Evaluation of furan photooxygenation as a device for construction of the zaragozic acid (squalestatin) core

Article abstract of DOI:10.1021/jo960963+

A practical application of the photooxygenation chemistry of 3-substituted furans to construction of the zaragozic acid/squalestatin backbone is described. Although addition of 3-lithiofuran to the tartrate-derived aldehyde 7 proceeds without chelation control to give a 1:1 mixture of diastereomeric alcohols 8, it is demonstrated initially that ready conversion to the polyfunctional intermediate 16 is possible by sequential treatment of 9 with singlet oxygen, sodium borohydride, and triisopropylsilyl triflate. The actual enantiocontrolled route consisted of oxidation of 8 to the ketone and Wittig olefination of the latter in advance of asymmetric dihydroxylation with AD-mix-β. Cnce this series of transformations had been accomplished, formation of the target product 30 was realized by an entirely comparable photooxygenation.

Full text of DOI:10.1021/jo960963+

J . Org. Chem. 1996, 61, 6685-6692
6685
Eva lu a tion of F u r a n P h otooxygen a tion a s a Device for
Con str u ction of th e Za r a gozic Acid (Squ a lesta tin ) Cor e
Naoyoshi Maezaki,† Harrie J . M. Gijsen,‡ Li-Qiang Sun, and Leo A. Paquette*
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
Received May 24, 1996X
A practical application of the photooxygenation chemistry of 3-substituted furans to construction
of the zaragozic acid/squalestatin backbone is described. Although addition of 3-lithiofuran to the
tartrate-derived aldehyde 7 proceeds without chelation control to give a 1:1 mixture of diastereomeric
alcohols 8, it is demonstrated initially that ready conversion to the polyfunctional intermediate 10
is possible by sequential treatment of 9 with singlet oxygen, sodium borohydride, and triisopropyl-
silyl triflate. The actual enantiocontrolled route consisted of oxidation of 8 to the ketone and Wittig
olefination of the latter in advance of asymmetric dihydroxylation with AD-mix-â. Once this series
of transformations had been accomplished, formation of the target product 30 was realized by an
entirely comparable photooxygenation.
The treatment of hypercholesterolemia, initiated more
than two decades ago,1 initially focused on inhibiting
HMG CoA reductase, an enzyme broadly involved in
endogenous steroid biosynthesis.2 More recently, chiefly
as a consequence of the isolation from fungi of the
zaragozic acids3 and the squalestatins,4 attention has
turned instead to squalene synthase. This enzyme
catalyzes the head-to-head coupling of farnesyl pyrophos-
phate to squalene5 and serves as the specific control point
for cholesterol biosynthesis.6 This therapeutic applica-
tion, as well as reputed anticancer7 and antifungal
properties,4a have prompted considerable synthetic inte-
rest in these highly oxygenated 2,8-dioxabicyclo[3.2.1]-
octanes. Successful routes to 18 and 29,10 have been
reported, and model studies abound.11
mizing on the requisite number of steps needed to arrive
at 1-3. Scheme 1 illustrates the retro-synthetic analysis
in its most simplified form. Thus, the extensively func-
Despite these remarkable successes, shorter routes to
these targets would prove highly desirable.12 To this end,
the process of furan photooxygenation13,14 has now been
examined in developmental form as a means for econo-
† Present address: Faculty of Pharmaceutical Sciences, Osaka
University, 1-6 Yamadaoka, Suita, Osaka 565, J apan.
‡ The Ohio State University Postdoctoral Fellow, 1995-1996.
X Abstract published in Advance ACS Abstracts, September 1, 1996.
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S0022-3263(96)00963-2 CCC: $12.00 © 1996 American Chemical Society

6686 J . Org. Chem., Vol. 61, No. 19, 1996
Maezaki et al.
Sch em e 1
Sch em e 3
Sch em e 2
hydride14 and capping of the resulting diol with triiso-
propylsilyl groups afforded 10 in 59% overall yield.
Comparable yields were obtained in ethanol or isopropyl
alcohol, while the use of methanol led to a considerable
reduction in overall yield.
tionalized intermediate 4 can potentially be reached by
combined oxidation of the three-CH2OR groups, vicinal
dihydroxylation of the double bond, and acetal hydrolysis.
Rapid access to 5 was viewed to be possible by singlet
oxygenation/reduction of 6, itself anticipated to be avail-
able by coupling of 3-lithiofuran to a suitable tartrate-
derived electrophilic partner. In this way, the entire
lower half of 4 would arise conveniently from the furan
building block introduced in this manner. A prerequisite
would be the ability to set the stereocenter properly at
C-5 (zaragozic acid numbering), a process already rec-
ognized to be controllable by means of the hydroxyl
protecting groups (see below).
In order to establish that arrival at 10 was notably
expedient and to confirm the structural assignment, the
alternate route shown in Scheme 3 was developed.
Wittig reagent 11, readily available from maleic anhy-
dride, triphenylphosphine, and ethanol,17 is now recog-
nized to afford 2-alkylidenesuccinic acid monoethyl esters
stereoselectively, with the R group of the original alde-
hyde positioned uniquely cis to the acetic acid substituent
in the product.18 In the present example, the formation
of 12 proved to be equally dependable (80%). Following
esterification, the dihydroxylation of 13 proceeded
smoothly to give diol 14 as a 1:1 mixture of diastereo-
mers. This intermediate was then converted into cyclic
carbonate 15 with carbonyldiimidazole.19 As hoped for,
the carbonate was readily cleaved with DBU even at 0
°C to give the desired allylic alcohol 16 exclusively (96%).
NOE studies revealed convincingly that olefin geometry
had been properly set. When attempts to effect the
dihydroxylation of 16 with osmium tetraoxide proved to
Resu lts a n d Discu ssion
In order to establish concept feasibility, the preliminary
study outlined in Scheme 2 was carried out first. Con-
densation of the known aldehyde 715 with 3-lithiofuran16
gave alcohol 8 as a 1:1 diastereomeric mixture. Following
silylation of the hydroxyl functionality, 9 was photooxy-
genated in ethanol containing rose bengal as the sensi-
tizer. The reaction temperature was maintained below
-55 °C in order to preserve the integrity of the resulting
endoperoxide. Direct reduction with sodium boro-
(17) Hudson, R. F.; Chopard, P. A. Helv. Chim. Acta 1963, 46, 2178.
(18) For synthetic applications of this reagent, consult: (a) McMurry,
J . E.; Donovan, S. F. Tetrahedron Lett. 1977, 2869. (b) Ro¨der, E.;
Krauss, H. Liebigs Ann. Chem. 1992, 177. (c) Paquette, L. A.; Schulze,
M. M. Heterocycles 1993, 35, 585.
(15) Mukaiyama, T.; Suzuki, K.; Yamada, T. Chem. Lett. 1982, 929.
(16) Fukuyama, Y.; Kawashima, Y.; Miwa, T.; Tokoroyama, T.
Synthesis 1974, 443.
(19) Kutney, J . P.; Ratcliffe, A. H. Synth. Commun. 1975, 5, 47.

Construction of the Zaragozic Acid Core
J . Org. Chem., Vol. 61, No. 19, 1996 6687
Sch em e 4
Sch em e 5
by hydrolysis with mercuric chloride and mercuric oxide
in aqueous methanol.22 Hydrolysis of 20 with 1 N
hydrochloric acid in THF provided the highly crystalline
lactone 22, X-ray crystallographic analysis of which
established that the improper configuration had been set
at C-5 (Figure 1, supporting information).23 This finding
proves that nucleophilic attack on 18 follows the Felkin-
Ahn model and takes place without chelation control. It
is noteworthy that an identical preference for the Felkin-
Ahn model has been reported for aldehyde 7 in its
reaction with a range of nucleophiles.15 In contrast, the
attack of Grignard reagents on the less conformationally
rigid di-MOM-protected congener of 7 occurs with che-
lation control, giving rise to products with the opposite
configuration.24
In addition to this required modification in the syn-
thetic protocol, we came to recognize that borohydride-
promoted cleavage of the endoperoxide from 20 also
resulted in reduction of the ester functionality, such that
ultimate silylation gave rise to 21 in modest yield.
Two approaches were subsequently investigated for
generating intermediates with the proper C-5 configu-
ration. The first of these consisted merely of reversing
the sequence of additions (Scheme 5). Although the
addition of lithio tris(methylthio)methane to 7 proceeded
efficiently, the abundance of sulfur atoms present in 23
introduced complications during the subsequent oxida-
tion to ketone 24. For example, recourse to the Dess-
Martin periodinane provided 24 in only 21% yield.
