Synthesis of methylene-expanded oxetanocin isonucleosides in both enantiomeric forms

Article abstract of DOI:10.1021/jo971890c

We report a novel route to isonucleosides of the 'methylene-expanded' oxetanocin class, in both the D- and L-enantiomeric forms, e.g., compounds L- (+)-2a, D-(-)-2a, and L-(-)-2b, beginning with the simple, known mono-p- bromobenzyl ether 3 of the very inexpensive 2-butene-1,4-diol. Sharpless asymmetric epoxidation of 3 gave either (-) or (+)-4 depending on the chirality of the tartrate used. The p-bromobenzyl ether was used since the epoxide product is crystalline and can be recrystallized to high optical purity. Opening of the epoxide with vinylmagnesium bromide gave the 1,3-diol 5, the primary alcohol of which was protected as the silyl ether 6. Treatment of 6 with iodonium bis(sym-collidine) perchlorate afforded the desired 5- (iodomethyl)tetrahydrofuran-3-ol 8 with loss of the bromobenzyl cation in the key step in the synthetic scheme. This iodide 8 was then converted into the bis(silyloxy)-protected alcohol 15 by acetylation to give the acetate 10, displacement of iodide with acetate, hydrolysis, and selective protection of the primary alcohols. The alcohol 6 could also be converted into 15 via initial acetylation and then iodocyclization to give 10. The diol 5 could also be converted into 15 by a similar route involving bis-acetylation and iodocyclization followed by functional group transformations. The tosylate of 15 was displaced with the anion of adenine or thymidine to give, after final desilylation, the desired isonucleosides-the D-adenosine analogue (-)-2a and the L-adenosine and thymidine analogues (+)-2a and (-)-2b. All of the stereochemistry of the final products is derived from the first step of the synthesis, namely, the Sharpless asymmetric epoxidation of 3. The biological activity of the new compounds L-(+)-2a and L-(-)-2b against HIV was determined in the anti-HIV drug-testing system of the National Cancer Institute. The adenosine analogue L-(+)-2a was inactive in this screen, while the thymidine analogue L-(-)-2b showed moderate anti-HIV activity (IC₅₀ > 2 x 10^-4 M, EC₅₀ = 8 x 10^-1⁷ M, TI₅₀ > 250).

Full text of DOI:10.1021/jo971890c

J . Org. Chem. 1998, 63, 347-355
347
Syn th esis of Meth ylen e-Exp a n d ed Oxeta n ocin Ison u cleosid es in
Both En a n tiom er ic F or m s1
Michael E. J ung*,2 and Christopher J . Nichols3
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569
Received October 13, 1997X
We report a novel route to isonucleosides of the ‘methylene-expanded’ oxetanocin class, in both the
D- and L-enantiomeric forms, e.g., compounds L-(+)-2a , D-(-)-2a , and L-(-)-2b, beginning with the
simple, known mono-p-bromobenzyl ether 3 of the very inexpensive 2-butene-1,4-diol. Sharpless
asymmetric epoxidation of 3 gave either (-) or (+)-4 depending on the chirality of the tartrate
used. The p-bromobenzyl ether was used since the epoxide product is crystalline and can be
recrystallized to high optical purity. Opening of the epoxide with vinylmagnesium bromide gave
the 1,3-diol 5, the primary alcohol of which was protected as the silyl ether 6. Treatment of 6 with
iodonium bis(sym-collidine) perchlorate afforded the desired 5-(iodomethyl)tetrahydrofuran-3-ol 8
with loss of the bromobenzyl cation in the key step in the synthetic scheme. This iodide 8 was
then converted into the bis(silyloxy)-protected alcohol 15 by acetylation to give the acetate 10,
displacement of iodide with acetate, hydrolysis, and selective protection of the primary alcohols.
The alcohol 6 could also be converted into 15 via initial acetylation and then iodocyclization to give
10. The diol 5 could also be converted into 15 by a similar route involving bis-acetylation and
iodocyclization followed by functional group transformations. The tosylate of 15 was displaced
with the anion of adenine or thymidine to give, after final desilylation, the desired isonucleosidessthe
D-adenosine analogue (-)-2a and the L-adenosine and thymidine analogues (+)-2a and (-)-2b. All
of the stereochemistry of the final products is derived from the first step of the synthesis, namely,
the Sharpless asymmetric epoxidation of 3. The biological activity of the new compounds L-(+)-2a
and L-(-)-2b against HIV was determined in the anti-HIV drug-testing system of the National
Cancer Institute. The adenosine analogue L-(+)-2a was inactive in this screen, while the thymidine
analogue L-(-)-2b showed moderate anti-HIV activity (IC50 > 2 × 10-4 M, EC50 ) 8 × 10-7 M, TI50
> 250).
In tr od u ction a n d Ba ck gr ou n d
L-ddC,10 and L-FddC,10b,c have antiviral activity equal to
or better than their D-enantiomers, in addition to having
lower cytotoxicity. Presumably these compounds (or
their triphosphate derivatives) interact with viral en-
zymes and inhibit viral DNA production without causing
significant damage to normal human DNA. For this
reason, many groups are working on ways to produce
modified nucleosides in the unnatural L-configuration in
order to test the antiviral activity and cytotoxicity in
hopes of producing safer antiviral agents. In this paper
The continuing search for new antiviral compounds has
recently led to the synthesis of a variety of natural and
nonnatural nucleoside analogues, including oxetanocins
A and G (1a ,b),4 its carbocyclic (1c,d )5 and azetidine6
analogues, and its methylene-expanded analogues such
as the tetrahydrofurandimethanols (2).7 These isonu-
cleosides show good activity against a broad spectrum of
viruses (HSV-1, HSV-2, HCMV, HBV, VZV, VV). The
starting materials for the syntheses of these compounds
are the natural sugars D-xylose7a and D-glucose.7b
(4) (a) Shimada, N.; Hasegawa, S.; Harada, T.; Tomisawa, T.; Fujii,
A.; Takita, T. J . Antibiot. 1986, 39, 1623. (b) Nakamura, H.; Hasegawa,
S.; Shimada, N.; Fujii, A.; Takita, T.; Iitaka, Y. J . Antibiot. 1986, 39,
1626. (c) Wilson, F. X.; Fleet, G. W. J .; Vogt, K.; Wang, Y.; Witty, D.
R.; Choi, S.; Storer, R.; Myers, P. L.; Wallis, C. J . Tetrahedron Lett.
1990, 31, 6931. (d) Norbeck, D. W.; Kramer, J . B. J . Am. Chem. Soc.
1988, 110, 7217. (e) Niitsuma, S.; Ichikawa, Y.-i.; Kato, K.; Takita, T.
Tetrahedron Lett. 1987, 28, 3967. (f) Nishiyama, S.; Yamamura, S.;
Kato, K.; Takita, T. Tetrahedron Lett. 1988, 29, 4739. (g) Hambalek,
R.; J ust, G. Tetrahedron Lett. 1990, 31, 5445.
(5) Slusarchyk, W. A.; Young, M. G.; Bisacchi, G. S.; Hockstein, D.
R.; Zahler, R. Tetrahedron Lett. 1989, 30, 6453.
(6) Hosono, F.; Nishiyama, S.; Tamamura, S.; Izawa, T.; Kato, K.;
Terada, Y. Tetrahedron 1994, 50, 13335.
It has also been shown that a variety of L-enantiomers
of known antiviral nucleosides, such as L-3TC,8 L-FTC,8a,9
(7) (a) Tino, J . A.; Clark, J . M.; Field, A. K.; J acobs, G. A.; Lis, K.
A.; Michalik, T. L.; McGreever-Rubin, B.; Slusarchyk, W. A.; Spergel,
S. H.; Sundeen, J . E.; Tuomari, A. V.; Weaver, E. R.; Young, M. G.;
Zahler, R. J . Med. Chem. 1993, 36, 1221. (b) Kakefuda, A.; Shuto, S.;
Nagahata, T.; Seki, J .-i.; Sasaki, T.; Matsuda, A. Tetrahedron 1994,
50, 10167. (c) For an example of a structurally similar compound, the
cyclopentene analogue in the L-series, with good anti-HIV activity,
see: Katagiri, N.; Shiraishi, T.; Sato, H.; Toyota, A.; Kaneko, C.; Yusa,
K.; Oh-hara, T.; Tsuruo, T. Biochem. Biophys. Res. Commun. 1992,
184, 154. Katagiri, N.; Shiraishi, T.; Toyota, A.; Sato, H.; Kaneko, C.;
Aikawa, T. Chem. Pharm. Bull. 1993, 41, 1027.
X Abstract published in Advance ACS Abstracts, December 15, 1997.
(1) Presented at the 214th National American Chemical Society
Meeting, Las Vegas, NV, September 1997; ORGN 295.
(2) American Chemical Society Arthur C. Cope Scholar, 1995.
(3) (a) Natural Sciences and Engineering Research Council (NSERC)
of Canada Scholar, 1992-1996. (b) Departmental Awardee for Excel-
lence during the First Year of Graduate Study, UCLA, 1993. (c)
Gregory Award Recipient for Excellence in Research, UCLA, 1995.
S0022-3263(97)01890-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/01/1998

348 J . Org. Chem., Vol. 63, No. 2, 1998
J ung and Nichols
Sch em e 1a
interesting to see if this reaction would proceed via the
alcohol to give the oxetane 7, which has all the appropri-
ate functionality necessary for its conversion to the
oxetanocins 1a ,b, or whether it would cyclize to give the
tetrahydrofuran 8, which would result from cyclization
through the benzyl ether oxygen and loss of a bromoben-
zyl cation.15 In the event, cyclization of 6 under these
conditions produced a good yield of the tetrahydrofuran
8 with none of the oxetane 7 being formed. This is an
example of a 5-exo iodoetherification of an ether in
preference to a 4-exo iodoetherification from an alcohol.16
Examination of the structure of compound 8 indicates,
however, that it should be easily converted to an L-
isonucleoside, since it contains the basic carbon frame-
work with the necessary functionality for attachment of
the 5′-hydroxyl group and the base at C2′. Since all of
the stereochemistry of the final isonucleosides is intro-
duced in the very first step, the Sharpless epoxidation,
we decided to prepare also the known D-isonucleosides
by starting with the epoxide (+)-4. Therefore the same
reaction sequence was carried out beginning with the
reaction of 3 with D-(+)-tartrate to give (+)-4 which was
then converted into the enantiomer of 8 (Scheme 1, yields
in parentheses).
Direct displacement of the iodide in the alcohol 8 with
potassium acetate to install an oxygen functionality at
C5 proved unsuccessful. We found it necessary to use
the iodoacetate 10, available by first protecting the
alcohol 6 as the ester 9 and subsequent iodoetherification
(Scheme 2). This iodo ester could have also been made
by acetylation of 8 with acetyl chloride, and indeed, this
reaction did work efficiently (81%) on the enantiomer of
8 to give the enantiomer of 10. Nucleophilic substitution
of the iodide 10 was quite difficult, presumably because
of the reduced reactivity of the halide due to the presence
of the inductively electron-withdrawing oxygen atom â
to the iodide.17 However, reaction of the iodide 10 with
10 equiv of potassium acetate in DMSO at 87 °C gave
the diacetate 11 in 41% yield (the enantiomer of 11 was
formed in 56% yield by this route). In some cases either
the eliminated product 12 or the furan 13 was also
isolated in small amounts (<10%). Deprotection of the
a
Reagents and conditions (yields of enantiomeric series in
parentheses): (a) L-(+)-DIPT, Ti(OiPr)4, tBuOOH, CH2Cl2, mol
sieves, -25 °C, 81%, 96% ee; (b) D-(+)-DIPT, Ti(OiPr)4, tBuOOH,
CH2Cl2, mol sieves, -25 °C, 70%, 100% ee; (c) CH2dCHMgBr, CuI,
THF, -78 °C f rt, 73% (71%); (d) TBSCl, Et3N, DMAP, CH2Cl2,
rt, 79% (85%); (e) Ag(coll)2ClO4, I2, CH2Cl2, rt, 52% (50%).
we report the efficient total synthesis of both enantiomers
of 2a as well as that of L-2b. We anticipate that this
work will help assess the viability of L-isonucleosides as
antiviral agents.
