Oxazoline N-oxide-mediated [2 + 3] cycloadditions: Application to a total synthesis of the hypocholesterolemic agent 1233A

Article abstract of DOI:10.1021/jo980813u

Oxetanone 1233A 1 has been synthesized in 22 steps and 3.43% overall yield from 3-methylglutaric anhydride. Asymmetric carbon at C₇ was introduced by a diastereoselective esterification of 3-methylglutaric anhydride, whereas the two asymmetric carbons at C₂' and C₃' were controlled by an asymmetric [2 + 3] cycloaddition using camphor-derived oxazoline N-oxide as dipole.

Full text of DOI:10.1021/jo980813u

6634
J . Org. Chem. 1998, 63, 6634-6642
Oxa zolin e N-Oxid e-Med ia ted [2 + 3] Cycloa d d ition s: Ap p lica tion to
a Tota l Syn th esis of th e Hyp och olester olem ic Agen t 1233A
Olivier Dirat, Cyrille Kouklovsky, and Yves Langlois*,†
Laboratoire de Synthe`se des Substances Naturelles, Associe´ au CNRS, ICMO, Baˆtiment 410,
Universite´ de Paris-Sud, 91405 Orsay, France
Received April 30, 1998
Oxetanone 1233A 1 has been synthesized in 22 steps and 3.43% overall yield from 3-methylglutaric
anhydride. Asymmetric carbon at C7 was introduced by a diastereoselective esterification of
3-methylglutaric anhydride, whereas the two asymmetric carbons at C2′ and C3′ were controlled by
an asymmetric [2 + 3] cycloaddition using camphor-derived oxazoline N-oxide as dipole.
In tr od u ction a n d Retr osyn th etic P la n n in g
cordingly, oxazoline N-oxide 3 prepared from the readily
available hydroxylaminoisoborneol hydrochloride 25 was
condensed with ester 4. A single adduct 5 was isolated
after 18 h at 80 °C. Compound 5, after functional group
transformation, was cleaved by an oxidative acidic hy-
drolytic process. The aldehyde intermediate was not
isolated but directly submitted to sodium chlorite oxida-
tion8 without protection of the primary and secondary
alcohols. The hydroxyacid 9 was thus conveniently
isolated in high yield with ketol 8, a precursor of the
chiral auxiliary 2.5 After tritylation, final lactonization
furnished in high yield the anticipated oxetanone 10
(Scheme 1).
This synthesis demonstrated the feasibility of â-lactone
synthesis through the [2 + 3] cycloaddition of oxazoline
N-oxides and prompt us to embark on a synthesis of
1233A 1. The anticipated retrosynthetic analysis is
presented in Scheme 2. To obtain the absolute configu-
rations requisite for carbons C2′ and C3′ in the natural
product, (-)-camphor has to be used as chiral inducer.
We also anticipated that the asymmetric center at C7 in
1 could be introduced by diastereoselective esterification
of the prochiral 3-methylglutaric anhydride. From a
tactic point of view, two options were still opened at this
stage: the Heck coupling, disconnection of C3-C4, can be
performed before or after removal of the chiral auxiliary,
this latter option being indicated in the retrosynthetic
scheme.
2-Oxetanone derivatives constitue a new class of
natural products of increasing importance with respect
of their various biological properties such as esterase
inhibitors, antibiotics, or hypocholesterolemic agents.1
Antibiotic 1233A 1 isolated from various species of fungi2
exhibits significant hypocholesterolemic activity and is
a potent inhibitor of 3-hydroxy-3-methylglutaryl coen-
zyme A synthase (HMG-CoA synthase).3 In the past this
compound has been the subject of several total syntheses
mainly from pharmaceutical companies.4 From a stra-
tegic point of view, the asymmetric carbon at C7, which
is disconnected by four carbons from the other asym-
metric centers on the oxetane ring, has to be introduced
separatly. In the previous syntheses, this asymmetric
center came from the terpenic chiral pool. The two other
asymmetric centers resulted from an asymmetric aldol
condensation,4a from an enzymatic resolution,4b or from
[2,3] Wittig rearrangement starting with an enantio-
merically pure allylic ether.4c
We described some years ago a new efficient asym-
metric [2 + 3] cycloaddition using camphor-derived
oxazoline N-oxides as dipoles.5 This method can be
considered as an “asymmetric hydroxyacylation” of alk-
enes. The usefulness of this process has been demon-
strated by several syntheses,5,6 and we applied particu-
liary this method to the synthesis of a model â-lactone.7
To test this method with an R,â-unsaturated ester
substituted by a long chain, a model study was first
developed with ethyl decenoate 4 as dipolarophile. Ac-
Syn th esis of Dip ola r op h ile
The synthesis started with the desymmetrization of
3-methylglutaric anhydride 14. This reaction was per-
formed under the Heathcock protocol9 with (R)-(+)-1-(1′-
naphthyl)ethanol 15 (Scheme 3). This alcohol was itself
obtained after reduction of the corresponding ketone with
the Corey’s oxaborolidine reagent10 and isolated in 99%
ee after recrystallization according to Fleming.11 Acid
ester 13 was thus obtained in 91% yield and 87% de.12
† Fax: 33 1 69 15 46 79. E-mail: langlois@icmo.u-psud.fr.
(1) Pommier, A.; Pons, J .-M. Synthesis 1995, 729.
(2) (a) Turner, W. B.; Alridge, D. C. Chem. Commun 1970, 639. (b)
Turner, W. B.; Alridge, D. C. J . Chem. Soc. C 1971, 3888.
(3) Omura, S.; Greenspan, M. D. J . Antibiot. 1987, 1356.
(4) Total syntheses: (a) Chiang, Y.-C.; Yang, S. S.; Heck, J .; Chabala,
J . C.; Chang, M. N. J . Org. Chem. 1989, 54, 570.(b) Mori, K.;
Takahashi, Y. Liebigs Ann. Chem. 1991, 1057.(c) Wovkulich, P. M.;
Shankaran, K.; Kiegiel, J .; Uskokovic, M. R. J . Org. Chem. 1993, 58,
832. (d) We thank Professor Kocienski for sending us a draft of his
paper concerning a new synthesis of 1233A (Dymock, B. W.; Kocienski,
P. J .; Pons, J .-M. Submitted for publication). Formal syntheses: (e)
Wattanasin, S.; Do, H. D.; Bhongle, N.; Kathawala, F. G. J . Org. Chem.
1993, 58, 1610. (f) Guanti, G.; Banfi, L.; Schmid, G. Tetrahedron Lett.
1994, 35, 4239.
(8) Dalcanale, E.; Montanari, F. J . Org. Chem. 1986, 51, 567.
(9) Thiesen, P. D.; Heathcock, C. H. J . Org. Chem. 1993, 58, 142.
(10) (a) Corey, E. J .; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh,
V. K. J . Am. Chem. Soc. 1987, 109, 1725. (b) Mathre, D. J .; J ones, T.
K.; Blacklock, T. J . J . Org. Chem. 1991, 56, 751.
(11) Fleming, I.; Ghosh, S. K. J . Chem. Soc., Chem. Commun. 1994,
99.
(5) Berranger, T.; Langlois, Y. J . Org. Chem. 1995, 60, 1720.
(6) (a) Berranger, T.; Langlois, Y. Tetrahedron Lett. 1995, 36, 5523.
(b) Kouklovsky, C.; Dirat, O.; Berranger, T.; Langlois, Y.; Tran-Huu-
Dau, M. E.; Riche, C. J . Org. Chem. 1998, 63, 5123.
(12) Diastereomeric excess was measured at this stage after esteri-
fication with methanol, see ref 9.
(7) Dirat, O.; Berranger, T.; Langlois, Y. Synlett 1995, 935.
S0022-3263(98)00813-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/29/1998

Oxazoline N-Oxide-Mediated [2 + 3] Cycloadditions
J . Org. Chem., Vol. 63, No. 19, 1998 6635
Sch em e 1a
a
Key: (a) HC(OMe)3, CaCO3, MS 4 Å, PhMe, 40 °C, 4 h; (b) 4, PhMe, 80 °C, 18 h; 67%; (c) DIBALH, PhMe; 85%; (d) m-CPBA, CH2Cl2;
(e) HCl (2 N), THF; (f) NaClO2, H2O2, NaH2PO4, MeCN, H2O; 88%; (g) TrCl, pyridine, 70 °C; 100%; (h) PhSO2Cl, pyridine; 87%.
Sch em e 2
Reduction of the acid functional group with borane-
dimethyl sulfide complex afforded in high yield the ester
alcohol 16 which was in turn protected as its THP
derivative 17. The ester group in compound 17 was
reduced with diisobutylaluminum hydride in toluene and
furnished aldehyde derivative 18a . This reduction was
contaminated with a small amount, ca. 15%, of the
corresponding primary alcohol 18b which was removed
by purification by column chromatography.13 At this
stage, it was difficult to separate the chiral auxiliary 15
and aldehyde 18a . For this reason, this mixture of
compounds was submitted to the following step. Accord-
ingly, this mixture was submitted to a mild reaction in
the presence of the Bestmann reagent14 and the alkyne
derivative 19 was isolated after purification in 83%
overall yield from ester 17. Chiral alcohol 15 was also
recovered in 98% yield and 99% ee. At this stage, an
enantiomeric excess of aldehyde 8a was also checked. An
enantiomeric excess of 87% was measured by the Court-
ieu method15 after sequential transformation of aldehyde
18a or alcohol 18b.16
was then examined. It turned out that a tetrahydropy-
ranyl protecting group was troublesome and the expected
carbometalation iodination occurred with a simultaneous
reductive ring opening of the tetrahydropyranyl ring.
