Total synthesis of (±)-momilactone A

Article abstract of DOI:10.1021/jo025873l

The first total synthesis of (±)-momilactone A was accomplished using a highly diastereoselective transannular Diels-Alder reaction on a trans-trans-cis macrocyclic triene.

Full text of DOI:10.1021/jo025873l

Tota l Syn th esis of (()-Mom ila cton e A
J ulie Germain and Pierre Deslongchamps*
Laboratoire de synthe`se organique, De´partement de chimie, Institut de Pharmacologie,
Universite´ de Sherbrooke, 3001, 12e avenue nord, Sherbrooke, Que´bec, Canada J 1H 5N4
Pierre.Deslongchamps@USherbrooke.ca
Received April 29, 2002
The first total synthesis of (()-momilactone A was accomplished using a highly diastereoselective
transannular Diels-Alder reaction on a trans-trans-cis macrocyclic triene.
In tr od u ction
a high level of synthetic challenge. Until now, no other
synthesis has been reported.4
Momilactone A (1) was first isolated in 1973 by Kato
et al. from the seed husk of Oryza sativa L. during studies
concerning the growth-regulating substances in higher
plants.1 Originally characterized as a growth and ger-
mination inhibitor, momilactone A was subsequently
identified as a phytoalexin-like compound by Cartwright
et al.2a,b Phytoalexins are produced by plants in response
to either infection by the blast fungus (Pyricularia oryzae)
or irradiation with UV light. The fact that 1 was
detectable in infected or irradiated leaf tissues but not
in healthy tissue was consistent with the proposed
function of momilactone as a plant phytoalexin.2d
Our synthetic plan is based on the convergent assembly
of fragments 4 and 5 via an aldol reaction, followed by
macrocyclization and simultaneous TADA cycloaddition
for the formation of the tricyclic skeleton 2b.5 We
anticipated that this advanced intermediate (2b) could
be converted to momilactone A (1) using a series of
chemical transformations on ring A and C. Appropriate
modifications of the malonate moiety could provide both
exocyclic substituents on ring C whereas functionalized
ring A could be obtained by a methylation-lactonization
sequence. The subunit 4 required for the aldol condensa-
tion will be accessed by neryl acetate (6) modifications
whereas 5 will be directly obtained by palladium cross-
coupling reaction between iodide 7 and stannane 8
(Scheme 1).
Many studies have also demonstrated that this diter-
pene inhibits the germination of lettuce seeds as well as
the growth of rice roots, and it is known to be a highly
antifungal and antimicrobial compound. Moreover, momi-
lactone A has been shown to participate in the plant
defense system against pathogens.2
We report herein the first synthesis of (()-momilactone
A (1) as well as the necessary studies that led to this
successful endeavor.
The structure of (-)-momilactone A (1), confirmed by
X-ray crystallographic and NMR analysis, displays an
unusual syn stereochemistry at C9-C10. This exhibits
a similarity to the tricycle 2b that has the same ring
junction stereochemistry at C5, C9, and C10 (steroid
numbering).
Resu lts a n d Discu ssion
Syn th esis of Dien e 5 a n d Dien op h ile 4. Synthesis
of the diene 5 (Scheme 2) started with protection of
3-butyn-1-ol as a TBDMS ether followed by hydro-
zirconation-iodination using Schwartz’s reagent6 to give
the trans vinylic iodide 10 in 88% yield as a single
detectable isomer. Deprotection of the silyl ether with
acidic Dowex resin7 afforded alcohol 11. Oxidation to
carboxylic acid 12 using J ones reagent followed by
esterification with chlorotrimethylsilane in MeOH8 led
Our past studies on the transannular Diels-Alder
(TADA) reaction have shown that 14-membered macro-
cycles having a trans-trans-cis olefin geometry can lead
to A.B.C[6.6.6] tricycles having a trans-syn-trans (TST)
ring junction stereochemistry. Thus, in one step, two
rings are generated and four asymmetric centers are
created with high stereoselectivity.3 This strategy could
therefore be applied to momilactone A, which represents
(3) (a) Deslongchamps, P. Aldrichim. Acta 1991, 24, 43. (b) Deslong-
champs, P. Pure Appl. Chem. 1992, 64, 1831. (c) Marsault, E.; Toro´,
A.; Nowak, P.; Deslongchamps, P. Tetrahedron 2001, 57, 4243.
(4) For model studies related to this subject: (a) Sicherer-Roetman,
A.; J ansen, B. J . M.; de Groot, Ae. Tetrahedron Lett. 1984, 25, 2593.
(b) Chu, M.; Coates, R. M. J . Org. Chem. 1992, 57, 4590.
(5) The synthesis of the tricycle 2b has been published: Germain,
J .; Deslongchamps, P. Tetrahedron Lett. 1999, 40, 4051.
(6) (a) Schwartz, J .; Labinger, J . A. Angew. Chem., Int. Ed. Engl.
1976, 15, 333. (b) Schwartz, J .; Hart, D. W.; Blackburn, T. F. J . Am.
Chem. Soc. 1975, 97, 679. (c) Chemin, D.; Linstrumelle, G. Synthesis
1993, 377.
(1) Kato, T.; Kabuto, C.; Sasaki, N.; Tsunagawa, M.; Aizawa, H.;
Fujita, K.; Kato, Y.; Kitahara, Y. Tetrahedron Lett. 1973, 39, 3861.
(2) (a) Kato, T.; Tsunagawa, M.; Sasaki, N.; Aizawa, H.; Fujita, K.;
Kato, Y.; Kitahara, Y.; Takahashi, N. Phytochemistry 1977, 16, 45. (b)
Cartwright, D. W.; Langcake, P.; Pryce, R. J .; Leworthy, D. P.; Ride,
J . P. Phytochemistry 1981, 535. (c) Mohan, R. S.; Yee, N. K. N.; Coates,
R. M.; Ren, Y. Y.; Stamenkovic, P.; West, C. A.; Mendez, I. Arch.
Biochem. Biophys. 1996, 330, 33. (d) West, C. A.; Wickham, K. A. Arch.
Biochem. Biophys. 1992, 293, 320. (e) Li, W. X.; Kodama, O.; Akatsuka,
T. Agric. Biol. Chem. 1991, 55, 1041. (f) Lee, C. W.; Yoneyama, K.;
Takeuchi, Y.; Konnai, M.; Tamogami, S.; Kodama, O. Biosci. Biotechnol.
Biochem. 1999, 63, 1318.
(7) Corey, E. J .; Ponder, J . W.; Ulrich, P. Tetrahedron Lett. 1980,
21, 137.
(8) Nakao, R.; Oka, K.; Fukumoto, T. Bull. Chem. Soc. J pn. 1981,
54, 1267.
10.1021/jo025873l CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/26/2002
J . Org. Chem. 2002, 67, 5269-5278
5269

Germain and Deslongchamps
SCHEME 1
SCHEME 3a
a
Reagents and conditions: (a) m-CPBA, CH2Cl2; (b) HClO4,
DME-H2O; (c) NaIO4, H2SO4, DME-H2O; (d) HCl-dioxane,
MeOH, then K2CO3, 40% over five steps; (e) TPAP, NMO, 4 Å MS,
CH2Cl2, 95%; (f) Ph3PMeI, PhLi, THF, 75%; (g) (Sia)2BH, THF,
H2O2-NaOH, MeOH, 80%; (h) DEAD, PPh3, MeI, toluene, 87%;
(i) NaH, CH2E2, THF-DMF, 70 °C, 86%; (j) TFA-H2O, CH2Cl2,
99%.
