A potential route to neuroprostanes and isoprostanes: Preparation of the four enantiomerically pure diastereomers of 13-F4t-NeuroP

Article abstract of DOI:10.1021/jo702600v

(Chemical Equation Presented) We report a potential synthetic route to the isoprostanes and the neuroprostanes that could allow ready access to each of the enantiomerically pure diastereomers of the several regioisomers of these important human metabolites. The key transformation in the synthesis is a highly diastereoselective thermal intramolecular ene reaction. A critical observation is that the four enantiomerically pure diastereomers of an intermediate acetylenic ester are easily separated from one another. Each of these four has been carried on to a different enantiomerically pure diastereomer of 13-F _4t-neuroprostane.

Full text of DOI:10.1021/jo702600v

A Potential Route to Neuroprostanes and Isoprostanes: Preparation
of the Four Enantiomerically Pure Diastereomers of 13-F4t-NeuroP
Douglass F. Taber,*,† P. Ganapati Reddy,† and Kyle O. Arneson‡
Department of Chemistry and Biochemistry, UniVersity of Delaware, Newark, Delaware 19716, and
Department of Pharmacology, Vanderbilt UniVersity School of Medicine, NashVille, Tennessee 37232
taberdf@udel.edu
ReceiVed December 11, 2007
We report a potential synthetic route to the isoprostanes and the neuroprostanes that could allow ready
access to each of the enantiomerically pure diastereomers of the several regioisomers of these important
human metabolites. The key transformation in the synthesis is a highly diastereoselective thermal
intramolecular ene reaction. A critical observation is that the four enantiomerically pure diastereomers
of an intermediate acetylenic ester are easily separated from one another. Each of these four has been
carried on to a different enantiomerically pure diastereomer of 13-F4t-neuroprostane.
SCHEME 1
Introduction
Isoprostanes (Scheme 1) are produced in vivo by nonenzy-
matic free radical-mediated oxidation of arachidonic acid 1. First
identified in human plasma samples in microgram quantities as
mixtures, the isoprostanes (e.g., 2) were shown to have structures
similar to the prostaglandins, but with cis-dialkyl stereochemistry
on the cyclopentane rings.1 The neuroprostanes were later
identified.2 They are structurally similar to the isoprostanes, but
are derived from cis-4,7,10,13,16,19-docosahexaenoic acid
(DHA, 3). The isoprostanes, prepared by total synthesis,3 have
been shown to have a wide range of biological activities.4 The
neuroprostanes are only available from natural sources in
microgram quantities as mixtures, so to explore the biological
activity, it will be necessary to also prepare them by total
synthesis.5 Even though the in vivo nonenzymatic synthesis
leads to racemic products, the individual enantiomers of each
† University of Delaware.
‡ Vanderbilt University School of Medicine.
(1) (a) For the isolation and identification of the isoprostanes, see: Morrow,
J. D.; Awad, J. A.; Boss, H. J.; Blair, I. A.; Roberts, L. J., II. Proc. Natl. Acad.
Sci. 1992, 89, 10721. (b) For isoprostane nomenclature, see: Taber, D. F.;
Morrow, J. D.; Roberts, L. J., II. Prostaglandins 1997, 53, 63.
(3) For leading references to synthesis of the isoprostanes, see: (a) Taber,
D. F.; Hoerrner, R. S. J. Org. Chem. 1992, 57, 441. (b) Hwang, S. W.; Adiyaman,
M.; Khanapure, S. P.; Schio, L.; Rokach, J. J. Am. Chem. Soc. 1994, 116, 10829.
(c) Pudukulathan, Z.; Manna, S.; Hwang, S. W.; Khanapure, S. P.; Lawson,
J. A.; FitzGerald, G. A.; Rokach, J. J. Am. Chem. Soc. 1998, 120, 11953. (d)
Taber, D. F.; Kanai, K. Tetrahedron 1998, 54, 11767. (e) Taber, D. F.; Kanai,
K.; Pina, R. J. Am. Chem. Soc. 1999, 121, 7773. (f) Taber, D. F.; Jiang, Q. J.
Org. Chem. 2001, 66, 1876. (g) Schrader, T. O.; Snapper, M. L. J. Am. Chem.
Soc. 2002, 124, 10998. (h) Taber, D. F.; Xu, M.; Hartnett, J. C. J. Am. Chem.
Soc. 2002, 124, 13121. (i) Durand, T.; Guy, A.; Vidal, J.-F.; Rossi, J.-C. J. Org.
Chem. 2002, 67, 3615. (j) Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2002,
43, 9249. (k) Durand, T.; Guy, A.; Henry, O.; Roland, A.; Bernad, S.; El Fngour,
S.; Vidal, J.-F.; Rossi, J.-C. Chem. Phys. Lipids 2004, 128, 15. (l) Schmidt, A.;
Boland, W. J. Org. Chem. 2007, 72, 1699.
(2) For the identification of the neuroprostanes, see: (a) Roberts, L. J., II.;
Montine, T. J.; Markesbery, W. R.; Tapper, A. R.; Hardy, P.; Chemtob, S.;
Dettbarn, W. D.; Morrow, J. D. J. Biol. Chem. 1998, 273, 13605. (b) Reich,
E. E.; Zackert, W. E.; Brame, C. J.; Chen, Y.; Roberts, L. J., II.; Hachey, D. L.;
Montine, T. J.; Morrow, J. D. Biochemistry 2000, 39, 2376. (c) Roberts, L J.,
II.; Fessel, J. P. Chem. Phys. Lipids 2004, 128, 173. (d) Yin, H.; Musiek, E. S.;
Gao, L.; Porter, N. A.; Morrow, J. D. J. Biol. Chem. 2005, 280, 26600. (e)
Roberts, L J., II.; Fessel, J. P.; Davies, S. S. Brain Pathol. 2005, 15, 143. (f)
Arneson, K. O.; Roberts, L J., II. Meth. Enzym. 2007, 433, 127. (g) For
neuroprostane nomenclature, see: Taber, D. F.; Roberts, L. J., II. Prostaglandins
Other Lipid Mediators 2005, 78, 14.
10.1021/jo702600v CCC: $40.75
Published on Web 03/15/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3467–3474 3467

Taber et al.
FIGURE 1. The eight families of the neuroprostanes.
of the neuroprostanes are expected4 to interact differently with
biological receptors. The only previous synthetic routes to
neuroprostanes have each begun with enantiomerically pure
starting materials.
SCHEME 2
While there are only four regioisomeric families of the
isoprostanes,1 there are eight regioisomeric families of the
neuroprostanes (Figure 1).2 It was therefore expedient to develop
a unified synthetic approach that would allow the preparation
of any of the neuroprostanes (or isoprostanes) from a single
advanced intermediate. We report the development of such a
stereodivergent synthetic route to the isoprostanes3 and the
neuroprostanes, culminating in the preparation of the four
enantiomerically pure diastereomers of 13-F4t-NeuroP 4a.
Given the results of Sarkar,6 it seemed likely that the thermal
intramolecular ene reaction of 14 would proceed with high
diastereocontrol to give 15, having the requisite cis-dialkyl
substitution on the cyclopentane ring. The key question was,
could the racemic diastereomers of 16 be separated? If they
could, then individual resolution of each of them would lead to
the four enantiomerically pure diastereomers of 16, each a
precursor to one of the four enantiomerically pure neuropros-
tanes or isoprostanes (Scheme 2).
