Toward the development of a general chiral auxiliary. A total synthesis of (+)-tetronolide via a tandem ketene-trapping [4 + 2] cycloaddition strategy

Article abstract of DOI:10.1021/ja0581346

A highly convergent, enantioselective total synthesis of the aglycone of the tetrocarcins, (+)-tetronolide, is described. The synthesis highlights the use of several new methods, including camphor auxiliary-directed asymmetric alkylation and the enantiose

Full text of DOI:10.1021/ja0581346

Published on Web 07/21/2006
Toward the Development of a General Chiral Auxiliary. A Total
Synthesis of (+)-Tetronolide via a Tandem Ketene-Trapping
[4 + 2] Cycloaddition Strategy
Robert K. Boeckman, Jr.,* Pengcheng Shao, Stephen T. Wrobleski,
Debra J. Boehmler, Geoffrey R. Heintzelman, and Antonio. J. Barbosa
Contribution from the Department of Chemistry, UniVersity of Rochester, P.O. Box 270216,
Hutchison Hall, Rochester, New York 14627-0216
Received November 30, 2005; E-mail: rkb@rkbmac.chem.rochester.edu
Abstract: A highly convergent, enantioselective total synthesis of the aglycone of the tetrocarcins,
(+)-tetronolide, is described. The synthesis highlights the use of several new methods, including camphor
auxiliary-directed asymmetric alkylation and the enantioselective preparation of acyclic mixed acetals bearing
chirality at the acetal center, and the highly efficient connection of the two major precursors via a ketene-
trapping/intramolecular [4 + 2] cycloaddition strategy.
stress-induced apoptotic pathway.7 The activation of caspase-
12, the central inducer caspase involved in ER-stress by
Introduction
The tetrocarcins A-H are members of a growing class of
naturally occurring, complex, bioactive, spirotetronic acid
containing natural products.1 More recently, three new members
of the class, the arisostatins A and B2 and the antibiotic AC6H,3
have been isolated and characterized (Chart 1). When originally
isolated, the tetrocarcins were found to possess activity against
some Gram-positive (e.g., Bacillus subtilis) but no Gram-nega-
tive microorganisms.1,4 Subsequently, it was found that tetro-
carcin A showed activity against sarcoma 180, P-388 leukemia,
and B16 melanoma, as well as Ehrlich carcinoma MH134
hepatoma, but not solid tumors.5 At that time, the mechanism
by which tetrocarcin A elicited the observed antitumor activity
was hypothesized to be inhibition of either DNA or protein
synthesis or both.5 More recent studies have found that tetro-
carcin A selectively inhibits the mitochondrial functions of the
Bcl-2 family of proteins that function as natural apoptosis inhib-
itors by down-regulating the activation of caspase-3, a natural
mediator of apoptosis.6 Tetrocarcin A was also found to induce
a significant up-regulation of members of the heat shock protein
family known to be involved in the endoplasmic reticulum (ER)-
tetrocarcin A treatment, is also in accord with this result. Thus,
the mechanism of the antitumor of action of tetrocarcin A
involves induction of the apoptotic machinery via both mito-
chondrial and ER signaling, neither of which are inhibited by
aberrant expression/function of important regulators of death
receptor- and drug-induced apoptosis, such as Bcl-2 and Bcl-
XL. Overexpression of members of the Bcl-2 family of anti-
apoptotic proteins is commonly encountered in multi-drug-
resistant (MDR) tumor cell lines.6,7 Since tetrocarcin A-induced
apoptosis is independent of the expression levels of Bcl-2 and
Bcl-XL and analogues have been prepared that separate the
antitumor and antimicrobial activity, tetrocarcin A appears to
be a promising candidate for further evaluation in preclinical
trials.8,9 Similarly, the arisostatins have been shown to inhibit
growth of the human squamous cell carcinoma cells by inducing
apoptosis. Exposure of human AMC HN-4 cells to arisostatin
A produced dose-dependent apoptosis featuring the expected
markers (morphological features and DNA fragmentation). In
addition, arisostatin A-induced apoptosis was associated with
the generation of reactive oxygen species. The cytotoxic effect
of arisostatin A on human AMC HN-4 cells is mediated by
caspase-3 activation, loss of mitochondrial transmembrane
potential, and release of cytochrome c into cytosol.10
(1) (a) Tomita, F.; Tamaoki, T.; Shirahata, K.; Kasai, M.; Morimoto, M.;
Ohkubo, S.; Mineura, K.; Ishii, S. J. Antibiot. 1980, 33, 668-670. (b)
Tomita, F.; Tamaoki, T. J. Antibiot. 1980, 33, 940-945. (c) Tamaoki, T.;
Kasai, M.; Shirahata, K.; Okubo, S.; Morimoto, M.; Mineura, K.; Ishii, S.;
Tomita, F. J. Antibiot. 1980, 33, 946-950. (d) Tamaoki, T.; Kasai, M.;
Shirahata, K.; Tomita, F. J. Antibiot. 1982, 35, 979-984. (e) Jpn. Kokai
Tyokko Koho, (Kyowa Hakko Kogyo Co., Ltd., Japan) Application: JP
80-128605 57053498 JP, p 12 pp, 1982.
(2) (a) Igarashi, Y.; Takagi, K.; Kan, Y.; Fujii, K.; Harada, K.-I.; Furumai, T.;
Oki, T. J. Antibiot. 2000, 53, 233-240. (b) Furumai, T.; Takagi, K.;
Igarashi, Y.; Saito, N.; Oki, T. J. Antibiot. 2000, 53, 227-232.
(3) Shimotohno, K. W.; Endo, T.; Furihata, K. J. Antibiot. 1993, 46, 682-
684.
The centerpiece of the structures of the tetrocarcins, arisos-
tatins, and AC6H is the spirotetronic acid aglycone (+)-
tetronolide (1).11 (+)-Tetronolide (1) is one member of a notable
group of complex spirotetronate aglycones that also includes
(7) Tinhofer, I.; Anether, G.; Senfter, M.; Pfaller, K.; Bernhardt, D.; Hara,
M.; Greil, R. FASEB J. 2002, 16, 1295-1297.
(4) Tamaoki, T.; Tomita, F.; Kawamura, F.; Saito, H. Agric. Biol. Chem. Tokyo
1983, 47, 59-65.
(8) Anether, G.; Tinhofer, I.; Senfter, M.; Greil, R. Blood 2003, 101, 4561-
(5) Morimoto, M.; Fukui, M.; Ohkubo, S.; Tamaoki, T.; Tomita, F. J. Antibiot.
1982, 35, 1033-1037.
4568.
(9) Kaneko, M.; Nakashima, T.; Uosaki, Y.; Hara, M.; Ikeda, S.; Kanda, Y.
Bioorg. Med. Chem. Lett. 2001, 11, 887-890.
(6) (a) Nakashima, T.; Miura, M.; Hara, M. Cancer Res. 2000, 60, 1229-
1235. (b) Hara, T.; Omura-Minamisawa, M.; Chao, C.; Nakagami, Y.; Ito,
M.; Inoue, T. Int. J. Radiat. Oncol., Biol., Phys. 2005, 61, 517-528.
(10) Kim, Y.-H.; Shin, H. C.; Song, D. W.; Lee, S.-H.; Furumai, T.; Park, J.-
W.; Kwon, T. K. Biochem. Biophys. Res. Commun. 2003, 309, 449-456.
9
10572
J. AM. CHEM. SOC. 2006, 128, 10572-10588
10.1021/ja0581346 CCC: $33.50 © 2006 American Chemical Society