Fortunately, this reaction can be performed in high yield
with the unprotected alcohol derivative 20 and afforded
the vinylic iodide 21 together with a small amount of the
regioisomer. It is worthy of note that neat trimethyl-
aluminum had to be used for this carbometalation; a
toluene solution of this reagent gave very poor yields.
Oxidation of primary alcohol in 21 was perfomed in
high yield under Swern conditions. After other prospec-
(15) Canet, I.; Meddour, A.; Loewenstein, A.; Pe´chine´, J . M.;
Courtieu, J . J . Am. Chem. Soc. 1995, 117, 6520.
(16) For measurement with this method, aldehyde 18a was oxidized
to the corresponding methyl ester which was in turn reduced with
LiAlD4:
With the acetylenic derivative 19 in hand the trisub-
stituted double bond introduction via a Negishi process17
(13) Alcohol 18b was recycled after Swern oxidation.
(14) Mu¨ller, S.; Liepold, B.; Roth, G. J .; Bestmann, H. J . Synlett
1996, 521.
(17) Negishi, E.-I.; Van Horn, D. E.; Yoshida, T. J . Am. Chem. Soc.
1985, 107, 6639.

6636 J . Org. Chem., Vol. 63, No. 19, 1998
Dirat et al.
Sch em e 3a
a
Key: (a) DMAP, CH2Cl2, -40 °C, 5 d; 91%; ed ) 87%; (b) BH3-DMS, THF; 97%; (c) DHP, PPTS, CH2Cl2; 95%; (d) DIBALH, PhMe;
(e) MeCOC(N2)PO(OMe)2; K2CO3, MeOH; 83%; (f) CSA, MeOH; (g) Cp2ZrCl2, Me3Al, I2, Cl(CH2)2Cl; 77%; (h) (ClCO)2, DMSO, Et3N, CH2Cl2;
98%; (i) BrPh3P(CH2)2CH(OCH2)2, BuLi, THF; 99%; (j) NH2OH‚HCl, KOH, DMF, EtOAc; (k) HCl (2 N), THF; 54%; (l) Ph3PCHCO2Et,
PhMe; 99%.
tive studies,18 a three-carbon homologation through a
Wittig olefination of the resulting aldehyde 22 furnished
the dioxolane derivative 23. After several unsuccessful
attempts to hydrogenate the C3-C4 double bond with
various catalysts or hydrides, diimide-mediated reduction
appeared as the best reagent for this step according to a
recent publication.19 Unexpectingely, compound 23 proved
to be unreactive under classical diimide reduction condi-
tions. Finally, it turned out that when diimide was
prepared from hydroxylamine hydrochloride,20 the dihy-
dro compound 24 was isolated without reduction of the
iodovinylic moiety. Classical acidic hydrolysis furnished
the aldehyde 25 which was submitted in turn to a second
Wittig olefination giving rise to the desired dipolarophile
26. At this stage, compound 26 was obtained in 12 steps
and in 28% overall yield from 3-methylglutaric anhydride
14.
dipolarophile 26 (Scheme 4). A single adduct 27 was
isolated in 58% yield after heating at 80 °C for 18 h. As
previously observed with â-substituted R,â-unsaturated
esters, the cycloaddition was regio- and stereoselective.21
Classical reduction of the ester group and protection of
the resulting alcohol 28 as its trityl ether furnished in
high yield compound 29.22
The following step of the synthesis was the assembly
of the dienic moiety on the side chain via Heck coupling
with tert-butyl crotonate. To avoid partial isomerization
of the C4-C5 double bond after the coupling, reaction
conditions using palladium diacetate, silver carbonate,
and triethylamine as described by the Hoffmann-La
Roche group4c were used. Consequently, the expected
coupling product 30 was obtained in 84% yield as a single
(E,E) isomer.
Compound 30 was then submitted to the oxidative
hydrolytic process developed in our laboratory.5 Thus,
oxidation of oxazolidine ring with m-chloroperbenzoic
acid in ether23 was followed by acidic hydrolysis affording
an aldehyde intermediate.24 To preclude any isomeriza-
tion at this stage, this compound was directly oxidized,
following a process described in our model study. Acid
alcohol 31 was isolated after purification in 65% overall
yield for these three steps.
Cycloa d d ition a n d Com p letion of th e Syn th esis
As in our previous work,5,7 oxazoline N-oxide (-)-3 was
prepared and submitted to in situ cycloaddition with
(18) Iodo alcohol 21 was transformed into the corresponding diiodo
derivative. Alkylation of this compound with homoenolate equivalent
obtained after deprotonation of tert-butylvinyl ether gave only poor
yield of aldehyde 25 (ca. ) 20%):
Formation of â-lactone was performed under Adam’s
conditions25 and furnished compound 32. Direct double
deprotection of the tert-butyl ester and trityl ether gave
(21) As in previous [2 + 3] cycloadditions in this series, the
stereoselectivity of this reaction was deduced after NOE and COSY
experiments. At this stage, we were not able to detect any minor
diastereomer at C7.
(22) It appeared that protection of primary alcohol was necessary
at this stage, since chlorite oxidation as in the model study failed to
give the expected acid.
(23) Diethyl ether as the solvent gave better yield than dichlo-
romethane because of better solubility.
(24) Trisubstituted C4-C5 double bond is probably not conjugated
with trisubstituted C2-C3 double bond for steric reasons. Nevertheless,
no side reaction occurred at this stage and oxazolidine nitrogen was
oxidized whithout epoxidation of the C4-C5 double bond.
(25) Adam, W.; Baeza, J .; J u-Chao, L. J . Am. Chem. Soc. 1972, 94,
2000.
For alkylation of such homoenolates, see: (a) Still, W. C.; Macdonald,
T. L. J . Org. Chem. 1976, 41, 3620. (b) Evans, D. A.; Andrews, G. C.;
Buckwalter, B. J . Am. Chem. Soc. 1974, 96, 5560.
(19) White, J . D.; Kim, T.-S.; Nambu, M. J . Am. Chem. Soc. 1997,
119, 103.
(20) Wade, P. A.; Amin, N. V. Synth. Commun. 1982, 12, 287. The
temperature of the diimide reduction used in this reaction condition
is probably determining.

Oxazoline N-Oxide-Mediated [2 + 3] Cycloadditions
J . Org. Chem., Vol. 63, No. 19, 1998 6637
Sch em e 4a
a
Key: (a) HC(OMe)3, CaCO3, MS4Å, PhMe, 40 °C, 4 h; (b) 26, PhMe, 80 °C, 18 h; 58%; (c) DIBALH, PhMe, -78 °C; 89%; (d) TrCl,
pyridine; 100%; (e) MeCHCHCO2tBu, Pd(OAc)2, Ag2CO3, Et3N, CH2Cl2; 84%; (f) m-CPBA, Et2O; (g) HCl (2 N), THF; (h) NaClO2, NaH2PO4,
MeCHC(Me)2, tBuOH, H2O; 65%; (i) PhSO2Cl, pyridine; 73%; (j) TsOH, PhH; (k) TFA, CH2Cl2; 60%.
stirred at 45 °C for 4 h. A solution of ethyl 2-decenoate 4 (720
mg, 3.4 mmol, 1.5 equiv) in 2 mL of toluene was then added,
the oil bath temperature raised to 80 °C, and the mixture
stirred overnight. After cooling to room temperature, the
reaction mixture was filtered through a pad of Celite, and the
filtrate was concentrated in vacuo. The residue was purified
by chromatography (10% diethyl ether/pentane, Rf ) 0.27) to
give the cycloadduct as a colorless oil (595 mg; 67% yield).
poor yield. Better results were obtained in a two-step
process.26 Thus, trityl ether acidolysis in the presence
of p-toluenesulfonic acid was followed by trifluroacetic
acid cleavage of the tert-butyl ester group affording 1233A
1 in 60% yield. Synthetic 1233A was identical in all
respects (TLC, IR, 1H and 13C NMR) to an authentic
sample of natural product.27
The overall yield of this synthesis from 3-methylglu-
taric anhydride 14, 3.43% for 22 steps (86% for each step),
is quite competitive with the previously published syn-
theses. This synthesis also demonstrates the usefulness
of the asymmetric [2 + 3] cycloaddition of oxazoline
N-oxides and the possible use of complex dipolarophiles
in these reactions.