Results and Discussion
Preparation of the Ene Substrate 14 and the Ene Cycliza-
tion. The preparation (Scheme 3) of the ene substrate 14 started
with the diacetate 13, readily available by singlet oxygenation
of cyclopentadiene.7 Ozonolysis8 followed by Wittig homolo-
gation of the intermediate aldehyde, deprotection, and silylation
delivered the diene 18. Monoepoxidation gave 19, which was
carried on by oxidative cleavage and homologation to 14.
The Alder ene reaction of substrates such as 14 can be carried
out either with Lewis acid catalysis9 or thermally.6,10 While the
Lewis acid protocol can be carried out at lower temperatures,
it is reported6b–d,9 to lead to products having the alkyl substit-
uents both cis and trans on the cyclopentane ring. In contrast,
thermal ene cyclizations had been found6 to give cleanly the
cis product. We were pleased to observe (Scheme 3) that the
thermal cyclization of 14 proceeded readily, delivering the
(4) For an overview of the physiological activity of the isoprostanes, see:
(a) Cracowski, J.-L.; Durand, T. Fundam. Clin. Pharmacol. 2006, 20, 417. (b)
Montine, T. J.; Quinn, J. F.; Kaye, J. A.; Morrow, J. D. Oxid. Stress Dis. 2006,
22, 147. (c) Montuschi, P.; Barnes, P.; Roberts, L. J., II. Current Med. Chem.
2007, 14, 703.
(5) For the only previous synthetic routes to neuroprostanes, leading from
carbohydrate precursors to a single enantiomerically pure diastereomer of the
neuroprostane, see: (a) Quan, L. G.; Cha, J. K. J. Am. Chem. Soc. 2002, 124,
12424. (b) Quan, L. G.; Cha, J. K. Chem. Phys. Lipids 2004, 128, 3. (c) Zanoni,
G.; Brunoldi, E. M.; Porta, A.; Vidari, G. J. Org. Chem. 2007, 72, 9698.
(6) (a) Sarkar, T. K.; Gangopadhyay, P.; Ghorai, B. K.; Nandy, S. K.; Fang,
J.-M. Tetrahedron Lett. 1998, 39, 8365. (b) Sarkar, T. K.; Ghorai, B. K.; Nandy,
S. K.; Mukherjee, B.; Banerji, A. J. Org. Chem. 1997, 62, 6006. (c) Sarkar,
T. K.; Ghorai, B. K.; Nandy, S. K.; Murkherjee, B. Tetrahedron Lett. 1994, 35,
6903. (d) Sarkar, T. K.; Nandy, S. K. Tetrahedron Lett. 1996, 37, 5195. (e)
Sarkar, T. K.; Nandy, S. K.; Ghorai, B. K.; Mukherjee, B. Synlett 1996, 97.
(7) Kaneko, C.; Sugimoto, A.; Tanaka, S. Synthesis 1974, 876.
(8) Jiang, L.; Burke, S. D. Org. Lett. 2002, 4, 3411.
(9) (a) Tietze, L. F.; Beifuss, U.; Ruther, M.; Ruhlmann, A.; Antel, J.;
Sheldrick, G. M. Angew. Chem., Int. Ed. 1988, 27, 1186. (b) Thomas, B. E.;
Loncharich, R. J.; Houk, K. N. J. Org. Chem. 1992, 57, 1354.
3468 J. Org. Chem. Vol. 73, No. 9, 2008

A Potential Route to Neuroprostanes and Isoprostanes
SCHEME 3
SCHEME 4
product 15 as a single diastereomer. The cis-dialkyl stereo-
chemistry of the cyclopentane was suggested by the 13C
chemical shifts of the methines attached to alkyl side chains
(13C δ 52.5 and δ 46.3). This assignment was later confirmed
by the X-ray structure of a 4-bromobenzoate derived from (R)-
16b. For a detailed discussion of the use of 13C to assign relative
configuration of a 1,2-dialkyl cyclopentane, see ref 3h.
Preparation and Resolution of the Side Chain Allylic
Alcohols. Selective debenzylation of 15 (Scheme 4) could be
effected with palladium on carbon, using 88% aqueous formic
acid as the reductant.11 If the reaction was run too long, the
allylic alcohol was hydrogenolyzed, leaving a propenyl side
chain. Oxidation of 20 followed by addition of the propargyl
zinc reagent12 led to the expected 1:1 mixture of racemic 16a
and 16b. The key observation was that 16a and 16b were readily
separable by preparative column chromatography.
Separately, because they reacted at quite different rates,
racemic 16a and 16b were subjected to R-selective3f acetylation
with Amano lipase AK and vinyl acetate. Initially, each
acetylation was run to about 40% conversion. The (R)-21 and
(R)-22 so prepared were deacetylated to give respectively (R)-
16a and (R)- 16b, which were shown individually (chiral HPLC)
to be >99% ee. The residual 16a from the initial acetylation
was again subjected to R-selective acetylation with Amano lipase
AK and vinyl acetate, and again, acetylation was run to about
40% conversion. The remaining (S)-16a was shown (chiral
HPLC) to be >99% ee. The relative and absolute configurations
of the products were assigned by comparison (optical rotation,
TLC behavior) with the analogous isoprostane intermediates that
had previously been described.3d–g These assignments were
confirmed (Supporting Information) by an X-ray structure of
the tris-4-bromobenzoate derived from (R)-16b.
The reaction of the lipase with racemic 16b was very slow.
Sufficient (R)-22 could be prepared this way, but the residual
(S)-16b had low ee (84%). The side chain hydroxyl of the
enriched (S)-16b was therefore inverted (Scheme 5) by Mit-
sunobu esterification13 with p-nitrobenzoic acid to give 23.
Hydrolysis followed by R-selective acetylation with Amano
lipase AK delivered, after hydrolysis of the acetate so prepared,
the alcohol (R)-16a. Mitsunobu inversion of the side chain
hydroxyl and again hydrolysis led to (S)-16b in high ee (>99%).
Preparation of the Four Enantiomerically Pure Diaste-
reomers of 13-F4t-neuroprostane. The ester of (S)-16a was
(10) For reviews on the intramolecular ene reaction, see: (a) Taber, D. F. In
Intramolecular Diels-Alder and Alder Ene Reactions; Springer-Verlag: New
York, 1984. (b) Mikami, K.; Shimizu, M. Chem. ReV. 1992, 92, 1021 For more
recent literature reports on intramolecular ene reactions, see ref 6 and: (c)
Thompson, S. K.; Heathcock, C. H. J. Org. Chem. 1992, 57, 5979. (d) Snider,
B. B.; Lu, Q. J. Org. Chem. 1994, 59, 8065. (e) Oppolzer, W.; Schroder, F.
Tetrahedron Lett. 1994, 35, 7939. (f) Sturla, S. J.; Kablaoui, N. M.; Buchwald,
S. L. J. Am. Chem. Soc. 1999, 121, 1976. (g) Xia, Q.; Ganem, B. Org. Lett.
2001, 3, 485. (h) Narhi, K.; Franzen, J.; Backvall, J.-E. J. Org. Chem. 2006, 71,
2914.
(11) (a) El Amin, B.; Anantharamaiah, G. M.; Royer, G. P.; Means, G. E. J.
Org. Chem. 1979, 44, 3442. (b) Jung, M. E.; Usui, Y.; Vu, C. T. Tetrahedron
Lett. 1987, 28, 5977.
(13) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Martin, S. F.; Dodge, J. A.