SCHEME 2a
acidic medium by treatment with aqueous perchloric acid
in DME, and the resulting diol was cleaved using an
acidic solution of sodium periodate to furnish the alde-
hyde 13.12 Exposure of this aldehyde to hydrochloric acid
in methanol followed by methanolysis of the acetate with
potassium carbonate afforded allylic alcohol 14 in 40%
yield from 6. To complete the dienophile, one-carbon
homologation was necessary. To this end, a three-step
sequence was applied by oxidation of alcohol 14 to the
aldehyde using Ley13 conditions, Wittig olefination with
Ph3PCH2, and regioselective hydroboration with disiamyl-
borane.14,15 This gave rise to the homologated product
15. The introduction of the malonate connector was
accomplished by transformation of 15 into iodide 1616
and subsequent displacement of the latter by sodium
dimethyl malonate at 70 °C. Finally, the dimethoxyacetal
17 was deprotected using a mixture of TFA-water (1:1)
in dichloromethane to furnish 4 in quantitative yield.
Cou p lin g, Ma cr ocycliza tion , a n d TADA Rea ction .
Having the diene and the dienophile in hand, both units
were coupled by an aldol reaction (Scheme 4). Thus,
condensation of the lithium enolate of 5 with aldehyde
4 at -78 °C provided two aldol adducts 18a and 18b in
an approximately 1.2:1 ratio for the syn and anti iso-
mers. The aldol reaction took place at the R position
of the carbonyl, and no isomerization of the double
a
Reagents and conditions: (a) TBDMSCl, imidazole, THF, 95%;
(b) Cp2Zr(H)Cl, I2, THF-toluene, 88%; (c) Dowex 50WX8, MeOH,
86%; (d) J ones reagent, 91%; (e) TMSCl, MeOH, 84%; (f)
E-Bu3SnCHdCHCH2OH (8), PdCl2(CH3CN)2, DMF, 50%; (g)
TBDMSCl, imidazole, THF, 95%.
to ester 7 in 84% yield. Stille9 coupling was applied
between iodide 7 and (E)-Bu3SnCHdCHCH2OH (8)10 to
produce the trans-trans diene exclusively in 50% yield.
The resulting alcohol was then protected as a TBDMS
ether to provide 5.
Construction of the cis dienophile 4, described in
Scheme 3, began with terminal olefin epoxidation of neryl
acetate 6 with m-chloroperoxybenzoic acid in dichloro-
methane.11 The corresponding epoxide was opened in
(12) Heissler, D.; J enn, T. Tetrahedron 1998, 54, 107.
(13) Ley, S. V.; Griffith, W. P. Aldrichim. Acta 1990, 23, 13.
(14) Leopold, E. J . Org. Synth. 1986, 64, 164.
(15) (a) Brown, H. C. Organic Synthesis via Boranes; J ohn Wiley
and Sons: New York, 1975. (b) Brown, H. C.; Zweifel, G. J . Am. Chem.
Soc. 1961, 83, 1241.
(9) Stille, J . K.; Groh, B. L. J . Am. Chem. Soc. 1987, 109, 813.
(10) Lipshutz, B. H.; Lindsley, C. J . Am. Chem. Soc. 1997, 119, 4555.
The alcohol
8
was obtained by reduction of the correspond-
ing aldehyde with NaBH4 in methanol. For characterization data:
Belanger, G.; Deslongchamps, P. J . Org. Chem. 2000, 65, 7070.
(11) Hashimoto, S.; Itoh, A.; Kitagawa, Y.; Yamamoto, H.; Nozaki,
H. J . Am. Chem. Soc. 1977, 99, 4192.
(16) (a) Loibner, H.; Zbiral, E. Helv. Chim. Acta 1976, 59, 2100. (b)
Mitsunobu, O. Synthesis 1981, 1.
5270 J . Org. Chem., Vol. 67, No. 15, 2002

Total Synthesis of (()-Momilactone A
SCHEME 4a
SCHEME 5
a
Reagents and conditions: (a) LDA, THF, -78 °C, then 4, -78
°C, 88%; (b) MOMCl, DIPEA, CH2Cl2; (c) Dowex 50WX8, MeOH;
SCHEME 6a
(d) HCA, PPh3, THF, -40 °C; (e) Cs2CO3, CH3CN, reflux.
bonds was detected in the course of the reaction.17 The
diastereomeric alcohols 18a and 18b were easily sepa-
rated by flash chromatography on silica gel. Both racemic
diastereoisomers were investigated in order to find out
which one would more conveniently lead to the synthesis
of momilactone A.
Both isomeric alcohols were subjected to the same
series of transformations. They were etherified using
MOMCl in dichloromethane, and the silyl groups were
removed under acidic conditions. Chlorination of the free
alcohols 20a and 20b was performed using Magid condi-
tions (HCA, PPh3, THF) to yield 21a and 21b in good
overall yield.18
a
Reagents and conditions: (a) HCl, MeOH, 60 °C, 90%; (b)
J ones reagent, 91%; (c) NaBH4, MeOH, -78 °C, 90%; (d) Nafion-
H, dimethoxymethane, reflux, 86%.
The key step of the synthesis was accomplished by slow
addition of these allylic chlorides into a suspension of
cesium carbonate in refluxing acetonitrile under high
dilution. The macrocyclization-cycloaddition took place
in a single step to afford the TST tricycles 2a and 2b in
40% and 60% yields, respectively.
The specific formation of the TST tricycle can be
explained by the sterically favored endo transition state
having a chair-boat-chair conformation as shown in
Scheme 5. The exo transition state suffers from steric
interactions between the pseudoaxial ester group and one
double bond of the diene. Also, the face selectivity is the
result of the orientation of the C4-carbomethoxy group
in a pseudoequatorial position. Pseudoaxial orientation
of this group leads to a steric interaction with the C10-
methyl (path b). The same conclusion can be reached for
the specific formation of the syn isomer 2a . In this case,
the OMOM group occupied a pseudoaxial orientation at
the transition state that further disfavored the formation
of the cis-syn-cis (CSC) isomer.
Thus, the transannular process allows complete control
in the formation of the TST stereochemistry. Also, a clear
advantage of such a strategy is the mild conditions by
which the cycloaddition took place with a nonactivated
dienophile. As a result, a tricycle containing four new
chiral centers is generated in one chemical operation from
an acyclic precursor in a completely stereocontrolled
manner. Clearly, it can be expected as previously dis-
cussed that with a nonactivated dienophile, an intermo-
lecular process or an intramolecular version on a simple
open-chain intermediate would not take place.19
Considerable experimentation was carried out on both
diastereomeric tricycles in order to determine which one
would more conveniently lead to 1. Preliminary results
showed that reactions on 2b were more selective than
2a . Thus, we decided to recycle 2a into 2b (Scheme 6).
For this purpose, the alcohol was liberated from its MOM
ether and was oxidized to â-ketoester 22 with J ones
reagent. Selective reduction by NaBH4 in methanol
afforded the equatorial alcohol 23. Protection of the latter
as a MOM ether using Nafion-H in refluxing dimethoxy-
methane led to 2b in 86% yield.