Efforts to optimize this transformation were not imple-
mented when it was made clear that the addition of
3-furyllithium to 24 failed completely to give rise to 25.
Pursuit of the second alternative pathway shown in
Scheme 6 proved to be very rewarding. Methylation of
18 proceeded in excellent yield to furnish alkene 26,
which underwent highly diastereoselective dihydroxyla-
tion with AD-mix-â25 to furnish a 21:1 mixture of diols
27 and 28. The stereochemical assignment was con-
firmed through LiAlH4 reduction of 20 to afford diol 28
selectively.
be highly inefficient, recourse was made to protection of
the free hydroxyl as the tert-butyldimethylsilyl ether.
However, this ploy did not remedy matters, and reductive
chemistry was undertaken in order to facilitate the
necessary production of a diol at this site.
The conversion of 16 to 10 proved to be far more
problematical than expected because of the overwhelming
tendency of derivatives of 16 to undergo SN2′ attack
during ester reduction with elimination of the allylic
oxygen functionality. In the end, the TBS ether 17 was
treated with diisobutylaluminum hydride at -78 °C f
-20 °C, and the unpurified diol so produced was directly
silylated. The resulting product (13%) proved to be
identical with 10 in all respects.
Consequently, these early studies provided several key
pieces of information: (a) a 3-substituted furan can be
introduced without risking loss of configuration; (b)
photooxygenation of the furan ring can be accomplished
without interference from other nearby oxygenated sub-
stituents; and (c) sodium borohydride reduction of the
endoperoxide can be achieved without reductive elimina-
tion of the oxygen center residing at C-5. Armed with
this information, we embarked on proper incorporation
of the carboxylic acid unit resident at C-5.
To this end, 8 was oxidized to 18 under Swern
conditions (91%) or with the Dess-Martin periodinane20
in 85% yield (Scheme 4). Treatment of 18 with lithiated
tris(methylthio)methane21 resulted in cleanly diastereo-
selective 1,2-addition to the carbonyl group. This single
product was transformed into the oily methyl ester 20
With 27 in hand, it proved an easy matter to silylate
its primary hydroxyl group selectively as in 29 (98%).
(22) Dailey, O. D., J r.; Fuchs, P. L. J . Org. Chem. 1980, 45, 216.
(23) The authors have deposited the atomic coordinates for the X-ray
structure with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK.
(20) (a) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
(b) Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(21) Seebach, D.; Geiss, K.-H.; Beck, A. K.; Graf, B.; Daum, H. Chem.
Ber. 1972, 105, 3280.
(24) Iida, H.; Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 1985,
26, 3255.
(25) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.

6688 J . Org. Chem., Vol. 61, No. 19, 1996
Maezaki et al.
cold (-78 °C), magnetically stirred solution of 3-bromofuran
(7.05 g, 48.0 mmol) in dry THF (120 mL) under N2. After 10
min, a solution of 7 (8.00 g, 32.0 mmol) in dry THF (12 mL)
was introduced, and stirring was maintained for 1.5 h at this
temperature. Following quenching with saturated NH4Cl
solution (30 mL), the separated aqueous layer was extracted
with ethyl acetate (2 × 50 mL), and the combined organic
phases were washed with water (30 mL) and brine (30 mL),
dried, and evaporated. Chromatography of the residue on
silica gel (elution with 20% ethyl acetate in hexanes) gave 8
(7.23 g, 72%) as a pale yellow oil: IR (film, cm-1) 3440, 1500,
1450; 1H NMR (300 MHz, CDCl3) δ 7.40 (br s, 1 H), 7.40-7.20
(m, 6 H), 6.38 (d, J ) 1.8 Hz, 0.5 H), 6.37 (d, J ) 1.4 Hz, 0.5
H), 4.81 (d, J ) 5.4 Hz, 0.5 H), 4.60-4.40 (m, 2.5 H), 4.15 (dt,
J ) 8.0, 4.8 Hz, 1 H), 4.00 (dd, J ) 7.9, 5.4 Hz, 1 H), 3.43 (d,
J ) 4.8 Hz, 2 H), 2.16 (br s, 1 H), 1.43 (s, 3 H), 1.42 (s, 3 H);
13C NMR (75 MHz, CDCl3) ppm 143.1, 139.7, 137.5, 128.4,
127.8, 127.7, 127.6, 113.9, 109.4, 108.7, 81.0, 76.9, 73.5, 70.6,
67.0, 27.1, 26.9; MS m/ z (M+) calcd 318.1468, obsd 318.1463.
[[(4R,5S)-5-[(Ben zyloxy)m et h yl]-2,2-d im et h yl-1,3-d i-
oxolan -4-yl]-3-fu r ylm eth oxy]-ter t-bu tyldim eth ylsilan e (9).
A solution of 8 (860 mg, 2.70 mmol) and 2,6-lutidine (0.31 mL,
2.7 mmol) in dry CH2Cl2 (10 mL) was treated with tert-
butyldimethylsilyl trifluoromethanesulfonate (0.47 mL, 2.7
mmol) at rt under N2. After 1 h, the reaction mixture was
diluted with CH2Cl2 (30 mL), washed with saturated NaHCO3
solution (20 mL), water (20 mL), and brine (20 mL), and then
dried. Following solvent evaporation, the residue was chro-
matographed on silica gel (elution with 10% ethyl acetate in
hexanes) to deliver 9 as a colorless oil (1.00 g, 86%): IR (film,
cm-1) 1490, 1475; 1H NMR (300 MHz, CDCl3) δ 7.45-7.20 (m,
7 H), 6.36 (t, J ) 1.3 Hz, 0.5 H), 6.30 (t, J ) 1.2 Hz, 0.5 H),
4.87 (d, J ) 5.0 Hz, 0.5 H), 4.77 (d, J ) 5.4 Hz, 0.5 H), 4.59 (d,
J ) 12.5 Hz, 0.5 H), 4.55 (d, J ) 12.3 Hz, 0.5 H), 4.49 (d, J )
12.3 Hz, 0.5 H), 4.49 (d, J ) 12.5 Hz, 0.5 H), 4.28 (ddd, J )
10.3, 6.7, 2.4 Hz, 0.5 H), 4.00 (ddd, J ) 10.3, 6.6, 2.6 Hz, 0.5
H), 3.88 (dd, J ) 10.3, 5.0 Hz, 0.5 H), 3.85 (dd, J ) 10.3, 5.4
Hz, 0.5 H), 3.50 (dd, J ) 10.4, 2.6 Hz, 0.5 H), 3.48 (dd, J )
10.4, 2.4 Hz, 0.5 H), 3.40 (dd, J ) 10.4, 6.6 Hz, 0.5 H), 3.33
(dd, J ) 10.4, 6.7 Hz, 0.5 H), 1.42 (s, 3 H), 1.41 (s, 3 H), 0.86
(s, 4.5 H), 0.84 (s, 4.5 H), 0.06 (s, 1.5 H), 0.03 (s, 1.5 H), -0.04
(s, 1.5 H), -0.07 (s, 1.5 H); 13C NMR (75 MHz, CDCl3) ppm
143.0, 142.6, 139.8, 139.6, 138.1, 128.3, 127.8, 127.6, 127.5,
126.5, 125.1, 109.8, 109.5, 108.9, 80.7, 80.1, 77.6, 76.8, 73.4,
73.3, 71.7, 71.1, 68.4, 27.3, 27.1, 26.9, 25.8, 25.7, 18.1, -4.8,
-5.0, -5.1; MS m/ z (M+) calcd 432.2326, obsd 432.2332.