Tetrahedron Lett. 1991, 32, 3017. (c) Buszek, K. R.; Jeong, Y. Tetrahedron
Lett. 1995, 36, 7189. (d) Cherney, R. J.; Wang, L. J. Org. Chem. 1996, 61,
2544.
(12) (a) Wu, W.-L.; Yao, Z.-J.; Li, Y.-L.; Xia, Y.; Wu, Y.-L. J. Org. Chem.
1995, 60, 3257. (b) Alcaide, B.; Almendros, P.; Aragoncillo, C. Org. Lett. 2000,
2, 1411.
J. Org. Chem. Vol. 73, No. 9, 2008 3469

Taber et al.
SCHEME 5
SCHEME 7
SCHEME 6
In a modification of our previous report,14 we prepared the
cis allylic bromide 34 (Scheme 7). Coupling of ethyl 4-pen-
tynoate 25 with cis-4-chloro-2-buten-1-ol 3217 gave 33. Bro-
mination of the alcohol 33 delivered the bromide 34. Coupling
of (S)-24a with the bromo ester 34 gave (S)-35a and the easily
separated SN2′ byproduct (not shown in the scheme) in about a
3:1 ratio. To our delight, partial hydrogenation of (S)-35a, using
P2-Ni,3a,16 afforded the required tetraene (S)-31a with only
traces of an over-reduced byproduct, which was also easily
separated. Desilylation followed by saponification delivered 13-
epi-ent-13-F4t-NeuroP (S)-4a. By using this same procedure, the
other three enantiomerically pure diastereomers (R)-16a, (R)-
16b, and(S)-16b were carried on to the corresponding 13-F4t-
NeuroPs (R)-4a, (R)-4b, and (S)-4b (Scheme 2). The synthetic
materials were shown to be congruent (GC retention time,
fragmentation) with the previously reported2 13-F4t-NeuroPs.
The enantiomeric purity of our final products is assumed, based
on the established enantiomeric purity of each of the four
precursors.
reduced (Scheme 6) to the alcohol, and the derived tosylate was
further reduced to give (S)-24a. The alkylation of (S)-24a with
cis-1,4-dichloro-2-butene (Scheme 6) using the protocol that we
had reported14 was successful, but in the process the residual
allylic chloride was converted into the unstable and so unusable
iodide. We next prepared the diyne 28 from 25 using the
previously described15 protocol. Despite an encouraging report,15
partial hydrogenation3a,16 of diynes 27 or 28 gave in our hands
only mixtures of over-reduced products, accompanied by some
dimer from 28. Alternatively, coupling of the diyne 28 with
(S)-24a did give the triyne 30. Once again, however, the partial
hydrogenaton of 30 was not successful, leading to a complex
mixture of products.
Although we have so far only prepared the trans neuropros-
tanes using this approach, we have previously shown3h in the
isoprostane series that Mitsunobu inversion followed by hy-
drolysis efficiently converted the trans to the cis series. Thus,
each of the eight enantiomerically pure diastereomers of an
isoprostane or a neuroprostane are accessible by using this
approach.
(14) (a) Taber, D. F.; Zhang, Z. J. Org. Chem. 2005, 70, 8093. (b) Taber,
D. F.; Zhang, Z. J. Org. Chem. 2006, 71, 926.
(15) Hansen, T. V.; Stenstrom, Y. Tetrahedron: Asymmetry 2001, 12, 1407.
(16) (a) Brown, C. A.; Ahuja, V. K. J. Org. Chem. 1973, 38, 2226. (b)
Magatti, C. V.; Kaminski, J. J.; Rothberg, I. J. Org. Chem. 1991, 56, 3102.
(17) Nelson, W. L.; Freeman, D. S.; Wilkinson, P. D.; Vincenzi, F. F. J. Med.
Chem. 1973, 16, 506.
3470 J. Org. Chem. Vol. 73, No. 9, 2008

A Potential Route to Neuroprostanes and Isoprostanes
stirred for 1 h, the reaction mixture was partitioned between CH2Cl2
and, sequentially, 1 M aqueous NaOH, water, and brine. The
combined organic extract was dried (Na2SO4) and concentrated to
give the crude aldehyde (1.07 g, quantitative yield) as a colorless
liquid; TLC Rf 0.66 (30% MTBE/petroleum ether); IR (neat) 2931,
2855, 1727, 1689 cm-1; 1H NMR (CDCl3): δ 9.17 (d, J ) 8.0 Hz,
1H), 7.65–7.52 (m, 8H), 7.46–7.28 (m, 12H), 6.11 (dd, J ) 15.6,
10.0 Hz, 1H), 5.76 (dd, J ) 15.6, 7.6 Hz, 1H), 3.98 (q, J ) 7.2
Hz, 2H), 3.92 (dt, J ) 6.8, 4.8 Hz, 1H), 3.81 (q, J ) 6.4 Hz, 1H),
3.16 (dt, J ) 8.4, 4.4 Hz, 1H), 2.90–2.83 (m, 1H), 2.19 (dd, J )
16.0, 5.6 Hz, 1H), 1.96–1.84 (m, 2H), 1.78 (dt, J ) 14.0, 5.6 Hz,
1H), 1.14 (t, J ) 7.2 Hz, 3H), 1.07 (s, 9H), 1.04 (s, 9H); 13C NMR
(CDCl3) δ u: 172.0, 134.0, 133.8, 133.7, 133.5, 60.5, 43.6, 33.5,
19.3, 19.1; d: 193.2, 155.4, 136.0, 135.9, 135.8, 134.7, 130.0, 129.9,
129.82, 129.8, 127.8, 127.73, 127.7, 76.4, 75.9, 52.8, 47.1, 27.1,
27.0, 14.2; HRMS calcd for C44H54NaO5Si2 741.3407 (M + Na),
found 741.3374.
Conclusion
It is apparent that the thermal ene cyclization of 14 is indeed
a powerful method for the construction of cis-2,3-dialkyl
cyclopentanes. We feel that this route to the isoprostanes and
the neuroprostanes is the most succinct and flexible yet
described, and that it will therefore become the standard
approach when the objective is to prepare each of the enantio-
merically pure diastereomers of one of these natural products.
The four enantiomerically pure diastereomers (R)-16a, (S)-16a,
(R)-16b, and (S)-16b are universal precursors for the synthesis
of any isoprostane or neuroprostane.18 We chose the 13-F4t-
NeuroPs as our initial target because they bear the technically
most challenging side chain of any of the neuroprostanes.
Studies are underway of the physiological activity of the
synthetic neuroprostanes we have prepared.