1H NMR (250 MHz, CDCl3): δ (ppm) 5.38 (1H, d, J ) 7.6
Hz), 4.35 (1H, dt, J ) 10.4 and 5.9 Hz), 4.18 (2H, m), 3.88
(1H, d, J ) 7.5 Hz), 3.27 (1H, d, J ) 7.5 Hz), 2.89 (1H, dd, J
) 7.6 and 10.4 Hz), 2.04 (1H, d, J ) 4.3 Hz), 1.68 (2H, m),
1.50 (2H, m), 1.35 (2H, m), 1.30-1.18 (13H, m), 0.95-0.70
(12H, m). 13C NMR (62.5 MHz, CDCl3): δ (ppm) 169.0, 98.6,
89.8, 78.4, 75.8, 60.9, 58.3, 49.2, 48.4, 45.8, 32.0, 31.6, 31.4,
29.5, 29.0, 25.7, 25.4, 22.6, 22.1, 18.9, 14.2, 14.0, 10.7. [R]20
D
) -113 (c ) 0.52, CHCl3). Mass (DCI NH3): m/z 394 (M + 1),
232, 199, 180 (100%). High-resolution mass spetctrum: calcd
for C23H39NO4 393.2879, found 393.2875.
Exp er im en ta l Section
Gen er a lities. 1H and 13C NMR spectra were recorded at
200, 250, 400, or 600 MHz and 50 or 62.5 MHz, respectively.
Optical rotations were recorded at 20 °C. Elemental analyses
were performed at the CNRS, Gif sur Yvette, France. Unless
otherwise stated, chromatographic purifications were per-
formed on 230-400 mesh silica gel (Merck 9385) using the
indicated solvent system. Dichloromethane, acetonitrile, DMF,
pyridine, and trimethyl orthoacetate were distilled from
calcium hydride. Toluene, diethyl ether, and THF were
distilled from sodium metal/benzophenone ketyl. Methanol
and ethanol were distilled from magnesium. Chloroform used
for optical measurements was filtered through basic alumina
before use. All nonaqueous reactions were performed under
an argon atmosphere using oven-dried glassware.
(2S,3S,3a S,4a S,5R,8S,8a R)-5,10,10-Tr im eth yl-2-h ep tyl-
5,8-m eth a n oocta h yd r o-2H-isoxa zolo[3,2-b]ben zoxa zole-
3-ca r boxylic Acid Eth yl Ester (5). To a suspension of
3-hydoxylamino-2-isoborneol hydrochloride 2 (0.5 g, 2.26 mmol),
calcium carbonate (226 mg, 2.26 mmol), and powdered 4 Å
molecular sieves (0.3 g) in toluene (10 mL) was added trimethyl
orthoformate (1.2 mL, 9 mmol, 4 equiv), and the mixture was
(2S,3S,3a S,4a S,5R,8S,8a R)-5,10,10-Tr im eth yl-2-h ep tyl-
5,8-m eth a n oocta h yd r o-2H-isoxa zolo[3,2-b]ben zoxa zole-
3-m eth a n ol (6). A solution of 5 (0.541 g, 1.37 mmol) in
toluene (15 mL) was cooled to -78 °C, and a diisobutylalumi-
num hydride solution (1.5 M in toluene, 2.29 mL, 3.44 mmol,
2.5 equiv) was added dropwise. After stirring for 1 h at -78
°C, the excess hydride reagent was neutralized by careful
addition of a saturated ammonium chloride solution with
subsequent warming to room temperature. The solution was
then extracted with diethyl ether (50 mL) and washed twice
with a 1 N sodium potassium tartrate solution (30 mL). The
aqueous phases were back-extracted with 30 mL of diethyl
ether, and the combined organic layer was washed with brine,
dried (Na2SO4), filtered, and concentrated in vacuo. Purifica-
tion by chromatography (25% diethyl ether/heptane, Rf ) 0.32)
gave the alcohol 6 (0.408 g, 85% yield) as a colorless oil.
1H NMR (200 MHz, CDCl3): δ (ppm) 5.33 (1H, d, J ) 6.6
Hz), 3.84 (1H, d, J ) 7.5 Hz), 3.74 (3H, m), 3.32 (1H, d, J )
7.5 Hz), 2.41 (1H, t, J ) 6.4 Hz), 2.17 (1H, m), 2.07 (1H, d, J
) 4.3 Hz), 1.65 (2H, m), 1.45 (2H, m), 1.35 (2H, m), 1.30-1.20
(10H, m), 0.95-0.70 (12H, m). 13C NMR (50 MHz, CDCl3): δ
(ppm) 100.2, 90.4, 77.6, 77.2, 59.7, 53.8, 49.4, 48.8, 45.6, 32.0,
31.7, 31.6, 29.6, 29.1, 25.8, 25.5, 22.6, 22.2, 18.8, 14.1, 10.9.
(26) Partial retritylation in the presence of trifluoroacetic acid was
observed when triphenylmethanol was present in the reaction medium.
(27) We thank Dr. C. J onhstone, Zeneca Pharmaceutical, Maccles-
field, U.K., for the generous gift of an authentic sample of 1233A.
[R]20 ) -106.5 (c ) 1.09, CHCl3). Mass (DCI NH3): m/z 352
D

6638 J . Org. Chem., Vol. 63, No. 19, 1998
Dirat et al.
(M + 1) (100%), 180. High-resolution mass spetctrum: calcd
for C21H37NO3 351.2773, found 351.2773.
(10H, broad s), 0.81 (3H, t, J ) 6.3 Hz). [R]20 ) -22.0 (c )
D
1.02, CHCl3). Mass (DCI NH3): m/z 442 (M+), 243 (100%).
High-resolution mass spectrum: calcd for C30H43O3 442.2508,
found 442.2506.
(2S,3S)-3-H yd r oxy-2-(h yd r oxym et h yl)d eca n oic Acid
(9b). To a solution of the alcohol 6 (0.249 g, 0.71 mmol) in
dichloromethane (10 mL) was added m-chloroperoxybenzoic
acid (0.246 g, 1.42 mmol, 2 equiv) in one portion. The solution
was stirred at room temperature for 30 min and then washed
four times with an aqueous 5% NaHCO3 solution (4 × 10 mL),
dried (Na2SO4), filtered, and concentrated in vacuo. The crude
nitrone 7 was used immediately in the next reaction.
The crude nitrone was redissolved in tetrahydrofuran (3
mL), and a 2 N hydrochloric acid solution (3 mL) was added.
The solution was stirred for 5 min at room temperature and
then extracted three times with 10 mL of dichloromethane.
The combined organic extracts were dried (Na2SO4), filtered,
and concentrated in vacuo to give a mixture of ketol 8 and
aldehyde 9a . This crude mixture was used in the next reaction
without further purification.
The above mixture was redissolved in acetonitrile (5 mL),
and 5 mL of a stock solution (prepared by dissolving 1.6 g of
sodium dihydrogen phosphate and 5 mL of 30% hydrogen
peroxide in 20 mL of water) was added. The mixture was
cooled to 10 °C, and a solution of sodium chlorite (0.12 g) in
water (1 mL) was added. The solution was stirred for 40 min
at 10 °C and then quenched by addition of 0.1 g of solid sodium
sulfite. The pH was raised to 14 by addition of solid sodium
carbonate and the solution extracted with ethyl acetate to
remove the unreacted ketol. The solution was then reacidified
to pH 1 by addition of 2 N hydrochloric acid solution and
extracted with ethyl acetate (3 × 10 mL). The combined
organic extracts were washed with brine, dried (Na2SO4),
filtered, and concentrated in vacuo to give the pure acid 9b
(0.135 g, 88% overall yield) as a colorless oil.
(3R,1′R)-5-Hydr oxy-3-m eth ylpen tan oic Acid (1′-r-Naph -
th yl)eth yl Ester (16). A solution of the known9 acid ester
13 (1.75 g, 5.83 mmol) in tetrahydrofuran (12 mL) was cooled
to 0 °C, and a 2 M solution of borane-dimethyl sulfide in
tetrahydrofuran (3.5 mL, 7 mmol, 1.2 equiv) was added
dropwise. The solution was stirred for 1 h at 0 °C and then
24 h at room temperature. The excess borane reagent was
quenched by careful addition of water (1 mL). The mixture
was diluted with diethyl ether (100 mL) and washed with a 1
N sodium hydroxide solution (25 mL). The aqueous layer was
back-extracted with 25 mL of diethyl ether, and the combined
organic layer was washed with brine, dried (Na2SO4), filtered,
and concentrated in vacuo to give the ester alcohol 16 as a
colorless oil (1.61 g, 97% yield), sufficiently pure for the next
reaction.
Rf ) 0.19 (50% diethyl ether/heptane). 1H NMR (200 MHz,
CDCl3): δ (ppm) 8.08 (1H, d, J ) 8.4 Hz), 7.87 (1H, d, J ) 7.8
Hz), 7.80 (1H, d, J ) 8.2 Hz), 7.60 (1H, d, J ) 7.1 Hz), 7.51
(3H, m), 6.67 (1H, q, J ) 6.6 Hz), 3.62 (2H, t, J ) 6.5 Hz),
2.43 (1H, dd, J ) 14.8 and 6.4 Hz), 2.38 (1H, dd, J ) 14.8 and
5.8 Hz), 2.20 (1H, m), 1.78 (3H, d, J ) 6.6 Hz), 1.50 (2H, m),
0.95 (3H, d, J ) 6.6 Hz). 13C NMR (50 MHz, CDCl3): δ (ppm)
172.6, 137.4, 133.8, 130.2, 128.9, 128.4, 126.3, 125.6, 125.3,
123.2, 123.1, 69.3, 60.4, 41.8, 39.3, 26.9, 21.6, 19.9. IR (film):
ν (cm-1) 3340, 3022, 2975, 2932, 1712, 1365, 1060. [R]20
)
D
+35.9 (c ) 0.87, CHCl3). Mass (DCI NH3): m/z 304 (M + 18),
286, 172 (100%), 155 (100%), 132 (100%), 115 (100%).
