 23,15,16 oxidation of which
would then lead to the desired alcohol 24.17 However, all
attempts to convert 22 into 23 were unsuccessful, and the
deconjugated ester 25 was obtained in 50-85% yields. We were
unable to suppress this deleterious side reaction.
arabinose. In order to prepare solandelactones B, D, F, and H
(5-8) from 16, it would be necessary to effect a transketalization
to provide the diastereomeric diester 18, which was predicted
to be thermodynamically more stable owing to the trans
relationship of the two side chains on the dioxolane ring.
In order to explore the feasibility of the plan in Scheme 2,
L-arabinose was converted into the known acetonide 17, which
was isolated as an anomeric, presumably thermodynamic,
mixture (ca. 4:1) (Scheme 3).10 The installation of the E-R,â-
unsaturated ester moiety found in 19 proved to be somewhat
problematic. Wittig reactions of stabilized ylides, such as
(alkoxycarbonylmethylene)triphenylphosphoranes, with sugar
lactols and R-alkoxy aldehydes were known to proceed with
low E-selectivity.11 Not surprisingly, the reaction of 17 with
methyl(triphenylphosphoranylidene)acetate under standard Wit-
tig conditions gave the R,â-unsaturated ester 19 and its Z-isomer
as a mixture (1:1) in 55% yield. The reaction was also conducted
in the presence of benzoic acid, which was known to enhance
trans selectivity,12 but there was no significant improvement in
the diastereomeric ratio. After some experimentation, it was
found that reaction of 17 with freshly prepared methyl-
(tributylphosphoranylidene)acetate13 and a catalytic amount of
benzoic acid gave 19 in 83% yield (E/Z ) 20:1). This method
for effecting trans selective olefination of 17 was developed
into a general method and extended to include a variety of other
R-alkoxy aldehydes and sugar lactols.14
We then adopted an alternative strategy for converting 16
into 24 that would involve the [2,3]-sigmatropic rearrangement
of an intermediate allylic selenoxide (Scheme 5).18 Although
we were unable to convert the mesylate 22 into the selenide 26
directly, we found that reaction of phenyl selenocyanate with
16 in the presence of tri-n-butylphosphine gave the phenylse-
lenide 26 in 55-64% yield together with variable amounts of
the deconjugated ester 25.19 When the selenide 26 was treated
(15) Ibuka, T.; Tanaka, M.; Nishii, S.; Yamamoto, Y. J. Am. Chem. Soc.
1989, 111, 4864-4872.
(10) Perigaud, C.; Gosselin, G.; Imbach, J. L. J. Chem. Soc., Perkin
Trans. I 1992, 1943-1952.
(16) Crump, R.; Fleming, I.; Urch, C. J. J. Chem. Soc., Perkin Trans. I
1994, 701-706.
(11) Wilcox, C. S.; Gaudino, J. J. J. Am. Chem. Soc. 1986, 108, 3102-
3104.
(17) (a) Tamao, K.; Kakui, T.; Akita, M.; Iwahara, T.; Kanatani, R.;
Yoshida, J.; Kumada, M. Tetrahedron 1983, 39, 983-990. (b) Fleming, I.;
Henning, R.; Plaut, H. J. Chem. Soc., Chem. Commun. 1984, 29-31. (c)
Fleming, I.; Winter, S. B. D. J. Chem. Soc., Perkin Trans. I 1998, 2687-
2700.
(18) Reich, H. J.; Yelm, K. E.; Wollowitz, S. J. Am. Chem. Soc. 1983,
105, 2503-2504.
(19) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485-1486.
(12) For some examples, see: (a) Corey, E. J.; Clark, D. A.; Goto, G.;
Marfat, A.; Mioskowski, C.; Samuelsson, B.; Hammarstrom, S. J. Am.
Chem. Soc. 1980, 102, 1436-1439. (b) Marriott, D. P.; Bantick, J. R.
Tetrahedron Lett. 1981, 22, 3657-3658. (c) Mulzer, J.; Kappert, M. Angew.
Chem., Int. Ed. Engl. 1983, 22, 63-64.
(13) Aspinall, I. H.; Cowley, P. M.; Mitchell, G.; Raynor, C. M.;
Stoodley, R. J. J. Chem. Soc., Perkin Trans. 1 1999, 2591-2599.
(14) Harcken, C.; Martin, S. F. Org. Lett. 2001, 3, 3591-3593.
J. Org. Chem, Vol. 73, No. 2, 2008 393

Davoren et al.
SCHEME 5
SCHEME 6
with hydrogen peroxide and pyridine, the trans R-hydroxyester
24 was obtained as a single isomer in 95% yield. The assignment
of the trans-geometry of the newly formed olefin was based
upon the observed vicinal coupling constant of 15.5 Hz for the
olefinic protons on C(9) and C(10), whereas the stereochemistry
of the hydroxyl group was assigned assuming that the reaction
proceeded via the more stable envelope transition state that is
usually observed for such rearrangements.20
retention of stereochemistry. Inasmuch as the 1,3-transposition
had previously been problematic, this new entry to the solan-
delactones was attractive because only one such transposition
was required and the reorganization could potentially be
postponed until late in the synthesis. The requisite C(1)-C(5)
and C(16)-C(22) subunits would be introduced by carbon-
carbon bond-forming reactions involving an epoxide opening
and a SN2 reaction, respectively, to provide the advanced
intermediates 28 and 29. The absolute stereochemistry of the
vicinal diol at C(11)-C(12) of 28 and 29 would be introduced
via a Sharpless enantioselective dihydroxylation of a diene
related to 30, which we envisioned would be accessible from
commercially available D-glyceraldehyde acetonide (31).
2.2.1. Assembly of the Central Core of C(6)-C(15). The
known dienoate 32 was first prepared in 72% yield as a mixture
(10:1) of E/Z isomers in a single step via the HWE olefination
of 31 with trans-triethyl phosphonocrotonate (Scheme 7).23
Heating 32 with an excess of Simmons-Smith reagent in a sealed
tube provided the cyclopropane 33 (72%), the stereochemistry
of which was tentatively assigned based upon analogy with the
literature.24 The diastereoisomeric cyclopropane was not isolated.
Use of dichloromethane as solvent consistently gave somewhat
higher yields (5-10% higher) of 33 than did dichloroethane,
although the latter solvent was more convenient for preparative
purposes as the reaction did not have to be performed in a sealed
tube. The chain extension of the unsaturated ester in 33 was
then initiated by reduction with DIBAL to provide the allylic
alcohol 34. The stereochemistry of the cyclopropanation step
was then unequivocally established by converting 34 in two
steps into the carbamate 36; X-ray analysis of a single crystal
of 36 confirmed the relative stereochemical relationship between
the two stereocenters at C(8)-C(10) and C(7). Having estab-
lished three of the requisite
Having successfully effected the key chirality transfer step,
we turned toward the diastereoselective installation of the
cyclopropane ring. Charette had showed that good to excellent
(6:1 to >200:1) facial selectivity in the cyclopropanations of
E-allylic alcohols could be achieved utilizing Et2Zn/CH2I2,21
a
reagent first described by Furukawa.22 Accordingly, we dis-
covered that heating 24 in CH2Cl2 with 2 equiv of Zn(CH2I)2
in a sealed tube at 65 °C resulted in complete consumption of
starting material and a 78% isolated yield of 27, the structure
of which was assigned based upon Charette’s results. Although
the synthesis of 27 in eight steps from L-arabinose did validate
the underlying feasibility of the original unified approach to
the solandelactones that is outlined in Scheme 2, the selenation
step leading to 26 proved to be problematic upon scale-up, and
yields dropped to 10-15%. Consequently, we turned to
developing an alternate plan.
2.2. Second-Generation Approach. Our second-generation
approach to the solandelactones was also designed to provide
access to all known members of the solandelactone family, and
the essential elements of the plan are exemplified for the
syntheses of the C(11)-epimeric solandelactones E (3) and F
(7) (Scheme 6). The allylic alcohol array at C(12)-C(14) would
be introduced by a stereoselective 1,3-transposition. The
preparation of 3 would thus entail an allylic 1,3-transposition
of a compound derived from 28 that proceeded with overall
inversion of the stereochemistry of the C(12) alcohol, whereas
the allylic transposition of 29 en route to 7 would require net
(20) (a) Hoffmann, R. W. Angew. Chem. 1979, 91, 625-634. (b)
Nishibayashi, Y.; Uemura, S. Top. Curr. Chem. 2000, 208, 201-235.
(21) Charette, A. B.; Lebel, H. J. Org. Chem. 1995, 60, 2966-2967.
(22) (a) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron 1968,
24, 53-58. (b) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron Lett.
1966, 3353-3354.
(23) Li, S.-K.; Xu, R.; Xiao, X.-S.; Bai, D.-L. Chinese J. Chem. 2000,
18, 910-923.
(24) Morikawa, T.; Sasaki, H.; Hanai, R.; Shibuya, A.; Taguchi, T. J.
Org. Chem. 1994, 59, 97-103.
394 J. Org. Chem., Vol. 73, No. 2, 2008

EnantioselectiVe Syntheses of Oxylipins
SCHEME 7
SCHEME 8
intermediate in the synthesis of solandelactone E (3), whereas
38 could be a precursor of solandelactone F (7).