Resu lts a n d Discu ssion
In the course of a synthesis of oxetanocins A and G
(1a ,b),11 the known epoxide (-)-412 was made from the
known monoprotected 2-butene-1,4-diol 3 (itself prepared
by simple alkylation of butenediol in 88% yield) in 96%
ee via a Sharpless epoxidation (Scheme 1). Addition of
vinylmagnesium bromide13 proceeded highly stereoselec-
tively to give primarily the 1,3-diol 5, with a small
inseparable impurity (presumably the 1,2-diol). After
selective protection of the primary alcohol to form the
silyl ether 6, we examined the course of an iodocyclization
reaction using iodonium bis(sym-collidine) [I(coll)2+] per-
chlorate,14 generated in situ from Ag(coll)2ClO4 and
iodine, since we had shown earlier11 that a vicinal dialkyl
effect had allowed the formation of the all-trans-2,3,4-
trisubstituted oxetanes from 2,3-disubstituted 3-butenols,
e.g., A giving mainly B in good yield. In this case, it was
(8) (a) Chang, C.-N.; Doong, S.-L.; Zhou, J . H.; Beach, J . W.; J eong,
L. S.; Chu, C. K.; Tsai, C.-h.; Cheng, Y.-c. J . Biol. Chem. 1992, 267,
13938. (b) Chang, C.-N.; Skalski, V.; Zhou, J . H.; Cheng, Y.-c. J . Biol.
Chem. 1992, 267, 22414. (c) Beach, J . W.; J eong, L. S.; Alves, A. J .;
Pohl, D.; Kim, H. O.; Chang, C.-N.; Coong, S.-L.; Schinazi, R. F.; Cheng,
Y.-C.; Chu, C. K. J . Org. Chem. 1992, 57, 2217. (d) Coates, J . A. V.;
Cammack, N.; J enkinson, H. J .; Mutton, I. M.; Pearson, B. A.; Storer,
R.; Cameron, J . M.; Penn, C. R. Antimicrob. Agents Chemother. 1992,
36, 202. (e) Schinazi, R. F.; Chu, C. K.; Peck, A.; McMillan, A.; Mathis,
R.; Cannon, D.; J eong, L.-S.; Beach, J . W.; Choi, W.-B.; Yeola, S.; Liotta,
D. C. Antimicrob. Agents Chemother. 1992, 36, 672.
(9) (a) Hoong, L. K.; Strange, L. E.; Liotta, D. C.; Koszalka, G. W.;
Burns, C. L.; Schinazi, R. F. J . Org. Chem. 1992, 57, 5563. (b) Furman,
P. A.; Davis, M.; Liotta, D. C.; Paff, M.; Frick, L. W.; Nelson, D. J .;
Dornsife, R. E.; Wurster, J . A.; Wilson, L. J .; Fyfe, J . A.; Tuttle, J . V.;
Miller, W. H.; Conderay, L.; Averett, D. R.; Schinazi, R. F.; Painter,
G. R. Antimicrob. Agents Chemother. 1992, 36, 2686.
(10) (a) Mansuri, M. M.; Farina, V.; Starrett, J . E., J r.; Benigni, D.
A.; Brankovan, V.; Martin, J . C. Bioorg. Med. Chem. Lett. 1991, 1, 65.
(b) Lin, T.-S.; Luo, M.-Z.; Liu, M.-C.; Pai, B.; Dutschman, G. E.; Cheng,
Y.-C. J . Med. Chem. 1994, 37, 798. (c) Gosselin, G.; Schinazi, R. F.;
Sommadossi, J .-P.; Mathe´, C.; Bergogne, M.-C.; Aubertin, A.-M.; Kirn,
A.; Imbach, J .-L. Antimicrob. Agents Chemother. 1994, 38, 1292.
(11) For a discussion of our approach to the oxetanocins, see: J ung,
M. E.; Nichols, C. J . Tetrahedron Lett. 1996, 37, 7667.
(12) (a) Svansson, L.; Kvarnstro¨m, I.; Classen, B.; Samuelsson. B.
J . Org. Chem. 1991, 56, 2993. (b) Chong, J . M.; Wong, S. J . Org. Chem.
1987, 52, 2596.
(13) Tius, M. A.; Fauq, A. H. J . Org. Chem. 1983, 48, 4131.
(14) Evans, R. D.; Magee, J . W.; Schauble, J . H. Synthesis 1988,
862.
two acetates with ammonia in methanol gave the diol
14 in nearly quantitative yield. Reprotection of the
primary alcohol of the diol 14 as the tert-butyldimethyl-
silyl (TBS) ether afforded the bis(silyl) ether 15 in 62%
yield (enantiomer of 15 in 77% yield). Again the enan-
(15) Rychnovsky, S. D.; Bartlett, P. A. J . Am. Chem. Soc. 1981, 103,
3963.
(16) (a) Amouroux, R.; Gerin, B.; Chastrette, M. Tetrahedron Lett.
1982, 23, 4341. (b) Hatakeyama, S.; Sakurai, K.; Takano, S. Hetero-
cycles 1986, 24, 633.
(17) We have observed this greatly reduced reactivity of alkyl
halides with electron-withdrawing groups in the â- or even γ-position
several times; for an example, see: J ung, M. E.; Parker, M. H. J . Org.
Chem. 1997, 62, 7094. Parker, M. H. Ph.D. Thesis, UCLA, 1997.

Synthesis of Methylene-Expanded Oxetanocins
J . Org. Chem., Vol. 63, No. 2, 1998 349
Sch em e 2a
Sch em e 4a
a
Reagents and conditions (yields of enantiomeric series in
parentheses): (a) AcCl, pyr, 0 °C, 90% (92%); (b) Ag(coll)2ClO4, I2,
rt, 52% (52%); (c) AcCl, pyr, 0 °C, (81%sent-10 only); (d) KOAc
(10 equiv), DMSO, 87 °C, 41% (56%); (e) NH3, MeOH, 0 °C f rt,
93% (98%); (f) TBSCl, Et3N, DMAP, CH2Cl2, 62% (77%).
Sch em e 3a
a
Reagents and conditions: (a) TsCl, pyr, 0 °C f rt, 18 h, 68%
(66%); (b) adenine, 18-crown-6, K2CO3, DMF, 90 °C, 18 h, 43%
22, 26% 21; (c) TBAF, THF, rt, 45 min, 80%; (d) same as step b,
44% ent-22, 29% ent-21; (e) same as step c, 83%; (f) thymine, 18-
crown-6, K2CO3, DMSO, 90 °C, 18 h, 23%; (g) TBAF, THF, rt, 1 h,
94%.
L-adenosine analogue 22 was obtained in 43% yield, along
with the product of E2 elimination, namely, the 2,5-
dihydrofuran 21 in 26% yield. Deprotection of 22 with
tetrabutylammonium fluoride proceeded in 80% yield to
give the L-isonucleoside L-(+)-2a . Similarly, the enanti-
omer of 20 (ent-20) produced the enantiomer of 21 (ent-
21) in 29% yield and the enantiomer of 22 (ent-22) in
44% yield. This latter compound (ent-22) was converted
to the known isonucleoside7 D-(-)-2a in 83% yield by
desilylation. The thymidine L-isonucleoside was also
made from the tosylate 20 by a similar route as follows.
Reaction of the tosylate 20 with thymine, potassium
carbonate, and 18-crown-6 in dimethyl sulfoxide gave the
protected isonucleoside 23 in 21% yield. Deprotection of
the silyl ethers with TBAF produced the product L-(-)-
2b, which is the enantiomer of the known compound
D-(+)-2b.
The biological activity of the new compounds L-(+)-2a
and L-(-)-2b against HIV was determined in the anti-
HIV drug-testing system of the National Cancer Insti-
tute. The adenosine analogue L-(+)-2a was inactive in
this screen, while the thymidine analogue L-(-)-2b
showed moderate anti-HIV activity (IC50 > 2 × 10-4 M,
EC50 ) 8 × 10-7 M, TI50 > 250).
a
Reagents and conditions (yields of enantiomeric series in
parentheses): (a) AcCl, pyr, CH2Cl2,
0 °C, 89% (89%); (b)
Ag(coll)2ClO4, I2, CH2Cl2, rt, 47% (43%), or I2, CH3CN, 0 °C f rt,
18 h (57%); (c) Ag(coll)2ClO4, I2, CH2Cl2, rt, ii. AcCl, pyr, 0 °C,
26%; (d) KOAc (10 equiv), DMSO, 93 °C, 60% (60%); (e) NH3,
MeOH, 0 °C f rt; (f) TBSCl (3 equiv), Et3N, DMAP, CH2Cl2, rt,
72% (71%) over two steps.
tiomer of 15 was also synthesized by exactly the same
route (Scheme 2, yields in parentheses).
The alcohol 15 was also accessible through a slightly
shorter route (Scheme 3). Protection of the original diol
5 with acetyl chloride gave the diacetate 16, which could
be cyclized with either I(coll)2+ClO4 or I2/CH3CN11 to
-
form the iododiacetate 17. The silylated compounds 6
and 9 could not be cyclized with I2/CH3CN due to
desilylation,18 presumably from traces of water in the
solvent. Compound 17 could also be obtained in one pot
in 26% yield from 5 by sequential treatment with
I(coll)2+ClO4-, acetyl chloride, and pyridine. Displace-
ment of the iodide 17 with acetate at 93 °C gave the
triacetate 18 in 60% yield, which could be completely
deprotected to the triol 19 with methanolic ammonia.
Selective protection of the two primary alcohols produced
the same bis-silylated alcohol 15 as before in 72% yield
for the last two steps. Again the enantiomer of 15 was
also synthesized by exactly the same route (Scheme 3,
yields in parentheses).
Con clu sion
We have developed a novel route to isonucleosides in
both the D- and L-enantiomeric forms, e.g., compounds
L-(+)-2a , D-(-)-2a , and L-(-)-2b, beginning with the
simple, known monoether of the very inexpensive
2-butene-1,4-diol 3. All of the stereochemistry of the final
products is derived from the first step of the synthesis,
Conversion of 15 to its tosylate 20 proceeded in good
yield (Scheme 4). When 20 is treated with adenine under
the conditions described by Tino et al.,7a the protected
(18) Vaino, A. R.; Szarek, W. A. Chem. Commun. 1996, 2351.

350 J . Org. Chem., Vol. 63, No. 2, 1998
J ung and Nichols
after column chromatography (SiO2, 80% ether/20% pentane)
and recrystallization 2.228 g of the epoxide (+)-4 (8.16 mmol,
70%). 1H NMR, 13C NMR, and IR of (+)-4 were identical with
namely, the Sharpless asymmetric epoxidation of 3 to
give the two enantiomeric epoxides (+)- and (-)-4. After
regioselective opening of the epoxides and functional
group conversions, the key step of the synthesis is the
iodoetherification of the olefinic p-bromobenzyl ethers 5,
6, 9, and 16 to give the corresponding tetrahydrofurans.
Final protecting group interconversions and introduction
of the bases afforded the desired isonucleosides. Further
research on the synthesis of novel modified nucleosides
and carbohydrates, especially those with the L-configu-
ration, is underway in our laboratories.19
those of (-)-4. [R]21 ) +16.5 (c ) 0.93, CHCl3). 31P NMR
D
(10% C6D6 in C6H6, 162 MHz) δ: 140.5, no peak at 138.3, 100%
ee.
