A Formal Total Synthesis of (+)-Tetronolide, the Aglycon of the Tetrocarcins: Enantio- and Diastereoselective Syntheses of the Octahydronaphthalene (Bottom-Half) and Spirotetronate (Top-Half) Fragments

Article abstract of DOI:10.1021/jo970960c

A formal total synthesis of (+)-tetronolide, the aglycon of the tetrocarcins, has been achieved by virtue of the development of highly diastereo- and enantioselective syntheses of the bottom- and top-half fragments 4 and 5 reported herein. These fragments previously served as key intermediates in Yoshii's pioneering total synthesis of (+)-tetronolide. The synthesis of the bottom-half octahydronaphthalene unit 4 features the intramolecular Diels-Alder reaction of tetraenal 20 and proceeds in 17 steps and 5-6% yield from D-glyceraldehyde pentylidene acetal 8. The synthesis of the spirotetronate fragment 5 features the highly enantioselective exo selective Diels-Alder reaction of triene 37 and chiral dienophile 25b and proceeds in 14 steps and 10% overall yield from cis-2-butene-1,4-diol (38). An enantioselective synthesis of Boeckman's top-half cyclohexene fragment 6 via the exo selective Diels-Alder reaction of diene 24 and dienophile 25a was also developed, but this route was deemed too inefficient for use in a projected total synthesis of the natural product. The syntheses of 5 and 6 provide important information on the utility of chiral dienophiles 25a and 25b in organic synthesis.

Full text of DOI:10.1021/jo970960c

8708
J . Org. Chem. 1997, 62, 8708-8721
A F or m a l Tota l Syn th esis of (+)-Tetr on olid e, th e Aglycon of th e
Tetr oca r cin s: En a n tio- a n d Dia ster eoselective Syn th eses of th e
Octa h yd r on a p h th a len e (Bottom -Ha lf) a n d Sp ir otetr on a te
(Top -Ha lf) F r a gm en ts
William R. Roush,* Melissa L. Reilly, Kazuo Koyama, and Bradley B. Brown
Department of Chemistry, Indiana University, Bloomington, Indiana 47405
Received May 30, 1997 (Revised Manuscript Received September 15, 1997X)
A formal total synthesis of (+)-tetronolide, the aglycon of the tetrocarcins, has been achieved by
virtue of the development of highly diastereo- and enantioselective syntheses of the bottom- and
top-half fragments 4 and 5 reported herein. These fragments previously served as key intermediates
in Yoshii’s pioneering total synthesis of (+)-tetronolide. The synthesis of the bottom-half
octahydronaphthalene unit 4 features the intramolecular Diels-Alder reaction of tetraenal 20 and
proceeds in 17 steps and 5-6% yield from D-glyceraldehyde pentylidene acetal 8. The synthesis of
the spirotetronate fragment 5 features the highly enantioselective exo selective Diels-Alder reaction
of triene 37 and chiral dienophile 25b and proceeds in 14 steps and 10% overall yield from cis-2-
butene-1,4-diol (38). An enantioselective synthesis of Boeckman’s top-half cyclohexene fragment
6 via the exo selective Diels-Alder reaction of diene 24 and dienophile 25a was also developed,
but this route was deemed too inefficient for use in a projected total synthesis of the natural product.
The syntheses of 5 and 6 provide important information on the utility of chiral dienophiles 25a
and 25b in organic synthesis.
Tetronolide (1) is the aglycon of the tetrocarcins, a
group of structurally related spirotetronate antibiotics
(e.g., tetrocarcins A-C, E1, E2, F, and F-1) isolated from
the culture broth of Micromonospora chaldea KY 11091.1-5
These antibiotics are complex glycosides, the full stereo-
structures of which have not been assigned. Tetrocarcins
A, B, and C, which share a common nitro sugar (tetronose)
as well as the deoxysugars L-amicetose and L-digitoxose,
display activity against experimental tumors such as
mouse sarcoma 180 and mouse leukemia P 388.2 Tetrono-
lide is structurally related to kijanolide (2)6 and chloro-
thricolide (3),7,8 the aglycons of kijanimicin and chloro-
thricin, which possess antibiotic activities.9,10 The
structure of tetronolide was assigned by an X-ray analy-
sis,1 and the absolute configuration was determined by
Yoshii in his pioneering total synthesis.11
Because of its structural complexity and interesting
biological activity, tetronolide has received considerable
attention as a synthetic target. In 1991 Yoshii reported
the first, and to date only, total synthesis11 of 1 via the
coupling of the bottom-half octahydronaphthalene frag-
X Abstract published in Advance ACS Abstracts, November 1, 1997.
(1) Hirayama, N.; Kasai, M.; Shirahata, K.; Ohashi, Y.; Sasada, Y.
Bull. Chem. Soc. J pn. 1982, 55, 2984.
(2) Tomita, F.; Tamaoki, T.; Shirahata, K.; Kasai, M.; Morimoto, M.;
Ohkubo, S.; Mineura, K.; Ishii, S. J . Antibiot. 1980, 33, 668.
(3) Tomita, F.; Tamaoki, T. J . Antibiot. 1980, 33, 940.
(4) Tamaoki, T.; Kasai, M.; Shirahata, K.; Ohkubo, S.; Morimoto,
M.; Mineura, K.; Ishii, S.; Tomita, F. J . Antibiot. 1980, 33, 946.
(5) Tamaoki, T.; Kasai, M.; Shirahata, K.; Tomita, F. J . Antibiot.
1982, 35, 979.
ment 411,12 and the top-half spirotetronate subunit 5.13
Marshall14,15 and Boeckman16 have developed syntheses
of bottom-half fragments related to 4, while Boeckman
(12) Takeda, K.; Kobayashi, T.; Saito, K.; Yoshii, E. J . Org. Chem.
1988, 53, 1092.
(13) Matsuda, K.; Nomura, K.; Yoshii, E. J . Chem. Soc., Chem.
Commun. 1989, 221.
(6) Mallams, A. K.; Puar, M. S.; Rossman, R. R.; McPhail, A. T.;
Macfarlane, R. D.; Stephens, R. L. J . Chem. Soc., Perkin Trans. 1 1983,
1497.
(7) Muntwyler, R.; Keller-Schierlein, W. Helv. Chim. Acta 1972, 55,
2071.
(8) Brufani, M.; Cerrini, S.; Fedeli, W.; Mazza, F.; Muntwyler, R.
Helv. Chim. Acta 1972, 55, 2094.
(14) Marshall, J . A.; Grote, J .; Shearer, B. J . Org. Chem. 1986, 51,
1633.
(15) Marshall, J . A.; Salovich, J . M.; Shearer, B. G. J . Org. Chem.
1990, 55, 2398.
(9) Waitz, J . A.; Horan, A. C.; Kalyanpur, M.; Lee, B. K.; Loebenberg,
D.; Marquez, J . A.; Miller, G.; Patel, M. G. J . Antibiot. 1981, 34, 1101.
(10) Schindler, P. W. Eur. J . Biochem. 1975, 51, 579 and references
therein.
(11) Takeda, K.; Kawanishi, E.; Nakamura, H.; Yoshii, E. Tetrahe-
dron Lett. 1991, 32, 4925.
(16) Boeckman, R. K., J r.; Barta, T. E.; Nelson, S. G. Tetrahedron
Lett. 1991, 32, 4091.
(17) Boeckman, R. K., J r.; Estep, K. G.; Nelson, S. G.; Walters, M.
A. Tetrahedron Lett. 1991, 32, 4095.
(18) Boeckman, R. K., J r.; Wrobleski, S. T. J . Org. Chem. 1996, 61,
7238.
S0022-3263(97)00960-2 CCC: $14.00 © 1997 American Chemical Society

Formal Total Synthesis of (+)-Tetronolide
J . Org. Chem., Vol. 62, No. 25, 1997 8709
Sch em e 1
has described a synthesis of R-hydroxy ester 6 as a
potential precursor to the top half of 1.17,18 We have
reported syntheses of octahydronaphthalene 7,19 corre-
sponding to the bottom halves of both kijanolide and
tetronolide, as well as an enantioselective synthesis of
spirotetronate (+)-5.20 We report herein a highly dia-
stereo- and enantioselective synthesis of Yoshii’s bottom-
half fragment 4, as well as the full details of our
enantioselective synthesis of the top-half fragment 5. This
work thus constitutes a formal total synthesis of tetrono-
lide.
the synthesis of 4 reported here, we wished to avoid the
introduction of a superfluous C(5)-hydroxyl group that
complicated our earlier synthesis of 7,19 and we also
wanted to avoid unwieldy protecting group switches
which would have been necessary had we chosen to
synthesize 4 from 7 or related series of intermediates.19,25
Because our supplies of 7 had been virtually exhausted
by the time we decided to initiate this synthesis of 4, we
developed the route summarized in Scheme 1.
D-Glyceraldehyde pentylidene ketal 826 served as the
starting material for this synthesis. This compound is
much less prone to hydration and oligomerization than
the corresponding acetonide27 which we used in our
earlier synthesis of 7.19 Thus, treatment of 8 with
tartrate (E)-crotylboronate (R,R)-9 provided homoallylic
alcohol 10 as an 88:12 mixture of easily separated
diastereomers.28-30 Protection of the hydroxyl group of
10 as a MOM ether and ozonolysis of the terminal alkene
provided the corresponding aldehyde, which was then
treated with the known phosphonate reagent 1225 using
Masamune’s LiCl-i-Pr2NEt conditions for the Wads-
En a n tio- a n d Dia ster eoselective Syn th esis of th e
Bottom -Ha lf F r a gm en t 4. All previous syntheses of
the octahydronaphthalene subunits of tetronolide (1) and
kijanolide (2) have utilized intramolecular Diels-Alder
reactions21-24 as the key step.11,12,15,16,19 In undertaking
(25) Roush, W. R.; Brown, B. B. J . Org. Chem. 1993, 58, 2162.
(26) Schmid, C. R.; Bradley, D. A. Synthesis 1992, 587.
(27) Hertel, L. W.; Grossman, C. S.; Kroin, J . S. Synth. Commun.
1991, 21, 151.
(28) Roush, W. R.; Palkowitz, A. D.; Ando, K. J . Am. Chem. Soc.
1990, 112, 6348.
(19) Roush, W. R.; Brown, B. B. J . Am. Chem. Soc. 1993, 115, 2268.
(20) Roush, W. R.; Koyama, K. Tetrahedron Lett. 1992, 33, 6227.
(21) Ciganek, B. Org. React. 1984, 32, 1.
(22) Fallis, A. G. Can. J . Chem. 1984, 62, 183.
(23) Craig, D. Chem. Soc. Rev. 1987, 16, 187.
(24) Roush, W. R. In Comprehensive Organic Synthesis; Trost, B.
M., Ed.; Pergamon Press: Oxford, 1991; Vol. 5; pp 513-550.
(29) Roush, W. R.; Hoong, L. K.; Palmer, M. A. J .; Straub, J . A.;
Palkowitz, A. D. J . Org. Chem. 1990, 55, 4117.
(30) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.;
Halterman, R. L. J . Am. Chem. Soc. 1990, 112, 6339.
(31) Blanchette, M. A.; Choy, W.; Davis, J . T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183.

8710 J . Org. Chem., Vol. 62, No. 25, 1997
Roush et al.
worth-Horner-Emmons reaction,31 thereby giving 13 in
72% yield. Hydrogenation of 13 over 10% Pd/C provided
14, the lithium enolate of which underwent a highly
diastereoselective alkylation reaction with MeI (93:7
diastereoselectivity, 83% yield).32 Removal of the pen-
tylidene ketal was accomplished by treatment of 15 with
60% formic acid in MeOH. Oxidative cleavage of the
resulting diol with KIO4 and KHCO3,26 followed by
Corey-Fuchs olefination of the intermediate aldehyde,
provided dibromoolefin 16 in 48% overall yield.33 Selec-
tive reduction of 16 with DIBAL in THF at -78 °C
provided the corresponding aldehyde (79%) which was
treated with (carbethoxyethylidene)triphenylphosphorane
in toluene at 60 °C. This two-step sequence provided a
9:1 mixture of olefin isomers, from which 17 was obtained
in 67% yield from 15. Dibromoolefin 17 underwent cross
coupling with vinylboronic acid 18 under Kishi’s modified
Suzuki cross-coupling conditions,34,35 thereby providing
tetraenoate 19 following protection of the primary hy-
droxyl as a TBS ether. Reduction of 19 with excess
DIBAL and reoxidation of the intermediate allylic alcohol
with TPAP and NMO36 provided tetraenal 20 in 74%
yield. A toluene solution of 20 was heated at 130 °C for
12 h to provide the desired cycloadduct 21 in 90% yield.
Analysis of the 1H NMR spectrum of the crude IMDA
reaction mixture failed to reveal the presence of any
diastereomeric cycloadducts, thereby indicating that the
stereoselectivity of this reaction was G98:E2. Finally,
reductive removal of the C(9)-Br steric directing group19,37
by using 5% Na(Hg) in MeOH provided the targeted
tetronolide bottom half fragment 4 in 74% yield from 20.
The stereostructure of 4 was assigned initially by spec-
troscopic comparisons with 7, especially in view of the
characteristic coupling constants summarized below.
Unambiguous verification of stereostructure was subse-
quently obtained by comparison of 4 ([R]20D -100° (c 0.6,
CHCl3)) with an authentic sample ([R]23D -101.2° (c 2.70,
CHCl3)) kindly provided by Professor Yoshii.11
prepared from spirolactone 23, which we had already
prepared via the Diels-Alder reaction of diene 2439 and
the chiral dienophile 25a .40,41
The Diels-Alder reaction of 24 and 25a was performed
by heating a mixture of 4 equiv of 24 and 25a (1 M) in
trichloroethylene at 150 °C for 42 h. Diene 24 proved to
be substantially less reactive than the conjugated trienes
used in our syntheses of the top halves of kijanolide42,43
and chlorothricolide,44,45 which necessitated that this
reaction be performed at a higher temperature for longer
reaction periods. Unfortunately, the instability of 25a
under these conditions limited the efficiency of the
reaction. The combined yield of the exo and endo
cycloadducts, 23a and 26, respectively, was only 10-15%
when the reaction was performed with 1 equiv of 24 but
increased to 46% (based on 25a ) when 4 equiv of the
diene was used. Fortunately, the excess diene could be
recovered efficiently (85% yield) at the conclusion of the
reaction; on the basis of consumed diene the combined
yield of cycloadducts was 75-80%.
En a n tio- a n d Dia ster eoselective Syn th esis of th e
Top -Ha lf Sp ir otetr on a te Su bstr u ctu r e. In contem-
plating a synthesis of a tetronolide top-half spirotetronate
precursor such as 5, we anticipated that the C(21) alkoxy
group and the C(22-23) olefin could be introduced by a
sequence involving either peroxidation or osmylation of
22 followed by oxidation of the primary hydroxymethyl
group with concomitant elimination of the C(22) alkoxy
substituent.38 In turn, we anticipated that 22 could be
The stereochemistry of the endo cycloadduct 26 was
assigned following conversion to the cis-fused lactone 27,
mp 110-112 °C.38,46 Under similar conditions, the major
cycloadduct, 23a , was converted to triol 28, thereby
confirming the assignment of 23a as an exo cycloadduct
(Scheme 2). Differentiation of the two primary hy-
droxymethyl groups was accomplished by treatment of
28 with benzaldehyde and ZnCl2 in Et2O, which provided
a ca. 6-7:1 mixture of the diastereomeric benzylidene
(32) Evans, D. A.; Ennis, M. D.; Mathre, D. J . J . Am. Chem. Soc.
1982, 104, 1737.
(33) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(34) Roush, W. R.; Moriarty, K. J .; Brown, B. B. Tetrahedron Lett.
1990, 31, 6509.
(35) Uenishi, J .; Beau, J .-M.; Armstrong, R. W.; Kishi, Y. J . Am.
Chem. Soc. 1987, 109, 4756.
(36) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13.
(37) Roush, W. R.; Kageyama, M.; Riva, R.; Brown, B. B.; Warmus,
J . S.; Moriarty, K. J . J . Org. Chem. 1991, 56, 1192.
(38) Takeda, K.; Shibata, Y.; Sagawa, Y.; Urahata, M.; Funaki, K.;
Hori, K.; Sasahara, H.; Yoshii, E. J . Org. Chem. 1985, 50, 4673.
(39) Naruta, Y.; Nagai, N.; Yokota, T.; Maruyama, K. Chemistry Lett.
1986, 1185.
(41) Roush, W. R.; Brown, B. B. J . Org. Chem. 1992, 57, 3380.
(42) Roush, W. R.; Brown, B. B. J . Org. Chem. 1993, 58, 2151.
(43) Roush, W. R.; Brown, B. B. Tetrahedron Lett. 1989, 30, 7309.
(44) Roush, W. R.; Sciotti, R. J . Tetrahedron Lett. 1992, 33, 4691.
(45) Roush, W. R.; Sciotti, R. J . J . Am. Chem. Soc. 1994, 116, 6457.
(46) Takeda, K.; Imaoka, I.; Yoshii, E. Tetrahedron 1994, 50, 10837.
(40) Roush, W. R.; Essenfeld, A. P.; Warmus, J . S.; Brown, B. B.
Tetrahedron Lett. 1989, 30, 7305.