(17) (a) House, H. O. Modern Synthetic Reactions; Benjamin: Menlo
Park, CA, 1972; p 555. (b) Robertson, P. A.; Katzenellenbogen, J . A. J .
Org. Chem. 1983, 48, 5288. (c) Takacs, J . M.; J aber, M. R.; Swanson,
B. J .; Mehrmen, S. J . Tetrahedron: Asymmetry 1998, 9, 4313.
(18) Magid, R. M.; Fruchey, O. S.; J ohnson, W. L.; Allen, T. G. J .
Org. Chem. 1979, 44, 359.
(19) Hall, D. H.; Mu¨ller, R.; Deslongchamps, P. Tetrahedron Lett.
1992, 33, 5221.
J . Org. Chem, Vol. 67, No. 15, 2002 5271

Germain and Deslongchamps
SCHEME 7a
SCHEME 8
ester in ring A was not reduced during this process (the
nonreactivity of this ester will be discussed below).
Hydrogenolysis of the CH2OH group of 26 was found to
be quite difficult. Most of the reported methods were tried
unsuccessfully. As an example, Barton’s reaction led to
the starting alcohol.22 Success was finally achieved using
a three-step sequence. First, treatment of 26 with tosyl
chloride, triethylamine, and DMAP in CH2Cl2 at reflux
for 18 h followed by hydrolysis of the ethoxyethyl ether
(without removal of the MOM ether) led to tosyl alcohol
27. Reduction of the tosylate with sodium borohydride
in DMSO gave methyl alcohol 28 in 93% yield.23,24
Interestingly, when these reduction conditions were
applied to the equatorial ethoxyethyl ether only decom-
position of the compound was observed. We speculate
that this step must occur via an intramolecular complex
of the neighboring alcohol and the boron reducing re-
agent. Oxidation of 28 to the corresponding aldehyde with
Dess-Martin periodinane25 followed by Wittig olefination
with methyltriphenylphosphonium bromide and KHMDS
afforded alkene 29. Completion of the C ring was thus
achieved in nine steps.
We next investigated the functional group manipula-
tions on the A ring. We envisaged obtaining the meth-
ylated â-ketolactone by an alkylation followed by iodo-
lactonization. Our initial approach (Scheme 8) was to
introduce the methyl group at C4 from either 2b or 23,
but all attempts (LDA, KHMDS, t-BuLi, NaH, etc.) failed
to provide 30. Starting material was always recovered.
Attempt deuteration at C4 also failed. These results
indicate that the enolate ion was not generated. One
possible explanation is that the ester is probably oriented
in a perpendicular fashion to the ring skeleton. In this
manner, it is stereoelectronically impossible to form the
enolate. The ester orientation may also explain its
reluctance toward hydrolysis or hydride reduction as both
a
Reagents and conditions: (a) KOH, MeOH, THF, 82-85%; (b)
(i) MeOCOCl, Et3N, 0 °C, THF, (ii) NaBH4, THF, 0 °C, 73%; (c)
ethyl vinyl ether, PPTS, CH2Cl2, 91%; (d) LiAlH4, THF, 0 °C, 93%;
(e) TsCl, Et3N, DMAP, CH2Cl2, reflux, 88%; (f) 0.5 M HCl, THF,
90%; (g) NaBH4, DMSO, 80 °C, 93%; (h) Dess-Martin periodinane,
CH2Cl2; (i) Ph3PCH3Br, KHMDS, THF, 70% from 28.
Mod el Stu d ies on th e A a n d C Rin gs. Having built
the momilactone skeleton, we were ready to explore
functional group manipulations on both A and C rings.
To obtain the appropriate C13 substituents, the mal-
onate entity had to be transformed into an equatorial
vinyl and an axial methyl group.
Success in the elaboration of the C ring (Scheme 7)
arose from the efficient differentiation of the malonate
ester. Accordingly, partial hydrolysis of the malonate 2b
produced the equatorial â monoacid 24 in 82-85% yield.20
The malonate ester is more susceptible to hydrolysis than
the ring A methyl ester due to an inductive effect of the
gem-diester moiety. Also, the selective hydrolysis of the
equatorial malonate ester must be due to less steric
hindrance in the process of generating the required
tetrahedral intermediate. Reduction of 24 was accom-
plished through its mixed anhydride with sodium boro-
hydride at 0 °C to give alcohol 25 in 73% yield.21 Attempts
to introduce the vinyl group by conventional oxidation
of the alcohol to an aldehyde followed by olefination
resulted only in deformylation. Therefore, protection of
alcohol 25 as an ethoxyethyl ether using standard
conditions followed by selective reduction of the axial R
ester with LiAlH4 in THF at 0 °C furnished the acid-
sensitive alcohol 26 in excellent yield. The equatorial R
(22) Barton, D. H. R.; McCombie, S. W. J . Chem. Soc., Perkin Trans.
1 1975, 1574.
(23) This reaction was found to be very sensitive. Important byprod-
ucts (the corresponding oxetane 28a and the deformylation product
28b) were obtained in addition to compound 28. To avoid these side
reactions, the concentration and the purity of the NaBH4 must be high.
(24) When a mesylate was used instead of a tosylate, a substantial
amount of the corresponding oxetane (28a ) was obtained during the
reduction process.
(25) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. (b)
Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(20) The structure of monoacid 24 was confirmed by X-ray diffraction
analysis. Crystallographic data (CCDC no. 115342) were deposited at
the Cambridge Crystallographic Data Centre.
(21) Honda, T.; Hallinan, K. O. Tetrahedron 1995, 51, 12211.
5272 J . Org. Chem., Vol. 67, No. 15, 2002

Total Synthesis of (()-Momilactone A
SCHEME 9a
SCHEME 10a
a
Reagents and conditions: (a) NBA, AgOAc, AcOH, 83%; (b)
Dess-Martin periodinane, CH2Cl2, 0 °C, 70%; (c) (i) AcOH-H2O,
90 °C, (ii) K2CO3, MeOH, 65%; (d) Cs2CO3, CH3I, CH3CN, 92%.
of the bromide by the neighboring acetate was realized
in wet acetic acid at 90 °C, which also hydrolyzed
the MOM ether. The resulting mixture of monoacetate-
diols was exposed to K2CO3 in MeOH to give triol 33
in 64% yield. Having three alcohols on the molecule, the
1,2-diol was protected as an acetonide, and the resulting
free alcohol 34 was oxidized to the ketone with Dess-
Martin periodinane. The successful protection confirms
the cis relationship of the 1,2-diol. Next, our plan was to
remove the acetonide in order to obtain the lactone, but
this strategy was abandoned as the hydrolysis of the
acetonide was not successful.30
a
Reagents and conditions: (a) NBA, AgOAc, AcOH, 85%; (b)
(i) AcOH-H2O, 90 °C, (ii) K2CO3, MeOH, 64%; (c) p-TsOH,
(MeO)2C(CH3)2, acetone, 99%; (d) Dess-Martin periodinane,
CH2Cl2, 86%.
faces of the carbonyl ester are somewhat hindered
(OMOM on one side and C6-H on the other) toward
nucleophilic attack.
As an alternative strategy, we decided to investigate
the methylation step using the â-ketoester 22. Several
conditions to introduce the equatorial R methyl group
with high selectivity at C4 were tried unsuccessfully.26
For instance, methylation of 22 (t-BuOK, t-BuOH, MeI,
80 °C; NaH, THF or toluene, MeI, reflux, etc.) gave a
mixture of isomers 31a and 31b in an approximatively
1:1 ratio resulting presumably from an early transition
state.