A Total Synthesis of (
+
)-Tetronolide
A R T I C L E S
Chart 1
Scheme 1
kijanolide, chlorothricolide, and several other related struc-
tures.12-14 Beginning in the mid 1980s, these materials have
attracted considerable attention among synthetic chemists,15-18
including our group,19 owing to their complex and intricate
architecture and promising biological activity. Efforts, thus far,
have resulted in one total synthesis17 and one formal total
synthesis of (+)-tetronolide,18 as well as the syntheses of (-)-
chlorothricolide16a related analogues16c,d and derivatives and an
advanced seco-acid intermediate toward kijanolide.16b
The majority of the efforts toward these spirotetronic acid
systems recognized the value of disconnection of this class of
(11) (a) Hirayama, N.; Kasai, M.; Shirahata, K.; Ohashi, Y.; Sasada, Y. Bull.
Chem. Soc. Jpn. 1982, 55, 2984-2987. (b) Hirayama, N.; Kasai, M.;
Shirahata, K.; Ohashi, Y.; Sasada, Y. Tetrahedron Lett. 1980, 21, 2559-
2550.
(12) (a) Furumai, T.; Takagi, K.; Igarashi, Y.; Saito, N.; Oki, T. J. Antibiot.
2000, 53, 227-232. (b) Hegde, V. R.; Patel, M. G.; Das, P. R.; Pramanik,
B.; Puar, M. S. J. Antibiot. 1997, 50, 126-134. (c) Shimotohno, K. W.;
Endo, T.; Furihata, K. J. Antibiot. 1993, 46, 682-684. (d) Luk, K.;
Readshaw, S. A. J. Chem. Soc., Perkin Trans. 1 1991, 1641-1644. (e)
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, 1497-1534.
(f) Mallams, A. K.; Puar, M. S.; Rossman, R. R.; McPhail, A. T.;
Macfarlane, R. D. J. Am. Chem. Soc. 1981, 103, 3940-3943.
(13) (a) Tanabe-Tochikura, A.; Nakashima, H.; Murakami, T.; Tenmyo, O.; Oki,
T.; Yamamoto, N. AntiViral Chem. Chemother. 1992, 3, 345-349. (b)
Tsunakawa, M.; Tenmyo, O.; Tomita, K.; Naruse, N.; Kotake, C.; Miyaki,
T.; Konishi, M.; Oki, T. J. Antibiot. 1992, 45, 180-188. (c) Kusumi, T.;
Ichikawa, A.; Kakisawa, H.; Tsunakawa, M.; Konishi, M.; Oki, T. J. Am.
Chem. Soc. 1991, 113, 8947-8948.
molecules into two major (upper and lower) fragments (Scheme
1). The only previously reported strategy for the critical
connection of the two major fragments for (+)-tetronolide was
due to the Yoshii group and involved an aldol condensation
between an R-metalated protected spirotetronate and a hy-
dronaphthalene carboxaldehyde.17a
(14) Coll, J. C.; Kearns, P. S.; Rideout, J. A.; Hooper, J. J. Nat. Prod. 1997,
60, 1178-1179 and references therein.
(15) (a) Roush, W. R.; Barda, D. A.; Limberakis, C.; Kunz, R. K. Tetrahedron
2002, 58, 6433-6454 and references therein. (b) Roush, W. R.; Chen, H.;
Reilly, M. L. Heterocycles 2002, 58, 259-282 and references therein. (c)
Yoshii, E.; Takeda, K. Rec. Prog. Chem. Synth. Antibiot. Relat. Microb.
Prod. 1993, 67-98.
(16) (a) Roush, W. R.; Sciotti, R. J. J. Am. Chem. Soc. 1998, 120, 7411-7419.
(b) Roush, W. R.; Sciotti, R. J. J. Org. Chem. 1998, 63, 5473-5482. (c)
Takeda, K.; Igarashi, Y.; Okazaki, K.; Yoshii, E.; Yamaguchi, K. J. Org.
Chem. 1990, 55, 3431-3434. (d) Ireland, R. E.; Varney, M. D. J. Org.
Chem. 1986, 51, 635-648.
(17) (a) Takeda, K.; Kawanishi, E.; Nakamura, H.; Yoshii, E. Tetrahedron Lett.
1991, 32, 4925-4928. (b) Takeda, K.; Kobayashi, T.; Saito, K.; Yoshii,
E. J. Org. Chem. 1988, 53, 1092-1095. (c) Takeda, K.; Urahata, M.; Yoshii,
E.; Takayanagi, H.; Ogura, H. J. Org. Chem. 1986, 51, 4735-4737. (d)
Takeda, K.; Kato, H.; Sasahara, H.; Yoshii, E. J. Chem. Soc., Chem.
Commun. 1986, 1197-1198. (e) Takeda, K.; Shibata, Y.; Sagawa, Y.;
Urahata, M.; Funaki, K.; Hori, K.; Sasahara, H.; Yoshii, E. J. Org. Chem.
1985, 50, 4673-4681.
(18) (a) Roush, W. R.; Reilly, M. L.; Koyama, K.; Brown, B. B. J. Org. Chem.
1997, 62, 8708-8721. (b) Roush, W. R.; Brown, B. B. J. Am. Chem. Soc.
1993, 115, 2268-2278. (c) Roush, W. R.; Koyama, K. Tetrahedron Lett.
1992, 33, 6227-6230.
(19) (a) Boeckman, R. K., Jr.; Estep, K. G.; Nelson, S. G.; Walters, M. A.
Tetrahedron Lett. 1991, 32, 4095-4098. (b) Boeckman, R. K., Jr.; Barta,
T. E.; Nelson, S. G. Tetrahedron Lett. 1991, 32, 4091-4094. (c) Boeckman,
R. K., Jr.; Wrobleski, S. T. J. Org. Chem. 1996, 61, 7238-7239.
In 1991, our group reported preliminary findings regarding
use of a similar disconnection through intermediates 2-4 but
involving a quite different strategy for coupling the major upper
and lower fragments, 5 and 6, employing a tandem ketene-
trapping/[4 + 2] cycloaddition sequence (Scheme 1).19a,b In
1996, we reported a new enantioselective synthesis of the upper
fragment, synthon 5, employing our camphor-derived auxiliary
to establish the chirality.19c In this paper, we report a full account
of all of our studies that culminated in an enantioselective total
synthesis of (+)-tetronolide (1). Our route highlights use of
auxiliary-mediated asymmetric alkylation, use of a chiral
auxiliary-mediated anchimerically assisted SN1 substitution in
a novel construction of a highly enantiomerically enriched mixed
acetal, and use of the aforementioned tandem ketene-trapping/
[4 + 2] cycloaddition strategy to efficiently and highly
stereoselectively connect major enantiomerically pure fragments
5 and 6.
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A R T I C L E S
Scheme 2
Boeckman et al.
Scheme 3
the lactam carbonyl would allow substitution/coupling with the
dienol ester 9 with overall retention of configuration at the acetal
center. We also believed that differential nonbonded interactions
within the dibromide 10 would permit kinetically controlled
formation of a single diastereomeric iminium ion intermediate,
thus leading to control over diastereoselectivity in the formation
of 7 and eventual control over absolute chirality at the mixed
acetal center in 7 upon removal of the chiral auxiliary. Our initial
selection of the (-)-(1R) antipode of 8 was based on our putative
mechanistic model. Assignment of the observed (if any) sense
of asymmetric induction awaited confirmation by experiment.
This concept was reduced to practice beginning with meta-
lation of divinyl ether (11)22 with Schlosser’s base23 at -78 °C
in THF and trapping with (n-Bu)3SnCl, affording 98% of the
sensitive R-stannylated divinyl ether 12 (Scheme 3). Tin-
lithium exchange using n-BuLi in THF at -78 °C followed by
in situ trapping with solid CO2 afforded the expected pure
lithium carboxylate 13 in 89% yield upon removal of the THF
and precipitation from pentane. Direct preparation of 13 was
attempted by in situ trapping of the metalated vinyl ether
intermediate produced by treatment with Schlosser’s base. While
the expected carboxylate salt was obtained, it proved to be a
mixture of K and Li salts that hampered further transformations
owing to diminished solubility of the mixed salt. Installation
of the lactam auxiliary was then accomplished by conversion
of 13 to a mixed anhydride with PhSO2Cl and in situ coupling
with the lithium salt derived from (-)-(1R)-lactam 8 (either
antipode of 8 can be prepared in four steps from the related
antipode of camphoric acid).21 This procedure afforded the
desired imide 14 in 77% yield (67% from divinyl ether). The
principal drawback was the relatively rapid formation of the
symmetrical anhydride leading to incomplete conversion. An
alternate concatenated “one-pot” procedure was later developed
that avoided use of tin reagents and employed the mixed
anhydride derived from ethyl chloroformate and the potassium
salt of lactam 8 (required to ensure regioselective attack on the
more reactive acyl group), affording 14 in 36% overall yield
from divinyl ether (three steps at 71%/step). With vinyl enol
pyruvoyl imide 14 in hand, the more reactive enol ether moiety
was brominated to afford in approximately quantitative yield
the unstable dibromide 10, which was used without purification.
Crude dibromide 10 was initially isolated as a ∼6:1 mixture of
Discussion
Construction of the Upper-Half Subunit: Cyclohexenol
5. Our strategy for the upper synthon cyclohexenol 5 is
embodied in the retrosynthetic analysis shown in Scheme 2.19a,c
The relative stereochemical arrangement of the substituents
present on the cyclohexene ring suggested the use of a [4 + 2]
cycloaddition as a key transformation. However, application of
that retrosynthesis required modification of the position of the
unsaturation in the six-membered ring. Fortunately, that modi-
fication fit nicely in the functional group manipulations neces-
sary to stereoselectively install the protected hydroxyl group
ultimately residing at C21 (tetronolide numbering, see Scheme
1). We chose to employ the intramolecular Diels-Alder (IMDA)
variant in order to take advantage of the concave shape of the
intermediate cis-decalin cycloadduct that we felt would ensure
high diastereoselectivity in the required functional group
manipulations. At the time, we reasoned that use of a tethered
diene and dienophile would provide not only control over
regiochemistry but also a likely preference for the required exo
transition state geometry. Subsequent reports by Roush and co-
workers have shown that this device is unnecessary as enolpyru-
vate ester dienophiles as a class show a strong preference for
cycloaddition via an exo transition state.15,16,18
The initial objective was preparation of enantiomerically pure
chiral acetal 7 that would serve as the lynchpin in the subsequent
[4 + 2] cycloaddition simultaneously exerting control over
regio- and relative stereochemistry in the resulting cycloadduct.
No precedent existed for the preparation of an enantiomerically
pure mixed acetal linkage, such as that found in 7, although we
had employed vinyl ethers to construct such mixed acetals in
racemic form employing Hg(II) to effect coupling followed by
reductive demercuration and using Br+ as the electrophile in
our published synthesis of racemic 5.19a,20
We adapted the latter process for enantioselective creation
of the required mixed acetal linkage, as shown in Scheme 3,
by incorporation of the 3-azacamphor lactam 821 into the
precursor electrophile, reasoning that anchimeric assistance by
(22) Brandsma, L.; Arens, J. F. Recl. TraV. Chim. Pays-Bas 1962, 81, 33-38.
(23) (a) Schlosser, M. Mod. Synth. Met. 1992, 6, 227-271. (b) Schlosser, M.;
Strunk, S. Tetrahedron Lett. 1984, 25, 741-744. (c) Schlosser, M. J.
Organomet. Chem. 1967, 8, 9-16. (d) Lochmann, L.; Pospisil, J.; Lim, D.
Tetrahedron Lett. 1966, 257-262.
(20) Boeckman, R. K., Jr.; Flann, C. J. Tetrahedron Lett. 1983, 24, 4923-
4926.
(21) Boeckman, R. K., Jr.; Nelson, S. G.; Gaul, M. D. J. Am. Chem. Soc. 1992,
114, 2258-2260.
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A Total Synthesis of (
+
)-Tetronolide
A R T I C L E S
Scheme 4
Scheme 5
diastereomers that we felt boded well for our ability to obtain
diastereoselectivity in the key substitution/coupling process and
demonstrated that the auxiliary (by whatever mechanism) was
able to exert remote control of diastereoselectivity in reactions
of the vinyl ether moiety in 14. As expected, dibromide 10
proved to be an extremely sensitive substance. Simply on
standing in solution overnight, the initial ∼6:1 mixture of
diastereomers of 10 underwent an autocatalytic isomerization
to a 1:1 mixture of diastereomers. Fortunately, use of either of
these mixtures of diastereomers of 10 in the subsequent coupling
procedure afforded 7 with the same high level of diastereose-
lectivity.
Remarkably, the choice of the alcohol employed for the
coupling with dibromide 10 also proved critical. Use of versions
of dienol ester 9 bearing terminal functional groups at lower
oxidation states than ester (acetal and protected alcohol) proved
unworkable owing to rapid decomposition of these materials
under the reaction conditions employed for coupling. Although
TBS-protected ester 9 can be assembled by sequential olefination
reactions beginning with the TBS ether of hydroxyacetaldehyde,
this sequence is suitable for preparation of only relatively small
quantities (1-10 g) of 9. Thus, we developed a convenient four-
step process beginning with commercial sorbaldehyde 15 (an
inconsequential E/Z mixture (5:1) of terminal double bond
isomers) and diisopropyl tert-butylphosphonoacetate 16,24 as
shown in Scheme 4. Condensation of 15 and 16 afforded the
sensitive and unstable triene 17. Sharpless catalytic dihydroxy-
lation25 afforded a mixture of diol esters 18 that were directly
converted to alcohol 9 by oxidation of 18 with NaIO4 in aqueous
THF and reduction of resulting muconaldehydic ester 19 with
NaBH4 in CH3OH/THF. This sequence afforded 9 in 67%
overall yield from 15 after the only required purification
(chromatography).
As shown in Scheme 5, the key highly diastereoselective
coupling of 9 and 10 was subsequently achieved by addition of
1 equiv of freshly prepared dibromide 10 to a heterogeneous
mixture containing 1.4 equiv of alcohol 9, 1.2 equiv of
2,6-lutidine, 1.06 equiv of AgOTf, and excess anhydrous Na2-
CO3 in CH2Cl2 at -78 °C followed by warming slowly to room
temperature over 16 h in the dark. Workup and chromatographic
purification delivered an inseparable mixture of diastereomeric
mixed acetals 7 (96:4) that proved suitable for further trans-
formations. During scale-up of this reaction, a minor byproduct
20 was isolated that shed light on the mechanism of this
transformation and validated our original design concept. A
plausible mechanism accounting for the sense of asymmetric
induction and production of 20 is outlined in Scheme 6.
We initially expected that we might effect the required
intramolecular [4 + 2] cycloaddition employing 7 as the
substrate. However, as is the case for analogous imides,21,26
7
proved unreactive thermally up to its decomposition point.
Normally Lewis acid promoters, such as CH3AlCl2, are em-
ployed.21,26 However, this effort proved fruitless despite exten-
sive experimentation, during which a variety of Lewis acid
promoters and reaction conditions were screened, owing to the
extreme sensitivity of the acetal linkage in 7 to Lewis acids.
Thus, we adopted the general sequence to the racemic top-
half synthon 5 previously developed in our group using an ethyl
ester.19a We converged with that previous sequence by cleavage
of the chiral imide moiety of 7 with Ti(OiPr)4, affording an
analogous isopropyl ester 21 in 95% yield, as detailed in Scheme
5. The sensitivity of 7 to Lewis acid is testament to the mildness
of this transesterification procedure. The thermal intramolecular
Diels-Alder (IMDA) reaction of ester 21, bearing the acetal-
tethered diene and dienophile, wherein the chirality of the acetal
linkage defines the facial selectivity in the Diels-Alder reaction,
proceeded smoothly under carefully defined reaction conditions
owing to the acid sensitivity of triene 7. Heating a 0.024 M
solution of 8 under Ar in the presence of BHT and Na2CO3 in
a 155 °C oil bath in either a sealed or open vessel (the former
is preferred) for ∼114 h affords a 1:5 mixture of trans-22 and
cis-23 bicyclic bromoacetals in 65% overall yield. The diaste-
(24) Ye, W.; Liao, X. Synthesis 1985, 986-988.
(25) Zhang, Y.; O’Doherty, G. A. Tetrahedron 2005, 61, 6337-6351.
(26) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988, 110,
1238-1256.
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A R T I C L E S
Scheme 6
Boeckman et al.
Scheme 7
reoselectivity favoring formation of cis bicyclic acetal 23 as
the major diastereomer via an exo transition state is consistent
with the observations of Roush mentioned earlier.15,16,18 In this
case, tethering the diene and dienophile may actually serve to
enhance the formation of the undesired trans isomer by favoring
the endo transition state owing to more favorable nonbonded
interactions within the tether in the transition state. Attempts
to increase the concentration or to raise the temperature led to
lower yields. The sensitivity of triene 7 precludes shortening
the reaction time by the usual means of increasing the rate. Use
of the bulkier isopropyl ester marginally improved the diaste-
reoselectivity (1:3-4 to 1:5) in favor of the desired cis Decalin
isomer. The subsequent transformation of the cis IMDA adduct
23 to the required differentially protected hydroxy ester 5 was
straightforward via the previously defined route.19a Epoxidation
of 23 with buffered mCPBA led to a single stereoisomeric
epoxide that was directly treated with DBU in THF at room
temperature to effect â-elimination to the unsaturated tert-butyl
ester 24 in 84% yield over two steps. The tert-butyl ester moiety
of 24 was cleaved by exposure to TFA at room temperature,
affording acid 25 in near quantitative yield. Acid 25 was then
sequentially selectively reduced by conversion to the mixed
anhydride with ethyl chloroformate followed by in situ reduction
with NaBH4 in methanol/THF and the primary allylic alcohol
selectively silylated with tert-butyldiphenylsilyl chloride (TBP-
SCl), affording alcohol 26 in 70% yield over four steps. The
remaining secondary alcohol was then protected with meth-
oxymethyl chloride (MOMCl) under the usual conditions.
Liberation of the tertiary alcohol required for coupling the upper
and lower major subunits was effected by regioselective
reductive fragmentation of the bromoacetal linkage with the Zn-
(Ag) couple in buffered methanol at reflux, affording hydroxy
ester 5 as the only observed regioisomer.27 The regioselectivity
of this transformation may result from both stereoelectronic and
steric factors. The oxygen adjacent to the angular ester moiety
in 26 would be expected to be the more electron deficient and
thus the better leaving group, and the conformation in which
the C-Br bond aligns itself antiperiplanar to that oxygen appears
to be less sterically congested. The absolute stereochemistry of
(+)-5 was tentatively assigned by analogy to the related ethyl
ester19c and confirmed by X-ray analysis of an advanced
intermediate (vide infra) as well as by conversion of (+)-5 to
(+)-tetronolide (1).
Construction of the Lower-Half Subunit: Tetraene Di-
oxolenone 6. Our sequence to prepare dioxolenone 6 com-
menced with diastereoselective alkylation of the lithium enolate
derived from propionimide 27 with allylic iodide 28 protected
as a methoxyphenylmethyl (MPM) ether to afford imide 29 as
a single diastereomer in 70% yield (Scheme 7).28 Reductive
removal of the auxiliary with LAH in ether, silylation of the
resulting primary alcohol with TBPSCl and imidazole, followed
by cleavage of the MPM group with DDQ in wet CH2Cl2
afforded the alcohol 30 employed in our previous route to 6 in
68% overall yield.19b
(28) Boeckman, R. K., Jr.; Boehmler, D. J.; Musselman, R. A. Org. Lett. 2001,
3, 3777-3780.
(27) Clark, R. D.; Heathcock, C. H. J. Org. Chem. 1973, 38, 3658.
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A Total Synthesis of (
+
)-Tetronolide
A R T I C L E S
Scheme 8
Scheme 9
As previously described,19b Sharpless epoxidation of 30
afforded the expected epoxide (8:1 dr) followed by benzylation
of the resulting epoxy alcohol, affording epoxide ether 31 in
75% yield for two steps.19b Completely regioselective opening
of the epoxide with the ate-complex derived from n-BuLi and
(CH3)3Al then provided alcohol 32 in 78% yield.29 Alcohol 32
was smoothly transformed to primary alcohol 33 in 77% yield
over two steps by MOM protection under standard conditions
and hydrogenolysis of the benzyl ether with H2 (1 atm) over
Pd/C in ethanol.
Scheme 10
Diphenyl phosphine oxide 34 was prepared in five steps from
commercial (E)-3-methyl-2-penten-4-yne-1-ol (35) by the se-
quence shown in Scheme 8. Protection of the hydroxyl function
as the MPM ether with NaH and MPMCl afforded the expected
ether 36 in 70% yield. Hydroxymethylation of the terminal
alkyne with n-BuLi and paraformaldehyde afforded the prop-
argyl alcohol 37 in near quantitative yield. Reduction of the
propargyl alcohol 37 with LAH in THF provided the (E,E)-
dienol 38 in 81% yield. Dienol 38 was converted to the (E,E)-
dienyl chloride 39 with NCS-DMS (98%), and 39 was alkylated
with LiPPh2 in THF affording 91% of the required phosphine
oxide 34.
Oxidation of alcohol 33 (Scheme 7) under Swern conditions30
afforded the unstable aldehyde that was directly subjected to
olefination with dienyl diphenyl phosphine oxide 34. Lithiation
of phosphine oxide 34 and condensation with the foregoing
aldehyde derived from 33 in the presence of HMPA afforded
(E,E,E)-triene alcohol 40 (>15:1 E,E,E isomer) in 91% overall
yield after removal of the TBPS group with TBAF in THF.
Finally, dioxenone 6 was assembled by Swern oxidation of 40
and Horner-Wadsworth-Emmons olefination of the resulting
aldehyde with dioxenone phosphonate 4131 in the presence of
HMPA, affording the E,E,E,E tetraene dioxolenone 6 [>12:1
(all other isomers)] in 78% overall yield for two steps.19b
Conjoining of the Lower- and Upper-Half Fragments. We
began our studies of the critical tandem ketene-trapping/[4 +
2] cycloaddition as shown in Scheme 9. Our initial approach
involved prior deblocking and closure of 5 to the related
γ-lactone 42.
However, despite considerable experimentation, all attempts
to couple lactone 42 with 6 to afford â-ketoester lactone 4 failed.
We surmised that the failure stemmed from impaired nucleo-
philicity of the tertiary OH group owing to a stereoelectronic
effect resulting from the enforced alignment of the lactone
carbonyl π-orbitals and the adjacent CO bond. In accord with
that hypothesis, heating a mixture of 5 (1.93 equiv) and 6 in
xylenes in a sealed tube afforded the desired â-ketoester 43,
resulting from tandem ketene-trapping/[4 + 2] cycloaddition,
as a single diastereomer in 69% yield (Scheme 10).
(29) (a) Pfaltz, A.; Mattenberger, A. Angew. Chem. 1982, 94, 79. (b) Flippin,
L. A.; Brown, P. A.; Jalali-Araghi, K. J. Org. Chem. 1989, 54, 3588-
3596.
(30) (a) Mancuso, A. J.; Swern, D. Synthesis 1981, 165-185. (b) Omura, K.;
We noted that 43 was unstable to prolonged heating eventu-
ally regenerating 5 and the methyl ketone derived from the
IMDA adduct of 6. We could partially overcome this limita-
tion by allowing the reaction to proceed to partial completion
Swern, D. Tetrahedron 1978, 34, 1651-1660.
(31) (a) Boeckman, R. K., Jr.; Kamenecka, T. M.; Nelson, S. G.; Pruitt, J. R.;
Barta, T. E. Tetrahedron Lett. 1991, 32, 2581-2584. (b) Sato, M.;
Ogasawara, H.; Komatsu, S.; Kato, T. Chem. Pharm. Bull. 1984, 32, 3848-
3856.
9
J. AM. CHEM. SOC. VOL. 128, NO. 32, 2006 10577

A R T I C L E S
Boeckman et al.
Scheme 11
Figure 1. ORTEP (40% probability thermal ellipsoids); final X-ray model
of diol 46.
(50-75%) affording 43 in 97% yield based on consumed 6
(excellent recovery of all materials). Prior work had established
the order of the steps as ketene trapping followed by IMDA
cycloaddition.19b Compared to related IMDA cycloadditions of
similar substrates,15-17 cyclization of the tetraene intermediate
derived from 5 and 6 was significantly more stereoselective.
We attribute the increased stereoselectivity to the additional
influence of double diastereoselection, whereby the desired
transition state becomes relatively more energetically favorable.
Direct closure of 43 to the spirotetronic acid 44 also failed
initially. We had originally anticipated that ketoester 43 might
be poorly aligned for intramolecular acylation,32 hence our
decision to attempt coupling of the derived γ-lactone. This
concept was validated by removal of the vinyl ether protecting
group in 43 prior to cyclization, permitting in situ generation
of the required activated γ-lactone, providing the desired
O-methyl spirotetronic acid 45 after methylation with TM-
SCHN2. The fact that cyclization required at least 2 equiv of
base provides support for a pathway proceeding via initial
conversion to a γ-lactone (Scheme 10).
The gross structure of O-methyl hydroxy spirotetronate 45
was not completely secure since spectroscopic data could not
readily distinguish which oxygen of the acyltetronic acid unit
had undergone methylation. Further, upon transformation to the
related aldehyde derived from primary alcohol 45 by oxidation,33
we observed the first of a series of four intermediates that
exhibited atropisomerism which we attribute to slow rotation
about the hindered C3-C4 bond. Epimerization at C20 during
oxidation was ruled out by re-reduction of the aldehyde to 45
with NaBH4, confirming the existence of atropisomers. To
conclusively resolve all the structural and stereochemical issues,
the TBDPS ether in 45 was removed with TAS-F,34 and the
resulting crystalline diol 46 was subjected to single-crystal X-ray
analysis that confirmed the structure and relative stereochemistry
of 45 in all respects (Figure 1).
effectively preventing bond rotation about the hindered C3-C4
bond (Figure 1).
Elaboration of 45 to Intermediates Bearing the Bridging
Macrocyclic Ring. The elaboration of the bridging macrocyclic
ring from alcohol 45 initially requires extension of the upper
side chain by three carbons to an (E)-R-methyl-R,â-unsaturated
aldehyde. This homologation to the (E)-enal 48 initially proved
troublesome owing to the strong tendency to form the Z isomer
of the enal under kinetic control. A number of literature
procedures that, based on existing precedent, were expected to
afford the desired (E)-enal 48 were attempted. For example,
condensation of aldehyde 47 derived from oxidation of 45 with
Dess-Martin periodinane (DMP)33 with lithiated TMSCH-
(CH3)CHdNtBu (49) as reported by Corey35 afforded mainly
the (Z)-R-methyl-R,â-unsaturated N-tert-butylimine. Modifica-
tion of the counterion to a more covalent metal, such as Mg,
by transmetalation of 49 with MgBr2‚Et2O afforded up to a 3:1
mixture (E:Z) of 48 after hydrolysis. Since the mixtures of the
E and Z aldehydes 48 were not easily separable on scale, we
chose to explore means to obtain more stereoselectivity in the
olefination.
We chose to employ a thermodynamically controlled olefi-
nation previously developed in our group involving addition of
(Z)-1-ethoxy-2-propenyl Grignard reagent prepared from the (Z)-
1-bromo-2-ethoxy-2-propene in ether/THF to aldehyde 47
followed by treatment of the crude alcohols with (CF3CO)2O
and CF3COOH in CH2Cl2.36 This procedure afforded exclusively
the desired (E)-enal 48 in 78% overall yield in two steps from
alcohol 45 (Scheme 11). (E)-Enal 48 was then straightforwardly
transformed to the allylic chloride 50. Removal of the MPM
group proceeded smoothly upon treatment of 48 with DDQ in
Alcohol 45, surprisingly, does not exhibit atropisomerism.
We were able understand this observation based upon the X-ray
data for diol 46 that revealed a macrocyclic H-bond between
the C16 oxygen function and the C19 hydroxyl group (tetronolide
numbering) stabilizing one of the two atropisomers, thus
(32) Lacey, R. N. J. Chem. Soc. 1954, 832-839.
(33) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156. (b)
Boeckman, R. K., Jr.; Shao, P.; Mullins, J. J. Org. Synth. 2000, 77, 141-
152.
(34) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey, D. S.;
Roush, W. R. J. Org. Chem. 1998, 63, 6436-6437.
(35) Corey, E. J.; Enders, D.; Bock, M. G. Tetrahedron Lett. 1976, 7-10.
(36) Boeckman, R. K., Jr.; Starrett, J. E., Jr.; Nickell, D. G.; Sum, P. E. J. Am.
Chem. Soc. 1986, 108, 5549-5559.
9
10578 J. AM. CHEM. SOC. VOL. 128, NO. 32, 2006