To a stirred solution of crude aldehyde (1.07 g, 1.5 mmol) in
1:1 mixture of THF and DMF (20 mL) was added activated zinc
dust (195 mg, 3.0 mmol) followed by propargyl bromide (357 mg,
3.0 mmol) at rt. After being stirred for 2 h the reaction mixture
was partitioned between water and MTBE. The combined organic
extract was dried (Na2SO4) and concentrated. The residue was
chromatographed on a TLC mesh silica gel to give alcohol 16a
(439 mg, 39% yield) and 16b (442 mg, 39% yield) as colorless
liquids. For 16a: TLC Rf 0.42 (30% MTBE/petroleum ether); IR
(neat) 3445, 3294, 1734, 1427 cm-1; 1H NMR (CDCl3) δ 7.65–7.52
(m, 8H), 7.46–7.28 (m, 12H), 5.24 (dd, J ) 15.2, 6.0 Hz, 1H),
5.06 (ddd, J ) 15.2, 9.6, 0.8 Hz, 1H), 4.07–3.97 (m, 3H), 3.83
(app quintet, J ) 7.2 Hz, 1H), 3.77 (q, J ) 6.4 Hz, 1H), 2.88 (app
dt, J ) 10.0, 3.3 Hz, 1H), 2.83–2.78 (m, 1H), 2.27–2.19 (m, 3H),
1.95 (dd, J ) 16.4, 10.0 Hz, 1H), 1.94 (t, J ) 2.8 Hz, 1H), 1.85
(quintet, J ) 7.2 Hz, 1H), 1.69 (dt, J ) 14.0, 5.2 Hz, 1H), 1.60 (d,
J ) 4.4 Hz, 1H), 1.19 (t, J ) 6.8 Hz, 3H), 1.06 (s, 9H), 1.05 (s,
9H); 13C NMR (CDCl3) δ u: 172.7, 134.3, 134.1, 134.0, 133.9,
80.4, 70.7, 60.2, 43.5, 33.7, 27.2, 19.2, 19.1; d: 136.0, 135.9, 135.8,
133.6, 129.9, 129.7, 129.6, 129.58, 129.5, 127.6, 127.55, 127.52,
127.5, 76.6, 70.5, 52.3, 46.3, 27.0, 26.9, 14.2. HRMS calcd for
C47H58NaO5Si2 781.3720 (M + Na), found 781.3756.
Alcohol 16b. TLC Rf 0.40 (30% MTBE/petroleum ether); IR
(neat) 3436, 3306, 2931, 1732 cm-1; 1H NMR (CDCl3) δ 7.64–7.59
(m, 8H), 7.54–7.29 (m, 12H), 5.24 (dd, J ) 15.2, 6.4 Hz, 1H),
5.10 (dd, J ) 15.2, 9.6 Hz, 1H), 4.08–3.99 (m, 3H), 3.82–3.78 (m,
1H), 3.75 (q, J ) 6.8 Hz, 1H), 2.85–2.77 (m, 2H), 2.31–2.20 (m,
3H), 1.96 (dd, J ) 16.0, 10.4 Hz, 1H), 1.93 (t, J ) 1.6 Hz, 1H),
1.83 (quintet, J ) 7.2 Hz, 1H), 1.68 (dt, J ) 14.0, 5.6 Hz, 1H),
1.60 (d, J ) 4.4 Hz, 1H), 1.19 (t, J ) 7.2 Hz, 3H), 1.06 (s, 9H),
1.04 (s, 9H); 13C NMR (CDCl3) δ u: 172.9, 134.3, 134.2, 134.0,
133.9, 80.4, 70.7, 60.3, 43.5, 33.8, 27.2, 19.2, 19.1; d: 135.93, 135.9,
135.82, 135.81, 133.8, 130.0, 129.7, 129.6, 129.56, 129.51, 127.6,
127.54, 127.5, 76.6, 76.5, 70.3, 52.2, 46.3, 27.0, 26.9, 14.2; HRMS
calcd for C47H58NaO5Si2 781.3720 (M + Na), found 781.3747.
Resolution of Racemic Alcohol 16a. To a stirred solution of
racemic alcohol 16a (1.04 g, 1.37 mmol) in vinyl acetate (28 mL)
was added Amano lipase AK (5.18 g, 5 mass equiv). The reaction
mixture was stirred at 55 °C (oil bath) for 20 h. The suspension
was filtered with MTBE, and the filtrate was concentrated under
reduced pressure. The residue was chromatographed to give acetate
(R)-21 (425 mg, 39% yield) and recovered alcohol 16a (620 mg)
as colorless syrups. The residual alcohol 16a was again subjected
to similar reaction conditions as given above to give (S)-16a (508
mg, 46% yield) accompanied by enriched (R)-21 (98 mg, 9% yield))
as colorless syrups. For (S)-16a: [R]D +17.0 (c 1.0, CH2Cl2). The
ee of (S)-16a was determined to be >99% by HPLC (column:
CHIRALCEL OD (Diacel Chemical Industry Ltd.); mobile phase:
0.5% 2-propanol in hexanes; flow: 1.0 mL/min; UV: 254 nm;
retention times: 15.7 min for (S)-16a and 18.7 min for (R)-16a)).
The other analytical data for (S)-16a were found to be identical
with those of the racemic 16.
Experimental Section
Ene Product 15. A solution of 14 (1.3 g, 1.60 mmol) in toluene
(26 mL) was taken up in a sealed tube and placed in a Parr pressure
reactor. Toluene (30 mL) was added to the reactor to maintain equal
pressure around the sealed tube, and the reactor was maintained at
200 °C for 24 h. The toluene was evaporated and the residue was
chromatographed to give 15 (1.12 g, 86% yield) as a colorless syrup;
TLC Rf 0.46 (10% MTBE/petroleum ether); IR (neat) 3070, 2930,
1743, 1111 cm-1; 1H NMR (CDCl3) δ 7.65–7.56 (m, 8H), 7.37–7.25
(m, 17H), 5.36 (dt, J ) 15.3, 5.8 Hz, 1H), 5.07 (dd, J ) 15.3, 9.8
Hz, 1H), 4.36 (s, 2H), 4.03 (dq, J ) 7.2, 3.2 Hz, 2H), 3.85–3.76
(m, 4H), 2.97–2.75 (m, 2H), 2.24 (dd, J ) 16.0, 5.4 Hz, 1H), 1.99
(dd, J ) 16.0, 9.8 Hz, 1H), 1.80 (quintet, J ) 7.2 Hz, 1H), 1.66
(dt, J ) 14.1, 4.8 Hz, 1H), 1.16 (t, J ) 7.2 Hz, 3H), 1.07 (s, 9H),
1.06 (s, 9H); 13C NMR (CDCl3) δ u:19 172.7, 138.4, 134.3, 134.2,
133.9, 71.6, 70.4, 60.2, 43.4, 33.6, 19.2, 19.1; d: 135.9, 135.84,
135.82, 130.8, 129.7, 129.6, 129.5, 129.4, 128.3, 127.7, 127.6,
127.53, 127.52, 127.5, 127.48, 76.6, 52.5, 46.3, 27.0, 26.9, 14.2;
HRMS calcd for C51H62NaO5Si2 833.4033 (M + Na), found
833.4023.
