Synthesis of 2-substituted ±-(2R,3R,5R)-tetrahydrofuran-3,5-dicarboxylic acid derivatives

Article abstract of DOI:10.1021/jo001551a

An efficient synthesis of 2-substituted (±)-(2R,3R,5R)-tetrahydrofuran-3,5-dicarboxylic acid derivatives has been developed. Starting from 5-norborne-2-ol, the key intermediate (±)-methyl 5,6-exo(isopropylidenedioxy)-2-oxabicyclo[2.2.1]heptane-3-exo-carboxylate (15) was synthesized in an efficient six-step sequence. The key transformation is the base-catalyzed methanolysis-rearrangement of (±)-6,7-exo,exo-(isopropylidenedioxy)-4-exo-iodo-2-oxabicyclo [3.2.1]octan-3-one (14). Further manipulation of the 3-substituent of (±)-methyl 5,6-exo,exo-(isopropylidenedioxy)-2-oxabicyclo[2.2.1] heptane-3-exo-carboxylate (15) followed by deprotection of the diol moiety and ring opening catalyzed by RuCl₃/NaIO₄ gave the title compounds in good yield.

Full text of DOI:10.1021/jo001551a

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2052 J . Org. Chem. 2001, 66, 2052-2056
Syn th esis of 2-Su bstitu ted
(()-(2R,3R,5R)-Tetr a h yd r ofu r a n -3,5-d ica r boxylic Acid Der iva tives†
Gary T. Wang,* Sheldon Wang, Yuanwei Chen, Robert Gentles, and Thomas Sowin
Department of Medicinal Chemistry Technologies (D-4CP), Pharmaceutical Product Division,
Abbott Laboratories, Abbott Park, Illinois 60064
gary.t.wang@abbott.com
Received November 2, 2000
An efficient synthesis of 2-substituted (()-(2R,3R,5R)-tetrahydrofuran-3,5-dicarboxylic acid deriva-
tives has been developed. Starting from 5-norborne-2-ol, the key intermediate (()-methyl 5,6-exo,exo-
(isopropylidenedioxy)-2-oxabicyclo[2.2.1]heptane-3-exo-carboxylate (15) was synthesized in an
efficient six-step sequence. The key transformation is the base-catalyzed methanolysis-rearrange-
ment of (()-6,7-exo,exo-(isopropylidenedioxy)-4-exo-iodo-2-oxabicyclo[3.2.1]octan-3-one (14). Further
manipulation of the 3-substituent of (()-methyl 5,6-exo,exo-(isopropylidenedioxy)-2-oxabicyclo[2.2.1]-
heptane-3-exo-carboxylate (15) followed by deprotection of the diol moiety and ring opening catalyzed
by RuCl3/NaIO4 gave the title compounds in good yield.
Sch em e 1
In tr od u ction
Recently, our research effort in a drug discovery pro-
ject required an efficient synthesis of 2-substituted
(()-(2R,3R,5R)-tetrahydrofuran-3,5-dicarboxylic acid de-
rivatives (1, Scheme 1), where the C2 substituent R
includes simple aliphatic or aryl groups as well as
subtituents containing other functionalities.
cation of 5-hydroxy-olefins (5-exo cyclization) or 4-hy-
droxy-olefins (5-endo cyclization) induced by halogens,6
mercury,7 selenium,8 or transition metals,9 and atom-
transfer radical cyclization of acyclic ethers.10 None of
these methods appears to be suitable for the synthesis
of 1.
We report here a novel synthesis of hitherto unknown
(()-methyl 5,6-exo,exo-(isopropylidenedioxy)-2-oxabicyclo-
[2.2.1]heptane-3-exo-carboxylate (3, R ) CO2Me) and its
An extensive literature search indicated that tetrahy-
drofurans of structure 1 are hitherto unknown. Even
though saturated five-membered ring heterocyclics such
as substituted tetrahydrofuran (THF) appear in a num-
ber of natural products,1,2 synthesis of this class of
compounds with desired substituents in a stereoselective
manner remains to be a significant challenge. Reduction
(catalytic hydrogenation) of furans represents one ap-
proach, which has the advantage that a variety of
substituents can be introduced into the precursor furans,
often regioseletively, via electrophilic substitution. How-
ever, this approach generally lacks stereoselectivity.
