A divergent synthesis of the Δ13-9-isofurans

Article abstract of DOI:10.1021/jo900767x

(Chemical Equation Presented) A stereodivergent total synthesis of the Δ¹³-9-isofurans has been developed. The four core substituted tetrahydrofurans were prepared by the Sharpless asymmetric epoxidation and Sharpless asymmetric dihydroxylation

Full text of DOI:10.1021/jo900767x

pubs.acs.org/joc
A Divergent Synthesis of the Δ13-9-Isofurans
Douglass F. Taber,* Peiming Gu, and Rui Li
Department of Chemistry and Biochemistry, University of Delaware, Newark,
Delaware 19716
taberdf@udel.edu
Received April 15, 2009
A stereodivergent total synthesis of the Δ13-9-isofurans has been developed. The four core substituted
tetrahydrofurans were prepared by the Sharpless asymmetric epoxidation and Sharpless asymmetric
dihydroxylation followed by cascade cyclization. The relative configuration at C-8 was inverted by
oxidation followed by immediate L-Selectride reduction. The relative configuration of the C-15 diaster-
eomers was assigned by (S)-Binol/LAH/EtOH reduction of the corresponding enone. This synthesis of the
Δ13-9-isofurans will provide sufficient material for further investigation of their biological activity.
Introduction
The isofurans (Figure 1), represented by SC-Δ13-9-IsoF
1aaa, are produced by human metabolism of arachidonic
acid.1,2 Previously,3 we prepared the two diastereomeric
isofurans that we judged were the closest in structure to the
enzymatically produced human hormone PGF2R. One of the
diastereomers was found to have significant bioactivity. On re-
preparation, however, no bioactivity was observed. Suspecting
that the initially observed bioactivity might have been due to a
minor contaminating diastereomer, we have developed a gene-
ral strategy for the preparation of each of the 32 of the enan-
tiomerically pure (ep) diastereomers of the Δ13-9-isofurans. As
the previous route to the isofurans had suffered from poor
regioselectivity in the dihydroxylation step, we have devised an
improved and much more robust route to the isofurans.
FIGURE 1. There are 32 ep diastereoisomers of SC-Δ13-9-IsoF.
(ep) diastereomers could be prepared by branching from
advanced intermediates. The eight substituted tetrahydro-
furans 2a-h (Scheme 1) would each lead to four of the final
32 diastereomers. The four intermediates 2a-d were to be
prepared from the previously unknown monotrityl ether
3 by Sharpless asymmetric epoxidation (SAE)4 followed
by Sharpless asymmetric dihydroxylation (SAD).3,5 We
planned to prepare the tetrahydrofurans 2e-h from the
Results and Discussion
Our interest was to develop a stereodivergent route to the
Δ13-9-isofurans, such that each of the enantiomerically pure
(1) (a) Fessell, J. P.; Porter, N. A.; Moore, K. P.; Sheller, J. R.; Roberts,
L. J. II. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 16713. (b) For a recent review,
see: John,U.;Galano,J.-M.;Durand, T.Angew.Chem., Int.Ed. 2008, 47, 5894.
(2) For a detailed account of isofuran nomenclature, see: Taber, D. F.;
Morrow, J. D.;Roberts, L. J. ProstaglandinsOther Lipid Mediators2004, 73, 47.
(3) (a) Taber, D. F.; Pan, Y.; Zhao, X. J. Org. Chem. 2004, 69, 7234.
(b) Taber, D. F.; Zhang, Z. J. Org. Chem. 2006, 71, 926.
(4) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
(5) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M; Xu, D.;
Zhang, X. L. J. Org. Chem. 1992, 57, 2768. (b) Xu, D.; Crispino, G. A.;
Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7570. (c) Kolb, H. C.;
VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
5516 J. Org. Chem. 2009, 74, 5516–5522
Published on Web 07/02/2009
DOI: 10.1021/jo900767x
r
2009 American Chemical Society

Taber et al.
JOCArticle
intermediates 2a-d by Mitsunobu esterification3,6 followed
by hydrolysis.
SCHEME 1
For this approach to the isofurans to be successful, there
were three central issues to be addressed (eq 1): (1) Would the
asymmetric dihydroxylation of the epoxy sulfonate derived
from 3 show matched vs unmatched diastereoselectivity? (2)
Could the stereocenters at C-8 and C-11 be inverted without
elimination? (3) Could the anticipated C-15 allylic alcohol
diastereomers be separated?
Preparation of the Monotrityl Ether 3. We prepared 3
(Scheme 2) from methyl 4-bromocrotonate 5. Reduction
by LiAlH4/AlCl37 afforded the allylic alcohol 6. This alcohol
were coupled8 with propargyl alcohol to give a mixture (2:1)
of the linear product 7a and the branched product 7b that
were not easily separable. The mixture was submitted to
LiAlH4 reduction to give the diols 8a and 8b. After protec-
tion with TrCl, the monoether 3 was readily purified.