(3R,1′R,2′′RS)-3-Met h yl-5-(2-t et r a h yd r op yr a n yloxy)-
p en ta n oic Acid (1′-r-n a p h th yl)eth yl Ester (17). To a
solution of the alcohol 16 (1.079 g, 3.77 mmol) in 20 mL of
dichloromethane were added pyridinium paratoluenesulfonate
(0.189 g, 0.74 mmol, 0.2 equiv) and dihydropyrane (1.03 mL,
10.33 mmol, 3 equiv). After stirring for 12 h at room temper-
ature, diethyl ether (50 mL) was added and the solution was
washed with brine, dried (Na2SO4), filtered, and concentrated
in vacuo. Purification by filtration through a pad of silica gel
(20% diethyl ether/heptane, Rf ) 0.45) gave the protected
alcohol 17 (1.327 g, 95% yield) as a colorless oil.
Rf ) 0.16 (5% methanol/ethyl acetate). 1H NMR (200 MHz,
CDCl3): δ (ppm) 6.66 (3H, broad s, exchangeable with D2O),
3.88 (3H, m), 2.66 (1H, m), 1.50 (2H, m), 1.24 (10H, broad s),
0.85 (3H, t, J ) 6.3, Hz). 13C NMR (62.5 MHz, CDCl3): δ (ppm)
177.2, 71.2, 61.9, 52.7, 35.2, 32.0, 29.6, 29.4, 25.9, 22.6, 14.2.
Mass (DCI NH3): m/z 236 (M + 18) (100%), 219 (M + 1), 218
(M+), 201, 190, 172.
(2S,3S)-3-Hydr oxy-2-(tr iph en ylm eth oxym eth yl)decan o-
ic Acid (9c). The acid 9b (0.044 g, 0.2 mmol) was dissolved
in pyridine (2 mL) and triphenylmethyl chloride (trityl chlo-
ride) (0.225 g, 0.8 mmol, 4 equiv) was added. The reaction
mixture was stirred overnight at 70 °C and then cooled to room
temperature, diluted with water (3 mL), and stirred 3 h. The
acid was extracted with diethyl ether (4 × 10 mL). The
combined organic layer was washed with brine, dried (Na2-
SO4), filtered, and concentrated in vacuo. The crude acid (200
mg) was used in the next reaction without purification. An
analytical sample was prepared by chromatography (ethyl
acetate, Rf ) 0.51).
1H NMR (200 MHz, CDCl3): δ (ppm) 8.08 (1H, d, J ) 8.4
Hz), 7.87 (1H, d, J ) 7.8 Hz), 7.80 (1H, d, J ) 8.2 Hz), 7.60
(1H, d, J ) 7.1 Hz), 7.51 (3H, m), 6.67 (1H, q, J ) 6.6 Hz),
4.53 (1H, m), 3.75 (2H, m), 3.40 (2H, m), 2.47 (1H, m), 2.20
(2H, m), 1.78 (3H, d, J ) 6.6 Hz), 1.50 (8H, m), 0.95 (3H, d, J
) 6.6 Hz). 13C NMR (50 MHz, CDCl3): δ (ppm) 172.1, 137.4,
133.7, 130.1, 128.8, 128.3, 126.1, 125.5, 125.2, 123.1, 123.0,
98.5, 69.0, 65.1, 62.0, 42.0, 36.1, 30.6, 27.7, 25.4, 21.6, 19.6,
19.4. IR (film): ν (cm-1) 3021, 2985, 1707, 1369, 1057. Mass
(DCI NH3): m/z 388 (M + 18), 304, 287, 172, 155 (100%), 132,
115, 102. Anal. Calcd for C23H30O4 (370.4931): C, 74.56; H,
8.16. Found: C, 74.38; H, 8.10.
(3R,2′′RS)-3-Meth yl-5-(2-tetr a h yd r op yr a n yloxy)p en ta -
n a l (18a ). A solution of compound 17 (1.39 g, 3.76 mmol) in
toluene (40 mL) was cooled to -78 °C, and a diisobutylalumi-
num hydride solution (1.5 M in toluene, 2.75 mL, 4.12 mmol,
1.3 equiv) was slowly added (one drop every 20 s). After
stirring for 30 min at -78 °C, the excess hydride reagent was
quenched by careful addition of a saturated ammonium
chloride solution (15 mL) and the mixture was warmed to room
temperature. The solution was then poured into 300 mL of
diethyl ether and washed twice with 150 mL of a 1 M sodium
potassium tartrate solution. The aqueous layers were ex-
tracted with 100 mL of ether, and the combined organic layers
were washed with brine, dried (Na2SO4), filtered, and concen-
trated in vacuo. TLC analysis of the crude product (50%
diethyl ether/heptane) showed the presence of four com-
pounds: some remaining starting material (Rf ) 0.62), the
aldehyde (Rf ) 0.46), (1-naphthyl)ethyl alcohol (Rf ) 0.40), and
some overreduction alcohol (Rf ) 0.05). Increasing the
DIBAL-H addition rate or reaction time resulted in an increase
in the yield of unwanted primary alcohol. Purification by
chromatography (25% diethyl ether/heptane) gave in order of
1H NMR (250 MHz, CDCl3): δ (ppm) 8.57 (1H, m), 7.38-
7.11 (15H, m), 3.86 (1H, dt, J ) 5.Hz), 3.42 (2H, ABX system),
2.64 (1H, dt, J ) 5.7 and 5.3 Hz), 1.28 (2H, m), 1.15 (10H,
broad s), 0.79 (3H, t, J ) 7 Hz). 13C NMR (62.5 MHz, CDCl3):
δ (ppm) 177.7, 143.5, 128.6, 127.2, 127.1, 87.0, 70.3, 62.5, 51.0,
34.8, 31.8, 29.4, 29.2, 25.6, 22.6, 14.1. [R]20D ) -1.7 (c ) 1.66,
CHCl3). High-resolution mass spectrum: calcd for C30H36O4
460.2613, found 460.2619.
(2S ,3S )-2-(Tr ip h e n ylm e t h oxym e t h yl)-â-d e ca n ola c-
ton e (10). The crude acid 9c was redissolved in pyridine (1
mL) and the solution cooled to 0 °C. Benzenesulfonyl chloride
(77 µL, 0.6 mmol, 3 equiv) was added by syringe, and the
mixture left for 18 h at 3 °C. The solution was then diluted
with water (3 mL) and extracted with diethyl ether (3 × 10
mL). The combined organic extracts were washed with brine,
dried (Na2SO4), filtered, and concentrated in vacuo. Purifica-
tion by chromatography (25% diethyl ether/heptane, Rf 0.20)
gave the title compound as a colorless oil (77 mg, 87% overall
yield from acid 9b).
1H NMR (200 MHz, CDCl3): δ (ppm) 7.40-7.10 (15H, m),
4.43 (1H, dt, J ) 6.7 and 4 Hz), 3.50 (1H, dd J gem ) 9.5 Hz, J
) 5.4 Hz), 3.30 (1H, ddd with J 2-3 ) 4 Hz), 3.20 (1H, dd, J gem
) 9.5 Hz, J ) 3.4 Hz), 1.80 (1H, m), 1.65 (1H, m), 1.35-1.10

Oxazoline N-Oxide-Mediated [2 + 3] Cycloadditions
J . Org. Chem., Vol. 63, No. 19, 1998 6639
elution the starting ester (42 mg, 3% recovery), followed by a
mixture of the aldehyde 18a and the chiral alcohol 15 (1.046
g), followed by the alcohol 18b (0.114 g,15% yield). The
aldehyde was carried into the next reaction as a mixture with
the naphthyl alcohol. An analytical sample was prepared by
preparative thin-layer chromatography (50% diethyl ether/
heptane).
and concentrated in vacuo. TLC analysis of the crude product
showed the presence of two regiomeric products, the less polar
being predominant. Purification by chromatography (25%
diethyl ether/heptane) gave in order of elution the title
compound 21 (Rf ) 0.30, 4.611 g, 77% yield from 19) as a
colorless oil, followed by its 5-iodo isomer (Rf ) 0.10, 0.555 g).
1H NMR (200 MHz, CDCl3): δ (ppm) 5.84 (1H, s), 3.68 (2H,
m), 2.19 (1H, dd, J ) 13.7 and 7 Hz), 2.02 (1H, dd, J ) 13.7
and 7.9 Hz), 1.78 (3H, s), 1.55 (1H, m), 1.37 (2H, m), 0.83 (3H,
d, J ) 6.6 Hz). 13C NMR (50 MHz, CDCl3): δ (ppm) 146.8,
75.6, 60.8, 47.6, 39.3, 27.6, 23.6, 19.3. IR (film): ν (cm-1) 3452,
1H NMR (200 MHz, CDCl3): δ (ppm) 9.73 (1H, s), 4.55 (1H,
m), 3.80 (2H, m), 3.40 (2H, m), 2.45 (1H, m), 2.20 (2H, m),
1.50 (8H, m), 0.95 (3H, d, J ) 6.6 Hz). 13C NMR (50 MHz,
CDCl3): δ (ppm) 202.7, 98.8, 65.1, 62.3, 50.9, 36.4, 30.7, 25.4,
20.1, 20.0, 19.6. IR (film): ν (cm-1) 3021, 2940, 2905, 2600,
1715, 1059. Anal. Calcd for C11H20O3 (200.2803): C, 65.97;
H, 10.07. Found: C, 66.12; H, 9.95.