Formal Total Synthesis of (+)-Tetronolide
J . Org. Chem., Vol. 62, No. 25, 1997 8711
Sch em e 2
acetals 29 (60-64%) and 30 (8-9%). Alternatively, when
the benzylidene acetal was introduced by treatment of
28 with PhCHO and p-TsOH in benzene, acetal 30 was
obtained as the major product, but in low yield (38%).
The stereochemistry of acetals 29 and 30 was assigned
by NMR methods. Acetal 30 displayed large coupling
diastereomers 31 and 32 in 81-86% combined yield. We
assumed that the major product derived from epoxidation
of the more accessible â-face, although we recognized that
the C(23)-hydroxymethyl group could have directed ep-
oxidation to the R-face.47 This possibility was probed and
ultimately rejected as a significant contribution to the
reaction stereoselectivity, by acylating the hydroxyl group
prior to the epoxidation reaction. This three-step reac-
tion sequence ((i) Ac2O, pyridine, (ii) MCPBA, (iii) K2-
CO3, MeOH) provided 31 with excellent selectivity, as
none of the unwanted R-epoxide 32 was detected. How-
ever, the yield of 31 was not improved (71%) relative to
the direct epoxidation of 29. As expected at the outset,
Swern oxidation48 of 31 led directly to the γ-hydroxy enal
33 via â-elimination of the intermediate â,γ-epoxy alde-
hyde.
constants between H19(ax)-H20 and between H23-H24
,
indicative of trans diaxial H/H relationships. These data
require that 30 adopts the conformation indicated in the
three-dimensional structure presented below. Although
we did not make a conclusive assignment of the acetal
center, examination of molecular models indicates that
the phenyl group must occupy an equatorial position in
30 if the molecule is to adopt the conformation indicated
by the J data. This conclusion allows us to assign the
configuration of the acetal center in 29 as (R), since 29
and 30 are acetal epimers. Not surprisingly, the 1H NMR
data for 29, specifically the small coupling constants
While these studies were in progress, Boeckman’s
synthesis of racemic tetronolide top-half precursor 6 was
published.17 At this stage, therefore, we decided to
converge with 6 as a means of verifying our stereochem-
ical assignments. Accordingly, the free hydroxyl group
of 33 was protected as a MOM ether; then the aldehyde
was reduced under Luche conditions49 and the resulting
primary hydroxymethyl group was protected as a TBDPS
ether, thereby providing 34 in 76% yield. The ben-
zylidene acetal of 34 was removed by hydrolysis in 80%
HOAc, giving diol 35 in 81% yield. Treatment of 35 with
ethyl vinyl ether and Hg(OAc)2 provided vinyl ether 36,
which was transesterified by exposure to NaOEt in EtOH
to complete the synthesis of 6. The identity of synthetic
J
20,19(ax), J 20,19(eq), J 23,24(ax), and J 23,24(eq) indicate that this
intermediate adopts a different cis-decalin conformation
than that of 30. Because the â-face of the C(21-22) olefin
of 29 appeared to be more exposed than that of 30, we
decided to use 29 to explore methods for introducing the
C(21)-â-hydroxyl and the C(22-23) olefin in the spirotet-
ronate unit of tetronolide.
1
6 was verified by comparison with H NMR data kindly
provided by Professor Boeckman. The optical rotation
of our synthetic sample ([R]25 +41.3° (c 1.0, CHCl3)) is
D
also in reasonable agreement with the value subse-
quently reported by Boeckman ([R]25D +34.4° (c 2.9, CH2-
Cl2)).18
(47) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. (Washington,
D.C.) 1993, 93, 1307.
(48) Tidwell, T. T. Synthesis 1990, 857.
Treatment of 29 with MCPBA in CH2Cl2 containing
suspended NaHCO3 provided a ca. 7:1 mixture of epoxide
(49) Luche, J .-L. J . Am. Chem. Soc. 1978, 100, 2226.

8712 J . Org. Chem., Vol. 62, No. 25, 1997
Roush et al.
Although we had accomplished the first enantioselec-
tive synthesis of 6, we were not pleased with the
selectivity or efficiency of the route summarized in
Scheme 2. Most problematic were the low efficiency of
the Diels-Alder reaction of 24 and 25a and the number
of steps required to differentiate the two hydroxymethyl
substituents of 28. We also were not pleased with the
low efficiency of the conversion of 35 to 36 (31%);
however, no effort was made to optimize this sequence
(e.g., by introduction of a bromoethyl acetal at the stage
of 28, by analogy to the work of Boeckman).17 In view of
the tremendous success we had achieved in the Diels-
Alder reactions of dienophiles 25a and 25b with conju-
gated trienes in our syntheses of the top halves of
kijanolide and chlorothricolide,42-45 we decided to pursue
instead a synthesis of Yoshii’s top-half fragment 5 via
the Diels-Alder reaction of 37 and dienophile 25b (which
typically exhibits higher diastereofacial selectivity than
25a ).41,42
(3 M) at 110 °C for 90 h. Under these conditions, the
desired exo cycloadduct 41 was obtained in 67% yield
together with 7% of the endo isomer 42. In addition, 14%
of triene 37 was recovered, and 5% of a mixture of
nonpolar products apparently resulting from the Diels-
Alder dimerization of 37 was also obtained. The reaction
is considerably faster at higher temperatures (150 °C,
20 h, 28% of 41; 120 °C, 22 h, 48% yield), but the yield of
41 is diminished owing to the increased rate of dimer-
ization of 37. Interestingly, cycloadducts with reversed
orientation of the diene and dienophile relative to that
depicted in 41 and 42 were not detected. Although we
were concerned at the outset that the regioselectivity of
this reaction might be problematic,55-58 the results sug-
gest that the enoate substituent is a very powerful
regiochemical directing element for this Diels-Alder
reaction.
1
The stereochemistry of 41 and 42 was assigned by H
NMR methods. In particular, a NOE observed between
the tert-butyl group and H24R (2.6%) of 41 defines the
stereochemistry of the acetal center relative to the
cyclohexenyl unit and confirms that the diene added to
the face of 25b opposite to the bulky tert-butyl group.41
Moreover, a weak NOE (1%) observed between the tert-
butyl group and C(23)-CH2OTBS unit requires that the
C(23) substituent occupies a pseudoaxial position on the
cyclohexenyl ring. This conclusion is supported by the
relatively small coupling constants observed between
H(23)-H(24ax) (J 23,24(ax) ) 6.8 Hz) and H(23)-H(24eq)
(J 23,24(eq) ) 3.6 Hz). In contrast, the C(23)-CH2OTBS
substituent occupies a pseudoequatorial position in endo
cycloadduct 42, as indicated by J 23,24(ax) ) 10.8 Hz and
The synthesis of 37 originated from enal 39, which was
prepared in two steps from cis-2-butene-1,4-diol (38) by
selective monosilylation50-52 and then PCC oxidation of
the resulting allylic alcohol.53 Olefination of 39 by
treatment with the lithium anion of methyl γ-(dimeth-
ylphosphono)tiglate 4054 (generated at -78 °C with
n-BuLi) at -78 to 23 °C in a solvent system of THF
containing 5 equiv of HMPA per equiv of 40 provided
trienoate 37 in 69% yield. In contrast, the yield of 37
ranged from 24 to 41% when bases such as BuLi or NaH
in Et2O or THF were used in the absence of a polar
aprotic solvent additive such as HMPA or DMPU.
A
significant competitive pathway under these conditions
is the Michael addition of 40 to 39. The yield of 37 was
58% when the reaction was performed in the presence of
5 equiv of DMPU rather than HMPA, and consequently
the THF-HMPA solvent system is preferred.
The key Diels-Alder reaction was performed by heat-
ing a mixture of 37 and 1.5 equiv of (R)-25b in toluene
J 23,24(eq) ) 6.0 Hz. Moreover, it is possible to assign the
stereochemistry of C(20) on the basis of the chemical
(50) Roush, W. R.; Blizzard, T. A. J . Org. Chem. 1984, 49, 1772. In
particular, see ref 23 cited therein.

Formal Total Synthesis of (+)-Tetronolide
J . Org. Chem., Vol. 62, No. 25, 1997 8713
shifts of H(20) (δ 3.57 for 41 and δ 3.38 for 42), since one
would expect the equatorial H(20) of 42 to be shielded
by adjacent carbonyl group.59 These characteristic NMR
data are very similar to those obtained for the exo and
endo cycloadducts 43-4460 in the kijanolide series42 and
45-46 in the chlorothricolide series.44
of these intermediates was determined to be G97% ee
by Mosher ester analysis18 of diol 50.
The synthesis of 5 proceeded by cis-dihydroxylation of
41 with catalytic OsO4 and 1.0 equiv of N-methylmor-
pholine oxide (NMO).61 Treatment of the resulting diol
with MOM-Cl and i-Pr2NEt in CH2Cl2 under standard
conditions then provided 47 in 78% overall yield; no other
isomers were detected. The primary TBS ether was
cleaved upon exposure of 47 to HF-Et3N in CH3CN, and
the alcohol was oxidized by using a modified Swern
protocol.48 When this oxidation was performed under
standard conditions using Et3N as the base, the â-alkoxy
aldehyde was obtained as the major product with only
minor amounts of enal 48. However, by using the more
basic DBU in place of Et3N, enal 48 [[R]22D +93.5° (c 1.0,
CHCl3)] was obtained directly from the oxidation se-
quence in 78% yield overall from 47. The stereochemistry
of 48 was unambiguously verified by X-ray analysis.62
After protection of the aldehyde as a dimethyl acetal (92%
yield), the unsaturated ester was selectively reduced by
treatment with 2.2 equiv of L-Selectride in THF at -20
°C (86% yield). Protection of the resulting allylic alcohol
as a SEM ether then provided 49 in 75% yield for the
three-step sequence from 48. The enantiomeric purity
The synthesis of spirotetronate 5 was completed by a
sequence initiated by the methanolysis of 49 with K2CO3
in MeOH and acylation of the resulting 3°-hydroxy
methyl ester with acetic anhydride (excess) in the pres-
ence of DMAP and Et3N in CH2Cl2. The resulting
R-acetoxy ester was treated with LiN(TMS)2 (1 equiv) in
a THF-HMPA mixture at -78 °C, and then the solution
was allowed to warm to 23 °C to complete the Dieckmann
cyclization.63 Addition of Me2SO4 directly to the reaction
mixture42,44 then provided 5 ([R]24 +134.3° (c 2.80,
D
CHCl3)) in 64% overall yield. The spectroscopic proper-
ties of spirotetronate 5 were identical with those of an
authentic sample ([R]23 +99.0° (c 3.02, CHCl3)) kindly
D
provided by Professor Yoshii.11
Su m m a r y. We have completed a formal total synthe-
sis of (+)-tetronolide, the aglycon of the tetrocarcins, by
virtue of our completion of highly diastereo- and enan-
tioselective syntheses of the bottom- and top-half frag-
ments 4 and 5 which served as key intermediates in
Yoshii’s pioneering total synthesis.11 Our synthesis of
the bottom-half octahydronaphthalene unit 4 proceeds
in 17 steps and 5-6% yield from D-glyceraldehyde
pentylidene acetal 8 and features the intramolecular
Diels-Alder reaction of tetraenal 20. Our synthesis of
the spirotetronate fragment 5 proceeds in 14 steps and
10% overall yield from cis-2-butene-1,4-diol (38), and
features the highly enantioselective exo selective Diels-
Alder reaction of triene 37 and chiral dienophile 25b. We
also developed an enantioselective synthesis of Boeck-
man’s top-half cyclohexene fragment 6 via the exo selec-
tive Diels-Alder reaction of diene 24 and dienophile 25a
(11 steps, 1.5% yield, from 24), but in the final analysis
this route was deemed too inefficient for use in a
projected total synthesis of the natural product.
(51) Roush, W. R.; Gillis, H. R.; Essenfeld, A. P. J . Org. Chem. 1984,
49, 4674. See, in particular, the procedures for the syntheses of 49-51
therein.
(52) McDougal, P. G.; Rico, J . G.; Oh, Y.-I.; Condon, B. D. J . Org.
Chem. 1986, 51, 3388.
(53) Corey, E. J .; Suggs, J . W. Tetrahedron Lett. 1975, 2647.
(54) Pattenden, G.; Weedon, B. C. L. J . Chem. Soc. C 1968, 1997.
(55) Corey, E. J .; Snider, B. B. J . Am. Chem. Soc. 1972, 94, 2549.
(56) Stork, G.; Nakahara, Y.; Nakahara, Y.; Greenlee, W. J . J . Am.
Chem. Soc. 1978, 100, 7775.
(57) Vedejs, E.; Campbell, J . B., J r.; Gadwood, R. C.; Rodgers, J .
D.; Spear, K. L.; Watanabe, Y. J . Org. Chem. 1982, 47, 1534.
(58) Okumura, K.; Okazaki, K.; Takeda, K.; Yoshii, E. Tetrahedron
Lett. 1989, 30, 2233.
(59) J ackman, L. M.; Sternhell, S. Applications of Nuclear Magnetic
Resonance Spectroscopy in Organic Chemistry, 2nd ed.; Pergamon
Press: Oxford, 1969.
(60) H24ax and H24eq of 43 partially overlap with the resonance for
the vinylic-Me group and are not fully resolved.
(61) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1973.
(62) Details of the X-ray strcture analysis of enal 48 are provided
in Report No. 92118 of the Indiana University Molecular Structure
Center. Final residuals are R(F) ) 0.0256 and Rw(F) ) 0.0279. We
thank Dr. J ohn C. Huffman for performing this analysis.
(63) Ireland, R. E.; Thompson, W. J . J . Org. Chem. 1979, 44, 3041.
(64) For general experimental details, see: Roush, W. R.; Brown,
B. B. J . Am. Chem. Soc. 1993, 115, 2268 or Roush, W. R.; Brown, B.
B. J . Org. Chem. 1993, 58, 2151. Unless otherwise noted, all compounds
purified by chromatography are sufficiently pure (>95% by 1H NMR
analysis) for use in subsequent reactions.
Work continues on the development of a workable
strategy for completion of a tetronolide total synthesis
(cf. ref 25), since the final stages of Yoshii’s synthesis
requires 15 steps from 4 and 5.11 Reports on these efforts
will appear in due course.
Exp er im en ta l Section 64
(3S ,4S ,5R )-4-H yd r oxy-5,6-(isop e n t ylid e n e d ioxy)-3-
m eth ylh ex-1-en e (10). To a solution of (R,R)-diisopropyl
tartrate (E)-crotylboronate (9)30 (39.5 mL of a 0.75 M stock

