Asymmetric synthesis of 1,2-dioxolane-3-acetic acids: Synthesis and configurational assignment of plakinic acid A

Article abstract of DOI:10.1021/jo0522254

The first asymmetric synthesis of 1,2-dioxolane-3-acetic acids is reported. Key features include the stereoselective opening of enantiomerically enriched oxetanes by hydrogen peroxide, conversion of the resulting 4-hydroperoxy-2- alkanols to 3-alkoxy-1,2-dioxolanes, and Lewis acid mediated homologation of the latter with a thioester silyl ketene acetal. The approach is modeled on 3,5-dimethyl-5-hexadecyl-1,2-dioxolane-3-acetic acid (1a), an unnamed natural product, and an optimized strategy is applied to the synthesis of four stereoisomers of plakinic acid A (2), allowing a configurational assignment of this incompletely characterized natural product.

Full text of DOI:10.1021/jo0522254

Asymmetric Synthesis of 1,2-Dioxolane-3-acetic Acids: Synthesis
and Configurational Assignment of Plakinic Acid A
Peng Dai, Tony K. Trullinger, Xuejun Liu, and Patrick H. Dussault*
Department of Chemistry, UniVersity of Nebraska-Lincoln, Lincoln, Nebraska 68588-0304
pdussault1@unl.edu
ReceiVed October 26, 2005
The first asymmetric synthesis of 1,2-dioxolane-3-acetic acids is reported. Key features include the
stereoselective opening of enantiomerically enriched oxetanes by hydrogen peroxide, conversion of the
resulting 4-hydroperoxy-2-alkanols to 3-alkoxy-1,2-dioxolanes, and Lewis acid mediated homologation
of the latter with a thioester silyl ketene acetal. The approach is modeled on 3,5-dimethyl-5-hexadecyl-
1,2-dioxolane-3-acetic acid (1a), an unnamed natural product, and an optimized strategy is applied to the
synthesis of four stereoisomers of plakinic acid A (2), allowing a configurational assignment of this
incompletely characterized natural product.
CHART 1. Plakinic Acids and Related Compounds
Introduction
The plakinic acids are a large family of marine natural
products that have been reported to display cytotoxicity against
fungal and cancer cell lines (Chart 1).1-9 The absolute stereo-
chemistry has not been established for any member of the family
and no asymmetric synthesis of a plakinic acid has yet been
reported. A racemic synthesis of 1b has been reported based
upon sequential inter- and intramolecular peroxymercurations
of a dienoate.10 This approach, while unquestionably efficient,
is neither stereoselective nor compatible with the side chain
(1) Patil, A. D. PCT Int. Appl. WO 8704708, 2987; Chem. Abstr. 1988,
109, 17027f.
(2) Phillipson, D. W.; Rinehart, K. L., Jr. J. Am. Chem. Soc. 1983, 105,
7735-7736.
(3) Davidson, B. S. J. Org. Chem. 1991, 56, 6722-6724.
(4) Horton, P. A.; Longley, R. E.; Kelly-Borges, M.; McConnell, O. J.;
Ballas, L. M. J. Nat. Prod. 1994, 57, 1374-1381.
(5) Chen, Y.; Killday, K. B.; McCarthy, P. J.; Schimoler, R.; Chilson,
K.; Selitrennikoff, C.; Pomponi, S. A.; Wright, A. E. J. Nat. Prod. 2001,
64, 262-264.
(6) Sandler, J. S.; Colin, P. L.; Hooper, J. N. A.; Faulkner, D. J. J. Nat.
Prod. 2002, 65, 1258-1261. This paper describes “epiplakinic acid H”,
which might be better described as plakinic acid G.
(7) Chen, Y.; McCarthy, P. J.; Harmody, D. K.; Schimoler-O’Rourke,
R.; Chilson, K.; Selitrennikoff, C.; Pomponi, S.; Wright, A. E. J. Nat. Prod.
2002, 65, 1509-1512.
(8) Rudi, A.; Afanil, R.; Gravalos, L, G.; Aknin, M.; Gaydou, E.; Vacelet,
J.; Kashman, Y. J. Nat. Prod. 2003, 66, 682-685.
(9) For reviews of peroxide natural products, see: Casteel, D. A. Nat.
Prod. Rep. 1999, 16, 55-73; 1992, 9, 289-311.
(10) Bloodworth, A. J.; Bothwell, B. D.; Collins, A. N.; Maidwell, N.
L. Tetrahedron Lett. 1996, 37, 1885-1888.
unsaturation present in many members of the family. We
recently reported a racemic approach to substituted dioxolanes,
including 1a, via Lewis acid mediated reactions of alkoxydiox-
10.1021/jo0522254 CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/22/2006
J. Org. Chem. 2006, 71, 2283-2292
2283

Dai et al.
SCHEME 2. Synthesis of 4-Hydroperoxy-2-alkanola
SCHEME 1. Retrosynthetic Approach to 1a
olanes with electron-rich alkenes.11 However, the utility of this
methodology was limited by the absence of methods for
asymmetric synthesis of alkoxydioxanes. We recently reported
a new method for synthesis of 1,3-peroxyalkanols that appeared
to offer a route to enantiomerically enriched alkoxydioxanes
and therefore dioxolane acetic acids.12 We now describe the
asymmetric synthesis of dioxolane 1a as well as four candidate
structures for plakinic acid A (2).13
a Reagents and conditions: (a) LiCCH, ethylenediamine; (b) Cp2ZrCl2,
AlMe3, n-BuLi, (CH2O)n; (c) Ti(OiPr)4, (-)-DET, 3, t-BuOOH, CH2Cl2/
pentane; (d) Dess-Martin periodinane; (e) MeMgBr; (f) Red-Al; (g)
t-BuOK, TsCl, t-BuOK, THF; (h) ethereal H2O2, Yb(OTf)3; (i) LiHMDS,
TBSCl; (j) NIS; (k) n-Bu3SnH, AIBN.
Results and Discussion
As an initial target on which to model our approach, we chose
1a, in which stereochemical issues are limited to the substitution
on the dioxolane ring (Scheme 1). As in the racemic studies,
introduction of the 1,2-dioxolane-3-acetic acid would be achieved
through reaction of a thioester silyl ketene acetal with an
alkoxydioxolane,11 a reaction that proceeds via an intermediate
peroxycarbenium ion. However, in contrast to the earlier work,
the 1,2-dioxolane would be derived from an enantiomerically
enriched 2,4-hydroperoxyalkanol prepared through opening of
a tertiary oxetane by hydrogen peroxide.12 Enantiomerically
enriched oxetanes are available from 2,3-epoxy alcohols, making
it possible to select the absolute stereochemistry of the dioxolane
acetic acid through the choice of asymmetric epoxidation
catalyst.
The synthesis began with allyl alcohol 3, derived from
carbalumination of octadecyne, (Scheme 2). Asymmetric ep-
oxidation under stoichiometric conditions and in the presence
of pentane as a nonpolar additive14 provided the 2,3-epoxyal-
cohol 4 in 84% enantiomeric excess.15 The derived aldehyde
underwent addition of MeMgBr to furnish a 3:1 mixture of
epimeric epoxy alcohols (5). As the hydroxyl-bearing stereo-
center would be eventually destroyed, we elected to carry on
the mixture of epimers. Red-Al reduction of the epoxy alcohols
provided an excellent yield of 2,4-diols (6),16 which were
subjected to one-pot tosylation/cyclization to form a mixture
of epimeric oxetanes.12,17,18 The oxetanes were accompanied by
a small amount of an elimination byproduct (8), which could
a
SCHEME 3
a Reagents and conditions: (a) LiHMDS, TBSCl; (b) Dess-Martin
periodinane; (c) Me3Al.
be recycled to oxetane via iodoetherification and reductive
dehalogenation.19 Yb(OTf)3-catalyzed opening of oxetane 7 with
ethereal H2O2 proceeded smoothly to provide 4-hydroperoxy-
2-alkanol 9.12 Selective protection of the hydroperoxide group
with a lithium amide and TBSCl cleanly furnished peroxyal-
kanol 10.
We briefly explored an alternate approach to peroxyalkanol
10 based upon homologation of a 3-peroxyalkanal (Scheme 3).
Hydroperoxyalkanol 12 was prepared via acid-catalyzed opening
of 2,2-disubstituted oxetane (11) with H2O2.12 Selective protec-
tion of the hydroperoxide proceeded in low yield; oxidation of
the resulting alcohol afforded the 3-methyl-3-peroxyalkanal (13).
Attempted homologation of 13 with MeMgBr, MeLi, or MeTi-
(OiPr)3 resulted only in fragmentation. Although conversion to
10 could be achieved in low yield with Me3Al,20 this approach
was ultimately abandoned in favor of the route described in
Scheme 2.
Peroxyketone 14, prepared in high yield via perruthenate
oxidation of alcohol 10, was deprotected to furnish a mixture
of 1,2-dioxolan-3-ols. These tended to decompose upon chro-
matography, and the crude product was directly subjected to
acid-catalyzed etherification to provide a nearly inseparable 1:1
mixture of cis- and trans-alkoxydioxolanes 15 (Scheme 4).
Treatment of the alkoxydioxolanes with TiCl4 and the trimeth-
ylsilyl ketene acetal of ethyl thioacetate furnished a 1:1 mixture
of thioesters cis-16 and trans-16. The derived aldehydes cis-
and trans-17 were separated and individually oxidized to furnish
diastereomerically pure samples of (+)-cis- 1a and (-)-trans-1a.
(11) Dussault, P. H.; Liu, X. Org. Lett. 1999, 1, 1391-1393. A related
approach to substituted 1,2-dioxolanes based upon Lewis acid mediated
reactions of 1,1-bisperoxyacetals has recently been reported: Ramirez, A.;
Woerpel, K. A. Org. Lett. 2005, 7, 4617-4620.
(12) Dussault, P. H.; Trullinger, T. K.; Noor-e-Ain, F. Org. Lett. 2002,
4, 4591-4593.
(13) Portions of this work were reported in doctoral dissertations:
Trullinger, T. K. University of Nebraska, Lincoln, NE, 2002. Dai, P.
University of Nebraska, Lincoln, NE, 2004.
(14) Bernet, B.; Vasella, A. Tetrahedron Lett. 1983, 24, 5491-5494.
(15) Based upon 19F NMR of the derived methoxytrifluoromethyl-
phenylacetates: Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95,
512-519.
(16) Ma, P.; Martin, V. S.; Masamune, S.; Sharpless, K. B.; Viti, S. M.