To solve this problem, we then turned our attention
toward the possibility of forming the lactone before the
alkylation step (Schemes 9 and 10). Methylation of
the resulting â-ketolactone should then lead to perfect
stereochemical control at C4. To build this lactone (cf.
39), we must obtain the â stereochemistry for the C6-
alcohol.27 For this, we used the modified version of the
Woodward reaction.28,29 Thus, treatment of 2b with N-
bromoacetamide (NBA) and silver acetate in acetic acid
gave rise to bromoacetate 32 with excellent stereoselec-
tivity. By NMR analysis, we assumed that the orientation
of the bromide was R and that of the acetate â but the
regiochemistry was not confirmed at this stage. However,
this is of no consequence for the next steps. Displacement
To avoid the use of protecting groups on the 1,2-diol,
we decided to change the sequence of reactions (Scheme
10). Starting from the free alcohol 23, obtained from 2b,
the alkene was submitted to NBA and silver acetate in
acetic acid to give bromoacetate 37 in good yield. Oxida-
tion of the alcohol to ketone 38 was accomplished with
the Dess-Martin periodinane. The structure of 38 was
assigned by 1H NMR and selective decoupling. Thus, the
C10-methyl controls the stereochemical outcome of this
process. Formation of the bromonium bridge must take
place on the R face (less hindered face) and the acetate
ion must react away from the methyl group providing
37. Subsequent displacement of the bromide was realized
under the same conditions as reported before followed
by methanolysis of the acetate to yield the lactone 39 in
65% yield. Thus, under basic conditions, epimerization
at C4 must have occurred and the axial ester was trapped
by the C6-alcohol to form the γ-lactone. Treatment of the
latter with Cs2CO3 and methyl iodide in acetonitrile
afforded, as expected, lactone 40 as the sole product in
92% yield.31 The ease with which this reaction was
performed results from the high reactivity of the enolate,
which is almost a bridgehead. Since it cannot be com-
pletely planar and therefore less conjugated with the
(26) In the literature, introduction of a methyl group at this position
on tricycles containing a â-ketoester affords mainly axial alkylation
product: (a) Spencer, T. A.; Weaver, T. D.; Villarica, R. M.; Friary, R.
J .; Posler, J .; Schwartz, M. A. J . Org. Chem. 1968, 33, 712. (b) Welch,
S. C.; Hagan, C. P.; White, D. H.; Fleming, W. P.; Trotter, J . W. J .
Am. Chem. Soc. 1977, 99, 549. (c) Czarny, M. R.; Maheshwari, K. K.;
Nelson, J . A.; Spenser, T. A. J . Org. Chem. 1975, 40, 2079. (d) Afonso,
A. J . Am. Chem. Soc. 1968, 90, 7375.
(27) Hydroxylation with OsO4 leads to the diol having R stereo-
chemistry.
(28) Woodward, R. B.; Brutcher, F. V. J . Am. Chem. Soc. 1958, 80,
209.
(30) This problem has been reported several times in the Forskolin
synthesis: (a) Ziegler, F. E.; J aynes, B. H. Tetrahedron Lett. 1988, 29,
2031. (b) Hashimoto, S.; Sakata, S.; Sonegawa, M.; Ikegami, S. J . Am.
Chem. Soc. 1988, 110, 3670. (c) Delpech, B.; Lett, R. Tetrahedron Lett.
1987, 28, 4061.
(29) J asserand, D.; Girard, J . P.; Rossi, J . C.; Granger, R. Tetra-
hedron Lett. 1976, 19, 1581.
(31) Goldsmith, D. J .; Thottathil, J . K. Tetrahedron Lett. 1981, 22,
2447.
J . Org. Chem, Vol. 67, No. 15, 2002 5273

Germain and Deslongchamps
SCHEME 11a
synthesis, the dehydration, was found to be problematic.
Despite the fact that the axial â alcohol is well aligned
antiperiplanar with the C8-hydrogen, trans diaxial elimi-
nation of H2O did not proceed using most of the reported
methods for dehydration (mesylation of the alcohol,
Martin sulfuran, acidic conditions, SOCl2, POCl3, Mit-
sunobu conditions, etc.). In each case, starting alcohol
was recovered. The nonformation of the mesylate deriva-
tive suggests that the secondary alcohol in 45 is quite
hindered. An examination of a molecular model supports
this idea. Fortunately, the synthesis of (()-momilactone
A was finally achieved using Burgess reagent in toluene
at reflux in 40-50% yield.33 Interestingly, this reagent
is normally used for syn elimination, although examples
of anti elimination are known.34 This successful reaction
is probably due to the formation of the highly reactive
sulfamate ester intermediate (by addition of the Burgess
reagent to the secondary alcohol) that decomposes at 110
1
°C to give the alkene. The H NMR and 13C NMR spectra
(CDCl3), IR, mass spectra, and HRMS of (()-momilactone
A were completely identical with the literature data of
the natural compound.1,2b
Su m m a r y
a
The first total synthesis of (()-momilactone A has been
achieved in a convergent fashion in 19 steps from the
two building blocks, diene 5 and dienophile 4. The longest
linear sequence is 29 steps: Scheme 3, 10 steps (6 to 4);
Scheme 4, 5 steps (5 to 2b); Scheme 7, 7 steps (2b to 28)
and Scheme 11, 7 steps (28 to 1).
Reagents and conditions: (a) HCl, MeOH, 60 °C, 90%; (b) NBA,
AgOAc, AcOH, 75%; (c) Dess-Martin periodinane, CH2Cl2, 0 °C,
83%; (d) Ph3PCH3Br, KHMDS, THF, 70%; (e) (i) AcOH-H2O, 90
°C, (ii) K2CO3, MeOH, 65%; (f) Cs2CO3, CH3I, CH3CN, 89%; (g)
Burgess reagent, toluene, reflux, 40-50%.
lactone, the reactivity is greater than that from a
conventional â-ketoester. Ring A was thus completed in
five steps.
During the course of these model studies, a synthetic
route was developed so as to obtain the desired substit-
uents with high stereoselectivity on both A and C rings
of the momilactone core.
This synthesis has a very high degree of chemoselec-
tivity, regioselectivity, and stereoselectivity at all the
steps except for the aldol condensation, which gives two
diastereoisomers. However, one isomer can be recycled
into the other one. The key features of this work is the
single operation for the macrocyclization and TADA steps
which takes place with complete stereocontrol producing
a single tricycle containing four new chiral centers from
each aldol isomer. A special note is made to the fact that
the TADA reaction works with a nonactivated dienophile
under very mild thermal conditions. Another interesting
and novel feature is the synthesis of the â-ketolactone
and its stereocontrolled methylation under mild condi-
tions. It is also interesting to point out the different
chemical reactivity of the three ester functions. The
transformation of the malonate ester into the desired C13
R methyl and â vinyl substituents requires several steps
but is selective and efficient.
F in a l Sequ en ce to (()-Mom ila cton e A. To obtain
momilactone A, we had to carry out the above steps in a
proper sequence. For the formation of the lactone, we
needed the double bond in the B ring. Consequently, the
vinyl group at C13 had to be introduced later in the
synthesis. Accordingly, the completion of the synthesis
is described in Scheme 11.