A Total Synthesis of (
+
)-Tetronolide
A R T I C L E S
Scheme 12
wet methylene chloride. The resulting crude primary alcohol
was directly converted to the corresponding primary allylic
chloride 50 upon exposure to a mixture of hexachloroacetone
and PPh3 in CH2Cl2 initially at -40 °C with warming to -25
°C for 15 min.
We examined a number of new macrocyclization sequences
mediated by conversion of the allylic chloride 50 to various
allylic organometallic reagents without success. Similar results
for other macrocyclization methods were obtained much earlier
by Yoshii and co-workers during their model studies of this
macrocycle formation.17d Among the various methods examined,
there were variants of Barbier cyclizations37 employing Mg,38
Zn,39 and Sm,40 including the method of Yamamoto employing
metallic Ba which is reported to permit R-selective addition to
carbonyl groups especially in the presence of 18-crown-6.41 The
results of most experiments led to uncharacterized product
mixtures. In those cases where we believe that cyclized products
were, in part, obtained, they were tentatively assigned as arising
from γ-addition of the proximal carbon of the allylic system to
the aldehyde, leading to the smaller (12-membered ring) of the
two macrocycles.
reasoned that removal of the O-methyl group might actually
promote macrocyclization by permitting facile bond rotation
around the C3-C4 bond. Thus, we were led to try macrocy-
clization of the tetronate sodium salt 51. We reasoned that the
Na+ ion could serve to template the macrocyclization through
coordination to both the sulfonate carbanion and the electro-
philic aldehyde oxygen in the transition state in the nonpolar
medium. Such a templated cyclization transition state seemed
all the more plausible owing to the observation of the macro-
cyclic H-bond in the solid-state structure of the diol 46 (Figure
1) and our earlier likely observation of such a templated
process.42 In the event, cyclization of 51 in the presence of
excess NaOtAm in benzene afforded the macrocyclic ketone
53 in 50% overall yield after the usual concatenated oxidation
and reductive desulfonylation operations (Scheme 12). Some
support for the hypothesis that cyclization is proceeding via a
metal-templated transition state is derived from addition of 18-
crown-6 to the reaction mixture during cyclization of 51, in
which the expected cyclization is suppressed and no ketone 53
is obtained after the usual further processing. Similar behavior
was noted in our earlier studies of such a probable templated
process.42
Thus, we adopted a strategy similar to that of Yoshii,
employing a Julia olefination/macrocyclization.10a,c Conversion
of allylic chloride 50 to allylic sulfone 51 was readily achieved
upon exposure of 50 to excess sodium benzenesulfinate in DMF
at room temperature for 1.5 h (Scheme 11). During this
transformation, it was noted that dealkylation of the O-
methyltetronate occurred, providing the readily purified sodium
salt of sulfone tetronic acid 51. As advanced intermediates, we
found the sodium salts of the tetronic acids, such as 51, to be
readily purified on silica gel and altogether simpler to handle
than the free tetronic acids. It was possible to acidify and
re-O-methylate 51 by treatment with TMSCHN2 to afford
O-methyl sulfone 52. The structure of 52 was verified by its
direct formation as a mixture with 51 upon treatment of 50
with only a slight excess of sodium benzenesulfinate in THF at
room temperature. Remarkably, cyclization failed when sul-
fone 52 was treated with NaOtAm in benzene, conditions
found to effect cyclization in the regioisomeric O-methyl-
tetronate series.10a It is possible that the regiochemistry of
methylation of the tetronate residue is responsible since the
Yoshii group apparently never encountered the presence of
atropisomers as we have observed for our intermediates 47,
48, 50, and 52. Slow rotation about the C3-C4 bond would
certainly be expected to impede cyclization, perhaps allowing
competing base-catalyzed processes to intervene. Thus, we
Final Stage Transformations of Ketone 53 to (+)-Tetrono-
lide (1). As previously reported for structurally related
derivatives,17a reduction of ketone 53 with L-Selectride and
direct protection with MOMCl/DIPEA afforded the fully
protected spirotetronate 54 in 71% yield over two steps
(Scheme 13). Desilylation of the base-sensitive 54 with TAS-
F,34 DMP oxidation in CH2Cl2,33 and acidic global deprotec-
tion afforded synthetic (+)-tetronolide (1) [mp 210-211 °C
(lit.17a
211-213 °C); [R]25 +72.6° (c 0.34, acetone) [lit.17a
D
+79.3° (c 1.0, acetone)]] spectroscopically identical (1H
NMR) in all respects with synthetic17a and natural (+)-
tetronolide (1). It is interesting to note that, with the exception
of (+)-tetronolide (1) itself, we found it easier to handle, purify,
and characterize the sodium salts of the final series of
intermediates as opposed to handling these intermediates as the
free tetronic acids.
(37) (a) Kagan, H. B. Tetrahedron 2003, 59, 10351-10372. (b) Banik, B. K.
Eur. J. Org. Chem. 2002, 2431-2444. (c) Luche, J.-L.; Sarandeses, L. A.
Organozinc Reagents 1999, 307-323. (d) Alonso, F.; Yus, M. Rec. Res.
DeV. Org. Chem. 1997, 1, 397-436. (e) Russo, D. A. Chem. Ind. (Dekker)
1996, 64, 405-439.
(38) (a) Wang, D.-K.; Dai, L.-X.; Hou, D.-L.; Zhang, Y. Tetrahedron Lett. 1996,
37, 4187-4188. (b) Crandall, J. K.; Magaha, H. S. J. Org. Chem. 1982,
47, 5368-5371.
The above-described total synthesis of (+)-tetronolide (1) is
shorter (∼27 steps along the longest linear sequence) and higher
yielding than the only previously described synthesis17a and
exemplifies the utility of notable new methodology for creation
of chiral mixed acetals19c and for connection of large molecular
fragments via a tandem ketene-trapping/[4 + 2] cycloaddition
strategy that is significantly more stereoselective overall than
similar, previously reported IMDA cycloadditions.
(39) Makosza, M.; Grela, K.; Fabianowski, W. Tetrahedron 1996, 52, 9575-
9580.
(40) (a) Williams, D. R.; Berliner, M. A.; Stroup, B. W.; Nag, P. P.; Clark, M.
P. Org. Lett. 2005, 7, 4099-4102. (b) Basu, M. K.; Banik, B. K.
Tetrahedron Lett. 2001, 42, 187-189. (c) Kunishima, M.; Yoshimura, K.;
Nakata, D.; Hioki, K.; Tani, S. Chem. Pharm. Bull. 1999, 47, 1196-1197.
(d) Kito, M.; Sakai, T.; Shirahama, H.; Miyashita, M.; Matsuda, F. Synlett
1997, 219-220. (e) Molander, G. A.; McKie, J. A. J. Org. Chem. 1991,
56, 4112-4120.
(41) (a) Yanagisawa, A.; Yamada, Y.; Yamamoto, H. Synlett 1997, 1090-1092.
(b) Yanagisawa, A.; Habaue, S.; Yasue, K.; Yamamoto, H. J. Am. Chem.
Soc. 1994, 116, 6130-6141.
(42) Boeckman, R. K., Jr.; Reeder, M. R. J. Org. Chem. 1997, 62, 6456-6457.
9
J. AM. CHEM. SOC. VOL. 128, NO. 32, 2006 10579

A R T I C L E S
Scheme 13
Boeckman et al.
TLC analysis (30% diethyl ether in hexanes) to ensure complete
consumption of 14 to give the slightly more polar dibromides 10. Upon
completion of the addition, the reaction mixture was quenched at -78
°C by the addition of 200 mL of saturated aqueous NaHCO3, and the
mixture was allowed to warm to room temperature. The phases were
separated, and the aqueous phase was extracted with two 75 mL portions
of CH2Cl2. The combined organic phases were washed with 100 mL
of brine, dried over MgSO4, filtered, and concentrated in vacuo to afford
18.2 g (∼100%) of the crude dibromide 10 as a pale yellow oil. Analysis
of the crude product mixture by 1H NMR (300 MHz, C6D6) indicated
a 6:1 mixture of diastereomers. Upon storage, the mixture equilibrated
to a ∼1:1 mixture of the diastereomers; however, either mixture was
suitable for use in the following transformation. Owing to the instability
of the dibromide, the crude product mixture was temporarily stored as
a solution in CH2Cl2 and used immediately without further purifica-
1
tion: IR (film) 2965, 1755, 1682, 1634, 1395, 1014 cm-1; H NMR
(300 MHz, C6D6) δ (major diastereomer) 5.82 (dd, J1 ) 5.1 Hz, J2 )
3.8 Hz, 1 H), 5.20 (d, J ) 3.7 Hz, 1 H), 4.96 (d, J ) 3.8 Hz, 1 H),
3.88 (d, J ) 2.1 Hz, 1 H), 3.66-3.40 (s, 3 H), 0.39 (s, 3 H); and δ
(minor diastereomer) 5.74 (dd, J1 ) 7.5 Hz, J2 ) 3.1 Hz, 1 H), 5.21
(m, 1H), 4.90 (d, J ) 3.8 Hz, 1 H), 4.03 (br s, 1 H), 3.66-3.40 (m, 2
H), 1.53 (m, 2 H), 1.25 (m, 2 H), 0.89 (s, 3 H), 0.77 (s, 3 H), 0.39
(s, 3 H); 13C NMR (75 MHz, C6D6) δ (major diastereomer) 176.0, 161.8,
153.4, 96.9, 81.9, 64.6, 55.6, 47.1, 35.1, 30.4, 26.1, 17.9, 16.7, 8.9;
and δ (minor diastereomer) 175.6, 161.5, 152.6, 97.1, 80.4, 64.2, 55.3,
46.9, 34.2, 29.8, 26.3, 17.8, 16.7, 9.0.
Experimental Section43
(+)-(1R,4S)-N-(2-Ethenyloxypropenoyl)-1,7,7-trimethyl-3-aza-
bicyclo[2.2.1]heptan-2-one (14).19c To a stirred suspension of 14.0 g
(0.117 mol) of the lithium salt 1319c (see Supporting Information) in
400 mL of THF at 0 °C were added successively 11.2 mL (15.5 g,
0.088 mol) of benzene sulfonyl chloride and 42.5 mL (32.7 g, 0.281
mol) of TMEDA, and stirring was continued at 0 °C for 4.5 h. During
this time, a solution of lithium salt 821 in THF was prepared by dropwise
addition of 39.3 mL of a 1.49 M solution of n-BuLi in hexanes (0.059
mol) to a solution of 8.95 g (0.059 mol) of 1,7,7-trimethyl-3-azabicyclo-
[2.2.1]heptan-2-one21 in 350 mL of THF at -78 °C followed by
warming to room temperature. After 4.5 h had elapsed, the reaction
mixture was recooled to -78 °C, and the aforementioned solution of
8 was added dropwise via cannula with vigorous stirring over 45 min.
After the addition was complete, the reaction mixture was allowed to
slowly warm to ambient temperature overnight (∼14 h). The reaction
mixture was then quenched by addition of 600 mL of water, the phases
were separated, and the aqueous phase was extracted with three 250
mL portions of Et2O. The combined organic phases were washed with
200 mL of brine, dried over MgSO4, filtered, and concentrated in vacuo
to afford 21.3 g of crude material as a brown liquid. Flash chroma-
tography on silica gel (with elution by 25% diethyl ether in hexanes)
provided 11.2 g (77%) of the divinyl imide 14 as a pale yellow oil
(+)-(1R,4S)-N-[2-[(1R)-2-Bromo-1-(5-tert-butoxycarbonyl-2,4-
pentadienyloxy)ethoxy]propenoyl]-1,7,7-trimethyl-3-azabicyclo-
[2.2.1]heptan-2-one (7).19c To a slurry of 13 g (47 mmol) of AgOTf
in 64 mL of CH2Cl2 was added solid Na2CO3 (ca. 7 g) at room
temperature. The mixture was cooled to -78 °C and 6.2 mL (5.7 g, 53
mmol) of 2,6-lutidine was added. After stirring for 10 min, a solution
of 11.5 g (62.3 mmol) of alcohol 9 (see Supporting Information) in 64
mL of CH2Cl2 was added dropwise via cannula over 15 min. After
stirring for an additional 5 min, a solution of 18.2 g (44.5 mmol) of
the crude dibromide 10 in 64 mL of CH2Cl2 was added dropwise via
cannula over 30 min. The reaction flask was covered with aluminum
foil to exclude light, and the mixture was allowed to stir under an argon
atmosphere for 16 h, during which time the reaction mixture was
allowed to slowly warm to room temperature. The reaction mixture
was diluted with 150 mL of Et2O and filtered through a pad of Celite
to remove the solids. The resulting filtrate was concentrated in vacuo
and the residue diluted with an additional 200 mL of Et2O; the resulting
precipitated solids were removed by filtration through a short pad of
silica gel on a bed of Celite, and the filter cake was washed with an
additional 200 mL of Et2O. The resulting clear filtrate was washed
successively with two 75 mL portions of ice cold 1 N HCl, two 75 mL
portions of saturated aqueous NaHCO3, and 50 mL of brine. The organic
phase was dried over MgSO4, filtered, and concentrated in vacuo to
afford 23.9 g of crude 7 as a clear, yellow oil (96:4 diastereomeric
mixture as determined by analysis by 500 MHz 1H NMR). Mixed acetal
7 was partially purified by flash chromatography on silica gel with
elution by 35% Et2O in hexanes to afford 18.2 g (67%) of a yellow oil
as a >96:4 diastereomeric product mixture, which was of sufficient
purity for further use (64% contained yield of 7). An analytical sample
of the major diastereomer 7 was obtained after a second purification
having [R]25 +151.2° (c 3.5, CH2Cl2). Imide 14 was stored until use
D
as a solution in methylene chloride over solid potassium carbonate to
prevent acid-catalyzed decomposition. Imide 14 had the following
spectroscopic characteristics: IR (film) 2966, 2877, 1758, 1682, 1641,
1
1356, 865 cm-1; H NMR (300 MHz, CDCl3) δ 6.48 (dd, J1 ) 13.8
Hz, J2 ) 5.9 Hz, 1 H), 4.98 (d, J ) 3.0 Hz, 1 H), 4.78 (d, J ) 3.0 Hz,
1 H), 4.78 (dd, J1 ) 13.7 Hz, J2 ) 1.5 Hz, 1 H), 4.50 (dd, J1 ) 6.2,
J2 ) 1.8 Hz, 1 H), 4.17 (d, J ) 2.1 Hz, 1 H), 2.02 (m, 1 H), 1.79
(m, 2 H), 1.64 (m, 1 H), 1.07 (s, 3 H), 1.01 (s, 3 H), 0.96 (s, 3 H); 13
C
NMR (75 MHz, CDCl3) 176.6, 163.0, 154.0, 147.0, 96.5, 96.1, 64.6,
55.8, 47.5, 30.3, 26.3, 18.1, 17.3, 9.1. HRMS (CI). Calcd for C14H19-
NO3 [M+]: m/z 249.1365. Found: m/z 249.1362.
by flash chromatography on silica gel as a colorless oil having [R]25
D
+43.3° (c 2.2, CH2Cl2): IR (film) 2970, 1754, 1706, 1682, 1621, 1394
1
cm-1; H NMR (300 MHz, CDCl3) δ (major isomer) 7.18 (dd, J1 )
(+)-(1R,4S)-N-[2-[(1R)-1,2-Dibromoethoxy]propenoyl-1,7,7-tri-
methyl-3-azabicyclo[2.2.1]heptan-2-one and (+)-(1R,4S)-N-[2-[(1S)-
1,2-Dibromoethoxy]propenoyl-1,7,7-trimethyl-3-azabicyclo[2.2.1]-
heptan-2-one (10).19c To a solution of 11.1 g (44.5 mmol) of imide 14
in 400 mL of CH2Cl2 was added solid Na2CO3 (ca. 10 g). After the
resulting mixture was cooled to -78 °C, 178 mL of a 0.25 M solution
of bromine in CH2Cl2 (44.5 mmol) was added dropwise with vigorous
stirring over 4 h. Progress of the reaction was closely monitored by
15.3 Hz, J2 ) 11.1 Hz, 1 H), 6.44 (dd, J1 ) 15.1 Hz, J2 ) 11.1 Hz, 1
H), 6.09 (dt, J1 ) 15.3 Hz, J2 ) 5.5 Hz, 1 H), 5.84 (d, J ) 15.3 Hz,
1 H), 5.31 (dd, J1 ) 7.4, J2 ) 2.9 Hz, 1 H), 4.84 (d, J ) 3.1 Hz, 1 H),
(43) The general experimental methods section along with additional experi-
mental details and procedures for routine transformations may be found in
the Supporting Information. See the Supporting Information available
paragraph for details as to how to access this information.
9
10580 J. AM. CHEM. SOC. VOL. 128, NO. 32, 2006