Preparation of the Four Core Tetrahydrofurans. The
monoether 3 was first carried on (Scheme 3, Table 1) to the
epoxy alcohol 9a by Sharpless asymmetric epoxidation with
the adjunct D-diethyl tartrate (D-DET) (Scheme 3). The
derived benzenesulfonate 10a was subjected to the Sharpless
asymmetric dihydroxylation with AD-mix followed by direct
treatment with K2CO3 in MeOH3,9 to give the cyclized
product. Using D-DET in the Sharpless asymmetric epoxida-
tion, when AD-mix R was employed (entry 1), it gave a 3:1
mixture of diastereomers that were not readily separable by
silica gel chromatography. We were pleased to observe that
the two diastereomers were readily separable after silylation
of the secondary hydroxyl group, leading to 2a and 2b. The
structure of 2a was confirmed by X-ray analysis of the
crystalline free alcohol (11a, Scheme 4). Alternatively, when
AD-mix β was used (entry 2), primarily (>9:1) the single
diastereomer 2b was found. Similarly, using L-DET in the
Sharpless asymmetric epoxidation and AD-mix R in the
dihydroxylation (entry 4) delivered primarily (>9:1) the
diastereomer 2d, whereas L-DET followed by AD-mix
β (entry 3) gave a 2:1 mixture of diastereomers of 2c
and 2d. Note that the major diastereomers prepared this
way showed >99% ee (chiral HPLC), while the minor
SCHEME 2
diastereomers (entry 1, entry 3) were about 67% ee and
53% ee, respectively (chiral HPLC). Only the high ee dia-
stereomers were carried on in the synthesis.
Inversion of the C-11 Stereochemistry. To achieve stereo-
divergence, it was necessary to invert the alcohols at C-11
(isofuran numbering, Scheme 4). Deprotection of the silyl
group of 2a with TBAF gave the free alcohol 11a. The
secondary alcohol at C-11 participated efficiently in Mitsuno-
bu esterification6 to give, after methanolysis, the inverted
(6) (a) Mitsunobu, O. Synthesis 1981, 1 and references cited therein .
(b) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
(7) (a) Jorgenson, M. J. Tetrahedron Lett. 1962, 559. (b) Brown, H. C.;
Hess, H. M. J. Org. Chem. 1969, 34, 2206.
(8) Taber, D.; Green, J. H.; Zhang, W.; Song, R. J. Org. Chem. 2000, 65,
5436.
(9) (a) For the development of this strategy, see: Taber, D. F.; Bhami-
dipati, R. S.; Thomas, M. L. J. Org. Chem. 1994, 59, 3442. (b) For a related
acid-catalyzed cyclization, see: Sivakumar, M.; Borhan, B. Tetrahedron Lett.
€
2003, 44, 5547. (c) For a recent application, see: Aho, J. E.; Salomaki, E.;
Rissanen, K.; Pihko, P. M. Org. Lett. 2008, 10, 4179.
J. Org. Chem. Vol. 74, No. 15, 2009 5517

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SCHEME 3
SCHEME 5
TABLE 1. Tetrahydrofurans by Sequential SAE and SAD
yielda (%)
SCHEME 6
entry
SAE
SAD
products
ratio
1
2
3
4
D-DET
D-DET
L-DET
L-DET
AD-mix R
AD-mix β
AD-mix β
AD-mix R
2a/2b
2b
2c/2d
2d
3:1
>9:1
2.2:1
>9:1
66
57
54
62
aCombined yield of the two diastereomers.
SCHEME 4
alcohol 13ab. Protection of 13ab with TBS gave the diaster-
eomer 4ab.
Construction of the Lower Side Chain. The next step in the
synthesis was the removal of the trityl group from 4aa
(Scheme 7). Formic acid13 worked well with 4aa but de-
stroyed 4ab. Deprotection of 4aa with 3 equiv of Et2AlCl at
-50 °C14 gave the desired alcohol 14aa accompanied by
some unidentified impurities. Fortunately, deprotection
of 4aa and related compounds with 5 equiv of Et2AlCl at
-78 °C for 10 min gave clean conversion to the primary
alcohol. Dess-Martin oxidation12 of the alcohol 14aa af-
forded the aldehyde. Horner-Emmons condensation of the
aldehyde with commercial dimethyl 2-oxoheptylphospho-
nate 15 gave the enone 16aa. Luche reduction15 of the enone
gave the allylic alcohols 17aaa and 17aab in a ratio of about
1:1. We were pleased to observe that these two diastereomers
were readily separable by silica gel chromatography.
Assignment of the C-15 Absolute Configuration. The enone
16aa (Scheme 7) was also reduced with LiAlH4/(S)-Binol/EtOH
at -100 °C, that was expected16 to give predominantly 17aaa.
alcohol 11e. Protection of 11e with TBS gave the tetrahydro-
furan diastereomer 2e. Similarly, 2b-d were converted to 2f-h.
Construction of the Upper Side Chain. Lewis acid BF3
3
OEt2-assisted10 opening (Scheme 5) of the epoxide 2a with
the lithium anion derived from the commercially available
4-pentynenitrile at low temperature gave efficient conversion
to the alkyne 12a. Partial hydrogenation using P-2 Ni
catalyst11 afforded the cis-alkene 13aa. Protection of 13aa
with TBS resulted in the trityl ether 4aa.
Inversion of the C-8 Stereochemistry. When Mitsunobu
inversion was attempted with alcohol 13aa (Scheme 6),
predominantly dehydration was observed. Fortunately,
oxidation12 followed by immediate L-Selectride reduction
of the alcohol 13aa gave predominantly the inverted
(13) Bessodes, M.; Komiotis, D.; Antonakis, K. Tetrahedron Lett. 1986,
27, 579.
(14) Koster, H.; Sinha, N. D. Tetrahedron Lett. 1982, 23, 2641.
(15) Germal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454.
(16) Noyori, R.; Tomino, I.; Yamada, M.; Nishizawa, M. J. Am. Chem.
Soc. 1984, 106, 6717.
(10) Sinha, S. C.; Keinan, E. J. Org. Chem. 1999, 64, 7067.
(11) Brown, C. A.; Ahuja, V. K. J. Chem. Soc., Chem. Commun. 1973,
553.