Starting from the methyl alcohol 28 (Scheme 7), the
MOM ether was cleaved in acidic medium and formation
of the bromoacetate from 41 was carried out using
the conditions described above to give 42 in 75% yield
and again with an excellent selectivity. Simultaneous
oxidation of both alcohols produced the corresponding
keto aldehyde in 83% yield. Selective Wittig homologa-
tion of the aldehyde to a vinyl group was performed
with Ph3PCH3Br and KHMDS. Displacement of the
bromide by the acetate group was accomplished followed
by methanolysis to yield lactone 44. The introduction
of the methyl group was realized using Cs2CO3 and
methyl iodide in acetonitrile. The methylated product
was obtained as a single isomer in 89% yield. X-ray
diffraction analysis of hydroxymomilactone A 45 rigor-
ously established the proposed structure and relative
stereochemistry.32 To our surprise, the last step of the
An appropriate asymmetric aldol condensation could
be used to produce the natural product with complete
relative and absolute stereochemical control.
Exp er im en ta l Section
Gen er a l P r oced u r es. All reactions were performed under
nitrogen atmosphere with oven (150 °C) or flame-dried glass-
ware. All solvents were distilled prior to use: ether and
tetrahydrofuran from sodium/benzophenone ketyl; toluene,
acetonitrile, dichloromethane, and dimethyl sulfoxide were
(33) (a) Atkins, G. M., J r.; Burgess, E. M. J . Am. Chem. Soc. 1968,
90, 4744. (b) Burgess, E. M.; Penton, H. R., J r.; Taylor, E. A. J . Org.
Chem. 1973, 38, 26. (c) Crabbe´, P.; Leo´n, C. J . Org. Chem. 1970, 35,
2594.
(32) Crystallographic data of compound 45 (CCDC no. 172789) have
been deposited at the Cambridge Crystallographic Data Centre.
(34) O’Grodnick, J . S.; Ebersole, R. C.; Wittstruck, T.; Caspi, E. J .
Org. Chem. 1974, 39, 2124.
5274 J . Org. Chem., Vol. 67, No. 15, 2002

Total Synthesis of (()-Momilactone A
distilled over calcium hydride and methanol from magnesium/
iodine. Most amines were dried over calcium hydride and
distilled. All other starting materials and reagents were
obtained commercially and used as such. For reaction workups,
all organic phases were dried over magnesium sulfate. Ana-
lytical thin-layer chromatography was carried out on precoated
glass plates (0.25 mm) with 60 F-250 silica gel (Merck). Flash
chromatography was performed with silica gel 60 (230-400
mesh). The following abbreviations were used for NMR data:
s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet;
br, broad. Chemical shifts are reported in ppm δ units relative
to chloroform (7.26 ppm for 1H NMR and 77.0 ppm for
decoupled 13C NMR) or benzene (128.4 ppm for decoupled
13C NMR) as internal standard. When necessary, decoupling
experiments were applied. Mass spectra (MS) were obtained
with electronic ionization (70 eV). Melting points of crystalline
compounds are uncorrected.
Meth yl (()-(5Z,11E,13E)-(9R,10R)-15-ter t-Bu tyld im eth -
ylsilyloxy-9-h yd r oxy-2,10-bis(m eth oxyca r bon yl)-6-m eth -
ylp en t a d eca -5,11,13-t r ien -1-oa t e (18a ) a n d Met h yl (()-
(5Z,11E,13E)-(9S,10R)-15-ter t-Bu t yld im et h ylsilyloxy-9-
h yd r oxy-2,10-bis(m eth oxyca r bon yl)-6-m eth ylp en ta d eca -
5,11,13-tr ien -1-oa te (18b). To a stirred solution of the ester
5 (2.26 g, 8.75 mmol) in tetrahydrofuran (50 mL) at -78 °C
was added LDA (2 M in hexane-THF-heptane, 4.2 mL, 3.0
mmol). The mixture was stirred for 20 min, and a solution of
the aldehyde 4 (1.12 g, 4.38 mmol) in tetrahydrofuran (2 mL)
was added. The resulting mixture was stirred at -78 °C for 3
h and was warmed to room temperature. Aqueous NH4Cl was
added, and volatiles were evaporated. Ethyl acetate was added,
and the layers were separated. The aqueous phase was
extracted with ethyl acetate, and the combined organic phases
were dried, filtered, and evaporated. Aldolic adducts were
separated by flash chromatography (ethyl acetate-hexane, 30:
70) to give the adducts 18a syn and 18b anti (2.02 g, 88%:
1.13 g syn, 0.89 g anti).
acetate-hexane, 30:70) to give the protected alcohol 19a (0.98
g, 82%) as a yellow oil: Rf ) 0.55 (30% ethyl acetate-hexane);
IR (film) ν 2953, 2931, 2856, 1736, 1436, 1360, 1254, 1149,
1099, 1036, 992, 837, 778 cm-1; 1H NMR (300 MHz, CDCl3) δ
6.35-6.09 (2H, m), 5.79-5.69 (2H, m), 5.07 (1H, t, J ) 6.0
Hz), 4.62 (2H, s), 4.21 (2H, d, J ) 4.8 Hz), 3.89 (1H, td, J )
11.2, 5.7 Hz), 3.73 (6H, s), 3.69 (3H, s), 3.36 (1H, m), 3.34 (3H,
s), 3.23 (1H, dd, J ) 9.5, 5.4 Hz), 2.11-1.88 (6H, m), 1.66 (3H,
s), 1.55 (2H, m), 0.90 (9H, s), 0.06 (6H, s); 13C NMR (75 MHz,
CDCl3) δ 172.7, 169.8, 136.3, 133.9, 132.9, 128.9, 126.6, 123.6,
96.5, 79.0, 63.2, 55.8, 53.4, 52.4, 51.9, 50.9, 30.8, 28.9, 27.4,
25.9, 25.4, 23.3, 18.3, -5.3; MS m/e 555 (M - Me)+, 513 (M -
C4H9)+; HRMS calcd for C28H47O9Si (M - Me)+ 555.2989, found
555.2983.
Meth yl (()-(5Z,11E,13E)-(9S,10R)-15-ter t-Bu tyld im eth -
ylsilyloxy-2,10-bis(m eth oxycar bon yl)-9-m eth oxym eth oxy-
6-m eth ylp en ta d eca -5,11,13-tr ien -1-oa te (19b). The proce-
dure used for the synthesis of 19a was applied for the
protection of 18b using alcohol 18b (0.89 g), diisopropylethyl-
amine (5.9 mL), chloromethyl methyl ether (1.9 mL) in
dichloromethane (50 mL) to give 19b (0.87 g, 90%) as a
colorless oil: Rf ) 0.50 (30% ethyl acetate-hexane); IR (film)
ν 2954, 2857, 1738, 1436, 1360, 1256, 1196, 1161, 1104, 1037,
1
994, 838, 778 cm-1; H NMR (300 MHz, CDCl3) δ 6.23-6.15
(2H, m), 5.75 (1H, m), 5.55 (1H, m), 5.05 (1H, t, J ) 6.8 Hz),
4.63 (2H, s), 4.19 (2H, d, J ) 4.3 Hz), 3.91 (1H, m), 3.72 (6H,
s), 3.69 (3H, s), 3.35 (3H, s), 3.38-3.26 (2H, m), 2.10-1.88 (6H,
m), 1.65 (3H, s), 1.56 (2H, m), 0.90 (9H, s), 0.06 (6H, s); 13C
NMR (75 MHz, CDCl3) δ 172.9, 169.8, 136.6, 134.1, 133.5,
128.6, 126.3, 123.4, 96.4, 78.5, 63.2, 55.9, 54.1, 52.4, 51.9, 50.9,
29.5, 28.9, 25.9, 25.9, 25.4, 23.3, 18.3, -5.3; MS m/e 555 (M -
Me)+, 513 (M - C4H9)+; HRMS calcd for C25H41O9Si (M -
C4H9)+ 513.2520, found 513.2527.