Starting from ribose or deoxy-ribose is another common
approach,3 which offers the advantage of inexpensive
chiral starting materials but suffers from limited option
of stereochemistry and functional groups that can be
introduced. A variety of methodologies have also been
developed for forming the THF ring from acyclic precur-
sors. These include cyclodehydration of 1,4-diols under
acid catalysis or Mitsunobu conditions,4,5 cycloetherifi-
(4) (a) Paquette, L. A.; Negri, J . T. J . Am. Chem. Soc. 1991, 113,
5072. (b) Negri, J . T.; Paquette, L. A.; J . Am. Chem. Soc. 1992, 114,
8835. (c) Carr. G.; Whittaker, D. J . Chem. Soc., Perkin Tran. 2 1989,
359. (d) Molnar, A.; Fe; foldi, K.; Bartok, M. Tetrahedron 1981, 37,
2149. (e) Milhaiovic, M. L.; Gojkovic, S.; Cekovic, Z. J . Chem. Soc.,
Perkin Trans. 1 1972, 2460. (f) Carr, G.; Dean, C.; Whittaker, D. J .
Chem. Soc., Perkin Trans 2 1988, 351. (g) Haggis, G. A.; Owen, L. N.
J . Chem. Soc. 1953, 389.
(5) (a) Njar, V. C. O.; Spiteller, G.; Wicha, J .; Caspi, E. Heterocycles
1989, 28, 1051. (b) Lee, B. H.; Miller, M. J . J . Org. Chem. 1983, 48,
24.
(6) (a) Lipshutz, B. H.; Barton, J . C. J . Am. Chem. Soc. 1992, 114,
1084. (b) Mihelich, E. D.; Hite, G. A. J . Am. Chem. Soc. 1992, 114,
7318. (c) Labelle, M.; Morton, H. E.; Guindon, Y.; Springer, J . P. J .
Am. Chem. Soc. 1988, 110, 4533. (d) Williams, D. R.; White, F. H.
Tetrahedron Lett. 1986, 27, 2195. (e) Beebe, X.; Schore, N. E.; Kurth,
M. J . J . Am. Chem. Soc. 1992, 114, 10061. (f) Marek, I.; Letrancois, J .
M.; Normant, J . F. Tetrahedron Lett. 1992, 33, 1747. (g) Evans, R. D.;
Magee, J . W.; Schauble, J . H. Synthesis 1988, 862.
* Corresponding author: Phone: (847)-937-2489. Fax: (847)-935-
0310.
† Dedicated to Prof. J oseph B. Lambert of Northwestern University
(Evanston, IL) on the occasion of his 60th birthday.
(1) Lord, M. D.; Negri, J . T.; Paquette, L. A. J . Org. Chem. 1995,
60, 191.
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1978, 43, 4220. (b) Maurer, B.; Hauser, A.; Ohloff. G. Helv. Chim. Acta
1980, 63, 2503. (c) Winter, M.; Kloti, R. Helv. Chim. Acta 1972, 55,
1916. (d) Renold, W.; Naf-Muller, R.; Keller, U.; Willhalm, B.; Ohloff,
G. Helv. Chim. Acta 1974, 57, 1301.
(3) (a) Togo, H.; Ishigami, S.; Yokoyama, M. Chem. Lett. 1992, 1673.
(b). Watanable, T.; Nishiyama, S.; Yamamura, S.; Kato, K. Takita, T.
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Tsuchimori, N. J . Am. Chem. Soc. 1990, 112, 9668. (d) Otter, B. A.;
Patil, S. A.; Klein. S.; Ealick, S. E.; J . Am. Chem. Soc. 1992, 114, 668.
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1985, 26, 3915. (b) Amouroux, R.; Chastrette, F.; Chasetrette, M. Bull.
Soc. Chim. Fr. 1982, 293. (c) Speziale, V.; Dao, H. G.; Lattes, A. J .
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10.1021/jo001551a CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/16/2001

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Tetrahydrofuran-3,5-dicarboxylic Acid Derivatives
Sch em e 2
J . Org. Chem., Vol. 66, No. 6, 2001 2053
Sch em e 3a
subsequent conversion to 1 via oxidative ring opening.
Together, this sequence provides a practical synthesis of
2-substituted (()-(2R,3R,5R)-tetrahydrofuran-3,5-dicar-
boxylic acid derivatives (1) with complete control of the
relative stereochemistry.