2.2.2. Elaborating the C(12)-C(22) Segment. Having
developed an efficient entry to the C(6)-C(15) central core of
the solandelactones, we began to explore various tactics for
introducing the side chains at C(6) and C(15) that would be
required for solandelactones E (3) and F (7) and for effecting
the 1,3-transposition. We decided to append the C(16)-C(22)
subunit first because compared to an unsaturated lactone ring
the double bonds were expected to be more tolerant of a number
of projected synthetic operations. Toward that end, the diol 37
was first converted into the bis-TBS ether 39, a reaction that
was sluggish and required prolonged reaction times or mild
heating to induce complete conversion (Scheme 9). The ester
of 39 was then reduced with DIBAL, and the intermediate allylic
alcohol was converted to its bromide 40 in 91% overall yield.
When 40 was allowed to react with 1-heptynyllithium in the
presence of CuBr‚SMe2, the desired enyne 41 was isolated in
95% yield. To examine the feasibility of the key allylic
transposition, the silyl protecting groups were selectively
removed by treating 41 with excess tetrabutylammonium
fluoride (TBAF) to afford the diol 42 in near quantitative yield.
With the diol 42 in hand, it was time to examine the 1,3-
chirality transfer. Both of the hydroxyl groups required protec-
tion prior to appending the C(1)-C(5) fragment, so a strategy
stereocenters, 34 was oxidized with catalytic tetrapropylammo-
nium perruthenate (TPAP)25 in the presence of N-methylmor-
pholine N-oxide (NMO) to give an intermediate R,â-unsaturated
aldehyde that was allowed to react with the anion of triethyl
phosphonoacetate to furnish 35 and small amounts of the
Z-isomer (E/Z ) 10:1) in 87% overall yield.
The stage was now set to install the chiral centers at C(11)
and C(12) via enantioselective dihydroxylation of the more
electron-rich, γ,δ-double bond of the dienoate 35.26 When 35
was treated with commercially available AD-mix R and AD-
mix â, significant amounts of starting material remained, even
after prolonged reaction times (48 h) at room temperature. After
some experimentation with standard conditions, we found that
use of modified AD mixtures, which were prepared by com-
bining increased amounts of (DHQ)2PHAL or (DHDQ)2PHAL
(8 mol %) and K2OsO2(OH)4 (5 mol %) with the usual quantities
of noncatalytic ingredients, led to more rapid and complete
conversions. When diene 35 was treated with modified AD-
mix â, the diol 37 was isolated as a single diastereomer (dr >
20:1) in 84% yield (Scheme 8). The same reaction of 35 with
modified AD-mix R provided an inseparable mixture (dr ) 3:1)
of diols 38 and 37, suggesting a mismatch of ligand and olefin.
The stereochemistry of 37 and 38 were assigned to be 11R,12R
and 11S,12S, respectively, by applying the Sharpless model.27
In accordance with our synthetic plan, diol 37 would be a key
SCHEME 9
(25) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639-666.
(26) Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem. Soc. 1992,
114, 7570-7571.
(27) Norrby, P.-O.; Kolb, H. C.; Sharpless, K. B. J. Am. Chem. Soc.
1994, 116, 8470-8478.
J. Org. Chem, Vol. 73, No. 2, 2008 395

Davoren et al.
SCHEME 10
SCHEME 11
we discovered that when the mixture (4:1) of 44 and 45 was
treated with o-NO2PhSeCN and Bu3P followed by reaction of
the intermediate nitrophenylselenide with H2O2 and pyridine,
the transposed alcohol 46 was obtained in 47% overall yield
from 43; none of the dienyne 47 was isolated.
was adopted that would first involve the selective protection of
the more hindered C(11) hydroxyl group. Anisylidine acetals
are known to undergo selective cleavage at the least hindered
carbon-oxygen bond using hydride reagents, and DIBAL is
commonly employed for this process because it usually provides
excellent regiocontrol.28 In the event, diol 42 was treated with
anisaldehyde dimethyl acetal in the presence of a catalytic
amount of TsOH to furnish the anisylidine acetal 43 as a mixture
(1:1) of diastereomers in 91% yield (Scheme 10). When 43 was
treated with DIBAL (3 equiv) in CH2Cl2 at -78 °C, an
inseparable mixture (4:1) of 44 and 45 was obtained in 82%
yield. In ancillary model studies, we discovered that use of a
combination of (i-Bu)3Al as a Lewis acid and NaCNBH3 as a
reducing agent in CH2Cl2 cleaved acetals having substitution
patterns similar to 43 with higher regioselectivity than DIBAL.
Unfortunately, reduction of 43 under these conditions was less
selective than DIBAL. In analogy with the conversion of 16
into 26 (Scheme 5), the mixture of 44 and 45 was allowed to
react with PhSeCN and Bu3P, and the intermediate selenide was
oxidized with H2O2 in the presence of pyridine to provide a
separable mixture (1:1) of 46 (ca. 23% yield) together with an
elimination product that was tentatively assigned the structure
of 47. The structure of 46 was assigned based upon the observed
coupling constant of 15.6 Hz for the vicinal protons on C(12)
and C(13) that is consistent with the E-olefin geometry, and
the preferred five-membered transition state that would lead to
the desired configuration at C(14). In a modified procedure,
2.2.3. Constructing the C(1)-C(7) Lactone. Owing to the
modest overall yield in converting 42 into 46, we elected to
postpone the allylic transposition sequence until later stage in
the synthesis. We thus turned to the task of appending a C(1)-
C(5) side chain that was suitably functionalized to elaborate
the unsaturated eight-membered lactone ring in solandelactones
E and F. We envisioned that these carbon atoms could be
introduced by the opening of a C(6)-C(7) epoxide. Toward
this end, the acetonide moiety in 41 was selectively hydrolyzed
in a biphasic system of CH2Cl2 and aqueous trifluoroacetic acid
(TFA) to provide the diol 48 in 82% yield (Scheme 11).29
A
modification of a Fraser-Reid protocol was then employed to
prepare 49 in nearly quantitative yield via sequential treatment
of 48 with NaH and N-tosylimidazole.30 Although the epoxide
49 was rather unstable and rearranged readily to the aldehyde
52, the crude epoxide was >95% pure and could be used directly
in subsequent reactions.
Our strategy for introducing the unsaturated, eight-membered
lactone onto 49 entailed opening of the epoxide ring with a
functionalized acetylide anion. However, treating 49 with the
dianion of 4-pentynoic acid under a variety of conditions led
only to recovered starting material or complex mixtures, and
(28) For an example used in the total synthesis of constanolactones A
and B, see: Da Silva, C. B.; Pale, P. Tetrahedron: Asymmetry 1998, 9,
3951-3954.
(29) Smith, A. B., III; Doughty, V. A.; Sfouggatakis, C.; Bennett, C. S.;
Koyanagi, J.; Takeuchi, M. Org. Lett. 2002, 4, 783-786.
(30) Hicks, D. R.; Fraser-Reid, B. Synthesis 1974, 203.
396 J. Org. Chem., Vol. 73, No. 2, 2008

EnantioselectiVe Syntheses of Oxylipins
SCHEME 12
none of the desired acid 50 was isolated. Wipf reported that
TBDPS-protected esters may be used as starting materials in a
variety of metal-catalyzed transformations,31 and it occurred to
us that the anion of the TBDPS ester of 4-pentynoic acid might
be employed as a nucleophile for opening epoxides, including
49. We conducted a simple model study and found that when
propylene oxide was treated with an alkynyl borane derived
from the TBDPS-protected pentynoic acid 53, the known
hydroxy acid 54 was isolated in unoptimized yield of 86% (eq
1).32 To our knowledge, this is the first example of a nucleophilic
ring opening of an epoxide with an alkynyl borane containing
a silyl ester. Although this reaction may be of general use in
synthesis, we were disappointed to find that, when 49 was used
as the reactant, a complex mixture of compounds was again
produced, from which only 5% of 51 could be isolated.
Eventually we discovered that reaction of the epoxide 49 with
the acetylide anion generated from tetrahydropyranyl-protected
4-pentyn-1-ol using a procedure reported by Yamaguchi gave
the desired alcohol 56, although the yields, which ranged from
45-67%, in this reaction were somewhat irreproducible (Scheme
12).33 Acylation of the free hydroxyl group in 56, followed by
acid-catalyzed acetal exchange with i-PrOH provided 57 in 80%
yield. Use of more conventional solvents, such as MeOH or
the previously described biphasic aqueous TFA/CH2Cl2 condi-
tions, for removing the tetrahydropyranyl protecting group
resulted in a significant loss of the silyl protecting groups.
Hydrogenation of both of the triple bonds in 57 using Lindlar’s
catalyst poisoned with excess quinoline provided the triene 58
as the only isolable stereoisomer in 94% yield. A two-stage
oxidation of the primary alcohol in 58 furnished the carboxylic
acid 59. Subsequent saponification of the acetate moiety in 59
then gave a hydroxy acid intermediate that underwent facile
lactonization using the Yamaguchi protocol to give lactone 60
in 77% overall yield from 59.34
with H2O2 provided the transposed diol 3, the transformation
proceeded in only 20% yield. Approximately 15% of starting
61 remained even under the best conditions, and none of the
other products of the reaction could be identified.
2.2.4. Completion of Synthesis and Revision of Structure.
It now remained to effect the 1,3-transposition of the allylic
alcohol at C(12) of 60. The sequence was initiated by treating
60 with TBAF to give the diol 61 (eq 2). In our previous
experiments such transpositions were performed on a protected
diol. However, owing to the different steric environments of
the two hydroxyl groups, we postulated that it might be possible
to effect this transformation on an unprotected diol. Such a tactic
would obviously eliminate the problems associated with selec-
tive protection of the more hindered hydroxyl group at C(11).