(12) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
5518 J. Org. Chem. Vol. 74, No. 15, 2009

Taber et al.
JOCArticle
SCHEME 7
18aab. Both 1aaa and 1aab and the methyl ester 18aab were
found to be congruent (1H, 13C NMR, [R]D) to the sub-
stances that we had previously3a prepared.
Using this approach, we have prepared all 32 of the
enantiomerically pure diastereomers of Δ13-9-IsoF. The full
experimental details for the preparation of a representative
six more of those diastereomers are included in the Support-
ing Information, along with physical characteristics and
spectroscopic data for each of the other 31 enantiomerically
pure diastereomers of the Δ13-9-isofurans.
Conclusion
We have developed a general route to the enantiomerically
pure diastereomers of Δ13-9-IsoF. The four key intermedi-
ates 2a-d were obtained by Sharpless asymmetric epoxida-
tion and Sharpless dihydroxylation, followed by cascade
cyclization. Mitsunobu inversion of each of these four key
intermediates (2a,b) gave the other four diastereomers (2e-
h). This approach has made each of the 32 ep diastereomers
of Δ13-9-IsoF, previously known only in microgram quan-
tities as mixtures, available in sufficient quantity to assess the
individual physiological activity of each. We believe that the
robust synthetic approach outlined here will allow ready
access both to the other regioisomeric isofurans and to the
neurofurans.18,19
SCHEME 8
Experimental Section
((2R,3R)-3-((E)-4-trityloxybut-2-enyl)oxiran-2-yl)methanol
(9a). To a stirred solution of diethyl D-tartrate (680 mg,
3.3 mmol) in CH2Cl2 (150 mL) was added Ti(OiPr)4 (924 mg,
3.3 mmol) at - 30 to - 20 °C. The reaction mixture was stirred
for 30 min at this temperature, and then a solution of 3 (1.11 g,
3.0 mmol) in CH2Cl2 (18 mL) was added over a period of 15 min.
After an additional 30 min at - 30 to -20 °C, tBuOOH (4.7 M in
CH2Cl2, 1.7 mL, 8.0 mmol) was added dropwise over a period of
5 min. The reaction mixture was stirred for 3 h at - 30 to -20 °C.
Aqueous L-(þ) tartaric acid (10%, 6 mL) was added, and then
the reaction mixture was stirred at -20 °C for 25 min, allowed to
warm to rt, and stirred for 40 min. Aqueous NaOH (1 N, 18 mL)
was added at 0 °C, and the resulting reaction mixture was stirred
for 1.5 h. The reaction mixture was then partitioned between
CH2Cl2 and water. The organic extract was dried (Na2SO4) and
concentrated. The residue was chromatographed to afford the
epoxide 9a as a colorless oil (879 mg, 76% yield from monotrityl
ether 3): TLC Rf (MTBE/petroleum ether=3/7)=0.28; [R]D
1
þ13.8 (c 1.0, CH2Cl2); H NMR δ 7.44-7.46 (m, 6 H), 7.20-
The major diastereomer from the reduction was contaminated
with the (S)-Binol. However, this material was found to be
congruent with the upper TLC spot from the Luche reduction
by 13C NMR (δ 72.4 vs 72.4, lower spot δ 72.6). This allowed us
to assign the absolute configurations at C-15 of the two
diastereomeric alcohols 17aaa (S) and 17aab (R).
7.30 (m, 9 H), 5.67-5.75 (m, 2 H), 3.87-3.91 (m, 1 H), 3.58-
3.63 (m, 3 H), 3.02-3.05 (m, 1 H), 2.93-2.95 (m, 1 H), 2.34-
2.37 (m, 2 H), 2.03 (t, 1 H, J=6.0 Hz); 13C NMR δ u20 144.2,
86.9, 64.6, 61.6, 34.4, d 130.1, 128.7, 127.9, 127.0, 126.0, 58.1,
55.0; IR (film) 3415, 2862, 1447, 1049, 751 cm-1; HRMS calcd
for C26H26O3Na 409.1774, found 409.1775.
Synthesis of the Isofurans. Desilylation of 17aaa with
TBAF gave the free alcohol (Scheme 8). The nitrile group
was hydrolyzed17 with 15% aqueous NaOH in EtOH at
85 °C, and the desired carboxylic acid 1aaa was isolated
in excellent yield. Isofuran 1aab was prepared in the same
way. The 13C NMR of the two free acids appeared to be
complicated, so the 1aab was converted to its methyl ester
(18) Browne, S. E.; Roberts, L. J. II; Dennery, P. A.; Doctrow, S. R.;
Beal, M. F.; Barlow, C.; Levine, R. Free Radical Biol. Med. 2004, 36, 938.
(19) (a) Durand, T; Guy, A.; Vidal, J-P; Viala, J.; Rossi, J.-C. Tetrahe-
dron Lett. 2000, 41, 3859. (b) Quan, L. G.; Cha, J. K. J. Am. Chem. Soc. 2002,
124, 12424. (c) Quan, L. G.; Cha, J. K. Chem. Phys. Lipids 2004, 128, 3.
(d) Kim, S.; Lawson, J. A.; Pratico, D.; FitzGerald, G. A.; Rokach, J.
Tetrahedron Lett. 2002, 43, 2801. (e) Durand, T.; Guy, A.; Herry, O..; et al.
Chem. Phys. Lipids 2004, 128, 14. (f) Rokach, J.; Kim, S.; Bellone, S..; et al.
Chem. Phys. Lipids 2004, 128, 35.