[(E)-2-[[(4R,5S)-5-[(Ben zyloxy)m et h yl]-2,2-d im et h yl-
1,3-d ioxola n -4-yl](ter t-b u t yld im et h ylsiloxy)m et h yl]-2-
bu ten ylen e]bis(tr iisop r op ylsila n e) (10). Into a dry ice/
acetone-cooled solution of 9 (150 mg, 0.35 mmol) and rose
bengal (10 mg, 9.8 µmol) in ethanol (10 mL) was bubbled
oxygen with concomitant irradiation from a 600 W tungsten
lamp. After 20 min, the reaction mixture was poured onto
sodium borohydride (52 mg, 1.4 mmol) in ethanol (2 mL)
precooled to the same temperature, with subsequent warming
to 0 °C during 1.5 h. The solvent was evaporated under
reduced pressure, and the unstable diol was rapidly filtered
through silica gel (elution with 30% ethyl acetate in hexanes),
concentrated (94 mg), and immediately dissolved in CH2Cl2
(5 mL) containing 2,6-lutidine (0.053 mL, 0.46 mmol). Triiso-
propylsilyl trifluoromethanesulfonate (0.12 mL, 0.46 mmol)
was added at rt, and the solution was stirred for 30 min prior
to dilution with CH2Cl2 (5 mL), washed with saturated
NaHCO3 solution (5 mL), water (5 mL), and brine (5 mL),
dried, and concentated. Chromatography of the residue on
silica gel (elution with 5% ethyl acetate in hexanes) gave 10
as a colorless oil (157 mg, 59%); IR (film, cm-1) 1465; 1H NMR
(300 MHz, CDCl3) δ 7.60-7.30 (m, 5 H), 5.74 (d, J ) 5.5 Hz,
0.5 H), 5.68 (d, J ) 5.5 Hz, 0.5 H), 4.57 (d, J ) 12.5 Hz, 0.5
H), 4.50 (s, 1 H), 4.47 (d, J ) 12.5 Hz, 0.5 H), 4.50-4.00 (m, 6
H), 3.87 (dd, J ) 8.0, 4.8 Hz, 0.5 H), 3.82 (dd, J ) 8.1, 5.0 Hz,
0.5 H), 3.60 (dd, J ) 10.4, 2.1 Hz, 0.5 H), 3.56 (dd, J ) 10.4,
2.7 Hz, 0.5 H) 3.43 (dd, J ) 10.4, 7.1 Hz, 0.5 H), 3.38 (dd, J )
10.4, 6.5 Hz, 0.5 H), 1.37 (s, 3 H), 1.33 (s, 3 H), 1.15-0.90 (m,
42 H), 0.84 (s, 4.5 H), 0.82 (s, 4.5 H), 0.02 (s, 1.5 H), -0.02 (s,
1.5 H), -0.03 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 138.5,
Sch em e 6
Sch em e 7
Submission of this intermediate to the photooxygenation
sequence led to the formation of 30 (Scheme 7), which
1
was easily distinguishable from 21 on the basis of its H
and 13C NMR spectral features.
In summary, the strategy of applying the photooxy-
genation of furans to enantiocontrolled construction of
the zaragozic acid/squalestatin core has met with success.
When advancing from acetonide 7, seven distinct labora-
tory steps passing through 8, 18, and 26-30 are required
to complete the sequence. In contemplating the di-MOM
equivalent of 7 as the starting material, one less step
would be necessary if chelation control were to operate
at a useful level. In line with precedent,7b 30 is recalci-
trant to dihydroxylation of its double bond under a
variety of conditions. A change in protect-ing groups is
clearly warrranted.
Exp er im en ta l Section
Melting points are uncorrected. 1H and 13C NMR spectra
were recorded at the indicated field strengths. High resolution
mass spectra were obtained at The Ohio State University
Chemical Instrumentation Center. Elemental analyses were
performed at the Scandinavian Microanalytical Laboratory,
Herlev, Denmark. All separations were effected under flash
chromatography on Merck silica gel HG254
. The organic
extracts were dried over anhydrous magnesium sulfate. Sol-
vents were reagent grade and in many cases dried before use.
(4S,5S)-5-[(Ben zyloxy)m eth yl]-r-3-fu r yl-2,2-d im eth yl-
1,3-d ioxola n e-4-m eth a n ol (8). n-Butyllithium (30.0 mL of
1.6 M in hexanes, 48.0 mmol) was added during 20 min to a

Construction of the Zaragozic Acid Core
J . Org. Chem., Vol. 61, No. 19, 1996 6689
138.3, 137.4, 130.8, 129.0, 128.2, 127.7, 127.6, 127.4, 109.1,
108.8, 80.0, 79.0, 77.2, 76.7, 73.7 73.4, 73.3, 72.7, 72.0, 71.4,
60.1, 59.8, 27.2, 27.0, 26.0, 25.8, 18.2, 18.0, 12.0, 11.9, -4.6,
-4.7, -4.8, -5.0; MS m/ z (M+) calcd 764.5263, obsd 764.5263.
Anal. Calcd for C42H80O6Si3: C, 65.91; H, 10.54. Found: C,
65.82; H, 10.51.
) 8.0 Hz, 1 H), 3.71 (dd, J ) 9.7, 3.2 Hz, 1 H), 3.68 (s, 3 H),
3.58 (dd, J ) 9.7, 5.8 Hz, 1 H), 3.09 (d, J ) 16.5 Hz, 1 H), 2.91
(d, J ) 16.5 Hz, 1 H), 1.39 (s, 6 H), 1.31 (t, J ) 7.1 Hz, 3 H);
13C NMR (75 MHz, CDCl3) ppm 173.3, 171.1, 137.2, 128.2,
127.7, 127.6, 109.7, 78.6, 77.5, 76.9, 75.9, 73.4, 70.5, 62.0, 51.6,
39.3, 26.8, 26.6, 13.8; MS m/ z (M+) calcd 426.1890, obsd
426.1894; [R]23 -2.0 (c 0.69, CHCl3).
1-Eth yl Hyd r ogen [(E)-[(4S,5S)-5-[(Ben zyloxy)m eth yl]-
2,2-d im eth yl-1,3-d ioxola n -4-yl]m eth ylen e]su ccin a te (12).
A solution of 7 (4.53 g, 18.1 mmol) in dry benzene (120 mL)
was treated with 11 (7.367 g, 18.1 mmol) and stirred under
N2 at 25 °C for 24 h. The solvent was evaporated, and the
residue was chromatographed on silica gel (elution with 30 f
50% ethyl acetate in hexanes) to give 12 (5.45 g, 80%) as a
yellowish oil: IR (film, cm-1) 1714, 1663, 1497; 1H NMR (300
MHz, CDCl3) δ 10.16 (m, 1 H), 7.31 (m, 5 H), 6.89 (d, J ) 8.0
Hz, 1 H), 4.69 (t, J ) 8.0 Hz, 1 H), 4.58 (d, J ) 12.0 Hz, 1 H),
4.52 (d, J ) 12.0 Hz, 1 H), 4.22 (q, J ) 7.2 Hz, 1 H), 4.21 (q,
J ) 7.2 Hz, 1 H), 4.00 (dt, J ) 8.0, 4.1 Hz, 1 H), 3.65 (dd, J )
10.8, 4.1 Hz, 1 H), 3.59 (dd, J ) 10.8, 4.1 Hz, 1 H), 3.52 (d, J
) 17.2 Hz, 1H), 3.43 (d, J ) 17.2 Hz, 1 H), 1.44 (s, 6 H), 1.28
(t, J ) 7.2 Hz, 3 H); 13C NMR (75 MHz, CDCl3) ppm 176.3,
166.1, 140.0, 137.7, 128.7, 128.3, 127.7, 110.3, 79.7, 74.4, 73.6,
68.4, 61.3, 32.7, 26.8. 26.7, 14.0; MS m/ z (M+) calcd 378.1678,
D
1-Eth yl Meth yl 2-[[(4S,5S)-5-[(Ben zyloxy)m eth yl]-2,2-
d im eth yl-1,3-d ioxola n -4-yl]h yd r oxym eth yl]m a lea te, Cy-
clic Ca r bon a te (15). A solution of 14 (1.84 g, 4.31 mmol) in
dry benzene (20 mL) was treated at 0 °C under N2 with N,N′-
carbonyldiimidazole (840 mg, 5.18 mmol), and stirring was
continued for 5 h at rt. The reaction mixture was washed with
water (10 mL), dried, and concentrated. Chromatography of
the residue on silica gel (elution with 15% ethyl acetate in
hexanes) provided 1.78 g (91%) of 15 as a colorless, oily 1:1
mixture of diastereomers: IR (film, cm-1) 1827, 1746, 1687,
1496; 1H NMR (300 MHz, CDCl3) δ 7.33 (m, 5 H), 4.84 (s, 0.5
H), 4.62 (d, J ) 6.0 Hz, 0.5 H), 4.59 (d, J ) 6.0 Hz, 0.5 H),
4.59 (d, J ) 5.8 Hz, 0.5 H), 4.57 (d, J ) 6.9 Hz, 0.5 H), 4.57 (d,
J ) 5.8 Hz, 0.5 H), 4.34 (q, J ) 7.1 Hz, 1 H), 4.30 (q, J ) 7.1
Hz, 0.5 H), 4.29 (q, J ) 7.1 Hz, 0.5 H), 4.40-4.18 (m, 1 H),
4.05 (dd, J ) 9.6, 6.9 Hz, 0.5 H), 3.98 (d, J ) 8.3 Hz, 0.5 H),
3.77 (dd, J ) 9.8, 4.5 Hz, 0.5 H), 3.74 (dd, J ) 10.9, 2.9 Hz,
0.5 H), 3.70 (s, 3 H), 3.61 (dd, J ) 10.9, 4.8 Hz, 0.5 H), 3.57
(dd, J ) 9.8, 6.5 Hz, 0.5 H), 3.44 (d, J ) 17.4 Hz, 0.5 H), 3.36
(s, 1 H), 3.08 (d, J ) 17.4 Hz, 0.5 H), 1.44 (s, 1.5 H), 1.42 (s, 3
H), 1.38 (s, 1.5 H), 1.33 (t, J ) 7.1 Hz, 1.5 H), 1.29 (t, J ) 7.1
Hz, 1.5 H); 13C NMR (75 MHz, CDCl3) ppm 169.0, 168.7, 168.5,
168.4, 152.6, 151.6, 137.7, 137.5, 128.4, 127.9, 127.7, 111.4,
111.3, 82.6, 82.2, 81.5, 80.0, 78.5, 77.1, 74.7, 73.7, 73.6, 72.7,
69.5, 69.4, 63.1, 52.3, 52.2, 36.4, 36.3, 27.2, 27.0, 26.8, 25.8,
13.8; MS m/ z (M+) calcd 452.1682, obsd 452.1684.