8714 J . Org. Chem., Vol. 62, No. 25, 1997
Roush et al.
solution, 29.6 mmol) and 4 Å molecular sieves in toluene at
-78 °C was slowly added a solution of D-glyceraldehyde
pentylidene ketal 826 (2.0 g, 12.6 mmol) in 30 mL of toluene.
The reaction mixture was allowed to stir at -78 °C for 4 h
and then was allowed to warm to room temperature overnight.
The white slurry (at 0 °C) was diluted with 0.5 N NaOH (60
mL) and was stirred for 3 h at room temperature. The toluene
layer was separated and washed with a saturated NaHCO3
solution (50 mL), dried (MgSO4), and concentrated in vacuo.
The aqueous phase was extracted with Et2O (3 × 50 mL). The
combined ethereal extracts were dried (MgSO4), concentrated
in vacuo, and combined with the toluene extracts. 1H NMR
analysis revealed that the crude product consisted of an 88:
12 mixture of 10 and the (3R,4R,5R)-diastereomer. Purifica-
tion of the crude product by silica gel chromatography (19:1
hexane-ether) provided 2.3 g (85% based on 8) of alcohol 10
with EtOAc (100 mL). The organic layer was separated and
washed with a saturated solution of NaCl (50 mL). The
combined aqueous extracts were extracted with EtOAc (5 ×
50 mL) and then were dried (MgSO4) and concentrated in
vacuo. Purification of the crude product by silica gel chroma-
tography (9:1 hexanes-ethyl acetate) provided 5.0 g (87%) of
the R,â-unsaturated oxazolidinone 13 as a colorless oil: Rf 0.85
(5:1 hexanes-ethyl ether); [R]20 +37.2° (c 0.9, toluene); 1H
D
NMR (400 MHz, CDCl3) δ 7.31 (d, J ) 15.5 Hz, 1 H), 7.19 (dd,
J ) 15.5, 8.1 Hz, 1 H), 4.71 (A of AB, J AB ) 7.0 Hz, 1 H), 4.64
(B of AB, J BA ) 7.0 Hz, 1 H), 4.48 (m, 1 H), 4.26 (t, J ) 9.1 Hz,
1 H), 4.20 (dd, J ) 8.9, 3.2 Hz, 1 H), 4.02 (m, 2 H), 3.79 (m 1
H), 3.66 (dd, J ) 5.6, 3.5 Hz, 1 H), 3.36 (s, 3 H), 2.79 (m, 1 H),
2.39 (m, 1 H), 1.59 (m, 4 H), 1.17 (d, J ) 7.0 Hz, 3 H), 0.90 (d,
J ) 6.9 Hz, 3 H), 0.86 (m, 9 H); 13C NMR (100 MHz, CDCl3) δ
164.7, 153.9, 152.1, 120.6, 112.6, 97.7, 82.1, 76.5, 67.1, 63.2,
58.4, 55.9, 39.5, 29.6, 29.0, 28.4, 17.9, 16.0, 14.5, 8.1, 8.0; IR
(neat) 1751, 1659, 1631 cm-1; high-resolution mass spectrum,
calcd for C21H36NO7 (M+ + 1) 414.2492, found 414.2480. Anal.
Calcd for C21H35NO7: C, 61.00; H, 8.53; N, 3.39. Found: C,
61.19; H, 8.75; N, 3.38.
as a colorless oil: Rf 0.26 (4:1 hexanes-ethyl acetate); [R]21
D
1
+15.1° (c 1.0, MeOH); H NMR (400 MHz, CDCl3) δ 5.85 (m,
1 H), 5.12 (m, 2 H), 4.03 (m, 2 H), 3.86 (m, 1 H), 3.63 (dd, J )
9.4, 5.1 Hz, 1 H), 2.40 (ddq, J ) 6.9, 7.7, 6.4 Hz, 1 H), 1.90 (d,
J ) 4.3 Hz, 1 H), 1.64 (m, 4 H), 1.00 (d, J ) 6.9 Hz, 3 H), 0.90
(dd, J ) 14.5, 7.2 Hz, 6 H); 13C NMR (100 MHz, CDCl3) δ 140.2,
116.9, 113.1, 77.7, 75.3, 66.3, 40.6, 29.7, 29.3, 16.7, 8.2, 8.0;
IR (neat) 3470, 1635 cm-1; high-resolution mass spectrum,
calcd for C12H23O3 (M+ + 1) 215.1647, found 215.1644.
(4S,4′S,5′S,6′R)-3-[5′-[(Meth oxym eth yl)oxy]-6′,7′-O-iso-
p en tylid en e-4′-m eth ylh ep ta n oyl]-4-isop r op yl-1,3-oxa zo-
lid in -2-on e (14). A stream of H2 was bubbled through a
solution of 13 (2.3 g, 5.57 mmol) in EtOAc (30 mL). To this
solution was added 120 mg of 10% Pd on carbon. H2 gas was
bubbled through the solution for an additional 10 min; then
the solution was allowed to stir under H2 for 4 h at room
temperature. The solution was filtered through a plug of
Celite, dried (MgSO4), and concentrated in vacuo. Purification
of the crude product by silica gel chromatography (5:1 hex-
anes-ethyl acetate) provided 14 (2.20 g, 95%) as a colorless
(3S ,4S ,5R )-4-(Me t h oxym e t h yl)-5,6-(isop e n t ylid e n e -
d ioxy)-3-m eth ylh ex-1-en e (11). To a solution of 10 (2.3 g,
10.7 mmol) in CH2Cl2 (20 mL) were added i-Pr2NEt (2.05 mL,
11.8 mmol) and chloromethyl methyl ether (0.813 mL, 10.7
mmol). The solution was warmed to reflux for 10 h. The
yellow solution was cooled to room temperature and then
washed with
a saturated NH4Cl solution (30 mL). The
aqueous phase was extracted with EtOAc (3 × 30 mL). The
combined organic extracts were then dried (MgSO4), filtered,
and concentrated in vacuo. Purification of the crude product
by silica gel chromatography (6:1 hexanes-ethyl acetate)
provided 2.5 g (90%) of 11 as a colorless liquid: Rf 0.54 (4:1
hexanes-ethyl acetate); [R]21D +12.0° (c 1.5, MeOH); 1H NMR
(400 MHz, CDCl3) δ 5.81 (m, 1 H), 5.02, (m, 2 H), 4.74 (A of
AB, J AB ) 6.8 Hz, 1 H), 4.67 (B of AB, J BA ) 6.8 Hz, 1 H), 4.02
(m, 2 H), 3.80 (m, 1 H), 3.61 (dd, J ) 5.4, 3.5 Hz, 1 H), 3.38 (s,
3 H), 2.53 (m, 1 H), 1.60 (m, 4 H), 1.10 (d, J ) 7.0 Hz, 3 H),
0.82 (dd, J ) 14.2, 7.5 Hz, 6 H); 13C NMR (100 MHz, CDCl3)
δ 139.8, 115.1, 112.2, 97.8, 82.2, 66.9, 55.8, 40.6, 29.7, 29.0,
16.8, 8.2, 8.0; IR (neat) 3070, 1670, 1462 cm-1; high-resolution
mass spectrum, calcd for C14H27O4 (M+ + 1) 259.1909, found
259.1920. Anal. Calcd for C14H26O4: C, 65.09; H, 10.14.
Found: C, 65.02; H, 9.93.
oil: Rf 0.89 (hexanes-ethyl ether); [R]20 +78.7° (c 1.4, THF);
D
1H NMR (400 MHz, CDCl3) δ 4.70 (A of AB, J AB ) 6.7 Hz, 1
H), 4.65 (B of AB, J BA ) 6.7 Hz, 1 H), 4.42 (m, 1 H) 4.22 (m,
2 H), 4.12 (m, 1 H), 4.05 (dd, J ) 7.8, 6.1 Hz, 1 H), 3.82 (t, J
) 7.8 Hz, 1 H), 3.60 (dd, J ) 5.9, 4.0 Hz, 1 H), 3.38, (s, 3 H),
2.97 (m, 2 H), 2.36 (m, 1 H), 1.97-1.78 (m, 2 H), 1.60 (m, 5
H), 0.99 (d, J ) 7.0 Hz, 3 H), 0.89 (m, 12 H); 13C NMR (100
MHz, CDCl3) δ 173.2, 112.5, 97.4, 82.0, 76.0, 67.2, 63.3, 58.4,
55.9, 35.0, 33.5, 29.7, 29.1, 28.4, 26.9, 18.0, 15.6, 14.6, 8.2, 8.1;
IR (neat) 1760, 1700 cm-1; high-resolution mass spectrum,
calcd for C21H38NO7 (M+ + 1) 416.2648, found 416.2629. Anal.
Calcd for C21H37NO7: C, 60.70; H, 8.98; N, 3.37. Found: C,
60.76; H, 9.03; N, 3.41.
(2′S,4S,4′S,5′S,6′R)-3-[5′-[(Meth oxym eth yl)oxy]-6′,7′-O-
isop en t ylid en e-4′-m et h ylh ep t -2′-en oyl]-4-isop r op yl-1,3-
oxa zolid in -2-on e (15). To a 0 °C solution of n-BuLi (7.5 mL
1.6 M in hexanes, 12 mmol) in THF (20 mL) was slowly added
NH(TMS)2 (3.9 mL, 19 mmol). The solution was stirred at 0
°C for 45 min, before being cooled to -78 °C and transferred
via cannula into a -78 °C solution of 14 (4.8 g, 11.6 mmol)
and MeI (7.0 mL, 112 mmol) in THF (110 mL). The reaction
mixture was warmed slowly to 0 °C and stirred for 2 h. The
reaction was then quenched by addition of a cold saturated
NaCl solution (10 mL). The organic layer was separated and
washed with saturated brine (2 × 100 mL). The combined
aqueous extracts were washed with EtOAc (5 × 100 mL), dried
(MgSO4), and concentrated in vacuo. 1H NMR analysis of the
crude reaction mixture revealed 15 as the major product of a
93:7 mixture (86% de). Purification of the crude product by
silica gel chromatography (9:1 hexane-Et2O) provided 15 (4.3
g, 87%) as a colorless oil: Rf 0.90 (5:1 hexanes-ethyl ether);
[R]20D +9.6° (c 1.1, toluene); 1H NMR (400 MHz, CDCl3) δ 4.64
(A of AB, J AB ) 6.7 Hz, 1 H), 4.61 (B of AB, J BA ) 6.7 Hz, 1
H), 4.42 (m, 1 H), 4.25 (m, 1 H), 4.18 (dd, J ) 8.8, 2.9 Hz, 1
H), 4.06 (m, 2 H), 3.92 (m, 1 H), 3.79 (m, 1 H), 3.54 (dd, J )
6.4, 3.5 Hz, 1 H), 3.34 (s, 3 H), 2.36 (m, 1 H), 1.86 (m, 1 H),
1.62 (m, 6 H), 1.18 (d, J ) 6.7 Hz, 3 H) 0.96 (d, J ) 7.0 Hz, 3
H), 0.89 (m, 12 H); 13C NMR (100 MHz, CDCl3) δ 177.5, 153.6,
112.6, 97.2, 82.0, 75.7, 67.8, 63.2, 58.5, 55.8, 35.3, 35.2, 33.0,
29.7, 29.1, 28.5, 18.0, 17.6, 15.7, 14.7, 8.2, 8.1; IR (neat) 2960,
2922, 1775, 1700, 1461, 1382, 1261 cm-1; high-resolution mass
spectrum, calcd for C21H36NO6 (M - OCH3)+ 398.2542, found
398.2493. Anal. Calcd for C22H39NO7: C, 61.52; H, 9.15; N,
3.26. Found: C, 61.34; H, 9.28; N, 3.11.
(2′E,4S,4′R,5′S,6′R)-3-[5′-[(Meth oxym eth yl)oxy]-6′,7′-O-
isop en t ylid en e-4′-m et h ylh ep t -2′-en oyl]-4-isop r op yl-1,3-
oxa zolid in -2-on e (13). A -78 °C solution of homoallylic ether
11 (1.7 g, 6.6 mmol) in 1:1 MeOH-CH2Cl2 (20 mL) was treated
with a stream of ozone in O2 until the solution turned blue.
The solution was then purged with nitrogen for 5 min.
Triphenylphosphine (8.4 g, 32 mmol) was added to the reaction
mixture, and the solution was allowed to warm to room
temperature and stir overnight. The solvents were removed
in vacuo. Purification of the crude product by silica gel
chromatography (9:1 hexane-Et2O) provided 1.4 g (82%) of
the corresponding aldehyde as a colorless oil: Rf 0.38 (4:1
hexanes-ethyl acetate); [R]20 -6.7° (c 1.0, toluene); 1H NMR
D
(400 MHz, CDCl3) δ 9.69 (s, 1 H), 4.69 (A of AB, J AB ) 7.0 Hz,
1 H), 4.66 (B of AB, J AB ) 7.0 Hz, 1 H), 4.14 (m, 2 H), 3.98 (m,
1 H), 3.80 (m, 1 H), 3.36 (s, 3 H), 2.76 (m, 1 H), 1.59 (m, 4 H),
1.21 (d, J ) 7.0 Hz, 3 H), 0.86 (t, J ) 7.5 Hz, 3 H), 0.85 (t, J
) 7.5 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 201.8, 113.5,
96.5, 79.3, 74.8, 68.0, 55.8, 48.6, 29.5, 28.6, 8.8, 8.1, 8.0; IR
(neat) 2970, 1725 cm-1; high-resolution mass spectrum, calcd
for C13H25O5 (M+ + 1) 261.1702, found 261.1712.
To a solution of flame-dried LiCl (5.78 g, 136 mmol) in CH3-
CN (60 mL) were added the phosphonate reagent 1225 (5.0 g,
16.2 mmol) and i-Pr2NEt (6.03 mL, 34.6 mmol). The solution
stirred at room temperature for 1 h; then a solution of the
above aldehyde (3.6 g, 13.8 mmol; combined from several runs)
in 20 mL of CH3CN was added. The resulting solution was
stirred at room temperature for 2 d. The solution was
quenched with pH 7 phosphate buffer (100 mL) and diluted