Allylic Alcohol 20. To a stirred solution of benzyl ether 15 (1.6
g, 1.97 mmol) in a mixture of 88% aqueous formic acid (6 mL)
and methanol (50 mL) was added 10% Pd/C (160 mg). After 24 h
at rt the catalyst was filtered off. The filtrate was concentrated and
the residue was chromatographed to yield 20 (743 mg, 78% yield
based on recovered starting material 15) as a colorless syrup,
accompanied by 15 (652 mg). For 20: TLC Rf 0.25 (30% MTBE/
petroleum ether); IR (neat) 3432, 3070, 2930, 1733 cm-1; 1H NMR
(CDCl3) δ 7.65–7.54 (m, 8H), 7.47–7.28 (m, 12H), 5.35 (dt, J )
15.2, 5.6 Hz, 1H), 5.01 (dd, J ) 15.2, 10.0 Hz, 1H), 4.02 (dq, J )
6.8, 1.2 Hz, 2H), 3.85 (d, J ) 5.6 Hz, 2H), 3.83–3.79 (m, 1H),
3.76 (q, J ) 6.8 Hz, 1H), 2.89 (app dt, J ) 9.2, 4.0 Hz, 1H),
2.83–2.76 (m, 1H), 2.20 (dd, J ) 16.0, 5.2 Hz, 1H), 1.93 (dd, J )
16.0, 10.0 Hz, 1H), 1.85 (quint, J ) 6.8 Hz, 1H), 1.69 (dt, J )
14.0, 5.6 Hz, 1H), 1.50 (br s, 1H), 1.18 (t, J ) 6.8 Hz, 3H), 1.06
(s, 9H), 1.04 (s, 9H); 13C NMR (CDCl3) δ u: 172.8, 134.3, 134.2,
134.1, 133.9, 63.3, 60.3, 43.5, 33.9, 19.2, 19.1; d: 136.0, 135.9,
135.8, 132.2, 129.7, 129.67, 129.61, 129.57, 129.51, 127.64, 127.57,
127.5, 127.4, 76.7, 76.6, 52.3, 46.4, 27.0, 26.9, 14.2; HRMS calcd
for C44H56NaO5Si2 743.3564 (M + Na), found 743.3565.
Racemic Alcohols 16a and 16b. To a stirred solution of allylic
alcohol 20 (1.1 g, 1.5 mmol) in CH2Cl2 (20 mL) was added
Dess-Martin periodinane (713 mg, 1.7 mmol) at rt. After being
(18) The intermediate ester 15 could also serve as a precursor for the synthesis
of other cis dialkyl cyclopentanes, including jasmonic acid and tuberonic acid.
For leading references to previous syntheses in these series, see: Nonaka, H.;
Wang, Y.-G.; Kobayashi, Y. Tetrahedron Lett. 2007, 48, 1745.
(19) 13C multiplicities were determined with the aid of a JVERT pulse
sequence, differentiating the signals for methyl and methine carbons as “d” from
methylene and quaternary carbons as “u”.
J. Org. Chem. Vol. 73, No. 9, 2008 3471

Taber et al.
Acetate (R)-21. TLC Rf 0.72 (30% MTBE/petroleum ether); [R]D
-9.8 (c 1.0, CH2Cl2); IR (neat) 3290, 2931, 1736, 1427 cm-1; 1H
NMR (CDCl3) δ 7.63–7.55 (m, 8H), 7.41–7.30 (m, 12H), 5.27 (dd,
J ) 15.2, 7.2 Hz, 1H), 5.18–5.12 (m, 2H), 4.06–3.97 (m, 2H), 3.82
(quintet, J ) 3.6 Hz, 1H), 3.75 (q, J ) 6.8 Hz, 1H), 2.95–2.89 (m,
1H), 2.84–2.79 (m, 1H), 2.41–2.30 (m, 2H), 2.20 (dd, J ) 16.0,
5.6 Hz, 1H), 1.99 (dd, J ) 16.0, 10.0 Hz, 1H), 1.98 (s, 3H), 1.87
(t, J ) 3.0 Hz, 1H), 1.80 (quintet, J ) 7.2 Hz, 1H), 1.66 (dt, J )
14.0, 5.0 Hz, 1H), 1.18 (t, J ) 7.2 Hz, 3H), 1.05 (s, 9H), 1.04 (s,
9H); 13C NMR (CDCl3) δ u: 172.6, 169.8, 134.3, 134.2, 133.9,
79.4, 70.5, 60.2, 43.4, 33.4, 24.6, 19.2, 19.1; d: 135.9, 135.8, 135.7,
132.1, 129.6, 129.57, 129.52, 129.5, 127.6, 127.53, 127.51, 127.5,
76.6, 76.4, 71.9, 52.5, 46.3, 27.0, 26.9, 21.1, 14.2; HRMS calcd
for C49H60NaO6Si2 823.3826 (M + Na), found 823.3848.
Alcohol (R)-16a. To a stirred solution of acetate (R)-21 (425
mg, 0.531 mmol) in ethanol (10 mL) was added K2CO3 (366 mg,
2.66 mmol). After the mixture was stirred at rt for 24 h it was
partitioned between water and MTBE. The combined organic extract
was dried (Na2SO4) and concentrated. The residue was chromato-
graphed to give (R)-16a (402 mg, quantitative yield) as a colorless
syrup. [R]D -17.3 (c 1.0, CH2Cl2). The ee of (R)-16a was
determined to be >99% by HPLC as described above (retention
times: 15.7 min for (S)-16a and 18.7 min for (R)-16a). The other
analytical data for (R)-16a were found to be identical with those
of the racemic 16a.
Resolution of Racemic Alcohol 16b. To a stirred solution of
racemic alcohol 16b (800 mg, 1.06 mmol) in vinyl acetate (21.6
mL) was added Amano lipase AK (4.0 g, 5 mass equiv). The
reaction mixture was stirred at 60 °C (oil bath) for 48 h. The
suspension was filtered with MTBE, and the filtrate was concen-
trated under reduced pressure. The residue was chromatographed
to give acetate (R)-22 (303 mg, 36% yield) and recovered alcohol
(S)-16b (458 mg, 57% yield) as colorless syrups. The ee of (S)-
16b was determined to be 84% by HPLC (column: CHIRALCEL
OD (Diacel Chemical Industry Ltd.); mobile phase: 0.5% 2-propanol
in hexanes; flow: 1.0 mL/min; UV: 254 nm; retention times: 16.8
min for (R)-16b and 21.9 min for (S)-16b). The other analytical
data for (R)-16b were found to be identical with those of the racemic
16b.
zoic acid (202 mg, 1.2 mmol) and PPh3 (472 mg, 1.8 mmol). The
reaction flask was then wrapped with aluminum foil, and then a
40% w/w solution of DEAD in toluene (783 mg, 1.8 mmol) was
added. After 1 h at rt, the toluene was evaporated and the residue
was chromatographed to give the 4-nitrobenzoate 23 (360 mg, 66%
yield) as a white foamy solid; TLC Rf 0.69 (30% MTBE/petroleum
ether); IR (neat) 3299, 2934, 1729, 1269 cm-1; 1H NMR (CDCl3)
δ 8.29 (d, J ) 8.8 Hz, 2H), 8.15 (d, J ) 8.8 Hz, 2H), 7.66–7.54
(m, 8H), 7.44–7.25 (m, 12H), 5.45–5.38 (m, 2H), 5.31 (ddd, J )
18.4, 9.2, 4.0 Hz, 1H), 4.15–4.00 (m, 2H), 3.85 (dt, J ) 6.8, 4.0
Hz, 1H), 3.78 (q, J ) 7.2, 1H), 2.96 (dt, J ) 9.8, 3.6 Hz, 1H),
2.88–2.81 (m, 1H), 2.55 (dd, J ) 5.6, 2.4 Hz, 2H), 2.25 (dd, J )
16.0, 5.6 Hz, 1H), 2.01 (dd, J ) 16.0, 10.0 Hz, 1H), 1.94 (t, J )
2.6 Hz, 1H), 1.85 (quintet, J ) 7.2 Hz, 1H), 1.69 (dt, J ) 14.4, 5.2
Hz, 1H), 1.21 (t, J ) 7.2 Hz, 3H), 1.08 (s, 9H), 1.03 (s, 9H); 13C
NMR (CDCl3) δ u: 172.5, 163.5, 150.6, 135.6, 134.2, 134.0, 133.9,
78.9, 71.0, 60.2, 43.4, 33.5, 24.7, 19.2, 19.1; d: 135.9, 135.83,
135.82, 135.8, 133.5, 130.8, 129.7, 129.6, 129.5, 129.46 128.8,
127.6, 127.55, 127.48, 127.5, 123.5, 76.5, 76.3, 73.7, 52.4, 46.4,
27.0, 26.9, 14.1; HRMS calcd for C54H61NNaO8Si2 930.3833 (M
+ Na), found 930.3865.