obsd 378.1671; [R]24 -34.7 (c 0.80, CHCl3).
D
1-Eth yl Meth yl [(E)-[(4S,5S)-5-[(Ben zyloxy)m eth yl]-2,2-
d im eth yl-1,3-d ioxola n -4-yl]m eth ylen e]su ccin a te (13). To
a mixture of 12 (3.18 g, 8.40 mmol) and triethylamine (3.51
mL, 25.2 mmol) in 1,1-dimethoxyethane (60 mL) was added
N-methyl-N-nitrosourea (2.60 g, 25.2 mmol) with stirring at
0 °C. After 2 days at rt, the solution was diluted with ethyl
acetate (60 mL), washed twice with saturated NaHCO3 solu-
tion (25 mL), water (25 mL), and brine (25 mL), and then dried
and concentrated. Purification of the residue on silica gel
(elution with 20% ethyl acetate in hexanes) gave 13 as a
colorless oil (3.16 g, 96%): IR (film, cm-1) 1742, 1715, 1664,
1497; 1H NMR (300 MHz, CDCl3) δ 7.32 (m, 5 H), 6.84 (d, J )
8.2 Hz, 1 H), 4.68 (t, J ) 8.2 Hz, 1 H), 4.59 (d, J ) 12.0 Hz, 1
H), 4.53 (d, J ) 12.0 Hz, 1 H), 4.22 (q, J ) 7.1 Hz, 1 H), 4.21
(q, J ) 7.1 Hz, 1 H), 4.00 (dt, J ) 8.2, 4.1 Hz, 1 H), 3.66 (dd,
J ) 10.9, 3.6 Hz, 1 H), 3.62 (s, 3 H), 3.59 (dd, J ) 10.9, 4.5 Hz,
1 H), 3.48 (d, J ) 16.8 Hz, 1 H), 3.38 (d, J ) 16.8 Hz, 1 H),
1.45 (s, 6 H), 1.28 (t, J ) 7.1 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 170.8, 166.2, 139.7, 137.8, 129.3, 128.3, 127.6,
127.5, 110.2, 79.9, 74.3, 73.6, 68.5, 61.2, 51.9, 32.6, 26.9, 14.1;
Anal. Calcd for C22H28O10: C, 58.40; H, 6.24. Found: C,
58.33; H, 6.38.
1-E t h yl Met h yl [[(4S,5S)-5-[(Ben zyloxy)m et h yl]-2,2-
d im eth yl-1,3-d ioxola n -4-yl]h yd r oxym eth yl]m a lea te (16).
To a solution of 15 (638 mg, 1.41 mmol) in dry THF (20 mL)
was added DBU (0.084 mL, 0.56 mmol) with stirring at 0 °C
under N2. After 1 h, the mixture was partitioned between
ethyl acetate (20 mL) and saturated NH4Cl solution (20 mL).
The aqueous layer was extracted with ethyl acetate (20 mL),
and the combined organic phases were washed with saturated
NH4Cl solution (10 mL), water (10 mL), and brine (10 mL)
prior to drying and solvent evaporation. The residue was
chromatographed on silica gel (elution with 30% ethyl acetate
in hexanes) to give 16 as a colorless oil (551 mg, 96%): IR
(film, cm-1) 3454, 1728, 1654, 1497; 1H NMR (300 MHz, CDCl3)
δ 7.31 (m, 5 H), 6.28 (d, J ) 1.5 Hz, 0.5 H), 6.19 (d, J ) 1.6
Hz, 0.5 H), 4.58 (s, 1 H), 4.57 (s, 1 H), 4.60-4.50 (m, 1 H),
4.26 (q, J ) 7.1 Hz, 1 H), 4.25 (q, J ) 7.1 Hz, 1 H), 4.25-4.10
(m, 1 H), 4.07 (dd, J ) 8.2, 2.7 Hz, 0.5 H), 3.94 (dd, J ) 7.6,
6.6 Hz, 0.5 H), 3.74 (s, 3 H), 3.68 (dd, J ) 10.0, 4.9 Hz, 0.5 H),
3.67 (dd, J ) 9.9, 5.0 Hz, 0.5 H), 3.61 (dd, J ) 10.0, 5.6 Hz,
0.5 H), 3.56 (dd, J ) 9.9, 5.6 Hz, 0.5 H), 1.41 (s, 1.5 H), 1.39
(s, 3 H), 1.38 (s, 1.5 H), 1.28 (t, J ) 7.1 Hz, 3 H); 13C NMR (75
MHz, CDCl3) ppm 166.6, 165.5, 165.3, 147.8, 146.5, 137.4,
128.4, 127.8, 127.7, 127.6, 122.1, 121.9, 110.0, 109.9, 80.1, 79.4,
77.3, 75.7, 73.7, 72.0, 70.5, 70.1, 69.9, 61.5, 61.4, 51.9, 51.8,
29.3, 26.9, 26.8, 26.7, 13.8; MS m/ z (M+) calcd 408.1784, obsd
408.1787.
MS m/ z (M+) calcd 392.1835, obsd 392.1836; [R]21 -57.8 (c
D
1.00, CHCl3).
1-Eth yl Meth yl 2-[[(4S,5S)-5-[(Ben zyloxy)m eth yl]-2,2-
d im eth yl-1,3-d ioxola n -4-yl]h yd r oxym eth yl]m a lea te (14).
A solution of 13 (3.18 g, 8.05 mmol) and N-methylmorpholine
N-oxide (1.42 g, 25.2 mmol) in acetone-water (8:1, 150 mL)
was treated with osmium tetraoxide (20 mg, 0.08 mmol) and
stirred for 1 week at rt. The reaction mixture was cooled to 0
°C, quenched with saturated NaHSO3 solution (40 mL), and
freed of acetone under reduced pressure. The product was
extracted into ethyl acetate (3 × 120 mL), dried, and concen-
trated. Purification of the product by chromatography on silica
gel (elution with 30% ethyl acetate in hexanes) afforded 14 as
a colorless, oily mixture of diastereomers (3.05 g, 89%). This
mixture was used without further purification.
Separation was achieved by a second chromatography as
above (elution with 20% ethyl acetate in hexanes).
For the less polar isomer: IR (film, cm-1) 3505, 1797, 1743,
Anal. Calcd for C21H28O8: C, 61.75; H, 6.91. Found: C,
61.47; H, 7.02.