Formal Total Synthesis of (+)-Tetronolide
J . Org. Chem., Vol. 62, No. 25, 1997 8715
(2′S,4S,4′S,5′S)-3-[5′-[(Meth oxym eth yl)oxy]-7′,7′-dibr om o-
2′,4′-d im eth ylh ep t-6′-en oyl]-4-isop r op yl-1,3-oxa zolid in -2-
on e (16). A mixture of oxazolidinone 15 (1.15 g, 2.68 mmol)
in 60% formic acid-MeOH (20 mL) was stirred at room
temperature for 2 h. The solvent was then removed in vacuo,
and the resulting oil was run through a column of silica gel
[R]20 -48.1° (c 1.0, toluene); 1H NMR (400 MHz, CDCl3) δ
D
9.61 (d, J ) 1.6 Hz, 1 H), 6.35 (d, J ) 8.9 Hz, 1 H), 4.63 (A of
AB, J AB ) 6.7 Hz, 1 H), 4.52 (B of AB, J BA ) 6.7 Hz, 1 H), 4.14
(dd, J ) 8.8, 6.4 Hz, 1 H), 3.37 (s, 3 H), 2.45 (m, 1 H), 1.84 (m,
1 H), 1.56 (m, 2 H), 1.09 (d, J ) 7.0 Hz, 3 H), 0.99 (d, J ) 7.0
Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 204.6, 137.4, 94.5, 92.5,
80.1, 55.9, 44.1, 34.9, 32.7, 14.9, 13.1; IR (neat) 2960, 2935,
1750, 1622, 1459 cm-1; high-resolution mass spectrum, calcd
for C11H19O379Br81Br (M+ + 1) 358.9680, found 358.9652.
(1:1 hexanes-EtOAc) to yield 750 mg (77%) of the diol as a
1
colorless oil: Rf 0.65 (EtOAc); [R]20 +3.7° (c 0.1, CDCl3); H
D
NMR (400 MHz, CDCl3) δ 4.72 (A of AB, J AB ) 6.7 Hz, 1 H),
4.59 (B of AB, J BA ) 6.7 Hz, 1 H), 4.42 (m, 1 H), 4.26 (m, 1 H),
4.19 (dd, J ) 9.1, 3.2 Hz, 1 H), 3.85 (m, 1 H), 3.69 (m, 3 H),
3.42 (s, 3 H), 3.35 (m, 1 H), 2.90 (br s, 2 H), 2.32 (m, 1 H),
1.82-1.48 (m, 3 H), 1.18 (d, J ) 6.7 Hz, 3 H), 0.95 (d, J ) 6.7
Hz, 3 H), 0.90 (d, J ) 7.2 Hz, 3 H), 0.86 (d, J ) 6.9 Hz, 3 H);
13C NMR (100 MHz, CDCl3) δ 177.4, 153.6, 99.0, 87.9, 71.1,
63.2, 63.1, 58.5, 56.1, 35.6, 35.4, 32.6, 28.4, 17.9, 17.4, 16.4,
14.7; IR (neat) 3450, 1770, 1695 cm-1; high-resolution mass
spectrum, calcd for C16H28NO6 (M+ - OCH3) 330.1916, found
330.1904. Anal. Calcd for C17H31NO7: C, 56.49; H, 8.65; N,
3.88. Found: C, 56.52; H, 8.44; N, 3.61.
A solution of the above aldehyde (125 mg, 0.35 mmol) and
(carbethoxyethylidene)triphenylphosphorane (500 mg, 1.4 mmol)
in 7 mL of toluene was heated to 60 °C for 30 h. The solution
was cooled, and the solvents were removed in vacuo. Purifica-
tion of the crude product by silica gel chromatography (9:1
hexanes-EtOAc) provided 135 mg (88%) of enoate 17: Rf 0.20
1
(4:1 hexanes-EtOAc); [R]20 -10.3° (c 0.7, CDCl3); H NMR
D
(400 MHz, CDCl3) δ 6.45 (dq, J ) 10.0, 1.2 Hz, 1 H), 6.38 (d,
J ) 9.2 Hz, 1 H), 4.65 (A of AB, J AB ) 6.8 Hz, 1 H), 4.52 (B of
AB, J BA ) 6.8 Hz, 1 H), 4.10-4.28 (m, 3 H), 3.38 (s, 3 H), 2.61
(m, 1 H), 1.86 (s, 3 H), 1.80 (m, 1 H), 1.50 (m, 1 H), 1.30 (m, 3
H), 1.17 (m, 1 H), 0.98 (d, J ) 6.8 Hz, 3 H), 0.95 (d, J ) 7.2
Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 168.4, 147.6, 137.0,
126.3, 94.4, 92.3, 79.4, 60.5, 55.7, 39.4, 35.3, 31.0, 19.6, 15.4,
To a slurry of KIO4 (834 mg, 3.62 mmol) and KHCO3 (33
mg, 0.33 mmol) in 25% aqueous THF (33 mL) at 0 °C was
added a solution of the above diol (750 mg, 2.08 mmol) in 5
mL of THF. The reaction mixture was allowed to warm to
room temperature and stirred overnight. The mixture was
filtered through Celite. The aqueous layer was separated and
washed with EtOAc (5 × 5 mL). The combined organic
extracts were dried (MgSO4) and concentrated in vacuo.
Purification of the resulting oil by silica gel chromatography
(9:1 hexanes-EtOAc) provided 0.60 g (88%) of the desired
14.3, 12.5; IR (neat) 2959, 2910, 1720, 1645, 1460, 1362 cm-1
;
high-resolution mass spectrum (FAB), calcd for C16H26O479Br2-
Na (M + Na)+ 463.0094, found 463.0042.
(E ,Z,E ,E )-(4S,5S,6S,7S)-7-[(Me t h oxym e t h yl)oxy]-14-
[(t er t -b u t yld im e t h ylsilyl)oxy]-9-b r om o-2,4,6,12-t e t r a -
m eth yltetr a d eca -2,8,10,12-tetr a en oa te (19). A solution of
dibromoolefin 17 (250 mg, 0.57 mmol) and Pd(PPh3)4 (50 mg,
0.04 mmol) in degassed THF (4 mL) was stirred at room
temperature for 30 min before being transferred to a degassed
solution of vinylboronic acid 1819 (300 mg, 2.1 mmol) in 1.5
mL of a 0.53 M aqueous thallium hydroxide (TlOH) solution
(0.79 mmol). The reaction mixture was stirred for 1 h at
ambient temperature; then the solution was diluted with
EtOAc and filtered through Celite. The aqueous layer was
separated and washed with EtOAc (3 × 15 mL). The combined
organic extracts were dried (MgSO4) and concentrated in
vacuo. Purification of the crude product by silica gel chroma-
tography (4:1 hexanes-EtOAc) provided 170 mg (65%) of
tetraenoate alcohol. When performed on a smaller scale (ca.
aldehyde as a colorless oil: Rf 0.62 (4:1 hexanes-EtOAc); [R]20
D
+119.3° (c 1.0, acetone); 1H NMR (400 MHz, CDCl3) δ 9.65 (d,
J ) 1.9 Hz, 1 H), 4.72 (A of AB, J AB ) 6.7 Hz, 1 H), 4.65 (B of
AB, J BA ) 6.7 Hz, 1 H), 4.42 (m, 1 H), 4.29 (m, 1 H), 4.19 (dd,
J ) 8.8, 3.0 Hz, 1 H), 3.76 (m, 1 H), 3.69 (dd, J ) 4.5, 1.8 Hz,
1 H), 3.40 (s, 3 H), 2.30 (m, 1 H), 2.07 (m, 1 H), 1.69 (m, 1 H),
1.55 (m, 1 H), 1.17 (d, J ) 6.7 Hz, 3 H), 1.08 (d, J ) 6.7 Hz, 3
H), 0.90 (d, J ) 6.9 Hz, 3 H), 0.86 (d, J ) 6.9 Hz, 3 H); 13C
NMR (100 MHz, CDCl3) δ 203.8, 176.8, 153.7, 97.3, 86.5, 63.4,
58.6, 56.1, 35.5, 34.9, 32.9, 28.5, 17.9, 17.7, 16.4, 14.8; IR (neat)
2961, 1780, 1758, 1692 cm-1; high-resolution mass spectrum,
calcd for C15H26NO5 (M+ - CHO) 300.1811, found 300.1804.
A solution of triphenylphosphine (5.05 g, 19.3 mmol) and
CBr4 (3.19 g, 9.62 mmol) in CH2Cl2 (12 mL) was stirred at 0
°C for 30 min. A solution of the aldehyde generated above
(434 mg, 1.32 mmol) in 3 mL of CH2Cl2 was slowly added to
the reaction mixture. The mixture was stirred at 0 °C for 10
min and then was diluted with EtOAc. The solvents were
removed in vacuo, and the resulting crude product was purified
via silica gel chromatography (4:1 hexane-EtOAc) to yield 453
mg (71%) of the desired dibromoolefin 16 as a colorless oil: Rf
50 mg of 17), the yield of this intermediate was 91%: Rf 0.10
1
(5:1 hexanes-EtOAc); [R]20 -6.6° (c 0.6, CH3CN); H NMR
D
(400 MHz, CDCl3) δ 6.80 (d, J ) 14.8 Hz, 1 H), 6.46 (dq, J )
10.0, 1.6 Hz, 1 H), 6.22 (d, J ) 14.8 Hz, 1 H), 5.90 (d, J ) 8.8
Hz, 1 H), 5.84 (t, J ) 6.8 Hz, 1 H), 4.63 (A of AB, J AB ) 6.8
Hz, 1 H), 4.53 (dd, J ) 8.8, 5.6 Hz, 1 H), 4.50 (B of AB, J BA
)
6.8 Hz, 1 H), 4.32 (d, J ) 6.8 Hz, 2 H), 4.18 (q, J ) 7.2 Hz, 2
H), 3.40 (s, 3 H), 2.65 (m, 1 H), 1.86 (s, 3 H), 1.82 (s, 3 H), 1.80
(m, 1 H), 1.58 (m, 1 H), 1.30 (t, J ) 7.2 Hz, 3 H), 1.20 (m, 1 H),
0.99 (m, 6 H); 13C NMR (100 MHz, CDCl3) δ 168.4, 147.8, 138.7,
135.0, 133.4, 131.7, 128.0, 126.7, 126.1, 94.3, 78.6, 60.4, 59.4,
55.6, 39.4, 35.7, 31.0, 19.5, 15.6, 14.2, 12.9, 12.4; IR (CDCl3)
3420, 1700, 1642 cm -1; high-resolution mass spectrum, calcd
for C22H34O479Br (M+ - OH) 441.1640, found 441.1674.
0.51 (4:1 hexanes-EtOAc); [R]20 +15.0° (c 9.5, CDCl3); 1H
D
NMR (400 MHz, CDCl3) δ 6.37 (d, J ) 8.9 Hz, 1 H), 4.64 (A of
AB, J AB ) 6.7 Hz, 1 H), 4.52 (B of AB, J BA ) 6.7 Hz, 1 H), 4.45
(m, 1 H), 4.27 (m, 1 H), 4.20 (dd, J ) 9.1, 2.9 Hz, 1 H), 4.12
(dd, J ) 8.6, 6.1 Hz, 1 H), 3.90 (m, 1 H), 3.38 (s, 3 H), 2.35 (m,
1 H), 1.80 (m, 1 H), 1.54-1.70 (m, 2 H), 1.19 (d, J ) 6.7 Hz, 3
H), 0.91 (m, 9 H); 13C NMR (100 MHz, CDCl3) δ 177.2, 153.6,
137.8, 94.7, 92.1, 80.4, 63.2, 58.5, 55.9, 35.5, 35.5, 35.2, 28.4,
18.0, 17.6, 15.4, 14.7; IR (CDCl3) 1775, 1695 cm-1; high-
A solution of tetraenoate alcohol (400 mg, 0.87 mmol),
imidazole (350 mg, 5.2 mmol), and tert-butyldimethylchlorosi-
lane (390 mg, 2.6 mmol) in DMF (17.4 mL) was stirred under
N2 at room temperature for 30 min, at which point TLC
analysis showed the reaction to be complete. The reaction
mixture was diluted with 1:1 H2O-brine and extracted with
EtOAc (3 × 50 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo. This produced
a yellow oil which was purified by silica gel chromatography
(12:1 hexane/EtOAc) to yield 465 mg (93%) of 19: [R]20D -2.7°
(c 0.9, CDCl3); 1H NMR (400 MHz, CDCl3) δ 6.67 (d, J ) 15.2
Hz, 1 H), 6.55 (dd, J ) 10.0, 1.6 Hz, 1 H), 6.17 (d, J ) 14.8 Hz,
1 H), 5.87 (d, J ) 9.2 Hz, 1 H), 5.77 (t, J ) 6.4 Hz, 1 H), 4.63
(A of AB, J AB ) 6.8 Hz, 1 H), 4.54 (m, 1 H), 4.50 (B of AB, J BA
) 6.8 Hz, 1 H), 4.35 (d, J ) 6.8 Hz, 2 H), 4.18 (q, J ) 7.2 Hz,
2 H), 3.39 (s, 3 H), 2.69 (m, 1 H), 1.87 (s, 3 H), 1.79 (s, 3 H),
1.53 (m, 1 H), 1.29 (t, J ) 7.2 Hz, 3 H), 1.27 (m, 1 H), 1.17 (m,
1 H), 0.97 (d, J ) 6.8 Hz, 3 H), 0.94 (d, J ) 7.2 Hz, 3 H), 0.90
(s, 9 H), 0.10 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 168.4,
147.9, 139.1, 135.2, 133.0, 131.2, 128.3, 126.2, 125.9, 94.3, 78.6,
76.7, 60.4, 60.3, 55.7, 39.5, 35.7, 31.0, 25.9, 19.6, 18.4, 15.6,
resolution mass spectrum, calcd for C17H28NO579Br81Br (M+
1) 486.0313, found 486.0337. Anal. Calcd for C17H27NO5Br2:
C, 42.08; H, 5.61; N, 2.89. Found: C, 42.20; H, 5.76; N, 2.87.
+
E t h yl (E)-(4S,6S,7S)-7-[(Met h oxym et h yl)oxy]-8,8-d i-
br om o-1,3,5-tr im eth yln on a -2,8-d ien oa te (17). To a -78 °C
solution of 16 (1.6 g, 3.3 mmol) in CH2Cl2 (15 mL) was slowly
added a -78 °C solution of DIBAL (8.8 mL, 1.0 M in CH2Cl2,
8.8 mmol). The reaction mixture was stirred for 1 h and then
was quenched by addition of MeOH (4 mL) and warmed to
room temperature. A saturated solution of Rochelle’s salt (10
mL) was added, and the mixture was stirred for 30 min. The
white slurry was then filtered through a fritted glass funnel.
The aqueous layer was washed (5 × 30 mL) with EtOAc; then
the combined organic extracts were dried (MgSO4) and con-
centrated in vacuo. Purification of the crude product by silica
gel chromatography (6:1 hexanes-EtOAc) provided 912 mg
(77%) of the desired aldehyde: Rf 0.45 (4:1 hexanes-EtOAc);

8716 J . Org. Chem., Vol. 62, No. 25, 1997
Roush et al.
14.3, 13.0, 12.5, -5.1; IR (benzene-d6) 2950, 2920, 1705, 1645,
1620, 1435 cm-1; high-resolution mass spectrum, calcd for
C24H40O579BrSi (M+ - t-Bu) 515.1828, found 519.1858.
mmol) and 5% Na(Hg) (425 mg) in MeOH (2 mL) was stirred
overnight at room temperature. The reaction mixture was
decanted away from insoluble material, and then K2CO3 (2 mg)
was added. The resulting solution was stirred for 2 h at
ambient temperature. The solution was diluted with EtOAc
(5 mL) and extracted with H2O (2 × 2 mL). The aqueous
extracts were washed with EtOAc (3 × 2 mL), and the
combined organic extracts were dried (MgSO4), filtered, and
concentrated in vacuo. Purification of the crude product by
silica gel chromatography (12:1 hexanes-EtOAc) provided
(E ,Z,E ,E )-(4S,5S,6S,7S)-7-[(Me t h oxym e t h yl)oxy]-14-
[(t er t -b u t yld im e t h ylsilyl)oxy]-9-b r om o-2,4,6,12-t e t r a -
m eth yltetr a d eca -2,8,10,12-tetr a en -1-a l (20). A solution of
tetraenoate 19 (421 mg, 0.73 mmol) in 5 mL of CH2Cl2 was
cooled to -78 °C. DIBAL (2.9 mL, 1.0 M in CH2Cl2) was added
slowly, and the resulting solution was stirred for 1 h. The
solution was then quenched with MeOH and was allowed to
stand at room temperature for 30 min. The solution was
diluted with a saturated solution of Rochelle’s salt (2 mL), and
the layers were separated. The aqueous layer was extracted
with EtOAc (3 × 5 mL), and then the combined organic
extracts were dried (MgSO4) and concentrated in vacuo to give
aldehyde 4 (16 mg, 82%) as a colorless oil: Rf 0.50 (4:1
1
hexanes-EtOAc); [R]20 -100° (c 0.6, CHCl3); H NMR (400
D
MHz, CDCl3) δ 9.43 (s, 1 H), 6.01 (d, J ) 10.2 Hz, 1 H), 5.44
(m, 2 H), 4.77 (AB, J AB ) 6.7 Hz, 1 H), 4.65 (B of AB, J AB
)
6.7 Hz, 1 H), 4.20 (m, 2 H), 3.45 (dd, J ) 11.0, 5.1 Hz, 1 H),
3.42 (s, 3 H), 2.37 (bs, 1 H), 2.31 (m, 1 H), 2.13 (t, J ) 9.5 Hz,
1 H), 1.73-1.53 (m, 6 H) 1.43 (m, 1 H), 1.09 (s, 3 H), 1.02 (d,
J ) 7.2 Hz, 3 H), 0.89 (s, 9 H), 0.69 (d, J ) 6.1 Hz, 3 H), 0.06
(s, 6 H); 13C NMR (100 MHz, CDCl3) δ 208.9, 133.3, 132.3,
126.8, 126.2, 95.4, 80.7, 60.4, 55.9, 54.5, 50.9, 43.9, 41.6, 36.0,
31.7, 28.5, 25.9, 21.0, 18.3, 15.2, 13.1, -5.0, -5.1; IR (neat)
2979, 2948, 2910, 2875, 1725, 1540, 1391, 1265, 1155, 1111,
1050 cm-1; high-resolution mass spectrum, calcd for C26H47O4-
Si (M+ + 1) 451.3244, found 451.3231.
the crude allylic alcohol: Rf 0.35 (4:1 hexanes-EtOAc); [R]20
D
-34.0° (c 2.7, CDCl3); 1H NMR (400 MHz, CDCl3) δ 6.67 (d, J
) 14.8 Hz, 1 H), 6.18 (d, J ) 14.8 Hz, 1 H), 5.89 (d, J ) 8.8
Hz, 1 H), 5.76 (t, J ) 6.0 Hz, 1 H), 5.20 (d, J ) 9.6 Hz, 1 H),
4.64 (A of AB, J AB ) 6.8 Hz, 1 H), 4.55 (dd, J ) 9.2, 5.6 Hz, 1
H), 4.52 (B of AB, J BA ) 6.8 Hz, 1 H), 4.36 (d, J ) 6.0 Hz, 2
H), 3.99 (s, 2 H), 3.37 (s, 3 H), 2.58 (m, 1 H), 1.87 (m, 1 H),
1.79 (s, 3 H), 1.72 (s, 3 H), 1.50 (m, 1 H), 1.42 (m, 1 H), 1.10
(m, 1 H), 0.84-0.96 (m, 15 H), 0.07 (s, 6 H); 13C NMR (100
MHz, CDCl3) δ 139.0, 135.1, 133.1, 132.9, 132.7, 131.1, 128.2,
125.9, 94.5, 78.6, 69.0, 60.3, 55.6, 40.1, 35.5, 29.6, 25.9, 20.6,
18.3, 15.5, 13.8, 13.0, -5.1; IR (neat) 3430 (br), 2960, 2930,
The identity of synthetic 4 was verified by comparison with
an authentic sample of 4 ([R]23D -101.2° (c 2.70, CHCl3)) kindly
provided by Professor Yoshii.11
1460, 1380 cm-1
.
2,4-Hexa d iyn e-1,6-d iol. To a solution of 4.10 g (41 mmol)
of cuprous chloride in 300 mL of acetone was added 6.3 mL of
TMEDA (42 mmol). Oxygen was bubbled through the solution
for 30 min; then propargyl alcohol (50 mL, 0.86 mol) was added
dropwise at 35-40 °C. The reaction mixture was stirred at
room temperature overnight (20 h) and then was diluted with
Et2O (500 mL) and washed sequentially with saturated NH4-
Cl and brine. The organic extracts were dried over MgSO4,
filtered, and concentrated to give a yellow white solid. The
crude product was recrystallized from ethyl acetate-benzene
to give 42.2 g (89%) of the known65-67 diyne as a white solid:
mp 113-114 °C; lit.67 mp 113-115 °C; 1H NMR (400 MHz,
acetone-d6) δ 4.44 (t, J ) 6.0 Hz, 2 H), 4.30 (d, J ) 6.0 Hz, 4
H).
The crude allylic alcohol from the preceding experiment
(theoretically 0.74 mmol) was added to a solution of TPAP (12
mg, 0.036 mmol), N-methylmorpholine N-oxide (129 mg, 1.09
mmol), and 4 Å molecular sieves (366 mg) in 4 mL of CH2Cl2.
The solution was stirred for 10 min and then was concentrated
in vacuo. Purification of the crude product by silica gel
chromatography provided 288 mg (74%) of tetraenal 20 as a
colorless oil: [R]20D -26.6° (c 0.01, CDCl3); 1H NMR (400 MHz,
CDCl3) δ 9.40 (s, 1 H), 6.68 (d, J ) 15.2 Hz, 1 H), 6.28 (dd, J
) 1.2, 10.0 Hz, 1 H), 6.18 (d, J ) 14.8 Hz, 1 H), 5.87 (d, J )
8.8 Hz, 1 H), 5.77 (t, 6.0 Hz, 1 H), 4.62 (A of AB, J AB ) 6.8, 1
H), 4.55 (dd, J ) 8.8, 5.6, 1 H), 4.50 (B of AB, J BA ) 6.8, 1 H),
4.35, (d, J ) 6.0 Hz, 2 H), 3.35 (s, 3 H), 2.90 (m, 1 H), 1.79 (m,
6 H), 1.60 (m, 2 H), 1.20 (m, 1 H), 1.04 (d, J ) 6.8 Hz, 3 H),
0.95 (d, J ) 6.5 Hz, 3 H), 0.84 (s, 9 H), 0.05 (s, 6 H); 13C NMR
(100 MHz, CDCl3) δ 195.6, 160.4, 139.2, 137.7, 135.3, 132.9,
130.9, 128.5, 125.7, 94.3, 78.6, 77.1, 60.3, 55.7, 39.4, 35.7, 31.4,
25.9, 19.4, 15.6, 13.0, 9.3, -5.1; IR (CDCl3) 3020, 3000, 2955,
2911, 1759 cm-1; high-resolution mass spectrum, calcd for
C26H46O479BrSi (M+ + 1) 529.2348, found 529.2351.
(2E,4E)-2,4-Hexa d ien e-1,6-d iol. To a 0 °C solution of Red-
Al (53 mL of a 3.4 M solution in toluene, 180 mmol) in 100
mL of THF was added 3.3 g (30 mmol) of the above diyne in
200 mL of THF. The reaction mixture was stirred at room
temperature for 12 h and then was cooled to 0 °C and
transferred via cannula to a flask containing 300 mL of
aqueous saturated Rochelle’s salt. The aqueous layer was
extracted with ethyl acetate. The combined organic extracts
were dried over MgSO4, filtered, and concentrated to give a
yellow solid. The crude product was recrystallized from ethyl
acetate/benzene to give 3.18 g (93%) of the known diene:38,65
mp 104-105 °C; lit.65 mp 105.5-106.5 °C; 1H NMR (400 MHz,
acetone-d6) δ 6.27 (m, 2H), 5.81 (m, 2 H), 4.11 (t, J ) 5.3 Hz,
4 H), 3.80 (t, J ) 5.3 Hz, 2 H); high-resolution mass spectrum,
calcd for C6H10O2 114.0680, found 114.0678.
2â-[(E)-3-[(ter t-Bu tyld im eth ylsilyl)oxy]-1-m eth ylp r op -
1-en yl]-5r-[(m et h oxym et h yl)oxy]-4-b r om o-1r,6r,8â-t r i-
m et h yl-1,2,4a r,5,6,7r,8,8a â-oct a h yd r on a p h t h a len e-1â-
ca r boxa ld eh yd e (21). A solution of tetraenal 20 (30 mg,
0.057 mmol), one crystal of BHT, and one drop of bis-
(trimethylsilyl)acetamide in degassed toluene (2 mL) was
heated to 130 °C in a sealed tube for 12 h. The tube was
cooled; then the contents were removed and concentrated in
vacuo. 1H NMR analysis of the crude product failed to reveal
the presence of any cycloadducts other than 21. Purification
of the crude product by silica gel chromatography (12:1
hexanes-EtOAc) provided 27 mg (90%) of 21 as a colorless
1,6-Bis[(ter t-b u t yld im et h ylsilyl)oxy]-(2E,4E)-h exa d i-
en e (24). To a solution of (2E,4E)-2,4-hexadiene-1,6-diol (2.00
g, 17.5 mmol) in DMF (40 mL) at room temperature were
added imidazole (3.56 g, 52.3 mmol) and tert-butyldimethylsilyl
chloride (5.80 g, 38.5 mmol). This solution was stirred for 48
h and then was diluted with 1:1 Et2O-hexane (400 mL) and
washed with 1:1 H2O-brine (200 mL). The organic extracts
were dried (MgSO4) and concentrated in vacuo. The crude
product was purified via silica gel chromatography (19:1
hexane/Et2O) to yield 5.72 g (95%) of the known39 diene 24 as
a white solid: 1H NMR (400 MHz, CDCl3) δ 6.20 (m, 2 H),
5.70 (m, 2 H), 4.18 (d, J ) 4.4 Hz, 4 H), 0.87 (s, 18 H), 0.04 (s,
12 H); 13C NMR (100 MHz, CDCl3) δ 132.1, 129.2, 63.4, 25.9,
18.3, -5.2; IR (CHCl3) 3000, 2955, 2930, 2859, 1471, 1452
oil: Rf 0.76 (4:1 hexanes-ethyl acetate); [R]20 -19.4° (c 0.4,
D
1
CDCl3); H NMR (400 MHz, toluene-d8) δ 9.33 (s, 1 H), 5.82
(dq, J ) 6.0, 0.8 Hz, 1 H), 5.50 (t, J ) 6.0 Hz, 1 H), 4.81 (A of
AB, J AB ) 6.8 Hz, 1 H), 4.67 (B of AB, J BA ) 6.8 Hz, 1 H),
4.04-4.16, (m, 2 H), 3.80 (dd, J ) 9.6, 4.4 Hz, 1 H), 3.28 (s, 3
H), 2.40 (m, 1 H), 2.10 (m, 2 H) 1.80 (m, 1 H), 1.40 (s, 3 H),
1.25 (m, 2 H), 1.10 (m, 1 H), 1.07 (m, 6 H), 0.98 (s, 9 H), 0.43
(d, J ) 6.8 Hz, 3 H), 0.05 (s, 6 H); 13C NMR (100 MHz, toluene-
d8) δ 205.5, 133.1, 131.7, 124.0, 96.9, 84.7, 82.7, 61.4, 60.0,
56.8, 55.3, 50.8, 47.0, 43.8, 40.4, 33.3, 29.7, 25.7, 18.2, 15.0,
13.8, -5.3; IR (CDCl3) 3019, 2950, 2920, 1728, 1537 cm-1; high-
resolution mass spectrum, calcd for C22H3679BrO4Si (M+ - t-Bu)
471.1566, found 471.1547.
(65) Bates, E. B.; J ones, E. R. H.; Whiting, M. C. J . Chem. Soc. 1954,
1854.
(66) Machinek, R.; Lu¨ttke, W. Synthesis 1975, 434, 255.
(67) Takahashi, A.; Endo, T.; Nozoe, S. Chem. Pharm. Bull. 1992,
40, 3181.
2â-[(E)-3-([ter t-Bu tyld im eth ylsilyl)oxy]-1-m eth ylp r op -
1-e n yl]-5r-[(m e t h oxym e t h yl)oxy]-1r,6r,8â-t r im e t h yl-
1,2,4a r,5,6,7r,8,8a â-octa h yd r on a p h th a len e-1â-ca r boxa l-
d eh yd e (4). A solution of hydronaphthalene 21 (23 mg, 0.043