3021, 2939, 2901, 1600, 1540, 1372, 1252, 738. [R]20 ) -3.5
D
(c ) 1.03, CHCl3). High-resolution mass spectrum: calcd for
C8H15IO 254.0169, found 254.0198. Anal. Calcd: C, 37.81;
H, 5.95. Found: C, 37.48; H, 6.07.
(4R,2′′RS)-4-Meth yl-6-(2-tetr a h yd r op yr a n yloxy)-1-h ex-
yn e (19). The crude aldehyde 18a (1.046 g) was dissolved in
methanol (30 mL), and solid potassium carbonate (1.12 g, 8.15
mmol) was added, followed by 1-diazo-2-oxopropyl diethyl
phosphonate (1.08 g, 5.62 mmol). The mixture was stirred 24
h at room temperature and then poured into a mixture of
aqueous 5% sodium bicarbonate solution (100 mL) and diethyl
ether (100 mL). The layers were separated, and the organic
layer was washed with brine, dried (Na2SO4), filtered and
concentrated in vacuo. Purification by chromatography (25%
diethyl ether/heptane) gave in order of elution the alkyne 19
(0.609 g, 83% overall yield) followed by the unreacted chiral
alcohol 15 (98% recovery), recovered >99% enantiomerically
pure as determined by chiral CPG (25 m â-cyclodextrin
column, 145 °C; retention times R isomer, 19.26 min; S isomer,
18.8 min).
(3S,5E)-6-Iod o-3,5-d im eth yl-5-h exen a l (22). A solution
of oxalyl chloride (825 µL, 9.45 mmol, 1.2 equiv) in dichlo-
romethane (40 mL) was cooled to -78 °C with stirring, and
dimethyl sulfoxide (1.34 mL, 18.9 mmol, 2.4 equiv) was slowly
added (gas evolution). After 30 min, a solution of the alcohol
21 (2 g, 7.874 mmol) in dichloromethane (10 mL) was added
at such a rate that the reaction temperature remained below
-60 °C. After 30 min, triethylamine (5.5 mL, 40 mmol, 5
equiv) was slowly added and the solution was allowed to warm
to room temperature. The mixture was partitioned between
20 mL of water and 200 mL of diethyl ether. The organic layer
was washed with brine, dried (Na2SO4), filtered, and concen-
trated in vacuo. Purification by filtration through a short pad
of silica gel (25% diethyl ether/heptane) gave the aldehyde 22
as a volatile, colorless liquid (1.94 g, 98% yield).
1H NMR (200 MHz, CDCl3): δ (ppm) 4.55 (1H, m), 3.80 (2H,
m), 3.45 (2H, m), 2.15 (2H, m), 1.95 (1H, t, J ) 2.6 Hz), 1.9-
1.7 (3H, m), 1.7-1.4 (6H, m), 0.95 (3H, d, J ) 6.6 Hz). 13C
NMR (50 MHz, CDCl3): δ (ppm) 98.8, 83.0, 69.4, 65.5, 62.3,
1H NMR (250 MHz, CDCl3): δ (ppm) 9.72 (1H, s), 5.88 (1H,
s), 2.5-2.1 (4H, m), 1.80 (3H, s), 1.75 (1H, m), 0.95 (3H, d, J
) 6.2 Hz). 13C NMR (62.5 MHz, CDCl3): δ (ppm) 201.8, 146.0,
76.5, 50.2, 46.9, 26.1, 23.6, 19.7. Mass (DCI NH3): m/z 270
(M + 18), 252 (M+), 167, 125 (M - 127), 106 (100%). IR
(film): ν (cm-1) 3021, 2940, 2902, 2606, 1716, 1605, 1447, 1370,
35.6, 30.8, 29.5, 25.9 (C3), 25.5, 19.6, 19.3. IR (film): ν (cm-1
)
3295, 3022, 2945, 2151, 1253, 726. [R]20 ) -3.1 (c ) 0.9,
D
CHCl3). Anal. Calcd for C12H20O2 (196.2920): C, 73.43; H,
10.27. Found: C, 73.05; H, 10.05.
1253, 735. [R]20 ) -5.3 (c ) 1.12, CHCl3). Anal. Calcd for
D
C8H13IO (252.0013): C, 38.12; H, 5.20. Found: C, 37.95; H,
4.92.
(S)-3-Meth yl-5-h exyn -1-ol (20). A solution of the alkyne
19 (4.522 g, 23 mmol) in methanol (50 mL) was treated at room
temperature with a catalytic amount of camphorsulfonic acid.
After 1 h, 20 mL of a saturated sodium carbonate solution and
200 mL of water were added and the solution was extracted
with 9/1 pentane/dichloromethane (3 × 50 mL). The combined
organic extracts were dried (Na2SO4), filtered, and carefully
concentrated in vacuo. The highly volatile crude alcohol 20
(2.58 g) was used immediately in the next reaction without
further purification.
(5S,2E,Z,7E) 2′-(5,7-Dim eth yl-8-iod o-2,7-octa d ien -1-yl)-
1′,3′-dioxolan e (23). 2-(1′,3′-Dioxolan-2′-yl)ethyltriphenylphos-
phonium bromide was prepared by refluxing a solution of
2-bromoethyl-1,3-dioxolane (6 g, 33.1 mmol) and triphenylphos-
phine (8.69 g, 33.1 mmol) in acetonitrile (30 mL) for 24 h. After
cooling to room temperature, the solvent was removed in vacuo
and the residue triturated with ethyl acetate (50 mL). The
yellow-brown phosphonium salt was collected by filtration (14
g, 95% yield).
Rf ) 0.24 (50% diethyl ether/heptane). 1H NMR (200 MHz,
CDCl3): δ (ppm) 3.64 (2H, dt, J ) 5.6 and 1.4 Hz), 2.12 (2H,
m), 1.93 (1H, t, J ) 2.6 Hz), 1.75 (1H, m), 1.45 (2H, m), 0.95
(3H, d, J ) 6.6 Hz).
1H NMR (250 MHz, DMSO-d6): δ (ppm) 8.00-7.65 (15H,
broad s), 5.01 (1H, t, J ) 6.7 Hz), 3.92 and 3.79 (4H, 2m), 3.65
(2H, m), 1.83 (2H, m).
A solution of the above phosphonium salt (3.16 g, 7.1 mmol,
2 equiv) in tetrahydrofuran (50 mL) was cooled to -78 °C with
stirring, and a 2.5 M n-butyllithium solution in hexanes (2.86
mL, 7.1 mmol, 2 equiv) was added dropwise. The orange
solution was stirred for 40 min at -78 °C; then a solution of
the aldehyde 22 (900 mg, 3.6 mmol) in tetrahydrofuran (20
mL) was added dropwise. The reaction mixture was allowed
to warm to -40 °C within 30 min, the cooling bath was then
removed, and the mixture was stirred 2 h at room tempera-
ture. The reaction was quenched by addition of a saturated
ammonium chloride solution (10 mL); the solution was diluted
with diethyl ether (300 mL). The organic layer was washed
with brine, dried (Na2SO4), filtered, and concentrated in vacuo.
The crude product was purified by filtration through a short
pad of silica gel, eluting with 25% diethyl ether/heptane.
Concentration in vacuo gave the title compound as a colorless
oil (1.19 g, 99% yield, stereochemistry unknown).
(3S,5E)-6-Iod o-3,5-d im eth yl-5-h exen -1-ol (21). A flame-
dried 250 mL flask was charged with zirconocene dichloride
(6.72 g, 23 mmol). Meanwhile, in a separate flask, a trim-
ethylaluminum solution in 1,2-dichloroethane was prepared
by adding neat trimethylaluminum (6.75 mL, 70 mmol, 3
equiv) (CAUTION: highly pyrophoric material) to dry 1,2-
dichloroethane (20 mL). This solution was transferred via
cannula to the flask containing zirconocene dichloride, and the
resulting lemon yellow solution was stirred for 15 min at room
temperature before being cooled to -5 °C. A solution of the
crude alkyne 20 (2.576 g, 23 mmol) in 1,2-dichloroethane was
added dropwise. The mixture was stirred for 24 h at room
temperature and then cooled to -20 °C. A solution of iodine
(30 g, 115 mmol, 5 equiv) in tetrahydrofuran (100 mL) was
slowly added via cannula. The dark solution was stirred 2 h
at -20 °C and then cooled to -50 °C. The excess trimethy-
laluminum reagent was quenched by careful addition of a 1/1
tetrahydrofuran/water solution (100 mL). After warming to
room temperature, the mixture was diluted with diethyl ether
(500 mL) and washed with water (100 mL). The aqueous layer
was extracted with diethyl ether (100 mL), and the combined
organic layer was washed with a 10% sodium thiosulfate
solution (200 mL) and then with brine, dried (Na2SO4), filtered,
Rf ) 0.68 (50% diethyl ether/pentane). 1H NMR (250 MHz,
CDCl3): δ (ppm) 5.82 (1H, s), 5.50 (2H, m), 4.85 (1H, t, J )
4.8 Hz), 3.95 and 3.83 (4H, 2m), 2.39 (2H, ddd, J ) 5, 5 and 1
Hz), 2.23 (1H, d, J ) 5.3 Hz), 2.18 (1H, d, J ) 6.1 Hz), 2.00
(2H, m), 1.77 (3H, s), 1.70 (1H, m), 0.80 (3H, d, J ) 6.6 Hz).