Although treatment of 61 with o-NO2PhSeCN in the presence
of (n-Bu)3P followed by oxidation of the intermediate selenide
On the basis of the original report of Shin,1 we believed we
had thus completed the first total synthesis of solandelactone F
(7). However, when we compared our 1H and 13C NMR spectral
data with those published for the respective solandelactones,
we found that our data were actually more consistent with those
(31) For a recent example, see: Wipf, P.; Pierce, J. G.; Zhuang, N. Org.
Lett. 2005, 7, 483-485.
(32) Seidel, W.; Seebach, D. Tetrahedron Lett. 1982, 23, 159-62.
(33) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391-394.
(34) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989-1993.
J. Org. Chem, Vol. 73, No. 2, 2008 397

Davoren et al.
SCHEME 13
somer 64 to increase the overall efficiency. Reaction of 63 with
o-NO2PhSeCN and (n-Bu)3P followed by oxidation of the
intermediate allylic selenide with H2O2 and [2,3]-sigmatropic
rearrangement of the allylic selenoxide thus delivered alcohol
65 as the sole product. The p-methoxybenzyl ether protecting
group on 65 was then cleaved using DDQ to give a diol that
was identical to the compound that was obtained directly from
the allylic transposition of 61 (cf eq 2). Because no epoxide
intermediates could be formed in this sequence, our structural
assignment of 3 and its identification as solandelactone E was
secured.
3. Summary
We designed a convergent approach to the oxylipins that
provides an effective solution to the numerous stereochemical
challenges posed by this important family of natural products.
The efficacy of the approach was validated in the first
enantioselective total synthesis of solandelactone E (3) in 23
steps from commercially available D-glyceraldehyde acetonide.
Comparison of spectral data for our synthetic solandelactone
with data in the literature led to a revision of the original
structural assignments of the C(11)-epimeric solandelactones,
a finding that was subsequently confirmed by White and co-
workers.9 Highlights of the synthesis include a diastereoselective,
acetal-directed cyclopropanation of an electron-deficient olefin,
a diastereoselective and enantioselective dihydroxylation that
can lead to both C(11) epimeric series of the solandelactones,
and a stereoselective 1,3-chirality transfer process featuring the
[2,3]-sigmatropic rearrangement of an allylic selenoxide. During
the course of these investigations, we also discovered and
developed an efficient procedure for the highly E-stereoselective
Wittig olefination of R-alkoxy aldehydes and sugar lactols, for
the regioselective reductive cleavage of anisylidine acetals, and
a potential method for opening substituted epoxides with alkynyl
silyl esters. The utility of these latter methods is being explored
in separate studies, the results of which will be reported in due
course.
reported for the C(11) epimeric natural product solandelactone
E (3). Our structural assignment of synthetic 3 seemed firmly
based upon the X-ray analysis of 34, the known stereochemical
preference for enantioselective dihydroxylations,27 and the
preferred stereoselectivity of [2,3]-sigmatropic rearrangements.35
Although these data were highly supportive of our assignment,
unambiguous proof of our structure was lacking. In subsequent
correspondence with Professor Shin, it became apparent that a
mistake had been made in correlating the names of the C(11)-
epimeric solandelactones with their respective structures in the
original paper,1 and he agreed that those assignments should
be revised in accord with our findings. Namely, the C(11)
stereochemistry depicted in that paper should be corrected to
C(11)S for solandelactones A, C, E, and G and C(11)R for
solandelactones B, D, F and H. In this context, it is noteworthy
that White has confirmed this revised assignment in a recent
report detailing the syntheses of solandelactones E and F.9
4. Experimental Section
(E)-Ethyl 3-((1S,2R)-2-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-
cyclopropyl)acrylate (33). Diiodomethane (5.4 mL, 67.2 mmol)
was added dropwise over 1 min to a stirred solution of Et2Zn
(1.0 M solution in hexane, 20.2 mL, 20.2 mmol) and diene 32 (3.8
g, 16.8 mmol) in anhydrous CH2Cl2 (200 mL) in a sealed tube at
room temperature. Once the addition was complete, the tube was
sealed, and the bottom third of the sealed tube was immersed in a
65 °C oil bath and stirred for 4 h whereupon the tube was removed
from the bath and cooled in a refrigerator at 5 °C for 12 h. Once
cooled, the tube was opened, and the contents were poured into a
separatory funnel containing aqueous 1 M HCl (100 mL). The
remaining salts in the sealed tube were dissolved with aqueous 1
M HCl (2 × 20 mL) and CH2Cl2 (2 × 20 mL) and then poured
into the funnel. The biphasic mixture was shaken until both layers
were transparent, and additional aqueous 1 M HCl was added as
necessary until both layers were transparent. The layers were
separated, and the organic layer was washed with saturated aqueous
NaHCO3 (50 mL) and saturated aqueous Na2S3O5 (30 mL), dried
(MgSO4), and concentrated under reduced pressure. The residue
was purified by flash chromatography eluting with hexanes/EtOAc
(9:1 to 5:1) to give 2.90 g (72%) of 33 as a clear oil; [R]22D + 28.4
Before White had verified our proposal for revising the
absolute stereochemistry at C(11) of the solandelactones, we
considered the possibility that the 1,3-allylic transformation of
61 might have occurred via epoxide intermediates to furnish
diastereoisomeric allylic selenides that could have delivered
solandelactone F (7) or the C(14) epimer of 3 upon oxidation
and [2,3]-sigmatropic rearrangement. That this was not the case
was established by an independent synthesis of 3 from 61 by a
five-step reaction sequence. Thus, diol 61 was treated with
anisaldehyde dimethyl acetal in the presence of a catalytic
amount of TsOH to furnish 62 (Scheme 13). Reductive cleavage
of the acetal moiety in 62 with NaCNBH3 and TFA gave
alcohols 63 and 64 as a separable mixture (1.2:1) of regioiso-
mers. When 64 was treated with DDQ in the presence of a pH
7 phosphate buffer, the starting acetal 62 was isolated in 65%
yield,36 thereby allowing the recycling of the undesired regioi-
(36) Oikawa, Y.; Nishi, T.; Yonemitsu, O. Tetrahedron Lett. 1983, 24,
4037-4040.
(35) Nishibayashi, Y.; Uemura, S. Top. Curr. Chem. 2000, 208, 2015.
398 J. Org. Chem., Vol. 73, No. 2, 2008

EnantioselectiVe Syntheses of Oxylipins
1
(c 3.50, CHCl3); H NMR (500 MHz) δ 6.42 (dd, J ) 15.1, 9.4
22.2, 21.9, 18.7, 18.1, 17.9, 16.3, 16.3, 14.0, 6.4, -4.4, -4.6, -4.6,
-4.8; IR (neat) 2930, 2858, 2360, 1472, 1368, 1252, 1125, 1065,
913, 836, 743, 668 cm-1; mass spectrum (CI) m/z 565, 549, 507,
433, 285 (base), 227. HRMS C32H61O4Si2 (M + 1) calcd 565.4108,
found 565.4090.
Hz, 1 H), 5.83 (dd, J ) 15.1, 0.5 Hz, 1 H), 4.14 (q, J ) 7.2 Hz, 2
H), 4.06 (dd, J ) 8.0, 5.5 Hz, 1 H), 3.71 (dd, J ) 7.0, 5.5 Hz, 1
H), 3.65 (dd, J ) 8.0, 7.0 Hz, 1 H), 1.51 (app dt, J ) 9.4, 4.6 Hz,
1 H), 1.39 (s, 3 H), 1.31 (s, 3 H), 1.24 (t, J ) 7.2 Hz, 3 H), 1.20
(ddd, J ) 8.5, 4.6, 2.5, 1.5 Hz, 1 H), 1.05 (app dt, J ) 8.5, 5.5 Hz,
1 H), 0.89 (dt, J ) 8.5, 5.0 Hz, 1 H); 13C NMR (125 MHz) δ
166.5, 151.3, 119.0, 109.1, 77.7, 69.0, 60.1, 26.6, 25.6, 24.5, 18.3,
14.3, 12.8; IR (neat) 2984, 2860, 1715, 1645, 1370, 1254, 1146,
1064 cm-1; mass spectrum (CI) m/z 241 (base) 183, 165. HRMS
C13H21O4 (M + 1) calcd 241.1440, found 241.1432.
(S)-1-((1R,2R)-2-((5R,6R)-6-((E)-Dec-1-en-4-ynyl)-2,2,3,3,8,8,9,9-
octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)cyclopropyl)ethane-
1,2-diol (48). A solution of trifluoroacetic acid (0.35 mL, 4.74
mmol) in H2O (1.8 mL) was added to a solution of acetonide 41
(1.34 g, 2.37 mmol) in CH2Cl2 (25 mL) at room temperature.
Stirring was continued for 6 h at room temperature, whereupon
saturated aqueous NaHCO3 (10 mL) was added. After 15 min the
layers were separated, and the organic layer was dried (MgSO4)
and concentrated under reduced pressure. The residue was purified
by flash chromatography eluting with hexanes/EtOAc (6:1) to
(4R,5R,E)-Ethyl 5-((1R,2R)-2-((S)-2,2-Dimethyl-1,3-dioxolan-
4-yl)cyclopropyl)-4,5-dihydroxypent-2-enoate (37). A dry mixture
of “super” AD-Mix â was prepared by combining K3FeCN6 (7.3
g, 22.5 mmol), K2CO3 (3.11 g, 22.5 mmol), K2OsO2(OH)4 (183
mg, 0.53 mmol), (DHQD)2PHAL (550 mg, 0.60 mmol), and
methanesulfonamide (1.43 g, 15.0 mmol). H2O (40 mL) and
t-BuOH (40 mL) were added to the mixture, and the resultant
mixture was stirred at room temperature until all of the solids were
dissolved (ca. 0.5 h). This solution of AD-Mix â was then
transferred into a second flask containing diene 35 (2.0 g, 7.51
mmol), and the solution was stirred for 8 h at room temperature.