(2R,3S)-1-[(4-Br om op h e n yl)m e t h oxy]-2-e t h e n yl-1,3-
bu ten ed iol (5). To a slurry of copper(I) iodide (204 mg, 1.07
mmol) in THF (90 mL) cooled to -78 °C was added vinylmag-
nesium bromide (1.00 M in ether, 20 mL, 20 mmol), and the
solution stirred for 10 min. The epoxide (-)-4 (1.386 g, 5.07
mmol) was added at -78 °C and the solution allowed to warm
to 21 °C overnight, which resulted in a deep-purple solution.
This was quenched at 21 °C with aq HCl (1 M, 22 mL), and
the mixture stirred for 20 min. Ether was added, and the
layers were separated. The aqueous phase was extracted twice
more with ether, the combined organic phase was washed with
brine and dried over MgSO4, and the solvent was removed in
vacuo. Column chromatography (SiO2, 50% ethyl acetate/50%
hexane) yielded 1.122 g of the diol 5 (3.73 mmol, 73%) as a
colorless oil. 1H NMR (CDCl3, 400 MHz) δ: 7.47 (2H, d, J )
8.5 Hz, Ar), 7.19 (2H, d, J ) 8.6 Hz, Ar), 5.88 (1H, ddd, J )
17.3, 10.4, 9.0 Hz, H5), 5.23 (1H, dd, J ) 10.4, 1.9 Hz, H4a),
5.17 (1H, ddd, J ) 17.3, 1.9, 0.9, H4b), 4.50 (1H, d, J ) 12.1
Hz, CH2Ar), 4.49 (1H, d, J ) 12.0 Hz, CH2Ar), 4.04 (1H, ddd,
J ) 7.1, 4.1, 4.1 Hz, H3), 3.77 (1H, dd, J ) 10.8, 6.1 Hz, H1),
3.75 (1H, dd, J ) 10.8, 5.8 Hz, H1′), 3.49 (1H, dd, J ) 9.6, 4.4
Hz, H4), 3.46 (1H, dd, J ) 9.6, 7.3 Hz, H4′), 2.39 (1H, dddd, J
) 8.9, 5.8, 5.8, 3.9 Hz, H2), 2.5-1.3 (2H, v br s, 2 OH). 13C
NMR (CDCl3, 100 MHz) δ: 136.8, 134.6, 131.6, 129.4, 121.8,
119.0, 72.9, 72.7, 71.1, 64.3, 48.6. IR (thin film): 3395 (br s),
2870 (m), 1640 (w), 1593 (w), 1489 (s), 1094 (s), 1071 (s), 1013
Exp er im en ta l Section
Gen er a l. All solvents were distilled prior to use: tetrahy-
drofuran (THF) from sodium/benzophenone; dichloromethane,
triethylamine, pyridine, and DMSO from calcium hydride; and
methanol from magnesium methoxide. Silver(I) bis(sym-
collidine) perchlorate was prepared from silver nitrate, sodium
perchlorate, and collidine as described.14 (Z)-4-[(4-Bromophe-
nyl)methoxy]-2-buten-1-ol (3) was prepared from 4-bromoben-
zyl bromide and cis-2-buten-1-ol as described.12 All other
reagents were used as provided except for L-(+)-diisopropyl
tartrate, D-(-)-diisopropyl tartrate, titanium tetraisopropoxide,
and acetyl chloride, which were distilled, and p-toluenesulfonyl
chloride, which was recrystallized. All reactions were con-
ducted under an inert atmosphere of argon. Enantiomeric
excesses of (-)- and (+)-4 were determined by the 31P NMR
method of Alexakis.20
(2S ,3R )-3-[[(4-B r o m o p h e n y l)m e t h o x y ]m e t h y l]o x i-
r a n em eth a n ol ((-)-4). To a solution of L-(+)-diisopropyl
tartrate (563 mg, 2.40 mmol) and oven-dried powdered 4-Å
molecular sieves in dichloromethane (50 mL) cooled to -25
°C was added titanium tetraisopropoxide (0.57 mL, 1.93 mmol),
and the mixture stirred for 15 min. With the temperature kept
at -25 °C, a solution of tert-butyl hydroperoxide in n-decane
(4.77 M, 4.1 mL, 19.6 mmol) was added, and the solution
stirred for an additional 15 min. The monoprotected (Z)-2-
butene-1,4-diol 3 (2.485 g, 9.66 mmol) in 5 mL of dichlo-
romethane was then added; the reaction mixture stirred at
-25 °C for 5 min and then was put into the freezer at -25 °C
for 3 days. Water (10 mL) was added, and the mixture stirred
for 1 h. A 30% solution of NaOH in brine (2 mL) was added,
and the mixture stirred for 1 h. The layers were separated,
and the aqueous layer was extracted twice with dichlo-
romethane and dried over MgSO4. The solution was filtered
through Celite and the solvent removed in vacuo. The crude
product was recrystallized from pentane/ether, giving 2.133 g
of the pure epoxide (-)-4 (7.81 mmol, 81%) as a colorless
solid: mp 52 °C. 1H NMR (CDCl3, 400 MHz) δ: 7.48 (2H, d,
J ) 8.4 Hz, Ar), 7.21 (2H, d, J ) 8.6 Hz, Ar), 4.56 (1H, d, J )
12.0 Hz, CH2Ar), 4.49 (1H, d, J ) 12.0 Hz, CH2Ar), 3.75 (2H,
br t, J ) 5.8 Hz, H1), 3.688 (1H, dd, J ) 11.1, 6.0 Hz, H4),
3.686 (1H, dd, J ) 11.1, 4.9 Hz, H4′), 3.29 (1H, ddd, J ) 5.4,
5.4, 4.5 Hz, H2 or H3), 3.23 (1H, ddd, J ) 5.6, 5.6, 4.5 Hz, H2
or H3), 2.01 (1H, br t, J ) 6.4 Hz, OH). 13C NMR (CDCl3, 100
MHz) δ: 136.5, 131.7, 129.5, 121.9, 72.7, 68.3, 60.7, 55.6, 54.8.
IR (KBr pellet): 3366 (br m), 3281 (br m), 1489 (m), 1399 (w),
(s), 924 (m), 804 (s) cm-1
. High-resolution MS (EI, m/z):
302.0342, calcd for C13H17O381Br 302.0341; 300.0356, calcd for
C
13H17O379Br 300.0361. [R]21 ) +2.9 (c ) 0.84, CHCl3).
D
(2S,3R)-1-[(4-Br om op h e n yl)m e t h oxy]-2-e t h e n yl-1,3-
bu ten ed iol (en t-5). As in the preparation of 5, copper(I)
iodide (181 mg, 0.95 mmol), vinylmagnesium bromide (1.00
M in ether, 19 mL, 19 mmol), and the epoxide (+)-4 (1.289 g,
4.72 mmol) yielded after column chromatography 1.014 g of
the diol ent-5 (3.37 mmol, 71%). 1H NMR, 13C NMR, IR, and
HRMS of ent-5 were identical with those of 5. [R]21 ) -3.8
D
(c ) 1.05, CHCl3).
(2S,3R)-1-[(4-Br om op h en yl)m eth oxy]-3-[[[(1,1-d im eth -
yleth yl)d im eth ylsilyl]oxy]m eth yl)-4-p en ten -2-ol (6). To
a solution of the diol 5 (493.6 mg, 1.64 mmol) in dichlo-
romethane (18 mL) at 21 °C were added sequentially triethyl-
amine (300 µL, 2.15 mmol), (N,N-dimethylamino)pyridine(20
mg, 0.16 mmol), and tert-butyldimethylsilyl chloride (298 mg,
1.98 mmol), and the mixture was stirred at 21 °C for 16 h.
Water was added, the layers were separated, and the aqueous
layer was extracted with dichloromethane. The combined
organic phase was washed with aq HCl (1 M), aq NaHCO3
(10%), and brine and dried over MgSO4. Removal of the
solvent in vacuo and column chromatography (SiO2, 20% ethyl
acetate/80% hexane) yielded 540.8 mg of the silyl ether 6 (1.302
mmol, 79%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ:
7.46 (2H, d, J ) 8.6 Hz, Ar), 7.20 (2H, d, J ) 8.6 Hz, Ar), 5.91
(1H, ddd, J ) 17.3, 10.4, 9.1 Hz, H4), 5.16 (1H, dd, J ) 10.4,
2.0 Hz, H5a), 5.10 (1H, ddd, J ) 17.3, 2.0, 0.9 Hz, H5b), 4.51
(1H, d, J ) 12.2 Hz, CH2Ar), 4.48 (1H, d, J ) 12.2 Hz, CH2-
Ar), 4.10 (1H, dddd, J ) 5.9, 5.9, 3.0, 3.0 Hz, H2), 3.78 (1H,
dd, J ) 9.9, 5.9 Hz, H6), 3.75 (1H, dd, J ) 9.9, 4.6 Hz, H6′),
3.457 (1H, dd, J ) 9.6, 5.3 Hz, H1), 3.455 (1H, dd, J ) 9.6, 6.6
Hz, overlapping with previous signal, H1′), 2.97 (1H, d, J )
2.8 Hz, OH), 2.33 (1H, br dq, J ) 9.1, 4.3 Hz, H3), 0.88 (9H, s,
t-Bu), 0.05 (6H, s, Me2Si). 13C NMR (CDCl3, 100 MHz) δ:
137.2, 134.9, 131.5, 129.4, 121.5, 118.1, 72.9, 72.6, 71.2, 65.7,
48.0, 25.9, 18.2, -5.53, -5.57. IR (thin film): 3478 (br w),
2928 (s), 2859 (s), 1256 (m), 1096 (s), 1013 (m), 837 (s), 777
(m) cm-1. High-resolution MS (EI, m/z): 417.1284, calcd for
C19H32O381BrSi 417.1284 (M + H)+; 415.1304, calcd for
1094 (s), 1049 (s), 1011 (s), 802 (m), 758 (m) cm-1. [R]21
)
D
-18.1 (c ) 0.96, CHCl3). 31P NMR (10% C6D6 in C6H6, 162
MHz) δ: 140.5 (2.0%), 138.3 (98.0%), 96% ee.
(2R ,3S )-3-[[(4-B r o m o p h e n y l)m e t h o x y ]m e t h y l]o x i-
r a n em et h a n ol ((+)-4). As in the preparation of (-)-4, D-
(-)-diisopropyl tartrate (668 mg, 2.85 mmol), titanium tetrai-
sopropoxide (0.700 mL, 2.37 mmol), tert-butyl hydroperoxide
(4.77 M in n-decane, 5.0 mL, 23.8 mmol), and the monopro-
tected (Z)-2-butene-1,4-diol 3 (2.978 g, 11.58 mmol) yielded
(19) (a) For a novel synthesis of L-ribose and 2-deoxy-L-ribose from
D-ribose and L-arabinose, see: J ung, M. E.; Xu, Y. Tetrahedron Lett.
1997, 38, 4199. (b) We have also developed a de novo synthesis of
2-deoxy-L-ribose: J ung, M. E.; Nichols, C. J . Manuscript in preparation.
(20) Alexakis, A.; Mutti, S.; Normant, J . F.; Mangeney, P. Tetrahe-
dron Asym. 1990, 1, 437.
C
19H32O379BrSi 415.1304 (M + H)+. [R]21 ) -9.2 (c ) 1.11,
D
CHCl3).