(20) 13C multiplicities were determined with the aid of a JVERT pulse
sequence, differentiating the signals for methyl and methine carbons as “d”
and for methylene and quaternary carbons as “u”.
(17) (a) Magatti, C. V.; Kaminski, J. J.; Rothberg, I. J. Org. Chem. 1991,
56, 3102. (b) Taber, D. F.; Hoerrner, R. S. J. Org. Chem. 1992, 57, 441.
J. Org. Chem. Vol. 74, No. 15, 2009 5519

Taber et al.
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1
((2R,3R)-3-((E)-4-Trityloxybut-2-enyl)oxiran-2-yl)methyl Ben-
zenesulfonate (10a). To a stirring solution of 9a (879 mg, 2.28
mmol) in CH2Cl2 (20 mL) were added DMAP (20 mg, cat) and
Et3N (806 mg, 7.98 mmol) at 0 °C. Then a solution of benzensul-
fonyl chloride (1.01 g, 5.70 mmol) in CH2Cl2 (4 mL) was added.
The reaction mixture was stirred for 30 min at 0 °C and then
partitioned between CH2Cl2 and water. The organic extract was
dried (Na2SO4) and concentrated. The residue was chromato-
graphed to give the desired epoxide 10a (1.14 g, 95% yield from
epoxide 9a): TLC Rf (MTBE/petroleum ether=2/8)=0.28; [R]D
þ14.7 (c 1.6, CH2Cl2); 1H NMR δ 7.90-7.93 (m, 2 H), 7.62-7.64
(m, 1 H), 7.52-7.58 (m, 2 H), 7.42-7.45 (m, 6 H), 7.21-7.32 (m, 9
H), 5.66-5.68 (m, 2 H), 4.24 (dd, 1 H, J=11.2 and 3.6 Hz), 4.01
(dd, 1 H, J=11.2 and 6.0 Hz), 3.57 (d, 2 H, J=3.6 Hz), 2.92-2.99
(m, 1 H), 2.87-2.88 (m, 1H), 2.32-2.33 (m, 2 H); 13C NMR δ u
144.1, 135.8, 86.9, 70.1, 64.5, 34.0, d 134.0, 130.5, 129.3, 128.6,
127.9, 127.8, 127.0, 125.2, 55.7, 54.0; IR (film) 3058, 1447, 1185,
863,753 cm-1; HRMS calcd for C32H30O5SNa 549.1731, found
549.1713.
(2S,3S,5S)-Tetrahydro-5-((S)-oxiran-2-yl)-2-(trityloxymethyl)fur-
an-3-yloxy)-tert-butyldimethylsilane (2a). To a stirred solution of 10a
(770 mg, 1.46 mmol) in a mixed tBuOH and H2O solution (v/v 1:1,
3 mL) was added AD-mix-R (2.13 g). After 10 min at room
temperature, methanesulfonamide (141 mg, 1.48 mmol) was added.
The reaction mixture was stirred for 60 h. NaHSO3 (2.18 g,
21.0 mmol) was added, and the mixture was stirred for 60 min.
The reaction mixture was partitioned between EtOAc and water.
The organic extract was dried (Na2SO4) and concentrated to afford
the diol crude (871 mg).
(c 0.60, CH2Cl2); H NMR δ 7.44-7.48 (m, 6 H), 7.19-7.30
(m, 9 H), 4.32 (d, 1 H, J=5.2 Hz), 4.06-4.08 (m, 1 H), 3.94 (dd, 1
H, J=2.0 and 5.2 Hz), 3.45 (dd, 1 H, J=5.6 and 9.6 Hz), 3.38
(dd, 1 H, J=5.6 and 9.6 Hz), 3.17-3.20 (m, 1 H), 2.77-2.82 (m,
2 H), 2.60 (dd, 1 H, J=2.8 and 4.8 Hz), 2.18-2.26 (m, 1 H),
1.75-1.79 (m, 1 H); 13C NMR δ u 143.8, 87.1, 62.8, 45.7, 36.0, d
128.8, 128.0, 127.2, 82.3, 77.8, 72.1, 53.7; IR (film) 3458, 1265,
1072, 756 cm-1; HRMS calcd for C26H26O4Na 425.1729, found
425.1733.
Alkyne 12a. To a stirred solution of 5-hexynenitrile (1.07 g,
11.44 mmol) in THF (10 mL) was added dropwise n-BuLi
(2.28 M in hexane, 4.1 mL, 9.36 mmol) at -78 °C over a period
of 5 min. After an additional 40 min at -78 °C, a solution of 2a
(1.00 g, 1.94 mmol) in THF (15 mL) was added, followed by the
addition of a solution of BF3 OEt2 (986 mg, 6.95 mmol) in THF
3
(3 mL) over a period of 3 min. The reaction mixture was stirred
for 40 min at -78 °C. The reaction mixture was quenched with
saturated aqueous NH4Cl. The mixture was partitioned be-
tween CH2Cl2 and water. The organic extract was dried
(Na2SO4) and concentrated. The residue was chromatographed
to afford 12a (1.08 g, 91% yield from 2a): TLC Rf (MTBE/
petroleum ether = 3/7) = 0.30; [R]D þ27.0 (c 1.0, CH2Cl2);
1H NMR δ 7.45-7.48 (m, 6 H), 7.20-7.30 (m, 9 H), 4.26-
4.27 (m, 1 H), 4.19-4.21 (m, 1 H), 3.97-4.01 (m, 1 H), 3.87-
3.93 (m, 1 H), 3.42 (dd, 1 H, J=6.8 and 10.0 Hz), 3.12 (dd, 1 H,
J=4.0 and 10.0 Hz), 2.73 (d, 1 H, J=2.8 Hz), 2.43-2.49 (m, 3 H),
2.33-2.37 (m, 3 H), 2.12-2.17 (m, 1 H), 1.93 (ddd, 1H, J=0.8 Hz,
4.4 and14.6 Hz), 1.81-1.88 (m, 2 H), 0.71 (bs, 9H), -0.03(s, 3 H),
-0.19 (s, 3 H); 13C NMR δ u 144.1, 119.3, 86.9, 79.5, 78.3, 64.0,
35.1, 24.8, 24.0, 18.0, 17.9, 16.2, d 128.8, 127.8, 127.0, 82.6, 80.0,
72.6, 71.1, 25.7, -4.9, -5.4; IR (film) 3454, 2932, 2048, 1256,
1072, 705 cm-1; HRMS calcd for C38H47NO4SiNa 632.3172,
found 632.3177.