J. Org. Chem. 1982, 47, 1378-1380; Minami, N.; Ko, S. S.; Kishi, Y. J.
Am. Chem. Soc. 1982, 104, 1109-1111.
(17) Balsamu, A.; Ceccarelli, G.; Crotti, P.; Macchia, F. J. Org. Chem.
1975, 40, 473-476.
(19) Evans, R. D.; Magee, J. W.; Schauble, J. H. Synthesis 1988, 862-
868.
(18) Picard, P.; LeClerq, D.; Bats, J.-P.; Moulines, J. Synthesis 1981,
550-551.
(20) Allen, J. L.; Paquette, K. P.; Porter, N. A. J. Am. Chem. Soc. 1998,
120, 9362-9363.
2284 J. Org. Chem., Vol. 71, No. 6, 2006

Asymmetric Synthesis of 1,2-Dioxolane-3-acetic Acids
SCHEME 4. Synthesis of (+)-cis-1a and (-)-trans-1aa
SCHEME 6. Plakinic Acid A Retrosynthesisa
a Illustrated for one stereoisomer.
SCHEME 7. Synthesis of Plakinic A Sidechaina
a Reagents and conditions: (a) TPAP, NMO; (b) aq HF, CH3CN/THF;
(c) 2-methoxyethanol, HCl (cat.); (d) TiCl4 (1.1 equiv) H2CdCH2(OTMS)SEt
(2.5-4 equiv), -50 to 0 °C; (e) DIBAL, CH2Cl2, -78 °C; (f) NaClO2,
NaH2PO4‚H2O, t-BuOH, 2-methyl-2-propene.
SCHEME 5. Preparation of (-)-cis-1a and (+)-trans-1a
The enantiomers, (-)-cis-1a and (+)-trans-1a, were prepared
from ent-4 by an identical route. (Scheme 5).
The disparity in the specific rotations for the two series led
us to assess enantiomeric purity of formation of diastereomeric
derivatives (eq 1). Our previous research had demonstrated
a Reagents and conditions: (a) Mg, crotonaldehyde; (b) (EtO)3CCH3,
propionic acid, 140 °C; (c) LAH; (d) Swern; (e) (E)-propenyl bromide,
t-BuLi, THF; (f) Zn, CBr4, PPh3; (g) n-BuLi; (h) Me3Al, Cp2ZrCl2 then
n-BuLi, (CH2O)n; (i) Ti(OiPr)4, (-)-DET, t-BuOOH.
resolution of racemic 3,5,5-trimethyl-1,2-dioxolane acetic acids
as diastereomeric thioesters.21 Application of this method to (+)-
and (-)-trans-1a revealed low and variable stereochemical
purity, suggesting that the oxetane openings proceeded with
highly inconsistent stereoselectivity.
The synthesis of the plakinic acid A side chain began with
Claisen homologation of allylic alcohol 20 to ester 21 (Scheme
7). Conversion to the corresponding aldehyde, followed by
addition of (E)-propenyllithium, furnished a 1:1 mixture of
diasteromeric allylic alcohols 22a and 22b, for which the relative
stereochemistry was determined by conversion to 2,4-disubsti-
tuted butyrolactones.22 Alternatively, use of propenylmagnesium
bromide as a nucleophile resulted in predominant formation of
22a and 22b, along with smaller amounts of the corresponding
(Z)-allylic alcohols 22c and 22d.23 An iteration of the Claisen/
DIBAL sequence on 22a (or 22d) produced ester 23. Homolo-
gation of the derived aldehyde furnished alkyne 24, which
underwent carbalumination and trapping with formaldehyde to
Lessons from the Model Synthesis: Synthesis of Candi-
date Structures for Plakinic Acid A. Any synthetic approach
to plakinic acid A faced the challenge of controlling both
dioxolane and side chain stereocenters. As before, our approach
was based upon installation of the 1,2-dioxolane acetic acid via
reaction of a thioester silyl ketene acetal with an enantiomeri-
cally enriched alkoxydioxolane (Scheme 6). However, drawing
upon our experience with the synthesis of 1a, the crucial oxetane
opening would be conducted on a single stereoisomer, using
the displaced secondary alcohol as an internal stereochemical
marker and resolving agent. The oxetane would arise from an
enantiomerically enriched 2,3-epoxy alcohol now containing
four stereocenters.
(22) Kiyooka, S.-i.; Li, Y.-N.; Shahid, K. A.; Okazaki, M.; Shuto, Y.
Tetrahedron Lett. 2001, 42, 7299-7301. See Supporting Information for
details.
(23) Alcohols 22a and 22d both underwent the Johnson Claisen reaction
to furnish ester 23, whereas 22b/22c furnished an epimeric ester under the
same conditions.
(21) Dussault, P. H.; Trullinger, T. K.; Cho-Shultz, S. Tetrahedron 2000,
56, 9213-9220.
J. Org. Chem, Vol. 71, No. 6, 2006 2285

Dai et al.
SCHEME 8. Synthesis of Oxetane 29a
SCHEME 9. Synthesis of cis-2a and trans-2aa
a Reagents and conditions: (a) Dess-Martin periodinane; (b) MeMgBr;
(c) (1) DEAD, PPh3, 4-NO2PhCO2H, (2) NaOMe, MeOH; (d) Red-Al; (e)
TsCl, t-BuOK, THF; (f) TsCl, t-BuOK; NaH.
furnish racemic alkenol 25. Asymmetric epoxidation furnished
separable diastereomers 26a and 26b, each found to be >80%
enantiomeric excess.17 Assignment of stereochemistry for 26a
and 26b is based upon a subsequent correlation of the C3 and
C5 centers (vide infra).
a Reagents and conditions: (a) TMSOTf, H2O2, ether, -78 °C; (b)
LiHMDS, TBSCl; (c) Dess-Martin periodinane; (d) HF, 2-methoxyethanol,
2 days; (e) TiCl4 (1.1 equiv) H2CdCH2(OTMS)SEt (16 equiv), -50 to 0
°C; (f) NaOMe, MeOH; (g) LiOH, 30% H2O2, THF.
At this point, we chose to carry forward stereoisomer 26a
(Scheme 8). Addition of methylmagnesium bromide to the
corresponding epoxyaldehyde furnished a mixture of diastere-
omeric epoxy alcohols 27a and 27b, which after separation were
individually reduced to the corresponding 1,3-diols, 28a and
28b. For preparative routes, the minor epoxy alcohol 27b was
epimerized to 27a via a Mitsonobu inversion.24 The syn
stereochemistry of the major diol (28a) was confirmed by
conversion to the 2,2-dimethyl-1,3-dioxane.25 Treatment of 28a
with a stoichometric quantity of toluenesulfonyl chloride and
excess t-BuOK produced a 5:1 mixture of oxetane 29 and
alkenol 30; similar results were obtained upon treatment of the
preformed monosulfonate with NaH. anti-1,3-Diol 28b under-
went cyclization in much poorer yield, but this problem was
rendered moot by the successful epimerization of 27b.
The presence of multiple alkenes meant that that the byprod-
uct of elimination (30) could not be “recycled” to oxetane 29
via iodoetherification as in the model system. However, this
byproduct did provide a means to determine the absolute
stereochemistry of the side chain stereocenters (eq 2). Ring-
closing metathesis of 30 furnished a cyclohexene, which was
hydrogenated to furnish the known cis-1,3-dimethyl cyclohex-
anol (32).26,27
(Scheme 9).12 The use of TMSOTf allowed performance of the
same reaction between -78 and 0 °C and reproducibly afforded
an 8:1 mixture of 33 and epi-33, which were easily separated
by semipreparative HPLC. The stereochemistry of the major
diastereomer was confirmed by reduction (Me2S) to the diol
and correlation with the syn-1,3-diol derived from reduction of
epoxy alcohol 26b. Selective silylation and oxidation furnished
peroxyketone 34, which underwent deprotection to provide the
1,2-dioxolane-3-ol. Acidic transetherification, an uneventful
reaction in the saturated model, proved problematic, with
strongly acidic conditions resulting in fragmentation to non-
peroxidic products whose identity would become clear later
(vide infra). However, treatment of 34 with HF and 2-meth-
oxyethanol achieved a one-pot conversion to a mixture of cis-
and trans-alkoxydioxolanes (35); TLC monitoring suggested this
transformation proceeds via a rapid deprotection (<1 h) followed
by a much slower transetherification (48 h). Addition of TiCl4
to a solution containing 35 and excess silyl ketene acetal
produced a 3.3:1 mixture of cis- and trans-36. The same
stereochemical outcome was observed regardless of whether the
starting material was cis-35, trans-35, or a mixture. The
corresponding methyl esters 37 were readily separated and the
individual diastereomers saponified to provide the cis-(3S,5S,7R,-
11S) and trans-(3R,5S,7R,11S) isomers of plakinic acid A (2).
In the course of our efforts to convert 35 to 36, we discovered
that premixing the Lewis acid and alkoxydioxolane, the optimal
protocol for the saturated series, resulted in the exclusive
formation of a nonperoxide product,28 which proved to be a
single diastereomer of a tetrahydrofuranyl ketone 38 (Table 1).
Opening of oxetane 29 with ethereal hydrogen peroxide in
the presence of Yb(OTf)3 proceeded at temperatures g0 °C to
provide a 4:1 ratio of hydroperoxyalkanols 33 and epi-33
(25) Rychnovsky, S. D., Rogers, B.; Yang, G. J. Org. Chem. 1993, 58,
3511-3115.
(26) Grubbs, R. H. Tetrahedron 2004, 60, 7117-7140.
(27) Reetz, M. T.; Steinbach, R.; Westermann, J.; Peter, R.; Wenderoth,
B. Chem. Ber. 1985, 118, 1441-1454.
(24) Dodge, J.; Trujillo, J. I.; Presnell, M. J. Org. Chem. 1994, 59, 234-
236. Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017-3020.
Roush, W. R.; Brown, R. J.; DiMare, M J. Org. Chem. 1983, 48, 3-93.
(28) Smith, L.; Hill, F. L. J. Chromatogr. 1972, 66, 101-109.
2286 J. Org. Chem., Vol. 71, No. 6, 2006

Asymmetric Synthesis of 1,2-Dioxolane-3-acetic Acids
TABLE 1. Inter- versus Intramolecular Reactions
ordera
SKA (equiv)
[35] (M)
36 (%)
38 (%)
A
B
B
B
B
4
4
8
8
16
0.05
0.05
0.05
0.2
78
20
15
6
70
79
86
88
0.2
5
a A ) TiCl4 then SKA; B ) SKA then TiCl4.