13C NMR (62.5 MHz, CDCl3): δ (ppm) 146.9, 130.9, 123.9,
103.9, 75.4, 64.9, 46.9, 34.2, 32.3, 31.4, 23.7, 19.2. IR (film):

6640 J . Org. Chem., Vol. 63, No. 19, 1998
Dirat et al.
ν (cm-1) 3020, 2975, 2947, 1608, 1417, 1372, 1262, 1128, 738.
dipolarophile (345 mg, 0.95 mmol, 100% recovery), followed
by the cycloadduct which was isolated as a colorless oil (0.732
g, 58% yield).
[R]20 ) +5.2 (c ) 0.54, CHCl3). Mass (DCI NH3): m/z 355
D
(M + 19), 338 (M + 2), 174, 130 (100%). Anal. Calcd for
C
13H21IO2 (336.0586): C, 46.44; H, 6.30. Found: C, 46.67; H,
1H NMR (400 MHz with COSY, CDCl3): δ (ppm) 5.79 (1H,
s), 5.40 (1H, d, J ) 7.6 Hz), 4.37 (1H, dt, J ) 10.4 and 6.1 Hz),
4.19 (2H, m), 3.89 (1H, d, J ) 7.6 Hz), 3.28 (1H, d, J ) 7.5
Hz), 2.90 (1H, dd, J ) 10.5 and 7.6 Hz), 2.15 (1H, dd, J ) 13.5
and 6.1 Hz), 2.05 (1H, d, J ) 4.3 Hz), 1.94 (1H, dd, J ) 13.4
and 8.4 Hz), 1.76 (3H, s), 1.68 (2H, m), 1.58 (1H, m), 1.53 (2H,
m), 1.35 (2H, m), 1.30-1.15 (6H, m), 1.26 (3H, t, J ) 7.1 Hz),
0.92-0.75 (12H, m). 13C NMR (50 MHz, CDCl3): δ (ppm)
169.0, 147.1, 98.6, 89.8, 78.3, 75.9, 75.2, 61.0, 58.3, 49.2, 48.4,
47.5, 45.9, 36.4, 32.1, 31.4, 30.8, 26.9, 25.5, 26.0, 23.7, 22.1,
19.2, 18.9, 14.2, 10.7. IR (film): ν (cm-1) 3017, 2965, 1728,
1607, 1452, 1372, 1268, 1032. Mass (DCI NH3): m/z 560 (M
5.95.
(6R,8E)-6,8-Dim eth yl-9-iodo-8-n on en al (25). Finely pow-
dered potassium hydroxide (59 g, 1 mol) was added to a
solution of hydroxylamine hydrochloride (62.2 g, 0.9 mol) in
dimethylformamide (185 mL). After stirring for 10 min at
room temperature, the solution was filtered under argon
atmosphere, the filtrate was cooled to 0 °C, and ethyl acetate
(38.5 mL) was added. Then 30 mL aliquots of this solution
were added every 30 min to compound 24 (1.161 g, 3.45 mmol)
at 100 °C. After heating for a total time of 3 h, the solution
was cooled to room temperature, a 1/1 heptane/diethyl ether
mixture was added (500 mL), and the resulting solution was
washed three times with 100 mL of a 5% sodium bicarbonate
solution and then with brine, dried (Na2SO4), filtered, and
concentrated in vacuo. The crude product was immediately
taken into the next reaction.
+ 1), 180 (100%). [R]20 ) +62.0 (c ) 1.08, CHCl3). Anal.
D
Calcd for C26H42NIO4 (559.2160): C, 55.81; H, 7.57; N, 2.50;
I, 22.68. Found: C, 55.42; H, 7.34; N, 2.17; I, 22.68. High-
resolution mass spectrum: found 559.2151.
(2R,3R,3a R,4R,4a R,5S,8R,8a S,5′S,7′E)-2-(5′,7′-Dim eth yl-
8′-iod o-7′-oct en -1′-yl)-5,10,10-t r im et h yl-5,8-m et h a n ooc-
ta h ydr o-2H-isoxa zolo[3,2-b]ben zoxa zole-3-m eth a n ol (28).
The above cycloadduct 27 (0.917 g, 1.64 mmol) was dried by
azeotropic evaporation with toluene and then dissolved in
toluene (30 mL), and the solution was cooled to -78 °C. A 1.5
M toluene solution of diisobutylaluminum hydride (3 mL, 4.5
mmol, 2.75 equiv) was added dropwise. The solution was
stirred for 2 h at -78 °C and then allowed to warm to -40 °C
in 1 h, and the excess hydride reagent was quenched by careful
addition of a saturated ammonium chloride solution (10 mL).
The cooling bath was removed and the solution allowed to
warm to room temperature. A 1 N sodium potassium tartrate
solution (100 mL) was added and the biphasic mixture
vigorously stirred overnight and then separated. The aqueous
phase was extracted with diethyl ether (100 mL), and the
combined organic layer was washed with brine, dried (Na2-
SO4), filtered, and concentrated in vacuo. Purification by
chromatography (50% diethyl ether/heptane, Rf ) 0.36) af-
forded the alcohol 28 (0.758 g, 89% yield) as a colorless oil.
1H NMR (250 MHz, CDCl3): δ (ppm) 5.77 (1H, s), 5.32 (1H,
d, J ) 6.5 Hz), 3.83 (1H, d, J ) 7.5 Hz), 3.72 (3H, m), 3.32
(1H, d, J ) 7.5 Hz), 2.40 (1H, broad s, exchangeable with D2O),
2.17 (2H, m), 2.07 (1H, d, J ) 4.4 Hz), 1.94 (1H, dd, J ) 13.3
and 8.1 Hz), 1.75 (3H, s), 1.68 (2H, m), 1.58 (1H, m), 1.53 (2H,
m), 1.35 (2H, m), 1.30-1.15 (6H, m), 0.92-0.75 (12H, m). 13C
NMR (62.5 MHz, CDCl3): δ (ppm) 147.1, 100.1, 90.4, 77.6, 77.3,
75.2, 59.7, 53.7, 49.4, 48.8, 47.5, 45.6, 36.3, 32.0, 31.6, 30.7,
The crude product was dissolved in tetrahydrofuran (30 mL)
and 2 N hydrochloric acid solution (30 mL) and stirred at reflux
for 3 h. The solution was basified by addition of solid
potassium carbonate and the product extracted with dichlo-
romethane (4 × 100 mL). The combined organic extracts were
dried (Na2SO4), filtered, and concentrated in vacuo. Purifica-
tion by chromatography (25% diethyl ether/heptane) gave the
aldehyde 25 as a light yellow oil (0.547 g, 54% yield).
1H NMR (200 MHz, CDCl3): δ (ppm) 9.73 (1H, t, J ) 1.5
Hz), 5.80 (1H, s), 2.41 (2H, td, J ) 7.3 and 1.5 Hz), 2.12 (1H,
dd, J ) 13.2 and 6.3 Hz), 1.96 (1H, dd, J ) 13.3 and 8.2 Hz),
1.77 (3H, s), 1.64 (3H, m), 1.32 (4H, m), 0.78 (3H, d, J ) 6.5
Hz). 13C NMR (50 MHz, CDCl3): δ (ppm) 202.7, 147.0, 75.3,
47.5, 43.9, 36.3, 30.7, 26.5, 23.7, 22.2, 19.2. IR (film): ν (cm-1
)
3020, 2900, 1703, 1455, 1254, 733. Mass (DCI NH3): m/z 312
(M + 18), 294 (M+), 243, 167 (M - 127), 106 (100%). [R]20
)
D
+0.8 (c ) 1.01, CHCl3). High-resolution mass spectrum: calcd
for C11H19IO 294.0482, found 294.0471.
(8R,2E,10E)-8,10-Dim eth yl-11-iod o-2,10-u n d eca d ien o-
ic Acid Eth yl Ester (26). A solution of the above aldehyde
(0.043 g, 0.15 mmol) (ethoxycarbonylidene)triphenylphosphorane
(0.1 g, 0.29 mmol, 2 equiv) in toluene (5 mL) was stirred at 80
°C for 4 h. The mixture was then cooled to room temperature
and the solvent evaporated in vacuo. The residue was
triturated with pentane (10 mL), filtered, and concentrated
in vacuo. Purification by chromatography (25% diethyl ether/
pentane) gave the pure R,â-unsaturated ester as a colorless
oil (54 mg, 99% yield).