Synthesis of Methylene-Expanded Oxetanocins
J . Org. Chem., Vol. 63, No. 2, 1998 351
(2R,3S)-1-[(4-Br om op h en yl)m eth oxy]-3-[[[(1,1-d im eth -
yleth yl)d im eth ylsilyl]oxy]m eth yl]-4-p en ten -2-ol (en t-6).
As in the preparation of 6, the diol ent-5 (1.107 g, 3.68 mmol),
triethylamine (0.65 mL, 4.66 mmol), (N,N-dimethylamino)-
pyridine (47 mg, 0.38 mmol), and tert-butyldimethylsilyl
chloride (669 mg, 4.44 mmol) yielded, after column chroma-
tography on silica gel, 1.291 g (3.11 mmol, 85%) of the silyl
ether ent-6 as a colorless oil. 1H NMR, 13C NMR, IR, and
459.1389 (M + H)+; 457.1408, calcd for C21H3479BrO4Si 457.1410
(M + H)+. [R]21 ) +2.2 (c ) 1.21, CHCl3).
D
(3S,4R)-4-(Acetyloxy)-5-[(4-br om op h en yl)m eth oxy]-3-
[[[(1,1-d im et h ylet h yl)d im et h ylsilyl]oxy]m et h yl]-1-p en -
ten e (en t-9). As in the preparation of 9, the alcohol ent-6
(1.173 g, 2.83 mmol), pyridine (1.35 mL, 16.7 mmol), and acetyl
chloride (0.60 mL, 8.44 mmol) yielded after chromatography
on silica gel 1.192 g of the acetate ent-9 (2.60 mmol, 92%) as
a colorless oil. 1H NMR, 13C NMR, IR, and HRMS of ent-9
were identical with those of 9. [R]21D ) -3.2 (c ) 0.88, CHCl3).
(2R,3R,4S)-4-(Ace t yloxy)-3-[[[(1,1-d im e t h yle t h yl)d i-
m et h ylsilyl]oxy]m et h yl]-2-(iod om et h yl)t et r a h yd r ofu -
r a n (10). To a solution of silver(I) bis(sym-collidine) perchlo-
rate (360 mg, 0.800 mmol) in dichloromethane (30 mL) at 21
°C was added iodine (202 mg, 0.796 mmol), and the solution
stirred in the dark for 20 min. A solution of the acetate 9
(333.9 mg, 0.730 mmol) in dichloromethane (5 mL) was then
added, and the mixture stirred for 18 h. The precipitate was
filtered and washed with dichloromethane, and the filtrate and
washings were combined, washed with aq Na2S2O3 (10%), aq
HCl (1 M), and brine, and dried over MgSO4. Column
chromatography (SiO2, 5% ethyl acetate/95% hexane f 8%
ethyl acetate/92% hexane) yielded 158.1 mg of the iodide 10
(0.382 mmol, 52%) as a colorless oil, as well as 61.3 mg of the
recovered acetate 9 (0.134 mmol, 18%). 1H NMR (CDCl3, 400
MHz) δ: 5.38 (1H, ddd, J ) 5.4, 4.0, 1.4 Hz, H4), 4.15 (1H, dd,
J ) 10.5, 3.9 Hz, H5), 3.839 (1H, dd, J ) 10.1, 6.4 Hz, H7),
3.838 (1H, dd, J ) 10.6, 1.5 Hz, overlapping with previous
signal, H5′), 3.77 (1H, ddd, J ) 9.2, 5.3, 4.0 Hz, H2), 3.68 (1H,
dd, J ) 10.1, 7.8 Hz, H7′), 3.58 (1H, dd, J ) 10.5, 3.6 Hz, H6),
3.34 (1H, dd, J ) 10.6, 5.1 Hz, H6′), 2.33 (1H, dddd, J ) 8.9,
7.8, 6.4, 5.4 Hz, H3), 2.06 (3H, s, OAc), 0.88 (9H, s, t-Bu), 0.058
(3H, s, MeSi), 0.055 (3H, s, MeSi). 13C NMR (CDCl3, 100 MHz)
δ: 170.4, 80.2, 75.6, 73.3, 60.0, 50.4, 25.8, 21.0, 18.2, 11.5,
-5.50, -5.52. IR (thin film): 2930 (m), 1744 (s), 1235 (s), 1090
HRMS of ent-6 were identical with those of 6. [R]21 ) +9.7
D
(c ) 1.12, CHCl3).
(3S,4R5R)-4-[[[(1,1-Dim eth yleth yl)d im eth ylsilyl]oxy]-
m eth yl]-5-(iod om eth yl)tetr a h yd r ofu r a n -3-ol (8). To a
solution of silver(I) bis(sym-collidine) perchlorate (83.5 mg,
0.186 mmol) in dichloromethane (3 mL) at 21 °C was added
iodine crystals (47.8 mg, 0.188 mmol), and the solution stirred
in the dark for 20 min. A yellow precipitate (AgI) formed. The
alcohol 6 was added in dichloromethane (2 mL), and the
solution stirred for 18 h. The precipitate was filtered and the
solution washed with aq Na2S2O3 (10%), aq HCl (1 M), and
brine and dried over MgSO4. Removal of the solvent in vacuo
and column chromatography (SiO2, 15% ethyl acetate/85%
hexane) gave 31.5 mg of the iodide 8 (0.085 mmol, 52%) as a
slightly yellow oil. 1H NMR (CDCl3, 400 MHz) δ: 4.53 (1H,
dddd, J ) 5.7, 4.3, 4.3, 2.2 Hz, H3), 4.06 (1H, dd, J ) 9.7, 4.1
Hz, H2), 4.00 (1H, dd, J ) 10.6, 4.9 Hz, H7), 3.90 (1H, dd, J )
10.6, 5.9 Hz, H7′), 3.88 (1H, dt, J ) 8.5, 4.8 Hz, overlapping
with previous signal, H5), 3.79 (1H, dd, J ) 9.7, 2.2 Hz, H2′),
3.44 (1H, dd, J ) 10.5, 5.0 Hz, H6), 3.27 (1H, dd, J ) 10.5, 4.7
Hz, H6′), 3.10 (1H, d, J ) 4.5 Hz, OH), 2.13 (1H, br dq, J )
8.4, 5.5 Hz, H4), 0.91 (9H, s, t-Bu), 0.107 (3H, s, MeSi), 0.103
(3H, s, MeSi). 13C NMR (CDCl3, 100 MHz) δ: 77.8, 75.4, 74.6,
61.1, 51.0, 25.8, 18.1, 10.5, -5.50, -5.54. IR (thin film): 3428
(br w), 2930 (m), 1472 (w), 1256 (m), 1078 (s), 837 (s), 777 (s)
cm-1
12H26IO3Si 373.0696 (M + H)+. [R]21 ) -23.0 (c ) 1.12,
. High-resolution MS (EI, m/z): 373.0699, calcd for
C
D
(m), 837 (s), 777 (m) cm-1
. High-resolution MS (EI, m/z):
CHCl3).
415.0802, calcd for C14H28IO4Si 415.0802 (M + H)+. [R]21
-42.5 (c ) 1.12, CHCl3).
)
D
(3R ,4S ,5S )-4-[[[(1,1-Dim e t h y le t h y l)d im e t h ylsily l]-
oxy]m eth yl]-5-(iod om eth yl)tetr a h yd r ofu r a n -3-ol (en t-8).
As in the preparation of 8, silver(I) bis(sym-collidine) perchlo-
rate (115 mg, 0.256 mmol), iodine (72.5 mg, 0.286 mmol), and
the alcohol ent-6 (93.3 mg, 0.225 mmol) gave after chroma-
tography on silica gel 41.7 mg of the iodide ent-8 (0.112 mmol,
50%) as a yellow oil. 1H NMR, 13C NMR, IR, and HRMS of
(2S ,3S ,4R )-4-(Ace t yloxy)-3-[[[(1,1-d im e t h yle t h yl)d i-
m et h ylsilyl]oxy]m et h yl]-2-(iod om et h yl)t et r a h yd r ofu -
r a n (en t-10). F r om en t-8: To a solution of the alcohol ent-8
(56.8 mg, 0.153 mmol) in dichloromethane (2 mL) cooled to 0
°C were added pyridine (75 µL, 0.93 mmol) and acetyl chloride
(33 µL, 0.46 mmol), and the solution stirred for 1 h at 0 °C.
Water and dichloromethane were added, the layers were
separated, and the aqueous layer was extracted with dichlo-
romethane. The combined organic phase was washed with aq
HCl (1 M) and the aqueous layer extracted with dichlo-
romethane. The combined organic layers were washed with
brine and dried over MgSO4. Column chromatography (SiO2,
10% ethyl acetate/90% hexane) yielded 51.4 mg of the acetate
ent-10 (0.124 mmol, 81%) as a colorless oil.
ent-8 were identical with those of 8. [R]21 ) +26.1 (c ) 0.90,
D
CHCl3).
(3R,4S)-4-(Acetyloxy)-5-[(4-br om op h en yl)m eth oxy]-3-
[[[(1,1-d im et h ylet h yl)d im et h ylsilyloxy]m et h yl]-1-p en -
ten e (9). To a solution of the alcohol 6 (417.2 mg, 1.004 mmol)
in dichloromethane (12 mL) cooled to 0 °C were added pyridine
(0.50 mL, 6.18 mmol) and acetyl chloride (0.22 mL, 3.09 mmol).
The solution was stirred for 18 h, with slow warming to 21
°C. Water and dichloromethane were added to the resulting
orange solution, the layers were separated, and the aqueous
layer was extracted once with dichloromethane. The combined
organic phase was washed with aq HCl (1 M) and the aqueous
layer again extracted with dichloromethane. The combined
organic phase was washed with brine and dried over MgSO4,
and the solvent was removed in vacuo. Column chromatog-
raphy (SiO2, 10% ethyl acetate/90% hexane) yielded 413.9 mg
of the acetate 9 (0.905 mmol, 90%) as a colorless oil. 1H NMR
(CDCl3, 400 MHz) δ: 7.45 (2H, d, J ) 8.5 Hz, Ar), 7.18 (2H, d,
J ) 8.6 Hz, Ar), 5.72 (1H, ddd, J ) 16.6, 11.0, 9.1 Hz, H2),
5.32 (1H, ddd, J ) 6.2, 4.9, 4.9 Hz, H4), 5.15-5.10 (2H, m, H1,
H1′), 4.48 (1H, d, J ) 12.3 Hz, CH2Ar), 4.43 (1H, d, J ) 12.3
Hz, CH2Ar), 3.569 (1H, d, J ) 6.6 Hz, H6), 3.567 (1H, d, J )
5.0 Hz, overlappingwith previous signal, H6′), 3.566 (1H, dd,
J ) 10.5, 6.2 Hz, overlapping with previous two signals, H5),
3.52 (1H, dd, J ) 10.5, 4.9 Hz, H5′), 2.55 (1H, br dq, J ) 9.1,
5.7 Hz, H3), 2.04 (3H, s, OAc), 0.87 (9H, s, t-Bu), 0.01 (3H, s,
MeSi), 0.00 (3H, s, MeSi). 13C NMR (CDCl3, 100 MHz) δ:
170.4, 137.2, 134.9, 131.5, 129.3, 121.5, 118.5, 72.2, 71.1, 69.8,
63.1, 47.4, 25.8, 21.1, 18.2, -5.5. IR (thin film): 2930 (m), 2859
(m), 1744 (s), 1372 (w), 1237 (s), 1105 (s), 839 (m) cm-1. High-
resolution MS (EI, m/z): 459.1386, calcd for C21H3481BrO4Si
F r om en t-9: As in the preparation of 10 from 9, silver(I)
bis(sym-collidine) perchlorate (542 mg, 1.21 mmol), iodine (282
mg, 1.11 mmol), and the acetate ent-9 (518.1 mg, 1.13 mmol)
yielded after chromatography on silica gel 243.2 mg of the
acetate ent-10 (0.590 mmol, 52%) as well as 80.3 mg of the
recovered acetate ent-9 (0.178 mmol, 15%). 1H NMR, 13C
NMR, IR, and HRMS of ent-10 were identical with those of
10. [R]21 ) +49.8 (c ) 0.82, CHCl3).