Formal Total Synthesis of (+)-Tetronolide
J . Org. Chem., Vol. 62, No. 25, 1997 8717
cm-1; high-resolution mass spectrum calcd for C14H29O2Si2 (M+
- C4H9) 285.1706, found 285.1689.
to yield the 532 mg (88%) of the desired diol: [R]23 +14.8 (c
D
1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 5.84 (dt, J ) 10.2,
3.2 Hz, 1 H), 5.46 (m, J ) 4.5 Hz, 2 H), 3.75 (dd, J ) 11.2, 4.8
Hz, 1 H), 3.67 (m, 3 H), 2.84 (m, 1 H), 2.66 (br s, 1 H), 2.13
(dd, J ) 14.0, 7.6 Hz, 1 H), 1.90 (m, 3 H), 1.78 (m, 4 H), 1.67
(m, 2 H), 1.16 (m, 5 H); IR (CHCl3) 3470, 1785 cm-1; high-
resolution mass spectrum calcd for C16H23O4 (M+ - OH)
279.1596, found 279.1612.
(2′R,3S,4S,6R)-Sp ir o[3,6-b is[[(ter t-b u t yld im et h ylsil-
yl)oxy]m eth yl]-1-cycloh exen e-[4,5′]-2′-cycloh exyl-1′,3′-d i-
oxola n -4′-on e] (23a ) (Diels-Ald er R ea ct ion of 24 a n d
25a ). A Carius tube was soaked in a 2-propanol-KOH bath
for 12 h. The tube was emptied, washed repeatedly with
distilled water, and dried in a 120 °C oven. The tube was then
treated with 250 µL of bis(trimethylsilyl)acetamide and sealed.
The contents were heated to reflux for 30 min; then the tube
was cooled to room temperature and rinsed with hexanes. A
solution of diene 24 (3.00 g, 8.75 mmol) and dienophile 25a 41
(402 mg, 2.21 mmol) in trichloroethylene (2.2 mL) was then
added to the Carius tube. Two crystals of BHT were added,
and the solution was degassed with a stream of nitrogen. The
tube was sealed and immersed in a 150 °C oil bath for 42 h.
The tube was then cooled, and the contents were concentrated
in vacuo to yield a crude solid. This material was purified by
silica gel chromatography (100% hexane-19:1 hexane/Et2O)
to yield 408 mg (35%, based on 25a ) of the desired exo adduct
23a and 78 mg (6.7%) of the endo isomer 26; 2.56 g (85%) of
To a solution of the above diol (532 mg, 1.80 mmol) in MeOH
(16 mL) was added K2CO3 (500 mg, 3.6 mmol). The solution
was stirred at room temperature for 1 h and then was diluted
with ethyl acetate and washed with NH4Cl (aq). The aqueous
layer was extracted with ethyl acetate, and the combined
organic extracts were further washed with brine, dried (Mg-
SO4), and concentrated in vacuo. The crude oil was then
triturated with hexane to yield 358 mg (91%) of 28 as a white
1
solid: mp 95-97 °C; [R]24 +23.2° (c 1.12, CHCl3); H NMR
D
(400 MHz, CDCl3) δ 5.74 (d, J ) 10.0 Hz, 1 H), 5.58 (d, J )
10.4 Hz, 1 H), 3.75 (s, 3 H), 3.70 (m, 3 H), 3.57 (m, 1 H), 2.83
(m, 1 H), 2.52 (m, 1 H), 2.34 (m, 1 H), 1.87 (d, J ) 14.4 Hz, 1
H); 13C NMR (100 MHz, CDCl3) δ 176.8, 128.4, 126.9, 77.1,
73.6, 65.5, 63.1, 52.8, 42.8, 36.1; IR (CHCl3) 3400 (br), 1723
cm-1; high-resolution mass spectrum, calcd for C10H17O5 (M+
+ 1) 217.1076, found 217.1092. Anal. Calcd for C10H16O5: C,
55.55; H, 7.46. Found: C, 55.40; H, 7.36.
diene 24 was also recovered.
1
Da ta for 23a : [R]23 -13.9° (c 1.0, CHCl3); H NMR (400
D
MHz, CDCl3) δ 5.82 (ddd, J ) 10.0, 4.0, 3.0 Hz, 1 H), 5.35 (d,
J ) 4.8 Hz, 1H), 5.31 (dt, J ) 10.4, 2.0 Hz, 1 H), 3.60 (m, 4 H),
2.80 (m, 1 H), 2.50 (m, 1 H), 1.97 (m, 2 H), 1.65 (m, 5 H), 1.15
(m, 6 H), 0.86 (s, 18 H), 0.01 (s, 12 H); 13C NMR (100 MHz,
CDCl3) δ 175.9, 129.1, 123.9, 106.9, 65.8, 63.0, 44.0, 42.2, 37.1,
32.2, 26.3, 26.2, 26.0, 25.9, 25.8, 25.6, 18.2, 18.1, -5.4, -5.7;
IR (CHCl3) 1785 cm-1; high-resolution mass spectrum, calcd
for C24H43O5Si2 (M+ - C4H9) 467.2649, found 467.2680. Anal.
Calcd for C28H52O5Si2: C, 64.07; H, 9.99. Found: C, 64.26; H,
10.26.
Meth yl (2R,4a S,7R,8a R)-7-(Hyd r oxym eth yl)-2-p h en yl-
4,4a ,7,8-tetr a h yd r oben zo[1,3]d ioxin e-8a -ca r boxyla te (29)
a n d Meth yl (2S,4a S,7R,8a R)-7-(Hyd r oxym eth yl)-2-p h en -
yl-4,4a ,7,8-t et r a h yd r ob en zo[1,3]d ioxin e-8a -ca r b oxyla t e
(30). To a solution of triol 28 (325 mg, 1.50 mmol) in
benzaldehyde (6.6 mL) was added a 1 M solution of ZnCl2 in
Et2O (1.8 mL, 1.8 mmol). The solution was stirred at room
temperature for 1 h and then was diluted with ethyl acetate,
washed with aqueous NaHCO3 and brine, dried (Na2SO4), and
concentrated in vacuo. The crude mixture was then purified
via silica gel chromatography (100% Et2O) to yield 294 mg
(64%) of the R-isomer (29; kinetic) and 41 mg (9%) of the
â-isomer (30; thermodynamic).
Da ta for 26: [R]23 48.6° (c 1.03, CHCl3); 1H NMR (400
D
MHz, CDCl3) δ 5.81 (d, J ) 10.4 Hz, 1 H), 5.63 (ddd, J ) 10.0,
3.6, 2.0 Hz, 1 H), 5.33 (d, J ) 4.0 Hz, 1 H), 3.64 (dd, J ) 10.0,
7.2 Hz, 1 H), 3.50 (m, 3 H), 2.50 (m, 2 H), 1.79 (m, 6 H), 1.30
(m, 7 H), 0.90 (s, 18 H), 0.00 (s, 12 H); IR (neat) 1789 cm-1
;
high-resolution mass spectrum, calcd for C28H53O5Si2 (M+
1) 525.3431, found 525.3449.
+
Da ta for 29: [R]20D +14.4° (c 1, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.45-7.29 (m, 5 H), 5.96 (m, 1 H), 5.75 (dt, J ) 10.0,
2.0 Hz, 1 H), 5.57 (s, 1 H), 4.13 (dd, J ) 11.8, 1.4 Hz, 1 H),
4.05 (dd, J ) 11.8, 3.0 Hz, 1 H), 3.86 (s, 3 H), 3.68 (dd, J )
10.8, 5.8 Hz, 1 H), 3.60 (dd, J ) 10.8, 4.4 Hz, 1 H), 2.82 (br s,
1 H), 2.48 (m, 1 H), 2.09 (m, 2 H), 1.60 (m, 1 H); IR (CHCl3)
3450 (br), 1730 cm-1; high-resolution mass spectrum, calcd for
C17H20O5 (M+) 304.1311, found 304.1338. Anal. Calcd for
C17H20O5: C, 67.09; H, 6.62. Found: C, 66.86; H, 6.75.
Da ta for 30: [R]20D +5.6 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.52-7.33 (m, 5 H), 5.80 (s, 1 H), 5.66 (m, 2 H), 4.24
(dd, J ) 11.4, 5.8 Hz, 1 H), 3.77 (s, 3 H), 3.71 (m, 2 H), 3.63
(dd, J ) 10.4, 4.8 Hz, 1 H), 3.27 (m, 1 H), 2.50 (m, 1 H), 2.44
(dd, J ) 10.8, 10.8 Hz, 1H), 2.20 (dd, J ) 10.8, 5.2 Hz, 1 H),
1.28 (m, 1 H); IR (CHCl3) 3450 (br), 1739 cm-1; high-resolution
mass spectrum, calcd for C17H20O5 (M+) 304.1310, found
304.1324.
(3a S,6S,7a S)-7a -Hyd r oxy-6-(h yd r oxym eth yl)-3a ,6,7,7a -
tetr a h yd r o-3H-isoben zofu r a n -1-on e (27). A 0 °C solution
of K2CO3 (60 mg, 0.43 mmol) and endo cycloadduct 26 (112
mg, 0.21 mmol) in MeOH (4 mL) was stirred for 1 h. The
reaction mixture was then diluted with ethyl acetate, washed
with NH4Cl (aq) and brine, dried with MgSO4, and concen-
trated. The crude product was purified via silica gel chroma-
tography (1:9 Et2O-hexane to 1:4 Et2O-hexane) to yield 89
mg (94%) of the desired methyl ester: 1H NMR (400 MHz,
CDCl3) δ 5.78 (d, J ) 10.0 Hz, 1 H), 5.56 (ddd, J ) 10.0, 4.4,
2.4 Hz, 1 H), 3.73 (s, 3 H), 3.50 (m, 4 H), 3.05 (m, 1 H), 2.49
(m, 1 H), 2.33 (m, 1 H), 1.80 (m, 2 H), 0.93 (m, 18 H), 0.03 (m,
12 H); IR (CHCl3) 3010, 2950, 1725 cm-1; high-resolution mass
spectrum, calcd for C18H35O5Si2 (M+ - C4H9) 387.2023, found
387.1946.
A 40 °C solution of the above ester (84 mg, 0.19 mmol) in
CH3CN (2.0 mL) was then treated with Et3N‚HF (92 mg, 0.75
mmol). The solution was stirred for 15 h and then was diluted
with ethyl acetate and washed with saturated NH4Cl (aq) and
brine. The organic extracts were dried with MgSO4 and
concentrated to yield 13 mg (37%) of the known38 lactone 27
Meth yl (2R,4a S,5R,6S,7R,8a R)-5,6-Ep oxy-7-(h yd r oxy-
m eth yl)-2-p h en yl-4,4a ,7,8-tetr a h yd r oben zo[1,3]d ioxin e-
8a -ca r boxyla te (31) a n d Meth yl (2R,4a S,5S,6R,7R,8a R)-
5,6-E p oxy-7-(h yd r oxym e t h yl)-2-p h e n yl-4,4a ,7,8-t e t r a -
h yd r oben zo[1,3]-d ioxin e-8a -ca r boxyla te (32). To a solu-
tion of 29 (150 mg, 0.49 mmol) in pyridine (3 mL) was added
Ac2O (71 µL, 0.75 mmol). The solution was stirred at room
temperature for 20 h and then was diluted with ethyl acetate
and washed with 1 N HCl. The organic layer was washed with
brine, dried (MgSO4), and concentrated. The crude mixture
was purified via silica gel chromatography (5:1 Et2O-hexane)
to yield 162 mg (95%) of the desired acetate: Rf 0.89 (5:1 Et2O-
hexane); 1H NMR (400 MHz, CDCl3) δ 7.49-7.31 (m, 5 H),
5.96 (m, 1 H), 5.77 (m, 1 H), 5.55 (s, 1 H), 4.24 (dd, 1 H), 4.09
(m, 3 H), 3.86 (s, 3 H), 2.84 (m, 1 H), 2.55 (m, 1 H), 2.04-1.93
(m, 2 H), 2.03 (s, 3 H); IR (CHCl3) 1735 cm-1; high-resolution
mass spectrum, calcd for C19H22O6 (M+) 346.1416, found
346.1389.
1
as a white solid: mp 110-112 °C; lit.38 mp 112-113 °C; H
NMR (400 MHz, CDCl3) δ 5.90 (d, J ) 10.4 Hz, 1 H), 5.71 (ddd,
J ) 10.0, 3.2, 2.8 Hz, 1 H), 4.52 (t, J ) 8.8 Hz, 1 H), 3.78 (t, J
) 9.6 Hz, 1 H), 3.66 (m, 2 H), 3.01 (m, 1 H), 2.78 (m, 1 H),
2.66 (m, 1 H), 1.88 (m, 1 H), 1.60 (m, 2 H); IR (CHCl3) 3440
(br), 1755 cm-1; high-resolution mass spectrum, calcd for
C9H13O4 (M+ + 1) 185.0821, found 185.0808.
Meth yl (1S,2S,5R)-1-Hyd r oxy-2,5-bis(h yd r oxym eth yl)-
cycloh ex-3-en e-1-ca r boxyla te (28). A solution of exo cy-
cloadduct 23a (1.07 g, 2.04 mmol) and Et3N‚HF (870 mg, 7.2
mmol) in CH3CN (10 mL) was heated at 40 °C for 42 h. After
being cooled to room temperature, the solution was diluted
with ethyl acetate and washed sequentially with NH4Cl (aq)
and brine. The organic extracts were dried with Na2SO4 and
concentrated in vacuo. The crude product was then purified
via silica gel chromatography (1:1 Et2O-hexane to 100% Et2O)
To a solution of the above methyl ester obtained (162 mg,
0.47 mmol) in CHCl3 (14 mL) were added NaHCO3 (60 mg,
0.7 mmol) and 80% MCPBA (106 mg, 0.5 mmol). This solution
was stirred at room temperature for 18 h and then was diluted