Meth yl (()-(5Z,11E,13E)-(9R,10R)-15-Hyd r oxy-2,10-bis-
(m eth oxyca r bon yl)-9-m eth oxym eth oxy-6-m eth ylp en ta -
d eca -5,11,13-tr ien -1-oa te (20a ). To a stirred solution of
compound 19a (0.85 g, 1.49 mmol) in methanol (11 mL) was
added acidic resin Dowex 50WX8. The mixture was stirred at
room temperature for 8 h and filtered, and solvent was
evaporated. The residue was purified by flash chromatography
(ethyl acetate-hexane, 1:1) to give the alcohol 20a (0.61 g,
90%) as an oil: Rf ) 0.17 (30% ethyl acetate-hexane); IR (film)
ν 3466, 2954, 2861, 1732, 1436, 1351, 1288, 1239, 1200, 1151,
1098, 1035, 994, 919 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.28-
6.06 (2H, m), 5.82-5.72 (2H, m), 5.03 (1H, t, J ) 6.2 Hz), 4.57
(2H, s), 4.13 (2H, d, J ) 5.6 Hz), 3.86 (1H, m), 3.68 (6H, s),
3.65 (3H, s), 3.31 (1H, m), 3.29 (3H, s), 3.20 (1H, dd, J ) 9.4,
4.7 Hz), 2.09 (1H, br s), 2.04-1.86 (6H, m), 1.62 (3H, s), 1.52
(2H, m); 13C NMR (75 MHz, CDCl3) δ 172.6, 169.8, 136.3, 133.7,
132.3, 130.5, 127.5, 123.6, 96.4, 79.1, 63.2, 55.8, 53.3, 52.5, 51.9,
51.0, 30.8, 29.0, 27.5, 25.4, 23.4; MS m/e 393 (M - H2O -
MOM)+; HRMS calcd for C21H29O7 (M - H2O - MOM)+
393.1913, found 393.1920.
Com p ou n d 18a : Rf ) 0.22 (20% ethyl acetate-hexane); IR
(film) ν 3534, 2954, 2857, 1732, 1436, 1378, 1256, 1158, 1056,
1
992, 838, 778 cm-1; H NMR (300 MHz, CDCl3) δ 6.32-6.12
(2H, m), 5.79-5.69 (2H, m), 5.09 (1H, t, J ) 6.9 Hz), 4.20 (2H,
d, J ) 4.8 Hz), 3.85 (1H, m), 3.72 (6H, s), 3.70 (3H, s), 3.36
(1H, t, J ) 7.3 Hz), 3.06 (1H, dd, J ) 9.5, 4.4 Hz), 2.75 (1H, d,
J ) 3.5 Hz), 2.12-1.88 (6H, 3m), 1.65 (3H, s), 1.47 (2H, m),
0.90 (9H, s), 0.06 (6H, s); 13C NMR (75 MHz, CDCl3) δ 173.8,
169.9, 136.3, 134.9, 133.4, 128.7, 125.6, 123.9, 71.1, 63.2, 54.8,
52.5, 52.1, 51.0, 32.2, 29.1, 27.7, 25.9, 25.8, 25.5, 23.2, 18.4,
-5.3; MS m/e 469 (M - C4H9)+; HRMS calcd for C23H37O8Si
(M - C4H9)+ 469.2258, found 469.2260.
Com p ou n d 18b: Rf ) 0.12 (20% ethyl acetate-hexane);
IR (film) ν 3522, 2954, 2857, 1732, 1436, 1256, 1215, 1159,
1
1056, 992, 962, 838, 777 cm-1; H NMR (300 MHz, CDCl3) δ
6.25-6.14 (2H, m), 5.74 (1H, m), 5.57 (1H, m), 5.09 (1H, t, J
) 6.8 Hz), 4.19 (2H, d, J ) 4.4 Hz), 3.75 (1H, m), 3.71 (6H, s),
3.69 (3H, s), 3.35 (1H, t, J ) 7.1 Hz), 3.09 (1H, dd, J ) 9.1, 8.2
Hz), 2.63 (1H, d, J ) 6.4 Hz), 2.16-1.88 (6H, 3m), 1.64 (3H,
s), 1.62 (1H, m), 1.36 (1H, m), 0.89 (9H, s), 0.05 (6H, s); 13C
NMR (75 MHz, CDCl3) δ 173.5, 169.9, 136.4, 134.1, 133.5,
128.6, 126.6, 123.9, 72.1, 63.2, 56.0, 52.5, 52.0, 51.0, 32.5, 29.1,
27.4, 25.9, 25.4, 23.2, 18.4, -5.3; MS m/e 469 (M - C4H9)+;
HRMS calcd for C23H37O8Si (M - C4H9)+ 469.2258, found
469.2260.
Meth yl (()-(5Z,11E,13E)-(9S,10R)-15-Hyd r oxy-2,10-bis-
(m eth oxyca r bon yl)-9-m eth oxym eth oxy-6-m eth ylp en ta -
d eca -5,11,13-tr ien -1-oa te (20b). The procedure used for the
synthesis of 20a was applied for the deprotection of 19b (0.87
g) to give the alcohol 20b (0.66 g, 95%) as a colorless oil: Rf )
0.14 (30% ethyl acetate-hexane); IR (film) ν 3468, 2954, 2933,
2909, 1735, 1436, 1349, 1256, 1219, 1162, 1103, 1033, 995, 920
1
cm-1; H NMR (300 MHz, CDCl3) δ 6.29-6.15 (2H, m), 5.89
(1H, m), 5.59 (1H, m), 5.06 (1H, t, J ) 6.2 Hz), 4.63 (2H, s),
4.18 (2H, t, J ) 5.8 Hz), 3.93 (1H, m), 3.72 (6H, s), 3.69 (3H,
s), 3.35 (3H, s), 3.34-3.25 (2H, m), 2.09-1.88 (6H, m), 1.64
(3H, s), 1.63 (1H, m), 1.45 (1H, m); 13C NMR (75 MHz, CDCl3)
δ 172.8, 169.8, 136.5, 133.9, 133.3, 129.8, 126.9, 123.4, 96.3,
78.3, 62.9, 55.8, 54.1, 52.5, 51.9, 51.0, 29.6, 28.9, 25.8, 25.4,
23.3; MS m/e 425 (M - OMe)+, 407 (M - H2O - OMe)+, 393
(M - H2O - MOM)+; HRMS calcd for C21H29O7 (M - H2O -
MOM)+ 393.1913, found 393.1922.
Meth yl (()-(5Z,11E,13E)-(9R,10R)-15-ter t-Bu tyld im eth -
ylsilyloxy-2,10-bis(m eth oxycar bon yl)-9-m eth oxym eth oxy-
6-m eth ylp en ta d eca -5,11,13-tr ien -1-oa te (19a ). To a stirred
solution of the alcohol 18a (1.10 g, 2.09 mmol) in dichloro-
methane (10 mL) at 0 °C were added diisopropylethylamine
(7.3 mL, 41.8 mmol) and chloromethyl methyl ether (2.4 mL,
31.3 mmol). The resulting mixture was stirred at 0 °C for 1 h
and at room temperature for 12 h. The mixture was filtered
through a silica pad, diluted in ethyl acetate, and washed with
water. The organic phase was dried, filtered, and evaporated.