D
(2R,3S,4S)-4-(Acetyloxy)-2-[(acetyloxy)m eth yl]-3-[[[(1,1-
d i m e t h y le t h y l)d i m e t h y ls i ly l]o x y ]m e t h y l]t e t r a h y -
d r ofu r a n (11). To a solution of the iodide 10 (141.5 mg, 0.341
mmol) in DMSO (3 mL) was added potassium acetate (315 mg,
3.21 mmol). The solution was heated at 87 °C for 16 h and
then cooled to 21 °C. Ether and water were added, the layers
were separated, and the aqueous layer was extracted twice
more with ether. The combined organic phase was washed
with brine and dried over MgSO4, and the solvent was removed
in vacuo. Column chromatography (SiO2, 10% ethyl acetate/
90% hexane f 20% ethyl acetate/80% hexane) yielded 48.4
mg of the diacetate 11 (0.140 mmol, 41%) as a colorless oil. 1H
NMR (CDCl3, 400 MHz) δ: 5.37 (1H, ddd, J ) 5.4, 4.0, 1.4
Hz, H4), 4.38 (1H, dd, J ) 11.3, 2.1 Hz, H6), 4.09 (1H, ddd, J
) 9.1, 6.8, 2.3 Hz, H2), 4.07 (1H, dd, J ) 10.7, 3.9 Hz,

352 J . Org. Chem., Vol. 63, No. 2, 1998
J ung and Nichols
overlapping with previous signal, H5), 4.03 (1H, dd, J ) 11.3,
6.5 Hz, overlapping with previous two signals, H6′), 3.85 (1H,
dd, J ) 10.7, 1.4 Hz, H5′), 3.84 (1H, dd, J ) 10.0, 7.0 Hz,
overlapping with previous signal, H7), 3.66 (1H, dd, J ) 10.0,
7.3 Hz, H7′), 2.33 (1H, dddd, J ) 9.0, 7.1, 7.1, 5.3 Hz, H3), 2.10
(3H, s, OAc), 2.07 (3H, s, OAc), 0.88 (9H, s, t-Bu), 0.052 (3H,
s, MeSi), 0.047 (3H, s, MeSi). 13C NMR (CDCl3, 100 MHz) δ:
170.9, 170.5, 79.1, 74.9, 73.3, 66.1, 59.7, 46.9, 25.8, 20.99, 20.90,
18.2, -5.51, -5.58. IR (thin film): 2955 (m), 1744 (s), 1373
(m), 1233 (s), 1094 (s), 839 (s), 777 (m) cm-1. High-resolution
MS (EI, m/z): 347.1890, calcd for C16H31O6Si 347.1890 (M +
of ent-14 were identical with those of 14. [R]21 ) +28.5 (c )
D
1.25, CHCl3).
(3R,4S)-4-(Acetyloxy)-3-[(a cetyloxy]m eth yl]-5-[(4-br o-
m op h en yl)m eth oxy]-1-p en ten e (16). To a solution of the
diol 5 (2.038 g, 6.77 mmol) in dichloromethane (50 mL) cooled
to 0 °C were added pyridine (4.0 mL, 47 mmol) and acetyl
chloride (1.9 mL, 27 mmol). The solution was stirred for 18
h, allowing to warm to 21 °C. Dichloromethane and water
were added, the layers were separated, and the aqueous layer
was extracted with dichloromethane. The combined organic
phase was washed with aq HCl (1 M) and brine and dried over
MgSO4. Removal of the solvent in vacuo and column chro-
matography (SiO2, 20% ethyl acetate/80% hexane) yielded
2.309 g of the diacetate 16 (5.99 mmol, 89%) as a colorless oil.
1H NMR (CDCl3, 400 MHz) δ: 7.46 (2H, d, J ) 8.5 Hz, Ar),
7.18 (2H, d, J ) 8.6 Hz, Ar), 5.69 (1H, ddd, J ) 17.1, 10.4, 9.1
Hz, H2), 5.24 (1H, ddd, J ) 6.0, 5.2, 4.2 Hz, H4), 5.21 (1H, dd,
J ) 10.5, 1.9 Hz, H1a), 5.18 (1H, ddd, J ) 17.1, 1.7, 0.9 Hz,
H)+. [R]21 ) -67.4 (c ) 0.80, CHCl3).
D
(2S,3R,4R)-4-(Acetyloxy)-2-[(acetyloxy)m eth yl]-3-[[[(1,1-
d i m e t h y le t h y l)d i m e t h y ls i ly l]o x y ]m e t h y l]t e t r a h y -
d r ofu r a n (en t-11). As in the preparation of 11, the iodide
ent-10 (56.6 mg, 0.137 mmol) and potassium acetate (134 mg,
1.37 mmol) yielded after treatment at 80 °C and chromatog-
raphy on silica gel (20% ethyl acetate/80% hexane) 26.4 mg of
the diacetate ent-11 (0.076 mmol, 56%) as a colorless oil. 1H
NMR, 13C NMR, IR, and HRMS of ent-11 were identical with
H
1b), 4.47 (1H, d, J ) 11.9 Hz, CH2Ar), 4.44 (1H, d, J ) 12.2
Hz, CH2Ar), 4.10 (1H, dd, J ) 11.1, 7.2 Hz, H6), 4.03 (1H, dd,
J ) 11.1, 6.6 Hz, H6′), 3.53 (1H, dd, J ) 10.2, 6.2 Hz, H5), 3.47
(1H, dd, J ) 10.2, 5.3 Hz, H5′), 2.79 (1H, dddd, J ) 9.0, 7.0,
7.0, 4.2 Hz, H3), 2.06 (3H, s, OAc), 2.04 (3H, s, OAc). 13C NMR
(CDCl3, 100 MHz) δ: 170.9, 170.4, 136.9, 133.2, 131.5, 129.2,
121.6, 119.7, 72.4, 70.5, 69.5, 63.7, 44.2, 21.0, 20.9. IR (thin
film): 1744 (s), 1489 (w), 1372 (m), 1233 (s), 1101 (m), 1037
(m) cm-1. High-resolution MS (EI, m/z): 387.0632, calcd for
those of 11. [R]21 ) +65.3 (c ) 1.22, CHCl3).
D
When performed on a larger scale and at 93 °C, the acetate
11 was isolated (31%) as well as the olefin 12 (8%). Another
experiment produced a 53% yield of 11 and a 4% yield of the
furan 13, which was isolated from the column as the dihydro-
furan 12 but subsequently eliminated acetic acid and rear-
ranged to 13.
12: 1H NMR (CDCl3, 400 MHz) δ 5.42 (1H, dd, J ) 5.2, 3.0
Hz, H4), 4.33 (1H, ddd, J ) 2.5, 2.2, 1.0 Hz, H6b), 4.15 (1H, dd,
J ) 10.7, 3.0 Hz, H5), 4.12 (1H, dd, J ) 10.7, 1.1 Hz, H5′), 3.84
(1H, br dd, J ) 2.3, 2.3 Hz, H6a), 3.810 (1H, dd, J ) 9.8, 8.3
Hz, overlapping with previous signal, H7), 3.805 (1H, dd, J )
9.8, 6.3 Hz, H7′), 3.06 (1H, ddddd, J ) 8.4, 6.3, 5.2, 2.3, 2.3
Hz, H3), 2.07 (3H, s, OAc), 0.88 (9H, s, t-Bu), 0.07 (3H, s, MeSi),
0.04 (3H, s, MeSi); 13C NMR (CDCl3, 100 MHz) δ 170.5, 161.1,
80.5, 74.0, 73.0, 59.5, 46.7, 25.7, 21.0, 18.1, -5.5, -5.6; IR (thin
film) 2957 (m), 2930 (m), 1746 (s), 1676 (m), 1237 (s), 1117
(m), 1082 (s), 837 (s), 777 (m) cm-1; high-resolution MS (EI,
m/z) 287.1679, calcd for C14H27O4Si 287.1679 (M + H)+.
13: 1H NMR (CDCl3, 360 MHz) δ 7.23 (1H, d, J ) 1.8 Hz,
H5), 6.32 (1H, d, J ) 1.7 Hz, H4), 4.51 (2H, s, H7), 2.26 (3H, s,
CH3), 0.91 (9H, s, t-Bu), 0.08 (6H, s, Me2Si); 13C NMR (CDCl3,
90 MHz) δ 162.4, 147.9, 140.0, 110.9, 57.1, 25.8, 18.3, 11.6,
-5.3; IR (thin film) 2928 (s), 2859 (s), 1472 (m), 1256 (m), 1077
(s), 837 (s), 775 (m) cm-1; high-resolution MS (EI, m/z)
226.1391, calcd for C12H22OSi 226.1389.
C
C
C
17H2281BrO5 387.0630 (M
17H2279BrO5 385.0651 (M
+
H)+; 385.0652, calcd for
H)+; 384.0580, calcd for
+
17H2179BrO5 384.0572. [R]21 ) +3.9 (c ) 0.67, CHCl3).
D
(3S,4R)-4-(Acetyloxy)-3-[(a cetyloxy)m eth yl]-5-[(4-br o-
m op h en yl)m eth oxy]-1-p en ten e (en t-16). As in the prepa-
ration of 16, the diol ent-5 (639.1 mg, 2.122 mmol), pyridine
(1.20 mL, 14.8 mmol), and acetyl chloride (0.67 mL, 9.4 mmol)
yielded, after chromatography on silica gel, 726 mg of the
diacetate ent-16 (1.88 mmol, 89%) as a colorless oil. 1H NMR,
13C NMR, IR, and HRMS of ent-16 were identical with those
of 16. [R]21 ) -3.8 (c ) 1.44, CHCl3).
D
(2R,3R,4S)-4-(Acet yloxy)-3-[(a cet yloxy)m et h yl]-2-(io-
d om eth yl)tetr a h yd r ofu r a n (17). F r om 16: To a solution
of silver(I) bis(sym-collidine) perchlorate (821 mg, 1.83 mmol)
in dichloromethane (35 mL) at 21 °C was added iodine crystals
(435 mg, 1.71 mmol), and the solution stirred for 20 min in
the dark. A solution of the diacetate 16 (500.2 mg, 1.298
mmol) in dichloromethane (5 mL) was added, and the mixture
stirred for 18 h. The precipitate was filtered and rinsed with
dichloromethane, and the filtrate and washings the combined
and washed with aq sodium thiosulfate (10%). The aqueous
layer was extracted once with dichloromethane, and the
combined organic phase was washed with aq HCl (1 M) and
brine and dried over MgSO4. Removal of the solvent in vacuo
and column chromatography (SiO2, 10% ethyl acetate/90%
hexane f 20% ethyl acetate/80% hexane) yielded 209.4 mg of
the iodide 17 (0.612 mmol, 47%) as a slightly yellow oil.
F r om 5: To a solution of silver(I) bis(sym-collidine) per-
chlorate (103 mg, 0.229 mmol) in dichloromethane (5 mL) at
21 °C was added iodine crystals (52 mg, 0.23 mmol), and the
solution stirred for 20 min. A solution of the diol 5 (67.6 mg,
0.224 mmol) in dichloromethane (2 mL) was added, and the
mixture stirred for 18 h. This mixture was then cooled to 0
°C, and pyridine (180 µL, 2.23 mmol) and acetyl chloride (160
µL, 2.25 mmol) were added. After stirring for 6 h, the solution
was allowed to warm to 21 °C, then aq sodium thiosulfate
(10%) was added, the layers were separated, and the aqueous
layer was extracted once with dichloromethane. The combined
organic phase was washed with aq HCl (1 M) and the aqueous
layer again extracted with dichloromethane. The combined
organic phase was washed with brine and dried over MgSO4.