1
1688, 1475; H NMR (300 MHz, CDCl3) δ 7.32 (m, 5 H), 4.57
(s, 2 H), 4.25 (q, J ) 7.1 Hz, 2 H), 4.20 (dt, J ) 8.6, 4.6 Hz, 1
H), 4.17 (dd, J ) 10.5, 8.6 Hz, 1 H), 3.67 (s, 3 H), 3.64 (dd, J
) 10.4, 4.9 Hz, 1 H), 3.56 (dd, J ) 10.4, 4.3 Hz, 1 H), 3.55 (d,
J ) 10.5 Hz, 1 H), 3.29 (d, J ) 16.5 Hz, 1 H), 2.72 (d, J ) 16.5
Hz, 1 H), 1.38 (s, 3 H), 1.37 (s, 3 H), 1.31 (t, J ) 7.1 Hz, 3 H);
13C NMR (75 MHz, CDCl3) ppm 173.1, 171.1, 137.8, 128.3,
127.5, 109.9, 76.3, 75.8, 75.2, 73.3, 72.8, 69.9, 62.5, 51.7, 41.4,
27.1, 26.7, 13.9; MS m/ z (M+) calcd 426.1890, obsd 426.1883;
1-E t h yl Met h yl [[(4R,5S)-5-[(Ben zyloxy)m et h yl]-2,2-
d im et h yl-1,3-d ioxola n -4-yl](ter t-b u t yld im et h ylsiloxy)-
m eth yl]m a lea te (17). A solution of 16 (199 mg, 0.49 mmol)
and 2,6-lutidine (0.23 mL, 1.95 mmol) in dry CH2Cl2 (10 mL)
was treated with tert-butyldimethylsilyl triflate (0.34 mL, 1.46
mmol), stirred at rt under N2 for 1.5 h, and washed sequen-
tially with saturated NaHCO3 solution (5 mL), water (5 mL),
and brine (5 mL) prior to drying and solvent evaporation. The
residue was purified by chromatography on silica gel (elution
with 20% ethyl acetate in hexanes), and 17 was obtained as a
colorless oil (250 mg, 98%): IR (film, cm-1) 1732; 1H NMR (300
MHz, CDCl3) δ 7.50-7.20 (m, 5 H), 6.18 (d, J ) 1.3 Hz, 0.5
H), 6.17 (d, J ) 1.3 Hz, 0.5 H), 4.75 (dd, J ) 4.3, 1.3 Hz, 0.5
[R]23 -10.7 (c 0.80, CHCl3).
D
For the more polar isomer: IR (film, cm-1) 3485, 1798, 1714,
1493; 1H NMR (300 MHz, CDCl3) δ 7.32 (m, 5 H), 4.61 (d, J )
12.2 Hz, 1 H), 4.55 (d, J ) 12.2 Hz, 1 H), 4.28 (q, J ) 7.1 Hz,
2 H), 4.40-4.15 (m, 1 H), 4.01 (t, J ) 8.0 Hz, 1 H), 3.75 (d, J

6690 J . Org. Chem., Vol. 61, No. 19, 1996
Maezaki et al.
H), 4.63-4.55 (m, 0.5 H), 4.61 (d, J ) 12.4 H, 0.5 H), 4.60 (d,
J ) 12.2 Hz, 0.5 H), 4.53 (d, J ) 12.4 Hz, 0.5 H), 4.51 (d, J )
12.2 Hz, 0.5 H), 4.23 (q, J ) 7.1 Hz, 2 H), 4.35-4.05 (m, 1 H),
3.97 (dd, J ) 8.2, 4.3 Hz, 0.5 H), 3.88 (dd, J ) 7.5, 5.4 Hz, 0.5
H), 3.74 (s, 1.5 H), 3.73 (s, 1.5 H), 3.75-3.60 (m, 0.5 H), 3.66
(dd, J ) 10.5, 2.6 Hz, 0.5 H), 3.55 (d, J ) 10.3, 6.1 Hz, 0.5 H),
3.47 (dd, J ) 10.5, 6.8 Hz, 0.5 H), 1.39 (s, 1.5 H), 1.38 (s, 3 H),
1.37 (s, 1.5 H), 1.29 (t, J ) 7.1 Hz, 1.5 H), 1.27 (t, J ) 7.1 Hz,
1.5 H), 0.89 (s, 4.5 H), 0.87 (s, 4.5 H), 0.11 (s, 1.5 H), 0.06 (s,
3 H), 0.04 (s, 1.5 H); 13C NMR (75 MHz, CDCl3) ppm 166.4,
166.3, 165.5, 165.4, 148.7, 147.3, 138.1, 128.3, 127.6, 127.5,
122.9, 121.9, 109.8, 109.6, 78.7, 78.6, 77.5, 76.2, 73.4, 72.9, 71.7,
71.6, 70.9, 61.5, 61.4, 51.9, 27.1, 27.0, 26.6, 25.8, 25.7, 18.1,
18.0, 13.9, 13.8, -4.8, -4.9, -5.1, -5.2; MS m/ z (M+) calcd
522.2649, obsd 522.2668.
82.0, 80.9, 79.1, 78.5, 73.6, 71.9, 27.1, 27.0, 15.4; MS m/ z (M+)
calcd 455.1021, obsd 455.1008; [R]25 +10.6 (c 1.31, CHCl3).
D
Meth yl (rR,4R,5S)-5-[(Ben zyloxy)m eth yl]-r-3-fu r yl-2,2-
d im eth yl-1,3-d ioxola n e-4-glycola te (20). A mixture of 19
(7.16 g, 16.2 mmol), mercuric oxide (5.61 g, 25.9 mmol), and
mercuric chloride (16.7 g, 61.4 mmol) in methanol-water (12:
1, 440 mL) was stirred at 60 °C for 2 h. After filtration, the
mercury salts were rinsed with CH2Cl2 (220 mL), and the
combined filtrates were concentrated under reduced pressure.
The residue was partitioned between water (200 mL), and
CH2Cl2 (160 mL), and the aqueous layer was further extracted
with CH2Cl2 (2 × 160 mL). The combined organic layers were
washed with NH4OAc (3 × 100 mL) and NH4Cl solutions (2 ×
100 mL), dried, and evaporated. Chromatography of the
residue on silica gel (elution with 20% ethyl acetate in hexanes)
gave 4.55 g (75%) of 20 along with 1.21 g (23%) of ketone 18.
Con ver sion of 17 to 10. A cold (-78 °C), magnetically
stirred solution of 17 (58 mg, 0.11 mmol) in dry toluene (3 mL)
was blanketed with N2 and treated dropwise with diisobutyl-
aluminum hydride (0.55 mL of 1.0 M in hexanes, 0.55 mmol).
After 30 min, an additional equivalent quantity of reducing
agent was added, and the temperature was raised to -20 °C
during 1.5 h. The reaction mixture was quenched with
saturated potassium sodium tartrate solution, and the organic
phase was dried and concentrated. Rapid filtration of the
residue through silica gel (50% ethyl acetate in hexanes as
eluent) gave the diol as an unstable colorless oil (8 mg, 15%),
which was immediately dissolved in dry CH2Cl2 (2 mL), treated
sequentially with 2,6-lutidine (0.008 mL, 0.067 mmol) and
triisopropylsilyl triflate (0.014 mL, 0.0050 mmol) under N2 at
rt, and stirred for 30 min. The reaction mixture was washed
with saturated NaHCO3 solution, dried, and evaporated. The
product was purified chromatographically as above (elution
with 5% ethyl acetate in hexanes) to give 11 mg (86%) of 10,
identical in all respects to the material described earlier.
1
For 20: colorless oil; IR (film, cm-1) 3515, 1780; H NMR
(300 MHz, CDCl3) δ 7.51 (dd, J ) 1.7, 0.8 Hz, 1 H), 7.40-7.20
(m, 6 H), 6.48 (dd, J ) 1.7, 0.8 Hz, 1 H), 4.53 (s, 2 H), 4.28 (s,
2 H), 3.73 (s, 3 H), 3.43 (dd, J ) 10.8, 2.7 Hz, 1 H), 3.36 (dd,
J ) 10.9, 4.3 Hz, 1 H), 1.41 (s, 3 H), 1.38 (s, 3 H); 13C NMR
(75 MHz, CDCl3) ppm 172.4, 142.9, 140.7, 137.8, 128.3, 127.8,
127.6, 124.0, 110.3, 109.6, 81.8, 76.4, 75.0, 73.4, 70.7, 53.1, 27.2,
26.8; MS m/ z (M+) calcd 376.1522, obsd 376.1506; [R]24D -17.0
(c 1.22, CHCl3).