A Total Synthesis of (
+
)-Tetronolide
A R T I C L E S
4.76 (d, J ) 3.2 Hz, 1 H), 4.34 (dd, J1 ) 14.1 Hz, J2 ) 5.6 Hz, 1 H),
4.24 (dd, J1 ) 14.1 Hz, J2 ) 5.6 Hz, 1 H), 4.14 (s, 1 H), 3.61 (dd, J1
) 11.2 Hz, J2 ) 2.9 Hz, 1 H), 3.48 (dd, J1 ) 11.2 Hz, J2 ) 7.5 Hz, 1
H), 2.03 (m, 1 H), 1.89-1.59 (m, 3 H), 1.50 (s, 9 H), 1.07 (s, 3 H),
1.00 (s, 3 H), 0.96 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ (major
diastereomer) 176.7, 165.7, 163.3, 153.4, 141.9, 135.6, 129.7, 123.7,
100.0, 94.1, 79.9, 65.7, 64.6, 55.8, 47.5, 30.4, 29.6, 27.8, 26.2, 18.1,
17.2, 9.1. HRMS (FAB+). Calcd for C24H34BrNO6 [M+]: m/z 512.1570.
Found: m/z 512.1572.
xylenes were removed by distillation at a reduced pressure (∼20 Torr)
to afford a pale yellow liquid. Further concentration in vacuo afforded
12.6 g of a yellow oil as the crude product mixture containing the two
cycloadducts cis-23 and a trans diastereomer 22 in a ∼5:1 ratio as
determined by 1H NMR analysis. The product mixture was purified by
flash chromatography on silica gel with elution by 25% Et2O in hexanes
to afford 4.8 g (53%) of the desired cis adduct 23 as a pale yellow oil
having [R]25 +71.3° (c 3.70, CH2Cl2): IR (film) 2978, 1726, 1426,
D
1367, 1158, 1000 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.05 (m, 1 H),
5.68 (br d, J ) 10.3 Hz, 1 H), 5.14 (sept, J ) 6.3 Hz, 1 H), 4.96 (t,
J ) 5.2 Hz, 1 H), 4.00 (d, J ) 11.8 Hz, 1 H), 3.86 (dd, J1 ) 11.8 Hz,
J2 ) 2.7 Hz, 1 H), 3.23 (m, 2 H), 2.98 (m, 1 H), 2.64 (m, 2 H), 1.98
(-)-(1R)-2-Bromo-1-[(2E,4E)-5-tert-butoxycarbonyl-2,4-pentadi-
enyloxy)-1-(1-isopropoxycarbonyl-1-ethenyloxy)ethane (21). To a
solution of 16.1 g (25.1 mmol) of partially purified 7 (dr > 96:4) in
100 mL of toluene was added 22.3 mL (75.3 mmol) of Ti(OiPr)4 at
room temperature. The resulting homogeneous solution was allowed
to stir at room temperature for 14 h. The reaction mixture was then
diluted with 600 mL of Et2O and quenched with 250 mL of H2O,
resulting in the formation of a heavy, white precipitate. The phases
were separated, and the aqueous phase containing the solids was
extracted with four 150 mL portions of Et2O. The cloudy organic phases
were combined, dried over MgSO4, filtered through a pad of Celite,
and the resulting clear filtrate was concentrated in vacuo to afford 20
g of crude material as a yellow oil. The crude material was purified by
flash chromatography on silica gel with elution by 30% Et2O in hexanes
to provide 10.0 g (95%) of 21 as a pale yellow oil having [R]25D -6.3°
(dd, J1 ) 14.0 Hz, J2 ) 7.8 Hz, 1 H), 1.47 (s, 9 H), 1.30 (m, 6 H); 13
C
NMR (100 MHz, CDCl3) δ 172.2, 171.3, 127.4, 126.0, 97.3, 80.4, 76.4,
69.2, 68.4, 37.8, 34.7, 33.0, 31.2, 28.0, 21.7, 21.6. HRMS (CI). Calcd
for C18H31BrNO6 [M + NH4+]: m/z 436.1335. Found: m/z 436.1352.
In addition to 22, 1.1 g (12%) of the trans cycloadduct above was
obtained during the course of chromatographic purification but was
not fully characterized.19c
(+)-tert-Butyl-2r-Bromomethyl-8aâ-isopropoxycarbonyl-(5,6)-â-
epoxy-4aâ,5,6,7,8,8a-hexahydro-4H-1,3-benzodioxin-7r-carboxy-
late. Successively as single portions, 4.4 g (32 mmol) of solid NaH2PO4‚
H2O and 8.3 g of solid 50 wt % mCPBA (24 mmol of contained peracid)
were added to a vigorously stirred solution of 6.7 g (16 mmol) of
cycloadduct 23 in 125 mL of CH2Cl2 at 0 °C. The cold bath was
removed, and the resulting cloudy reaction mixture was allowed to
warm to ambient temperature and was stirred for 21 h. The cloudy
reaction mixture was cooled to 0 °C and 50 mL of 10% aqueous sodium
sulfite was slowly added over 3 min. The mixture was allowed to warm
to ambient temperature, whereupon the phases were separated, and the
aqueous phase was extracted with three 50 mL portions of CH2Cl2.
The combined organic phases were successively washed with two 50
mL portions of 10% aqueous K2CO3 solution and 50 mL of brine. The
organic phase was dried over K2CO3, filtered, and concentrated in vacuo
to afford 7.7 g of the crude, but clean, title epoxide as a pale yellow
oil which was used in subsequent transformations without further
purification. An analytical sample of the â-epoxide was obtained by
flash chromatography on silica gel with elution by 35% Et2O in hexanes
to yield pure â-epoxide as a colorless oil having [R]25D +29.4° (c 3.70,
CH2Cl2): IR (film) 2977, 1726, 1242, 1141 cm-1; 1H NMR (300 MHz,
CDCl3) δ 5.09 (sept, J ) 6.3 Hz, 1 H), 4.93 (t, J ) 5.1 Hz, 1 H), 4.15
(d, J ) 12.2 Hz, 1 H), 3.84 (dd, J1 ) 12.3 Hz, J2 ) 2.1 Hz, 1 H), 3.74
(d, J ) 3.6 Hz, 1 H), 3.30 (d, J ) 3.8 Hz, 1 H), 3.24 (d, J ) 5.1 Hz,
2 H), 2.96 (d, J ) 7.3 Hz, 1 H), 2.36 (br s, 1 H), 2.30 (d, J ) 14.3 Hz,
1 H), 1.86 (dd, J1 ) 14.3 Hz, J2 ) 7.3 Hz, 1 H), 1.48 (s, 9 H), 1.27 (d,
J ) 6.3 Hz, 6 H); 13C NMR (100 MHz, CDCl3) δ 171.4, 170.7, 97.5,
80.9, 75.2, 69.4, 68.2, 54.5, 52.0, 37.1, 34.2, 30.9, 29.7, 28.0, 21.6.
HRMS (CI). Calcd for C18H31BrNO7 [M + NH4+]: m/z 452.1284.
Found: m/z 452.1275.
(c 1.4, CH2Cl2): ΙR (film) 2978, 1709, 1649, 1622, 1368, 1134 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.17 (dd, J1 ) 15.3 Hz, J2 ) 11.0 Hz,
1 H), 6.40 (dd, J1 ) 15.3 Hz, J2 ) 11.0 Hz, 1 H), 6.10 (dt, J1 ) 15.3
Hz, J2 ) 5.5 Hz, 1 H), 5.84 (d, J ) 15.4 Hz, 1 H), 5.61 (d, J ) 2.1 Hz,
1 H), 5.22 (t, J ) 5.2 Hz, 1 H), 5.11 (sept, J ) 6.2 Hz, 1 H), 5.02 (d,
J ) 2.2 Hz, 1 H), 4.38 (dd, J1 ) 14.1 Hz, J2 ) 5.2 Hz, 1 H), 4.24 (dd,
J1 ) 14.1 Hz, J2 ) 5.2 Hz, 1 H), 3.54 (m, 2 H), 1.49 (s, 9 H), 1.31 (d,
J ) 6.2 Hz, 6 H); 13C NMR (100 MHz, CDCl3) δ 166.0, 162.0, 149.1,
142.1, 135.8, 130.0, 124.0, 102.3, 100.8, 80.3, 69.3, 66.6, 31.5, 30.2,
21.6. HRMS (CI). Calcd for C18H31BrNO6 [M + NH4+]: m/z 436.1335.
Found: m/z 436.1355.
(2R,4aR,7S,8aS)-tert-Butyl-2r-bromomethyl-8aâ-isopropoxycar-
bonyl-4aâ,7,8,8a-tetrahydro-4H-1,3-benzodioxin-7r-carboxylate (23)
and (2R,4aS,7R,8aS)-tert-Butyl-2r-bromomethyl-8aâ-isopropoxy-
carbonyl-4ar,7,8,8a-tetrahydro-4H-1,3-benzodioxin-7â-carboxy-
late (22). A 2 L round-bottom flask equipped with a magnetic stirring
bar was soaked in concentrated NH4OH for at least 12 h, then emptied
and rinsed 10 times with deionized water, and dried overnight in an
oven. Once dry, the flask was allowed to cool to room temperature
under an argon atmosphere. Just prior to use, a silylating solution
[prepared by adding TMSCl (25 mL) to a solution of Et3N (50 mL) in
500 mL of dry, distilled CH2Cl2] was poured into the dry flask and
allowed to stand for 30 min. The flask was emptied and rinsed 10 times
with dry, distilled CH2Cl2. The flask was then flame-dried and allowed
to cool to room temperature under an argon atmosphere. Triene 21
(9.0 g, 22 mmol) was freed of any traces of acid by stirring over solid
K2CO3 as a solution in CH2Cl2 (100 mL) for at least 30 min. The
solution was then filtered and concentrated in vacuo, and 2.4 g (11
mmol) of BHT was added to the resulting oil. The oily mixture was
then dried azeotropically by dissolution in 5 mL of dry benzene
followed by concentration in vacuo, and the process was repeated two
more times. The resulting oil was dissolved in 500 mL of freshly
distilled xylenes (distilled from sodium benzophenone ketyl) and
transferred via cannula under Ar to the previously prepared reaction
flask. The solution was diluted with additional distilled xylenes to a
total volume of ∼900 mL, and ca. 18 g of solid anhydrous NaHCO3
was added. The flask was equipped with a reflux condenser and placed
in a preheated 155 °C oil bath, where the mixture was kept at reflux
under Ar for 114 h. At this time, TLC analysis of the reaction mixture
(25% Et2O in hexanes) indicated the complete consumption of triene
21. The solution was allowed to cool to room temperature and then
filtered through a pad of Celite to remove the solid NaHCO3. The
(+)-tert-Butyl-2r-bromomethyl-8aâ-isopropoxycarbonyl-5â-hy-
droxy-4aâ,7,8a-tetrahydro-4H-1,3-benzodioxin-7-carboxylate (24).
A stirred solution of 7.7 g (∼16 mmol) of crude epoxide prepared as
above in 150 mL of anhydrous THF under Ar was treated with 3.6 mL
(24 mmol) of DBU at room temperature, and stirring was continued at
room temperature for 20 h. The reaction mixture was diluted with 200
mL of Et2O and washed with three 50 mL portions of 1 N aqueous
HCl. The combined aqueous washes were then extracted with two 50
mL portions of Et2O, and the combined organic phases were succes-
sively washed with 50 mL of saturated aqueous NaHCO3 and 50 mL
of brine. The resulting organic phase was dried over MgSO4, filtered,
and concentrated in vacuo to afford 7.6 g of crude products as a clear
colorless oil. Purification by flash chromatography on silica gel with
elution by 70% Et2O in hexanes provided 5.9 g (84%) of hydroxy diester
24 as a clear colorless oil having [R]25D + 24.2° (c 2.40, CH2Cl2): IR
(film) 3498, 2980, 1708, 1666, 1369, 1249 cm-1; 1H NMR (300 MHz,
CDCl3) δ 6.88 (s, 1 H), 5.16 (sept, J ) 6.3 Hz, 1 H), 4.95 (t, J ) 5.0
9
J. AM. CHEM. SOC. VOL. 128, NO. 32, 2006 10581

A R T I C L E S
Boeckman et al.
Hz, 1 H), 4.86 (m, 1 H), 4.31 (d, J ) 11.6 Hz, 1 H), 3.84 (d, J ) 11.6
Hz, 1 H), 3.36 (m, 2 H), 2.58 (s, 2 H), 2.43 (d, J ) 7.2 Hz, 1 H), 2.08
(d, J ) 9.3 Hz, 1 H), 1.49 (s, 9 H), 1.32 (d, J ) 6.3 Hz, 6 H); 13C
NMR (100 MHz, CDCl3) δ 171.6, 165.1, 138.4, 127.5, 96.8, 81.1, 78.9,
69.7, 64.8, 39.9, 34.7, 31.8, 28.0, 21.62, 21.59. HRMS (CI). Calcd for
C18H31BrNO7 [M + NH4+]: m/z 452.1284. Found: m/z 452.1289.
were separated. The aqueous phase was extracted with three 30 mL
portions of Et2O, and the combined organic phases were washed with
10 mL of brine, dried over MgSO4, and concentrated in vacuo to provide
6.0 g of crude products as a yellow oil. Purification by flash
chromatography on silica gel with elution by 50% Et2O in hexanes
gave 4.0 g (70% overall yield from 25) of pure alcohol 26 as a pale
yellow oil having [R]25 +9.93° (c 2.90, CH2Cl2): ΙR (film) 3439,
D
(+)-2r-Bromomethyl-8aâ-isopropoxycarbonyl-5â-hydroxy-4aâ,7,-
8a-tetrahydro-4H-1,3-benzodioxin-7-carboxylic acid (25). Hydroxy
diester 24 (4.4 g, 10 mmol) was dissolved in 40 mL of anhydrous TFA
at room temperature under Ar, and the solution was allowed to stir for
30 min. The reaction mixture was concentrated in vacuo, and the
resulting oil was dissolved in 30 mL of benzene and reconcentrated in
vacuo. The process was repeated two more times with additional 30
mL portions of benzene to afford 3.8 g (100%) of the pure acid 25 as
2931, 2857, 1730, 1589, 1428, 1106 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.70 (d, J ) 7.3 Hz, 4 H), 7.44-7.39 (m, 6 H), 5.79 (s, 1 H), 5.18
(sept, J ) 6.2 Hz, 1 H), 4.97 (t, J ) 4.1 Hz, 1 H), 4.71 (m, 1 H), 4.33
(d, J ) 11.7 Hz, 1 H), 4.11 (s, 2 H), 3.84 (d, J ) 11.5 Hz, 1 H), 3.39
(m, 2 H), 2.44 (d, J ) 18.4 Hz, 1 H), 2.22 (d, J ) 18.4 Hz, 1 H),
2.05-1.99 (m, 2 H), 1.32 (d, J ) 6.2 Hz, 6 H), 1.10 (s, 9 H); 13C
NMR (100 MHz, CDCl3) δ 172.0, 135.6, 133.6, 133.5, 133.3, 129.7,
127.7, 123.6, 96.9, 79.2, 69.3, 66.3, 65.2, 65.0, 40.8, 35.9, 31.9, 26.8,
21.6, 19.2. HRMS (CI). Calcd for C30H43BrNO6Si [M + NH4+]: m/z
620.2043. Found: m/z 620.2048.
a white solid having mp 68-70 °C and [R]25 +14.2° (c 4.70, CH2-
D
Cl2): ΙR (film) 3854-2878, 2982, 1698, 1662, 1466, 1250, 1104 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.11 (s, 1 H), 5.17 (sept, J ) 6.3 Hz,
1H), 4.98 (t, J ) 3.9 Hz, 1 H), 4.92 (m, 1 H), 4.32 (d, J ) 11.5 Hz,
1 H), 3.86 (d, J ) 11.5 Hz, 1H), 3.38 (m, 2 H), 2.62 (m, 2 H), 2.12 (d,
J ) 9.3 Hz, 1 H), 1.33 (d, J ) 6.3 Hz, 6 H); 13C NMR (100 MHz,
CDCl3) δ 171.4, 170.8, 142.1, 125.5, 96.7, 78.7, 70.0, 64.9, 64.8, 39.7,
34.3, 31.9, 21.63, 21.59. HRMS (CI). Calcd for C14H23BrNO7 [M +
NH4+]: m/z 396.0658. Found: m/z 396.0649.
(+)-Isopropyl-2r-bromomethyl-7-(tert-butyldiphenylsilyloxym-
ethyl)-5â-methoxymethoxy-4aâ,5,8,8a-tetrahydro-4H-1,3-benzodioxin-
8aâ-carboxylate. Freshly distilled MOMCl (2.5 mL, 33 mmol) was
added dropwise to a solution of 4.0 g (6.6 mmol) of alcohol 26, 23
mL (133 mmol) of diisopropylethylamine, and 0.1 g (0.66 mmol) of
DMAP in 15 mL of CH2Cl2 at room temperature. The resulting mixture
was warmed to 40 °C for 6 h, whereupon an additional 2.5 mL (33
mmol) of MOMCl was introduced, and the mixture was allowed to
stir for an additional 6 h at 40 °C. The reaction mixture was allowed
to cool to room temperature and stirred overnight (14 h) then quenched
by addition of 10 mL of water and 20 mL of Et2O. The mixture was
allowed to stir vigorously for 1 h, then the phases were separated and
the organic phase was diluted with an additional 75 mL portion of
Et2O. After washing the organic phase with three 25 mL portions of 1
N HCL, the aqueous washes were combined and back-extracted with
three 50 mL portions of Et2O. The combined organic phases were
washed with 25 mL of saturated aqueous NaHCO3, dried over MgSO4,
filtered, and concentrated in vacuo to provide 6.0 g of crude products
as a reddish-yellow oil. Purification by flash chromatography on silica
gel with elution by 30% Et2O in hexanes afforded 3.6 g (84%) of the
(+)-Isopropyl-2r-Bromomethyl-5â-hydroxy-7-hydroxymethyl-
4aâ,5,8,8a-tetrahydro-4H-1,3-benzodioxin-8aâ-carboxylate. A solu-
tion of 3.96 g (10 mmol) of 25 and 1.7 mL (12 mmol) of Et3N in 30
mL of CH2Cl2 was added dropwise via cannula to a solution of 1.0
mL (11 mmol) of ethyl chloroformate in 20 mL of CH2Cl2 at 0 °C.
The resulting cloudy-white reaction mixture was allowed to stir at 0
°C for 30 min and then was filtered through a pad of Celite to remove
the solids which had formed. The Celite pad was washed with an
additional 10 mL of THF, and the resulting clear, pale yellow filtrate
was added dropwise via cannula to a slurry of 0.76 g (20 mmol) of
NaBH4 in 25 mL of THF and 3.9 mL of MeOH at -40 °C. The
resulting mixture was allowed to stir at -40 °C for 30 min and then
was allowed to warm to 0 °C and was stirred for an additional 40 min.
At this time, the reaction mixture was quenched at 0 °C by the
successive addition of 10 mL of 5% aqueous NaOH, 10 mL of brine,
and 50 mL of Et2O. The resulting mixture was allowed to warm to
ambient temperature and was stirred vigorously for 45 min. The phases
were separated, and the aqueous phase was extracted with three 30
mL portions of Et2O. All of the organic phases were combined and
washed with 20 mL of brine, dried over MgSO4, and concentrated in
vacuo to afford 3.5 g (∼100%) of the crude title diol as a clear, colorless
oil which was used without further purification. An analytical sample
was obtained by flash chromatography on silica gel with elution by
80% EtOAc in hexanes to afford pure title diol as a clear, colorless oil
pure titled MOM ether as a pale yellow oil having [R]25 +23.5° (c
D
1.70, CH2Cl2): ΙR (film) 2923, 2849, 1732, 1423, 1236, 1104 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.68 (d, J ) 6.6 Hz, 4 H), 7.45-7.38
(m, 6 H), 5.97 (s, 1 H), 5.16 (sept, J ) 6.2 Hz, 1 H), 4.97 (t, J ) 4.2
Hz, 1 H), 4.84 (s, 2 H), 4.64 (m, 1 H), 4.21 (d, J ) 11.8 Hz, 1 H), 4.08
(s, 2 H), 3.82 (d, J ) 11.8 Hz, 1 H), 3.45 (s, 3 H), 3.38 (m, 2 H), 2.40
(d, J ) 18.3 Hz, 1 H), 2.23-2.15 (m, 2 H), 1.30 (d, J ) 6.2 Hz, 6 H),
1.08 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ 171.6, 135.3, 133.5, 129.4,
127.4, 120.9, 96.9, 96.8, 79.0, 72.3, 69.1, 65.9, 65.1, 55.4, 38.7, 35.4,
31.6, 26.5, 21.4, 21.3, 19.0. HRMS (CI). Calcd for C32H47BrNO7Si
[M + NH4+]: m/z 664.2305. Found: m/z 664.2276.
having [R]25 +29.7° (c 3.60, CH2Cl2): ΙR (film) 3351, 2981, 1727,
D
1466, 1255, 1130 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.81 (s, 1 H),
5.15 (sept, J ) 6.3 Hz, 1 H), 4.91 (t, J ) 4.0 Hz, 1 H), 4.70 (br s, 1
H), 4.28 (d, J ) 11.9 Hz, 1 H), 4.02 (m, 2 H), 3.82 (d, J ) 11.7 Hz,
1 H), 3.37 (m, 2 H), 3.28 (br s, 1 H), 2.96 (br s, 1 H), 2.43 (d, J )
18.4 Hz, 1 H), 2.24 (d, J ) 18.4 Hz, 1 H), 2.04 (d, J ) 8.8 Hz, 1 H),
1.32 (d, J ) 6.1 Hz, 6 H); 13C NMR (100 MHz, CDCl3) δ 172.0, 134.1,
124.1, 96.9, 79.3, 69.6, 65.3, 65.2, 64.8, 40.4, 35.8, 31.9, 21.6. HRMS
(CI). Calcd for C14H23NO5Br [M + NH4 - H2O]+: m/z 364.0760.
Found: m/z 364.0751.
(+)-Isopropyl-3-(tert-butyldiphenylsilyloxymethyl)-6r-ethenyl-
oxymethoxy-1r-hydroxy-5â-methoxymethoxy-3-cyclohexene-1-car-
boxylate (5). Zinc-silver couple was freshly prepared using a
modification of the Heathcock procedure.27 Accordingly, 25 g of
powdered zinc metal was activated by stirring in 100 mL of 10%
aqueous HCl for 4 min. The aqueous HCl was decanted, and the freshly
activated zinc was successively washed with two 100 mL portions of
acetone and 100 mL of Et2O. After the Et2O wash was decanted, a
suspension of 0.83 g of silver(I) acetate in 20 mL of refluxing acetic
acid was added to the zinc metal and the resulting mixture was allowed
to stir for 1 min. The acetic acid was decanted, and the resulting black
Zn-Ag couple was successively washed with 60 mL of acetic acid,
four 100 mL portions of Et2O, and four 100 mL portions of reagent-
grade methanol. At this time, 2.0 g of solid NaHCO3 was added to the
couple, and the mixture was washed with four additional 100 mL
portions of methanol. After decanting the final methanol wash, the moist
Zn-Ag couple was transferred to a solution of 3.0 g (4.6 mmol) of
the MOM ether, prepared as immediately above, containing 2.0 g of
(+)-Isopropyl-2r-Bromomethyl-7-(tert-butyldiphenylsilyloxym-
ethyl)-5â-hydroxy-4aâ,5,8,8a-tetrahydro-4H-1,3-benzodioxin-8aâ-
carboxylate (26). To a solution of 3.5 g (∼10 mmol) of crude diol, as
obtained immediately above, in 50 mL of CH2Cl2 at 0 °C was
successively treated 0.12 g (0.96 mmol) of DMAP, 2.0 mL (14 mmol)
of Et3N, and 2.8 mL (11 mmol) of tert-butyldiphenylchlorosilane. The
resulting mixture was allowed to slowly warm to room temperature
and was stirred for 17 h. At this time, the reaction mixture was
partitioned between 15 mL of water and 50 mL of Et2O, and the phases
9
10582 J. AM. CHEM. SOC. VOL. 128, NO. 32, 2006