To a stirred solution of 4-nitrobenzoate 23 (360 mg, 0.4 mmol)
in ethanol (10 mL) was added K2CO3 (274 mg, 1.98 mmol). After
the mixture was stirred at rt for 24 h, it was partitioned between
water and MTBE. The combined organic extract was dried (Na2SO4)
and concentrated. The residue was chromatographed to give
enriched (R)-16a (297 mg, 99% yield) as a colorless syrup.
Resolution of the above enriched (R)-16a with Amano lipase AK
(1.49 g, 5 mass equiv) and vinyl acetate (8 mL) followed by
hydrolysis of the acetate in the same manner as described for
racemic 16a afforded again (R)-16a (223 mg, 75% yield), [R]D
-17.5 (c 1.0, CH2Cl2). The ee of (R)-16a was determined to be
>99% by HPLC (as described above).
Mitsunobu inversion of (R)-16a followed by hydrolysis in the
same manner as described for enriched (S)-16b again gave (S)-
16b (152 mg, 68% yield, 2 steps). [R]D -18.2 (c 1.0, CH2Cl2).
The ee of (S)-16b was determined to be >99% by HPLC (as
described above). The other analytical data for (S)-16b were found
to be identical with those of the racemic 16b.
Acetate (R)-22. TLC Rf 0.71 (30% MTBE/petroleum ether);
[R]D +28.5 (c 1.0, CH2Cl2); IR (neat) 3292, 2931, 1737, 1427 cm-1
;
Alkyne (S)-24a. To a stirred solution of (S)-16a (508 mg, 0.67
mmol) in THF (3.4 mL) was added a 1 M solution of LAH in
THF (0.7 mL, 0.70 mmol) at 0 °C. After being stirred for 2 h the
reaction was quenched with saturated aqueous Na2SO4 (0.5 mL),
the white solid was filtered with MTBE, and the filtrate was
concentrated to give the diol (455 mg, 95% yield) as a colorless
syrup; TLC Rf 0.15 (50% MTBE/petroleum ether); [R]D +10.0 (c
1.0, CH2Cl2); IR (neat) 3305, 2930, 1427 cm-1; 1H NMR (CDCl3)
δ 7.67–7.60 (m, 6H), 7.57–7.43 (m, 2H), 7.42–7.28 (m, 12H), 5.25
(dd, J ) 15.2, 6.4 Hz, 1H), 5.15 (dd, J ) 15.2, 9.4, 1H), 4.03
(quintet, J ) 5.2 Hz, 1H), 3.90–3.82 (m, 2H), 3.41 (app q, J ) 5.6
Hz, 2H), 2.76–2.71 (m, 1H), 2.30 (quintet, J ) 7.2 Hz, 1H), 2.28
(dd, J ) 6.0, 2.8 Hz, 2H), 1.95 (t, J ) 2.8 Hz, 1H), 1.84 (quintet,
J ) 7.2 Hz, 1H), 1.69 (dt, J ) 14.4, 4.4 Hz, 1H), 1.64 (d, J ) 4.4
Hz, 1H), 1.38–1.32 (m, 3H), 1.07 (s, 9H), 1.05 (s, 9H); 13C NMR
(CDCl3) δ u: 134.4, 134.3, 134.2, 134.1, 80.5, 70.7, 61.7, 43.5,
31.7, 27.4, 19.2, 19.1; d: 135.94, 135.91, 135.89, 135.85, 133.3,
130.6, 129.7, 129.6, 129.59, 129.5, 127.6, 127.56, 127.54, 127.52,
77.7, 77.2, 70.5, 53.0, 46.8, 27.0, 26.9; HRMS calcd for
C45H56NaO4Si2 739.3615 (M + Na), found 739.3609.
1H NMR (CDCl3) δ 7.64–7.54 (m, 8H), 7.39–7.29 (m, 12H),
5.21–5.19 (m, 2H), 5.13–5.09 (m, 1H), 4.09–3.97 (m, 2H), 3.82
(q, J ) 3.6 Hz, 1H), 3.78 (dd, J ) 13.2, 7.2 Hz, 1H), 2.91–2.86
(m, 1H), 2.85–2.77 (m, 1H), 2.38–2.27 (m, 2H), 2.22 (dd, J ) 16.0,
5.2 Hz, 1H), 2.00 (s, 3H), 1.98 (dd, J ) 16.8, 9.6 Hz, 1H), 1.84 (t,
J ) 2.8 Hz, 1H), 1.80 (quintet, J ) 7.2 Hz, 1H), 1.66 (dt, J )
14.0, 4.8 Hz, 1H), 1.18 (t, J ) 7.2 Hz, 3H), 1.06 (s, 9H), 1.04 (s,
9H); 13C NMR (CDCl3) δ u: 172.6, 169.0, 134.3, 134.2, 134.0,
133.9, 79.4, 70.5, 60.1, 43.4, 33.4, 24.5, 19.2, 19.1; d: 135.9, 135.88,
135.84, 135.8, 132.7, 129.6, 129.56, 129.5, 129.2, 127.6, 127.5,
127.4, 76.6, 76.5, 71.8, 52.3, 46.4, 21.1, 14.2; HRMS calcd for
C49H60NaO6Si2 823.3826 (M + Na), found 823.3808.
Alcohol (R)-16b. To a stirred solution of acetate (R)-22 (304
mg, 0.38 mmol) in ethanol (7.5 mL) was added K2CO3 (262 mg,
1.9 mmol). After the mixture was stirred at rt for 12 h it was
partitioned between water and MTBE. The combined organic extract
was dried (Na2SO4) and concentrated. The residue was chromato-
graphed to give (R)-16b (288 mg, quantitative yield) as a colorless
syrup. [R]D +19.0 (c 1.0, CH2Cl2). The ee of (R)-16b was
determined to be >99% by HPLC (column: CHIRALCEL OD
(Diacel Chemical Industry Ltd.); mobile phase: 0.5% 2-propanol
in hexanes; flow: 1.0 mL/min; UV: 254 nm; retention times: 16.8
min for (R)-16b and 21.9 min for (S)-16b). The other analytical
data for (R)-16b were found to be identical with those of the racemic
16.
To a stirred solution of crude diol (455 mg, 0.64 mmol) in
CH2Cl2 (1.8 mL) was added Et3N (0.22 mL, 1.59 mmol) followed
by TsCl (133 mg, 0.70 mmol) and a catalytic amount of DMAP (5
mg). After being stirred for 24 h the mixture was partitioned
between water and CH2Cl2. The combined organic extract was dried
(Na2SO4) and concentrated. The residue was chromatographed to
give the monotosylate (310 mg, 56% yield) as a foamy solid; TLC
Rf 0.65 (50% MTBE/petroleum ether); [R]D +16.9 (c 1.0, CH2Cl2);
Alcohol (S)-16b (using double Mitsunobu inversion of alco-
hol (S)-16b with 84% ee). To a stirred solution of enriched (S)-
16b (458 mg, 0.6 mmol) in toluene (6 mL) were added 4-nitroben-
IR (neat) 3293, 2930, 1427 cm-1
.