The residue was purified by flash chromatography (ethyl
Meth yl (()-(5Z,11E,13E)-(9R,10R)-15-Ch lor o-2,10-bis-
(m eth oxyca r bon yl)-9-m eth oxym eth oxy-6-m eth ylp en ta -
J . Org. Chem, Vol. 67, No. 15, 2002 5275

Germain and Deslongchamps
d eca -5,11,13-tr ien -1-oa te (21a ). To a stirred solution of the
alcohol 20a (0.61 g, 1.3 mmol) in tetrahydrofuran (40 mL) at
-40 °C were added triphenylphosphine (0.39 g, 1.5 mmol) and
hexachloroacetone (0.22 mL, 0.15 mmol). The mixture was
stirred at -40 °C for 25 min, and toluene (1 mL) was added.
Solvents were evaporated, and the residue was purified by
flash chromatography (hexane, then ethyl acetate-hexane 30:
70) to give chloride 21a (0.59 g, 85% from 19a ) as an oil: Rf )
0.49 (30% ethyl acetate-hexane); IR (film) ν 2953, 1734, 1436,
1259, 1150, 1099, 1035, 994 cm-1; 1H NMR (300 MHz, CDCl3)
δ 6.32 (1H, dd, J ) 14.8, 10.3 Hz), 6.13 (1H, m), 5.92-5.70
(2H, m), 5.09 (1H, t, J ) 6.2 Hz), 4.60 (2H, s), 4.09 (2H, d, J
) 7.3 Hz), 3.91 (1H, q, J ) 5.2 Hz), 3.73 (6H, s), 3.69 (3H, s),
3.36 (1H, m), 3.33 (3H, s), 3.22 (1H, dd, J ) 9.4, 4.7 Hz), 2.10-
1.86 (6H, m), 1.66 (3H, s), 1.53 (2H, m); 13C NMR (75 MHz,
CDCl3) δ 172.4, 169.7, 136.2, 133.5, 132.9, 130.4, 127.3, 123.7,
96.4, 78.9, 55.8, 53.3, 52.4, 51.9, 50.9, 44.9, 30.84, 28.9, 27.4,
25.3, 23.2; MS m/e 443 (M - OMe)+; HRMS calcd for C22H32O7-
Cl (M - OMe)+ 443.1836, found 443.1841.
(9H, m), 0.77 (3H, s), 0.85 (1H, m); 13C NMR (75 MHz, CDCl3)
δ 173.3, 172.6, 171.3, 132.9, 131.9, 94.6, 72.9, 55.4, 54.9, 52.5,
51.7, 51.4, 47.3, 37.7, 37.1, 36.9, 36.1, 32.4, 27.4, 25.6, 24.1,
23.4; MS m/e 406 (M - MeOH)•+; HRMS calcd for C22H30O7
(M - MeOH)+ 406.1991, found 406.1999.
(()-(1R,2R,5S,7R,10R,11S,12S)-5,11-Bis(m eth oxycar bon -
yl)-12-m eth oxym eth oxy-1-m eth yltr icyclo[8.4.0.02,7]tetr a -
d ec-8-en e-5-ca r boxylic Acid (24). To a stirred solution of
the tricycle 2b (0.30 g, 0.70 mmol) in THF (10 mL) was added
at 0 °C a solution of KOH (1 M in MeOH, 1.7 mL). The solution
was stirred at room temperature for 4 h, and the volatile
compounds were evaporated. Water was added, and the
mixture was extracted with ether. The aqueous phase was
acidified to pH 2 and was extracted with ethyl acetate. The
combined organic phases were dried, filtered, and evaporated
to give monoacid 24 (241 mg, 83%) as an amorphous solid: mp
140-142 °C (ethyl acetate and hexane); IR (film) ν 3561-2500,
2951, 1731, 1720, 1436, 1377, 1288, 1269, 1211, 1099, 1036,
916, 732 cm-1; 1H NMR (300 MHz, CDCl3) δ 10.80 (1H, br s),
5.70-5.59 (2H, m), 4.68 (1H, d, J ) 6.8 Hz), 4.57 (1H, d, J )
6.8 Hz), 3.78 (3H, m), 3.76 (1H, m), 3.71 (3H, s), 3.31 (3H, s),
2.72 (1H, dd, J ) 12.4, 10.4 Hz), 2.63 (1H, m), 2.51 (1H, m),
2.10-1.92 (2H, m), 1.82-1.20 (9H, m), 0.83 (3H, s); 13C NMR
(75 MHz, CDCl3) δ 177.6, 175.1, 170.9, 134.2, 129.9, 95.2, 77.7,
55.3, 54.9, 52.7, 51.7, 51.0, 49.5, 44.5, 37.1, 36.6, 36.0, 32.1,
31.3, 27.3, 24.1, 23.9; MS m/e 392 (M - MeOH)+; HRMS calcd
for C21H28O7 (M - MeOH)+ 392.1835, found 392.1825.
Meth yl (()-(5Z,11E,13E)-(9S,10R)-15-Ch lor o-2,10-bis-
(m eth oxyca r bon yl)-9-m eth oxym eth oxy-6-m eth ylp en ta -
d eca -5,11,13-tr ien -1-oa te (21b). The procedure used for the
synthesis of 21a was applied for chlorination of alcohol 20b
using alcohol 20b (0.66 g), triphenylphosphine (0.42 g), and
hexachloroacetone (0.24 mL) in tetrahydrofuran (45 mL) to
give chloride 21b (0.64 g, 90% from 19b) as a colorless oil: Rf
) 0.36 (30% ethyl acetate-hexane); IR (film) ν 2953, 1736,
1437, 1349, 1251, 1150, 1099, 1035, 994, 919, 665 cm-1 1H
;
(()-(1R,2R,5S,7R,10R,11S,12S)-5-Hyd r oxym eth yl-5,11-
b is(m et h oxyca r b on yl)-12-m et h oxym et h oxy-1-m et h yl-
tr icyclo[8.4.0.02,7]tetr a d ec-8-en e (25). To a stirred solution
of monoacid 24 (0.13 g, 0.30 mmol) in tetrahydrofuran (10 mL)
was added triethylamine (43 µL, 0.30 mmol) followed by
methylchloroformate (24 µL, 0.30 mmol) at 0 °C. The mixture
was stirred for 20 min, and triethylamine salts were filtered.