Resu lts a n d Discu ssion
Our retrosynthetic analysis indicated that 2-oxabicyclo-
[2.2.1]hept-5-ene 2 or 5,6-dihydroxy-2-oxabicyclo[2.2.2]-
heptane 3 would serve as ideal precursors for the
synthesis of 1 (Scheme 1). The bicyclic olefin 2 or diol 3
could be easily converted into the desired THF system 1
via oxidative ring opening with complete control of the
relative stereochemistry. The C2 substituent R can either
be set in the precursors 2 or 3, or subjected to further
manipulation after the ring opening.
Our initial effort was focused on the intermediacy of
methyl 2-oxabicyclo[2.2.1]hept-5-ene-3-exo-carboxylate (2,
R) CO2Me), which seemingly can be prepared via the
Diels-Alder reaction of cyclopentadiene 4 and methyl
glyoxylate 5. Such Diels-Alder reaction, if feasible, would
normal give the endo-adduct 6 which assumingly can be
epimierized to the desired exo-adduct (Scheme 2). Diels-
Alder addition of electron-deficient aldehydes such as
glyoxylate esters with electron-rich 1,3-dienes such as
Danishesky’s diene has been amply documented,11,12 and
the addition of 5 to cyclohexadiene has also been re-
ported.13 Surprisingly, the addition of aldehyde dieno-
philes to cyclopentadiene has not been described.
a
(a) DMSO, (COCl)2, DCM, -78 °C to r.t, 85%; (b) OsO4,
NMMO, r.t. 3 h, 90%; (c) 2,2-dimethoxypropane, TsOH, r,t. 1 h,
90%; (d) LDA, t-BuMe2SiCl, -78 °C; (e) Br2, DCM, 0 °C, 76%.
by retro-Diels-Alder reaction) and could not be isolated
on preparative scale.
We then turned our attention to developing an syn-
thetic route utilizing diols of type 3 as the intermediates.
Vogel and co-workers described the Baeyer-Villiger
reaction of R-bromo ketone 3-exo-bromo-5,6-exo,exo-(iso-
propylidenedioxy)-7-oxabicyclo[2.2.1]heptan-2-one, giving
the R-bromo bicyclic lactone, (()-3-exo-bromo-6,7-exo,exo-
(isopropylidenedioxy)-2,8-dioxabicyclo[3.2.1]octan-3-
one. This R-bromo bicyclic lactone was, in turn, trans-
formed into methyl 5,6-exo,exo-(isopropylidenedioxy)-2,7-
dioxabicyclo[2.2.1]heptane-3-exo-carboxylate upon metha-
nolysis in basic MeOH.14 We anticipated that this se-
quence of reactions can be adopted for the synthesis of
our key intermediate, 2-oxabicyclo[2.2.1]heptane system
3.
Thus, commercially available 5-norbornen-2-ol (7) was
converted to the protected dihydroxy ketone 9 via stan-
dard procedure of Swern oxidation, dihydroxylation and
protection (Scheme 3). We initially sought to follow the
exact reaction sequence of Auberson and Vogel.14 Accord-
ingly, ketone 9 was converted to the enol silyl ether 10
according to literature procedure.15 Treatment of 10 with
Br2 in CH2Cl2 gave the desired R-bromo ketone 11. The
ratio of exo:endo bromide was found to be substantially
temperature dependent. At -55 °C, the exo-bromide (δ
3.72 for C2 H) dominated in a 2:1 ratio over the endo-
bromide. This ratio was reduced to 1:1 at -78 °C but
increased to 10:1 when the reaction was carried out at 0
°C. The R-bromo ketone 11 was then subjected to
Baeyer-Villiger conditions, with disappointing results.
With MCPBA as the reagent, no reaction was observed.
Urea hydrogen peroxide complex has been used to react
with trifluoroacetic anhydride to generate per-trifluoro-
acetic acid which is known to be a stronger oxidant,16 and
the reagent of choice for Auberson and Vogel.14 Several
variations of this procedure were tried; all failed to effect
the conversion of 11 to the corresponding lactone 12.