3472 J. Org. Chem. Vol. 73, No. 9, 2008

A Potential Route to Neuroprostanes and Isoprostanes
To a stirred solution of the monotosylate (310 mg, 0.36 mmol)
in THF (2.0 mL) was added a 1 M solution of LiEt3BH in THF
(3.56 mL, 3.56 mmol). After the mixture was stirred at rt for 3 h
it was partitioned between water and MTBE. The combined organic
extract was dried (Na2SO4) and concentrated. The residue was
chromatographed to give (S)-24a (207 mg, 42% yield from (S)-
16a) as a colorless syrup; TLC Rf 0.81 (30% MTBE/petroleum
ether); [R]D +10.0 (c 1.0, CH2Cl2); IR (neat) 3307, 2930, 1427
3439 cm-1; 1H NMR (CDCl3) δ 7.66–7.63 (m, 6H), 7.60–7.57 (m,
2H), 7.41–7.31 (m, 12H), 5.27 (dd, J ) 15.2, 6.4 Hz, 1H), 5.15
(dd, J ) 15.2, 9.6 Hz, 1H), 4.03 (quintet, J ) 6.0 Hz, 1H),
3.88–3.81 (m, 2H), 2.81–2.76 (m, 1H), 2.28–2.26 (m, 2H), 2.13
(quintet, J ) 7.2 Hz, 1H), 1.95 (t, J ) 2.8 Hz, 1H), 1.87 (quintet,
J ) 7.2 Hz, 1H), 1.67 (dt, J ) 14.4, 4.0 Hz, 1H), 1.52 (d, J ) 4.4
Hz, 1H), 1.17–0.99 (m, 2H), 1.07 (s, 9H), 1.06 (s, 9H), 0.66 (t, J
) 7.2 Hz, 3H); 13C NMR (CDCl3) δ u: 134.6, 134.4, 134.33, 134.3,
80.5, 70.6, 43.7, 27.4, 21.1, 19.3, 19.2; d: 136.0, 135.94, 135.9,
132.7, 131.0, 129.6, 129.52, 129.5, 129.47, 127.5, 77.2, 77.1, 70.7,
52.6, 52.2, 27.1, 27.0, 12.5; HRMS calcd for C45H56NaO3Si2
723.3666 (M + Na), found 723.3645.
2.33–2.21 (m, 2H), 2.14 (quintet, J ) 7.2 Hz, 1H), 1.85 (quintet,
J ) 7.2 Hz, 1H), 1.67 (dt, J ) 14.4, 4.0 Hz, 1H), 1.62 (d, J )
4.4 Hz, 1H), 1.25 (t, J ) 7.2 Hz, 3H), 1.16–0.98 (m, 2H), 1.07
(s, 9H), 1.06 (s, 9H), 0.66 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3)
δ u: 172.12, 134.7, 134.4, 134.35, 134.3, 80.4, 79.7, 78.1, 77.9,
60.6, 43.7, 34.0, 28.0, 21.7, 21.6, 21.1, 19.2, 19.1, 14.8; d:
135.94, 135.92, 135.9, 133.2, 130.5, 129.52, 129.50, 129.46,
129.44, 127.5, 126.2, 126.0, 77.3, 77.2, 71.0, 52.7, 52.2, 27.0,
26.9, 14.3, 12.5; HRMS calcd for C56H70NaO5Si2 901.4659 (M
+ Na), found 901.4641.
Tetraene (S)-31a. To a stirred suspension of Ni(OAc)2 ·4H2O
(312 mg, 1.25 mmol) in ethanol (1.0 mL) was added a 1 M solution
of NaBH4 in ethanol (2.5 mL, 2.5 mmol) under an H2 atmosphere.
After the black suspension was stirred for 5 min, ethylenediamine
(83 mg, 1.38 mmol) was added followed by (S)-35a (110 mg, 0.125
mmol) in ethanol (0.5 mL). The reaction flask was evacuated and
purged with H2 three times and then H2 gas was bubbled through
the stirring solution for 5 min. The reaction mixture was stirred
under H2 atmosphere for 30 min, and then filtered through a pad
of silica gel with MTBE. The filtrate was concentrated and the
residue was chromatographed to give (S)-31a (85 mg, 77% yield)
as a colorless oil. TLC Rf 0.35 (15% MTBE/petroleum ether); [R]D
+4.6 (c 1.0, CH2Cl2); IR (neat) 3469, 2958, 2931, 1734 cm-1; 1H
NMR (CDCl3) δ 7.67–7.63 (m, 6H), 7.62–7.58 (m, 2H), 7.43–7.29
(m, 12H), 5.49–5.27 (m, 6H), 5.24 (dd, J ) 15.2, 6.4, Hz, 1H),
5.09 (dd, J ) 15.2, 9.8 Hz, 1H), 4.11 (q, J ) 7.2 Hz, 2H), 3.90–3.81
(m, 3H), 2.80–2.74 (m, 3H), 2.72–2.69 (m, 2H), 2.38–2.31 (m, 4H),
2.23–2.07 (m, 3H), 1.86 (quintet, 7.2 Hz, 1H), 1.67 (dt, J ) 14.4,
4.0 Hz, 1H), 1.27 (d, J ) 3.6 Hz, 1H), 1.24 (t, J ) 7.2 Hz, 3H),
1.18–1.09 (m, 1H), 1.08 (s, 9H), 1.06 (s, 9H), 1.03–0.98 (m, 1H),
0.66 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3) δ u: 173.2, 134.7,
134.5, 134.4, 134.3, 60.4, 43.8, 35.1, 34.3, 30.6, 30.3, 22.8, 21.1,
19.3, 19.2; d: 136.0, 135.9, 134.4, 130.6, 129.8, 129.54, 129.52,
129.49, 129.46, 129.0, 128.7, 128.67, 128.2, 128.0, 127.9, 127.7,
127.5, 127.2, 125.4, 77.4, 77.3, 72.3, 52.7, 52.2, 27.1, 27.0, 14.3,
12.5; HRMS calcd for C56H74NaO5Si2 905.4972 (M + Na), found
905.4979.
Triol (S)-36a. A solution of tetraene (S)-31a (70 mg, 0.079 mmol)
in THF (0.1 mL) was treated with a 1 M solution of TBAF in THF
(0.79 mL, 0.79 mmol) and the mixture was stirred for 72 h. The
reaction mixture was partitioned between EtOAc and water. The
combined organic extract was dried (Na2SO4) and concentrated.
The residue was chromatographed to give (S)-36a (24 mg, 75% yield)
as a colorless oil. TLC Rf 0.16 (EtOAc); [R]D +3.7 (c 1.0, CH2Cl2);
IR (neat) 3344, 2958, 2927, 1733 cm-1; 1H NMR (CDCl3) δ 5.57
(dd, J ) 15.2, 7.2 Hz, 1H), 5.52–5.35 (m, 7H), 4.12 (q, J ) 7.2
Hz, 2H), 4.09 (q, J ) 6.8 Hz, 1H), 3.99–3.93 (m, 2H), 2.79–2.71
(m, 5H), 2.6–3.4 (broad, 3H), 2.46–2.21 (m, 6H), 2.28–2.22 (m,
1H), 2.00–1.94 (m, 1H), 1.63 (dt, J ) 14.4, 4.0 Hz, 1H), 1.39–1.21
(m, 2H), 1.23 (t, J ) 6.8 Hz, 3H), 0.92 (t, J ) 7.2 Hz, 3H); 13C
NMR (CDCl3) δ u: 173.3, 60.4, 42.5, 35.3, 34.3, 30.6, 30.3, 22.7,
21.9; d: 135.0, 130.7, 129.9, 129.0, 128.8, 128.6, 128.2, 125.3, 76.4,
76.3, 72.5, 53.5, 52.4, 14.2, 12.8; HRMS calcd for C24H38NaO5
429.2617 (M + Na), found 429.2625.