A Total Synthesis of (
+
)-Tetronolide
A R T I C L E S
solid NaHCO3 in 40 mL of methanol at room temperature. The resulting
mixture was heated to a gentle reflux in a 70 °C oil bath for 18 h then
allowed to cool to room temperature. The reaction mixture was diluted
with 200 mL of Et2O, filtered through a pad of Celite, and the resulting
filtrate was concentrated in vacuo to give a white semisolid. The crude
material was dissolved in 250 mL of Et2O, dried over MgSO4, and
refiltered through a pad of Celite to remove the solids. Concentration
of the resulting filtrate in vacuo then provided 2.5 g of crude material
as a clear, colorless oil. Rapid flash chromatography on silica gel with
elution by 30% Et2O in hexanes afforded 2.4 g (92%) of pure 5 as a
71.5, 70.2, 55.3, 55.2, 47.3, 40.5, 37.2, 31.9, 23.7, 23.6, 18.6, 17.6,
15.1, 13.4. Anal. Calcd for C24H33NO4: C, 72.15; H, 8.32. Found: C,
71.80; H, 8.37.
(2S,3S,5S)-1-(Benzyloxy)-6-(tert-butyldiphenylsilyloxy)-3,5-dimethyl-
2-hexanol (32).4 A solution of 1.3 g (2.8 mmol) of epoxide 31 at -30
°C was treated successively with 3.1 mL (6.2 mmol) of a 2.0 M solution
of Me3Al in hexanes and 2.0 mL (3.1 mmol) of a 1.54 M solution of
n-BuLi in hexanes giving a white heterogeneous mixture which was
allowed to warm to 0 °C and stirred for 3 h. The reaction mixture was
quenched at 0 °C by careful dropwise addition of 10 mL of 1 M aqueous
HCl causing vigorous gas evolution. After the addition was complete,
the mixture was allowed to warm to room temperature, 30 mL of
additional 1 M aqueous HCl was added, and the layers were separated.
The aqueous portion was extracted with three 30 mL portions of Et2O,
and the combined organic extracts were washed with 10 mL of brine,
dried (MgSO4), and concentrated in vacuo to provide 1.37 g of a pale
yellow oil as the crude product mixture. Purification by flash chroma-
tography on silica gel (30% Et2O in hexanes) afforded 1.06 g (78%)
of diastereomerically pure alcohol 32 as a pale yellow oil: IR (film)
clear, colorless oil having [R]25 +33.5° (c 2.50, CH2Cl2): ΙR (film)
D
3499, 3071, 2932, 1726, 1620, 1471, 1242 cm-1; 1H NMR (300 MHz,
C6D6) δ 7.73 (m, 4 H), 7.17 (m, 6 H), 6.24 (dd, J1 ) 14.3 Hz, J2 ) 6.8
Hz, 1 H), 6.13 (s, 1 H), 4.94 (sept, J ) 6.2 Hz, 1 H), 4.56 (d, J ) 6.9
Hz, 1 H), 4.46 (d, J ) 6.9 Hz, 1 H), 4.29 (m, 1 H), 4.19 (dd, J1 ) 14.2
Hz, J2 ) 1.6 Hz, 1 H), 3.95 (m, 5 H), 3.77 (s, 1 H), 3.17 (s, 3 H), 2.62
(m, 2 H), 1.90 (d, J ) 17.3 Hz, 1 H), 1.12 (s, 9 H), 1.01 (d, J ) 6.3
Hz, 3 H), 0.97 (d, J ) 6.3 Hz, 3 H); 13C NMR (75 MHz, C6D6) δ
175.5, 151.7, 136.0, 135.6, 134.0, 130.1, 127.4, 121.5, 96.6, 87.1, 75.0,
74.1, 69.8, 66.9, 65.9, 55.5, 45.7, 37.2, 27.1, 21.8, 21.5, 19.6. HRMS
(FAB+). Calcd for C32H44BrNaO7Si [M + Na+]: m/z 591.2754.
Found: m/z 591.2776.
1
3400, 2979, 1694, 1620, 1590 cm-1; H NMR (300 MHz, CDCl3) δ
7.72 (m, 4 H), 7.42 (m, 11 H), 4.60 (s, 2 H), 3.53 (m, 5 H), 2.32 (br
s, 1 H), 1.77 (m, 2 H), 1.30 (m, 2 H), 1.11 (s, 9 H), 0.92 (d, J ) 6.6
Hz, 3 H), 0.89 (d, J ) 6.8 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ
135.4, 129.2, 128.2, 127.5, 127.4, 127.3, 74.4, 73.1, 72.2, 69.5, 35.5,
33.1, 32.9, 26.6, 19.0, 15.9, 14.8; MS (EI) m/z 355, 291, 199, 91. HRMS
(CI). Calcd for C31H42O3Si (M+): m/z 490.2903. Found: m/z 490.2921.
(1S,4R)-2-[(2S,4E)-6-p-Methoxyphenylmethoxy-2-methylhex-4-
enoyl]-1,7,7-trimethyl-2-azabicyclo[2.2.1]heptan-3-one (29).28 To a
room temperature solution of 56 g (0.22 mol) of (E)-1-bromo-4-
methoxyphenylmethoxy-2-butene44 (see Supporting Information) in 225
mL of dry acetonitrile under inert atmosphere was added 39 g (0.29
mol) of anhydrous K2CO3, followed by 36 g (0.24 mol) of anhydrous
NaI. The yellow slurry was stirred at room temperature under argon
for 20 min, diluted with 250 mL of water and 250 mL of ether, washed
with 250 mL of 10% aqueous sodium thiosulfate, 200 mL of brine,
dried over MgSO4, and concentrated in vacuo to give 61 g (93%) of
(E)-1-iodo-4-p-methoxyphenylmethoxy-2-butene (28)44 as an oil, which
was stored in the dark for 2 h prior to use (note: without addition of
stabilizers, iodide 28 is completely decomposed after 24 h of storage):
(2E,4E,5S,6E,9S,11S)-9-(tert-Butyldiphenylsilyloxy)-5-meth-
oxymethoxy-1-(4-methoxyphenylmethoxy)-3,9,11-trimethyldodecatri-
2,4,6-ene.19b Oxidation to (2S,3S,5S)-6-(tert-Butyldiphenylsilyloxy)-
3,5-dimethyl-2-methoxymethoxyhexanal. Procedure A: A room
temperature solution of 7.0 g (15.7 mmol) of alcohol 33 in 150 mL of
CH2Cl2 was treated with 10.0 g (23.6 mmol) of solid 1,1,1-triacetoxy-
1,1-dihydro-1,2-benziodoxol-3(1H)-one [Dess-Martin periodinane
(DMP)]7 added in one portion. The resulting clear solution was stirred
at room temperature for 2.5 h or until TLC showed an absence of the
alcohol 33. The solution was then diluted with 250 mL of ether, and
the resulting solids were removed by suction filtration. The filtrate was
washed with 100 mL of 5% K2CO3 and the organic phase concentrated
in vacuo. The resulting residue was redissolved in 150 mL of ether
and stirred over solid K2CO3. After removal of the solids by suction
filtration, concentration of the filtrate in vacuo afforded 6.9 g (99%)
of crude (2S,3S,5S)-6-(tert-butyldiphenylsilyloxy)-3,5-dimethyl-2-meth-
oxymethoxyhexanal as a clear oil which was used as obtained for the
next transformation: IR (film) 2980, 1730, 1460, 1110, 700 cm-1; 1H
NMR (300 MHz, CDCl3) δ 9.61 (d, J ) 2 Hz, 1 H), 7.64 (m, 4 H),
7.20-7.40 (m, 6 H), 4.69 (m, 1 H), 4.43 (m, 1 H), 3.68 (dd, J1 ) 6
Hz, J2 ) 2 Hz, 1 H), 3.43 (m, 2 H), 3.38 (s, 3 H), 2.02 (m, 1 H), 1.72
(m, 1 H), 1.39 (m, 1 H), 1.20 (m, 1 H), 1.04 (s, 9 H), 0.95 (d, J ) 7
Hz, 3 H), 0.85 (d, J ) 7 Hz, 3 H); MS (EI) 355, 323, 263, 199.
Procedure B: A magnetically stirred solution of 2.1 mL (3.01 g, 23.7
mmol) of oxalyl chloride, freshly distilled (from CaH2), in 70 mL of
CH2Cl2 was cooled to -78 °C and treated with 3.7 mL (4.05 g, 51.8
mmol) of DMSO, freshly distilled (from CaH2), dropwise via syringe.
The resulting solution was stirred at -78 °C for 15 min, at which time
a solution of 9.6 g (21.6 mmol) of alcohol 33 in 30 mL of CH2Cl2 was
added via cannula. After an additional 35 min of stirring at -78 °C,
15.1 mL (10.93 g, 108 mmol) of triethylamine, freshly distilled (from
CaH2), was added dropwise via syringe at -78 °C. After an additional
10 min at -78 °C, the mixture was allowed to warm to room
temperature over 30 min. The reaction mixture was then diluted with
200 mL of ether, and the resulting solids were removed by suction
filtration. The filtrate was concentrated in vacuo and another 200 mL
portion of ether added and the filtration repeated. The resulting filtrate
was then washed four times with 50 mL of saturated NaCl solution,
dried thoroughly over anhydrous MgSO4, suction filtered, and the filtrate
concentrated in vacuo to afford 9.6 g (∼100%) of (2S,3S,5S)-6-(tert-
1
IR (film) 1152 cm-1; H NMR (400 MHz, CDCl3) δ 7.28 (dd, J ) 7,
2 Hz, 2 H), 6.89 (dd, J ) 7, 2 Hz, 2 H), 5.99-6.02 (m, 1 H), 5.79-
5.85 (m, 1 H), 4.45 (s, 2 H), 3.98 (d, J ) 5 Hz, 2 H), 3.90 (dd, J ) 8,
1 Hz, 2 H) and 3.82 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 159.2,
130.4, 130.0, 129.4, 128.6, 113.8, 71.9, 69.1, 55.3, 4.72; LRMS (API)
318 (M+).
To a -78 °C solution of 16 mL (0.116 mol) of diisopropylamine in
115 mL of dry THF under Ar was added 97 mL (1.2 M in hexanes,
0.116 mol) of n-butyllithium over 10 min. The solution was warmed
to 0 °C for 25 min and then transferred by cannula into a 0 °C mixture
of 15 g (0.07 mol) of 2721 in 150 mL of anhydrous THF over 25 min,
such that the internal temperature did not exceed 10 °C. After stirring
an additional 15 min, the solution was transferred by cannula into 60.8
g (0.19 mol) of neat 28 at room temperature over 45 min, such that the
internal temperature did not exceed 30 °C. After 3.5 h, 250 mL of
saturated aqueous NH4Cl was added, the aqueous phase was acidified
to pH ) 7 with 50 mL of 10% aqueous HCl, and the mixture was
extracted four times with 125 mL portions of ether. The combined
ethereal extracts were washed successively with 100 mL of 10%
aqueous HCl and 100 mL of brine, dried over MgSO4, and concentrated
in vacuo. Flash chromatography on silica gel (with elution by 10%
EtOAc in hexanes, v/v) provided 19.9 g (70%) of 29 as a colorless oil:
IR (film) 1741, 1694, 1613, 973 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.25 (d, J ) 9 Hz, 2 H), 6.88 (dd, J1 ) 7 Hz, J2 ) 2 Hz, 2 H), 5.66-
5.62 (m, 2 H), 4.42 (s, 3 H), 3.93 (d, J ) 4 Hz, 2 H), 3.68 (dd, J1 )
13 Hz, J2 ) 7 Hz, 1 H), 2.45-2.39 (m, 1 H), 2.36 (d, J ) 4 Hz, 1 H),
2.26-2.18 (m, 1 H), 2.08-1.96 (m, 2 H), 1.44 (s, 3 H) 1.08 (d, J ) 7
Hz, 3 H), 1.00 (s, 3 H), 0.90 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ
178.3, 177.9, 159.1, 130.8, 130.4, 129.3, 128.9, 128.2, 113.7, 73.0,
(44) Kizil, M.; Murphy, J. A. Tetrahedron 1997, 53, 16847-16858.
9
J. AM. CHEM. SOC. VOL. 128, NO. 32, 2006 10583