Unable to convert the R-bromo ketone 11 to the
corresponding lactone 12, we then sought to alternate
In our hands, no cycloaddition was observed after
refluxing freshly distilled cyclopentadiene and methyl
glyoxylate in toluene (120 °C) over extended time (5
days). We then examined this reaction under Lewis acid
catalysis. With BF3‚Et2O at -78 °C or ZnCl2 at 0 °C, a
complex mixture was obtained which contained only trace
amount of the adduct as indicated by mass spectrometry.
With MgBr2 (0 °C to ambient temperature), a relatively
clean reaction was observed with the formation of one
1
major high Rf product whose H NMR and mass spectra
were consistent with the expected adduct. However, this
material was very unstable (presumably decomposition
(10) (a) Udding, J . H.; Tuijp, K. J . M.; Zanden, M. N. A.; Hiemstra,
H.; Speckamp. W. N. J . Org. Chem. 1994, 59, 1993. (b) Rawal, V. H.;
Singh, S. P.; Dufour, C.; Michoud, C.; J . Org. Chem. 1991, 56, 5245.
(c) Hanessian, S. Leger, R. J . Am. Chem. Soc. 1992, 114, 3115. (d)
Beckwith, A. L. J .; O’Shea, D. M. Tetrahedron Lett. 1986, 27, 4525. (e)
Molander, G. A.; Harring, L. S. J . Org. Chem. 1990, 55, 6171.
(11) Reviews: (a) Weinreb, S. In Comprehensive Organic Synthesis;
Pergamon Press: New York, 1991; Vol. 5, pp 401-449. (b) Weinreb,
S.; Staib, R. R. Tetrahedron 1982, 38, 3087.
(12) (a) Schaus, S. E.; Branalt, J . J acobsen, E. N. J . Org. Chem.
1998, 63, 403. (b) Danishesky, S. J . Aldrichimica Acta 19, 59. (c)
Daneshesky, S.; Kerwin, J . F.; Kobayashi, S. J . Am. Chem. Soc. 1982,
104, 358. (d) Bednarski, M.; Danishesky, S. J . J . Am. Chem. Soc. 1983,
105, 3716. (e) Danishesky, S. J .; Pearson, W. H.; Harvey, D. F. J . Am.
Chem. Soc. 1984, 106, 2455.
(14) Auberson, Y.; Vogel, P. Helv. Chim. Acta 1989, 72, 278.
(15) Helmchen, G.; Krotz, A.; Neumann, H. P.; Ziegler, M. L. Liebigs
Ann. Chem. 1993, 1313.
(16) (a) Ballini, R.; Marcantoni, E.; Petrini, M. Tetrahedron Lett.
1992, 33, 4835. (b) Schultz, A.; Malachowski, W. P.; Pan, Y. J . Org.
Chem. 1997, 62, 1223.
(13) (a) Yao, S.; J ohannsen, M.; Hazell, R. G.; J orgensen, K. A. J .
Org. Chem. 1998, 63, 118. (b) J ohannsen, M.; J orgensen, K. A. J . Chem.
Soc., Perkin, Trans. 2, 1997, 1183. (c) J ohannsen, M.; J orgensen, K.
A. J . Org. Chem. 1995, 60, 5757. (d) Achmatowicz, O.; J urczak, J .;
Pyrek, J . S. Rocz. Chem. 1975, 49, 1831.

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2054 J . Org. Chem., Vol. 66, No. 6, 2001
Sch em e 4a
Wang et al.
mation), confirming the exo-configuration of the iodo-
substituent. When 14 was treated with K2CO3 in metha-
nol according to the procedure of Auberson and Vogel,14
it was converted smoothly to the key intermediate 15 in
80% yield. The exo configuration of the methyl ester
functionality of 15 was readily established based on the
NMR studies. The C3 proton appeared at 3.8 ppm and
did not couple with the C4 proton, indicating the endo-
disposition of this proton.
The intermediate 15 can be deprotected directly and
subjected to oxidative ring opening to give the desired
THF derivative (1, R ) CO2Me). Alternatively, the
carboxymethyl functionality of 15 can be elaborated into
other desirable groups at this stage before the deprotec-
tion and ring opening. As an illustration, we chose to
reduce the ester 15 to the aldehyde 16 with DIBALH.