Bromoester 34. To a stirred solution of ethyl-4-pentynoate
(1.09 g, 7.94 mmol) in DMF (8 mL) were added K2CO3 (2.41
g, 17.5 mmol), NaI (2.63 g, 17.5 mmol), and CuI (1.58 g, 8.34
mmol). After the mixture was stirred for 30 min at rt, cis-4-
chloro-2-buten-1-ol (1.27 g, 11.9 mmol) was added and the
stirring was continued for an additional 24 h. The reaction
mixture quenched with saturated aqueous NH4Cl and then
partitioned between water and MTBE. The combined organic
extract was dried (Na2SO4) and concentrated. The residue was
chromatographed to give the alcohol 33 (680 mg, 44% yield) as
a colorless liquid. TLC Rf 0.35 (30% MTBE/petroleum ether);
1
IR (neat) 3414, 2982, 2924, 1732 cm-1; H NMR (CDCl3) δ
5.88 (dtt, J ) 15.2, 5.6, 1.6 Hz, 1H), 5.68 (dtt, J ) 15.2, 5.2,
1.6 Hz, 1H), 4.16 (q, J ) 7.2 Hz, 2H), 4.13 (dq, J ) 7.2, 1.2
Hz, 2H), 2.93 (dt, J ) 5.2, 1.6 Hz, 2H), 2.55–2.46 (m, 4H),
1.99 (s, 1H), 1.27 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3) δ u:
172.2, 80.6, 77.6, 63.0, 60.6, 33.9, 21.6, 14.7; d: 130.5, 126.7,
14.2; HRMS calcd for C11H17O3 197.1178 (M + H+), found
197.1178.
To a stirred solution of alcohol 33 (175 mg, 1.34 mmol) in
CH2Cl2 (5 mL) was added PPh3 (351 mg, 1.34 mmol). The mixture
was cooled to 0 °C. CBr4 (444 mg, 1.34 mmol) was then added
portionwise over 5 min and the mixture was stirred at 0 °C for 1 h.
The reaction mixture was concentrated and the residue was
chromatographed to give bromoester 34 (172 mg, 74% yield) as a
colorless liquid. TLC Rf 0.81 (30% MTBE/petroleum ether); IR
(neat) 2980.9, 1734.4 1170.3 cm-1 1H NMR (CDCl3) δ 5.96
;
(tqunitet, J ) 7.6, 1.8 Hz, 1H), 5.74 (dtt, J ) 15.2, 5.2, 1.2 Hz,
1H), 4.16 (q, J ) 7.2 Hz, 2H), 3.97 (ddd, J ) 7.2, 1.6, 0.8 Hz,
2H), 2.96–2.94 (m, 2H), 2.52–2.51 (m, 4H), 1.27 (t, J ) 7.2 Hz,
3H); 13C NMR (CDCl3) δ u: 172.1, 81.2, 76.8, 60.6, 33.9, 32.4,
21.6, 14.8; d: 130.4, 127.6, 14.3; HRMS calcd for C11H16BrO2 (Br
) 79) 259.0334 (M + H+), found 259.0329.
Dienediyne (S)-35a. To a stirred solution of (S)-24a (172 mg,
0.25 mmol) in DMF (0.3 mL) were added K2CO3 (136 mg, 0.98
mmol), NaI (148 mg, 0.98 mmol), and CuI (98 mg, 0.52 mmol)
at rt. After the mixture was stirred for 30 min bromoester 34
(127 mg, 0.49 mmol) was added. The reaction mixture was
stirred for 48 h and then partitioned between MTBE and,
sequentially, aqueous NH4Cl and water. The combined organic
extract was dried (Na2SO4) and concentrated. The residue was
chromatographed to afford (S)-35a (110 mg, 51% yield) as a
colorless oil. TLC Rf 0.20 (15% MTBE/petroleum ether); [R]D
13-epi-ent-13-F4t-NeuroP (S)-4a. To a stirred solution of (S)-
36a (24 mg, 0.059 mmol) in THF (1.2 mL) was added a solution
of LiOH·H2O (49.5 mg, 1.18 mmol) in water (1.2 mL) at rt. After
being stirred for 10 h the mixture was acidified to pH 2.0 and then
partitioned between water and EtOAc. The combined organic extract
was dried (Na2SO4) and concentrated. The residue was chromato-
graphed with a 75–100% EtOAc/PE gradient to give (S)-4a (22
mg, quantitative) as a colorless oil. TLC Rf 0.03 (EtOAc); [R]D
+18.8 (c 1.0, MeOH); IR (neat) 3333, 2928, 1710 cm-1; 1H NMR
(acetone-d6) δ 5.57 (dd, J ) 15.2, 6.4 Hz, 1H), 5.53–5.40 (m, 7H),
4.09 (q, J ) 6.4 Hz, 1H), 3.94 (dt, J ) 7.2, 3.8 Hz, 1H), 3.88 (q,
J ) 6.8 Hz, 1H), 2.85–2.74 (broad, 4H), 2.68 (app dt, J ) 13.2,
3.6 Hz, 1H), 2.46–2.23 (m, 7H), 1.98 (quintet, J ) 7.6 Hz, 1H),
1.57 (dt, J ) 14.0, 4.8 Hz, 1H), 1.46–1.30 (m, 2H), 0.93 (t, J )
+11.2 (c 1.0, CH2Cl2); IR (neat) 3501, 2931, 2858, 1735 cm-1
;
1H NMR (CDCl3) δ 7.67–7.63 (m, 6H), 7.62–7.58 (m, 2H),
7.43–7.29 (m, 12H), 5.67–5.57 (m, 2H), 5.26 (dd, J ) 15.6, 6.2
Hz, 1H), 5.14 (dd, J ) 15.6, 9.8 Hz, 1H), 4.15 (q, J ) 7.2 Hz,
2H), 4.00 (quintet, J ) 5.6 Hz, 1H), 3.88–3.83 (m, 2H),
2.94–2.83 (m, 4H), 2.82–2.75 (m, 1H), 2.52–2.47 (m, 4H),
J. Org. Chem. Vol. 73, No. 9, 2008 3473

Taber et al.
7.4 Hz, 3H); 13C NMR (CDCl3) δ u: 173.8, 43.7, 36.0, 33.9, 30.9,
30.5, 23.0, 22.1; d: 135.7, 129.5, 129.3, 129.2, 129.1, 129.0, 127.0,
76.0, 75.9, 72.4, 53.6, 52.0, 12.8; HRMS calcd for C22H34NaO5
401.2304 (M + Na), found 401.2318.
Supporting Information Available: General experimental
procedures, experimental procedures, and spectra for all new
compounds, and details of the X-ray structure of the tris-4-
bromobenzoate derived from (R)-16a. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the National Institutes of Health
(GM42056) for support of this work.
JO702600V
3474 J. Org. Chem. Vol. 73, No. 9, 2008