SCHEME 10. Synthesis of cis-2b and trans-2ba
FIGURE 1. Comparison of selected spectral data
TABLE 2. Comparison of Selected 13C Shifts
peak
2-Me ester
cis-37b
C2
C3
C4
C5
44.3
83.7
55.6
86.8
45.5
25.2
23.9
20.0
22.7
44.3
83.7
55.7
86.8
45.5
25.2
23.9
20.0
22.7
C6
C14
C15
C16
C17
TABLE 3. Comparison of Specific Rotations
a Reagents and conditions: see Scheme 9.
The formation of this byproduct appears to result from intramo-
lecular attack of the side chain alkene on the distal oxygen of
the developing peroxycarbenium ion; an analogous reaction may
explain the decomposition of 34 (or, more likely, the derived
1,2-dioxan-3-ol) in the presence of strongly acidic conditions.
Although peroxides have been shown to undergo 5-exo nucleo-
philic attack on alkene-derived halonium ions,29 we are unaware
of 5-exo nucleophilic attack of an alkene on a protonated or
complexed peroxide. In contrast, the corresponding 3-exo
cyclizations are well established.30 In the end, we found the
fragmentation could be minimized by use of higher reactant
concentrations and by addition of Lewis acid into a premixed
solution containing alkoxydioxolane and excess silyl ketene
acetal.
a Assumed.
natural product is a cis-3,5-disubstituted 1,2-dioxane closely
related to cis-37b.2
The similarity of plakinic acid A and cis-37b is also evident
from a comparison of 13C chemical shifts (Table 2).
Comparison of the specific rotations for (+)-cis-1a, (-)-cis-
1a, (-)-cis-37b, and 2-methyl ester suggests the large and
negative specific rotation for the latter is best accommodated
by 3R,5R stereochemistry across the 1,2-dioxolane (Table 3).
Given that plakinic acid A and (-)-cis-37b appear to share
the same 3R,5R stereochemistry and display nearly identical
1H and 13C chemical shifts in the vicinity of the 1,2-dioxolane
subunit, we hypothesize that the two structures differ only at
the remote C11 stereocenter. The most likely configuration for
plakinic acid A is 3R,5R,7R,11R:
Two additional plakinic A stereoisomers, trans-3S,5R,7R,11S
and cis-3R,5R,7R,11S, were prepared similarly from hydroper-
oxyalkanol epi-33b, the minor product of the oxetane opening
(Scheme 10).
Comparison of the chemical shifts and coupling constants of
H4/H4′and H6/H6′ for the four synthetic isomers and the literature
values for plakinic acid methyl ester (Figure 1) suggests the
J. Org. Chem, Vol. 71, No. 6, 2006 2287

Dai et al.
tography (8% EA/Hex) to afford ester 21 (7.23 g, 33.2 mmol, 85%)
as a pale yellow oil: Rf ) 0.66 (10% EA/Hex); 1H NMR δ 7.18-
7.41 (5H), 6.42 (d, 1H, 15.9), 6.15 (dd, 1H, 15.9, 7.5), 4.13 (q,
3H, 7.1), 2.87 (m, 1H), 2.40 (m, 2H), 1.25 (t, 3H, 7.1), 1.16 (d,
3H, 6.8); 13C NMR δ 172.4, 137.4,134.2, 128.8, 128.4, 127.1, 126.1,
60.2, 41.7, 34.1, 20.2, 14.2; FT-IR ν 3027, 2981, 2933, 1733, 1449,
1369, 1174, 1030, 965, 747, 691; EI-HRMS calcd for C14H18O2
(M+) 218.1307, found 218.1308.
(2E,4R*,6S*,7E)- and (2E,4S*,6S*,7E)-6-Methyl-8-phen-
ylocta-2,7-dien-4-ol (22a and 22b). LiAlH4 (2.02 g, 53.3 mmol)
was added in small portions to a solution of ester 21 (7.74 g, 35.5
mmol) in THF (200 mL). The mixture was stirred under N2 for 1
h and then cooled to 0 °C. The reaction mixture was quenched by
addition of Na2SO4‚10H2O (50 g) and the resulting slurry was stirred
for 1 h. The filtrate (Celite) was concentrated to furnish a pale
yellow oil that was used directly for the next step.
To a -60 °C solution of oxalyl chloride (6.2 mL, 71 mmol) in
CH2Cl2 (300 mL) under N2 was added dropwise DMSO (10.3 mL,
142 mmol). The mixture was stirred for 10 min, and then a solution
of the alcohol described above was added dropwise as a solution
in CH2Cl2 (50 mL). The reaction mixture was stirred for 20 min,
and then triethylamine (26.5 mL, 190 mmol) was added. After
stirring for 10 min, the reaction was allowed to warm to room
temperature. The reaction was quenched by addition of H2O (200
mL), and the aqueous layer was extracted with CH2Cl2 (2 × 200
mL). The combined organic layers were sequentially washed with
NaHCO3 (200 mL) and brine (200 mL) and then dried over MgSO4.
The residue obtained upon filtration and concentration was purified
by flash chromatography (10% EA/Hex) to afford the aldehyde
(5.19 g, 84% over two steps) as a clear colorless oil: Rf ) 0.40
(15% EA/Hex); 1H NMR δ 9.78 (t, 1H, 2.2), 7.18-7.37 (5H), 6.42
(d, 1H, 16.0), 6.16 (dd, 1H, 16.0, 8.6), 2.96 (m, 1H), 2.57 (ddd,
1H, 16.4, 7.2, 2.2), 2.47 (ddd, 1H, 16.4, 6.9, 2.2), 1.19 (d, 3H,
6.9); 13C NMR δ 202.0, 137.5, 133.9, 129.1, 128.5, 127.3, 126.1,
50.3, 31.8, 20.4; FT-IR ν 3032, 2964, 1722, 1453, 700; HRMS
calcd for C12H14O (M+) 174.1045, found 174.1041.
Conclusion
In conclusion, we have described the first asymmetric
synthesis of 1,2-dioxolane-3-acetic acids. The core of the
approach is the asymmetric synthesis of γ-hydroperoxyalkanols
through regiospecific and stereoselective acid-promoted opening
of enantiomerically enriched and diastereomerically pure 2,4,4-
trisubstituted oxetanes with hydrogen peroxide. The peroxyal-
kanols are converted to 3-alkoxy-1,2-dioxolanes, which undergo
Lewis acid mediated reaction with a silyl ketene acetal to install
the 1,2-dioxolane acetic acid headgroup. The strategy is applied
to the asymmetric synthesis of the unnamed plakinate 1a as
well as candidate structures for plakinic acid A, allowing an
assignment of configuration for this incompletely characterized
natural product.
Experimental Section
General procedures are described in Supporting Information.
“Standard drying and purification” refers to drying over Na2SO4,
concentration of the filtrate at 20-50 mmHg, and purification of
the residue by flash chromatography using the indicated eluting
solvent. Although no safety problems were experienced in the
course of this work, standard safety precautions should be employed
for all work with organic peroxides or H2O2.31
(2E)-1-Phenylbut-2-en-1-ol (20). Into a flame-dried three-neck
round-bottom flask equipped with a condenser and a dropping
funnel under N2 were added ether, Mg turnings, (7.20 g, 300 mmol)
and a tiny crystal of I2. Bromobenzene (23.6 g, 150 mmol, in 40
mL of ether) was added dropwise with reaction initiated by gentle
heating (∼40 °C). Following completion of addition, the reaction
was refluxed for 30 min and then cooled to 0 °C prior to dropwise
addition of a solution of crotonaldehyde (8.40 g, 120 mmol) in 40
mL of ether. The reaction was allowed to warm to room temperature
and stirred for 30 min prior to quenching with 10% aqueous H2-
SO4 (100 mL) and ice (100 g). The aqueous layer was extracted
with ether (3 × 100 mL). The combined organic layers were
sequentially washed with saturated aqueous NaHCO3 (250 mL) and
brine (250 mL). Standard drying and purification (20% EA/Hex)
afforded 20 (16.6 g, 112 mmol, 93%) as a clear pale yellow oil:
To a solution of (E)-1-bromo-1-propene (0.95 g, 8.26 mmol) in
15 mL of THF at -78 °C under N2 atmosphere was added t-BuLi
(1.5 M solution in pentane, 11.1 mL, 16.6 mmol) dropwise. After
30 min, aldehyde (1.29 g, 7.41 mmol, in 5 mL of THF) was added
dropwise. The reaction was stirred at -78 °C for 10 min, after
which the reaction was allowed to warm to room temperature and
stirred for 30 min. The reaction was quenched by addition of
aqueous 1 M HCl (20 mL). The aqueous layer was extracted with
ether (3 × 15 mL). The combined organic layers were washed with
saturated aqueous NaHCO3 (50 mL) and brine (50 mL). Standard
drying and purification (15% EA/Hex) afforded the syn alcohol
syn-22a (754 mg, 47%) followed by the anti alcohol anti-22b (730
mg, 46%), both as pale yellow oils. [The relative stereochemical
assignments for 22a and 22b are based upon conversion to trans-
2-methyl-4-(E-2-propenyl)-butyrolactone (from 22a) and the cis
isomer (from 22b). Details are provided in Supporting Information.]
1
Rf ) 0.50 (30% EA/Hex); H NMR δ 7.26-7.46 (5H), 5.75 (m,
2H), 5.15 (d, 1H, 5.5), 2.04 (br. s, 1H), 1.73 (d, 3H, 5.7); 13C NMR
δ 143.4, 133.6, 128.5, 127.5, 127.4, 126.2, 75.3, 17.7; FT-IR 3352,
3061, 3028, 2916, 2855, 1492, 1450, 1070, 1003, 965, 753, 698;
EI-HRMS calcd for C10H12O (M+) 148.0888, found 148.0889.