The aldehyde 16 was then reacted with isobutyl magnu-
sium bromide to give alcohol 17, which was oxidized to
ketone 18a . The diol moiety of 18a was then deprotected
and oxidative ring opening with NaIO4 in the presence
of catalytic amount of RuCl3 gave (()-(2R,3R,5R)-2-(3′-
methyl-1′-oxobutyl)tetrahydrofuran-3,5-dicarboxylic acid,
19a , in good yield.
a
(a) MCPBA, CHCl3, then aluminum oxide, 50%; (b) LHMDS,
I2, -78 °C, 0.5 h, 81%; (c) K2CO3, MeOH, r.t., 0.5 h, 80-90%; (d)
DIBALH, DCM, -78 °C, 1 h, 80%; (e) isobutylmagnesium bromide,
0 °C, 1 h; (f) DMSO, (COCl)2, DCM, -78 °C to r.t, 51% for three
steps; (g) 2 N HCl, MeOH, 40 °C, 2 h, 98%; (h) RuCl3‚H2O, NaIO4,
r.t., 4 h; (i) MeI, CH2Cl2, DIEA, 68% for two steps.
To confirm the structure of the THF derivatives thus
obtained, 19a was converted to the corresponding di-
methyl ester 19b, and NMR studies were carried out on
19b. Proton signals were assigned based on COSY
experiments in both CDCl3 and DMSO-d6, and NOEs
were measured in ROESY spectrum. A modest NOE was
observed between H3 and H5, indicating the cis-relation-
ship of the two carboxyl groups. A weak NOE was also
observed between H3 and side-chain proton H6 while no
NOE was observed between protons H2 and H3, indicat-
ing that the C2 substituent and C3 carboxyl group were
trans to each other.20 Additionally, a single-crystal X-ray
structure of a compound derived from 19 was obtained,
providing direct prove of the configuration of 19.21
the reaction sequence by carrying out the Baeyer-
Villiger rearrangement first (Scheme 4). Thus, when
ketone 9 was treated with MCPBA, a mixture of two
lactones (regioisomers) was obtained in quantitative
yield. The regioselectivity of the Baeyer-Villiger reation
of 2-norbornanones has been shown to be dependent on
the substitution pattern.17 With ketone 9, the ratio of the
two regioisomers was found to be 1:1 (NMR result) and
varied little with different reagents (MCPBA or peracetic
acid) and temperature (ambient temperature, 0 °C, -20
°C). These two regioisomeric lactones were found insepa-
ratable chromatographically. By serendipity, we discov-
ered that the undesired (methylene-migrated) lactone
decomposed completely when the mixture was treated
with aluminum oxide for 30 min, giving the desired
(methine migrated) lactone 13. This result is consistent
with reported poor stability of the methylene-migrated
lactones of 2-norbornanone.18
R-Halogenation of lactone 13 was the next hurdle.
When the lithium enolate of 13 generated with LHMDS
was treated with Br2, the expected R-bromolactone was
obtained but in a consistently low yield (∼20%). Fortu-
nately, the iodination procedure described by Rathke and
Lindert worked satisfactorily.19 Thus, when a solution of
the lithium enolate of 13 in THF was cannulated to a
solution of I2 in THF at - 78 °C, a clean reaction was
observed, giving the iodolactone 14 in 81% yield. An X-ray
crystal structure of 14 was obtained (Supporting Infor-
In summary, we have developed a practical synthesis
of the unprecedented 2-substituted (()-(2R,3R,5R)-tet-
rahydrofuran-3,5-dicarboxylic acids such as compound
19. The synthesis utilizes inexpensive starting material
and offers complete control of the relative stereochem-
istry. It is conceivable that both the bicyclic intermediate
15 or THF derivative 19 can be valuable intermediates
for the synthesis of structurally more complex com-
pounds.
Exp er im en ta l Section
Gen er a l Meth od s. Commercially available solvents were
used as received, and reagents were purchased from Aldrich
Chem. Co. (Milwaukee, WI), unless noted otherwise. THF
solvent was distilled from Na-benzophenone. Column chro-
matography was performed with the solvent systems indicated
using E. Merck silica gel 60 (70-230 mesh). Unless noted
otherwise, all the reactions were conducted under an atmo-
sphere of nitrogen and organic solutions were dried with
(17) Hamley, P.; Holmes, A. B.; Marshall, D. R.; Mackinnon, J . W.