A R T I C L E S
Boeckman et al.
butyldiphenylsilyloxy)-3,5-dimethyl-2-methoxymethoxyhexanal suitable
for further use.
ether, and the resulting solids were removed by suction filtration. The
resulting filtrate was then washed successively twice with 100 mL of
half saturated NaCl solution, twice with 40 mL of saturated NaCl
solution, dried thoroughly over anhydrous MgSO4, suction filtered
through a pad of SiO2, and concentrated in vacuo to afford 8.20 g
(∼100%) of (2S,4S,5S,6E,8E,10E)-12-(4-methoxybenzyloxy)-5-meth-
oxymethoxy-2,4,10-trimethyldodecatri-6,8,10-enal suitable for further
Condensation of (2S,3S,5S)-6-(tert-Butyldiphenylsilyloxy)-3,5-
dimethyl-2-methoxymethoxyhexanal and Phosphine Oxide 34.
Phosphine oxide 34 (10.9 g, 26.04 mmol) was dissolved in 120 mL of
anhydrous THF, and 20 mL of freshly distilled HMPA (from CaH2)
was cooled to -78 °C. A 16.8 mL portion of a 1.55 M solution of
n-BuLi in hexanes (26 mmol) was added via syringe dropwise with
magnetic stirring to give a deep red solution. After stirring 10 min at
-78 °C, a solution of 9.6 g (21.7 mmol) of (2S,3S,5S)-6-(tert-
butyldiphenylsilyloxy)-3,5-dimethyl-2-methoxymethoxyhexanal, pre-
pared above, in 60 mL of anhydrous THF was added dropwise. After
stirring for an additional 10 min at -78 °C, the reaction mixture was
allowed to warm to room temperature and stirred for an additional 1
h. The reaction mixture was quenched with 100 mL of half-saturated
NaHCO3, the phases were separated, and the aqueous phase was
extracted twice with 100 mL of ether. The combined organic phases
were washed twice with 50 mL of saturated NaCl solution dried briefly
over anhydrous MgSO4 and concentrated. The residue was dissolved
in CH2Cl2 and filtered rapidly through a short plug of silica gel, washing
twice with 50 mL of CH2Cl2. Concentration of the eluates in vacuo
afforded 13.0 g (92%) of the title triene as a clear oil: IR (film) 2970,
1500, 1240, 1100, 690 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.64 (m,
4 H), 7.38 (m, 8 H), 6.86 (d, J ) 10 Hz, 2 H), 6.23 (m, 3 H), 5.67 (t,
J ) 7 Hz, 1 H), 5.52 (m, 1 H), 4.67 (m, 2 H), 4.47 (m, 2 H), 4.42 (s,
2 H), 4.02 (d, J ) 7 Hz, 2 H), 3.79 (s, 3 H), 3.79 (m, 1 H), 3.44 (m,
2 H), 3.32 (s, 3 H), 1.74 (s, 3 H), 1.74 (m, 2 H), 1.23 (m, 2 H), 1.02
(s, 9 H), 0.88 (d, J ) 7 Hz, 3 H), 0.83 (d, J ) 7 Hz, 3 H); MS (Nermag)
656 [M+]. HRMS (CI). Calcd for C41H57O5Si [M + H+]: m/z 657.3975.
Found: m/z 657.3982.
1
use: IR (film) 2920, 1720, 12.40, 1090, 1030, 780 cm-1; H NMR
(300 MHz, CDCl3) δ 9.61 (d, J ) 1 Hz, 1 H), 7.24 (d, J ) 10 Hz, 2
H), 6.86 (d, J ) 10 Hz, 2 H), 6.24 (m, 3 H), 5.67 (t, J ) 7 Hz, 1 H),
5.52 (dd, J1 ) 12 Hz, J2 ) 8 Hz, 1 H), 4.68 (m, 1 H), 4.48 (m, 1 H),
4.43 (s, 2 H), 4.14 (d, J ) 7 Hz, 2 H), 3.84 (dd, J1 ) 8 Hz, J2 ) 7 Hz,
1 H), 3.79 (s, 3 H), 3.38 (s, 3 H), 2.39 (m, l H), 1.77 (s, 3 H), 1.77 (s,
1 H), 1.54 (m, 2 H), 1.07 (d, J ) 7 Hz, 3 H), 0.88 (d, J ) 7 Hz, 3 H).
Condensation of (2S,4S,5S,6E,8E,10E)-12-(4-Methoxybenzyloxy)-
5-methoxymethoxy-2,4,10-trimethyldodecatri-6,8,10-enal and Di-
oxenone Phosphonate 41. To a magnetically stirred solution of 3.6
mL (2.59 g, 25.6 mmol) of diisopropylamine, freshly distilled (from
CaH2), in 10 mL of anhydrous THF at 0 °C was added 16.6 mL of a
1.54 M solution of n-BuLi in hexanes (25.6 mmol) via syringe. The
resulting clear yellow solution was stirred at 0 °C for 15 min, and then
the mixture was cooled to -78 °C. A solution of 7.48 g (25.6 mmol)
of phosphonate 41 (see Supporting Information) in 10 mL of anhydrous
THF was added at -78 °C slowly via cannula, and the resulting
heterogeneous mixture was warmed to 0 °C, affording a clear yellow
solution. After the reaction mixture had been recooled to -78 °C, 20
mL of HMPA, freshly distilled from CaH2, was added via syringe. After
an additional 30 min stirring at -78 °C, a solution of 8.20 g (19.7
mmol) of (2S,4S,5S,6E,8E,10E)-12-(4-methoxybenzyloxy)-5-meth-
oxymethoxy-2,4,10-trimethyldodecatri-6,8,10-enal in 30 mL of anhy-
drous THF was added at -78 °C slowly via cannula. The resulting
mixture was allowed to warm slowly to room temperature and was
stirred overnight, by which time TLC analysis showed no remaining
aldehyde. The reaction mixture was diluted with 200 mL of ether and
200 mL of half saturated NaCl solution with good stirring. After
separation of the phases, the aqueous phase was extracted twice with
100 mL of ether. The combined organic phases were washed twice
with 100 mL of saturated aqueous NaCl solution, dried over anhydrous
MgSO4, suction filtered through a pad of SiO2, and concentrated in
vacuo. The residue was purified by flash chromatography with elution
by 9:7 (v/v) ether/hexanes to afford 8.52 g (78%) of pentaene 6 as a
pale yellow oil: IR (film) 2940, 1730, 1600, 1380, 1250, 1040, 730
cm-1.1H NMR (300 MHz, CDCl3) δ 7.38 (d, J ) 10 Hz, 2 H), 6.84 (d,
J ) 10 Hz, 2 H), 6.23 (m, 3 H), 5.66 (t, J ) 7 Hz, 1 H), 5.43 (m 1 H),
5.40 (s, 1 H), 4.66 (m, 1 H), 4.44 (m, 1 H), 4.43 (s, 2 H), 4.13 (d, J )
7 Hz, 2 H), 3.85 (m, 1 H), 3.79 (s, 3 H), 3.34 (s, 3 H), 2.62 (m, 1 H),
1.82 (s, 3 H), 1.77 (s, 3 H), 1.68 (m, 7 H), 1.50 (m, 1 H), 1.10 (m, 1
H), 0.96 (d, J ) 7 Hz, 3 H), 0.88 (d, J ) 7 Hz, 3 H); MS (EI) 450,
313, 173, 121, 45. This material should be used in the subsequent step
as soon as practicable. If short-term storage is required, degas
thoroughly with nitrogen and store at -78 °C under nitrogen with the
addition of a crystal of BHT. HRMS (CI). Calcd for C33H47O7 (M +
H+): m/z 555.3322. Found: m/z 555. 3212.
(2S,4S,5S,6E,8E,10E)-12-(4-Methoxybenzyloxy)-5-methoxymethoxy-
2,4,10-trimethyldodecatri-6,8,10-en-1-ol (40).19b To a solution of 13.0
g (19.8 mmol) of protected triene, prepared as immediately above, in
200 mL of anhydrous THF was added dropwise 60 mL of a 1 M
solution of tetrabutylammonium fluoride in THF (15.68 g, 60 mmol).
After 3 h, the reaction was quenched with 50 mL of pH ∼ 9 aqueous
NH3/NH4Cl solution, the phases were separated, and the aqueous phase
was extracted three times with 100 mL of ether. The combined organic
phases were then washed twice with saturated NaCl solution, dried
over MgSO4, and concentrated in vacuo in the presence of a crystal of
BHT. The residue was purified by flash chromatography on silica gel
with by 19:1 EtOAc/hexanes affording 8.24 g (99%) of trienol 40 as
a clear oil: IR (film) 3460, 2960, 1610, 1510, 1250, 1040, 630 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.24 (d, J ) 10 Hz, 2 H), 6.86 (d, J )
10 Hz, 2 H), 6.23 (m, 3 H), 5.64 (t, J ) 7 Hz, 1 H), 5.53 (m, 1 H),
4.68 (m, 1 H), 4.49 (m, 1 H), 4.43 (s, 2 H), 4.12 (d, J ) 7 Hz, 2 H),
3.83 (m, 1 H), 3.79 (s, 3 H), 3.44 (m, 2 H), 3.36 (s, 3 H), 2.38 (m, l
H), 1.77 (s, 3 H), 1.77 (m, 1 H), 1.43-1.10 (m, 3 H), 0.88 (m, 6 H);
MS (EI) 418 [M+]. HRMS (CI). Calcd for C25H39O5 [M + H+]: m/z
419.2798. Found: m/z 419.2775.
(1E,3S,5S,6S,7E,9E,11E)-6-[13-(4-[Methoxybenzyloxy])-6-(meth-
oxymethoxy)-1,3,5,11-tetramethyltridecatetra-1,7,9,11-en-1-yl]-2,2-
dimethyl-4H-1,3-dioxene-4-one (6).19b Oxidation to (2S,4S,5S,6E,8E,-
10E)-12-(4-Methoxybenzyloxy)-5-methoxymethoxy-2,4,10-
trimethyldodecatri-6,8,10-enal. A solution of 1.9 mL (2.77 g, 21.8
mmol) of freshly distilled oxalyl chloride (from CaH2) in 100 mL of
CH2Cl2 was cooled to -78 °C, and the resulting magnetically stirred
solution was treated with 3.7 mL (4.05 g, 51.8 mmol) of freshly distilled
(from CaH2) DMSO added dropwise via syringe causing gas evolution.
The resulting solution was stirred at -78 °C for 15 min at which time
a solution of 8.24 g (19.7 mmol) of trienol 40 in 50 mL of CH2Cl2 was
added via cannula. After an additional 35 min of stirring at -78 °C,
13.7 mL (9.97 g, 98.5 mmol) of triethylamine, freshly distilled (from
CaH2), was added dropwise via syringe at -78 °C. After an additional
10 min at -78 °C, the mixture was allowed to warm to room
temperature. The reaction mixture was then diluted with 150 mL of
(-)-â-Ketoester 43. A pressure tube was base-washed by soaking
in concentrated NH4OH for at least 12 h. The reaction tube was then
emptied and successively rinsed with copious amounts of deionized
water and reagent-grade acetone, dried in an oven for at least 12 h,
and allowed to cool to room temperature under Ar. A solution of 1.5
g (2.7 mmol) of alcohol 5, 0.77 g (1.4 mmol) of pentaene 6, and a
catalytic amount of BHT (∼10 mg) in 50 mL of CH2Cl2 was allowed
to stir over ∼2 g of anhydrous K2CO3 for 1 h. The solution was filtered
through a pad of Celite and concentrated in vacuo, and the resulting
oil was azeotropically dried with three 5 mL portions of anhydrous
benzene. The resulting oil was dissolved in 20 mL of freshly distilled
xylenes [distilled from sodium benzophenone ketyl], and the solution
was transferred via cannula under Ar to the previously prepared pressure
9
10584 J. AM. CHEM. SOC. VOL. 128, NO. 32, 2006

A Total Synthesis of (
+
)-Tetronolide
A R T I C L E S
tube. The reaction tube was flushed with Ar and thoroughly degassed
using three freeze-thaw cycles under vacuum (∼0.1 Torr). The tube
was sealed under vacuum and placed in a preheated 140 °C oil bath
for 5 h. Upon cooling to ambient temperature, the xylenes were removed
by distillation under reduced pressure to afford 2.3 g of crude material
as a pale yellow oil. Purification by flash chromatography on silica
gel with gradient elution using 30-60% Et2O in hexanes provided 0.55
CaH2) was prepared in 4 mL of anhydrous THF. After cooling the
solution to -78 °C, 0.19 mL of a 0.6 M solution of NaN(TMS)2 in
toluene (115 µmol) was added, and the resulting clear, pale yellow
reaction mixture was allowed to warm to room temperature and was
stirred for 18 h. The reaction mixture was partitioned between 20 mL
of Et2O and 3 mL of 1 N aqueous HCl solution. The phases were
separated, and the aqueous phase was extracted with three 5 mL portions
of Et2O. The combined organic phases were dried over Na2SO4, filtered,
and concentrated in vacuo to afford 0.14 g of the crude product as a
pale yellow oil. The crude material was used in the next transformation
without further purification. An analytical sample of spirotetronic acid
was obtained by further purification by flash chromatography on silica
gel with elution by 33% acetone in hexanes to afford a white solid.
This material was freed of metal ions by partitioning between 3 mL of
CH2Cl2 and 3 mL of 1 N HCl. The phases were separated, and the
acidic aqueous phase was extracted with two 3 mL portions of CH2-
Cl2. The combined organic phases were dried over Na2SO4, filtered,
and concentrated in vacuo to afford pure hydroxy spirotetronic acid as
a clear, colorless oil: IR (film) 3406, 3072, 2933, 1748, 1614, 1514,
1250, 1113, 1039 cm-1; UV (90% aq MeOH) λmax (ꢀ) 230 nm
g of recovered alcohol 5 and 0.99 g (69%) of â-ketoester 43 as a clear,
1
colorless oil having [R]25 -5.41° (c 2.20, CH2Cl2) that by H NMR
D
analysis exists as a 9:1 equilibrium mixture of keto and enol forms.
The keto form of 43 has the following spectroscopic characteristics:
1
IR (film) 2932, 1738, 1708, 1614, 1513, 1248, 1105, 1040 cm-1; H
NMR (300 MHz, CDCl3) δ 7.68 (m, 4 H), 7.47-7.40 (m, 6 H), 7.24
(d, J ) 8.5 Hz, 2 H), 6.84 (d, J ) 8.5 Hz, 2 H), 6.42 (dd, J1 ) 14.2
Hz, J2 ) 6.8 Hz, 1 H), 6.03 (d, J ) 10.3 Hz, 1 H), 5.85 (s, 1 H),
5.48-5.39 (m, 2 H), 4.95 (sept, J ) 6.2 Hz, 1 H), 4.74 (d, J ) 6.6 Hz,
1 H), 4.70-4.61 (m, 3 H), 4.36 (m, 2 H), 4.21-3.80 (m, 9 H), 3.79 (s,
3 H), 3.62 (dd, J1 ) 9.9 Hz, J2 ) 5.6 Hz, 1 H), 3.48 (dd, J1 ) 10.9 Hz,
J2 ) 5.6 Hz, 1 H), 3.38 (s, 3 H), 3.35 (s, 3 H), 3.35 (m, 2 H), 2.96 (d,
J ) 18.0 Hz, 1 H), 2.66 (m, 1 H), 2.50 (m, 2 H), 2.30 (m, 1 H), 2.06
(m, 1 H), 1.92 (m, 1 H), 1.50 (m, 2 H), 1.45 (s, 3 H), 1.26 (s, 3 H),
1.23 (d, J ) 6.2 Hz, 3 H), 1.19 (d, J ) 6.2 Hz, 3 H), 1.08 (s, 9 H),
1.00 (d, J ) 7.0 Hz, 3 H), 0.60 (d, J ) 6.0 Hz, 3 H); 13C NMR (75
MHz, CDCl3) δ 205.0, 169.5, 166.2, 159.6, 151.9, 139.1, 138.2, 136.0,
134.03, 133.98, 131.2, 130.1, 129.8, 128.2, 127.3, 126.4, 117.8, 114.2,
95.8, 87.3, 81.4, 81.2, 72.3, 72.2, 69.8, 66.8, 66.4, 65.0, 57.5, 56.2,
56.1, 55.7, 53.4, 47.8, 46.2, 44.5, 41.8, 38.2, 32.3, 32.2, 30.9, 27.3,
23.5, 22.1, 21.9, 19.8, 19.2, 13.8. HRMS (FAB-). Calcd for C62H83O13-
Si [M - H+]: m/z 1063.5603. Found: m/z 1063.5632.
1
(∼17000), 257 nm (∼10000), 276 nm (9000); H NMR (300 MHz,
CDCl3) δ 7.66 (d, J ) 6.8 Hz, 4 H), 7.45-7.35 (m, 6 H), 7.26 (d, J )
8.9 Hz, 2 H), 6.87 (d, J ) 8.9 Hz, 2 H), 6.03 (d, J ) 10.2 Hz, 1 H),
5.94 (s, 1 H), 5.44-5.41 (m, 2 H), 4.78 (d, J ) 6.7 Hz, 1 H), 4.69 (d,
J ) 7.0 Hz, 1 H), 4.66 (d, J ) 6.7 Hz, 1 H), 4.56 (d, J ) 6.9 Hz, 1 H),
4.40 (s, 2 H), 4.10-4.04 (m, 4 H), 3.90-3.80 (m, 1 H), 3.82 (s, 3 H),
3.61-3.55 (m, 2 H), 3.42 (s, 3 H), 3.35 (s, 3 H), 3.27 (d, J ) 6.4 Hz,
2 H), 2.64 (d, J ) 17.5 Hz, 1 H), 2.42-2.30 (m, 2 H), 2.18 (m, 1 H),
2.08 (m, 1 H), 1.90 (d, J ) 17.7 Hz, 1 H), 1.65-1.50 (m, 3 H), 1.57
(s, 3 H), 1.45 (s, 3 H), 1.28 (d, J ) 4.3 Hz, 1 H), 1.07 (s, 9 H), 1.05
(m, 3 H), 0.60 (br s, 3 H); 13C NMR (75 MHz, CDCl3) δ 204.4, 200.1,
167.5, 159.4, 138.1, 135.4, 133.9, 133.2, 133.1, 130.1, 129.7, 129.0,
127.6, 126.3, 125.8, 125.5, 121.7, 113.7, 100.7, 96.6, 95.2, 83.0, 80.9,
73.4, 73.0, 67.6, 65.8, 58.0, 55.61, 55.59, 52.6, 50.8, 45.6, 43.3, 41.3,
38.0, 35.1, 31.9, 31.1, 26.7, 21.8, 19.2, 15.4, 14.1, 13.5. HRMS (FAB+).
Calcd for C57H74NaO12Si (M+ + Na): m/z 1001.4847. Found: m/z
1001.4860. Calcd for C57H73Na2O12Si (M+ - H + 2Na): 1023.4667.
Found: 1023.4682.
Methyl Spirotetronate 45. Removal of the Vinyl Ether: Prepara-
tion of the Hydroxy â-Ketoester. To a solution of 0.375 g (0.353
mmol) of â-ketoester 43 in 20 mL of methanol was added 9 mg (0.035
mmol) of pyridinium p-toluenesulfonate, and the mixture was allowed
to stir at 40 °C for 14 h. After cooling to ambient temperature, the
reaction mixture was concentrated in vacuo, and the resulting residue
was dissolved in 25 mL of Et2O. The cloudy solution was filtered
through a plug of silica gel eluting with additional Et2O, and the clear
filtrate was concentrated in vacuo to afford 0.39 g of the crude product
mixture as a clear, colorless oil. The crude material was purified by
flash chromatography on silica gel with gradient elution using 80-
100% Et2O in hexanes to yield 0.315 g (86%) of pure hydroxy
â-ketoester as a white solid having [R]25D -17.0° (c 3.10, CH2Cl2). 1H
NMR analysis revealed that the hydroxy â-ketoester exists as a ∼9:1
equilibrium mixture of keto and enol forms. The keto form of the
primary alcohol had the following spectroscopic characteristics: IR
Methylation of the Spirotetronic Acid: Preparation of Methyl
Hydroxy Spirotetronate 45. A solution of 0.14 g (∼96 µmol) of the
crude hydroxy spirotetronic acid, prepared as immediately above, in
1.25 mL of benzene and 0.5 mL of methanol was cooled to 0 °C. To
this mixture was added dropwise 0.15 mL of a 2.0 M solution of
TMSCHN2 in hexanes (300 µmol) with the concomitant evolution of
gas. The resulting clear, bright yellow solution was allowed to warm
to ambient temperature and was stirred for 30 min. The reaction mixture
was concentrated in vacuo to afford the crude material as a yellow oil.
Purification by flash chromatography on silica gel with elution by 70%
Et2O in hexanes afforded 0.060 g (62% overall from 43) of pure methyl
hydroxy spirotetronate 45 as a clear, colorless oil: IR (film) 3454, 2932,
1746, 1682, 1613, 1504, 1248, 1038 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.67 (d, J ) 5.9 Hz, 4 H), 7.43-7.38 (m, 6 H), 7.24 (d, J ) 8.5 Hz,
2 H), 6.88 (d, J ) 8.5 Hz, 2 H), 6.04 (d, J ) 10.3 Hz, 1 H), 5.91 (s,
1 H), 5.64 (m, 1 H), 5.52 (m, 1 H), 4.78 (d, J ) 6.7 Hz, 1 H), 4.72 (d,
J ) 6.9 Hz, 1 H), 4.66 (d, J ) 6.8 Hz, 1 H), 4.62 (d, J ) 6.9 Hz, 1 H),
4.41 (dd, J1 ) 17.4 Hz, J2 ) 11.0 Hz, 2 H), 4.25 (s, 3 H), 4.20-4.08
(m, 2 H), 4.06 (s, 2 H), 4.00-3.87 (m, 2 H), 3.82 (s, 3 H), 3.50 (dd,
J1 ) 10.9 Hz, J2 ) 5.2 Hz, 1 H), 3.42-3.38 (m, 2 H), 3.42 (s, 3 H),
3.38 (s, 3 H), 3.19 (br s, 1 H), 2.68 (d, J ) 17.9 Hz, 1 H), 2.40-2.23
(m, 2 H), 2.17 (m, 1 H), 2.03 (m, 1 H), 1.89 (d, J ) 17.9 Hz, 1 H),
1.60-1.50 (m, 3 H), 1.52 (s, 3 H), 1.46 (d, J ) 2.8 Hz, 3 H), 1.06 (s,
9 H), 1.03 (d, J ) 7.0 Hz, 3 H), 0.55 (d, J ) 6.0 Hz, 3 H); 13C NMR
(100 MHz, CDCl3) δ 204.2, 195.2, 184.5, 169.4, 159.5, 138.8, 135.4,
135.0, 133.3, 130.2, 129.6, 129.0, 127.6, 126.4, 126.1, 120.9, 113.8,
99.9, 96.4, 95.3, 86.9, 80.9, 73.9, 73.1, 67.3, 65.9, 65.3, 59.1, 55.6,
55.1, 52.5, 51.2, 46.2, 45.7, 41.1, 37.6, 35.7, 31.8, 30.2, 30.1, 26.7,
(film) 3478, 2931, 1738, 1710, 1613, 1514, 1248, 1106, 1039 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.78-7.65 (m, 4 H), 7.45-7.38 (m, 6
H), 7.26 (d, J ) 8.5 Hz, 2 H), 6.85 (d, J ) 8.5 Hz, 2 H), 6.04 (d, J )
10.3 Hz, 1 H), 5.91 (s, 1 H), 5.51-5.40 (m, 2 H), 5.09 (sept, J ) 6.2
Hz, 1 H), 4.78 (d, J ) 6.7 Hz, 1 H), 4.78-4.74 (m, 2 H), 4.66 (d, J )
6.6 Hz, 1 H), 4.46-4.37 (m, 3 H), 4.22-3.79 (m, 6 H), 3.79 (s, 3 H),
3.72-3.65 (m, 1 H), 3.55-3.46 (m, 1 H), 3.43 (s, 3 H), 3.41 (s, 3 H),
3.41-3.38 (m, 2 H), 2.90 (d, J ) 18.1 Hz, 1 H), 2.66-2.60 (m, 2 H),
2.48 (m, 1 H), 2.30 (m, 1 H), 2.16 (m, 1 H), 2.07 (m, 1 H), 1.94 (m,
1 H), 1.55-1.45 (m, 2 H), 1.50 (s, 3 H), 1.30 (d, J ) 6.3 Hz, 3 H),
1.26 (s, 3 H), 1.24 (d, J ) 6.3 Hz, 3 H), 1.09 (s, 9 H), 1.02 (d, J ) 7.0
Hz, 3 H), 0.62 (d, J ) 5.3 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ
205.0, 169.9, 166.2, 159.6 139.3, 136.8, 136.0, 134.0, 133.9, 131.1,
130.1, 129.8, 128.1, 127.4, 127.2, 126.3, 119.6, 114.2, 96.4, 95.9, 83.3,
81.4, 72.9, 72.2, 70.2, 66.9, 66.4, 60.5, 57.5, 56.2, 56.1, 55.7, 53.5,
48.5, 47.6, 44.6, 41.7, 38.1, 32.3, 31.4, 30.9, 27.3, 23.33, 22.1, 22.0,
19.8, 19.4, 13.8. HRMS (FAB-). Calcd for C60H81O13Si (M - H+):
m/z 1037.5446. Found: m/z 1037.5424.
Dieckmann Condensation of the Hydroxy â-Ketoester: Prepara-
tion of the Spirotetronic Acid. A solution of 0.10 g (96 µmol) of the
preceding primary alcohol and 0.2 mL of freshly distilled HMPA (from
9
J. AM. CHEM. SOC. VOL. 128, NO. 32, 2006 10585