1
Data for 22a: Rf ) 0.34 (20% EA/Hex); H NMR δ 7.20-7.40
Ethyl (4E)-3-methyl-5-phenylpent-4-enoate (21). A solution
of propionic acid (289 mg, 3.9 mmol), triethyl orthoacetate (71.4
mL, 63.2 g, 390 mmol), and alkenol 20 (5.77 g, 39 mmol) in xylene
(500 mL) was heated to reflux for 6 h. After removal of solvent at
reduced pressure, the oily residue was purified by flash chroma-
(5H), 6.45 (d, 1H, 16.0), 6.11 (dd, 1H, 16.0, 8.2), 5.66 (dq, 1H,
15.3, 6.2), 5.52 (dd, 1H, 15.3, 6.9), 4.13 (m, 1H), 2.58 (m, 1H),
1.90 (br. s, 1H), 1.71 (d, 3H, 6.2), 1.71 (ddd, 1H, 13.8, 8.6, 5,5),
1.53 (ddd, 1H, 13.8, 9.0, 4.7), 1.13 (d, 3H, 6.7); 13C NMR δ 137.6,
135.8, 134.5, 128.7, 128.4, 126.8, 126.2, 125.9, 70.8, 44.4, 33.8,
21.1, 17.6; FT-IR ν 3351, 3025, 2965, 1493, 1450, 1371, 1062,
967, 747, 694; HRMS calcd for C15H20O (M+) 216.1514, found
(29) Bloodworth, A. J.; Courtneidge, J. L.; Eggelte, H. J. J. Chem. Soc.,
Chem. Commun. 1983, 1267-1268.
(30) Dussault, P. In ActiVe Oxygen in Chemistry; Foote, C. S., Valentine,
J. S., Greenberg, A., Liebman, J. F., Eds.; Blackie Academic and
Professional: London, 1995; pp 152-155.
(31) Medard, L. A. Accidental Explosions: Types of ExplosiVe Sub-
stances; Ellis Horwood Limited: Chichester, 1989; Vol. 2. Patnaik, P. A.
ComprehensiVe Guide to the Hazardous Properties of Chemical Substances;
Van Nostrand Reinhold: New York, 1992. Shanley, E. S. In Organic
Peroxides; Swern, D., Ed.; Wiley-Interscience: New York, 1972; Vol.3, p
341. Jones, C. W. Applications of Hydrogen Peroxide and DeriVatiVes;
Royal Society of Chemistry: Cambridge, 1999.
1
216.1521. Data for 22b: Rf ) 0.31 (20% EA/Hex); H NMR δ
7.19-7.40 (5H), 6.37 (d, 1H, 16.0), 6.13 (dd, 1H, 16.0, 8.2), 5.70
(dq, 1H, 15.3, 6.4), 5.50 (ddq, 1H, 15.3, 7.2, 1.2), 4.14 (m, 1H),
2.46 (m, 1H), 1.86 (br. s, 1H), 1.74 (dd, 3H, 6.2, 1.2), 1.71 (m,
1H), 1.53 (dt, 1H, 13.2, 6.6), 1.14 (d, 3H, 6.7); 13C NMR δ 137.6,
136.3, 134.1, 128.4, 128.3, 126.9, 126.8, 125.9, 71.3, 44.2, 34.1,
20.8, 17.6; FT-IR ν 3375, 3025, 2966, 2925, 1493, 1450, 1372,
1064, 967, 748, 694; HRMS calcd for C15H20O (M+) 216.1514,
found 216.1517.
2288 J. Org. Chem., Vol. 71, No. 6, 2006

Asymmetric Synthesis of 1,2-Dioxolane-3-acetic Acids
Ethyl (3R*,4E,7S*,8E)-3,7-Dimethyl-9-phenylnona-4,8-di-
enoate (23). By a process similar to that employed for synthesis
of 21, allylic alcohol 22a (1.31 g, 6.06 mmol) was converted to 23
(1.47 g, 5.14 mmol, 85%) as a pale yellow oil: Rf ) 0.68 (10%EA/
83.1, 69.2, 40.0, 37.2, 35.82, 26.3, 19.83, 19.79; FT-IR ν 3311,
2924, 2855, 1457, 1377, 1270, 1072, 700; HRMS calcd for C17H22O
(M+) 238.1721, found 238.1723.
(2E,5R*,6E,9S*,10E)-3,5,9-Trimethyl-11-phenylundeca-2,6,10-
trien-1-ol (25). To a flame-dried three-neck flask was added bis-
(cyclopentadienyl) zirconium dichloride (6.14 g, 21 mmol) and
CH2Cl2 (200 mL). The solution was cooled to 0 °C, after which
was slowly added Me3Al (21.0 mL, nominally 2.0 M in toluene,
42 mmol). After the lemon yellow solution had stirred for 10 min,
a solution of alkyne 24 (5.0 g, 21.0 mmol) in CH2Cl2 (10 mL) was
added over a period of 30 min. The reaction was allowed to warm
to room temperature and stirred overnight, resulting in a clear,
orange solution. Removal of solvent in vacuo (rotary evaporator,
warm water bath) afforded a precipitate that was extracted with
dry hexane (4 × 25 mL), with each extract transferred via cannula
into a common oven-dried flask. The hexane extracts were cooled
to -78 °C and treated with n-BuLi (8.4 mL, nominally 2.5 M in
hexanes, 21 mmol), resulting in a yellow precipitate that was
redissolved by addition of THF (200 mL). After 15 min, the
resulting dark-red solution was transferred via cannula into a
suspension of paraformaldehyde (3.15 g, 5 equiv) in THF (50 mL).
The solution was stirred overnight and then quenched with 3 M
HCl. The aqueous layer was extracted with ether (2 × 100 mL).
The combined organic layers were washed sequentially with
saturated aqueous sodium bicarbonate (200 mL) and brine (200
mL). Standard drying and purification (20% EA/hex) afforded allyl
alcohol 25 (4.8 g, 77%) as a pale yellow oil: Rf ) 0.31 (20% EA/
1
Hex); H NMR δ 7.18-7.40 (5H), 6.36 (d, 1H, 16.0), 6.15 (dd,
1H, 16.0, 7.4), 5.43 (m, 2H), 4.12 (q, 2H, 7.15), 2.66 (m, 1H),
2.00-2.46 (5H), 1.25 (t, 3H, 7.15), 1.08 (d, 3H, 6.7), 1.05 (d, 3H,
6.7); 13C NMR δ 172.4, 137.7, 136.0, 135.8, 128.3, 128.0, 127.1,
126.7, 125.9, 60.0, 41.8, 39.9, 37.0, 33.6, 20.4, 19.6, 14.2; FT-IR
ν 3030, 2969, 2932, 1730, 1453, 1374, 1178, 1029, 972, 753, 701;
HRMS calcd for C19H26O2 (M+) 286.1933, found 286.1922.
[(1E,3S*,5E,7R*)-3,7-Dimethyldeca-1,5-dien-9-yn-1-yl]ben-
zene (24). LiAlH4 (1.63 g, 43.2 mmol) was added in small portions
to a solution of ester 23 (8.24 g, 28.8 mmol) in THF (100 mL).
The mixture was stirred for 1 h at room temperature and then cooled
to 0 °C before quenching with Na2SO4‚10H2O (50 g). The resulting
slurry was stirred for 1 h and filtered through Celite. The filtrate
was concentrated to afford the alcohol as a pale yellow oil, which
was used without further purification.
To a solution of (COCl)2 (3.80 mL, 43.5 mmol) in CH2Cl2 (200
mL) under N2 atmosphere at -60 °C was added dropwise DMSO
(6.31 mL, 87 mmol). The mixture was stirred for 10 min, and then
a solution of crude alcohol in CH2Cl2 (30 mL) was added dropwise.
The reaction mixture was stirred for 20 min, and then NEt3 (24.0
mL, 170 mmol) was added. The mixture was stirred at -60 °C
and then warmed to room temperature and quenched with H2O (150
mL). The separated aqueous layer was extracted with CH2Cl2 (2
× 100 mL), and the combined organic layers were washed
sequentially with NaHCO3 (150 mL) and brine (150 mL). The dried
solution (MgSO4) was filtered and concentrated. The residue was
purified by flash chromatography (10% EA/Hex) to afford the
aldehyde (5.92 g, 24.5 mmol, 85% over two steps) as a pale yellow
oil: Rf ) 0.37 (20% EA/Hex); 1H NMR δ 9.70 (t, 1H, 2.4), 7.17-
7.37 (5H), 6.34 (d, 1H, 15.9), 6.11 (dd, 1H, 15.9, 7.5), 5.43 (m,
2H), 2.74 (m, 1H), 2.29-2.46 (3H), 2.10 (m, 2H), 1.07 (d, 3H,
6.6), 1.06 (d, 3H, 6.7); 13C NMR δ 202.6, 137.7, 136.0, 135.7,
128.4, 128.2, 127.69, 126.8, 125.9, 50.4, 39.9, 37.19, 31.6, 20.7,
19.8; FT-IR ν 2955, 2928, 2854, 1722, 1458, 1379, 1271, 1120,
1071, 964, 744, 694; HRMS calcd for C17H22O (M+) 242.1671,
found 242.1680.
1
Hex); H NMR δ 7.17-7.37 (5H), 6.34 (d, 1H, 16.0), 6.12 (dd,
1H, 16.0, 7.4), 5.31-5.40 (3H), 4.13 (d, 2H, 6.9), 2.29-2.37 (2H),
1.90-2.12 (4H), 1.62 (d, 3H, 0.7), 1.29 (br. s, 1H), 1.07 (d, 3H,
6.7), 0.95 (d, 3H, 6.7); 13C NMR δ 138.3, 137.9, 137.6, 136.4,
128.5, 127.9, 126.8, 126.16, 125.9, 125.0, 59.3, 47.40, 40.03, 37.21,
34.53, 20.36, 19.69, 16.2; FT-IR ν 3363, 3024, 2958, 2923, 1599,
1493, 1452, 1377, 967, 748, 694; HRMS calcd for C20H28OLi (M
+ Li)+ 291.2330, found 291.2296.
(2R,3R,5R,6E,9S,10E)- and (2R,3R,5S,6E,9R,10E)-2,3-Epoxy-
3,5,9-trimethyl-11-phenyl-undeca-6,10-dien-1-ol (26a and 26b).