M. J . Chem. Soc., Perkin Trans. 1 1991, 1793.
(18) (a)Krow, G. R. Tetrahedron 1981, 37, 2697. (b) Deslongchamps,
P. Tetrahedron 1978, 34, 1651.
(19) Rathke, M. W.; Lindert, A. Tetrahedron Lett. 1971, 43, 3995.
(20) Summary of NOEs observed from the ROESY spectrum of 19b:
1
MgSO4. H NMR spectra were recorded on a GE AE-300 (300
MHz) using tetramethylsilane as an internal standard. El-
ementary analysis were performed by Robertson Micolit
Laboratories, Madison, NJ . X-ray crystallography of compound
14 was performed by Dr. Roger Henry of The Analytical
Chemistry Department, Pharmaceutical Discovery, Abbott
Laboratories.
(21) Wang, G. T., Wang, S.-X., Chen, Y-w.; Gentles, R. G. Bioorg.
Med. Chem. Lett., manuscript in preparation.

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Tetrahydrofuran-3,5-dicarboxylic Acid Derivatives
J . Org. Chem., Vol. 66, No. 6, 2001 2055
(()-5,6-exo,exo-Dih yd r oxylbicyclo[2.2.1]h ep t a n -2-on e
(8). In a three-necked flask equipped with a mechanical stirrer,
a N2 inlet, and an additional funnel, a solution of oxalyl
chloride (2.0 M in DCM, 136 mL, 0.272 mol) in DCM (250 mL)
was cooled to -78 °C, and a solution of DMSO (40 mL) in 40
mL of DCM was added dropwise over 30 min. After stirring
for an additional 5 min, a solution of 5-norboren-2-ol (24 mg,
0.218 mol) in 40 mL of DCM was added dropwise. The solution
was then stirred for another 10 min, and triethylamine (150
mL) was added over 40 min. The mixture was stirred for 10
min at -78 °C and then allowed to warm to 0 °C over 1 h.
Water (250 mL) was added. Following the separation of two
layers, the organic layer was washed with 0.2 N HCl (4 × 200
mL) and brine (2 × 200 mL). After drying (MgSO4), the
solution was concentrated to about 80 mL. The residue was
distilled with a 12 in. Vigerex column at reduced pressure to
give (()-bicyclo[2.2.1]hept-5-en-2-one, bp 100-105 °C /15
36.51, 80.70, 82.49, 82.55, 83.24, 110.83, 167.95. Anal. Calcd
for C10H14O4: 60.59% C, 7.12% H. Found: 60.52% C, 6.97%
H.
(()-6,7-exo,exo-(Isop r op ylid e n e d ioxy)-4-exo-iod o-2-
oxa bicyclo[3.2.1]octa n -3-on e (14). To a mixture of lithium
bis(trimethylsilyl)amide (1.0 M in THF, 32.6 mL) and distilled
THF (60 mL), cooled to -78 °C, was added a solution of 13
(5.87 g, 29.6 mmol) in 60 mL of THF over 30 min. After stirring
for another 30 min, this solution was then cannulated into a
flask containing a solution of iodine (8.3 g, 32.6 mmol) in 60
mL of THF cooled to -78 °C over 30 min. The resulting
solution was stirred for another 10 min and quenched with
300 mL of 5% aqueous citric acid. The mixture was then
extracted with EtOAc (3 × 100 mL). The combined EtOAc
solution was washed with 10% aqueous Na2S2O3 solution (2
× 100 mL) and brine (2 × 200 mL) and dried (MgSO4). After
filtration, the solution was evaporated and the residue chro-
matograhed on a silica gel column eluting with 15-25% EtOAc
in hexane, giving 7.55 g of white crystalline solid. Yield: 79.0%.
1
mmHg, 20.1 g, 86.0%. H NMR (CDCl3): 1.85 (dd, 1H), 1.90-
2.00 (m, 2H), 3.00 (bs, 1H), 3.20 (bs, 1H), 6.01 (t, 1H), 6.58 (t,
1H).
1
MS (DCI-NH3): m/z 342 for (M + NH4), base peak. H NMR
A solution of (()-bicyclo[2.2.1]hept-5-en-2-one (10.8 g, 0.1
mol) and N-methyl morpholine oxide (12.7 g, 0.12 mol) in 300
mL of 90% THF-water was cooled with a water bath. A
solution of osmium tetraoxide (2.5 wt % in t-BuOH, 8.0 mL)
was added. After stirring for 5 h at ambient temperature, the
solvents were evaporated, and the resulting residue was dried
in vacuo. The residue was then taken up in 100 mL of EtOAc,
dried (MgSO4), and filtered. The filtrate was passed through
a short silica gel plug, eluting further with EtOAc. Concentra-
tion of the EtOAc solution gave 8 as a thick oil (14.5 g) which
was used directly for the next step.