Solid Na2SO3 (4.73 g, 37.5 mmol) was added, and stirring continued
for an additional 12 h. The layers were separated, and the aqueous
layer was extracted with EtOAc (2 × 50 mL). The combined
organic extracts were dried (MgSO4) and concentrated under
reduced pressure. The residue was purified by flash chromatogra-
phy, eluting with hexanes/EtOAc (2:1 to 1:3) to give a pale-yellow
solid contaminated with excess methanesulfonamide. The mixture
was triturated with CHCl3, and the crystalline impurity was removed
to give 1.76 g (78%) of diol 37 as a pale-yellow wax: mp 41-43
1
provide 1.02 g (82%) of 48 as a clear oil; H NMR (500 MHz) d
5.92 (ddt, J ) 15.5, 4.5, 2.0 Hz, 1 H), 5.64 (dtd, J ) 15.5, 4.5, 2.0
Hz, 1 H), 4.18 (dt, J ) 4.5, 2.0 Hz, 1 H), 3.66 (br, 1 H), 3.53 (dd,
J ) 10.7, 6.7 Hz, 1 H), 3.44 (app t, J ) 4.5 Hz, 1 H), 3.04-3.01
(m, 1 H), 2.92 (dt, J ) 4.5, 2.0 Hz), 2.14 (tt, J ) 7.2, 2.0 Hz, 2 H),
1.90 (br, 2 H), 1.48 (p, 7.2 Hz, 2H), 1.36-1.27 (comp, 4 H), 1.00
(dtd, J ) 9.7, 5.2, 5.2 Hz, 1H), 0.98 (s, 9 H), 0.87 (s, 9 H), 0.86-
0.81 (m, 1 H), 0.53 (app dt, J ) 8.7, 4.7 Hz, 1 H), 0.42 (app dt, J
) 8.7, 4.7 Hz, 1 H), 0.03 (s, 3 H), 0.03 (s, 3 H), 0.03 (s, 3 H), 0.02
(s, 3 H); 13C NMR (125 MHz) d 130.0, 125.6, 82.9, 76.9, 76.2,
75.1, 75.0, 66.4, 31.1, 28.8, 25.9, 25.8, 22.2, 21.9, 18.7, 18.2, 18.0,
17.6, 16.4, 14.0, 6.0, -4.4, -4.6, -4.7, -4.8; IR (neat) 3382, 2929,
2857, 1471, 1253, 1079, 835, 774 cm-1; mass spectrum (CI) m/z
523, 507, 468, 393, 375, 279 (base), 245, 185. HRMS C29H55O4-
Si2 (M - 1) calcd 523.3639, found 523.3639.
(5R,6R)-5-((E)-Dec-1-en-4-ynyl)-2,2,3,3,8,8,9,9-octamethyl-6-
((1R,2R)-2-((S)-oxiran-2-yl)cyclopropyl)-4,7-dioxa-3,8-disilade-
cane (49). Sodium hydride (60% suspension in mineral oil, 223
mg, 5.58 mmol) was added to a solution of diol 48 (997 mg, 1.86
mmol) in anhydrous THF (19 mL) at 0 °C. After 15 min at 0 °C,
1-(p-toluenesulfonyl)imidazole (413 mg, 1.86 mmol) was added.
Stirring was continued for an additional 3 h at 0 °C, whereupon
the ice bath was removed and stirring continued for 12 h at room
temperature. Et2O (20 mL) and saturated aqueous NaHCO3 (10 mL)
were added to the reaction mixture, and the layers were separated.
The organic layer was further washed with saturated aqueous NH4-
Cl (10 mL) and brine (10 mL). The combined organic layers were
dried (MgSO4) and concentrated under reduced pressure to provide
975 mg (99%) of 49 as a pale-yellow oil which was used without
°C; [R]22 + 8.4 (c 2.53, CHCl3); H NMR (500 MHz) δ 6.97
1
(ddd, J )D15.7, 5.0, 1.7 Hz, 1 H), 6.11 (dt, J ) 15.7, 1.6 Hz, 1 H),
4.23 (td, J ) 5.0, 1.5 Hz, 1 H), 4.17 (dq, J ) 7.2, 1.7 Hz, 2 H),
4.03 (dd, J ) 7.4, 4.8 Hz, 1 H), 3.69 (dd, J ) 7.8, 4.8 Hz, 1 H),
3.65 (app t, J ) 7.4 Hz, 1 H), 2.99 (dd, J ) 8.5, 5.0 Hz, 1 H), 1.40
(s, 3 H), 1.31 (s, 3 H), 1.26 (dt, J ) 7.2, 1.7 Hz, 3 H), 1.05 (app
ddt, J ) 8.5, 7.8, 5.0 Hz, 1 H), 0.93 (app tt, J ) 8.5, 5.0 Hz, 1 H),
0.68 (app dt, J ) 8.5, 5.0 Hz, 1 H), 0.58 (dt, J ) 8.5, 5.0 Hz, 1 H);
13C NMR (100 MHz) δ 166.3, 146.4, 122.0, 109.1, 78.3, 74.6, 76.7,
68.7, 60.6, 26.7, 25.5, 18.5, 18.1, 14.2, 7.9; IR (neat) 3413, 2978,
2884, 2332, 1718, 1261, 1059, 668 cm-1; mass spectrum (CI) m/z
301, 283, 265, 243 (base), 225, 207. HRMS C15H25O6 (M+1) calcd
301.1651, found 301.1654.
1
further purification; H NMR (400 MHz) δ 5.86 (ddt, J ) 15.4,
(5R,6R)-5-((E)-dec-1-en-4-ynyl)-6-((1R,2R)-2-((S)-2,2-dimethyl-
1,3-dioxolan-4-yl)cyclopropyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-di-
oxa-3,8-disiladecane (41). 1-Heptyne (0.90 mL, 6.87 mmol) and
n-butyllithium (2.5 M solution in hexanes, 2.23 mL, 5.58 mmol)
was added to a solution of CuBr·SMe2 (132 mg, 0.64 mmol) in
THF (42 mL) at -78 °C. Stirring was continued for 1.5 h at -78
°C, whereupon a solution of allylic bromide 40 (2.36 g, 4.29 mmol)
in THF (5 mL) was added dropwise. The -78 °C bath was
removed, and stirring continued for 8 h at room temperature. Et2O
(10 mL) and saturated aqueous NH4Cl (20 mL) were added, and
stirring was continued for an additional 12 h at room temperature.
The layers were separated, and the organic layer was dried (MgSO4),
and concentrated under reduced pressure. The residue was purified
by flash chromatography eluting with hexanes/EtOAc (20:1) to
4.5, 2.0 Hz, 1 H), 5.59 (dtd, J ) 15.4, 5.2, 1.6 Hz, 1 H), 4.13 (app
dt, J ) 4.5, 1.6 Hz, 1 H), 3.55 (app t, J ) 4.2, 1 H), 2.90 (ddd, J
) 6.8, 4.4, 2.0 Hz, 2 H), 2.71 (dd, J ) 5.0, 4.0 Hz, 1 H), 2.60
(ddd, J ) 6.8, 4.0, 2.6 Hz, 1 H), 2.55 (dd, J ) 5.0, 2.6 Hz, 1 H),
2.13 (tt, J ) 7.2, 2.4 Hz, 2 H), 1.47 (p, J ) 7.2 Hz, 2 H), 1.37-
1.24 (comp, 4 H), 1.09-1.03 (m, 1 H), 0.89 (s, 9 H), 0.84 (s, 9 H),
0.88-0.75 (comp, 4 H), 0.45-0.39 (comp, 2 H), 0.03 (s, 3 H),
0.02 (s, 3 H), 0.02 (s, 3 H), 0.00 (s, 3 H); 13C NMR (75 MHz) δ
130.3, 125.0, 82.7, 77.0, 75.6, 74.3, 54.2, 47.3, 31.1, 28.8, 25.9,
25.7, 22.2, 21.8, 18.7, 18.2, 18.0, 16.3, 15.1, 14.0, 4.5, -4.3, -4.6,
-4.7, -4.8; IR (neat) 2928, 2857, 2363, 1471, 1253, 1124, 1076,
836 cm-1; mass spectrum (CI) m/z 507.3687, 491, 449, 375, 279
(base), 227. HRMS C29H55O3Si2 (M + 1) calcd 507.3690, found
507.3687.