27.0, 26.0, 25.5, 23.7, 22.2, 19.2, 18.7, 10.9. IR (film): ν (cm-1
)
Rf ) 0.78 (50% diethyl ether/heptane). 1H NMR (200 MHz,
CDCl3): δ (ppm) 6.89 (1H, dt, J ) 15.5 and 7 Hz), 5.76 (1H,
s), 5.75 (1H, dt, J ) 17 and 1 Hz), 4.12 (2H, q, J ) 7.1 Hz),
2.11 (3H, m), 1.91 (1H, dd, J ) 13.3 and 8.2 Hz), 1.72 (3H, s),
1.55 (1H, m), 1.45-0.90 (6H, m), 1.22 (3H, t, J ) 7.1 Hz), 0.73
(3H, d, J ) 6.6 Hz). 13C NMR (50 MHz, CDCl3): δ (ppm) 166.7,
149.2, 147.1, 121.3, 75.2, 60.1, 47.5, 36.3, 32.2, 30.8, 28.2, 26.5,
23.7, 19.2, 14.3. IR (film): ν (cm-1) 3018, 2958, 1705, 1646,
1453, 1297, 1042, 740. Mass (DCI NH3): m/z 382 (M + 18),
3440, 3018, 2965, 1608, 1451, 1375, 1270, 1031, 743. Mass
(DCI NH3): m/z 518 (M + 1) (100%). [R]20D ) +59.3 (c ) 0.95,
CHCl3). Anal. Calcd for C24H40NIO3 (517.2053): C, 55.70; H,
7.79; N, 2.71; I, 24.52. Found: C, 55.43; H, 7.85; N, 2.50; I,
24.31.
(2R,3R,3a R,4R,4a R,5S,8R,8a S,5′S,7′E)-2-(5′,7′-Dim eth yl-
8′-iodo-7′-octen -1′-yl)-5,10,10-tr im eth yl-3-[(1,1,1-tr iph en yl)-
m et h oxym et h yl]-5,8-m et h a n ooct a h yd r o-2H -isoxa zolo-
[3,2-b]ben zoxa zole (29). A solution of the alcohol 28 (0.594
g, 1.15 mmol) in pyridine (20 mL) was treated with trityl
chloride (1.3 g, 4.66 mmol, 4 equiv) and the solution stirred
overnight at 70 °C. After cooling to room temperatrure, the
mixture was diluted with water and with brine (10 mL each)
and extracted with diethyl ether (3 × 50 mL). The combined
organic extracts were washed with brine, dried (Na2SO4),
filtered, and concentrated in vacuo. The remaining pyridine
was coevaporated with toluene. The residue was taken up
with pentane (20 mL) and filtered to remove the trityl
impurities. This operation was repeated twice. The crude
product was purified by chromatography (25% diethyl ether/
heptane) to give the protected alcohol 29 as a colorless oil
(0.872 g, 100% yield).
365 (M + 1) (100%), 256, 239, 163. [R]20 ) -4.0 (c ) 0.62,
D
CHCl3). Anal. Calcd for C15H25IO2 (364.0901): C, 49.46; H,
6.92; I, 34.84. Found: C, 49.83; H, 6.95; I, 34.46.
(2R,3R,3a R,4R,4a R,5S,8R,8a S,5′S,7′E)-2-(5′,7′-Dim eth yl-
8′-iod o-7′-oct en -1′-yl)-5,10,10-t r im et h yl-5,8-m et h a n ooc-
tah ydr o-2H-isoxazolo[3,2-b]ben zoxazole-3-car boxylic Acid
Eth yl Ester (27). Trimethyl orthoformate (1.2 mL, 3.21
mmol, 1.42 equiv) was added to a suspension of (1S)-3-
hydroxylaminoisoborneol hydrochloride (-)-3 (0.5 g, 2.26
mmol), flame-dried calcium carbonate (0.5 g, 5 mmol, 2.2
equiv), and powdered 4Å molecular sieves (0.6 g) in toluene
(10 mL). The white suspension was stirred at 40 °C for 4 h,
and the dipolarophile 26 (1.17 g, 3.21 mmol, 1.42 equiv) was
added. The temperature was raised to 80 °C and the reaction
mixture stirred for 18 h. After cooling to room temperature,
the suspension was filtered through a pad of Celite and
concentrated in vacuo. Purification by chromatography (10%
diethyl ether/heptane) gave, in order of elution, the excess
1H NMR (200 MHz, CDCl3): δ (ppm) 7.40-7.10 (15H, m),
5.81 (1H, s), 5.26 (1H, d, J ) 6.9 Hz), 3.61 (1H, ddd, J ) 10.3,
7.3 and 2.8 Hz), 3.51 (1H, d, J ) 7.6 Hz), 3.44 (1H, dd, J ) 9.4
and 6.0 Hz), 3.15 (1H, d, J ) 7.5 Hz), 2.95 (1H, dd, J ) 9.4
and 7.1 Hz), 2.25 (1H, m), 2.16 (1H, dd, J ) 14 and 6.4 Hz),

Oxazoline N-Oxide-Mediated [2 + 3] Cycloadditions
J . Org. Chem., Vol. 63, No. 19, 1998 6641
2.04 (1H, d, J ) 4.1 Hz), 1.95 (1H, dd, J ) 14 and 8.5 Hz),
1.78 (3H, s, Me-C7′), 1.68 (2H, m), 1.58 (1H, m), 1.53 (2H, m),
1.35 (2H, m), 1.30-1.15 (6H, m), 0.92-0.75 (12H, m). 13C
NMR (62.5 MHz, CDCl3): δ (ppm) 147.2, 143.9, 128.7, 127.9,
127.2, 99.0, 89.8, 86.9, 79.7, 76.5, 75.2, 60.4, 51.5, 49.2, 48.5,
47.5, 45.6, 36.4, 32.4, 31.5, 30.8, 27.0, 25.9, 25.5, 23.7, 22.2,
19.2, 18.9, 10.9. IR (film): ν (cm-1) 3080, 3050, 3018, 2965,
1608, 1450, 1372, 1275, 1121, 742. Mass (DCI NH3): m/z 760
concentrated in vacuo. Purification by preparative TLC on
silica gel (10% methanol/dichloromethane, Rf ) 0.45) gave the
pure acid as a colorless oil (97 mg, 65% yield for three steps).
1H NMR (200 MHz, CDCl3): δ (ppm) 7.40-7.10 (15H, m),
5.65 (1H, s), 5.56 (1H, s), 3.88 (1H, m), 3.57-3.48 (2H, m), 2.68
(1H, m), 2.18 (3H, s), 2.00 (1H, m), 1.87 (1H, m), 1.76 (3H, s),
1.58 (1H, m), 1.53 (2H, m), 1.48 (9H, s), 1.30-1.15 (6H, m),
0.75 (3H, d, J ) 6.6 Hz). Mass (electrospray): m/z 663.7 (M
+ Na) (100%). High-resolution mass spectrum: calcd for
(M + 1) (100%), 634, 180. [R]20 ) +18.3 (c ) 1.34, CHCl3).
D
Anal. Calcd for C43H54NIO3 (759.3150): C, 67.97; H, 7.16; N,
1.84; I, 16.70. Found: C, 68.12; H, 7.03; N, 1.55; I, 17.02.
(2R,3R,3a R,4R,4a R,5S,8R,8a S,5′S,7′E)-2-[10′-(1,1)-Di-
m eth yleth yloxyca r bon yl-5′,7′,9′-tr im eth yl-7′,9′-d eca d ien -
1′-yl]-3-[(1,1,1-tr ip h en yl)m eth oxym eth yl]-5,10,10-tr im e-
t h yl-5,8-m et h a n ooct a h yd r o-2H -isoxa zolo[3,2-b]b en zox-
a zole (30). To a stirred solution of the protected alcohol 29
(0.872 g, 1.15 mmol) in dichloromethane/absolute ethanol (6
mL/1.4 mL) were successively added tert-butyl crotonate (6.5
mL), silver carbonate (0.35 g, 1.26 mmol, 1.1 equiv), triethy-
lamine (350 µL, 2.53 mmol, 2.2 equiv), and finally a solution
of palladium(II) acetate (0.035 g, 0.11 mmol, 0.1 equiv) in
dichloromethane (6 mL). The mixture was stirred for 3 h at
room temperature in the dark and then filtered through a
short pad of silica gel, eluting with diethyl ether. The filtrate
was concentrated in vacuo and the residue purified by chro-
matography (25% diethyl ether/heptane, Rf ) 0.48) to give the
dienic ester 30 as a single (E,E) isomer (colorless oil, 0.708 g,
84% yield).
C
41H52O6Na (M + Na) 663.3662, found 663.3664.
(2E,4E,2′R,3′R,7R)-[3′-(Tr ip h en yl)m et h oxym et h yl-4′-
oxo-2′oxeta n yl]-3,5,7-tr im eth yl-2,4-u n d eca d ien oic Acid
1,1-Dim eth yleth yl Ester (32). A solution of the acid 31
(0.034 g, 53 µmol) in pyridine (0.5 mL) was treated at 0 °C
with benzenesulfonyl chloride (25 µL, 160 µmol, 3 equiv) and
then left overnight in a refrigerator (3 °C). After warming to
room temperature, water (5 mL) was added and the product
extracted three times with diethyl ether (3 × 10 mL). The
combined organic extracts were washed with brine, dried (Na2-
SO4), filtered, and concentrated in vacuo. Purification by
chromatography (50% diethyl ether/heptane, Rf ) 0.59) gave
the â-lactone 32 as a colorless oil (0.024 g, 73% yield).