To a -20 °C solution of Ti(Oi-Pr)4 (2.2 mL, 7.2 mmol) in CH2Cl2
(40 mL) containing a few 4 Å molecular sieves was added D-(-
)-diethyltartrate (1.76 g, 8.7 mmol) dropwise. Next was added a
solution of the allyl alcohol (1.37 g, 4.84 mmol) in a small amount
of CH2Cl2 over a period of 15-20 min (syringe pump). The solution
was stirred for 20 min, after which tert-butyl hydroperoxide (2.9
mL, nominally 5 M in nonane, dried for 30 min with 4 Å molecular
sieves) was added over 40 min. After the consumption of starting
material (TLC), the reaction was quenched by addition of 10%
aqueous tartaric acid (excess) and 10% aqueous Na2SO3 (10 mL)
and stirred until the organic layer clarified, ca. 30 min. The aqueous
layer was extracted with ether (3 × 50 mL), and the combined
organic layers were washed with brine (100 mL). Standard drying
and purification (30% EA/hex) afforded 1.35 g (93%) of a 1:1
mixture of diastereomers that were separated by semipreparative
HPLC (17% EA/Hex): 26b eluted at 38 min whereas 26a eluted
at 49 min; both were pale yellow oils. Data for 26a: Rf ) 0.53
(40%EA/Hex); [R]D ) -17.1 (CHCl3, c ) 2.0) 81% ee determined
by 1H NMR of its Mosher ester; 1H NMR δ 7.16-7.37 (5H), 6.33
(d, 1H, 15.9), 6.12 (dd,1H, 15.9, 7.5), 5.41 (dt, 1H, 15.3, 6.9), 5.27
(dd, 1H, 15.3, 8.2), 3.77 (dd, 1H, 12.1, 4.1), 3.61 (dd, 1H, 12.1,
6.9), 2.88 (dd, 1H, 6.9, 4.1), 2.35 (m, 2H), 2.09 (m, 2H), 1.76 (dd,
1H, 13.6, 5.3), 1.67 (br. s, 1H), 1.27 (s, 3H), 1.25 (dd, 1H, 13.6,
9.9), 1.08 (d, 3H, 6.7), 1.00 (d, 3H, 6.7); 13C NMR δ 137.7, 136.9,
136.0, 128.5, 128.2, 127.2, 126.9, 125.9, 63.6, 61.5, 60.5, 46.3,
40.0, 37.3, 34.5, 21.8, 20.1, 16.8; FT-IR ν 3423, 3061, 3027, 2961,
1494, 1453, 1381, 1255, 1026, 970, 750, 698; HRMS calcd for
C20H28O2Li (M + Li)+ 307.2249, found 307.2251. Data for 26b:
Rf ) 0.49 (40%EA/Hex); [R]D ) +28.0 (CHCl3, c 4.0) 82% ee
To a suspension of Zn dust (681 mg, 10.4 mmol) in CH2Cl2 (50
mL) was added CBr4 (3.46 g, 10.4 mmol) and Ph3P (2.73 g, 10.4
mmol). The reaction was stirred for 12 h at room temperature, after
which was added the aldehyde (1.26 g, 5.21 mmol). The reaction
was stirred for 30 min and then poured into pentane (300 mL).
The resulting brown cloudy mixture was filtered through Celite
and concentrated under vacuum. The residue was purified by flash
chromatography to afford the dibromoalkene (1.87 g, 90%) as a
1
pale yellow oil: Rf ) 0.81 (10%EA/Hex); H NMR δ 7.17-7.37
(5H), 6.37 (t, 1H, 7.1), 6.36 (d, 1H, 16.0), 6.14 (dd, 1H, 16.0, 7.5),
5.37 (m, 2H), 2.36 (m, 1H), 2.27 (m, 1H), 2.01-2.20 (4H), 1.09
(d, 3H, 6.7), 1.00 (d, 3H, 6.8); 13C NMR δ 137.8, 137.5, 136.18,
136.16, 128.5, 128.1, 127.8, 126.8, 126.0, 88.8, 40.2, 40.1, 37.3,
36.0, 20.4, 19.9; FT-IR ν 3026, 2959, 2924, 2914, 1600, 1492,
1449, 1374, 964, 775,746, 692.
To a solution of the dibromoalkene (6.16 g, 15.4 mmol) in THF
(100 mL) at -78 °C under N2 was added n-BuLi (nominally 2.6
M in hexane, 11.9 mL, 30.9 mmol) over 30 min. The reaction was
stirred at -78 °C for 1 h, after which the solution was allowed to
warm to room temperature. After 2 h the reaction was cooled to 0
°C and quenched with 3 M HCl (100 mL). The aqueous layer was
extracted with ether (2 × 100 mL) and the combined organic layers
were washed with saturated NaHCO3 (150 mL) and brine (150 mL).
Standard drying and purification (5% EA/Hex) afforded the alkyne
24 (3.31 g, 90% over two steps) as a pale yellow oil: Rf ) 0.73
1
(10% EA/Hex); H NMR δ 7.17-7.40 (5H), 6.37 (d, 1H, 16.0),
1
6.18 (dd, 1H, 16.0, 7.4), 5.47 (m, 2H), 2.33-2.44 (2H), 2.05-
2.23 (4H), 1.98 (t, 1H, 2.6), 1.11 (d, 3H, 6.7), 1.10 (d, 3H, 6.7);
13C NMR δ 137.9, 136.2, 135.9, 128.4, 128.0, 127.5, 126.8, 126.0,
determined by H NMR of the ester formed with (S)-Mosher acid
chloride: 1H NMR δ 7.17-7.37 (5H), 6.33 (d, 1H, 15.9), 6.14 (dd,-
1H, 15.9, 7.4), 5.39 (m, 2H), 3.82 (dd, 1H, 12.1, 4.2), 3.67 (dd,
J. Org. Chem, Vol. 71, No. 6, 2006 2289

Dai et al.
1H, 12.1, 6.7), 2.94 (dd, 1H, 6.7, 4.2), 2.34 (m, 2H), 2.09 (m, 2H),
1.78 (dd, 1H, 13.8, 6.8), 1.68 (br. s, 1H), 1.28 (s, 3H), 1.25 (dd,
1H, 13.8, 8.6), 1.08 (d, 3H, 6.7), 0.97 (d, 3H, 6.7); 13C NMR δ
137.8, 137.4, 136.2, 128.4, 128.1, 126.8, 126.6, 125.9, 63.0, 61.4,
60.5, 45.8, 40.0, 37.3, 33.8, 20.8, 19.9, 16.7; FT-IR ν 3417, 2963,
2928, 1454, 1382, 1254, 1027, 971, 751, 699; HRMS calcd for
C20H28O2Li (M + Li)+ 307.2249, found 307.2246.
(2S,3R,4R,6R,7E,10S,11E)- and (2R,3R,4R,6R,7E,10S,11E)-
3,4-Epoxy-4,6,10-trimethyl-12-phenyl-dodeca-7,11-dien-2-ol (27a
and 27b). To a stirred 0 °C solution of epoxy alcohol 26a (2.19 g,
7.3 mmol) in CH2Cl2 (70 mL) was added pyridine (2.26 mL, 28
mmol). After 10 min, Dess Martin periodinane (4.45 g, 10.5 mmol)
was added in one portion. After stirring at 0 °C for 2 h, the reaction
was judged complete (TLC) and was quenched with saturated
aqueous sodium thiosulfate (100 mL) and saturated sodium
bicarbonate (aqueous, 100 mL). The mixture was stirred for 30
min and then extracted with ether (2 × 50 mL). The combined
organic layers were dried with Na2SO4 and then MgSO4. The
concentrated filtrate was purified by elution (8% EA/Hex) through
a plug of silica gel to afford the 2,3-epoxyaldehyde (ca. 1.8 g) which
was used without further purification.
(1.59 g, 5.3 mmol) in THF (70 mL) was dropwise added Red-Al
(15 mL, nominally 65 wt % in toluene). After stirring overnight,
the reaction was judged complete (TLC) and was quenched by slow
addition of excess Rochelle’s salt (gas evolution). The mixture was
diluted with ethyl acetate (50 mL) and stirred until the layers cleared
(ca. 1 h). The separated aqueous layer was extracted with ether (2
× 50 mL), and the combined organic layers were washed with brine
(2 × 50 mL). Standard drying and purification (30% EA/hex)
afforded diol 28a (1.54 g, 97%) as a pale yellow oil: Rf ) 0.28
1
(30% EA/Hex); [R]D ) +23.1 (CHCl3, c 1.0); H NMR δ 7.17-
7.36 (5H), 6.33 (d, 1H, 16.0), 6.11 (dd, 1H, 16.0, 7.8), 5.54 (dt,
1H, 15.0, 7.2), 5.40 (dd, 1H, 15.0, 9.2), 4.17 (m, 1H), 4.01 (br. s,
1H), 2.77 (br. s, 1H), 2.37 (m, 2H), 2.12 (m, 2H), 1.80 (dd, 1H,
14.1, 10.5), 1.61 (dd, 1H, 14.6, 10.6), 1.44 (m, 2H), 1.22 (s, 3H),
1.14 (d, 3H, 6.0), 1.08 (d, 3H, 6.7), 0.98 (d, 3H, 6.7); 13C NMR δ
138.7, 137.6, 135.6, 128.9, 128.6, 128.4, 126.9, 126.0, 74.8, 64.6,
50.0, 46.5, 39.9, 37.5, 34.1, 29.3, 23.9, 23.5, 20.2; FT-IR ν 3374,
3025, 2964, 2926, 1493, 1453, 1374, 1329, 1177, 1134, 967, 918,
748, 694; HRMS calcd for C21H32O2Li (M + Li)+ 323.2562, found
323.2568.
(2R,4R)-2-[(2R,3E,6S,7E)-2,6-Dimethyl-8-phenyl-octa-3,7-di-
enyl]-2,4-dimethyloxetane (29) and (4S,6R,7E,10S,11E)-4,6,10-
Trimethyl-12-phenyl-dodeca-1,7,11-triene-4-ol (30). To a 0 °C
solution of diol 28a (1.44 g, 4.56 mmol) in THF (80 mL) was added
t-BuOK (540 mg, 4.82 mmol, one portion) followed by a solution
of p-TsCl (908 mg, 4.76 mmol) in THF (9 mL) over a period of
30 min. The reaction was stirred for an additional 30 min and then
allowed to warm to room temperature. After the consumption of
diol 28a, (TLC, ca. 3 h) the reaction was recooled to 0 °C and
treated with NaH (500 mg, 60% dispersion in mineral oil). The
reaction was stirred overnight and quenched by addition of water
(100 mL). The aqueous layer was extracted with ether (2 × 50
mL). The combined organic layers were washed with brine (100
mL). Standard drying and purification (10% EA/Hex) afforded the
oxetane 29 (0.99 g, 72%) and trienol 30 (190 mg, 14%), each as
To a -78 °C solution of MeMgBr (nominally 3 M in ether, 2.89
mmol, 8.7 mmol) in THF (60 mL) was added a solution of the
epoxyaldehyde (1.72 g, assume 5.77 mmol) in a small amount of
THF over 1 h (syringe pump). After 1 h, the reaction was allowed
to warm to room temperature and stirred for an additional 30 min
prior to being quenched with saturated aqueous NH4Cl (20 mL).