(rS ,4R ,5S )-5-[(Be n zyloxy)m e t h yl]-r-[(t er t -b u t yld i-
m eth ylsiloxy)-m eth yl]-r-[(E)-3-(ter t-bu tyldim eth ylsiloxy)-
1-[(ter t -b u t yld im et h ylsiloxy)m et h yl]p r op en yl]-2,2-d i-
m eth yl-1,3-d ioxola n e-4-m eth a n ol (21). A slow stream of
O2 was passed through a solution of 20 (165 mg, 0.44 mmol)
and rose bengal (10 mg) in ethanol (10 mL). This solution was
cooled to -78 °C, irradiated with a tungsten lamp for 10 min,
and poured into a precooled (-78 °C) mixture of sodium
borohydride (52 mg, 1.39 mmol) in ethanol (2 mL). The
temperature was raised to 0 °C during 1.5 h, at which point
the mixture was concentrated to 25% of its volume under
reduced pressure and diluted with ethyl acetate (75 mL). The
organic phase was washed with brine (2 × 20 mL), dried, and
concentrated to leave a residue that was dissolved in dry DMF
(2 mL) and treated with tert-butyldimethylsilyl chloride (211
mg, 1.4 mmol) and imidazole (191 mg, 2.8 mmol). This
mixture was stirred at rt for 2.5 days, diluted with ethyl
acetate (75 mL), and washed with brine (2 × 20 mL) prior to
drying and concentration under reduced pressure. Flash
chromatography of the residue on silica gel (elution with 10%
ethyl acetate in hexanes) afforded 21 (80 mg, 26%) as a
colorless oil: IR (film, cm-1) 3539; 1H NMR (300 MHz, CDCl3)
δ 7.36-7.24 (m, 5 H), 5.93 (t, J ) 5.7 Hz, 1 H), 4.59 (s, 2 H),
4.36 (dd, J ) 5.6, 1.9 Hz, 2 H), 4.27 (d, J ) 11.6 Hz, 1 H), 4.19
(d, J ) 11.6 Hz, 1 H), 4.17 (ddd, J ) 5.9, 5.9, 2.6 Hz, 1 H),
4.07 (d, J ) 8.3 Hz, 1 H), 3.83 (d, J ) 10.1 Hz, 1 H), 3.73 (dd,
J ) 10.4, 2.6 Hz, 1 H), 3.57 (dd, J ) 10.4, 6.2 Hz, 1 H), 3.55
(d, J ) 10.1 Hz, 1 H), 3.26 (s, 1 H), 1.37 (s, 6 H), 0.90 (s, 9 H),
0.89 (s, 9 H), 0.88 (s, 9 H), 0.065 (s, 6 H), 0.061 (s, 6 H), 0.05
(s, 3 H), 0.04 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 138.3,
136.8, 132.6, 128.2, 127.6, 127.4, 108.7, 78.6, 76.8, 75.8, 73.3,
71.6, 67.2, 60.3, 58.7, 27.1, 26.9, 25.94, 25.85, 18.3, 18.2, -5.15,
-5.18, -5.4, -5.46, -5.52; MS m/ z molecular ion too elusive
to be accurately mass measured.
(4R ,5S )-5-[(Be n zyloxy)m e t h yl]-2,2-d im e t h yl-1,3-d i-
oxola n -4-yl 3-F u r yl Keton e (18). A solution of oxalyl
chloride (4.7 mL, 54 mmol) in dry CH2Cl2 (100 mL) at -78 °C
under N2 was treated dropwise with DMSO (4 mL, 58.5 mmol)
and stirred for 10 min. Following the addition of 8 (9.3 g, 29.2
mmol) in CH2Cl2 (50 mL) and a 30-min wait, triethylamine
(18.76 mL, 135 mmol) was introduced and the reaction mixture
was allowed to warm to rt during 1.5 h and diluted with water.
The organic phase was washed with brine, dried, and concen-
trated to leave a residue that was chromatographed on silica
gel (elution with 10% ethyl acetate in hexanes) to give 18 as
a colorless oil (8.4 g, 91%): IR (film, cm-1) 1666, 1560, 1511;
1H NMR (300 MHz, CDCl3) δ 8.40 (br s, 1 H), 7.43 (br s, 1 H),
7.40-7.20 (m, 5 H), 6.84 (br s, 1 H), 4.65 (d, J ) 7.2 Hz, 1 H),
4.64 (s, 2 H), 4.45 (ddd, J ) 7.2, 5.2, 3.2 Hz, 1 H), 3.82 (dd, J
) 10.8, 3.2 Hz, 1 H), 3.68 (dd, J ) 10.8, 5.2 Hz, 1 H), 1.53 (s,
3 H), 1.42 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 193.0, 149.6,
143.0, 137.4, 127.9, 127.2, 124.4, 110.7, 108.6, 80.5, 76.2, 73.1,
69.6, 26.5, 25.8; MS m/ z (M+) calcd 316.1311, obsd 316.1315;
[R]26 -39.1 (c 1.44, CHCl3).
D
Tr im eth yl (rR,4R,5S)-5-[(Ben zyloxy)m eth yl]-r-3-fu r yl-
2,2-d im eth yl-tr ith io-1,3-d ioxola n e-4-or th oglycola te (19).
A cold (-78 °C), magnetically stirred solution of tris(methyl-
thio)methane (0.37 mL, 2.76 mmol) in dry THF (10 mL) was
treated with n-butyllithium (1.72 mL of 1.6 M in hexanes, 2.76
mmol) under N2. After 15 min, a solution of 18 (436 mg, 1.38
mmol) in dry THF (2 mL) was introduced, and stirring was
maintained at -78 °C for 1 h and at -20 °C for 30 min. The
reaction mixture was quenched with saturated NH4Cl solution
(5 mL) and extracted with ethyl acetate (2 × 10 mL). The
combined organic layers were washed with brine (5 mL), dried,
and evaporated to leave a residue that was chromatographed
on silica gel (elution with 10% ethyl acetate in hexanes) to
give 609 mg (94%) of 19 as a colorless oil: IR (film, cm-1) 3450;
1H NMR (300 MHz, C6D6) δ 7.66 (dd, J ) 1.5, 0.9 Hz, 1 H),
7.35-7.00 (m, 6 H), 6.86 (dd, J ) 1.5, 0.4 Hz, 1 H), 5.00 (d, J
) 4.9 Hz, 1 H), 4.45 (d, J ) 12.3 Hz, 1 H), 4.40 (d, J ) 12.3
Hz, 1 H), 4.11 (ddd, J ) 8.0, 4.7, 3.5 Hz, 1 H), 3.96 (s, 1 H),
3.82 (dd, J ) 10.3, 3.5 Hz, 1 H), 3.72 (dd, J ) 10.3, 4.7 Hz, 1
H), 1.93 (s, 9 H), 1.40 (s, 3 H), 1.27 (s, 3 H); 13C NMR (75 MHz,
C6D6) ppm 142.7, 141.1, 128.5, 127.9, 127.8, 125.4, 113.5, 110.1,
(3R,4R,5S)-5-[(Ben zyloxy)m et h yl]-4,5-d ih yd r o-3,4-d i-
h yd r oxy[3,3′-bifu r a n ]-2(3H)-on e (22). A solution of 20 (825
mg, 2.19 mmol) in THF (20 mL) was treated with 1 N HCl (20
mL), heated at 70 °C for 10 h, cooled, and diluted with
saturated NaHCO3 solution (50 mL). The mixture was
extracted with ethyl acetate (2 × 50 mL) and the combined
organic layers were washed with water (50 mL) and brine (50
mL), dried, and evaporated. Recrystallization of the solid from
30% ethyl acetate in hexanes gave 22 (577 mg, 87%) as
colorless needles, mp 100-101 °C; IR (KBr, cm-1) 3500, 3240,
1800; 1H NMR (300 MHz, CDCl2) δ 7.46 (br s, 1 H), 7.42 (br s,
1 H), 7.33 (m, 5 H), 6.46 (br s, 1 H), 4.58 (br s, 2 H), 4.50 (m,
1 H), 4.41 (d, J ) 4.4 Hz, 1 H), 4.10-3.75 (m, 2 H), 3.62 (m, 2
H); 13C NMR (75 MHz, CDCl3) ppm 175.6, 144.4, 140.9, 137.0,
128.6, 128.1, 127.9, 121.6, 108.5, 78.9, 74.1, 73.9 (2 C), 67.5;
MS m/ z (M+) calcd 304.0947, obsd 304.0941; [R]23 +10.1 (c
D
1.08, CHCl3).