1H NMR (200 MHz, CDCl3): δ (ppm) 7.40-7.10 (15H, m),
5.65 (1H, s), 5.56 (1H, s), 4.48 (1H, dt, J ) 6.6 and 4.0 Hz),
3.56 (1H, dd, J ) 9.6 and 5.4 Hz), 3.37 (1H, ddd, J ) 5.4, 4.0
and 3.4 Hz), 3.26 (1H, dd, J ) 9.6 and 3.4 Hz), 2.18 (3H, s),
2.04 (1H, dd, J ) 12.6 and 5.7 Hz), 1.87 (1H, m), 1.76 (3H, s),
1.58 (1H, m), 1.53 (2H, m), 1.47 (9H, s), 1.40-1.15 (6H, m),
0.79 (3H, d, J ) 6.4 Hz). 13C NMR (50 MHz, CDCl3): δ (ppm)
169.5, 166.8, 152.7, 143.3, 140.3, 129.7, 128.5, 128.0, 127.2,
119.3, 86.9, 79.6, 75.5, 58.7, 56.8, 48.9, 36.7, 34.1, 30.8, 28.3,
26.7, 25.2, 19.5, 19.3, 18.3. IR (film): ν (cm-1) 3080, 3050,
3015, 2965, 1820, 1719, 1623, 1152, 720. Mass (electro-
1H NMR (250 MHz, CDCl3): δ (ppm) 7.40-7.10 (15H, m),
5.64 (1H, s), 5.56 (1H, s), 5.24 (1H, d, J ) 6.9 Hz), 3.61 (1H,
ddd, J ) 10.3, 7.3 and 2.8 Hz), 3.52 (1H, d, J ) 7.5 Hz), 3.45
(1H, dd, J ) 9.5 and 6.0 Hz), 3.16 (1H, d, J ) 7.5 Hz), 2.97
(1H, dd, J ) 9.5 and 7.2 Hz), 2.23 (1H, m), 2.20 (3H, s), 2.16
(1H, m), 2.04 (1H, d, J ) 3.8 Hz), 1.98 (1H, m), 1.77 (3H, s),
1.68 (2H, m), 1.58 (1H, m), 1.53 (2H, m), 1.48 (9H, s), 1.35
(2H, m), 1.30-1.15 (6H, m), 0.92-0.75 (12H, m). 13C NMR
(62.5 MHz, CDCl3): δ (ppm) 166.7, 152.7, 143.9, 140.5, 129.5,
128.7, 127.7, 126.9, 119.2, 99.0, 89.8, 86.9, 79.7, 79.4, 76.5, 60.4,
51.5, 49.3, 48.9, 48.5, 45.6, 36.7, 32.4, 31.5, 30.8, 28.3, 27.1,
spray): m/z 645.5 (M + Na) (100%). [R]20 ) +3.3 (c ) 1.07,
D
CHCl3). Anal. Calcd for C41H50O5 (622.8527): C, 79.06; H,
8.09. Found: C, 79.42; H, 8.08.
1233-A (1). A few crystals of p-toluenesulfonic acid hydrate
were added to a solution of the â-lactone 32 (0.011 g, 0.17
mmol) in benzene/dichloromethane (1 mL/0.2 mL). The solu-
tion was stirred for 2 h at room temperature and then diluted
with water (5 mL) and extracted with dichloromethane (3 × 5
mL). The combined organic extracts were washed with brine,
dried (Na2SO4), filtered, and concentrated in vacuo. The crude
product was purified by preparative TLC on silica gel (50%
diethyl ether/heptane). The polar fractions (Rf < 0.2) were
collected and taken into the next reaction.
25.9, 25.5, 22.2, 19.4, 19.2, 18.9, 18.3, 10.9. IR (film): ν (cm-1
)
3080, 3050, 3019, 2964, 1721, 1622, 1453, 1153, 740. Mass
(DCI NH3): m/z 774 (M + 1), 243, 180 (100%). [R]20D ) +38.1
(c ) 0.99, CHCl3). High-resolution mass spectrum: calcd for
C
51H67NO5 773.5019, found 773.5014. Anal. Calcd: C, 79.13;
H, 8.72; N, 1.81. Found: C, 78.92; H, 8.35; N, 1.70.
(2E ,4E ,7R ,12R ,13S )-12-H yd r oxy-3,5,7-t r im e t h yl-13-
[(1,1,1-tr ip h en yl)m eth oxym eth yl]-2,4-tetr a d eca d ien e-1,-
14-d ioic Acid 1-(1,1-Dim eth yleth yl) Ester (31). A solution
of compound 30 (0.186 g, 0.24 mmol, 1 equiv) in diethyl ether
(5 mL) was treated with m-chloroperoxybenzoic acid (0.166 g,
1 mmol, 4 equiv) and the clear and colorless solution was
stirred for 1 h at room temperature. An aqueous 10% sodium
bicarbonate/10% sodium thiosulfate solution (10 mL) was
added and the biphasic solution vigorously stirred for 1 h.
Diethyl ether (20 mL) was added, and the layers were
separated. The organic layer was washed with a 5% NaHCO3
solution (3 × 10 mL) and then washed with brine, dried (Na2-
SO4), filtered, and concentrated in vacuo to a white foam. This
crude product was used immediately in the next reaction.
This crude nitrone was dissolved in tetrahydrofuran (3 mL),
and a 2 N hydrochloric acid solution (3 mL) was added. The
turbid solution was stirred for 30 min at room temperature
and then diluted with water (5 mL) and extracted three times
with ethyl acetate (3 × 20 mL). The combined organic extracts
were washed with brine, dried (Na2SO4), filtered, and concen-
trated in vacuo. The resulting crude aldehyde was used
immediately in the oxidation reaction.
The crude detritylated material was dissolved in dichlo-
romethane (1 mL), the solution was cooled to 0 °C, and
trifluoroacetic acid (1 mL) was added. The bright yellow
solution was stirred at 0 °C for 40 min, toluene (3 mL) was
added, and the mixture was concentrated in vacuo. Synthetic
1233-A 1 was obtained by preparative TLC on silica gel (10%
methanol/dichloromethane, Rf ) 0.40; authentic sample Rf )
0.40) as a nearly colorless solid (3.4 mg, 60% overall yield for
deprotection steps).
1H NMR (600 MHz, CDCl3): δ (ppm) 5.71 (1H, s, C4-H), 5.67
(1H, s, C2-H), 4.57 (1H, ddd, J ) 7.2, 6.2, and 4.2 Hz, C2′-H),
4.04 (1H, dd, J ) 11.6 and 4.9 Hz, one of CH2-OH), 3.87 (1H,
dd, J ) 11.6 and 4.0 Hz, one of CH2-OH) 3.39 (1H, q, J ) 4.2
Hz, C3′-H), 2.23 (3H, s, Me-C3), 2.06 (1H, dd, J ) 13.1 and 6.2
Hz, one of C6-H), 2.00-1.80 (2H, m, C11-H × 2), 1.84 (1H, dd,
J ) 13.2 and 7.9 Hz, one of C6-H), 1.79 (3H, s, Me-C5), 1.70-
1.55 (1H, m, C7-H), 1.50-1.05 (6H, m, C8-H × 2, C9-H × 2,
C
10-H × 2), 0.82 (3H, d, J ) 6.5 Hz, Me-C7). 13C NMR (150
MHz, CDCl3): δ (ppm) 171.5 (C1), 169.7 (C4′), 157.1 (C3), 142.1
(C5), 129.5 (C4), 116.6 (C2), 74.9 (C2′), 58.6 (C3′), 58.0 (CH2-OH),
49.0 (C6), 36.5 (C8), 34.0 (C11), 30.9 (C7), 26.6 (C9), 25.2 (C10),
20.0 (Me-C3), 19.4 (Me-C7), 18.5 (Me-C5). IR (film): ν (cm-1
)
The crude aldehyde (in mixture with camphor-derived ketol)
was dissolved in tert-butyl alcohol (2 mL) and 2-methyl-2-
butene (0.5 mL). Then 1 mL of a freshly prepared aqueous
10% sodium chlorite/sodium dihydrogen phosphate solution
was added and the solution stirred for 1 h at room tempera-
ture. Water was added (5 mL) and the solution extracted three
times with ethyl acetate (3 × 15 mL). The combined organic
extracts were washed with brine, dried (Na2SO4), filtered, and
3019, 2933, 2850, 1816 (â-lactone), 1684, 1616, 1419, 1210, 770.
[R]20D ) +27.0 (c ) 0.90, CHCl3); [R]20D lit.4a ) +28.6 (c ) 0.62,
CHCl3). Mass (electrospray): m/z 347.3 (M + Na) (100%).
Ack n ow led gm en t. Glaxo-Wellcome is gratefully
acknowledged for a grant to O.D. and Dr. A. Meddour
for NMR measurements in chiral medium.

6642 J . Org. Chem., Vol. 63, No. 19, 1998
Dirat et al.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of
synthetic intermediates 16-32 and of synthetic 1 and 2D
spectra in chiral medium for the determination of the enan-
tiomeric excess of 18 (33 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
J O980813U