provide 2.29 g (95%) of 41 as a pale-yellow oil; [R]22 + 9.8 (c
D
0.85, CHCl3); 1H NMR (500 MHz) d 5.86 (ddt, J ) 15.5, 4.5, 2.0
Hz, 1 H), 5.59 (dtd, J ) 15.5, 5.0, 1.5, 1 H), 4.13 (app dt, J ) 4.5,
1.5 Hz, 1 H), 3.95 (dd, J ) 8.0, 6.0 Hz, 1 H), 3.64 (app t, J ) 8.0,
1 H), 3.42 (app t, J ) 4.5 Hz, 1 H), 3.36 (dt, J ) 8.0, 6.0 Hz, 1 H),
2.92 (dt, J ) 5.0, 2.0 Hz, 2 H), 2.14 (tt, J ) 7.2, 2.0 Hz, 2 H), 1.47
(p, J ) 7.6 Hz, 2 H), 1.39 (s, 3 H), 1.30 (s, 3 H), 1.36-1.26 (comp,
4 H), 0.92-0.84 (comp, 23 H), 0.58 (dt, J ) 9.4, 4.7 Hz, 1H),
0.47 (dt, J ) 9.4, 4.7 Hz, 1 H), 0.02 (s, 3 H), 0.02 (s, 3 H), 0.02
(s, 3 H), 0.01 (s, 3 H); 13C NMR (125 MHz) δ 130.1, 125.4, 108.4,
82.8, 80.8, 76.9, 75.4, 75.1, 69.4, 31.1, 28.8, 26.8, 25.9, 25.9, 25.8,
(1R)-1-((1R,2R)-2-((5R,6R)-6-((E)-Dec-1-en-4-ynyl)-
2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)cyclo-
propyl)-7-(tetrahydro-2H-pyran-2-yloxy)hept-3-yn-1-ol (56). n-
Butyllithium (2.45 M in hexane, 2.35 mL, 5.89 mmol) was added
to a solution of 2-(4-pentynyloxy)tetrahydro-2H-pyran (1.23 g, 7.36
mmol) in anhydrous THF (30 mL) at -78 °C. Stirring was
continued for 1 h at -78 °C, whereupon BF3·OEt2 (0.56 mL, 4.41
mmol) was added and the mixture was stirred at -78 °C for an
additional 45 min. The reaction was cooled to -100 °C for 15 min,
and epoxide 49 dissolved in THF (10 mL) was added dropwise.
J. Org. Chem, Vol. 73, No. 2, 2008 399

Davoren et al.
Stirring was continued for 2 h at -100 °C, and AcOH (1 mL) was
added. After 5 min at -100 °C, the ice bath was removed, and
saturated aqueous NH4Cl (30 mL) was added. When the reaction
reached room temperature (ca. 30 min), the layers were separated,
and the aqueous layer was extracted with ether (2 × 20 mL). The
combined organic layers were dried (MgSO4) and concentrated
under reduced pressure. The residue was purified by flash chro-
matography eluting with hexanes/EtOAc (100:3) to give 549 mg
with hexanes/EtOAc (6:1 to 3:1) to provide 596 mg (87%) of
alcohol 57 as a pale-yellow oil; H NMR (500 MHz) δ 5.85 (ddt,
1
J ) 15.5, 4.6, 2.0 Hz, 1 H), 5.59 (dtd, J ) 15.5, 5.5, 1.5 Hz, 1 H),
4.39 (dt, J ) 7.5, 4.3 Hz, 1 H), 4.11 (app dt, J ) 4.6, 1.5 Hz, 1 H),
3.69 (dt, J ) 6.2, 1.5 Hz, 2 H), 3.35 (app t, J ) 4.6 Hz, 1 H), 2.91
(dt, J ) 5.5, 2.0 Hz, 2 H), 2.50 (ddt, J ) 17.0, 4.3, 2.5 Hz, 1 H),
2.41 (ddt, J ) 17.0, 7.5, 2.5 Hz, 1 H), 2.21 (tt, J ) 6.5, 2.5 Hz, 2
H), 2.15 (tt, J ) 7.2, 2.0 Hz, 2 H), 2.02 (s, 3 H), 1.85 (br, 1 H),
1.67 (p, J ) 6.2 Hz, 2 H), 1.46 (p, J ) 7.2 Hz, 2 H), 1.38-1.24
(comp, 4 H), 1.05 (app dt, J ) 8.5, 4.6 Hz, 1 H), 0.99-0.92 (m, 1
H), 0.92-0.83 (comp, 21 H), 0.48 (app dt, J ) 8.5, 4.9 Hz, 1 H),
0.45 (app dt, 8.4, 4.9 Hz, 1 H), 0.01 (s, 3 H), 0.00 (s, 3 H), 0.00 (s,
3 H), 0.00 (s, 3 H); 13C (125 MHz) δ 170.6, 130.1, 125.9, 82.56,
81.0, 77.0, 76.9, 75.6, 75.4, 75.3, 61.7, 31.3, 31.1, 28.8, 25.8, 25.8,
24.8, 22.2, 21.9, 21.1, 18.7, 18.1, 17.9, 17.9, 15.4, 14.0, 7.0, -4.4,
-4.6, -4.7, -4.9; IR (neat) 3435, 2929, 2557, 1743, 1471, 1369,
1251, 1075, 836 cm-1; mass spectrum (CI) m/z 633, 615, 573, 501,
441, 353 (base) 309, 279. HRMS C36H65O5Si2 (M + 1) calcd
633.4371, found 633.4357.
(R,Z)-1-((1R,2R)-2-((5R,6R)-6-((1E,4Z)-Deca-1,4-dienyl)-
2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)cyclo-
propyl)-7-hydroxyhept-3-enyl acetate (58). A vacuum (0.5 mm
Hg), using a 20-gauge needle plunged through a standard rubber
septum, was pulled on a solution of dialkyne 57 (54 mg, 0.085
mmol), quinoline (11 µL), and Lindlar’s catalyst (11 mg) in
anhydrous MeOH (1.7 mL) at room temperature. Stirring was
continued under vacuum for 5 sec, or until the reaction began to
gently reflux, whereupon the reaction vessel was backfilled with
H2 gas. This procedure was repeated six times. Stirring was
continued for 15 min at room temperature, whereupon the reaction
was diluted with CH2Cl2 (3 mL) and filtered through a pad of Celite.
The solvent was removed under reduced pressure, and the residue
was purified by flash chromatography eluting with hexanes/EtOAc
(10:1) to give 51 mg (94%) of triene 58 as a colorless oil; 1H NMR
(400 MHz) δ 5.61-5.50 (comp, 2 H), 5.46-5.31 (comp, 4 H),
4.34 (dt, J ) 7.6, 5.6 Hz, 1 H), 4.06 (dd, J ) 4.6, 2.8 Hz, 1 H),
3.61 (t, J ) 6.6 Hz, 2 H), 3.26 (dd, J ) 5.5, 4.6 Hz, 1 H), 2.78-
2.75 (m, 2 H), 2.42-2.38 (comp, 2 H), 2.10 (app sex, J ) 7.6 Hz,
2 H), 2.03-1.98 (m, 2 H), 1.60 (dp, J ) 6.8, 2.6 Hz, 2 H), 1.53
(br, 1 H), 1.36-1.21 (comp, 6 H) 1.02-0.90 (comp, 2 H), 0.88-
0.84 (comp, 21 H), 0.51 (dt, J ) 8.6, 5.2 Hz, 1 H), 0.46 (dt, J )
8.6, 5.2 Hz, 1 H), 0.01 (s, 3 H), 0.01 (s, 3 H), 0.00 (s, 3 H), -0.01
(s, 3 H); 13C (100 MHz) δ 170.7, 131.3, 130.8, 129.9, 129.2, 127.0,
125.7, 77.2, 76.3, 75.9, 62.1, 32.6, 32.3, 31.5, 30.2, 29.3, 27.1, 25.8,
25.8, 23.5, 22.5, 21.2, 18.9, 18.1, 17.9, 17.7, 14.0, 7.3, -4.3, -4.5,
-4.5, -4.9; IR (neat) 3446, 2929, 2857, 1740, 1471, 1370, 1250,
1076, 836 cm-1; mass spectrum (CI) 637, 621, 577, 505, 489, 445,
373, 355, 313, 281 (base). HRMS C36H69O5Si2 (M + 1) calcd
637.4684, found 637.4674.
1
(55%) of 56 as a clear oil; H NMR (400 MHz) δ 5.87 (ddt, J )
15.4, 4.4, 1.6 Hz, 1 H), 5.60 (dtd, J ) 15.6, 4.6, 1.6 Hz, 1 H), 4.56
(dd, J ) 4.4, 2.8 Hz, 1 H), 4.12 (dt, J ) 4.4, 1.6 Hz, 1 H), 3.87-
3.76 (comp, 2 H), 3.50-3.42 (comp, 2 H), 3.33 (app dt, J ) 4.4,
1.6 Hz, 1 H), 3.06 (tdd, J ) 7.4, 3.6, 1.6 Hz, 1 H), 2.91 (app dt, J
) 4.6, 1.6 Hz, 2 H), 2.51-2.45 (m, 1 H), 2.32 (ddt, J ) 16.4, 7.4,
2.4 Hz, 1 H), 2.27 (tt, J ) 7.2, 1.4 Hz, 2 H), 2.14 (tt, J ) 7.2, 2.4
Hz, 2 H), 2.00 (br, 1 H), 1.83-1.65 (comp, 4 H), 1.59-1.45 (comp,
6 H), 1.37-1.26 (comp, 4 H), 0.96-0.81 (comp, 23 H), 0.52-
0.45 (comp, 2 H), 0.02 (s, 3 H), 0.02 (s, 3 H), 0.02 (s, 3 H), 0.01
(s, 3 H); 13C (100 MHz) δ 130.3, 125.6, 98.8, 82.5, 82.1, 77.2,
77.2, 75.8, 75.4, 73.7, 65.9, 62.2, 31.1, 30.7, 29.1, 28.8, 27.6, 25.9,
25.8, 25.4, 22.2, 21.9, 20.1, 19.5, 18.7, 18.1, 17.9, 16.8, 15.7, 14.0,
6.7, -4.4, -4.5, -4.5, -4.8; IR (neat) 3467, 2929, 2856, 1471,
1360, 1252, 1121, 835 cm-1; mass spectrum (CI) m/z 673, 657,
573, 543, 327, 279 (base) 179. HRMS C39H69O5Si2 (M - 1) calcd
673.4684, found 673.4694.