A R T I C L E S
Boeckman et al.
20.6, 19.2, 16.7, 15.7, 13.4. HRMS (FAB+). Calcd for C58H76NaO12Si
at 0 °C for 15 min, then 10 mL of aqueous saturated Na2CO3 solution
was cautiously added, and the phases were separated. The aqueous phase
was extracted two times with 15 mL portions of CH2Cl2, dried over
Na2SO4, and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel with elution by 67% ether in hexanes to
afford 245 mg (85%) of unsaturated aldehyde 48 as a colorless semisolid
having [R]25D -125.0° (c 0.37, CHCl3). Unsaturated aldehyde 48 also
[M + Na+]: m/z 1015.5004 Found: m/z 1015.4947.
(-)-Methyl Formyl Spirotetronate 47. A solution of 398 mg of
methyl hydroxy spirotetronate 45 (0.40 mmol) in 15 mL of dry CH2-
Cl2 was cooled to 0 °C in an ice bath, and 342 mg (0.81 mmol) of
DMP33 in 10 mL of CH2Cl2 was added dropwise over 3 min. The
resulting reaction mixture was allowed to warm to room temperature
and was stirred for 70 min. The reaction was then quenched by addition
of 10 mL of saturated aqueous Na2CO3, and the resulting mixture was
stirred at room temperature for 20 min. After dilution with 50 mL of
ether and 30 mL of water, the phases were separated and the aqueous
phase was extracted two times with 30 mL portions of ether. The
combined organic phases were washed with 10 mL of saturated NaCl
solution, dried over Na2SO4, and concentrated to afford the crude
products as a yellow oil. Purification of this material by flash
chromatography on silica gel with elution by 60% ether in hexanes
afforded 364 mg (92%) of the methyl formyl spirotetronate 47 as
exists as a mixture of atropisomers: IR (film) 2934, 1745, 1718 cm-1
;
both rotamers, 1H NMR (400 MHz, CDCl3) δ 9.38, 9.32 (s, 1 H), 7.64
(m, 4 H), 7.30 (m, 6 H), 7.23, 7.04 (d, J ) 8.3-8.22 Hz, 2 H), 6.85,
6.73 (d, J ) 8.3-8.2 Hz, 2 H), 6.39 (d, J ) 10.5 Hz, 1 H), 5.9 (m, 2
H), 5.5, 5.2 (m, 1 H), 4.71 (d, J ) 6.7 Hz, 1 H), 4.59 (m, 2 H), 4.45
(m, 2 H), 4.43 (s, 3 H), 4.15 (m, 4 H), 4.03 (s, 3 H), 3.90 (s, 3 H), 3.71
(s, 3 H), 3.38 (s, 6 H), 3.24, 3.23 (s, 3 H), 2.75 (m, 1 H), 2.2 (m, 2 H),
1.9 (m, 2 H), 1.78, 1.73 (s, 3 H), 1.5 (m, 6 H), 1.04 (s, 9 H), 0.98 (d,
J ) 7.0 Hz, 3 H), 0.52, 0.42 (d, J ) 5.9-4 Hz, 3 H); both rotamers,
13C NMR (100 MHz, CDCl3) δ 210.9, 210.3, 195.5, 194.9, 192.7, 168.6,
167.1, 159.2, 148.8, 148.4, 138.7, 135.5, 135.1, 133.2, 129.8, 129.6,
127.7, 126.3, 121.3, 113.7, 96.0, 95.3, 88.2, 80.6, 75.1, 72.3, 66.4, 66.2,
65.9, 65.8, 55.7, 55.5, 55.2, 53.0, 45.9, 44.7, 41.1, 37.8, 37.7, 31.8,
30.3, 29.7, 26.8, 20.8, 19.2, 16.8, 13.4, 9.8. HRMS (FAB+). Calcd for
C61H78NaO12Si [M + Na+]: m/z 1053.5160 Found: m/z 1053.5154.
colorless semisolid having [R]25 -176.5° (c 1.19, CH2Cl2). Methyl
D
formyl spirotetronate 47 was found to exist as a mixture of atropiso-
1
mers: IR (film) 2934, 1727, 1710, 1499, 1036 cm-1; H NMR (400
MHz, CDCl3) (major rotamer) δ 9.66 (s, 1 H), 7.64 (d, J ) 7.2 Hz, 2
H), 7.43-7.36 (m, 6 H), 7.24 (d, J ) 8.4 Hz, 2 H), 6.84 (d, J ) 8.4
Hz, 2 H), 6.0 (m, 2 H), 5.65 (m, 1 H), 5.5 (m, 1 H), 4.7 (m, 4 H), 4.62
(d, J ) 6.7 Hz, 2 H), 4.4 (d, J ) 3.3 Hz, 2 H), 4.28 (s, 3 H), 4.1 (m,
3 H), 3.77 (s, 3 H), 3.71 (m, 3 H), 3.48 (m, 1 H), 3.38 (s, 3 H), 3.01
(d, J ) 10.5 Hz, 1 H), 2.67 (m, 1 H), 2.3 (m, 1 H), 2.18 (m, 1 H), 1.9
(m, 3 H), 1.56 (s, 3 H), 1.50 (m, 5 H), 1.42 (s, 3 H), 1.04 (s, 9 H), 0.95
(d, J ) 6.6 Hz, 3 H), 0.49 (d, J ) 6.1 Hz, 3 H); (minor rotamer) δ
9.73 (s, 1 H), 7.64 (d, J ) 7.2 Hz, 2 H), 7.43-7.36 (m, 6 H), 7. 02 (d,
J ) 8.0 Hz, 2 H), 6.73 (d, J ) 8.0 Hz, 2 H), 6.0 (m, 2 H), 5.65 (m, 1
H), 5.5 (m, 1 H), 5.3 (m, 1 H), 4.7 (m, 4 H), 4.62 (d, J ) 6.7 Hz, 2 H),
4.4 (d, J ) 3.3 Hz, 2 H), 4.28 (s, 3 H), 4.0 (m, 3 H), 3.77 (s, 3 H),
3.71 (m, 3 H), 3.48 (m, 1 H), 3.38 (s, 3 H), 2.67 (m, 1 H), 2.3 (m, 1
H), 2.18 (m, 1 H), 1.9 (m, 3 H), 1.56 (s, 3 H), 1.50 (m, 5 H), 1.42 (s,
3 H), 1.04 (s, 9 H), 0.95 (d, J ) 6.6 Hz, 3 H), 0.72 (d, J ) 6.0 Hz, 3
H); both rotamers, 13C NMR (100 MHz, CDCl3) δ 207.9, 200.1, 199.4,
168.6, 159.0, 139.2, 135.8, 135.5, 135.4, 133.1, 130.5, 129.7, 129.1,
127.7, 127.2, 126.6, 120.3, 113.6, 99.5, 96.2, 95.3, 95.2, 85.2, 80.8,
72.2, 71.8, 66.6, 66.0, 65.7, 55.8, 55.6, 55.1, 52.4, 41.2, 37.8, 36.4,
34.6, 31.8, 31.5, 30.1, 26.7, 22.6, 20.7, 20.6, 19.2, 16.9, 14.1, 13.4.
HRMS (FAB+). Calcd for C58H74NaO12Si [M + Na+]: m/z 1013.4847
Found: m/z 1013.4839. The structure and stereochemistry of the methyl
formyl spirotetronate 47 was further secured by reduction of that
material back to methyl hydroxy spirotetronate 45 with NaBH4 in
methanol.
(-)-Allylic Chloride 50. To a solution of 120 mg (0.12 mmol) of
PMB ether aldehyde 48 in 10 mL of CH2Cl2 was added 1 mL of water,
followed by a solution of 0.55 g (2.4 mmol) of DDQ in 20 mL of
CH2Cl2. After stirring at ambient temperature for 1 h, the reaction
mixture was quenched with 20 mL of aqueous half-saturated NaHCO3,
the phases were separated, and the aqueous phase was extracted three
times with 7 mL portions of CH2Cl2. The combined organic phases
were washed with 5 mL of saturated NaCl solution, dried over Na2-
SO4, and concentrated in vacuo to give the crude alcohol as a light
yellow oil which was used without purification below.
To a solution of the above crude alcohol and 86 mg (0.326 mmol)
of hexachloroacetone in 15 mL of anhydrous CH2Cl2 was added
dropwise a solution of 86 mg (0.326 mmol) of triphenylphosphine in
5 mL of CH2Cl2 over 2 min at -40 °C. After warming the resulting
mixture to and stirring at -25 °C for 15 min, the reaction was quenched
with 10 mL of aqueous half-saturated NaHCO3 solution, the phases
were separated, and the aqueous phase was extracted with 10 mL of
CH2Cl2. The combined organic phases were dried over Na2SO4 and
concentrated in vacuo. The crude chloride 50 was further purified by
flash chromatography on silica gel with CH2Cl2 as initial eluent to
remove nonpolar material and then 60% ether in hexanes to provide
84 mg of the pure allylic chloride 50 (75% yield) as a colorless oil
having [R]25 -135.0° (c 0.62, CH2Cl2). Chloride 50 also exists as a
D
(-)-(E)-r,â-Unsaturated Aldehyde 48. A solution of 260 mg (1.58
mmol) of (Z)-1-ethoxy-2-bromo-1-propene15 in 3 mL of anhydrous THF
was cooled to -78 °C, and 1.6 mL of tert-BuLi in hexanes (1.7 M,
2.72 mmol) was added dropwise over 3 min. The resulting solution
was stirred at -78 °C for 30 min, and 60 mg (0.32 mmol) of MgBr2
in 20 mL of dry ether was added by cannula transfer at -78 °C over
5 min. After stirring the resulting mixture at -78 °C for 20 min, a
solution of 278 mg (281 µmol) of aldehyde 47 (dried azeotropically
by repeated dissolution in anhydrous benzene and evaporation under
reduced pressure) in 10 mL of ether was then transferred by cannula
into the solution of the vinyl Grignard reagent at -78 °C, and the
resulting mixture was stirred at -78 °C for 10 min, then warmed to
-20 °C over 30 min. At -20 °C, the reaction was quenched with a
mixture of 2 mL of saturated aqueous NaHCO3 solution and 10 mL of
saturated NaCl solution. The phases were separated, and the aqueous
phase was extracted two times with 25 mL portions of ether. The
combined organic phases were washed with 20 mL of brine, dried over
Na2SO4, and concentrated in vacuo to afford a light yellow oil. This
crude material was dissolved in 50 mL of CH2Cl2, and 0.5 mL (3.5
mmol) of trifluoroacetic anhydride was added at 0 °C, followed by 0.5
mL (6.5 mmol) of trifluoroacetic acid. The resulting solution was stirred
mixture of atropisomers: IR (CH2Cl2) 3053, 2933, 1682, 1493 cm-1
;
1H NMR (400 MHz, CDCl3) (major rotamer) δ 9.38 (s, 1 H), 7.65 (m,
4 H), 7.39 (m, 6 H), 6.51 (d, J ) 9.8 Hz, 1 H), 6.01 (d, J ) 8.9 Hz,
1 H), 5.88 (s, 1 H), 5.70 (t, J ) 8.2 Hz, 1 H), 5.4 (m, 2 H), 4.72 (d, J
) 6.7 Hz, 1 H), 4.64 (d, J ) 7.0 Hz, 1 H), 4.60 (d, J ) 7.0 Hz, 1 H),
4.52 (d, J ) 6.7 Hz, 1 H), 4.50 (m, 2 H), 4.26 (s, 3 H), 4.08 (s, 3 H),
3.8 (m, 3 H), 3.50 (m, 1 H), 3.36 (s, 3 H), 3.23 (s, 3 H), 2.80 (m, 1 H),
2.30 (m, 1 H), 2.00 (m, 2 H), 1.78 (s, 3 H), 1.74 (s, 3 H), 1.56 (s, 1 H),
1.55 (s, 1 H), 1.13 (s, 3 H), 1.03 (s, 9 H), 0.98 (d, J ) 7.0 Hz, 3 H),
0.55 (d, J ) 5.9 Hz, 3 H); (minor rotamer) δ 9.38 (s, 1 H), 7.65 (m,
4 H), 7.39 (m, 6 H), 6.52 (d, J ) 9.6 Hz, 1 H), 6.01 (d, J ) 8.9 Hz,
1 H), 5.88 (s, 1 H), 5.70 (t, J ) 8.2 Hz, 1 H), 5.4 (m, 2 H), 4.72 (d, J
) 6.7 Hz, 1 H), 4.64 (d, J ) 7.0 Hz, 1 H), 4.60 (d, J ) 7.0 Hz, 1 H),
4.52 (d, J ) 6.7 Hz, 1 H), 4.50 (m, 2 H), 4.26 (s, 3 H), 4.08 (s, 3 H),
3.8 (m, 3 H), 3.50 (m, 1 H), 3.36 (s, 3 H), 3.23 (s, 3 H), 2.8 (m, 1 H),
2.3 (m, 1 H), 2.0 (m, 2 H), 1.78 (s, 3 H), 1.74 (s, 3 H), 1.56 (s, 1 H),
1.55 (s, 1 H), 1.13 (s, 3 H), 1.03 (s, 9 H), 0.98 (d, J ) 7.0 Hz, 3 H),
0.43 (d, J ) 6.1 Hz, 3 H); both rotamers, 13C NMR (100 MHz, CDCl3)
δ 210.3, 209.8, 195.8, 194.6, 192.5, 168.8, 167.0, 148.4, 148.3, 144.2,
141.3, 135.6, 135.2, 133.2, 129.7, 127.71, 125.8, 125.3, 121.2, 95.9,
88.4, 88.1, 80.7, 74.9, 66.9, 66.7, 65.9, 56.0, 55.5, 53.5, 52.6, 50.3,
9
10586 J. AM. CHEM. SOC. VOL. 128, NO. 32, 2006