To a stirred solution of the crude diol (499 mg) in MeOH (7.5
mL) at 0 °C was added powdered K2CO3 (307 mg, 2.23 mmol).
After an additional 2.5 h at 0 °C, the reaction mixture was
partitioned between EtOAc and water. The organic extract was
dried (Na2SO4) and concentrated. The residue was chromato-
graphed to afford the mixture of alcohol 11a and 11b (244 mg,
two steps, 72% yield from 10a).
Alkene 13aa. To a stirred solution of Ni(OAc)4 4H2O
3
(259 mg, 1.04 mmol) in EtOH (8 mL) was added a NaBH4
solution in EtOH (1 M, 1.0 mL, 1.0 mmol). The black mixture
was evacuated and backfilled with H2 three times. Ethylenedia-
mine (70 uL, 0.95 mmol) was added, followed by alkyne 12aa
(317 mg, 0.52 mmol) in EtOH (5 mL). The reaction mixture was
stirred for 2.5 h at rt under H2. The reaction mixture was diluted
in MTBE and filtered through a pad of silical gel. The filtrate
was concentrated, and the residue was chromatographed to
afford the desired alkene 13aa as a colorless oil (301 mg, 95%
yield from the alkyne 12aa): TLC Rf (MTBE/petroleum ether=
3/7)=0.37; [R]D þ24.2 (c 1.0, CH2Cl2); 1H NMR δ 7.64-7.66
(m, 6 H), 7.38-7.48 (m, 9 H), 5.75-5.81 (m, 1 H), 5.61-5.65 (m,
1 H), 4.43-4.46 (m, 1 H), 4.22-4.26 (m, 1 H), 4.12-4.14 (m, 1
H), 4.04-4.08 (m, 1 H), 3.61 (dd, 1 H, J=6.4 Hz and 10,0 Hz),
3.32 (dd, 1 H, J=4.0 and 10.0 Hz), 2.83 (s, 1 H), 2.50 (t, 2 H, J=
7.2 Hz), 2.29-2.41 (m, 1 H), 2.11-2.15 (m, 1 H), 1.89-1.93 (m, 2
H), 0.90 (s, 9 H), 0.16 (s, 3 H), 0.00(s, 3 H); 13C NMR δ u 144.1,
119.7, 86.9, 63.9, 34.7, 31.8, 26.1, 25.3, 17.9, 16.5, d 130.0, 128.8,
127.9, 127.8, 127.0, 82.4, 80.6, 72.6, 71.8, 25.7, -4.9, -5.5; IR
(film) 3440, 2933, 2245, 2048. 1448, 1072, 774, 704 cm-1; HRMS
calcd for C38H49NO4SiNa 634.3329, found 634.3329.
To a stirred solution of the mixture of alcohols (360 mg,
0.90 mmol) in CH2Cl2 (7 mL) were added TBSCl (405 mg,
2.69 mmol), imidazole (350 mg, 5.15 mmol), and DMAP (6 mg,
cat) at room temperature. After an additional 40 min, the
reaction mixture was partitioned between CH2Cl2 and water.
The organic extract was dried (Na2SO4) and concentrated. The
residue was chromatographed to afford 2b (110 mg, 24% yield
from mixture of 11a and 11b, 17% yield for three steps from
10a): TLC Rf (MTBE/petroleum ether=1/9)=0.46; [R]D -23.8
(c 1.0, CH2Cl2). Further elution gave 2a as a colorless oil (316
mg, 68% yield from the mixture of 11a and 11b, 49% yield for
three steps from 10a): TLC Rf (MTBE/petroleum ether=1/9)=
0.31; [R]D þ42.2 (c 1.0, CH2Cl2); 1H NMR δ 7.46-7.49 (m, 6 H),
7.19-7.29 (m, 9 H), 4.29-4.31 (m, 1 H), 4.05-4.09 (m, 1 H),
3.79-3.83 (m, 1 H), 3.43 (dd, 1 H, J=6.8 and 10.0 Hz), 3.13 (dd,
1 H, J=4.0 and 10.0 Hz), 3.04-3.10 (m, 1 H), 2.78 (dd, 1 H, J=
4.0 and 5.2 Hz), 2.70 (dd, 1 H, J=2.4 and 5.2 Hz), 2.23-2.30 (m,
1 H), 1.95 (ddd, 1H, J=2.0 Hz, 3.6 and 14.6 Hz), 0.70 (s, 9 H), -
0.03 (s, 3 H), -0.18 (s, 3 H); 13C NMR δ u 144.1, 86.9, 64.2, 46.9,
38.9, 17.8, d 128.8, 127.7, 126.9, 83.2, 78.6, 72.5, 54.0, 25.7, -4.8,
-5.4; IR (film) 2930, 2857, 1254, 1074, 835 cm-1; HRMS calcd
for C32H40O4SiNa 539.2594, found 539.2572.