The separated aqueous layer was extracted with ether (2 × 30 mL).
The combined organic layers were washed with brine (50 mL) and
dried over Na2SO4. The procedure was repeated on 700 mg of
epoxyaldehyde, and the combined batches were purified by
chromatography (22% EA/hex) to afford syn-epoxy alcohol 27a
(1.29 g, 71%) followed by anti-epoxy alcohol 27b (0.46 g, 25%)
both as pale yellow oils. Data for 27a: Rf ) 0.38 (30% EA/Hex);
1
[R]D ) +32.3 (CHCl3, c 1.0); H NMR δ 7.17-7.37 (5H), 6.34
pale yellow oils. Data for 29: Rf ) 0.68 (30% EA/Hex); [R]D
)
(d, 1H, 16.0), 6.14 (dd, 1H, 16.0, 7.5), 5.40 (m, 2H), 3.70 (dq, 1H,
7.9, 6.3), 2.61 (d, 1H, 7.9), 2.35 (m, 2H), 2.10 (m, 2H), 1.78 (dd,
1H, 13.6, 6.5), 1.36 (s, 3H), 1.35 (d, 3H, 6.3), 1.27 (dd, 1H, 13.6,
8.0), 1.26 (br. s, 1H), 1.08 (d, 3H, 6.6), 1.00 (d, 3H, 6.7); 13C NMR
δ 137.8, 137.5, 136.2, 128.4, 128.1, 126.8, 126.5, 125.9, 66.3, 66.2,
60.9, 45.9, 40.0, 37.3, 33.9, 20.9, 20.7, 19.9, 16.8; FT-IR ν 3439,
3025, 2962, 1492, 1452, 1381, 1267 (epoxy), 1060, 966, 945, 925,
747, 694; HRMS calcd for C21H30O2Li (M + Li)+ 321.2406, found
321.2414. Data for 27b: Rf ) 0.30 (30% EA/Hex); [R]D ) +27.7
1
+20.9 (CHCl3, c 1.0); H NMR δ 7.16-7.37 (5H), 6.33 (d, 1H,
15.8), 6.14 (dd, 1H, 15.8, 7.6), 5.38 (m, 2H), 4.75 (m, 1H), 2.26-
2.40 (3H), 2.04-2.20 (3H), 1.67 (d, 2H, 6.6), 1.44 (s, 3H), 1.35
(d, 3H, 6.0), 1.08 (d, 3H, 6.8), 0.97 (d, 3H, 6.7); 13C NMR δ 138.6,
137.9, 136.3, 131.4, 128.4, 128.0, 126.7, 125.9, 81.5, 71.1, 50.5,
40.5, 40.0, 37.3, 33.0, 26.9, 24.3, 21.6, 19.9; FT-IR ν 3024, 2961,
2921, 1492, 1450, 1374, 1265, 1051 (oxetane), 965, 892, 746, 694;
HRMS calcd for C21H30OLi (M + Li)+ 305.2457, found 305.2455.
Data for 30: Rf ) 0.63 (30% EA/Hex); [R]D ) +20.8 (CHCl3, c
1.0); 1H NMR δ 7.16-7.37 (5H), 6.33 (d, 1H, 15.9), 6.10 (dd, 1H,
15.9, 7.6), 5.85 (m, 1H), 5.43 (m, 2H), 5.09 (m, 2H), 2.31-2.44
(2H), 2.19 (m, 2H), 2.10 (m, 2H), 2.20 (br. s, 1H), 1.52 (dd, 1H,
14.2, 9.8), 1.44 (dd, 1H, 14.2, 3.8), 1.18 (s, 3H), 1.08 (d, 3H, 6.7),
0.98 (d, 3H, 6.7); 13C NMR δ 139.2, 137.7, 135.9, 134.3, 128.44,
128.36, 127.8, 126.8, 126.0, 118.0, 72.9, 48.2, 47.6, 40.0, 37.5,
33.8, 27.0, 23.4, 20.2; HRMS calcd for C21H30O (M+) 298.2296,
found 298.2291.
1
(CHCl3, c 1.0); H NMR δ 7.16-7.36 (5H), 6.34 (d, 1H, 16.0),
6.13 (dd, 1H, 16.0, 7.5), 5.38 (m, 2H), 3.70 (dq, 1H, 8.0, 6.5),
2.69 (d, 1H, 8.0), 2.33 (m, 2H), 2.10 (m, 2H), 1.78 (dd, 1H, 13.7,
6.7), 1.28 (s, 3H), 1.27 (br. s, 1H), 1.24 (d, 3H, 6.5), 1.24 (1H),
1.08 (d, 3H, 6.9), 0.96 (d, 3H, 6.9); 13C NMR δ 137.8, 137.4, 136.2,
128.4, 128.1, 126.8, 126.6, 125.9, 67.8, 66.9, 61.1, 46.0, 40.0, 37.3,
33.9, 20.7, 19.9, 19.1, 17.3; FT-IR ν 3438, 3025, 2963, 2925, 2869,
1492, 1452, 1382, 1267 (epoxy), 1060, 967, 945, 925, 748, 694;
HRMS calcd for C21H30O2Li (M + Li)+ 321.2406, found 321.2395.
Mitsunobu Inversion of 27b to 27a.24 To a solution of epoxy
alcohol 27b (90 mg, 0.30 mmol) in toluene (4 mL) were added
Ph3P (94 mg, 0.36 mmol) and p-nitrobenzoic acid (60 mg, 0.36
mmol), followed by diethyl azodicarboxylate (63 mg, 0.36 mmol).
The reaction was stirred at room temperature for 30 min, after which
the cloudy mixture was concentrated. The residue was redissolved
in hexane/ether (1:1) and eluted through a plug of silica. The crude
p-nitrobenzoate (150 mg) was dissolved in MeOH (3 mL) and
treated with NaOMe (30 mg). After 20 min, the reaction was
quenched by addition of saturated aqueous NH4Cl (3 mL) and ether
(5 mL). The aqueous layer was extracted with ether (2 × 5 mL),
and the combined organic layers were washed with brine (10 mL).
Standard drying and purification (22% EA/Hex) afforded epoxy
alcohol 27a (78 mg, 87%) identical to the sample described above.
(2S,4R,6R,7E,10S,11E)-4,6,10-Trimethyl-12-phenyl-dodeca-
7,11-diene-2,4-diol (28a). To a 0 °C solution of epoxy alcohol 27a
(1R,5R)-1,5-Dimethyl-cyclohexan-1-ol (32). To a 25 mL round-
bottom flask covered with foil was added trienol 30 (50 mg, 0.17
mmol, in 15 mL of CH2Cl2) and a “second generation” ruthenium
carbene (14 mg, 0.017 mmol).26 The reaction was stirred at room
temperature under N2 atmosphere for 3 h. Silica gel (50 mg) was
added, and the solution was concentrated. The residue was loaded
onto the top of a column of flash silica and eluted with 15% EA/
Hex to afford 1,3-dimethyl-2-cyclohexenol (20 mg, 88%) as a
colorless oil: Rf ) 0.22 (20% EA/Hex); 1H NMR 5.54-5.64 (2H),
2.68 (br. s, 1H), 1.96-2.18 (2H), 1.75 (m, 1H), 1.33 (s, 3H), 1.16-
1.28 (2H), 1.00 (d, 3H, 7.0); 13C NMR δ 134.0, 124.1, 72.3, 44.1,
40.2, 30.3, 29.2, 21.1. The cyclohexenol was hydrogenated over
Pd/C to afford cis-1,3-dimethylcyclohexanol 32 (21 mg, ∼100%).32
(32) Senda, Y.; Ishiyama, J.; Imaizumi, S. Tetrahedron 1975, 31, 1601-
1605.
2290 J. Org. Chem., Vol. 71, No. 6, 2006

Asymmetric Synthesis of 1,2-Dioxolane-3-acetic Acids
(2R,4S,6R,7E,10S,11E)- and (2R,4R,6R,7E,10S,11E)-4-Hy-
droperoxy-12-phenyl-4,6,10-trimethyldodeca-7,11-dien-2-ol (33
and epi-33). To a flame-dried round-bottom flask was added
oxetane 29 (0.790 g, 2.65 mmol) and fresh prepared H2O2/ether
(25 mL).12,33 CAUTION: Anhydrous solutions of H2O2 should be
used behind a shield. Unused reagent should neVer be stored but
immediately quenched with a reducing agent such as 10% aqueous
Na2SO3. The solution was cooled to -78 °C, and TMSOTf (2.7
mL of 1.0 M solution in THF) was added dropwise. After 45 min,
oxetane had disappeared (TLC), and the reaction was quenched
with H2O (25 mL) and 4 drops of BHT solution (0.1 M in CH2Cl2).
The separated organic layer was washed with water (2 × 25 mL)
to remove residual H2O2. Standard drying and purification (25%
EA/Hex) afforded a pale yellow oil (560 mg, 64%) containing an
8:1 mixture of two diastereomers (analytical HPLC as well as crude
NMR) that were separated by semipreparative HPLC (25% EA/
Hex). The minor product (epi-33) eluted at 29 min, followed by
33 at 33 min. Data for 33: Rf ) 0.38 (30% EA/Hex); [R]D ) +20.0
747, 693, 671; HRMS calcd for C27H44O3SiLi (M + Li)+ 451.3220,
found 451.3204.