A Total Synthesis of (
+
)-Tetronolide
A R T I C L E S
46.0, 44.8, 40.9, 40.5, 37.5, 34.7, 31.7, 30.2, 26.7, 19.2, 17.1, 16.3,
15.0, 13.4, 9.9. HRMS (FAB-). Calcd for C53H6935ClO10Si [M+]: m/z
928.4349. Found: m/z 928.4367.
based on conversion) as an amorphous white solid having [R]25D -9.40
° (c 0.50, acetone): IR (film) 3054, 1634, 1407 cm-1 1H NMR (400
:
MHz, (CD3)2CO) δ 7.64 (d, J ) 7.0 Hz, 4 H), 7.38 (m, 6 H), 6.43 (d,
J ) 7.1 Hz, 1 H), 5.94 (d, J ) 10.2 Hz, 1 H), 5.87 (s, 1 H), 5.59 (m,
1 H), 5.28 (m, 1 H), 4.72 (d, J ) 6.5 Hz, 1 H), 4.64 (d, J ) 6.5 Hz,
1 H), 4.55 (d, J ) 6.9 Hz, 1 H), 4.50 (d, J ) 8.7 Hz, 1 H), 4.07 (s, 2
H), 3.81 (s, 1 H), 3.4 (m, 2 H), 3.36 (s, 3 H), 3.09 (m, 1 H), 2.95 (m,
1 H), 2.72 (d, J ) 14 Hz, 1 H), 2.4 (br s, 1 H), 2.3 (br s, 1 H), 1.95 (m,
3 H), 1.76 (s, 3 H), 1.23 (s, 3 H), 1.18 (s, 3 H), 1.03 (s, 9 H), 0.94 (d,
J ) 6.5 Hz, 3 H), 0.62 (br s, 3 H); 13C NMR (100 MHz, (CD3)2CO) δ
199.7, 142.6, 137.8, 133.1, 127.7, 126.4, 121.6, 119.5, 97.7, 95.4, 85.2,
81.8, 75.0, 69.8, 66.6, 55.6, 55.3, 53.4, 50.9, 46.5, 43.8, 41.5, 40.6,
38.1, 32.3, 31.0, 29.6, 29.3, 26.8, 22.5, 19.2, 15.1, 14.1, 13.8, 13.6,
12.9. HRMS (FAB-). Calcd for C52H65O10Si [M - Na+]: m/z 877.4347
Found: m/z 877.4344.
(-)-Fully Protected Spirotetronic Acid Sodium Salt 54. To a
-78 °C solution of ketone 53 (24 mg, 26.6 µmol) in 5 mL of dry THF
was added 0.27 mL (1 M in THF) of L-Selectride over 2 min, then the
resulting reaction mixture was stirred for an additional 20 min. The
reaction was quenched by addition of 2 mL of saturated aqueous
NaHCO3 solution, diluted with 10 mL of brine and 20 mL of EtOAc,
extracted twice with 10 mL of EtOAc, dried over Na2SO4, and
concentrated in vacuo to give 31 mg of crude secondary alcohol as a
white solid.
(-)-Sulfone Sodium Salt 51. To a solution of 84 mg (0.09 mmol)
of allylic chloride 50 in 3 mL of DMF was added 73 mg (0.45 mmol)
of PhSO2Na. The resulting clear solution was stirred at room temper-
ature for 1.5 h, diluted with 20 mL of H2O and 30 mL of ether, extracted
twice with 20 mL of ether, washed with 10 mL of brine, dried over
Na2SO4, and concentrated in vacuo. Purification by flash chromatog-
raphy on silica gel (1:1 acetone/hexane) afforded 75 mg (80%) of the
sulfone sodium salt 51 as an off white amorphous solid having [R]25
D
-97.0° (c 0.49, acetone): IR (film) 2988, 1687, 1625 cm-1; 1H NMR
(400 MHz, CDCl3) δ 9.55 (s, 1 H), 7.7 (m, 4 H), 7.4 (m, 8 H), 7.0 (m,
3 H), 6.55 (d, J ) 8.9 Hz, 1 H), 6.17 (s, 1 H), 5.93 (d, J ) 9.2 Hz, 1
H), 5.32 (m, 1 H), 5.25 (m, 1 H), 4.7 (m, 2 H), 4.6 (m, 4 H), 4.20 (m,
2 H), 3.80 (s, 1 H), 3.50 (br m, 4 H), 3.37 (s, 3 H), 3.28 (s, 3 H), 2.82
(m, 1 H), 2.3 (m, 2 H), 2.07 (m, 2 H), 1.85 (s, 3 H), 1.66 (s, 3 H), 1.61
(s, 3 H), 1.46 (m, 2 H), 1.05 (s, 9 H), 0.99 (d, J ) 7.0 Hz, 3 H), 0.60
(br s, 3 H); 13C NMR (100 MHz, CDCl3) δ 204.9, 195.1, 192.7, 180.2,
162.8, 151.6, 149.9, 143.3, 139.7, 136.3, 135.5, 133.7, 133.2, 129.7,
129.2, 128.9, 127.7, 125.1, 124.8, 120.1, 109.8, 98.4, 95.9, 94.5, 86.2,
80.8, 75.3, 75.1, 66.1, 65.4, 56.4, 55.9, 55.0, 51.9, 51.3, 45.1, 44.1,
41.3, 38.1, 36.6, 32.7, 32.0, 29.6, 26.6, 25.2, 22.6, 19.3, 15.3, 14.6,
13.5, 9.8. HRMS (FAB-). Calcd for C58H71O12SSi [M - Na+]: m/z
1019.4436. Found: m/z 1019.4452.
To a solution of the crude alcohol in 5 mL of CH2Cl2 were added
sequentially 0.4 mL (2.2 mmol) of diisopropylethylamine, and 84 µL
(1.1 mmol) of MOMCl. The resulting reaction mixture was heated to
reflux for 15 h, then diluted with 25 mL of EtOAc, washed with twice
with 10 mL of 1 N HCl and brine, then with 1 mL of saturated aqueous
NaHCO3 solution and 5 mL of brine. The organic phases were combined
and dried over Na2SO4, filtered, and concentrated in vacuo to give 54.
This material was further purified by flash chromatography on silica
gel (with elution by 25% acetone in hexanes) to afford 18 mg of pure
fully protected spirotetronic acid sodium salt 54 (71% for two steps)
as an amorphous white solid having [R]25D -13.85° (c 0.65, acetone):
(-)-Macrocyclic Keto Spirotetronic Acid Sodium Salt 53. To a
solution of the sulfone sodium salt 51 (73 mg, 70 µmol) in 5 mL of
dry benzene was added 0.8 mL of sodium tert-pentoxide solution (0.7
M in benzene). The resulting solution was stirred at room temperature
for 10 min, and another 0.8 mL of sodium tert-pentoxide solution was
added. This process was repeated twice more (in total, 2.8 mmol (40
equiv) of sodium tert-pentoxide was added). The reaction mixture was
stirred at room temperature for additional 15 min, then quenched by
addition of 5 mL of saturated NaHCO3, diluted with 15 mL of brine
and 30 mL of EtOAc, extracted twice with 10 mL of ethyl acetate,
dried over K2CO3, and concentrated in vacuo to afford an oily material,
which solidified upon addition of 10 mL of ether. It was then filtered
through a plug of Celite, washed three times with 30 mL of ether, and
finally, the desired product was rinsed out with 50 mL of acetone and
concentrated in vacuo to afford a mixture of four diastereomers, which
were carried on. The ether portion was evaporated to recover starting
material 51 (13 mg, 17%) as an oily material.
1
IR (film) 2930, 1709, 1681, 1586, 1563 cm-1; H NMR (400 MHz,
(CD3)2CO) δ 7.7 (m, 4 H), 7.4 (m, 6 H), 5.96 (s, 1 H), 5.91 (d, J )
10.2 Hz, 1 H), 5.4 (m, 1 H), 5.3 (m, 2 H), 4.69 (d, J ) 6.6 Hz, 1 H),
4.66 (d, J ) 6.8 Hz, 1 H), 4.60 (d, J ) 6.8 Hz, 1 H), 4.56 (d, J ) 6.6
Hz, 1 H), 4.54 (s, 2 H), 4.3 (d, J ) 8.4 Hz, 1 H), 4.41 (m, 2 H), 3.98
(s, 1 H), 3.78 (m, 1 H), 3.45 (m, 1 H), 3.31 (s, 3 H), 3.28 (s, 3 H), 3.24
(s, 3 H), 2.8 (m, 4 H), 2.7 (d, J ) 14 Hz, 1 H), 2.2 (m, 2 H), 1.85 (d,
J ) 14 Hz, 1 H), 1.54 (s, 3 H), 1.42 (s, 3 H), 1.26 (s, 3 H), 1.04 (s, 9
H), 0.97 (d, J ) 7.1 Hz, 3 H), 0.58 (d, J ) 4.9 Hz, 3 H); 13C NMR
(100 MHz, (CD3)2CO) δ 201.2, 200.9, 175.0, 138.0, 137.7, 137.1, 136.8,
134.9, 131.2, 129.2, 128.9, 127.1, 123.8, 123.4, 99.1, 97.8, 96.4, 95.3,
85.5, 82.8, 79.5, 78.0, 68.0, 56.1, 55.8, 52.8, 45.6, 40.1, 32.9, 31.7,
31.1, 27.8, 20.4, 17.1, 15.9, 15.4, 14.6. HRMS (FAB-). Calcd for
C54H71O11Si [M - Na+]: m/z 923.4766. Found: m/z 923.4723.
(+)-Tetronolide (1). An 18 mg sample of the Na salt of tetronic
acid 54 (0.023 mmol) was dissolved in 3 mL of CH3CN, and 80 mg
(0.23 mmol) of TAS-F was added. The resulting clear solution was
heated at 40 °C for 16 h, then diluted with 15 mL of EtOAc, 10 mL of
brine, and 3 mL of 1 N HCl. Aqueous layer was extracted twice with
10 mL of EtOAc, washed with 1 mL of saturated aqueous NaHCO3
solution, 10 mL of brine, dried over Na2SO4, and concentrated in vacuo
to give the crude primary allylic alcohol.
To a -78 °C solution of DMSO (68 mg, 870 µmol) in 5 mL of
CH2Cl2 was added 122 mg (580 µmol) of trifluoroacetic anhydride,
and the resulting solution was stirred for additional 10 min. The mixture
of diastereomers in 3 mL of CH2Cl2 was then added by cannula transfer.
The reaction mixture was allowed to warm to 0 °C over 10 min and
then recooled with dry ice acetone bath. Triethylamine was then added
by syringe, and the resulting reaction mixture was stirred at -78 °C
for 10 min and allowed to warm to 0 °C over 10 min. The reaction
mixture was quenched by addition of 5 mL of saturated aqueous
NaHCO3 solution, diluted with 10 mL of brine and 15 mL of CH2Cl2,
extracted twice with 10 mL of CH2Cl2, dried over Na2SO4, and
concentrated in vacuo to give the crude sulfone.
Aluminum foil (Reynolds wrapping foil, 200 mm × 5 mm) was
polished with sand paper and dipped into 2% HgCl2 aqueous solution
for 15 s. This strip was rinsed with ethanol and ether and was cut (4
pieces, 2 mm × 5 mm each) directly into a solution of the crude sulfone
in 6 mL of THF/H2O (9:1) and stirred vigorously for 10 min. This
process was repeated two more times. The reaction mixture was stirred
for 30 min at 0 °C and 2.5 h at room temperature, diluted with 20 mL
of EtOAc, and filtered through a plug of Celite. The filtrate was washed
twice with 20 mL of brine and was concentrated in vacuo to afford 48
mg of a white solid. It was further purified by flash chromatography
on silica gel (3:7 acetone/hexane) to afford the keto spirotetronic acid
sodium salt of 53 (26 mg, 50% for three operations or ∼75%/operation
To a solution of the crude alcohol in 5 mL of CH2Cl2 was added
134 mg (0.32 mmol) of DMP.33 The resulting slightly cloudy mixture
was stirred at room temperature for 1.5 h, then quenched by addition
of 5 mL of saturated aqueous Na2CO3 solution and stirred for 10 min.
Ten milliliters of CH2Cl2 and 5 mL of H2O were added, extracted twice
with 10 mL of EtOAc, dried over Na2SO4, and concentrated in vacuo
to afford the crude cyclohexenyl aldehyde.
A solution of the above aldehyde in 3 mL of methanol and 1 mL of
3 N HCl was heated at 65 °C for 1 h. This clear solution was diluted
9
J. AM. CHEM. SOC. VOL. 128, NO. 32, 2006 10587

A R T I C L E S
Boeckman et al.
with 25 mL of EtOAc and 15 mL of brine, extracted twice with 10
mL of EtOAc, dried over Na2SO4, and concentrated in vacuo. This
was purified by flash chromatography on silica gel (7:3 acetone/hexane)
to afford 10.2 mg of (+)-tetronolide (1) as a white solid that was further
purified by recrystallization from acetone/hexane to give 6.8 mg (62%
over three steps) of (+)-tetronolide (1) as a white solid having mp
210-212 °C (lit.10a 211-213 °C) and [R]D25 +72.6° (c 0.34, acetone)
[lit.10a +79.3 (c 1.0, acetone)] and 1H NMR spectroscopic data identical
to the reported10a,17 values: 1H NMR (400 MHz, CDCl3) δ 9.54 (s, 1
H), 6.89 (s, 1 H), 6.05 (d, J ) 10.2 Hz, 1 H), 5.45 (m, 1 H), 5.32 (d,
J ) 9.8 Hz, 1 H), 5.15 (d, J ) 7.1 Hz, 1 H), 4.72 (d, J ) 8.5 Hz, 1 H),
4.25 (s, 1 H), 3.64 (m, 1 H), 3.26 (d, J ) 4.2 Hz, 1 H), 2.97 (t, J ) 7.6
Hz, 1 H), 2.81 (d, J ) 18.8 Hz, 1 H), 2.58 (d, J ) 18.8 Hz, 1 H), 2.3
(m, 3 H), 2.1 (m, 3 H), 1.61 (s, 3 H), 1.6 (m, 2 H), 1.51 (s, 3 H), 1.39
(s, 3 H), 1.03 (d, J ) 7.0 Hz, 3 H), 0.62 (d, J ) 4.6 Hz, 3 H); 13C
NMR (100 MHz, CDCl3) δ 206.4, 201.3, 192.4, 167.0, 149.3, 144.8,
136.4, 136.2, 125.9, 122.5, 117.0, 100.9, 83.9, 75.9, 72.8, 69.3, 54.2,
51.1, 45.2, 42.8, 41.5, 39.2, 34.6, 31.9, 31.0, 29.6, 22.0, 15.8, 15.0,
14.3, 12.9. HRMS (FAB-). Calcd for C32H39O8 [M - H+]: m/z
551.2645. Found: m/z 551.2629.
for support of our studies. We thank Professors E. Yoshii and
K. Takeda for provision of NMR spectra of their synthetic and
natural (+)-tetronolide (1). We thank Drs. Thomas Barta,
Kimberly Estep, and Professor Scott Nelson for important early
contributions to this work. We also thank Drs. Rene Lachicotte
and William Brennessel of the University of Rochester X-ray
Crystallographic Facility for performing the X-ray crystal-
lographic analysis of diol 46.
Supporting Information Available: Experimental procedures
for numbered intermediates 9, 12, 13, 16-19, 29-31, 33, 34,
36-39, and 41 along with unnumbered isolated intermediates.
Copies of 1H NMR and most IR spectra for numbered
intermediates 5-7, 9,12-14, 16-19, 21, 23-26, 28-34, 36-
39, 41, 43, 45, 47, 50, 51, 53, and 54 and unnumbered isolated
intermediates; 1H NMR spectra of our synthetic, Yoshii’s
synthetic, and natural tetronolide (+)-1, and X-ray crystal-
lographic data for diol 46. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank NIGMS of the NIH (GM-
30345) and the National Science Foundation (CHE-0305790)
JA0581346
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10588 J. AM. CHEM. SOC. VOL. 128, NO. 32, 2006