Removal of the solvent in vacuo and column chromatography
(SiO2, 25% ethyl acetate/75% hexane) yielded 20.3 mg of the
iodide 17 (0.059 mmol, 26%) as a slightly yellow oil. 1H NMR
(CDCl3, 400 MHz) δ: 5.49 (1H, ddd, J ) 5.4, 4.0, 1.4 Hz, H4),
4.34 (1H, dd, J ) 11.3, 7.2 Hz, H7), 4.19 (1H, dd, J ) 10.7, 4.0
Hz, H5), 4.10 (1H, dd, J ) 11.3, 7.1 Hz, H7′), 3.86 (1H, dd, J )
10.7, 1.5 Hz, H5′), 3.74 (1H, ddd, J ) 9.0, 4.3, 4.3 Hz, H2), 3.54
(3S,4R,5R)-4-[[[(1,1-Dim eth yleth yl)d im eth ylsilyl]oxy]-
m eth yl]-5-(h yd r oxym eth yl)-3-tetr a h yd r ofu r a n ol (14). To
a solution of the diacetate 11 (36.8 mg, 0.106 mmol) in
methanol (10 mL) cooled to 0 °C was added vigorously a stream
of ammonia gas for 5 min. The solution was stirred for 18 h
and allowed to warm to 21 °C. Removal of the solvent in vacuo
followed by column chromatography (SiO2, 60% ethyl acetate/
40% hexane) yielded 25.8 mg of the diol 14 (0.098 mmol, 93%)
as a white solid: mp 47 °C. 1H NMR (CDCl3, 400 MHz) δ:
4.51 (1H, m, H3), 4.06 (1H, dt, J ) 9.2, 4.2 Hz, H5), 3.98 (1H,
dd, J ) 9.6, 4.1 Hz, H2), 3.96 (1H, dd, J ) 11.0, 5.3 Hz,
overlapping with previous signal, H7), 3.90 (1H, dd, J ) 10.6,
5.5 Hz, H7′), 3.79 (1H, dd, J ) 9.6, 2.1 Hz, H2), 3.77 (1H, br
ddd, J ) 11.8, 4.0, 4.0 Hz, overlapping with previous signal,
H6), 3.57 (1H, br ddd, J ) 11.6, 7.1, 4.5 Hz, H6′), 3.13 (1H, d,
J ) 4.5 Hz, 3-OH), 2.27 (1H, br t, J ) 5.7 Hz, 6-OH), 2.20
(1H, br dq, J ) 9.3, 5.4 Hz, H4), 0.90 (9H, s, t-Bu), 0.10 (3H, s,
MeSi), 0.09 (3H, s, MeSi). 13C NMR (CDCl3, 100 MHz) δ: 79.9,
75.5, 74.5, 63.5, 60.8, 46.5, 25.8, 18.1, -5.57, -5.63. IR (thin
film): 3409 (br s), 2930 (m), 1092 (m), 1049 (m), 839 (m), 779
(m). High-resolution MS (EI, m/z): 263.1683, calcd for
C
12H27O4Si 263.1679 (M + H)+. [R]21 ) -36.7 (c ) 1.25,
D
CHCl3).
(3R,4S,5S)-4-[[[(1,1-Dim eth yleth yl)d im eth ylsilyl]oxy]-
m eth yl]-5-(h yd r oxym eth yl)-3- tetr a h yd r ofu r a n ol (en t-
14). As in the preparation of 14, the diacetate ent-11 (18.4
mg, 0.053 mmol) yielded, after column chromatography on
silica gel, 13.6 mg of the diol ent-14 (0.052 mmol, 98%) as a
white solid: mp 50-51 °C. 1H NMR, 13C NMR, IR, and HRMS

Synthesis of Methylene-Expanded Oxetanocins
J . Org. Chem., Vol. 63, No. 2, 1998 353
(1H, dd, J ) 10.8, 3.9 Hz, H6), 3.31 (1H, dd, J ) 10.8, 4.7 Hz,
H6′), 2.48 (1H, dddd, J ) 9.0, 7.2, 7.2, 5.5 Hz, H3), 2.08 (3H, s,
OAc), 2.07 (3H, s, OAc). 13C NMR (CDCl3, 100 MHz) δ: 170.6,
170.3, 79.3, 75.1, 73.4, 60.7, 47.4, 20.9, 20.8, 9.9. IR (thin
72.5, 63.4, 59.0 (C-4 signal obscured by residual MeOH-d4).
IR (thin film): 3366 (br s), 2932 (m), 1233 (s) cm-1
. High-
resolution MS (EI, m/z): 149.0815, calcd for C6H13O4 149.0814
(M + H)+. [R]21 ) -67.7 (c ) 0.47, MeOH).
D
film): 1740 (s), 1370 (m), 1235 (s), 1040 (m) cm-1
.
High-
(3R,4S,5S)-4,5-Bis(h yd r oxym eth yl)-3-tetr a h yd r ofu r a -
n ol (en t-19). As in the preparation of 19, the triacetate ent-
18 (114.3 mg, 0.417 mmol) was converted to 67.7 mg of the
crude triol ent-19 as a white solid, which was directly used in
the preparation of ent-15. 1H NMR, 13C NMR, IR, and HRMS
resolution MS (EI, m/z): 343.0049, calcd for C10H16IO5 343.0043
(M + H)+. [R]21 ) -52.4 (c ) 1.16, CHCl3).
D
(2S,3S,4R)-4-(Acet yloxy)-3-[(a cet yloxy)m et h yl]-2-(io-
d om eth yl)tetr a h yd r ofu r a n (en t-17). To a solution of the
diacetate ent-16 (25.9 mg, 0.067 mmol) in acetonitrile (1 mL)
at 0 °C was added iodine crystals (57.7 mg, 0.227 mmol), and
the solution stirred for 18 h, allowing to warm to 21 °C. Ether
was added, the solution was washed with aq sodium thiosul-
fate (10%), and the aqueous layer was extracted with ether.
The organic layer was washed successively with aq HCl (1 M)
and water, each time extracting the aqueous layer once more
with ether. The combined organic phase was washed with
brine and dried over MgSO4, followed by removal of the solvent
in vacuo. Column chromatography (SiO2, 20% ethyl acetate/
80% hexane) yielded 13.0 mg of the iodide ent-17 (0.038 mmol,
57%) as a slightly yellow oil.
of ent-19 were identical with those of 19. [R]21 ) +41.4 (c )
D
1.02, MeOH).
(3S ,4R ,5R )-4,5-B is [[[(1,1-d im e t h y le t h y l)d im e t h y l-
silyl]oxy]m eth yl]-3-tetr a h yd r ofu r a n ol (15). F r om 19: To
a suspension of the crude triol 19 (41.5 mg) in dichloromethane
(3 mL) at 21 °C weres added triethylamine (135 µL, 0.969
mmol), (N,N-dimethylamino)pyridine (12 mg, 0.099 mmol), and
tert-butyldimethylsilyl chloride (130 mg, 0.863 mmol), and the
mixture stirred for 18 h. The solution was decanted from some
residual solid, and the solid was rinsed with dichloromethane.
The combined organic phase was washed with aq HCl (1 M)
and the aqueous layer extracted with dichloromethane. The
combined organic layers were washed with aq sodium bicar-
bonate (10%) and brine and dried over MgSO4. Removal of
the solvent in vacuo and column chromatography (SiO2, 20%
ethyl acetate/80% hexane) yielded 75.2 mg of 15 (0.200 mmol,
72% from 18) as a colorless oil.
F r om 14: To a solution of the diol 14 (23.7 mg, 0.090 mmol)
in dichloromethane (1.5 mL) at 21 °C were added triethyl-
amine (26 µL, 0.187 mmol), a small amount of (N,N-dimethyl-
amino)pyridine, and tert-butyldimethylsilyl chloride (20.3 mg,
0.135 mmol), and the solution stirred for 18 h. Dichlo-
romethane and water were added to the mixture, the layers
were separated, and the aqueous layer was extracted with
dichloromethane. The combined aqueous phase was washed
with aq HCl (1 M), aq sodium bicarbonate (10%), and brine
and dried over MgSO4. Removal of the solvent in vacuo and
column chromatography (SiO2, 20% ethyl acetate/80% hexane
f 60% ethyl acetate/40% hexane) yielded 21.2 mg of the
alcohol 15 (0.056 mmol, 62%) as a colorless oil. 1H NMR
(CDCl3, 400 MHz) δ: 4.49 (1H, dddd, J ) 5.7, 4.2, 4.2, 2.2 Hz,
H3), 3.99 (1H, dd, J ) 10.5, 4.6 Hz, H7), 3.96 (1H, ddd, J )
8.8, 4.5, 4.5 Hz, H5), 3.94 (1H, dd, J ) 9.8, 4.1 Hz, H2), 3.88
(1H, dd, J ) 10.5, 6.6 Hz, H7′), 3.76 (1H, dd, J ) 9.5, 2.3 Hz,
H2′), 3.69 (1H, dd, J ) 10.6, 4.3 Hz, H6), 3.67 (1H, dd, J )
10.6, 4.9 Hz, H6′), 3.24 (1H, d, J ) 4.3 Hz, OH), 2.26 (1H, dddd,
J ) 8.5, 6.5, 5.7, 4.7 Hz, H4), 0.90 (9H, s, t-Bu), 0.89 (9H, s,
t-Bu), 0.09 (3H, s, MeSi), 0.08 (3H, s, MeSi), 0.06 (6H, s, Me2-
Si). 13C NMR (CDCl3, 100 MHz) δ: 79.4, 75.4, 74.6, 64.5, 61.2,
47.2, 25.9, 25.8, 18.3, 18.1, -5.37, -5.41, -5.52, -5.57. IR
(thin film): 3433 (br m), 2930 (s), 1472 (m), 1256 (s), 1088 (s),
837 (s) cm-1. High-resolution MS (EI, m/z): 377.2551, calcd
for C18H41O428Si2 377.2543 (M + H)+. [R]21D ) -26.0 (c ) 0.90,
CHCl3).
On a larger scale, as in the preparation of 17 from 16, the
diacetate ent-16 (710.5 mg, 1.84 mmol), silver(I) bis(sym-
collidine) perchlorate (925 mg, 2.06 mmol), and iodine (525 mg,
2.07 mmol) afforded 269.8 mg (0.789 mmol, 43%) of the iodide
ent-17. In each case, 1H NMR, 13C NMR, IR, and HRMS of
ent-17 were identical with those of 17. [R]21 ) +47.9 (c )
D
0.86, CHCl3).