(()-5,6-exo,exo-(Isop r op ylid en ed ioxy)b icyclo[2.2.1]-
h ep ta n -2-on e (9). A solution of 8 (14.5 g, crude) in 250 mL of
2,2-dimethoxypropane was cooled to 0 °C, and p-TsOH (125
mg) was added. The solution was stirred for 30 min when TLC
indicated complete reaction. The solution was directly loaded
on to a aluminum oxide (neutral) column and eluted with 15-
30% EtOAc in hexane, giving 11.9 g of a white solid (65% for
two steps). MS (DCI-NH3): m/z 200 for (M + NH4), base peak.
1H NMR (CDCl3): 1.34 (s, 3H), 1.50 (s, 3H), 1.63-1.74 (m, 2H),
2.12-2.20 (m, 2H), 2.70-2.76 (m, 2H), 4.28 (d, 1H), 4.34 (d,
1H). 13C NMR (CDCl3): 21.1, 25.3, 31.2, 39.4, 39.5, 55.3, 76.8,
81.2, 111.2, 214.0. Anal. Calcd for C10H14O3: 65.92% C, 7.75%
H. Found: 66.01% C, 7.79% H.
(()-2-[Dim e t h yl(t er t -b u t yl)siloxy]-5,6-exo,exo-(iso-
p r op ylid en ed ioxy)bicyclo[2.2.1]h ep ta n -2-en e (10). Com-
pound 10 was prepared according to the literature procedure.15
(()-3-Br om o-5,6-exo,exo-(isop r op ylid en ed ioxy)bicyclo-
[2.2.1]h ep ta n -2-on e (11), A solution of bromine (0.196 mL,
3.80 mmol) in 30 mL of CH2Cl2 was added dropwise to a flask
containing 10 (1.02 g, 3.45 mmol) and 10 mL of CH2Cl2 cooled
to 0 °C over 30 min. The reaction was then quenched with 60
mL of saturated NaHCO3 solution. After separating two
phases, the aqueous phase was washed with brine (2 × 30 mL)
and dried. After filtration and concentration, flash chroma-
tography on silica gel column (20% EtOAc-hexane) gave 0.61
g of a solid (60%). MS (ESI-): m/z 259, 261 for (M - H), base
peak. 1H NMR (CDCl3): 1.35 (s, 3H), 1.50 (s, 3H), 2.20 (bs,
2H), 2.86 (bs, 2H), 3.70 (s, 1H), 4.24-4.40 (m, 2H).
(CDCl3): 1.30 (s, 3H), 1.45 (s, 3H), 1.55 (s, 1H), 2.12-2.20 (m,
1H), 2.42 (d, 1H), 2.80 (m, 1H), 4.56 (d, 1H), 4.54 (d, 1H), 4.70
(m, 2H). Anal. Calcd for C10H13IO4: 37.06% C, 4.04% H, 39.15%
I. Found: 37.08% C, 3.98% H, 39.55% I.
(()-Meth yl 5,6-exo,exo-(Isop r op ylid en ed ioxy)-2-oxa -
bicyclo[2.2.1]h ep ta n e-3-exo-ca r boxyla te (15). To a solution
of compound 14 (7.55 g, 23.3 mmol) in 300 mL of MeOH
(predried with 4 Å sieves) was added K2CO3 (3.54 g, 25.6
mmol). The mixture was stirred vigorously for 30 min. The
undissolved potassium carbonate was removed by filtration,
and the filtrate was concentrated to dryness. The residue was
triturated with EtOAc several times until complete extraction
of the product (TLC). The EtOAc solution was then concen-
trated and directly chromatographed on a silica gel column
eluting with 10-25% EtOAc in hexane, giving 4.86 g of a white
solid. Yield: 92.0%. MS (DCI-NH3): m/z 246 for (M + NH4),
1
base peak. H NMR (CDCl3): 1.30 (s, 3H), 1.45 (s, 3H), 1.62
(d, 1H), 1.85 (d, 1H), 2.82 (s, 1H), 3.78 (s, 3H), 3.80 (s, 1H),
4.20 (d, 1H), 4.30 (d, 1H), 4.40 (s, 1H). Anal. Calcd for
C
11H16O5: 57.88% C, 7.07% H. Found: 57.98% C, 7.10% H.