8718 J . Org. Chem., Vol. 62, No. 25, 1997
Roush et al.
with ethyl acetate and washed with aqueous NaHCO3 and
brine. The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo to yield 173 mg of crude epoxide, which
was used in the next step without further purification: 1H
NMR (400 MHz, CDCl3) δ 7.48-7.36 (m, 5 H), 5.55 (s, 1 H),
4.38 (dd, 1 H), 4.28 (m, 2 H), 4.08 (m, 1 H), 3.82 (s, 3 H), 3.37
(m, 2 H), 2.54 (m, 1 H), 2.04 (s, 3 H), 2.03 (m, 1 H), 1.85 (m, 1
H), 1.23 (m, 1 H); IR (CHCl3) 1735 cm-1; high-resolution mass
spectrum, calcd for C19H22O7 (M+) 362.1366, found 362.1375.
To a 0 °C solution of the crude epoxide (173 mg, 0.47 mmol
theoretically) in MeOH (5 mL) was added K2CO3 (103 mg, 0.75
mmol). This solution was stirred at 0 °C for 1.5 h and then
was warmed to room temperature, diluted with ethyl acetate,
and washed with aqueous NH4Cl. The aqueous extracts were
extracted with additional ethyl acetate. The combined organic
extracts were washed with brine, dried (MgSO4), and concen-
trated. The crude product was purified via silica gel chroma-
tography (9:1 Et2O/hexane) to yield 112 mg (71% over three
with brine, dried (Na2SO4), and concentrated in vacuo. The
crude product was purified via silica gel chromatography (30%
ethyl acetate-hexane to 100% ethyl acetate) to yield 82 mg
(91%) of the corresponding allylic alcohol: [R]25D +29.3° (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.48-7.32 (m, 5 H), 5.89
(s, 1 H), 5.63 (s, 1 H), 4.85 (A of AB, J AB ) 7.0 Hz, 1 H), 4.80
(B of AB, J AB ) 7.0 Hz, 1 H), 4.76 (m, 1 H), 4.28 (d, J ) 12.0
Hz, 1 H), 3.99 (m, 3 H), 3.85 (s, 3 H), 3.44 (s, 3 H), 2.48 (d, J
) 18.4 Hz, 1 H), 2.34 (d, J ) 18.4 Hz, 1 H), 2.29 (dd, J ) 9.2,
1.8 Hz, 1 H), 1.74 (br s, 1 H); IR (CHCl3) 3400 (br), 1736 cm-1
;
high-resolution mass spectrum, calcd for C19H24O7 (M+)
364.1522, found 364.1506. Anal. Calcd for C19H24O7: C, 62.63;
H, 6.64. Found: C, 62.62; H, 6.57.
To solution of the above allylic alcohol (70 mg, 0.19 mmol)
in DMF (0.5 mL) were added TBDPS-Cl (65 µL, 0.25 mmol)
and imidazole (17 mg, 0.25 mmol). This solution was stirred
for 12 h at room temperature and then was diluted with Et2O,
washed with aqueous NH4Cl and brine, dried (Na2SO4), and
concentrated in vacuo. The crude product was then purified
via silica gel chromatography (1:10 to 2:3 Et2O-hexane) to
yield 107 mg (92%) of 34: [R]25D +14.8° (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.67-7.36 (m, 15 H), 5.99 (s, 1 H), 5.64
(s, 1 H), 4.85 (A of AB, J AB ) 7.2 Hz, 1 H), 4.82 (B of AB, J AB
) 7.2 Hz, 1 H), 4.76 (dd, J ) 8.6, 1.8 Hz, 1 H), 4.29 (d, J )
11.8 Hz, 1 H), 4.06 (m, 2 H), 3.98 (d, J ) 11.8 Hz, 1 H), 3.85
(s, 3 H), 3.44 (s, 3 H), 2.41 (d, J ) 18.4 Hz, 1 H), 2.31 (d, J )
8.8 Hz, 1 H), 2.27 (d, J ) 18.4 Hz, 1 H), 1.06 (s, 9 H); IR (CHCl3)
1733 cm-1; high-resolution mass spectrum, calcd for C31H33O7-
Si (M+ - C4H9) 545.1996, found 545.1976.
steps) of the desired â-epoxy alcohol 31: [R]24 +13.8° (c 1.0,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.49-7.37 (m, 5 H), 5.59
(s, 1 H), 4.33 (dd, J ) 12.2, 1.0 Hz, 1 H), 4.08 (dd, J ) 12.2,
2.6 Hz, 1 H), 3.85 (s, 3 H), 3.81 (d, J ) 5.6 Hz, 2 H), 3.42 (A of
AB, J AB ) 4.0 Hz, 1 H), 3.38 (B or AB, J AB ) 4.0 Hz, 1 H), 2.55
(m, 1 H), 2.47 (dd, J ) 6.0, 1.6 Hz, 1 H), 1.89 (m, 2 H); IR
(CHCl3) 3150 (br), 1763 cm-1; high-resolution mass spectrum,
calcd for C17H20O6 (M+) 320.1260, found 320.1229.
Direct epoxidation of 29 with MCPBA provided â-epoxide
31 in 70-75% yield, along with 11% of the R-epoxide 32: [R]20
D
+14.0° (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.50-7.33
(m, 5 H), 5.56 (s, 1 H), 4.25 (dd, J ) 11.4, 5.8 Hz, 1 H), 4.14
(dd, J ) 11.6, 4.0 Hz, 1 H), 3.90 (dd, J ) 10.4, 8.0 Hz, 1 H),
3.89 (s, 3 H), 3.69 (dd, J ) 10.0, 6.0 Hz, 1 H), 3.35 (m, 2 H),
2.84 (m, 1 H), 2.32 (m, 1 H), 1.87 (dd, J ) 10, 6 Hz, 1 H), 1.78
(dd, J ) 10, 7 Hz, 1 H); IR (CHCl3) 3440 (br), 1728 cm-1; high-
resolution mass spectrum, calcd for C17H20O6 (M+) 320.1260,
found 320.1264.
Meth yl (1R,5S,6R)-1-Hyd r oxy-3-[[(ter t-bu tyld ip h en yl-
silyl)oxy]m et h yl]-6-(h yd r oxym et h yl)-5-(m et h oxym et h -
oxy)cycloh ex-3-en eca r boxyla te (35). A solution of 34 (89
mg, 0.15 mmol) in 80% HOAc (3 mL) was heated to 80 °C for
1 h. The solution was then cooled to room temperature, diluted
with ethyl acetate, washed with aqueous NaHCO3, dried
(Na2SO4), and concentrated in vacuo. Purification of the crude
product via silica gel chromatography (1:1 Et2O-hexane to
Meth yl (2R,4a S,5S,8a R)-7-F or m yl-5-h yd r oxy-2-p h en yl-
4,4a,5,8-tetr ah ydr oben zo[1,3]dioxin e-8a-car boxylate (33).
To a -78 °C solution of (COCl)2 (40 µL, 0.46 mmol) in CH2Cl2
(2.0 mL) was added DMSO (64 µL, 0.9 mmol) followed, 10 min
later, by a -78 °C solution of alcohol 31 (110 mg, 0.34 mmol)
in CH2Cl2. The solution became white and was stirred for 30
min. Et3N (300 µL, 2.1 mmol) was then added, and the cooling
bath was removed. The reaction was stirred at room temper-
ature for 1 h and then was diluted with ethyl acetate and
extracted with NaHCO3 (aq) and brine. The crude product
was purified via silica gel chromatography (90% Et2O in
hexane) to yield 71 mg (65%) of R,â-unsaturated aldehyde 33:
[R]24D -16.5° (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.47
(s, 1 H), 7.44-7.32 (m, 5 H), 6.75 (s, 1 H), 5.65 (s, 1 H), 5.08
(dd, J ) 9.2, 2.4 Hz, 1 H), 4.39 (A of AB, J AB)12.0 Hz, 1 H),
4.02 (B of AB, J BA)12.0 Hz, 1 H), 3.86 (s, 3 H), 2.69 (d, J )
19.2 Hz, 1 H), 2.54 (m, 1 H), 2.23 (d, J ) 9.2 Hz, 1 H), 1.23 (s,
1 H); IR (CHCl3) 3400 (br), 1734, 1687 cm-1; high-resolution
mass spectrum, calcd for C17H18O6 (M+) 318.1103, found
318.1096. Anal. Calcd for C17H18O6: C, 64.14; H, 5.70.
Found: C, 63.94; H, 5.79.
Meth yl (2R,4a S,5S,8a R)-7-[[(ter t-Bu tyld ip h en ylsilyl)-
oxy]m eth yl]-5-(m eth oxym eth oxy)-2-p h en yl-4,4a ,5,8-tet-
r a h yd r oben zo[1,3]d ioxin e-8a -ca r boxyla te (34). A solution
of alcohol 33 (87 mg, 0.27 mmol), i-Pr2NEt (480 µL, 2.7 mmol),
and MOM-Cl (210 µL, 2.8 mmol) in CH2Cl2 (4 mL) was stirred
at room temperature for 16 h. The solution was then diluted
with Et2O, washed with NH4Cl (aq) and brine, dried (Na2SO4),
and concentrated in vacuo. The crude product was purified
via silica gel chromatography (3:1 to 7:1 Et2O-hexane) to yield
91 mg (91%) of the MOM ether: [R]24D -8.0° (c 1.0, CHCl3);1H
NMR (400 MHz, CDCl3) δ 9.51 (s, 1 H), 7.46-7.36 (m, 5 H),
6.92 (s, 1 H), 5.67 (s, 1 H), 5.00 (m, 1 H), 4.89 (dd, J ) 10.2,
7.0 Hz, 2 H), 4.29 (m, 1 H), 4.04 (m, 1 H), 3.88 (s, 3 H), 3.49 (s,
3 H), 2.67 (m, 1 H), 2.57 (m, 1 H), 2.37 (m, 1 H); IR (CHCl3)
1740, 1695 cm-1; high-resolution mass spectrum, calcd for
C19H22O7 (M+) 362.1366, found 362.1359.
100% Et2O) yielded 62 mg (81%) of diol 35: [R]25 +45.0° (c
D
1
1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 7.67-7.37 (m, 10
H), 5.93 (s, 1 H), 4.79 (A of AB, J AB ) 6.8 Hz, 1 H), 4.75 (B of
AB, J AB ) 6.8 Hz, 1 H), 4.44 (br d, J ) 9.2 Hz, 1 H), 4.06 (s, 2
H), 3.91 (dd, J ) 11.6, 4.4 Hz, 1 H), 3.80 (s, 3 H), 3.77 (dd, J
) 11.6, 3.0 Hz, 1 H), 3.41 (s, 3 H), 2.59 (d, J ) 17.6 Hz, 1 H),
2.18 (m, 1 H), 2.01 (d, J ) 17.6 Hz, 1 H), 1.05 (s, 9 H); IR
(CHCl3) 3490 (br), 1729 cm-1; high-resolution mass spectrum,
calcd for C24H29O7Si (M+ - C4H9) 457.1682, found 457.1674.
Anal. Calcd for C28H38O7Si: C, 65.34; H, 7.44. Found: C,
65.82; 7.03.
Meth yl (1R,5S,6R)-1-Hyd r oxy-3-[[(ter t-bu tyld ip h en yl-
silyl)oxy]m e t h yl]-5-(m e t h oxym e t h oxy)-6-[(vin yloxy)-
m eth yl]cycloh ex-3-en eca r boxyla te (36). To a solution of
diol 35 (46 mg, 0.089 mmol) in ethyl vinyl ether (1 mL) was
added Hg(OAc)2 (3.0 mg, 0.009 mmol). This solution was
stirred at room temperature for 19 h and then was diluted
with ethyl acetate, washed with aqueous NaHCO3, dried (Na2-
SO4), and concentrated. Purification of the crude product via
silica gel chromatography (1:1 Et2O-hexane) yielded 15 mg
(31%) of the desired vinyl ether 36: [R]25 +42.6° (c 0.98,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.72-7.35 (m, 10 H),
6.37 (dd, J ) 14.0, 6.8 Hz, 1 H), 5.93 (s, 1 H), 4.74 (d, J ) 6.8
Hz, 1 H), 4.68 (d, J ) 7.2 Hz, 1 H), 4.20 (dd, J ) 14.4, 2.0 Hz,
1 H), 4.18 (m, 1 H), 4.07 (br s, 1 H), 4.02 (dd, J ) 6.8, 2.0 Hz,
1 H), 3.93 (dd, J ) 10.2, 7.4 Hz, 1 H), 3.85 (dd, J ) 10.4, 2.8
Hz, 1 H), 3.77 (s, 3 H), 3.59 (s, 1 H), 3.39 (s, 3 H), 2.62 (d, J )
17.2 Hz, 1 H), 2.43 (m, 1 H), 2.20 (s, 1 H), 2.02 (d, J ) 17.2
Hz, 1 H), 1.07 (s, 9 H); IR (CHCl3) 3510 (br), 1729 cm-1; high-
resolution mass spectrum, calcd for C26H31O7Si (M+ - C4H9)
483.1839, found 483.1864.
Eth yl (1R,5S,6R)-1-Hyd r oxy-3-[[(ter t-bu tyld ip h en ylsi-
lyl)oxy]m eth yl]-5-(m eth oxym eth oxy)-6-[(vin yloxy)m eth -
yl]cycloh ex-3-en eca r boxyla te (6). A solution of 36 (14 mg,
0.026 mmol) in EtOH (0.4 mL) was added to a solution of
NaOEt (38 mg, 0.56 mmol) in 1 mL of EtOH. This solution
was stirred for 3 h at room temperature and then was diluted
with ethyl acetate, washed with aqueous NH4Cl and brine,
dried (Na2SO4), and concentrated in vacuo. Purification of the
crude product by silica gel chromatography (5% to 20% Et2O-
To a 0 °C solution of the above aldehyde (90 mg, 0.25 mmol)
in 5 mL of MeOH were added CeCl3‚7H2O (94 mg, 0.25 mmol)
and NaBH4 (10 mg, 0.25 mmol). This solution stirred at 0 °C
for 30 min and then was diluted with ethyl acetate, washed