(2S,3S,5S)-2-((Trityloxy)methyl)-tetrahydro-5-((S)-oxiran-2-
yl)furan-3-ol (11a). To a stirred solution of 2a (1.57 g, 3.3 mmol)
in THF (20 mL) at room temperature was added a Bu4NF
solution in THF (1M, 6.6 mL, 6.6 mmol) at 0 °C. After an
additional 5 h, the mixture was partitioned between CH2Cl2 and
water. The organic extract was dried (Na2SO4) and concen-
trated. The residue was chromatographed to afford 11a as
a solid (1.15 g, 96% yield from 2a). A 50 mg portion was
crystallized from 1.0 mL of 1:5 CH2Cl2/hexanes: mp=142 °C;
TLC Rf (MTBE/petroleum ether = 3/7) = 0.33; [R]D þ13.3
Alkene 4aa. To a stirred solution of 13aa (348.3 mg,
0.57 mmol) in CH2Cl2 (8 mL) were added TBSCl (430 mg,
2.85 mmol), imidazole (371 mg, 5.70 mmol), and DMAP (5 mg,
cat.) at room temperature. After an additional 17 h, the reaction
mixture was partitioned between CH2Cl2 and water. The or-
ganic extract was dried (Na2SO4) and concentrated. The residue
was chromatographed to afford 4aa (349 mg, 84% yield from
13aa): TLC Rf (MTBE/petroleum ether=1/9)=0.50; [R]D þ14.2
(c 1.0, CH2Cl2); 1H NMR δ 7.70-7.72 (m, 6 H), 7.43-7.53 (m, 9
H), 5.87-5.91 (m, 1 H), 5.65-5.68 (m, 1 H), 4.45-4.48 (m, 1 H),
4.13-4.17 (m, 1 H), 4.03-4.06 (m, 1 H), 3.89-3.94 (m, 1 H),
3.57-3.60 (m, 1 H), 3.29 (dd, 1 H, J=2.4 and 10.0 Hz), 2.78-
2.85 (m, 1 H), 2.42-2.50 (m, 6 H), 1.92-1.97 (m, 3 H), 1.10
5520 J. Org. Chem. Vol. 74, No. 15, 2009

Taber et al.
JOCArticle
(s, 9 H), 0.92 (s, 9 H), 0.31 (s, 3 H), 0.27 (s, 3 H), 0.14 (s, 3 H), 0.00
(s, 3 H); 13C NMR δ u 144.3, 119.9, 86.6, 64.7, 38.8, 32.3, 26.4,
25.5, 18.1, 17.9, 16.4, d 128.9, 128.9, 127.7, 126.9, 82.5, 79.6,
74.4, 73.0, 25.9, 25.8, -4.0, -4.3, -4.8, -5.4; IR (film) 3432,
2932, 2264, 1253, 1078, 834 cm-1; HRMS calcd for C44H63NO4-
Si2Na 748.4193, found 748.4192.
1252, 1073, 834 cm-1; HRMS calcd for C32H61NO4Si2Na
602.4033, found 602.4025. Further elution gave 17aab (41 mg,
35% yield from the enone 16aa): TLC Rf (Et2O/CH2Cl2/petro-
leum ether=1/3/6)=0.33; [R]D þ6.9 (c 1.0, CH2Cl2); 1H NMR δ
5.68-5.81 (m, 2 H), 5.58-5.64 (m, 1 H), 5.37-5.42 (m, 1 H),
4.25-4.29 (m, 1 H), 4.03-4.13 (m, 2 H), 3.82-3.86 (m, 1 H),
3.64-3.70 (m, 1 H), 2.65 (d, 1 H, J=9.6 Hz), 2.42-2.48 (m,1 H),
2.31-2.35 (m, 2 H), 2.18-2.25 (m, 4 H), 1.81-1.86 (m, 1 H),
1.60-1.75 (m, 4 H), 1.49-1.55 (m, 2 H), 1.37-1.44 (m, 1 H),
1.26-1.36 (m, 3 H), 0.88-0.90 (m, 21 H), 0.01-0.09 (m, 12 H);
13C NMR δ u 119.9, 38.6, 37.1, 32.2, 31.8, 26.4, 25.3, 25.2, 22.6,
18.2, 18.1, 16.5, d 136.8, 128.7, 128.0, 127.8, 83.9, 79.7, 74.1,
74.0, 72.6, 25.90 (3), 25.87 (3), 14.1, -4.1, -4.3, -4.6, -4.9; IR
(film) 3449, 2932, 2250, 1254, 1074, 835 cm-1; HRMS calcd for
C32H61NO4Si2Na 602.4037, found 602.4023.
Isofuran 1aaa. To a stirred solution of 17aaa (45 mg,
0.078 mmol) in THF (0.8 mL) was added a 1 M solution of
Bu4NF (1.0 M in THF, 1.0 mL). After an additional 1.5 h at rt,
the reaction mixture was partitioned between CH2Cl2 and H2O.
The organic extract was concentrated to afford the crude triol.