(1R)-1-((1R,2R)-2-((5R,6R)-6-((E)-Dec-1-en-4-ynyl)-
2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)cyclo-
propyl)-7-(tetrahydro-2H-pyran-2-yloxy)hept-3-ynyl Acetate.
Acetic anhydride (0.28 mL, 2.98 mmol) and Et3N (1.26 mL, 8.93
mmol) were added to a solution of alcohol 56 (402 mg, 0.60 mmol)
and 4-dimethylaminopyridine (7 mg, 0.06 mmol) in anhydrous CH2-
Cl2 (12 mL) at room temperature. Stirring was continued for 3.5 h
at room temperature, whereupon a 1 M solution of aqueous HCl
(10 mL) was added. The layers were separated, and the organic
layer was washed with saturated aqueous NaHCO3 (5 mL), dried
(MgSO4), and concentrated under reduced pressure. The residue
was purified by silica gel flash chromatography eluting with
hexanes/EtOAc (20:1) to provide 391 mg (92%) of the acetate as
1
a pale-yellow oil; [R]22 + 3.7 (c 0.37, CHCl3); H NMR (400
D
MHz) δ 5.86 (J ) 15.2, 4.6, 2.0 Hz, 1 H), 5.60 (dtd, J ) 15.2, 5.0,
1.6 Hz, 1 H), 4.56 (br, 1 H), 4.37 (app dt, J ) 7.5, 4.8 Hz, 1 H),
4.12 (dt, J ) 4.6, 1.6 Hz, 1 H), 3.85-3.81 (m, 1 H), 3.76 (dt, J )
9.2, 6.6 Hz, 1 H), 3.49-3.45 (m, 1 H), 3.42 (dtd, J ) 9.0, 6.0, 3.0
Hz, 1 H), 3.33 (app t, J ) 4.6 Hz, 1 H), 2.92 (app dt, J ) 5.0, 2.0
Hz, 2 H), 2.52 (ddt, J ) 16.8, 4.8, 2.2 Hz, 1 H), 2.43 (ddt, J )
16.8, 7.5, 2.2 Hz, 1 H), 2.24-2.20 (m, 2 H), 2.15 (tt, J ) 7.2, 2.4
Hz, 2 H), 2.04 (s, 3 H), 1.83-1.65 (comp, 4 H), 1.57-1.44 (comp,
6 H), 1.38-1.25 (comp, 4 H), 1.07 (dtd, J ) 9.6, 4.8, 4.8 Hz, 1
H), 0.95 (dtd, J ) 9.4, 4.8, 4.8 Hz, 1 H), 0.88 (s, 3 H), 0.87 (s,
3H), 0.86-0.81 (m, 3 H), 0.51 (dt, J ) 9.0, 4.8 Hz, 1 H), 0.46 (dt,
J ) 9.0, 4.8 Hz, 1 H), 0.02 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H), 0.01
(s, 3H); 13C (100 MHz) δ 170.5, 130.1, 125.8, 98.7, 82.5, 81.1,
77.3, 76.2, 75.6, 75.5, 75.3, 66.1, 62.1, 31.1, 30.7, 29.2, 28.8, 25.9,
25.8, 25.5, 24.8, 22.2, 21.9, 21.1, 19.5, 18.7, 18.1, 17.9, 17.6, 15.7,
14.0, 7.0, -4.4, -4.6, -4.6, -4.8; IR (neat) 2929, 2857, 1743,
1471, 1237, 1033, 836 cm-1; mass spectrum (CI) m/z 717, 658,
617, 525, 437, 279 (base) 161. HRMS C41H73O6Si2 (M + 1) calcd
717.4946, found 717.4919.
(R,Z)-8-((1R,2R)-2-((5R,6R)-6-((1E,4Z)-Deca-1,4-dienyl)-
2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)cyclo-
propyl)-3,4,7,8-tetrahydro-2H-oxocin-2-one (60). 2,4,6-Trichlo-
robenzoyl chloride (1.06 mL, 1.03 mmol) was added to a solution
of hydroxy acid (210 mg, 0.34 mmol) and Et3N (0.24 mL, 1.72
mmol) in anhydrous THF (3.5 mL) at room temperature. Stirring
was continued for 1 h at room temperature, whereupon the formed
triethylamine hydrochloride salt was removed by filtration through
a short plug of Celite. The filtrate was diluted with anhydrous
toluene (300 mL) and added dropwise over 3 h via an addition
funnel into a refluxing solution of 4-dimethylaminopyridine (842
mg, 6.90 mmol) in anhydrous toluene (40 mL). After the addition
was complete, the reaction was refluxed for an additional 4 h and
concentrated under reduced pressure. The solid was dissolved in
CH2Cl2 (30 mL) and washed with 1 M aqueous HCl (2 × 30 mL)
and aqueous saturated NaHCO3 (10 mL), dried (MgSO4), and
concentrated under reduced pressure. The residue was purified by
flash chromatography eluting with hexanes/EtOAc (30:1) to provide
(R)-1-((1R,2R)-2-((5R,6R)-6-((E)-Dec-1-en-4-ynyl)-2,2,3,3,8,8,9,9-
octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)cyclopropyl)-7-hy-
droxyhept-3-ynyl Acetate (57). p-Toluenesulfonic acid (318 mg,
1.67 mmol) was added to a solution of the product of the previous
experiment (776 mg, 1.08 mmol) in anhydrous i-PrOH (11.0 mL)
at room temperature. Stirring was continued for 6 h at room
temperature, whereupon saturated aqueous NaHCO3 (5 mL) and
Et2O (20 mL) were added. Stirring was continued for an additional
5 min at room temperature, the layers were separated, and the
organic layer was dried (MgSO4) and concentrated under reduced
pressure. The residue was purified by flash chromatography eluting
1
165 mg (81%) of lactone 60 as a pale-yellow oil; H NMR (400
MHz) δ 5.76 (dd, J ) 11.2, 6.4 Hz, 1 H), 5.70 (dd, J ) 11.2, 7.6
400 J. Org. Chem., Vol. 73, No. 2, 2008

EnantioselectiVe Syntheses of Oxylipins
Hz, 1 H), 5.62-5.53 (comp, 2 H), 5.44-5.31 (comp, 2 H), 4.08-
4.07 (m, 1 H), 3.88 (ddd, J ) 10.4, 8.6, 1.8 Hz, 1 H), 3.33 (app t,
J ) 4.6 Hz, 1 H), 3.85 (dtd, J ) 12.4, 8.6, 5.9 Hz, 1 H), 2.78-
2.75 (m, 2 H), 2.71 (ddd, J ) 13.2, 5.9, 2.9 Hz, 1 H), 2.55 (ddd,
J ) 16.0, 10.4, 5.6 Hz, 1 H), 2.30-2.22 (comp, 2 H), 2.10-2.05
(m, 1 H), 2.01 (q, J ) 7.2 Hz, 2 H), 1.36-1.25 (comp, 6 H), 1.03-
0.98 (comp, 2 H), 0.92-0.85 (comp, 21 H), 0.59-0.52 (comp, 2
H), 0.02 (s, 6 H), 0.01 (s, 3 H), 0.00 (s, 3 H); 13C NMR (100 MHz)
δ 177.2, 132.7, 131.1, 130.2, 129.4, 128.8, 127.2, 82.8, 76.1, 76.0,
37.9, 34.6, 31.7, 30.5, 29.6, 27.4, 26.1, 24.7, 22.8, 18.7, 18.3, 18.2,
14.3, 7.9, -4.1, -4.2; IR (neat) 2929, 2857, 1751, 1472, 1253,
1083, 836 cm-1; mass spectrum (CI) m/z 591, 574, 539, 533, 460,
441, 327, 309 (base), 282. HRMS C34H63O4Si2 (M + 1) calcd
591.4265, found 591.4260.
(R,Z)-8-((1R,2R)-2-((1R,2R,3E,6Z)-1,2-Dihydroxydodeca-3,6-
dienyl)cyclopropyl)-3,4,7,8-tetrahydro-2H-oxocin-2-one (61). A
solution of tetrabutylammonium fluoride (264 mg, 0.84 mmol) in
THF (1 mL) was added to a solution of bis-silyl ether 60 (165 mg,
0.28 mmol) at 0 °C. The solution was stirred at 0 °C for 20 min,
whereupon the bath was removed and stirring continued for an
additional 3 h at room temperature. The reaction mixture was
concentrated under reduced pressure, and the residue was purified
by flash chromatography eluting with hexanes/EtOAc (2:1) to give
72 mg (72%) of diol 61 as a clear oil; [R]22D + 5.6 (c 0.55, CHCl3);
1H NMR (500 MHz) δ 5.78-5.68 (comp, 3 H), 5.50 (ddt, J )
15.5, 7.0, 1.5 Hz, 1 H), 5.45-5.40 (m, 1 H), 5.43-5.29 (m, 1 H),
4.00 (ddd, J ) 10.0, 8.0, 1.5 Hz, 1 H), 3.98 (appt, J ) 7.0 Hz, 1
H), 2.93 (app t, J ) 7.0 Hz, 1 H), 2.82 (app ddt, J ) 15.0, 9.0, 6.0
Hz, 1 H), 2.77 (app dt, J ) 7.5, 1.5 Hz, 2 H), 2.70 (ddd, J ) 13.5,
6.0, 3.0 Hz, 1 H), 2.59 (ddd, J ) 17.0, 10.0, 6.0 Hz, 1 H), 2.50 (br,
1 H), 2.4 (br, 1 H), 2.29-2.21 (comp, 2 H), 2.11-2.06 (m, 1 H),
1.99 (dq, J ) 7.2, 1.2 Hz, 2 H), 1.37 (p, J ) 7.2 Hz, 2 H), 1.30-
1.21 (comp, 4 H), 1.12 (app dtd, J ) 9.0, 5.0, 5.0 Hz, 1 H), 0.92-
0.84 (comp, 4 H), 0.67 (app dt, J ) 9.0, 5.0 Hz, 1 H), 0.55 (app dt,
J ) 9.0, 5.0 Hz, 1 H); 13C NMR (100 MHz) δ 177.0, 132.7, 132.6,
131.4, 129.1, 128.2, 126.2, 81.0, 77.0, 76.4, 37.7, 34.1, 31.4, 30.1,
29.2, 27.1, 24.4, 22.5, 19.8, 19.6, 14.0, 8.7; IR (neat) 3406, 2928,
2856, 1747, 1458, 1213, 1054, 967 cm-1; mass spectrum (CI) m/z
363, 345, 327, 195 179 (base) 149. HRMS C22H33O3 (M + 1 -
H2O) calcd 345.2429, found 345.2420.