Construction of the Zaragozic Acid Core
J . Org. Chem., Vol. 61, No. 19, 1996 6691
Anal. Calcd for C16H16O6: C, 63.14; H, 5.30. Found: C,
63.18; H, 5.36.
layers were dried and concentrated. Chromatography of the
residue on silica gel (elution with 33% ethyl acetate in hexanes)
gave 27 (7.94 g, 95%) as a colorless oil (â/R ) 21:1); H NMR
1
Tr im eth yl (4S,5S)-5-[(Ben zyloxy)m eth yl]-2,2-d im eth -
yltr ith io-1,3-d ioxola n e-4-or th oglycola te (23). To a solu-
tion of tris(methylthio)methane (2.0 mL, 15 mmol) in dry THF
(50 mL) was added n-butyllithium in hexanes (9.4 mL of 1.6
M, 15 mmol) at -78 °C. After 15 min, a solution of 7 (1.88 g,
7.5 mmol) in dry THF (5 mL) was introduced dropwise, and
stirring was continued for 1 h at -78 °C. The temperature
was raised to -20 °C over 30 min, at which point 30 mL of
saturated NH4Cl solution was added. The separated aqueous
phase was extracted with ethyl acetate (2 × 40 mL), and the
combined organic layers were dried and evaporated. Flash
chromatography of the residue on silica gel (elution with 25%
ethyl acetate in hexanes) gave 2.70 g (89%) of 23 as a colorless
(300 MHz, C6D6) δ 7.31 (dd, J ) 1.7, 0.8 Hz, 1 H), 7.19-7.01
(m, 5 H), 6.92 (t, J ) 1.7 Hz, 1 H), 6.06 (dd, J ) 1.7, 0.8 Hz, 1
H), 4.36 (ddd, J ) 6.3, 4.0, 2.3 Hz, 1 H), 4.24 (d, J ) 12.1 Hz,
1 H), 4.23 (d, J ) 8.1 Hz, 1 H), 4.14 (d, J ) 12.1 Hz, 1 H), 3.77
(d, J ) 11.2 Hz, 1 H), 3.52 (d, J ) 11.2 Hz, 1 H), 3.31 (br, 1 H),
3.24 (dd, J ) 11.0, 2.0 Hz, 1 H), 2.81 (dd, J ) 11.0, 4.0 Hz, 1
H), 2.53 (br, 1 H), 1.38 (s, 3 H), 1.31 (s, 3 H); 13C NMR (75
MHz, CDCl3) ppm 143.2, 139.5, 137.8, 128.2, 127.5, 127.4,
124.6, 109.7, 107.7, 81.0, 76.3, 73.1, 71.3, 69.9, 69.5, 27.0, 26.8;
MS m/ z (M+) calcd 348.1573, obsd 348.1563; [R]23 -20.0 (c
D
1.28, EtOAc).
Anal. Calcd for C19H24O6: C, 65.49; H, 6.95. Found: C,
64.95; H, 6.85.
oil consisting of a 1:1 mixture of diastereomers: IR (film, cm-1
)
1
3464; H NMR (300 MHz, CDCl3) δ 7.38-7.23 (m, 5 H), 4.63
(s, 1 H), 4.57 (s, 1 H), 4.53-4.42 (m, 1 H), 4.25 (t, J ) 6.9 Hz,
0.5 H), 4.15 (ddd, J ) 5.2, 5.2, 8.5 Hz, 0.5 H), 3.84-3.56 (m, 3
H), 3.26 (d, J ) 3.8 Hz, 0.5 H), 3.19 (d, J ) 11.0 Hz, 0.5 H),
2.18 (s, 4.5 H), 2.13 (s, 4.5 H), 1.46 (s, 1.5 H), 1.44 (s, 3 H),
1.42 (s, 1.5 H); 13C NMR (75 MHz, CDCl3) ppm 138.3, 137.8,
128.4, 128.3, 128.2, 127.74.127.68, 127.5, 110.3, 109.8, 78.4,
77.8, 77.5, 77.4, 76.6, 74.7, 74.3, 73.6, 73.3, 71.4, 70.1, 27.2,
27.1, 26.8, 26.6, 13.9, 13.5; MS m/ z (M+ - SCH3) calcd
357.1194, obsd 357.1198.
(S)-1-[[(4R,5S)-5-[(Ben zyloxy)m eth yl]-2,2-d im eth yl-1,3-
d ioxola n -4-yl]-1-(3-fu r yl)-1,2-eth a n ed iol (28). A cold (0
°C), magnetically stirred solution of 20 (270 mg, 0.72 mmol)
in dry THF (3 mL) was treated with lithium aluminum hydride
(56 mg, 1.47 mmol), stirred at 0 °C for 30 min and at rt for 30
min, and diluted with ether (20 mL) prior to being quenched
with a few drops of 1 N NaOH solution. After 30 min of
stirring, anhydrous MgSO4 was introduced. The mixture was
agitated for 1 h, filtered, and freed of solvent to leave a residue
that was purified chromatographically (silica gel, elution with
30% ethyl acetate in hexanes). There was isolated 208 mg
Tr im eth yl (4R,5S)-5-[(Ben zyloxy)m eth yl]-2,2-d im eth -
yltr ith io-1,3-d ioxola n e-4-or th oglycola te (24). A solution
of 23 (469 mg, 1.16 mmol) in dry CH2Cl2 (10 mL) was treated
with the Dess-Martin periodinane (591 mg, 1.36 mmol),
stirred at rt for 45 min, and diluted with ether (70 mL). The
organic phase was washed with saturated NaHCO3/5% Na2S2O3
solution (25 mL), water (25 mL), and brine (25 mL), dried, and
evaporated. Flash chromatography of the residue on silica gel
(elution with 15% ethyl acetate in hexanes) furnished 100 mg
1
(83%) of 28 as a colorless oil: IR (film, cm-1) 3410; H NMR
(300 MHz, CDCl3) δ 7.43-7.28 (m, 7 H), 6.42 (dd, J ) 6.8, 1.6
Hz, 1 H), 4.59 (s, 2 H), 4.29 (s, 1 H), 4.12 (d, J ) 8.1 Hz, 1 H),
3.87 (ddd, J ) 8.1, 7.6, 4.5 Hz, 1 H), 3.81 (br d, J ) 12 Hz, 1
H), 3.71 (dd, J ) 9.2, 4.5 Hz, 1 H), 3.66 (d, J ) 11.3 Hz, 1 H),
3.56 (dd, J ) 9.2, 7.6 Hz, 1 H), 2.42 (br s, 1 H), 1.38 (s, 3 H),
1.32 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 142.6, 140.2,
136.7, 128.6, 128.2, 128.0, 126.1, 109.5, 109.3, 81.3, 75.3, 73.9,
73.1, 70.8, 67.9, 26.8, 26.7; MS m/ z (M+) calcd 348.1573, obsd
348.1559.