(3S,5S)-3-[(2R,3E,6S,7E)- and (3S,5R)-3-[(2R,3E,6S,7E)-3,5-
Dimethyl-2,6-dimethyl-8-phenyl-octa-3,7-dienyl]-5-(2-methoxy-
ethoxy)-1,2-dioxolane (cis-35 and trans-35). To a solution of
silylperoxy ketone 34 (242 mg, 0.54 mmol) in 2-methoxyethanol
(15 mL) in a Teflon bottle was added HF (48 wt % in water, 1
mL, CAUTION). Conversion of ketone to an initial product,
presumably 1,2-dioxolan-3-ol, was complete in ca. 1 h (TLC). After
this initial product had also disappeared (48 h, TLC), the reaction
was quenched with saturated aqueous NaHCO3 (15 mL) and diluted
with ether (20 mL). The aqueous layer was extracted with ether (2
× 10 mL). Standard drying and purification (15% EA/hex, using
silica gel pretreated with 2.5% Et3N) afforded a 3:2 mixture (NMR)
of diastereomeric alkoxydioxolanes (184 mg, 88%) as a pale yellow
oil. A small portion of the products was separated by careful flash
chromatography (10% EA/Hex) to afford individual samples of cis-
35 and trans-35. Data for cis-35: Rf ) 0.45 (20% EA/Hex); [R]D
) +150° (CHCl3, c 1.0); 1H NMR δ 7.16-7.36 (5H), 6.32 (d, 1H,
16.0), 6.12 (dd, 1H, 16.0, 7.6), 5.38 (dt, 1H, 15.2, 6.5), 5.29 (dd,
1H, 15.2, 8.5), 3.73 (m, 1H), 3.61 (m, 2H), 3.51 (m, 1H), 3.39 (s,
3H), 2.58 (d, 1H, 13.3), 2.32 (m, 2H), 2.20 (d, 1H, 13.3), 2.08 (m,
2H), 1.64 (m, 2H), 1.46 (s, 3H), 1.31 (s, 3H), 1.08 (d, 3H, 7.0),
0.99 (d, 3H, 7.0); 13C NMR δ 137.8, 137.6, 136.1, 128.5, 128.2,
126.9, 126.8, 125.9, 108.2, 86.5, 72.2, 61.0, 59.0, 58.6, 44.8, 40.0,
37.3, 34.1, 24.9, 22.7, 20.2, 20.1; FT-IR ν 3025, 2958, 2925, 1493,
1451, 1375, 1307, 1203, 1130, 1073, 966, 748, 694; HRMS calcd
for C24H36O4Li (M + Li)+ 395.2774, found 395.2763. Data for
trans-35: Rf ) 0.38 (20% EA/Hex); [R]D ) -41.3° (CHCl3, c 0.7);
1H NMR (400 MHz) 7.16-7.36 (5H), 6.32 (d, 1H, 16.0), 6.12 (dd,
1H, 16.0, 7.3), 5.38 (dt, 1H, 15.3, 6.5), 5.29 (dd, 1H, 15.3, 7.3),
3.73 (m, 1H), 3.60 (m, 2H), 3.52 (m, 1H), 3.39 (s, 3H), 2.53 (d,
1H, 12.6), 2.35 (d, 1H, 12.6), 2.31 (m, 2H), 2.07 (m, 2H), 1.72
(dd, 1H, 14.2, 5.5), 1.56 (dd, 1H, 14.2, 7.4), 1.45 (s, 3H), 1.35 (s,
3H), 1.07 (d, 3H, 6.5), 1.02 (d, 3H, 6.7); 13C NMR δ 138.6, 137.8,
136.2, 128.5, 128.1, 126.8, 126.4, 126.0, 108.1, 86.2, 73.2, 60.9,
59.0, 58.8, 46.9, 40.1, 37.3, 33.7, 22.7, 22.4, 20.0, 19.6; FT-IR ν
3025, 2958, 2925, 1493, 1451, 1375, 1307, 1203, 1130, 1073, 966,
748, 694; HRMS calcd for C24H36O4Li (M + Li)+ 395.2774, found
395.2787.
1
(CHCl3, c 1.0); H NMR δ 9.44 (s, 1H, OOH), 7.16-7.36 (5H),
6.32 (d, 1H, 16.0), 6.11 (dd, 1H, 16.0, 7.2), 5.54 (dt, 1H, 15.0,
7.1), 5.40 (dd, 1H, 15.0, 8.7), 4.16 (m, 1H), 2.52 (br. s, 1H, OH),
2.33 (m, 2H), 2.08 (m, 2H), 1.90 (dd, 1H, 15.6, 9.7), 1.61 (d, 1H,
15.6), 1.55 (dd, 1H, 14.2, 7.9), 1.48 (dd, 1H, 14.2, 4.7), 1.28 (s,
3H), 1.18 (d, 3H, 6.1), 1.08 (d, 3H, 6.7), 1.00 (d, 3H, 6.7); 13C
NMR δ 138.8, 137.7, 136.0, 128.5, 128.2, 126.9, 126.7, 125.9, 84.6,
64.8, 44.7, 42.4, 40.3, 37.3, 33.3, 24.6, 23.7, 23.5, 20.0; FT-IR ν
3320, 3025, 2963, 2928, 1493, 1453, 1375, 1127, 968, 748, 696;
HRMS calcd for C21H32O3Li (M + Li)+ 339.2507, found 339.2511.
Data for epi-33: Rf ) 0.43 (30% EA/Hex); [R]D ) +19.5 (CHCl3,
1
c 1.7); H NMR (400 MHz) 9.21 (s, 1H, OOH), 7.16-7.37 (5H),
6.33 (d, 1H, 15.9), 6.13 (dd, 1H, 15.9, 7.5), 5.42 (m, 2H), 4.17 (m,
1H), 2.76 (br. s, 1H, OH), 2.28-2.38 (2H), 2.12 (m, 2H), 1.9d
(dd, 1H, 15.2, 9.7), 1.74 (dd, 1H, 14.3, 8.9), 1.57 (dd, 1H, 14.3,
3.9), 1.39 (dd, 1H, 15.2, 1.0), 1.28 (d, 3H, 6.2), 1.17 (s, 3H), 1.08
(d, 3H, 6.7), 1.00 (d, 3H, 6.8); 13C NMR δ 139.1, 137.8, 136.2,
128.4, 128.2, 126.8, 126.3, 125.9, 84.3, 64.6, 45.5, 45.3, 40.0, 37.4,
32.8, 24.7, 23.6, 21.8, 20.0; FT-IR ν 3340, 3024, 2960, 1494, 1454,
1376, 1127, 968, 747, 694; HRMS calcd for C21H32O3Li (M +
Li)+ 339.2507, found 339.2509.
(4S,6R,7E,10S,11E)-4-(tert-Butyldimethyl)silylperoxy-12-phenyl-
4,6,10-trimethyl Dodeca-7,11-dien-2-one (34). To a 0 °C solution
of hydroperoxyalkanol 33a (441 mg, 1.27 mmol) was added
dropwise a solution of LiN(TMS)2 (1.27 mL, nominally 1 M in
THF) over a period of ca. 30 min. The reaction was stirred for an
additional 5 min, whereupon a solution of tert-butyldimethylsilyl
chloride (181 mg, 1.27 mmol) in THF (4 mL) was added over a
period of 30 min. After an additional 30 min, the reaction was
judged complete (TLC) and was quenched with saturated aqueous
NH4Cl (excess). The solution was extracted with ether (2 × 10
mL), and the combined organic extracts were dried with Na2SO4
and MgSO4. The filtrate was concentrated and purified by filtration
through a short plug of silica gel (10% EA/hex) to afford 587 mg
(quant) of the silylperoxyalkanol.
By a procedure similar to that employed for the oxidation of
alcohol 26a, the peroxyalkanol (436 mg, 0.943 mmol) was oxidized
to silylperoxyketone 34 (347 mg, 80%) as a pale yellow oil: Rf )
0.62 (20%EA/Hex); [R]D ) +9.8 (CHCl3, c 2.6); 1H NMR δ 7.16-
7.36 (5H), 6.33 (d, 1H, 16.0), 6.13 (dd, 1H, 16.0, 7.6), 5.35 (m,
2H), 2.74 (d, 1H, 14.1), 2.71 (d, 1H, 14.1), 2.33 (m, 2H), 2.17 (s,
3H), 2.07 (m, 2H), 1.67 (dd, 1H, 14.3, 7.7), 1.59 (dd, 1H, 14.3,
4.9), 1.26 (s, 3H), 1.07 (d, 3H, 6.7), 0.97 (d, 3H, 6.6), 0.94 (s, 9H),
0.15 (s, 3H), 0.14 (s, 3H); 13C NMR δ 208.1, 139.1, 137.9, 136.3,
128.4, 128.1, 126.8, 126.04, 125.96, 84.4, 50.9, 44.0, 40.0, 37.4,
32.9, 32.1, 26.2, 23.4, 22.3, 20.0, 18.2, -5.48; FT-IR ν 3025, 2956,
2929, 2858, 1710, 1493, 1459, 1359, 1251, 966, 888, 835, 784,
The relative stereochemistry for cis- and trans-35 was assigned
through (1) NOE enhancements between the H4/H4′ and the C3 and
C5 methyl groups and (2) the chemical shifts of H4 and H4′ relative
to literature reports for similar compounds. Details are provided in
Supporting Information.
(3RS,5S)-3,5-Dimethyl-5-[(2R,3E,6S,7E)-2,6-dimethyl-8-phen-
yl-octa-3,7-dienyl]-1,2-dioxolane-3-acetic Acid, Ethyl Thioester
(cis- and trans-36). To a -78 °C solution containing a mixture of
cis- and trans- 35 (127 mg, 0.33 mmol), and the trimethylsilyl
ketene acetal of ethyl thioacetate (466 mg, 2.65 mmol) in CH2Cl2
(4 mL) was added TiCl4 (0.36 mL, 1 M in CH2Cl2) over 10 min.
The solution was stirred for 5 min and then quenched with saturated
aqueous NaHCO3 (10 mL) and ether (10 mL). The separated
aqueous layer was extracted with ether (2 × 10 mL). Standard
drying and purification (10% EA/Hex) afforded an inseparable 3.3:1
mixture (NMR) of cis- and trans-3-alkanoate dioxolanes 36 (125
mg, 0.167 g, 88%) as a pale yellow oil, accompanied by a small
amount of tetrahydrofuranyl ketone 38 (6 mg, 0.017 mmol, 5%),
also as a pale yellow oil. Data for 36: Rf ) 0.29 (10% EA/Hex);
1H NMR δ 7.17-7.35 (5H), 6.34 (d, 1H, 15.9), 6.13 (dd, 1H, 15.9,
7.5), 5.39 (m, 1H), 5.32 (dd, 1H, 15.3, 8.7), 2.81-2.96 (m, 4H),
2.55 (d, 0.77H, 12.6), 2.44 (d, 0.23H, 12.6), 2.28-2.39 (2H), 2.18
(d, 0.23H, 12.6), 2.11 (m, 2H), 2.01 (d, 0.77H, 12.6), 1.56-1.74
(2H), 1.41 (s, 2.3H), 1.40 (s, 0.7H), 1.33 (s, 2.3H), 1.31 (s, 0.7H),
1.26 (t, 3H, 6.7), 1.08 (d, 3H, 6.7), 1.01 (d, 3H, 6.7); 13C NMR δ
196.7, 196.5, 138.4, 137.89, 137.86, 136.25, 136.22, 128.5, 128.2,
126.87, 126.83, 126.6, 126.0, 86.8, 86.7, 84.13, 84.09, 56.7, 56.5,
53.1, 52.7, 46.5, 45.7, 40.0, 37.37, 37.32, 34.0, 33.8, 31.6, 24.9,
24.4, 23.9, 23.66, 23.62, 22.78, 22.73, 22.7, 22.2, 20.1, 14.63, 14.57;
(33) Saito, I.; Nagata, R.; Yuba, K.; Matsuura, T. Tetrahedron Lett. 1983,
24, 1737-1740.