Formal Total Synthesis of (+)-Tetronolide
J . Org. Chem., Vol. 62, No. 25, 1997 8719
hexane) yielded 13 mg (90%) of the known17,18 ethyl ester 6:
[R]25D +41.3° (c 1.0, CHCl3); lit.18 [R]25D +34.4° (c 2.9, CH2Cl2);
1H NMR (400 MHz, CDCl3) δ 7.60-7.32 (m, 10 H), 6.38 (dd, J
) 14.6, 6.8 Hz, 1 H), 5.93 (br s, 1 H), 4.79 (d, J ) 6.8 Hz, 1 H),
4.69 (d, J ) 6.8 Hz, 1 H), 4.1-4.3 (m, 4 H), 4.07 (br s, 2 H),
4.03 (dd, J ) 6.8, 2.2 Hz, 1 H), 3.98 (dd, J ) 10.0, 7.2 Hz, 1
H), 3.85 (dd, J ) 10.2, 3.0 Hz, 1 H), 3.61 (s, 1 H), 3.40 (s, 3 H),
2.62 (br d, J ) 17.2 Hz, 1 H), 2.44 (m, 1 H), 2.01 (d, J ) 17.2
Hz, 1 H), 1.29 (t, J ) 7.0 Hz, 3 H), 1.05 (s, 9 H); IR (CHCl3)
3520 (br), 1726 cm-1; high-resolution mass spectrum, calcd for
C27H33O7Si (M+ - C4H9) 497.1995, found 497.2018.
in toluene (0.57 mL, 3 M) was heated in sealed Carius tube at
110 °C for 90 h. Evaporation of the solvent in vacuo afforded
an oily residue which consisted of a 7:1 mixture of 41 (exo)
and 42 (endo), along with recovered triene 37, as determined
1
by H NMR analysis. This mixture was purified by silica gel
chromatography. Elution of the column with 8% ether-
hexane afforded recovered 37 (73 mg, 14%), and further elution
with 10% ether-hexane afforded the exocycloadduct 41 as a
white solid (516 mg, 67%): mp 102-104 °C; Rf 0.40 (1:5 ether-
hexane); [R]24 -91.3° (c 1.0, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ 6.64 (dd, J ) 10.8, 1.6 Hz, 1 H), 5.88 (ddd, J ) 10.0,
3.2, 2.8 Hz, 1 H), 5.42 (td, J ) 10.8, 2.8 Hz, 1 H), 5.07 (s, 1 H),
3.75 (s, 3 H), 3.60-3.70 (m, 2 H), 3.57 (ddd, J ) 10.8, 2.8, 2.4
Hz, 1 H), 2.60-2.65 (m, 1 H), 2.09 (dd, J ) 14.4, 3.6 Hz, 1 H),
2.03 (dd, J ) 14.4, 6.8 Hz, 1 H), 1.88 (d, J ) 1.6 Hz, 3 H), 0.94
(s, 9 H), 0.88 (s, 9 H), 0.05 (s, 6 H); 13C NMR (CDCl3) δ 174.7,
168.1, 137.7, 130.7, 129.2, 124.8, 109.7, 79.3, 65.5, 52.0, 40.9,
36.7, 34.9, 30.2, 25.8, 23.3, 18.2, -5.4; IR (CHCl3) 2960, 1785,
1715 cm-1; high-resolution mass spectrum, calcd for C24H40O6-
Si (M+) 452.2594, found 452.2621. Anal. Calcd for C24H40O6-
Si: C, 63.68; H, 8.91. Found: C, 63.68; H, 8.91.
The 1H NMR spectrum of 6 was in excellent agreement with
NMR data kindly provided by Professor Boeckman.17,18
4-[(ter t-Bu t yld im et h ylsilyl)oxy]-2(E)-b u t en -1-a l (39).
n-Butyllithium (4.4 mL, 2.7 M in hexane, 11.9 mmol) was
added dropwise to a -78 °C solution of cis-2-butene-1,4-diol
(1.0 mL, 12.2 mmol) in 19 mL of THF. The solution was stirred
for 5 min; then a solution of TBDMS-Cl (1.72 g, 11.4 mmol) in
5 mL of THF was added. The reaction mixture was allowed
to warm to ambient temperature over a 2 h period and then
was heated just below reflux for 3 h. The solution was
concentrated in vacuo, hexane-ether (7:1, 25 mL) was added,
and the solution was filtered through a short plug of silica gel.
Concentration of the filtrate in vacuo provided a 97:3 mixture
of the mono-TBS ether and the bis-TBS ether (1H NMR
analysis). Separation of this mixture by chromatography over
silica gel (10 g; 5:1 hexane-Et2O) yielded the desired mono-
TBS ether (2.14 g, 87% yield): 1H NMR (400 MHz, CDCl3) δ
5.67 (m, 2 H), 4.23 (d, J ) 4.3 Hz, 2 H), 4.18 (dd, J ) 5.3, 5.3
Hz, 2 H), 2.03 (br d, J ) 4.9 Hz, -OH), 0.89 (s, 9 H), 0.06 (s,
6 H); IR (CHCl3) 3615, 1463 cm-1; mass spectrum, m/e 189
(M+ - CH3 + H2). Anal. Calcd for C10H22O2Si: C, 59.35; H,
10.96. Found: C, 59.05; H, 10.99.
Further elution of the column with 12% ether-hexane
afforded an inseparable oily mixture containing the endo
adduct 42 (95 mg). This mixture was treated with HF‚NEt3
(52 mg, 0.45 mmol) in CH3CN (2 mL) at 40 °C for 16 h.
Purification of the crude mixture by silica gel chromatography
gave desilylated endo adduct (46 mg) as a colorless oil.
Treatment of this compound (46 mg, 0.14 mmol) with TBDMS-
Cl (26 mg, 0.16 mmol) and imidazole (12 mg, 0.18 mmol) in
anhydrous DMF (1 mL) at 23 °C for 16 h afforded endo
cycloadduct 42 (59 mg, 7% from 37) as a colorless oil: Rf 0.35
(1:5 ether-hexane); [R]24D +153.2° (c 1.0, CHCl3); 1H NMR (400
MHz, CDCl3) δ 6.53 (ddd, J ) 10.4, 3.2, 1.6 Hz, 1 H), 5.80 (d,
J ) 10.4, Hz, 1 H), 5.48 (ddd, J ) 10.4, 4.8, 2.4 Hz, 1 H), 5.28
(s, 1 H), 3.72 (s, 3 H), 3.50-3.65 (m, 2 H), 3.38 (ddt, J ) 10.4,
4.8, 1.6 Hz, 1 H), 2.50-2.60 (m, 1 H), 1.90 (dd, J ) 13.6, 10.8
Hz, 1 H), 1.88 (d, J ) 1.2 Hz, 3 H), 1.83 (dd, J ) 13.6, 6.0 Hz,
1 H), 0.96 (s, 9 H), 0.90 (s, 9 H), 0.05 (s, 6 H); 13C NMR (CDCl3)
δ 172.9, 167.9, 137.4, 129.7, 128.7, 124.0, 107.7, 79.2, 66.0, 51.9,
39.3, 35.4, 34.5, 29.3, 25.8, 23.3, 18.2, 12.7, -5.4; IR (CHCl3)
2950, 1785, 1710 cm-1; high-resolution mass spectrum, calcd
for C24H40O6Si (M+) 452.2594, found 452.2606. Anal. Calcd
for C24H40O6Si: C, 63.68; H, 8.91. Found: C, 63.66; H, 8.90.
A solution of the mono-TBS ether (1.00 g, 4.94 mmol) in dry
CH2Cl2 (5 mL) was added to a suspension of pyridinium
chlorochromate (1.70 g, 7.89 mmol) and Celite (2.00 g) in dry
CH2Cl2 at 23 °C. The mixture was stirred for 3 h and then
was diluted with Et2O and filtered through a layer of Celite.
The filtrate and ether washings were combined. Removal of
the solvent in vacuo gave an oily residue, which was purified
by silica gel chromatography (10% ether-hexane as eluent)
to afford the known enal 39 as a pale yellow oil (838 mg,
85%): Rf 0.45 (2:5 ether-hexane); 1H NMR (400 MHz, CDCl3)
δ 9.60 (d, J ) 8.0 Hz, 1 H), 6.88 (dt, J ) 15.6, 3.2 Hz, 1 H),
6.40 (ddt, J ) 15.6, 8.0, 2.2 Hz, 1 H), 4.45 (dd, J ) 3.2, 2.2 Hz,
(1S,2R,2′R,3S,4S,6R)-Sp ir o[1,2-bis(m eth oxym eth oxy)-
3-[2-(m et h oxyca r b on yl)-1(E)-p r op en -1-yl]-6-[[(ter t-b u -
t yld im et h ylsilyl)oxy]m et h yl]cycloh exa n e-[4,5′]-2′-ter t-
bu tyl-1′,3′-d ioxola n -4′-on e (47). A 2.5% solution of OsO4 in
t-BuOH (0.63 mL, 0.06 mmol) was added to a suspension of
41 (513 mg, 1.13 mmol) and N-methylmorpholine N-oxide
monohydrate (153 mg, 1.13 mmol) in 2:1 acetone-water (10
mL), and the solution was stirred for 7 h at 23 °C. The
resultant clear solution was diluted with EtOAc and brine. The
aqueous layer was separated and extracted with EtOAc. The
combined organic layers were washed with brine and dried
over Na2SO4. Removal of the solvent in vacuo gave a solid
residue, which was purified by silica gel chromatography (80%
ether-hexane as eluent) to afford the cis-â-diol as a white solid
(451 mg, 82%). An analytical sample was recrystallized from
EtOAc-hexane: mp 86-88 °C; Rf 0.76 (5:1 ether-hexane);
2 H), 0.93 (s, 9 H), 0.10 (s, 6 H); IR (CHCl3) 2960, 1685 cm-1
;
high-resolution mass spectrum, calcd for C10H20O2Si (M+),
200.1233, found 200.1236.
Met h yl 8-[(ter t-Bu t yld im et h ylsilyl)oxy]-2-m et h yl-
2(E),4(E),6(E)-octa tr ien oa te (37). A solution of n-BuLi in
hexane (1.30 mL, 2.5 M, 3.25 mmol) was added slowly to a
-78 °C solution of methyl γ-(dimethylphosphono)tiglate 4054
(725 mg, 3.26 mmol) in anhydrous THF (18 mL). The mixture
was stirred for 15 min at -78 °C; then HMPA (2.9 mL, 16.7
mmol) was added. The mixture was stirred for an additional
15 min; then a solution of enal 39 (540 mg, 2.70 mmol) in
anhydrous THF (4 mL) was added. The reaction mixture was
stirred for 15 min at -78 °C and then was allowed to warm to
23 °C and stirred for an additional 30 min. The reaction
mixture was diluted with Et2O and poured into saturated
aqueous NH4Cl. The aqueous layer was separated and
extracted with Et2O. The combined ethereal layers were dried
over Na2SO4 and concentrated in vacuo. Purification of the
crude mixture by silica gel chromatography (10% ether-
hexane as eluent) provided trienoate 37 as a white solid (551
mg, 69%): mp 47-49 °C; Rf 0.60 (2:5 ether-hexane); 1H NMR
(400 MHz, CDCl3) δ 7.21 (dd, J ) 10.8, 1.2 Hz, 1 H), 6.35-
6.60 (m, 3 H), 5.95 (dt, J ) 15.6, 4.4 Hz, 1 H), 4.28 (dd, J )
4.4, 1.2 Hz, 2 H), 3.76 (s, 3 H), 1.96 (d, J ) 1.2 Hz, 3 H), 0.92
[R]24 +8.3° (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.69
D
(dd, J ) 10.8, 1.6 Hz, 1 H), 5.11 (s, 1 H), 4.16 (t, J ) 3.2 Hz,
1 H), 3.91 (br d, J ) 10.8 Hz, 1 H), 3.77 (s, 3 H), 3.60-3.80
(m, 2 H), 3.30 (t, J ) 10.8 Hz, 1 H), 2.25-2.40 (m, 3 H), 1.90
(d, J ) 1.6 Hz, 3 H), 0.93 (s, 9 H), 0.89 (s, 9 H), 0.06 (s, 6 H);
13C NMR (CDCl3) δ 173.6, 167.8, 135.6, 134.3, 110.2, 82.5, 69.1,
68.7, 63.7, 52.1, 43.7, 42.2, 35.0, 29.9, 25.8, 23.3, 18.2, 13.2,
-5.5; IR (CHCl3) 3560, 3440, 1785, 1710 cm-1; high-resolution
mass spectrum, calcd for C24H42O8Si (M+), 486.2649; found
486.2647. Anal. Calcd for C24H42O8Si: C, 59.23; H, 8.70.
Found: C, 59.41; H, 8.64.
(s, 9 H), 0.09 (s, 6 H); IR (CHCl3) 2960, 2860, 1700, 1615 cm-1
;
high-resolution mass spectrum, calcd for C16H28O3Si (M+),
296.1808, found 296.1815.
A mixture of methoxymethyl chloride (990 µL, 13.0 mmol),
the diol prepared above (418 mg, 0.86 mmol), and N,N-
diisopropylethylamine (2.3 mL, 13.2 mmol) in anhydrous CH2-
Cl2 (5 mL) was stirred for 22 h at 23 °C. The reaction mixture
was diluted with Et2O and poured into brine. The aqueous
layer was separated and extracted with Et2O. The combined
ethereal layers were washed with 0.5 N HCl and brine and
(2′R,3S,4S,6R)-Sp ir o[3-[2-(m eth oxyca r bon yl)-1(E)-p r o-
p en -1-yl]-6-[[(ter t-b u t yld im et h ylsilyl)oxy]m et h yl]-1-cy-
cloh exen e-[4,5′]-2′-ter t-bu tyl-1′,3′-d ioxola n -4′-on e] (41). A
mixture of triene 37 (508 mg, 1.71 mmol), freshly prepared
dienophile (R)-25b41 (401 mg, 2.57 mmol), and BHT (10 mg)

8720 J . Org. Chem., Vol. 62, No. 25, 1997
Roush et al.
dried over Na2SO4. Removal of the solvent in vacuo gave an
oily residue, which was purified by silica gel chromatography
(40% ether-hexane as eluent) to give 47 as a colorless oil (470
mg, 0.04 mmol) in anhydrous MeOH (3 mL) was stirred for 3
h at 23 °C. The reaction mixture was diluted with Et2O and
washed with saturated aqueous NaHCO3 and brine; the
combined extracts were dried over Na2SO4. Removal of the
solvent in vacuo afforded a solid residue, which was purified
by silica gel chromatography (30% Et2O-hexane as eluent) to
give the corresponding dimethyl acetal as a white solid (207
mg, 92%). An analytical sample was recrystallized from
EtOAc-hexane: mp 120-122 °C; Rf 0.67 (5:1 ether-hexane);
[R]20D +61.2° (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.72
(dd, J ) 10.8, 1.6 Hz, 1 H), 6.00 (br s, 1 H), 5.21 (s, 1 H), 4.71
(d, J ) 7.3 Hz, 1 H), 4.61 (s, 1 H), 4.58 (d, J ) 7.3 Hz, 1 H),
4.43 (br d, J ) 10.8 Hz, 1 H), 3.76 (s, 3 H), 3.31 (s, 6 H), 3.30
(s, 3 H), 3.11 (t, J ) 10.8 Hz, 1 H), 2.66 (dt, J ) 18.0, 2.8 Hz,
1 H), 2.32 (d, J ) 18.0 Hz, 1 H), 1.89 (d, J ) 1.6 Hz, 3 H), 0.92
(s, 9 H); 13C NMR (CDCl3) δ 172.7, 167.7, 136.4, 133.7, 132.4,
125.9, 110.6, 103.7, 95.6, 82.2, 74.2, 55.5, 53.2, 52.7, 51.9, 45.7,
35.0, 33.1, 23.3, 13.2; IR (CHCl3) 2960, 2930, 1790 cm-1; high-
resolution mass spectrum, calcd for C22H34O9 (M+) 442.2203,
found 442.2158. Anal. Calcd for C22H34O9: C, 59.71; H, 7.74.
Found: C, 59.83; H, 7.48.
mg, 95%): Rf 0.62 (2:1 ether-hexane); [R]22 +17.8° (c 1.0,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 6.67 (dd, J ) 10.8, 1.6
Hz, 1 H), 5.09 (s, 1 H), 4.74 (s, 2 H), 4.66 (d, J ) 7.2 Hz, 1 H),
4.49 (d, J ) 7.2 Hz, 1 H), 4.15 (br s, 1 H), 3.92 (dd, J ) 11.2,
2.8 Hz, 1 H), 3.78 (t, J ) 10.8 Hz, 1 H), 3.74 (s, 3 H), 3.63 (dd,
J ) 10.8, 6.0 Hz, 1 H), 3.47 (t, J ) 11.2 Hz, 1 H), 3.39 (s, 3 H),
3.31 (s, 3 H), 2.3-2.4 (m, 1 H), 2.32 (dd, J ) 14.0, 6.4 Hz, 1
H), 1.89 (d, J ) 1.6 Hz, 3 H), 1.66 (d, J ) 14.0 Hz, 1 H), 0.93
(s, 9 H), 0.89 (s, 9 H), 0.05 (s, 6 H); 13C NMR (CDCl3) δ 173.3,
167.9, 137.0, 132.8, 110.3, 96.3, 95.0, 83.2, 73.0, 72.3, 63.3, 55.7,
55.4, 51.9, 42.8, 42.1, 35.0, 30.2, 25.8, 23.4, 18.1, 13.2, -5.5;
IR (CHCl3) 3015, 2950, 1785, 1710 cm-1; high-resolution mass
spectrum, calcd for C27H47O9Si (M+ - OCH3) 543.2989, found
543.2990. Anal. Calcd for C28H50O10Si: C, 58.51; H, 8.77.
Found: C, 58.69; H, 8.76.
(2′R,3S,4S,5S)-Sp ir o[1-for m yl-3-(m eth oxym eth oxy)-4-
[2-(m eth oxyca r bon yl)-1(E)-p r op en -1-yl]-1-cycloh exen e-
[5,5′]-2′-ter t-bu tyl-1′,3′-d ioxola n -4′-on e] (48). Et3N‚HF (189
mg, 1.56 mmol) was added to a 23 °C solution of 47 (443 mg,
0.77 mmol) in anhydrous CH3CN (8 mL). The reaction mixture
was heated at 40 °C for 16 h. At this point, the reaction
mixture was diluted with EtOAc and poured into brine. The
aqueous layer was separated and extracted with EtOAc. The
combined organic layers were washed with brine, dried over
Na2SO4, and concentrated in vacuo. Purification of the crude
mixture by silica gel chromatography (80% Et2O-hexane as
A 1.0 M solution of L-Selectride in THF (1.0 mL, 1.0 mmol)
was added dropwise to a -20 °C solution of the above acetal
(203 mg, 0.46 mmol) in anhydrous THF (4.6 mL). After being
stirred for 4 h at -20 °C, the reaction mixture was diluted
with Et2O and poured into brine. The aqueous layer was
separated and extracted with Et2O. The combined ethereal
layers were washed with brine, dried over Na2SO4, and
concentrated in vacuo. Purification of the crude mixture by
silica gel chromatography (80% ether-hexane as eluent)
afforded the corresponding primary allylic alcohol as a white
solid (164 mg, 86%). An analytical sample was recrystallized
from EtOAc-hexane: mp 85-87 °C; Rf 0.29 (5:1 ether-
eluent) afforded the primary alcohol as a colorless oil (326 mg,
1
92%): Rf 0.41 (ether); [R]22 +26.5° (c 1.1, CHCl3); H NMR
D
(400 MHz, CDCl3) δ 6.67 (dd, J ) 10.8, 1.6 Hz, 1 H), 5.10 (s,
1 H), 4.75 (s, 2 H), 4.70 (d, J ) 7.0 Hz, 1 H), 4.49 (d, J ) 7.0
Hz, 1 H), 4.13 (t, J ) 2.7 Hz, 1 H), 3.97 (dd, J ) 10.8, 2.7 Hz,
1 H), 3.75 (s, 3 H), 3.60-3.80 (m, 2 H), 3.47 (t, J ) 10.8 Hz, 1
H), 3.40 (s, 3 H), 3.31 (s, 3 H), 2.30-2.40 (m, 3 H), 1.89 (d, J
) 1.6 Hz, 3 H), 0.93 (s, 9 H); 13C NMR (CDCl3) δ 173.1, 167.9,
136.8, 132.9, 110.2, 96.4, 95.0, 83.0, 73.2, 72.7, 63.2, 55.7, 55.5,
51.9, 42.6, 41.8, 34.9, 30.3, 23.3, 13.1; IR (CHCl3) 3420, 2950,
1785, 1710, 1345, 1280, 1100, 1050, 920 cm-1; high-resolution
mass spectrum, calcd for C21H33O9 (M+ - OCH3) 429.2124,
found 429.2134. Anal. Calcd for C22H36O10: C, 57.38; H, 7.88
Found: C, 57.03; H, 7.54.
hexane); [R]24 +82.6° (c 1.0, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ 5.98 (br s, 1 H), 5.48 (dd, J ) 10.4, 1.6 Hz, 1 H), 5.23
(s, 1 H), 4.71 (d, J ) 7.0 Hz, 1 H), 4.63 (d, J ) 7.0 Hz, 1 H),
4.60 (s, 1 H), 4.33 (br d, J ) 10.4 Hz, 1 H), 4.04 (s, 2 H), 3.35
(s, 3 H), 3.30 (s, 3 H), 3.29 (s, 3 H), 3.03 (t, J ) 10.4 Hz, 1 H),
2.64 (dt, J ) 18.0, 2.8 Hz, 1 H), 2.29 (d, J ) 18.0 Hz, 1 H),
1.67 (d, J ) 1.6 Hz, 3 H), 0.92 (s, 9 H); 13C NMR (CDCl3) δ
173.4, 142.0, 132.4, 126.6, 119.4, 110.7, 103.8, 95.9, 82.9, 75.0,
67.6, 55.5, 53.3, 52.7, 44.8, 35.0, 33.2, 23.4, 14.5; IR (CHCl3)
3440, 2960, 1785 cm-1; high-resolution mass spectrum, calcd
for C21H34O8 (M+) 414.2254, found 414.2231. Anal. Calcd for
C21H34O8: C, 60.85; H, 8.27. Found: C, 60.61; H, 8.28.
A solution of the above primary alcohol (306 mg, 0.66 mmol)
in anhydrous CH2Cl2 (4 mL) was added to a -78 °C solution
of oxalyl chloride (83 µL, 0.95 mmol) and DMSO (130 µL, 1.83
mmol) in anhydrous CH2Cl2 (6 mL). The reaction mixture was
stirred for 30 min at -78 °C; then DBU (670 µL, 4.48 mmol)
was added, and the mixture was allowed to warm to 23 °C.
The reaction mixture was stirred for 30 min and then was
diluted with Et2O and poured into brine. The aqueous layer
was separated and extracted with Et2O. The combined
ethereal layers were washed with brine, dried over Na2SO4,
and concentrated in vacuo. Purification of the crude product
by silica gel chromatography (40% ether-hexane as eluent)
afforded enal 48 as a white solid (224 mg, 85%). An analytical
sample was recrystallized from EtOAc-hexane: mp 137-139
A mixture of the allylic alcohol prepared above (157 mg, 0.38
mmol), N,N-diisopropylethylamine (86 µL, 0.49 mmol), and
[2-(trimethylsilyl)ethoxy]methyl chloride (81 µL, 0.46 mmol)
in anhydrous CH2Cl2 (4 mL) was stirred for 4 h at 23 °C. The
reaction mixture was diluted with Et2O and poured into brine.
The aqueous layer was separated and extracted with Et2O.
The combined ethereal layers were washed with brine and
dried over Na2SO4. Removal of the solvent in vacuo gave an
oily residue, which was purified by silica gel chromatography
(30% ether-hexane as eluent) to give SEM ether 49 as a
colorless oil (197 mg, 95%): Rf 0.67 (2:1 ether-hexane); [R]23
D
+48.1° (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.97 (br s,
1 H), 5.46 (dd, J ) 10.2, 1.2 Hz, 1 H), 5.22 (s, 1 H), 4.70 (d, J
) 7.0 Hz, 1 H), 4.62 (s, 2 H), 4.61 (d, J ) 7.0 Hz, 1 H), 4.33 (br
d, J ) 10.2 Hz, 1 H), 3.96 (s, 2 H), 3.61 (t, J ) 8.4 Hz, 2 H),
3.59 (t, J ) 8.6 Hz, 1 H), 3.34 (s, 3 H), 3.30 (s, 3 H), 3.28 (s, 3
H), 3.02 (t, J ) 10.2 Hz, 1 H), 2.64 (dt, J ) 18.0, 2.8 Hz, 1 H),
2.27 (d, J ) 18.0 Hz, 1 H), 1.67 (d, J ) 1.2 Hz, 3 H), 0.93 (t, J
) 8.3 Hz, 2 H), 0.91 (s, 9 H), 0.01 (s, 9 H); 13C NMR (CDCl3)
δ 173.5, 139.0, 132.3, 126.5, 122.2, 110.6, 103.8, 95.9, 93.3, 82.9,
74.7, 71.9, 65.1, 55.5, 53.3, 52.7, 44.9, 35.0, 33.2, 23.4, 18.1,
14.8, -1.4; IR (CHCl3) 2950, 1785 cm-1; high-resolution mass
spectrum, calcd for C27H48O9Si (M+) 544.3068, found 544.3052.
Anal. Calcd for C27H48O9Si: C, 59.53; H, 8.88. Found: C,
59.39; H, 8.57.
°C; Rf 0.61 (5:1 ether-hexane); [R]22 +93.5° (c 1.0, CHCl3);
D
1H NMR (400 MHz, CDCl3) δ 9.55 (s, 1 H), 6.83 (br s, 1 H),
6.71 (dd, J ) 10.8, 1.6 Hz, 1 H), 5.22 (s, 1 H), 4.76 (d, J ) 7.0
Hz, 1 H), 4.66 (br d, J ) 7.0 Hz, 1 H), 4.61 (dd, J ) 10.8, 2.8
Hz, 1 H), 3.78 (s, 3 H), 3.37 (s, 3 H), 3.16 (t, J ) 10.8 Hz, 1 H),
2.77 (dt, J ) 18.4, 2.8 Hz, 1 H), 2.62 (d, J ) 18.4 Hz, 1 H),
1.89 (d, J ) 1.6 Hz, 3 H), 0.92 (s, 9 H); 13C NMR (CDCl3) δ
192.2, 172.2, 167.6, 146.9, 137.1, 135.1, 134.4, 110.9, 96.3, 81.4,
74.3, 55.8, 52.1, 45.6, 35.0, 31.4, 23.2, 13.2; IR (CHCl3) 2980,
1790, 1715, 1685, 1245, 1135, 1035 cm-1; high-resolution mass
spectrum, calcd for C20H28O8 (M+) 396.1784, found 396.1805.
Anal. Calcd for C20H28O8: C, 60.59; H, 7.12. Found: C, 60.32;
H, 7.13.
The stereostructure of 48 was unambiguously verified by
En a n tiom er ic P u r ity Deter m in a tion . A 1.0 M solution
of DIBAL-H in THF (0.46 mL, 0.46 mmol) was slowly added
to a 0 °C solution of 49 (56 mg, 0.10 mmol) in anhydrous CH2-
Cl2 (1 mL). This mixture was allowed to warm to 23 °C and
stirred for 1 h. The reaction mixture was diluted with Et2O
and poured into brine. The aqueous layer was separated and
extracted with Et2O. The combined ethereal layers were dried
X-ray analysis.62
(2′R ,3S ,4S ,5S )-Sp ir o[1-(d im e t h oxym e t h yl)-3-(m e t h -
o x y m e t h o x y )-4-[2-m e t h y l-3-[[2-(t r im e t h y ls ily l)e t h -
oxy]m et h oxy]-1(E)-p r op en -1-yl]-1-cycloh exen e-[5,5′]-2′-
ter t-bu tyl-1′,3′-d ioxola n -4′-on e (49). A mixture of enal 48
(201 mg, 0.51 mmol) and pyridinium p-toluenesulfonate (10