1
(21%) of 24 as a colorless oil: IR (film, cm-1) 1703; H NMR
(300 MHz, CDCl3) δ 7.34-7.24 (m, 5 H), 5.25 (d, J ) 7.3 Hz,
1 H), 4.65 (d, J ) 12.3 Hz, 1 H), 4.54 (d, J ) 12.3 Hz, 1 H),
4.42 (ddd, J ) 3.4, 6.1 , 7.3 Hz, 1 H), 3.71 (dd, J ) 3.4, 10.7
Hz, 1 H), 3.62 (dd, J ) 6.1, 10.7 Hz, 1 H), 1.95 (s, 9 H), 1.49 (s,
3 H), 1.48 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 197.7, 137.8,
128.4, 128.1, 127.7, 112.2, 79.5, 79.3, 75.0, 73.4, 69.6, 27.5, 26.2,
13.1; MS m/ z (M+ - SCH3) calcd 355.1038, obsd 355.1039;
(rR ,4R ,5S )-5-[(Be n zyloxy)m e t h yl]-R-[(t er t -b u t yld i-
m eth ylsiloxy)m eth yl]-R-3-fu r yl-2,2-dim eth yl-1,3-dioxolan e-
4-m eth a n ol (29). A solution of 27 (801 mg, 2.3 mmol), tert-
butyldimethylsilyl chloride (416 mg, 2.76 mmol), and imidazole
(235 mg, 3.45 mmol) in DMF (2 mL) was stirred at rt for 15 h,
quenched with water (8 mL), and extracted with ether. The
combined organic phases were washed with water and brine,
dried, and concentrated to leave a residue that was purified
by flash chromatography on silica gel (elution with 10% ethyl
acetate in hexanes). There was isolated 1.042 g (98%) of 29
as a colorless oil: IR (film, cm-1) 3453; 1H NMR (200 MHz,
C6D6) δ 7.56 (dd, J ) 1.7, 0.8 Hz, 1 H), 7.25-7.06 (m, 5 H),
7.00 (t, J ) 1.7 Hz, 1 H), 6.43 (dd, J ) 1.7, 0.8 Hz, 1 H), 4.60
(d, J ) 8.3 Hz, 1 H), 4.38 (ddd, J ) 6.0, 3.9, 2.1 Hz, 1 H), 4.30,
4.18 (ABq, J ) 22.9, 12.0 Hz, 2 H), 3.80, 3.72 (ABq, J ) 15.8,
9.2 Hz, 2 H), 3.35 (dd, J ) 10.8, 2.1 Hz, 1 H), 2.88 (dd, J )
10.8, 4.0 Hz, 1 H), 2.79 (s, 1 H), 1.48 (s, 3 H), 1.40 (s, 3 H),
0.90 (s, 9 H), -0.10 (s, 3 H), -0.20 (s, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 142.4, 139.4, 138.0, 128.1, 127.4, 127.3, 126.0,
109.0, 108.8, 77.5, 75.9, 73.0, 71.6, 70.5, 68.1, 27.0, 26.9, 25.7,
[R]25 +10.2 (c 1.5, CHCl3).
D
(4S,5S)-4-[(Ben zyloxy)m eth yl]-5-[1-(3-fu r yl)vin yl]-2,2-
d im et h yl-1,3-d ioxola n e (26). A suspension of methyltri-
phenylphosphonium bromide (1.738 g, 4.87 mmol) in dry THF
(10 mL) at 0 °C under N2 was treated dropwise with n-
butyllithium (2.76 mL of 1.6 M in hexanes, 4.42 mmol),
warmed to rt for 1 h, and recooled to 0 °C during the addition
of 18 (700 mg, 2.21 mmol) in THF (5 mL). After 1 h at rt, the
reaction mixture was quenched with saturated NH4Cl solution
and extracted with ethyl acetate. The combined organic
phases were washed with water and brine prior to drying and
concentration. The residue was purified by chromatography
on silica gel (elution with 5% ethyl acetate in hexanes) to give
677 mg (97%) of 26 as a colorless oil: IR (film, cm-1) 1453,
1370, 1166; 1H NMR (200 MHz, C6D6) δ 7.69 (t, J ) 1.1 Hz, 1
H), 7.26-7.06 (m, 5 H), 7.01 (t, J ) 1.8 Hz, 1 H), 6.31 (dd, J
) 1.8, 0.8 Hz, 1 H), 5.31 (t, J ) 1.2 Hz, 1 H), 5.22 (d, J ) 1.4
Hz, 1 H), 4.82 (dd, J ) 8.4, 0.8 Hz, 1 H), 4.36, 4.26 (ABq, J )
19.8, 12.2 Hz, 2 H), 4.01 (ddd, J ) 6.9, 4.0, 2.9 Hz, 1 H), 3.48
(dd, J ) 11.1, 2.9 Hz, 1 H), 3.33 (dd, J ) 11.1, 4.0 Hz, 1 H),
1.45 (s, 3 H), 1.42 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm
142.7, 139.5, 137.9, 136.5, 128.2, 127.5, 122.9, 113.7, 109.2,
108.8, 80.0, 79.2, 73.4, 69.2, 27.0, 26.8; MS m/ z (M+) calcd
18.1, -5.5, -5.7; MS m/ z (M+) 462.2437, obsd 462.2449; [R]23
-6.5 (c 0.55, EtOAc).
D
Anal. Calcd for C25H38O6Si: C, 64.90; H, 8.28. Found: C,
65.09; H, 8.33.
(rR ,4R ,5S )-5-[(Be n zyloxy)m e t h yl]-R-[(t er t -b u t yld i-
m eth ylsiloxy)m eth yl]-R-[(E)-3-(ter t-bu tyldim eth ylsiloxy)-
1-[(ter t -b u t yld im et h ylsiloxy)m et h yl]p r op en yl]-2,2-d i-
m eth yl-1,3-d ioxola n e-4-m eth a n ol (30). A solution of 29
(231 mg, 0.50 mmol) in ethanol (8 mL) containing rose bengal
(10 mg) was photo-oxygenated at -78 °C in the predescribed
manner for 15 min and poured into a precooled (-78 °C)
mixture of sodium borohydride (76 mg, 2 mmol) in ethanol (4
mL). After being warmed to 0 °C during 2 h, the reaction
mixture was concentrated and extracted with ethyl acetate.
The organic solution was washed with brine, dried, and
evaporated to leave an oil that was dissolved in DMF (2 mL)
and treated with tert-butyldimethylsilyl chloride (301 mg, 2.0
mmol) and imidazole (204 mg, 3.0 mmol). The mixture was
stirred at rt for 24 h and processed in the predescribed manner
314.1518, obsd 314.1514; [R]23 -8.3 (c 2.53, EtOAc).
D
(R)-1-[[(4R,5S)-5-[(Ben zyloxy)m eth yl]-2,2-d im eth yl-1,3-
d ioxola n -4-yl]-1-(3-fu r yl)-1,2-eth a n ed iol (27). A mixture
of AD-mix-â (33.6 g) in tert-butyl alcohol (120 mL) and water
(120 mL) was stirred at rt until both phases were clear. After
the mixture was cooled to 0 °C, 26 (7.545 g, 24 mmol) was
added in one portion and the heterogeneous slurry was stirred
vigorously at 0 °C for 10 h, quenched by addition of sodium
sulfite (36 g), warmed to rt, and stirred for 1 h. The product
was extracted into ethyl acetate, and the combined organic

6692 J . Org. Chem., Vol. 61, No. 19, 1996
Maezaki et al.
to give after silica gel chromatography (elution with 5% ethyl
Ack n ow led gm en t. Partial support of this work by
the National Institutes of Health and Eli Lilly and Co.
is gratefully acknowledged. We thank Dr. J udith Gal-
lucci for the crystallographic analysis and Dr. Kurt
Loening for his assistance with nomenclature.
acetate in hexanes) 30 as a colorless oil (213 mg, 60%): IR
1
(film, cm-1) 3395; H NMR (300 MHz, C6D6) δ 7.47-7.14 (m,
5 H), 6.33 (t, J ) 5.8 Hz, 1 H), 4.72-4.67 (m, 1 H), 4.58-4.56
(m, 3 H), 4.53 (d, J ) 2.8 Hz, 1 H), 4.52 (d, J ) 2.8 Hz, 1 H),
4.47, 4.41 (ABq, J ) 17.9, 11.9 Hz, 2 H), 4.06, 3.98 (ABq, J )
23.4, 9.8 Hz, 2 H), 3.88 (dd, J ) 10.9, 2.3 Hz, 1 H), 3.70 (dd, J
) 9.8, 4.7 Hz, 1 H), 3.24 (s, 1 H), 1.54 (s, 3 H), 1.53 (s, 3 H),
1.04 (s, 9 H), 1.01 (s, 9 H), 1.00 (s, 9 H), 0.17 (s, 6 H), 0.13 (s,
6 H), 0.12 (s, 6 H); 13C NMR (75 MHz, CDCl3) ppm 138.2, 137.3,
131.2, 128.1, 127.4, 127.2, 109.0, 79.0, 76.1, 75.3, 73.1, 71.7,
67.0, 59.9, 58.8, 27.2, 26.8, 25.8, 25.7, 25.6, 18.2, 18.0, -5.3,
-5.4, -5.6, -5.7; MS m/ z molecular ion too elusive to be
Su p p or tin g In for m a tion Ava ila ble: Copies of the high-
field 1H and 13C NMR spectra of those compounds for which
elemental analyses are not reported and an ORTEP diagram
of 22 (31 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
accurately mass measured; [R]23 -3.2 (c 0.86, EtOAc).
D
Anal. Calcd for C37H70O6Si3: C, 62.49; H, 9.92. Found: C,
62.52; H, 9.70.
J O960963+