(()-3-exo-F or m yl-5,6-exo,exo-(isop r op ylid en ed ioxy)-2-
oxa bicyclo[2.2.1]h ep ta n e (16). To a well-stirred solution of
compound 15 (0.82 g, 3.62 mmol) in 30 mL of anhydrous DCM
at -78 °C was added a solution of diisobutylaluminum hydride
in toluene (1.0 M, 5.77 mL) dropwise. The mixture was then
stirred at -78 °C for 1 h and quenched with 2 mL of MeOH
and 15 mL of saturated aqueous sodium potassium tartrate
solution. The mixture was then stirred vigorously and allowed
to warm to ambient temperature over 1 h. The phases were
separated, and the aqueous phase was extracted with Et2O (5
× 50 mL). After drying, solvent removal gave 0.8 g of an oil
as the crude product which was used directly for the next step.
(()-3-exo-(1′-Hyd r oxy-3′-m eth ylbu tyl)-5,6-exo,exo-(iso-
p r op ylid en ed ioxy)-2-oxa bicyclo[2.2.1]h ep ta n e (17). To a
solution of the aldehyde 16 (0.99 g, 5.0 mmol) in 50 mL of
anhydrous THF at -78 °C was added a solution of isobutyl-
magnesium chloride (2.0 M in ether, 30 mL) dropwise over 30
min. The mixture was then allowed to warm to ambient
temperature over 2 h and quenched with 100 mL of saturated
aqueous NH4Cl solution. The solution was then extracted with
Et2O (3 × 100 mL). The combined etheral solution was washed
with brine (3 × 100 mL) and dried. After filtration, evaporation
of solvent gave crude 17 as an oil (1.28 g) which was used
directly for the next step.
(()-6,7-exo,exo-(Isopr opyliden edioxy)-2-oxabicyclo[3.2.1]-
octa n -3-on e (13). To a solution of 9 (14.76 g, 0.081 mol) in
500 mL of DCM was added NaHCO3 (13.6 g, 0.16 mol). The
mixture was cooled with a water bath, and MCPBA (30.3 g,
∼60%) was added portionwise over 30 min. The solution was
then stirred for 2 h at ambient temperature and washed with
10% aqueous Na2S2O5 (500 mL), saturated NaHCO3 solution
(3 × 200 mL), and brine (3 × 200 mL). The organic solution
was then dried (MgSO4), filtered, and concentrated. The
residue was loaded onto an aluminum oxide (neutral) column
and allowed to stand for 30 min and then eluted with 10-
25% EtOAc in hexane, giving 7.7 g of a white solid (50% yield).
(()-3-exo-(1′-Oxo-3′-m eth ylbu tyl)-5,6-exo,exo-(isop r op y-
lid en ed ioxy)-2-oxa bicyclo[2.2.1]h ep ta n e (18a ). A solution
of oxalyl chloride (2.0 M in DCM, 3.76 mL, 7.3 mmol) was
mixed with 10 mL of anhydrous DCM, and the solution was
cooled to -78 °C. A solution of DMSO (1.06 mL) in 10 mL of
anhydrous DCM was then added dropwise. After stirring for
10 min, a solution of alcohol 17 (∼1.28 g, 5.0 mmol) in
anhydrous DCM (10 mL) was added dropwise, and the solution
was stirred for another 10 min. Triethylamine (4.3 mL) in 10
mL of DCM was then added. The mixture was then stirred at
-78 °C for 2 h and allowed to warm to ambient temperature.
1
MS (DCI-NH3): m/z 216 for (M + NH4), base peak. H NMR
(CDCl3): 1.30 (s, 3H), 1.45 (s, 3H), 1.84 (d, 1H), 2.10-2.20 (m,
1H), 2.48-2.56 (m, 2H), 2.80 (dd, 1H), 4.56 (d, 1H), 4.60 (s,
1H), 4.70 (d, 1H). 13C NMR (CDCl3): 23.79, 25.58, 29.17, 35.97,