Formal Total Synthesis of (+)-Tetronolide
J . Org. Chem., Vol. 62, No. 25, 1997 8721
over Na2SO4 and concentrated in vacuo. Purification of the
crude mixture by silica gel chromatography (ether as eluent)
produced 50 as a colorless oil (43 mg, 90%): Rf 0.33 (ether);
1H NMR (400 MHz, CDCl3) δ 5.93 (d, J ) 1.6 Hz, 1 H), 5.48
(dd, J ) 10.8, 1.6 Hz, 1 H), 4.67 (d, J ) 7.0 Hz, 1 H), 4.66 (s,
2 H), 4.61 (d, J ) 7.0 Hz, 1 H), 4.57 (s, 1 H), 4.14 (br d, J ) 7.0
Hz, 1 H), 4.01 (d, J ) 11.6 Hz, 1 H), 3.94 (d, J ) 11.6 Hz, 1 H),
3.5-3.7 (m, 4 H), 3.40 (dd, J ) 11.2, 6.4 Hz, 1 H), 3.33 (s, 3
H), 3.29 (s, 6 H), 2.72 (dd, J ) 10.4, 1.6 Hz, 1 H), 2.65 (s, 1 H),
2.16 (d, J ) 18.4 Hz, 1 H), 2.08 (d, J ) 18.4 Hz, 1 H), 1.73 (d,
J ) 1.6 Hz, 3 H), 0.92 (t, J ) 10.0 Hz, 2 H), 0.01 (s, 9 H); 13C
NMR (CDCl3) δ 136.8, 134.6, 125.2, 152.1, 104.7, 96.0, 94.2,
75.6, 74.1, 73.4, 68.5, 65.4, 55.4, 53.4, 53.3, 45.0, 33.4, 18.0,
14.8, -1.5; IR (CHCl3) 3450, 2950 cm-1; high-resolution mass
spectrum, calcd for C21H39O7Si (M+ - CH3O) 431.2465, found
431.2494.
separated and extracted with Et2O. The combined ethereal
extracts were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The crude product was purified by
silica gel chromatography (50% ether-hexane as eluent) to
give the corresponding acetate as a colorless oil (65 mg, 92%):
Rf 0.47 (5:1 ether-hexane); [R]23 +54.2° (c 1.0, CHCl3); 1H
D
NMR (400 MHz, CDCl3) δ 5.94 (br s, 1 H), 5.41 (dd, J ) 10.4,
1.6 Hz, 1 H), 4.55-4.65 (m, 5 H), 4.19 (br d, J ) 7.2 Hz, 1 H),
3.94 (s, 2 H), 3.63 (s, 3 H), 3.61 (t, J ) 8.4 Hz, 2 H), 3.34 (s, 3
H), 3.29 (s, 3 H), 3.27 (s, 3 H), 3.03 (dd, J ) 10.4, 7.2 Hz, 1 H),
3.00 (dt, J ) 18.4, 2.4 Hz, 1 H), 2.85 (d, J ) 18.4 Hz, 1 H),
2.03 (s, 3 H), 1.66 (d, J ) 1.6 Hz, 3 H), 0.93 (t, J ) 8.4 Hz, 2
H), 0.01 (s, 9 H); 13C NMR (CDCl3) δ 170.4, 169.7, 136.9, 133.9,
124.2, 123.0, 103.7, 95.7, 93.6, 82.6, 74.2, 72.6, 65.1, 55.5, 53.1,
52.9, 52.2, 45.2, 29.4, 21.2, 18.1, 14.5, -1.5; IR (CHCl3) 2950,
2885, 1750 (sh), 1735 cm-1; high-resolution mass spectrum,
calcd for C25H44O10Si (M+) 532.2704, found 532.2686. Anal.
Calcd for C25H44O10Si: C, 56.37; H, 8.33. Found: C, 56.07; H,
8.03.
To a solution of this diol (20 mg, 0.04 mmol) in anhydrous
CH2Cl2 (0.5 mL) were added either (S)-(-)-MTPA-Cl or (R)-
(+)-MTPA-Cl (13 µL, 0.06 mmol), Et3N (18 µL, 0.13 mmol),
and catalytic DMAP. These reaction mixtures were stirred
for 12 h at ambient temperature. The mixtures were diluted
with Et2O, washed with brine, and dried over Na2SO4.
Concentration of the ethereal layers in vacuo yielded the crude
Mosher ester derivatives that were purified by silica gel
chromatography (60% ether-hexane as eluent, the diastere-
omeric MTPA derivatives do not separate) to give (S)-(-)-
MTPA derivative (28 mg, 95%) and (R)-(+)-MTPA derivative
(27 mg, 92%), respectively. The purified esters were examined
A 1.0 M solution of lithium hexamethyldisilazide (220 µL,
0.22 mmol) was slowly added to a -78 °C solution of the
R-acetoxy methyl ester (51 mg, 0.096 mmol) in a mixture of
HMPA (350 µL, 2.01 mmol) and anhydrous THF (1 mL). This
reaction mixture was stirred for 30 min at -78 °C and then
allowed to warm to 23 °C over a 1 h period. The mixture was
stirred for 15 min at 23 °C and then was treated with
(MeO)2SO4 (23 µL, 0.24 mmol). This mixture was stirred for
2 h before being diluted with Et2O and poured into brine. The
aqueous layer was separated and extracted with Et2O. The
combined ethereal layers were washed with brine, dried over
Na2SO4, and concentrated in vacuo. Purification of the crude
material by silica gel chromatography (80% ether-hexane as
eluent) produced 5 as a white solid (42 mg, 85%). An
analytical sample was recrystallized from EtOAc-hexane: mp
1
by high-field HNMR analysis. The (S)-(-)-MTPA derivative
51b showed characteristic signals at δ 4.28 and 4.35 (d, J )
11.2 Hz, each 1 H, CH2OMTPA), 4.62 (s, 2 H, CH3OCH2O).
The (R)-(+)-MTPA derivative 51a , however, showed charac-
teristic signals at δ 4.22 and 4.41 (d, J ) 11.2 Hz, each 1 H,
CH2OMTPA), 4.52 and 4.58 (d, J ) 7.2 Hz, each 1 H, CH3-
OCH2O). In this way, the enantiomeric purity of 50 was
determined to be >97% ee.
65-66 °C; Rf 0.36 (5:1 ether-hexane); [R]23 +134.3° (c 2.8,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.98 (br s, 1 H), 5.22
(dd, J ) 10.0, 1.2 Hz, 1 H), 4.98 (1 H, s), 4.66 (d, J ) 7.0 Hz,
1 H), 4.57 (s, 3 H), 4.56 (d, J ) 7.0 Hz, 1 H), 4.31 (br d, J )
10.0 Hz, 1 H), 3.90 (d, J ) 12.4 Hz, 1 H), 3.86 (d, J ) 12.4 Hz,
1 H), 3.78 (s, 3 H), 3.57 (t, J ) 8.4 Hz, 2 H), 3.30 (s, 6 H), 3.28
(s, 3 H), 2.92 (t, J ) 10.0 Hz, 1 H), 2.64 (dt, J ) 18.0, 2.8 Hz,
1 H), 2.10 (d, J ) 18.0 Hz, 1 H), 1.64 (d, J ) 1.2 Hz, 3 H), 0.91
(t, J ) 8.4 Hz, 2 H), 0.01 (s, 9 H); 13C NMR (CDCl3) δ 183.2,
171.6, 137.8, 132.1, 126.9, 121.7, 104.4, 96.2, 93.6, 88.9, 85.6,
75.0, 72.5, 65.1, 59.2, 55.4, 53.4, 53.3, 42.8, 32.5, 18.0, 14.4,
-1.5; IR (CHCl3) 2950, 1745, 1635 cm-1; high-resolution mass
spectrum, calcd for C25H42O9Si (M+) 514.2598, found 514.2601.
Anal. Calcd for C25H42O9Si: C, 58.34; H, 8.23. Found: C,
58.57; H, 8.44.
(5S,6S,7S)-4-Meth oxy-6-[2-m eth yl-3-[[2-(tr im eth ylsilyl)-
eth oxy]m eth oxy]-1(E)-p r op en -1-yl]-7-(m eth oxym eth oxy)-
9-(d im e t h oxym e t h yl)-1-oxa sp ir o[4.5]d e ca -3,8-d ie n -2-
on e (5). Anhydrous K2CO3 (95 mg, 0.69 mmol) was added to
a solution of 49 (188 mg, 0.35 mmol) in anhydrous MeOH (3.5
mL). The mixture was stirred for 20 h at 23 °C and then was
diluted with Et2O and poured into brine. The aqueous layer
was separated and extracted with Et2O. The combined
ethereal layers were washed with brine, dried over Na2SO4,
and concentrated in vacuo. Purification of the crude product
by silica gel chromatography (50% ether-hexane as eluent)
afforded the corresponding tertiary R-hydroxy methyl ester as
a colorless oil (140 mg, 83%): Rf 0.44 (5:1 ether-hexane); [R]24
D
+58.3° (c 1.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.97 (br s,
1 H), 5.43 (dd, J ) 10.4, 1.2 Hz, 1 H), 4.66 (d, J ) 6.8 Hz, 1
H), 4.58 (s, 3 H), 4.57 (d, J ) 6.8 Hz, 1 H), 4.24 (br d, J ) 10.4
Hz, 1 H), 3.91 (s, 2 H), 3.70 (s, 3 H), 3.59 (t, J ) 8.4 Hz, 2 H),
3.35 (s, 1 H), 3.31 (s, 6 H), 3.29 (s, 3 H), 2.95 (t, J ) 10.4 Hz,
1 H), 2.60 (dt, J ) 18.0, 2.8 Hz, 1 H), 2.16 (d, J ) 18.0 Hz, 1
H), 1.65 (d, J ) 1.2 Hz, 3 H), 0.92 (t, J ) 8.4 Hz, 2 H), 0.01 (s,
9 H); 13C NMR (CDCl3) δ 175.7, 137.0, 132.5, 126.7, 123.6,
104.8, 96.1, 93.4, 76.8, 74.9, 72.6, 65.0, 55.3, 53.4, 53.3, 52.8,
The spectroscopic properties of spirotetronate 5 were identi-
cal with those of an authentic sample ([R]23 +99.0° (c 3.02,
D
CHCl3)) kindly provided by Professor Yoshii.11
Ack n ow led gm en t. Financial support provided by
grants from the National Institutes of Health (GM
26782 and RR 10537) is gratefully acknowledged.
45.0, 34.6, 18.1, 14.4, -1.5; IR (CHCl3) 3515, 2950, 1730 cm-1
;
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
4-6 (synthetic and authentic), 10, 17, 19, 20, 21, 26, 30, 31,
32, 34, 36, 39, and 37 (19 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.
high-resolution mass spectrum, calcd for C23H42O9Si (M+)
490.2598, found 490.2588. Anal. Calcd for C23H42O9Si: C,
56.30; H, 8.63. Found: C, 56.06; H, 8.34.
A solution of the above R-hydroxy ester (65 mg, 0.13 mmol),
acetic anhydride (75 µL, 0.79 mmol), Et3N (220 µL, 1.58 mmol),
and DMAP (2 mg, 0.02 mmol) in anhydrous CH2Cl2 (2 mL)
was stirred for 48 h at 23 °C. The reaction mixture was diluted
with Et2O and poured into brine. The aqueous layer was
J O970960C