(2R,3S,4S)-4-(Acetyloxy)-2,3-bis[(a cetyloxy)m eth yl]tet-
r a h yd r ofu r a n (18). To a solution of the iodide 17 (183.0 mg,
0.535 mmol) in DMSO (4 mL) at 21 °C was added potassium
acetate (510 mg, 5.20 mmol), and the solution was heated at
93 °C for 18 h. The solution was allowed to cool to 21 °C, water
and ether were added, and the layers were separated. The
aqueous layer was extracted three times with ether, and the
combined organic phase was washed with brine and dried over
MgSO4. Removal of the solvent in vacuo followed by column
chromatography (SiO2, 25% ethyl acetate/75% hexane f 50%
ethyl acetate/50% hexane) yielded 87.4 mg (0.319 mmol, 60%)
of the triacetate 18 as a colorless oil. 1H NMR (CDCl3, 400
MHz) δ: 5.40 (1H, ddd, J ) 5.4, 4.1, 1.5 Hz, H4), 4.32 (1H, dd,
J ) 11.1, 7.4 Hz, H6), 4.31 (1H, br q, J ) 6.6 Hz, H2), 4.13-
4.07 (4H, m, H5, H6′, H7, H7′), 3.86 (1H, dd, J ) 10.7, 1.5 Hz,
H2), 2.48 (1H, br quin, J ) 7.2 Hz, H3), 2.10 (3H, s, OAc), 2.08
(3H, s, OAc), 2.05 (3H, s, OAc). 13C NMR (CDCl3, 100 MHz)
δ: 170.8, 170.7, 170.3, 78.8, 74.5, 73.4, 65.2, 60.7, 43.5, 20.91,
20.85, 20.79. IR (thin film): 1740 (s), 1372 (m), 1233 (s), 1040
(m) cm-1. High-resolution MS (EI, m/z): 275.1135, calcd for
C
12H19O7 275.1131 (M + H)+. [R]21D ) -74.8 (c ) 0.97, CHCl3).
(2S,3R,4R)-4-(Acetyloxy)-2,3-bis[(a cetyloxy)m eth yl]tet-
r a h yd r ofu r a n (en t-18). As in the preparation of 18, the
iodide ent-17 (252.3 mg, 0.737 mmol) and potassium iodide
(719 mg, 7.33 mmol) were heated in DMSO (10 mL) at 97 °C
for 30 h and yielded after workup 120.5 mg of the triacetate
ent-18 (0.439 mmol, 60%) as a colorless oil. 1H NMR, 13C
NMR, IR, and HRMS of ent-18 were identical with those of
(3R ,4S ,5S )-4,5-B is [[[(1,1-d im e t h y le t h y l)d im e t h y l-
silyl]oxy]m et h yl]-3-t et r a h yd r ofu r a n ol (en t -15). From
ent-19: As in the preparation of 15 from 19, the crude triol
ent-19 (67.7 mg), triethylamine (210 µL, 1.51 mmol), (N,N-
dimethylamino)pyridine (26 mg, 0.21 mmol), and tert-bu-
tyldimethylsilyl chloride (190 mg, 1.26 mmol) yielded after
chromatography on silica gel 111.2 mg of ent-15 (0.295 mmol,
71% from ent-18) as a colorless oil.
18. [R]21 ) +68.7 (c ) 0.42, CHCl3).
D
(3S,4R,5R)-4,5-Bis(h yd r oxym eth yl)-3-tetr a h yd r ofu r a -
n ol (19). To a solution of the triacetate 18 (76.4 mg, 0.279
mmol) in methanol (15 mL) cooled to 0 °C was added a vigorous
stream of ammonia for 7.5 min. The solution was stirred
overnight and allowed to warm to 21 °C. The solvent was
removed in vacuo, chloroform was added, and the solution
stirred. The chloroform was decanted, leaving behind a
precipitate which was dissolved in methanol. The methanol
was removed in vacuo, yielding 41.5 mg of the crude triol 19
as a white solid, which was used directly in the synthesis of
15. 1H NMR (MeOH-d4, 400 MHz) δ: 4.38 (1H, ddd, J ) 5.0,
3.6, 1.3 Hz, H3), 3.91 (1H, dd, J ) 9.5, 3.6 Hz, H2), 3.856 (1H,
ddd, J ) 9.1, 5.0, 4.1 Hz, H5), 3.848 (1H, dd, J ) 10.9, 6.8 Hz,
overlapping with previous signal, H7), 3.71 (1H, dd, J ) 9.5,
1.4 Hz, H2′), 3.650 (1H, dd, J ) 11.7, 3.8 Hz, H6), 3.649 (1H,
dd, J ) 10.8, 6.4 Hz, overlapping with previous signal, H7′),
3.53 (1H, dd, J ) 11.7, 5.1, H6′), 2.13 (1H, dddd, J ) 9.3, 6.8,
6.8, 5.1 Hz, H4). 13C NMR (MeOH-d4, 100 MHz) δ: 81.1, 74.9,
F r om en t-14: To a solution of the diol ent-14 (37.8 mg,
0.144 mmol) in dichloromethane (2 mL) were added triethyl-
amine (40 µL, 0.29 mmol), (N,N-dimethylamino)pyridine (3.7
mg, 0.030 mmol), and tert-butyldimethylsilyl chloride (25.6 mg,
0.170 mmol), and the solution stirred for 18 h. TLC control
(50% ethyl acetate/50% hexane) showed an incomplete reaction
so more triethylamine (30 µL, 0.22 mmol) and tert-butyldi-
methylsilyl chloride (25 mg, 0.166 mmol) were added, and the
mixture stirred for an additional 24 h. Workup as in the
preparation of 15 from 14 and column chromatography (SiO2,
20% ethyl acetate/80% hexane f 60% ethyl acetate/40%
hexane) yielded 41.8 mg of the alcohol ent-15 (0.110 mmol,
77%) as a colorless oil, as well as 3.4 mg of the unreacted diol
1
ent-14 (0.013 mmol, 9%). In either case, H NMR, 13C NMR,

354 J . Org. Chem., Vol. 63, No. 2, 1998
J ung and Nichols
IR, and HRMS of ent-15 were identical with those of 15. [R]21
) +16.5 (c ) 0.55, CHCl3).
121.3, 86.1, 75.0, 65.3, 59.7, 25.88, 25.85, 18.35, 18.24, -5.40,
-5.42, -5.45 (2C); IR (thin film) 2955 (s), 2930 (s), 2856 (s),
D
(2R ,3S ,4S )-2,3-B is [[[(1,1-d im e t h y le t h y l)d im e t h y l-
silyl]oxy]m et h yl]-4-[(4-m et h ylp h en yl)su lfon yl]oxy]t et -
r a h yd r ofu r a n (20). To a solution of the alcohol 15 (16.2 mg,
0.043 mmol) in pyridine (0.5 mL) cooled to 0 °C was added
p-toluenesulfonyl chloride (82 mg, 0.43 mmol), and the solution
stirred for 18 h, allowing to warm to 21 °C. The solution was
diluted with ethyl acetate, washed with aq sodium bicarbonate
(10%), aq HCl (1 M), and brine, and dried over MgSO4.
Removal of the solvent in vacuo and column chromatography
(SiO2, 10% ethyl acetate/90% hexane f 25% ethyl acetate/75%
hexane) yielded 15.5 mg of the tosylate 20 (0.029 mmol, 68%)
1472 (m), 1256 (s), 1090 (s), 1007 (m), 839 (s), 777 (s) cm-1
;
high-resolution MS (EI, m/z) 357.2282, calcd for C18H37O328Si2
357.2281 (M - H)+.
9-[(3S,4S,5S)-Tetr a h yd r o-4,5-bis[[[(1,1-d im eth yleth yl)-
d i m e t h y ls i ly l]o x y ]m e t h y l]-3-fu r a n y l]-9H -p u r i n -6-
a m in e (en t-22) a n d (2S)-2,5-Dih yd r o-2,3-bis[[[(1,1-d im e-
th yleth yl)d im eth ylsilyl]oxy]m eth yl]fu r a n (en t-21). As in
the preparation of 22, the tosylate ent-20 (10.2 mg, 0.019
mmol), adenine (7.6 mg, 0.056 mmol), 18-crown-6 (6.6 mg,
0.025 mmol), and potassium carbonate (12.1 mg, 0.087 mmol)
yielded after chromatography on silica gel 4.2 mg of the purine
ent-22 (0.0085 mmol, 44%) as a white solid, as well as 2.0 mg
of the dihydrofuran ent-21 (0.0056 mmol, 29%) as a colorless
oil. The 1H NMR, 13C NMR, IR, and HRMS of ent-22 were
identical with those of 22, and those of ent-21 were identical
with those of 21. For ent-22: [R]21D ) -35.8 (c ) 0.46, CHCl3).
9-[(3R,4R,5R)-Tet r a h yd r o-4,5-b is(h yd r oxym et h yl)-3-
fu r a n yl]-9H-p u r in -6-a m in e ((+)-2a ). To a solution of the
bis(silyl) ether 22 (43.9 mg, 0.089 mmol) in THF (3 mL) at 21
°C was added a solution of tetrabutylammonium fluoride in
THF (1 M, 0.35 mL, 0.35 mmol), and the mixture stirred for
45 min. Removal of the solvent in vacuo and column chro-
matography (SiO2, 15% methanol/85% dichloromethane) fol-
lowed by recrystallization by adding methanol and allowing
it to evaporate slowly gave 18.9 mg (0.071 mmol, 80%) of the
isonucleoside (+)-2a as a white solid. 1H and 13C NMR
matched that of (-)-2a previously prepared:7 mp ) 172 °C.
1H NMR (DMSO-d6, 500 MHz) δ: 8.28 (1H, s, adenine), 8.14
(1H, s, adenine), 7.22 (2H, br s, NH2), 5.01 (1H, m), 5.00 (1H,
t, J ) 5.6 Hz, OH), 4.94 (1H, t, J ) 5.0 Hz, OH), 4.00 (1H, dd,
J ) 9.5, 4.2 Hz), 3.97 (1H, dd, J ) 9.5, 6.0 Hz), 3.78 (1H, ddd,
J ) 7.6, 4.5, 3.6 Hz), 3.71 (1H, ddd, J ) 11.8, 5.2, 3.2 Hz),
3.63-3.53 (3H, m), 2.52 (1H, dddd, J ) 7.5, 5.5, 5.5, 5.0 Hz).
13C NMR (DMSO-d6, 100 MHz) δ: 156.4, 152.8, 149.7, 139.6,
119.1, 82.9, 71.9, 62.4, 60.9, 57.4, 49.6. IR (KBr pellet): 3402
1
as a colorless oil. H NMR (CDCl3, 400 MHz) δ: 7.79 (2H, m,
OTs), 7.34 (2H, m, OTs), 5.14 (1H, ddd, J ) 5.5, 2.6, 2.6 Hz,
H4), 3.90 (1H, ddd, J ) 8.4, 3.4, 3.4 Hz, H2), 3.85 (2H, d, J )
2.7 Hz, H5, H5′), 3.79 (1H, dd, J ) 10.9, 3.2 Hz, H6), 3.70 (1H,
dd, J ) 10.2, 6.6 Hz, H7), 3.64 (1H, dd, J ) 10.2, 7.5 Hz, H7′),
3.59 (1H, dd, J ) 10.9, 3.6 Hz, H6′), 2.48 (1H, dddd, J ) 8.3,
7.4, 6.8, 5.5 Hz, H3), 2.45 (3H, s, MeAr), 0.87 (9H, s, t-Bu),
0.86 (9H, s, t-Bu), 0.03 (6H, s, Me2Si), 0.01 (6H, s, Me2Si). 13C
NMR (CDCl3, 100 MHz) δ: 144.8, 134.0, 129.9, 127.8, 82.8,
81.7, 72.6, 64.9, 60.0, 46.4, 25.9, 25.8, 21.6, 18.3, 18.2, -5.36,
-5.47, -5.51, -5.55. IR (thin film): 2955 (m), 2930 (m), 2859
(m), 1372 (m), 1256 (m), 1179 (s), 1094 (s), 897 (m), 839 (s)
cm-1
25H47O6S28Si2 531.2632 (M + H)+. [R]21 ) -32.4 (c ) 0.52,
. High-resolution MS (EI, m/z): 531.2634, calcd for
C
D
CHCl3).