7.6, 7.4; IR (neat) 3009, 2929, 2855, 1746, 1614, 1516, 1248, 1213,
1077, 966 cm-1; mass spectrum (CI) m/z 481, 436, 373, 345 (base),
327, 315, 315, 287. HRMS C30H41O5 (M + 1) calcd 481.2954.
found 481.2956.
(R,Z)-8-((1R,2R)-2-((1R,2R,3E,6Z)-2-Hydroxy-1-(4-methoxy-
benzyloxy)dodeca-3,6-dienyl)cyclopropyl)-3,4,7,8-tetrahydro-
2H-oxocin-2-one (63) and (R,Z)-8-((1R,2R)-2-((1R,2R,3E,6Z)-1-
Hydroxy-2-(4-methoxybenzyloxy)dodeca-3,6-dienyl)cyclopropyl)-
3,4,7,8-tetrahydro-2H-oxocin-2-one (64). Trifluoroacetic acid (14
µL, 0.19 mmol) was added to a solution of anisylidine acetal 62
(30 mg, 0.06 mmol) and NaCNBH3 (39 mg, 0.62 mmol) in
anhydrous THF (1 mL) at 0 °C. Stirring was continued for 15 min
at 0 °C, whereupon the ice bath was removed and the reaction was
warmed to room temperature. Stirring was continued for an
additional 1 h at room temperature, and an aqueous solution of 1
M HCl (0.5 mL) was added. The layers were separated, and the
aqueous layer extracted with Et2O (2 mL). The combined organic
layers were washed with saturated aqueous NaHCO3 (1 mL) and
brine (1 mL), dried (MgSO4), and concentrated under reduced
pressure. The residue was purified by flash chromatography eluting
with hexanes/EtOAc (10:1) to give 11 mg (34%) of cyclopropyl
alcohol 64 (less polar) as a pale-yellow oil and 14 mg (47%) of
allylic alcohol 63 (more polar) as a pale-yellow oil and an additional
1
3 mg (10%) of a mixture of 63 and 64. For 63: H NMR (400
MHz) δ 7.22 (d, J ) 8.6 Hz, 2 H), 6.86 (d, J ) 8.6 Hz, 2 H),
5.81-5.69 (comp, 3 H), 5.50 (ddt, J ) 15.4, 7.0, 1.5 Hz, 1 H),
5.45-5.31 (comp, 2 H), 4.68 (d, J ) 11.0 Hz, 1 H), 4.45 (d, 11.0
Hz, 1 H), 4.08-4.03 (comp, 2 H), 3.78 (s, 3 H), 2.88-2.76 (comp,
4 H), 2.71 (ddd, J ) 13.2, 5.6, 2.8 Hz, 1 H), 2.61 (ddd, J ) 14.0,
10.0, 6.0 Hz, 1 H), 2.53 (br, 1 H), 2.31-2.23 (comp, 2 H), 2.15-
2.07 (m, 1 H), 2.00 (app q, J ) 7.2 Hz, 2 H), 1.33 (p, J ) 7.2 Hz,
2 H), 1.29-1.23 (comp, 4 H), 1.14 (app tt, J ) 8.8, 4.4 Hz, 1 H),
0.94 (app tt, J ) 8.8, 4.4 Hz, 1 H), 0.86 (t, J ) 7.2 Hz, 3 H), 0.67
(dt, J ) 8.6, 5.2 Hz, 1 H), 0.48 (dt, J ) 8.6, 5.2 Hz, 1 H); 13C
NMR (75 MHz) δ 176.7, 159.4, 132.8, 132.0, 131.3, 130.1, 129.4,
129.2, 128.1, 126.4, 113.9, 84.3, 80.8, 75.4, 72.3, 55.3, 37.6, 34.0,
31.5, 30.1, 29.3, 27.1, 24.4, 22.5, 20.6, 18.0, 14.0, 7.9; IR (neat)
3469, 3009, 2929, 2856, 1746, 1612, 1514, 1454, 1248, 1212, 1172,
1052, 967 cm-1; mass spectrum (CI) m/z 483, 466, 448, 436, 345,
317, 299 (base), 257, 195. HRMS C30H43O5 (M + 1) calcd
1
483.3110, found 483.3102. For 64: H NMR (500 MHz) δ 7.21
(8R,Z)-8-((1R,2R)-2-((4R,5R)-5-((1E,4Z)-Deca-1,4-dienyl)-2-(4-
methoxyphenyl)-1,3-dioxolan-4-yl)cyclopropyl)-3,4,7,8-tetrahy-
dro-2H-oxocin-2-one (62). p-Toluenesulfonic acid (4 mg, 0.02
mmol) was added to a solution of p-anisaldehyde dimethyl acetal
(25 µL, 0.14 mmol) and diol 61 (38 mg, 1.08 mmol) in anhydrous
DMF (0.5 mL) at room temperature. Stirring was continued for 20
min at room temperature, whereupon saturated aqueous NaHCO3
(2 mL) and Et2O (5 mL) were added. The layers were separated,
and the organic layer was dried (MgSO4) and concentrated under
reduced pressure. The residue was purified by flash chromatography
eluting with hexanes/EtOAc (5:1) to give 40 mg (80%) of
anisylidine acetal 62, an inconsequential mixture of C(23) diaster-
(d, J ) 8.5 Hz, 2 H), 6.86 (dt, J ) 8.6,. 2.4 Hz, 2 H), 5.79-5.67
(comp, 3 H), 5.49-5.43 (m, 1 H), 5.39-5.33 (comp, 2 H), 4.54
(app d, J ) 11.0 Hz, 1 H), 4.25 (app d, J ) 11.0 Hz, 1 H), 3.92
(app dt, J ) 9.0, 1.5 Hz, 1 H), 3.79 (s, 3 H), 3.63 (dd, J ) 8.0, 7.0
Hz, 1 H), 3.00 (app t, J ) 7.0 Hz, 1 H), 2.88-2.77 (comp, 3 H),
2.71 (ddd, J ) 13.6, 6.0, 3.0 Hz, 1 H), 2.61 (ddd, J ) 16.0, 9.0,
6.0 Hz, 1 H), 2.30-2.23 (comp, 2 H), 2.11-2.07 (m, 1 H), 2.01
(app q, J ) 7.0 Hz, 2 H), 1.35 (p, J ) 7.0 Hz, 2 H), 1.30-1.25
(comp, 4 H), 1.12 (app tt, J ) 9.0, 5.0 Hz, 1 H), 0.82 (t, J ) 7.1
Hz, 3 H), 0.82 (app tt, J ) 9.0, 5.0 Hz, 1 H), 0.61 (app dt, J ) 8.5,
5.0 Hz, 1 H), 0.54 (app dt, J ) 8.5, 5.0 Hz, 1 H); 13C NMR (125
MHz) δ 177.0, 159.3, 135.1, 132.6, 131.5, 130.2, 129.5, 128.4,
127.0, 126.2, 113.9, 83.8, 81.6, 75.9, 69.6, 55.3, 37.7, 34.3, 31.5,
30.3, 29.2, 27.1, 24.4, 22.5, 19.8, 19.5, 14.0, 8.8; IR (neat) 3540,
1
eomers, as a clear oil; H NMR (400 MHz) δ 7.38 (dd, J ) 8.4,
2.4 Hz, 2 H), 6.88 (dd, J ) 8.4, 2.4 Hz, 2 H), 5.92-5.68 (comp,
4 H), 5.55-5.42 (comp, 2 H), 5.37-5.31 (comp, 1 H), 4.28 (app
t, J ) 7.6 Hz, 0.5 H), 4.25 (app t, J ) 7.6 Hz, 0.5 H), 4.01 (dt, J
) 7.6, 1.5 Hz, 0.5 H), 3.97 (dt, J ) 7.6, 1.5 Hz, 0.5 H), 3.80 (s,
1.5 H), 3.79 (s, 1.5 H), 3.33 (app t, J ) 7.6 Hz, 0.5 H), 3.30 (app
t, J ) 7.6 Hz, 0.5 H), 2.88-2.78 (comp, 3 H), 2.74-2.67 (comp,
1 H), 2.67-2.58 (comp, 1 H), 2.32-2.23 (comp, 2 H), 2.12-2.07
(comp, 1 H), 2.00 (app q, J ) 7.1 Hz, 2 H), 1.36-1.23 (comp, 6
H), 1.17 (dt, J ) 8.8, 4.8 Hz, 0.5 H), 1.16 (dt, J ) 8.8, 4.8 Hz, 0.5
H), 1.04-0.95 (comp, 1 H), 0.87 (t, J ) 6.8 Hz, 1.5 H), 0.86 (t, J
) 6.8 Hz, 1.5 H), 0.74 (app dt, J ) 8.6, 4.8 Hz, 1 H), 0.63 (app dt,
3010, 2927, 2856, 1745, 1612, 1513, 1454, 1248, 1212, 1052 cm-1
;
mass spectrum (CI) m/z 483, 466, 447, 345, 299, 121 (base). HRMS
C30H43O5 (M + 1) calcd 483.3110, found 483.3102.