J. Org. Chem, Vol. 71, No. 6, 2006 2291

Dai et al.
FT-IR ν 3025, 2963, 2925, 2871, 1686, 1493, 1453, 1375, 1307,
1012, 968, 748, 694; HRMS calcd for C25H36O3SLi (M + Li)+
(3S,5S)-3,5-Dimethyl-5-[(2R,3E,6S,7E)-2,6-dimethyl-8-phenyl-
octa-3,7-dienyl]-1,2-dioxolane-3-acetic Acid (cis-2a). To a 0 °C
solution of methyl ester cis-37a (14.4 mg, 0.037 mmol) in THF/
H2O (4:1, 2 mL) were added H2O2 (aqueous 30%, 25 ul) and LiOH
(4.5 mg). The reaction was allowed to warm to room temperature
and stirred overnight. Aqueous Na2SO3 (10%, 2 mL) was added,
and the solution was acidified to pH 2 with 10% aqueous HCl.
The resulting solution was extracted with ether (2 × 5 mL).
Standard drying and purification (10/89/1 EA/Hex/AcOH) afforded
cis-2a (12.8 mg, 92%) as a pale yellow oil: Rf ) 0.21 (10/89/1
1
423.2545, found 423.2550. Data for 38: H NMR δ 7.17-7.37
(5H), 6.36 (d, 1H, 15.4), 5.98 (dd, 1H, 15.4, 8.0), 3.85 (d, 1H, 7.9,
6.1), 3.54 (dt, 1H, 9.1, 2.0), 2.68 (d, 1H, 14.1), 2.55 (m, 1H), 2.44
(d, 1H, 14.1), 2.21 (s, 3H), 1.30-1.88 (5H), 1.25 (s, 3H), 1.09 (d,
3H, 7.0), 1.03 (d, 3H, 7.0); 13C NMR δ 207.9, 137.6, 135.2, 129.5,
128.5, 126.9, 126.0, 74.4, 72.8, 67.0, 54.6, 41.0, 37.4, 34.2, 32.5,
29.4, 23.9, 21.8, 17.0; FT-IR ν 3025, 2962, 2929, 2872, 1710, 1453,
1376, 968, 749; HRMS calcd for C21H29O2Cl (M+) 348.1856, found
348.1848.
1
EA/Hex/AcOH); [R]D ) +91° (CHCl3, c 0.6); H NMR δ 7.16-
(3S,5S)- and (3R,5S)-3,5-Dimethyl-5-[(2R,3E,6S,7E)-2,6-di-
methyl-8-phenyl-octa-3,7-dienyl]-1,2-dioxolane-3-acetic Acid,
Methyl Ester (cis-37a) and (trans-37a). To a solution of thioesters
36 (31 mg, 0.075 mmol) in MeOH (4 mL) was added sodium
methoxide (66 mg, 1.2 mmol). The reaction was stirred until the
starting material had disappeared (ca 30 min, TLC) and then
quenched with saturated aqueous NH4Cl (saturated 5 mL). The
layers were separated, and the aqueous layer was extracted with
ether (2 × 5 mL). The combined organic layers were washed with
brine and dried over Na2SO4. The filtered solution was concentrated
to afford a 3.3:1 mixture of cis- and trans-dioxolane methyl esters
(30 mg, quant yield) as a pale yellow oil that could be separated
by semipreparative HPLC (5% EA/Hex), with cis-37a (major)
eluting at 29 min and trans-37a (minor) eluting at 31 min. Data
for cis-37a: Rf ) 0.53 (20% EA/Hex); [R]D ) +81.5° (CH2Cl2, c
1.0); 1H NMR δ 7.16-7.36 (5H), 6.33 (d, 1H, 16.2), 6.12 (dd, 1H,
16.2, 7.6), 5.39 (dt, 1H, 15.2, 6.9), 5.30 (dd, 1H, 15.2, 8.0), 3.68
(s, 3H), 2.72 (d, 1H, 14.3), 2.59 (d, 1H, 14.3), 2.52 (d, 1H, 12.6),
2.36 (m, 1H), 2.30 (m, 1H), 2.09 (m, 2H), 2.06 (d, 1H, 12.6), 1.63
(dd, 1H, 15.3, 5.7), 1.57 (dd, 1H, 15.3, 8.0), 1.42 (s, 3H), 1.33 (s,
3H), 1.08 (d, 3H, 7.0), 1.00 (d, 3H, 7.0); 13C NMR δ 171.1, 137.9,
137.8, 136.2, 128.5, 128.2, 126.83, 126.76, 126.0, 86.7, 83.8, 56.6,
51.6, 45.7, 44.3, 40.0, 37.3, 33.9, 24.7, 23.9, 22.7, 20.0; FT-IR ν
3025, 2957, 2926, 2870, 1738, 1493, 1452, 1375, 1346, 1308, 1210,
1154, 1015, 968, 748, 694; HRMS calcd for C24H34O4Li (M +
Li)+ 393.2617, found 393.2611. Data for trans-37a: Rf ) 0.49
(20% EA/Hex); [R]D ) +14.9° (CH2Cl2, c 1.0); 1H NMR δ 7.16-
7.36 (5H), 6.33 (d, 1H, 15.8), 6.12 (dd, 1H, 15.8, 7.0), 5.39 (dt,
1H, 16.0, 7.0), 5.31 (dd, 1H, 16.0, 7.5), 3.69 (s, 3H), 2.72 (d, 1H,
14.4), 2.62 (d, 1H, 14.4), 2.42 (d, 1H, 12.6), 2.34 (m, 2H), 2.21 (d,
1H, 12.6), 2.09 (m, 2H), 1.72 (dd, 1H, 14.0, 5.5), 1.57 (dd, 1H,
14.0, 6.7), 1.41 (s, 3H), 1.30 (s, 3H), 1.07 (d, 3H, 6.7), 1.01 (d,
3H, 6.7); 13C NMR δ 171.0, 138.4, 137.9, 136.2, 128.5, 128.1,
126.8, 126.6, 126.0, 86.6, 83.8, 56.7, 51.7, 46.4, 44.0, 40.1, 37.3,
33.7, 24.3, 23.5, 22.7, 20.0; FT-IR ν 3035, 2960, 2926, 1739, 1493,
1453, 1375, 1346, 1213, 970, 749, 695; HRMS calcd for C24H34O4-
Li (M + Li)+ 393.2617, found 393.2630. The relative stereochem-
ical assignments for cis-37a and trans-37a are based upon NOE
and chemical shift correlations similar to those described earlier.
7.36 (5H), 6.32 (d, 1H, 16.0), 6.12 (dd, 1H, 16.0, 7.5), 5.39 (dt,
1H, 15.3, 6.8), 5.28 (dd, 1H, 15.3, 8.2), 2.72 (d, 1H, 14.9), 2.66 (d,
1H, 14.9), 2.47 (d, 1H, 12.6), 2.32 (m, 2H), 2.08 (d, 1H, 12.6),
2.07 (m, 2H), 1.61 (m, 2H), 1.44 (s, 3H), 1.34 (s, 3H), 1.08 (d,
3H, 6.7), 0.99 (d, 3H, 6.7); 13C NMR δ 174.9, 137.8, 137.7, 136.2,
128.5, 128.2, 126.92, 126.86, 125.9, 86.9, 83.7, 56.8, 45.6, 44.1,
40.0, 37.3, 33.9, 24.7, 23.6, 22.7, 20.1; FT-IR ν 3000-3300 (br.),
3024, 2958, 2921, 1709, 1453, 1376, 1307, 968, 748, 695; HRMS
calcd for C23H32O4Li (M + Li)+ 379.2461, found 379.2454.
(3R,5S)-3,5-Dimethyl-5-[(2R,3E,6S,7E)-2,6-dimethyl-8-phenyl-
octa-3,7-dienyl]-1,2-dioxolan-3-acetic Acid (trans-2a). By similar
procedure as described for cis-2a, trans-37a (15.0 mg, 0.0389
mmol) was converted to trans-2a (13.2 mg, 91%) as a pale yellow
oil: Rf ) 0.21 (10/89/1 EA/Hex/AcOH); [R]D ) +0.8° (CHCl3, c
0.7); 1H NMR δ 7.17-7.35 (5H), 6.33 (d, 1H, 15.9), 6.14 (dd, 1H,
15.9, 7.5), 5.35 (m, 2H), 2.72 (d, 1H, 14.8), 2.66 (d, 1H, 14.8),
2.39 (d, 1H, 12.6), 2.31 (m, 2H), 2.23 (d, 1H, 12.6), 2.09 (m, 2H),
1.73 (dd, 1H, 14.0, 5.5), 1.57 (dd, 1H, 14.0, 7.8), 1.43 (s, 3H),
1.31 (s, 3H), 1.07 (d, 3H, 6.7), 1.00 (d, 3H, 6.7); 13C NMR δ 175.8,
138.3, 138.0, 136.2, 128.5, 128.1, 126.8, 126.6, 125.9, 86.7, 83.7,
56.9, 46.3, 43.9, 40.0, 37.3, 33.7, 24.0, 23.4, 22.7, 20.0; FT-IR ν
3000-3300 (br), 3024, 2957, 2921, 1709, 1453, 1375, 1307, 968,
748, 694; HRMS calcd for C23H32O4Li (M + Li)+ 379.2461, found
379.2458.
Acknowledgment. This project was supported by NIH (GM
45571) and the University of Nebraska-Lincoln. NMR spectra
were acquired, in part, on instruments purchased with funding
from NSF (MRI 0079750 and CHE 0091975).
Supporting Information Available: General experimental
procedures; experimental procedures and spectral listings associated
with synthesis of cis- and trans-1a and cis- and trans-2b. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO0522254
2292 J. Org. Chem., Vol. 71, No. 6, 2006