(2S ,3S ,4R )-2,3-B is [[[(1,1-d im e t h y le t h y l)d im e t h y l-
silyl]oxy]m eth yl]-4-[[(4-m eth ylp h en yl)su lfon yl]oxy]tet-
r a h yd r ofu r a n (en t-20). As in the preparation of 20, the
alcohol ent-15 (37.5 mg, 0.100 mmol) and p-toluenesulfonyl
chloride (50.2 mg, 0.262 mmol) yielded after chromatography
on silica gel 35.0 mg of the tosylate ent-20 (0.066 mmol, 66%)
as a colorless oil, as well as 11.8 mg of the unreacted alcohol
ent-15 (0.031 mmol, 31%). 1H NMR, 13C NMR, IR, and HRMS
of ent-20 were identical with those of 20. [R]21 ) +36.3 (c )
D
0.90, CHCl3).
(w), 3326 (w), 3206 (m), 1649 (s), 1613 (m), 1020 (m) cm-1
.
9-[(3R,4R,5R)-Tetr a h yd r o-4,5-bis[[[(1,1-d im eth yleth yl)-
d i m e t h y ls i ly l]o x y ]m e t h y l]-3-fu r a n y l]-9H -p u r i n -6-
a m in e (22) a n d (2R)-2,5-Dih yd r o-2,3-bis[[[(1,1-d im eth yl-
eth yl)d im eth ylsilyl]oxy]m eth yl]fu r a n (21). To a solution
of the tosylate 20 (96.3 mg, 0.181 mmol) in N,N-dimethylfor-
mamide (2.5 mL) at 21 °C were added adenine (79.3 mg, 0.587
mmol), 18-crown-6 (60.7 mg, 0.230 mmol), and potassium
carbonate (99.7 mg, 0.721 mmol), and the solution heated to
90 °C for 18 h. After the mixture cooled to 21 °C, the N,N-
dimethylformamide was removed by Kugelrohr distillation at
reduced pressure and the residue purified by column chroma-
tography (SiO2, 100% dichloromethane f 5% isopropyl alcohol/
95% dichloromethane) which yielded 38.7 mg of the purine 22
(0.078 mmol, 43%) as a white solid, as well as 16.7 mg of the
dihydrofuran 21 (0.047 mmol, 26%) as a colorless oil.
High-resolution MS (EI, m/z): 265.1171, calcd for C11H15N5O3
265.1175. [R]21 ) +22.9 (c ) 0.51, 1:1 MeOH/H2O).
D
(3S,4S,5S)-9-[Tetr ah ydr o-4,5-bis(h ydr oxym eth yl)-3-fu r a-
n yl]-9H-p u r in -6-a m in e ((-)-2a ). As in the preparation of
(+)-2a , the bis(silyl) ether ent-22 (36.5 mg, 0.074 mmol) and
tetrabutylammonium fluoride (1 M in THF, 0.30 mL, 0.30
mmol) yielded after two purifications by column chromatog-
raphy (SiO2, 15% methanol/85% dichloromethane; SiO2, 100%
dichloromethane f 15% methanol/85% dichloromethane) 16.2
mg of (-)-2a (0.061 mmol, 83%) as a white solid. 1H NMR,
13C NMR, IR, and HRMS were identical with those of (+)-2a
and matched those of (-)-2a previously prepared:7 mp ) 174
°C (lit.7 mp ) 185-195 °C dec). [R]21 ) -26.4 (c ) 0.52, 1:1
D
MeOH/H2O).
5-Me t h yl-1-[(3R ,4R ,5R )-t e t r a h yd r o-4,5-b is[[[(1,1-d i-
m e t h y le t h y l)d im e t h y ls ily l]o x y ]m e t h y l]-3-fu r a n y l]-
2,4(1H,3H)-p yr im id in ed ion e (23). To a solution of the
tosylate 20 (100.9 mg, 0.190 mmol) in DMSO (1 mL) were
added potassium carbonate (108.7 mg, 0.786 mmol), thymine
(46.9 mg, 0.372 mmol), and 18-crown-6 (50.5 mg, 0.191 mmol),
and the solution was heated to 90 °C for 18 h. Cooling of the
solution to 21 °C followed by two successive purifications by
column chromatography (SiO2, 50% ethyl acetate/50% hexane
f 100% ethyl acetate; SiO2, 10% ethyl acetate/90% hexane f
25% ethyl acetate/75% hexane) yielded 21.1 mg of 23 (0.044
mmol, 23%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ:
8.69 (1H, br s, thymine), 7.43 (1H, q, J ) 1.2 Hz, thymine),
5.11 (1H, ddd, J ) 6.3, 3.9, 2.2 Hz, H3), 3.97 (1H, dd, J ) 11.1,
2.9 Hz, H6), 3.94 (1H, dd, J ) 10.6, 2.1 Hz, overlapping with
previous signal, H2), 3.88 (1H, dd, J ) 10.6, 6.4 Hz, H2′), 3.843
(1H, ddd, J ) 7.9, 3.3, 3.3 Hz, overlapping with previous signal,
H5), 3.840 (1H, dd, J ) 10.0, 5.5 Hz, overlapping with previous
two signals, H7), 3.77 (1H, dd, J ) 11.1, 3.6 Hz, H6′), 3.74 (1H,
dd, J ) 10.1, 3.8 Hz, overlapping with previous signal, H7′),
2.34 (1H, ddtdd, J ) 8.1, 5.4, 4.0, 4.0 Hz, H4), 1.92 (3H, d, J )
1.2 Hz, thymine), 0.90 (9H, s, t-Bu), 0.89 (9H, s, t-Bu), 0.084
(3H, s, MeSi), 0.082 (3H, s, MeSi), 0.07 (3H, s, MeSi), 0.05 (3H,
22: mp ) 142 °C; 1H NMR (CDCl3, 400 MHz) δ 8.34 (1H, s,
adenine), 8.20 (1H, s, adenine), 5.70 (2H, br s, NH2), 5.13 (1H,
ddd, J ) 5.5, 3.6, 3.6 Hz, H3), 4.09 (1H, dd, J ) 10.0, 3.4 Hz,
H2), 4.06 (1H, dd, J ) 9.8, 5.4 Hz, H2′), 4.00 (1H, dd, J ) 10.8,
3.5 Hz, H6), 3.94 (1H, ddd, J ) 7.4, 3.5, 3.5 Hz, H5), 3.86 (1H,
dd, J ) 10.1, 5.4 Hz, H7), 3.84 (1H, dd, J ) 10.8, 3.7 Hz,
overlapping with previous signal, H6′), 3.78 (1H, dd, J ) 10.1,
4.6 Hz, H7′), 2.66 (1H, m, H4), 0.91 (9H, s, t-Bu), 0.87 (9H, s,
t-Bu), 0.12 (3H, s, MeSi), 0.10 (3H, s, MeSi), 0.06 (3H, s, MeSi),
0.05 (3H, s, MeSi); 13C NMR (CDCl3, 100 MHz) δ 155.2, 152.7,
149.9, 139.6, 119.3, 82.5, 73.1, 64.0, 62.6, 57.5, 50.2, 26.0, 25.8,
18.6, 18.2, -5.26, -5.36, -5.52 (2C); IR (thin film) 3366 (w),
3281 (w), 3244 (w), 3129 (m), 2928 (m), 1682 (s), 1603 (s), 1306
(m), 1252 (s), 1117 (m), 835 (s), 779 (m) cm-1; high-resolution
MS (EI, m/z) 494.2981, calcd for C23H44H5O328Si2 494.2983 (M
+ H)+; [R]21 ) +36.3 (c ) 0.50, CHCl3).
D
21: 1H NMR (CDCl3, 400 MHz) δ 5.77 (1H, br sextet, J )
1.7 Hz, H4), 4.71-4.60 (3H, m), 4.33 (1H, br d, J ) 14.8 Hz,
H7), 4.19 (1H, br d, J ) 14.9 Hz, H7′), 3.69 (1H, dd, J ) 10.5,
4.5 Hz, H6), 3.67 (1H, dd, J ) 10.5, 5.0 Hz, H6′), 0.91 (9H, s,
t-Bu), 0.88 (9H, s, t-Bu), 0.08 (6H, s, Me2Si), 0.052 (3H, s,
MeSi), 0.050 (3H, s, MeSi); 13C NMR (CDCl3, 100 MHz) δ 141.6,

Synthesis of Methylene-Expanded Oxetanocins
J . Org. Chem., Vol. 63, No. 2, 1998 355
s, MeSi). 13C NMR (CDCl3, 100 MHz) δ: 163.6, 150.9, 137.3,
111.6, 82.7, 72.2, 63.4, 62.2, 58.2, 49.6, 26.0, 25.8, 18.6, 18.2,
12.7, -5.3, -5.4, -5.5, -5.6. IR (thin film): 3195 (w), 3065
(w), 1692 (s), 1472 (w), 1256 (m), 837 (s), 777 (m) cm-1. High-
resolution MS (EI, m/z): 485.2871, calcd for C23H45N2O528Si2
2.8 Hz), 3.66 (1H, br ddd, J ) 8.0, 3.1, 3.1 Hz), 3.57-3.49 (3H,
m), 2.26 (1H, m, H4), 1.77 (3H, d, J ) 0.9 Hz, thymine). 13C
NMR (DMSO-d6, 125 MHz) δ: 164.0, 151.3, 138.3, 109.6, 82.9,
71.5, 61.8, 60.8, 57.9, 48.9, 12.6. IR (KBr pellet): 3389 (br m),
3179 (br m), 3036 (br w), 1698 (s). High-resolution MS (EI,
m/z): 256.1060, calcd for C11H16N2O5 256.1059. [R]21D ) -11.6
(c ) 0.30, MeOH).
485.2867 (M + H)+. [R]21 ) +4.1 (c ) 1.04, CHCl3).
D
5-Met h yl-1-[(3R,4R,5R)-t et r a h yd r o-4,5-b is(h yd r oxy-
m eth yl)-3-fu r a n yl]-2,4(1H,3H)-p yr im id in ed ion e ((-)-2b).
To a solution of the bis(silyl) ether 23 (20.7 mg, 0.043 mmol)
in THF (2 mL) at 21 °C was added a solution of tetrabutyl-
ammonium fluoride (1 M in THF, 170 µL, 0.17 mmol), and
the mixture stirred for 60 min. Removal of the solvent in
vacuo and two successive purifications with column chroma-
tography (SiO2, 10% methanol/90% dichloromethane; SiO2,
100% dichloromethane f 10% methanol/90% dichloromethane)
followed by recrystallization by dissolving in methanol and
letting it slowly evaporate yielded 10.3 mg of the isonucleoside
(-)-2b (0.040 mmol, 94%) as a white solid. 1H and 13C NMR
matched that of (+)-2b previously prepared:7 mp ) 86 °C (lit.7
mp ) 93-96 °C for (+)-2b). 1H NMR (DMSO-d6, 500 MHz) δ:
11.23 (1H, s, thymine), 7.67 (1H, q, J ) 1.0 Hz, thymine), 4.99
(1H, t, J ) 5.6 Hz, OH), 4.94 (1H, ddd, J ) 6.5, 4.5, 3.0 Hz),
4.85 (1H, t, J ) 4.9 Hz, OH), 3.85 (1H, dd, J ) 10.0, 2.9 Hz),
3.77 (1H, dd, J ) 10.1, 6.6 Hz), 3.72 (1H, ddd, J ) 11.9, 5.1,
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM47228), the University of California
Universitywide AIDS Research Program (R97-LA-139),
and the Agricultural Research Division of the American
Cyanamid Company for generous financial support. We
also thank the Antiviral Evaluations Branch of the
National Cancer Institute for the anti-HIV test data.
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H and
13C NMR spectra for all compounds described in the article
(76 pages). This material is contained in libraries on micro-
fiche, 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 instructions.
J O971890C