(R,Z)-8-((1R,2R)-2-((1S,2E,4S,6Z)-4-Hydroxy-1-(4-methoxy-
benzyloxy)dodeca-2,6-dienyl)cyclopropyl)-3,4,7,8-tetrahydro-
2H-oxocin-2-one (65). Tributylphosphine (28 µL, 0.11 mmol) was
added dropwise to a solution of 63 (9 mg, 0.02 mmol) and o-NO2-
PhSeCN (13 mg, 0.06 mmol) at room temperature. The reaction
turned from a pale yellow to dark brown. Stirring was continued
for 1 h at room temperature, whereupon the reaction was concen-
trated under reduced pressure and filtered through a short plug of
silica gel eluting with hexanes/EtOAc (5:1). The eluted material
was concentrated under reduced pressure. Pyridine (50 µL) and
30% H2O2 (0.5 mL) were added to a solution of the crude mixture
J ) 8.6, 4.8 Hz, 0.5 H), 0.58 (app dt, J ) 8.6, 4.8 Hz, 0.5 H); 13
C
(100 MHz) δ 176.8, 176.8, 160.3, 160.2, 134.8, 134.1, 132.6, 131.6,
131.6, 130.3, 130.3, 128.1, 127.9, 127.8, 126.8, 126.3, 125.9, 125.8,
113.7, 113.6, 103.3, 102.9, 84.6, 84.0, 83.3, 80.9, 80.9, 55.2, 37.7,
34.3, 34.2, 31.4, 30.0, 29.2, 27.1, 24.4, 22.5, 19.9, 18.3, 18.0, 14.0,
J. Org. Chem, Vol. 73, No. 2, 2008 401

Davoren et al.
in CH2Cl2 (1 mL) at room temperature, and the solution was stirred
for 3 h whereupon 1 M HCl (0.5 mL) was added. The layers were
separated, and the organic layer was washed with saturated aqueous
NaHCO3 (0.5 mL), dried (MgSO4), and concentrated under reduced
pressure. The residue was purified by flash chromatography eluting
with hexanes/EtOAc (5:1) to give 5 mg (56%) of allylic alcohol
solution of 65 (5 mg, 0.01 mmol) in CH2Cl2 (0.5 mL) and a pH 7
phosphate buffer (0.1 mL) at room temperature. Stirring was
continued for 1 h at room temperature, whereupon the reaction was
washed with H2O (0.2 mL) and saturated aqueous NaHCO3 (0.2
mL), dried (MgSO4), and concentrated under reduced pressure. The
residue was purified by flash chromatography eluting with pentanes/
Et2O (1:1) to provide 2.5 mg (71%) of solandelactone E (3) as a
clear oil; 1H NMR (500 MHz) δ 5.84-5.70 (comp, 4 H), 5.57 (dtt,
J ) 11.0, 7.4, 1.5, 1 H), 5.36 (dtt, J ) 11.0, 7.0, 1.8 Hz, 1 H), 4.17
(br ddd, J ) 7.0, 5.5, 0.0 Hz, 1 H), 4.02 (ddd, J ) 10.0, 8.0, 1.5
Hz, 1 H), 3.65 (dd, J ) 7.5, 4.5 Hz, 1 H), 2.88-2.80 (m, 1 H),
2.71 (ddd, 13.5, 6.0, 3.0 Hz, 1 H), 2.61 (ddd, J ) 14.0, 10.4, 5.6
Hz, 1 H), 2.32-2.25 (comp, 3 H), 2.24 (ddd, J ) 14.0, 7.5, 1.5
Hz, 1 H), 2.13-2.08 (m, 2 H), 2.03 (app q, J ) 7.1 Hz, 2 H), 1.52
(br, 1 H), 1.37-1.24 (comp, 6 H), 1.12 (tt, J ) 8.5, 5.5 Hz, 1 H),
0.99 (dtd, J ) 8.5, 8.5, 5.0 Hz, 1 H), 0.87 (t, J ) 7.1 Hz, 3 H),
1
65 as a pale-yellow oil. H NMR (400 MHz) δ 7.20 (d, J ) 8.8
Hz, 2 H), 6.85 (d, J ) 8.8 Hz, 2 H), 5.80-5.40 (comp, 5 H), 5.40-
5.33 (m, 1 H), 4.49 (d, J ) 11.8 Hz, 1 H), 4.28 (d, J ) 11.8 Hz,
1 H), 4.20 (app q, J ) 6.4 Hz, 1 H), 3.94 (ddd, J ) 10.0, 8.4, 1.6
Hz, 1 H), 3.79 (s, 3 H), 3.28 (app t, J ) 6.4 Hz, 1 H), 2.84 (dtd,
J ) 12.0, 8.8, 6.0 Hz, 1 H), 2.70 (ddd, J ) 13.2, 5.6, 3.2 Hz, 1 H),
2.63 (ddd, J ) 13.6, 10.0, 5.4 Hz, 1 H), 2.39-2.24 (comp, 4 H),
2.15-2.08 (m, 1 H), 2.04 (app q, J ) 7.1 Hz, 2 H), 1.66 (br, 1 H),
1.34 (p, J ) 7.1 Hz, 2 H), 1.31-1.23 (comp, 4 H), 1.07-0.95
(comp, 2 H), 0.86 (t, J ) 7.1 Hz, 3 H), 0.66 (dt, J ) 8.6, 5.2 Hz,
1 H), 0.54 (dt, J ) 8.6, 5.2 Hz, 1 H); 13C NMR (75 MHz) δ 177.0,
159.1, 135.1, 133.9, 132.7, 130.6, 130.0, 129.1, 128.3, 124.1, 113.7,
81.4, 80.5, 71.6, 69.6, 55.3, 37.7, 35.4, 34.3, 31.5, 29.3, 27.4, 24.4,
22.5, 22.1, 21.0, 14.0, 8.0; IR (neat) 3447, 3011, 2928, 2856, 1745,
1612, 1513, 1247, 1051 cm-1; mass spectrum (CI) m/z 483, 465,
436, 365, 345 (base), 327, 283, 219. HRMS C30H43O5 (M + 1)
calcd 483.3110, found 483.3112.
0.72 (dt, J ) 9.0, 5.0 Hz, 1 H), 0.59 (dt, J ) 8.5, 5.0 Hz, 1 H); 13
C
NMR (125 MHz) δ 176.9, 134.0, 133.2, 132.8, 131.7, 128.1, 124.0,
80.9, 74.4, 71.4, 37.7, 35.3, 34.2, 31.5, 29.3, 27.4, 24.4, 23.4, 22.5,
20.6, 14.0, 8.0.
Acknowledgment. We thank the National Institutes of
Health (GM 31077), the Robert A. Welch Foundation, Pfizer,
Inc., and Merck Research Laboratories for generous support of
this research. We are also grateful to Prof. Jongheon Shin
(College of Pharmacy, Seoul National University) for providing
spectral data for solandelactones E and F and for helping to
clarify the origin of the structural misassignment for the C(11)
epimeric solandelactones. We also thank Justin Leong for his
help in synthesizing various key intermediates.
Solandelactone E (3). Procedure A. Tributylphosphine (35 µL,
0.138 mmol) was added dropwise over 0.5 min to a solution of
diol 61 (10 mg, 0.028 mmol) and 2-nitrophenyl selenocyanate (31
mg, 0.138 mmol) in anhydrous THF (0.28 mL) at room temperature.
The mixture was stirred for 1 h at room temperature, whereupon
the mixture was concentrated under reduced pressure and filtered
through a short plug of silica gel eluting with hexanes/EtOAc (5:
1). The filtrate was concentrated under reduced pressure, and the
residue was dissolved in CH2Cl2 (1 mL) at 0 °C, whereupon
pyridine (0.05 mL) and a 30% aqueous solution of H2O2 (1 mL)
were added. The solution was stirred for 5 h at 0 °C, whereupon 1
M aqueous HCl (0.5 mL) was added. The layers were separated,
and the organic layer was washed with saturated aqueous NaHCO3
(0.5 mL), dried (MgSO4), and concentrated under reduced pressure.
The residue was purified by flash chromatography eluting with
hexanes/EtOAc (2:1) to give 2 mg (20% over 2 steps from 61) of
solandelactone E (1) as a clear oil. Procedure B. 2,3-Dichloro-
5,6-dicyano-p-benzoquinone (12 mg, 0.05 mmol) was added to a
Supporting Information Available: Summary of general
experimental practices, experimental procedures, and spectral
characterization for compounds 16, 18, 19-22, 24-27, 34-36, 39,
40, 42-46, 52, 54, and 59, copies of 1H NMR spectra for all new
1
compounds, a tabular comparison of H and 13C NMR data for
synthetic and natural 1, and crystallographic data CIF file for 36.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO701739V
402 J. Org. Chem., Vol. 73, No. 2, 2008