The crude triol was dissolved in EtOH (1.0 mL), and then 15%
aqueous NaOH (2.0 mL) was added. After an additional 16 h at
85 °C, the reaction mixture was cooled to rt and acidified with
NaH2PO4 (0.5 M, 3 mL) and AcOH (3 mL). The mixture was
partitioned beween CH2Cl2 and water. The organic extract was
concentrated, and the residue was chromatographed to give
1aaa (26 mg, 89% yield from 17aaa): TLC Rf (Et2O/0.5 M
aqueous NaH2PO4/HOAc=90/9/1)=0.35; [R]D þ25.0 (c 0.5,
CH2Cl2), [R]D þ35.4 (c 0.58, CH3OH); 1H NMR δ 5.98 (s, 3 H),
5.81-5.82 (m, 2 H), 5.44-5.49 (m, 2 H), 4.08-4.16 (m,4 H),
3.86-3.87 (m, 1 H), 2.35 (s, 1 H), 2.02-2.27 (m, 7 H), 1.70 (s, 2
H), 1.22-1.53 (m, 9 H), 0.86-0.91 (m, 3 H); 13C NMR δ u 36.7,
34.1, 31.8, 26.4, 25.2, 24.4, 22.6, d 137.5, 131.6, 126.0, 125.9,
84.0, 80.4, 73.1, 72.0, 71.8, 30.3, 14.1; the carbonyl carbon was
not observed; IR (film) 3334, 2925, 1708, 1018 cm-1; HRMS
calcd for C20H34O6Na 393.2253, found 393.2246.
Isofuran 1aab. The reaction was performed with the alcohol
17aab (36 mg, 0.062 mmol) in the same manner as described for
the preparation of isofuran 1aaa to give isofuran 1aab (24 mg,
92% yield from 17aab): TLC Rf (Et2O/0.5 M aqueous NaH2-
PO4/HOAc=90/9/1)=0.38; [R]D þ15.6 (c 0.48, CH2Cl2), [R]D
þ23.1 (c 0.50, CH3OH); 1H NMR δ 5.71-5.88 (m, 3 H), 5.43-
5.48 (m, 3 H), 4.05-4.20 (m, 4 H), 3.89 (s, 1 H), 2.36 (s, 2 H),
2.04-2.27 (m, 6 H), 1.70-1.73 (m, 2 H), 1.43-1.57 (m, 3 H),
1.25-1.36 (m, 7 H), 0.86-0.89 (m, 3 H); 13C NMR δ u 178.1,
36.5, 34.2, 32.0, 31.8, 26.4, 25.2, 24.4, 22.6, d 136.5, 131.3, 126.2,
126.2, 83.1, 80.3, 72.7, 72.3, 71.8, 30.3, 14.1; the carbonyl carbon
was not initially observed, but when 1aab was prepared by
saponification of the ester 18aab, the carbonyl was evident; IR
(film) 3447, 3034, 2926, 1708, 1240, 1018 cm-1; HRMS calcd for
C20H34O6Na 393.2253, found 393.2246.
Ester 18aab. To a stirred solution of isofuran 1aab (8 mg,
0.021 mmol) in MeOH/benzene (1:4, 0.5 mL) was added tri-
methylsilyl diazomethane (2.0 M in Et2O, 50 uL). The mixture
was stirred at room temperature for 20 min. The mixture was
concentrated, and the residue was chromatographed to afford the
ester 18aab (8 mg, 96% yield from the isofuran 1aab): TLC Rf
(acetone/CH2Cl2=4/1)=0.38; [R]D þ23.8 (c 0.38, CH2Cl2), [R]D
þ23.1 (c 0.55, CH3OH); 1H NMR δ 5.81-5.87 (m, 1 H), 5.73 (dd,
J=15.6 and 5.2 Hz, 1 H), 5.44-5.51 (m, 2 H), 4.88 (s, 1 H), 4.79 (s,
1 H), 4.18-4.20 (m, 1 H), 4.11-4.16 (m, 2 H), 4.02-4.08 (m, 1 H),
3.85-3.90 (m, 1 H), 3.70-3.85 (m, 1 H), 3.67 (s, 3 H), 2.32 (t, 2 H,
J=7.2 Hz), 2.03-2.29 (m, 5 H), 1.66-1.74 (m, 3 H), 1.41-1.60 (m,
2 H), 1.21-1.38 (m, 6 H), 0.87 (t, 3 H, J=6.4 Hz); 13C NMR
δ u 174.0, 36.5, 34.0, 33.4, 32.2, 31.7, 26.7, 25.3, 24.7, 22.6, d 136.4,
131.2, 126.5, 126.2, 83.1, 80.2, 72.8, 72.2, 71.8, 51.5, 14.1; HRMS
calcd for C21H36O6Na 407.2404, found 407.2410.
Alcohol 14aa. To a stirred solution of 4aa (20 mg,
0.0275 mmol) in CH2Cl2 (4 mL) was added diethyl aluminum
chloride (1 N in hexane, 0.15 mL, 0.15 mmol) at - 78 °C. After
an additional 10 min, the reaction mixture was quenched with
water and filtered through a pad of silica gel, washing with
methanol. The filtrate was concentrated, and the residue was
chromatographed to give the desired alcohol 14aa (11.2 mg,
84% yield from the ether 4aa): TLC Rf (MTBE/petroleum ether
=3/7)=0.32; [R]D -5.2 (c 1.0, CH2Cl2); 1H NMR δ 5.58-5.61
(m, 1 H), 5.38-5.41 (m, 1 H), 4.50 (dd, 1 H, J=6.0 and 13.2 Hz),
3.79-3.83 (m, 2 H), 3.72-3.75 (m, 2 H), 3.63-3.68 (m, 1 H),
2.32-2.40 (m, 4 H), 2.17-2.25 (m, 4 H), 1.78-1.83 (m, 1 H),
1.70-1.76 (m, 2 H), 0.88 (s, 18 H), 0.07 (s, 12 H); 13C NMR δ u
119.7, 62.7, 38.1, 32.5, 26.5, 25.3, 18.1, 18.0, 16.5, d 128.8, 127.7,
81.1, 79.4, 73.8(2), 25.9, 25.8, -4.2, -4.4, -4.6, -5.2; IR (film)
2932, 2256, 1254, 1079, 835 cm-1; HRMS calcd for C25H49NO4-
Si2Na 506.3098, found 506.3097.
Enone 16aa. To a stirred solution of 14aa (64 mg, 0.13 mmol)
in CH2Cl2 (1.5 mL) was added Dess-Martin periodinane
(111 mg, 0.26 mmol). After an additional 40 min at rt, the
reaction mixture was directly poured on the silica gel and
chromatographed to afford the crude aldehyde (53 mg).
To a stirred suspension of NaH (26 mg, 0.66 mmol) in THF
(5 mL) was added dimethyl 2-oxoheptylphosphonate 15
(244 mg, 1.10 mmol) at 0 °C. After an additional 1 h at 0 °C, a
solution of the crude aldehyde (53 mg) in THF (1 mL) was
added. After an additional 40 min at 0 °C, the mixture was
partitioned between CH2Cl2 and saturated aqueous NH4Cl. The
organic extract was dried (Na2SO4) and concentrated. The
residue was chromatographed to afford 16aa (64 mg, 84% yield
from 14aa): TLC Rf (MTBE/petroleum ether=3/7)=0.73; [R]D
þ5.9 (c 1.0, CH2Cl2); 1H NMR δ 6.79 (dd, 1 H, J=4.2 and 16.0
Hz), 6.26 (dd, 1 H, J=1.6 and 16.0 Hz), 5.59-5.64 (m, 1 H),
5.39-5.45 (m, 1 H), 4.42-4.46 (m, 1 H), 4.28 (dt, 1 H, J=1.6 and
5.6 Hz), 3.86 (q, 1 H, J=5.2 Hz), 3.74 (q, 1 H, J=7.2 Hz), 2.54-
2.58 (m, 2 H), 2.43-2.50 (m, 1 H), 2.19-2.35 (m, 6 H), 1.82-
1.89 (m, 1 H), 1.70-1.77 (m, 2 H), 1.59-1.66 (m, 2 H), 1.25-
1.37 (m, 4 H), 0.86-0.90 (m, 21 H), 0.09 (s, 6 H), 0.05 (s, 3 H),
0.02 (s, 3 H); 13C NMR δ u 200.5, 119.7, 39.9, 38.3, 32.4, 31.5,
26.3, 25.3, 23.8, 22.5, 18.1, 18.0, 16.5, d 142.7, 130.8, 128.9,
127.6, 82.3, 80.1, 74.3, 73.8, 25.9, 25.8, 13.9, -4.1, -4.3, -4.7, -
5.0; IR (film) 3442, 2929, 2250, 1641, 833, 775 cm-1; HRMS
calcd for C32H59NO4Si2Na 600.3880, found 600.3876.
Alcohols 17aaa and 17aab. To a stirred solution of 16aa
(118 mg, 0.20 mmol) in MeOH (6 mL) was added CeCl3 7H2O
3
(74 mg, 0.20 mmol). After 5 min, NaBH4 (12 mg) was added. The
mixture was stirred for an additional 30 min at rt, and then the
reaction mixture was filtered through a pad of silica gel, washing
with MTBE, the filtrate was concentrated, and the residue was
chromatographed to give the desired alcohol 17aaa (45 mg, 38%
yield from the enone 16aa): TLC Rf (Et2O/CH2Cl2/petroleum
1
ether = 1/3/6) = 0.23; [R]D þ4.5 (c 1.0, CH2Cl2); H NMR δ
5.75-5.82 (m, 2 H), 5.58-5.62 (m, 1 H), 5.36-5.43 (m, 1 H),
4.28-4.31 (m, 1 H), 4.06-4.15 (m, 2 H), 3.84 (q, 1 H, J=4.8 Hz),
3.66 (q, 1 H, J=7.2 Hz), 2.65 (d, 1 H, J=9.6 Hz), 2.39-2.47 (m, 1
H), 2.30-2.34 (m, 2 H), 2.17-2.27 (m, 4 H), 1.83-1.87 (m, 1 H),
1.68-1.76 (m, 2 H), 1.50-1.56 (m, 4 H), 1.26-1.43 (m, 4 H),
0.87-0.90 (m, 21 H), 0.03-0.08 (m, 12 H); 13C NMR δ u: 119.8,
38.3, 37.1, 32.3, 31.8, 26.4, 25.3, 25.2, 22.6, 18.2, 18.1, 16.5 d:
136.3, 128.7, 127.9, 127.6, 83.5, 79.7, 74.3, 74.0, 72.4, 25.9 (3),
25.9 (3), 14.1, -4.1, -4.3, -4.6, -4.9; IR (film) 2931, 2250, 1464,
J. Org. Chem. Vol. 74, No. 15, 2009 5521

Taber et al.
JOCArticle
Acknowledgment. We thank the National Institutes
of Health (GM42056) for support of this work. We thank
Dr. John Dykins for mass spectrometric measurements,
supported by the NSF (0541775), and Dr. Glenn Yap for
X-ray analysis.
Supporting Information Available: General experimental
procedures, experimental procedures and spectra for all new
compounds, and details of the X-ray structural analysis of 11a.
This material is available free of charge via the Internet at http://
pubs.acs.org.
5522 J. Org. Chem. Vol. 74, No. 15, 2009