The filtrate was added to a suspension of NaBH4 (0.01 g, 0.33
mmol) in THF, and the resulting mixture was stirred for 15 h
at 0 °C. A saturated aqueous solution of KHSO4 was added,
and the mixture was stirred for 1 h. The solvent was
evaporated, water was added, and the mixture was extracted
with ethyl acetate. The combined organic phases were dried,
filtered, and evaporated. The crude product was purified by
flash chromatography (ethyl acetate-hexane, 1:1) to give the
alcohol 25 (92 mg, 73%) as a yellowish oil: Rf ) 0.29 (50% ethyl
acetate-hexane); IR (film) ν 3478, 2948, 1731, 1435, 1204,
NMR (300 MHz, CDCl3) δ 6.31-6.12 (2H, m), 5.81 (1H, m),
5.67 (1H, dd, J ) 14.5, 9.8 Hz), 5.06 (1H, t, J ) 6.2 Hz), 4.64
(2H, s), 4.05 (2H, d, J ) 7.3 Hz), 3.90 (1H, m), 3.73 (6H, s),
3.69 (3H, s), 3.32 (3H, s), 3.36-3.25 (2H, m), 2.05-1.89 (6H,
m), 1.69 (3H, s), 1.66 (1H, m), 1.49 (1H, m); 13C NMR (75 MHz,
CDCl3) δ 172.2, 169.8, 136.5, 133.2, 133.0, 129.0, 123.6, 96.4,
78.5, 55.9, 54.0, 52.5, 51.9, 50.9, 44.8, 29.7, 28.9, 26.1, 25.4,
23.3; MS m/e 443 (M - OMe)+, 438 (M - HCl)•+; HRMS calcd
for C22H32O7Cl (M - OMe)+ 443.1836, found 443.1841.
(()-(1R,2R,7R,10R,11S,12S)-5,5,11-Tr is(m eth oxycar bon -
yl)-12-methoxymethoxy-1-methyltricyclo[8.4.0.02,7]tetradec-
8-en e (2b). To a stirred suspension of cesium carbonate (1.7
g, 5.2 mmol) in acetonitrile (750 mL) at reflux was added over
15 h via syringe pump, a solution of the chloride 21b (0.49 g,
0.70 mmol) in acetonitrile (5 mL). At the end of the addition,
the mixture was stirred for an additional 3 h. The mixture
was cooled to room temperature, cesium carbonate was filtered
on a Celite pad, and solvent was evaporated. The residue was
purified by flash chromatography (ethyl acetate-hexane, 30:
70) to give tricycle 2b (275 mg, 60%) as a yellowish foam: Rf )
0.43 (30% ethyl acetate-hexane); IR (film) ν 2952, 2892, 1730,
1435, 1374, 1237, 1152, 1095, 1035, 992, 915, 802, 732, 671
1154, 1098, 1036, 917, 732, 672 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 5.69-5.60 (2H, m), 4.69 (1H, d, J ) 6.9 Hz), 4.58
(1H, d, J ) 6.8 Hz), 3.77 (1H, m), 3.75 (3H, m), 3.72 (3H, s),
3.56 (2H, s), 3.32 (3H, s), 2.74 (1H, dd, J ) 12.4, 10.4 Hz),
2.45 (1H, m), 2.32 (1H, m), 2.10-1.95 (2H, m), 1.80-1.09 (10H,
m), 0.83 (3H, s); 13C NMR (75 MHz, CDCl3) δ 175.6, 174.9,
134.9, 129.4, 95.1, 77.6, 70.9, 55.2, 51.9, 51.8, 51.5, 49.6, 49.5,
44.4, 37.0, 36.7, 36.3, 31.8, 31.3, 27.3, 24.2, 23.8; MS m/e 348
(M - C2H6O2)•+; HRMS calcd for C20H28O5 (M - C2H6O2)+
348.1937, found 348.1942.
1
cm-1; H NMR (300 MHz, CDCl3) δ 5.63-5.51 (2H, m), 4.60
(1H, d, J ) 6.8 Hz), 4.49 (1H, d, J ) 6.9 Hz), 3.73 (1H, m),
3.68 (3H, s), 3.63 (3H, s), 3.62 (3H, s), 3.23 (3H, s), 2.64 (1H,
dd, J ) 12.0, 10.4 Hz), 2.52 (1H, m), 2.39 (1H, m), 2.01-1.87
(2H, m), 1.71-1.18 (9H, m), 0.75 (3H, s); 13C NMR (75 MHz,
CDCl3) δ 174.9, 172.5, 171.2, 134.3, 129.8, 95.2, 77.6, 55.3, 54.9,
52.6, 52.5, 51.6, 51.0, 49.5, 44.5, 37.0, 36.8, 36.0, 32.3, 31.3,
27.3, 24.1, 23.9; MS m/e 376 (M - MOM), 406 (M - MeOH)+;
HRMS calcd for C22H30O7 (M - MeOH)+ 406.1991, found
406.1999.
(()-(1R,2R,5R,7R,10R,11S,12S)-5-(1-E t h oxyet h yl)oxo-
m eth yl-5-h yd r oxym eth yl-11-m eth oxyca r bon yl-12-m eth -
oxym eth oxy-1-m eth yltr icyclo[8.4.0.02,7]tetr adec-8-en e (26).
To a stirred solution of the alcohol 25 (0.10 g, 0.25 mmol) in
dichloromethane (15 mL) was added ethyl vinyl ether (24 µL,
0.30 mmol) followed by PPTS (0.02 g, 0.09 mmol). The mixture
was stirred at room temperature for 1 h, and an aqueous
solution of NaHCO3 was added. The mixture was extracted
with dichloromethane, and the combined organic phases were
dried, filtered, and evaporated. The crude product was purified
by flash chromatography (ethyl acetate-hexane, 1:1) to give
the protected alcohol (108 mg, 91%): Rf ) 0.67 (50% ethyl
acetate-hexane); IR (film) ν 2947, 2894, 1733, 1436, 1377,
(()-(1R,2R,7R,10R,11S,12R)-5,5,11-Tr is(m eth oxycar bon -
yl)-12-m eth oxym eth oxy-1-m eth yltr icyclo[8.4.0.02,7]tetr a -
d ec-8-en e (2a ). The procedure used for the synthesis of 2b
was applied for the macrocyclization of chloride 21a using
chloride 21a (0.65 g), cesium carbonate (1.47 g), and acetoni-
trile (950 mL) to give tricycle 2a (0.24 g, 40%) as a yellowish
foam: Rf ) 0.34 (30% ethyl acetate-hexane); IR (film) ν 2952,
2872, 1732, 1435, 1379, 1240, 1206, 1168, 1096, 1037, 917
1213, 1154, 1133, 1101, 1041, 921, 877 cm-1 1H NMR (300
;
cm-1
;
1H NMR (300 MHz, CDCl3) δ 5.63 (1H, m), 5.55 (1H,
MHz, CDCl3) δ 5.70-5.56 (2H, m), 4.70-4.61 (2H, m), 4.54
(1H, d, J ) 6.8 Hz), 3.78 (1H, td, J ) 10.6, 5.6 Hz), 3.68 (3H,
s), 3.67 (3H, s), 3.65-3.30 (4H, 3 m), 3.28 (3H, s), 2.74 (1H,
dd, J ) 12.4, 10.4 Hz), 2.45 (1H, m), 2.33 (1H, m), 2.08-1.94
m), 4.65 (1H, d, J ) 7.1 Hz), 4.50 (1H, d, J ) 7.0 Hz), 4.15
(1H, m), 3.77 (3H, s), 3.70 (6H, s), 3.30 (3H, s), 2.78 (1H, dd,
J ) 12.0, 2.9 Hz), 2.62 (1H, m), 2.51-2.41 (2H, m), 1.90-1.25
5276 J . Org. Chem., Vol. 67, No. 15, 2002

Total Synthesis of (()-Momilactone A
(2H, m), 1.78-1.39 (6H, m), 1.29-1.10 (3H, m), 1.22 (3H, d, J
) 5.3 Hz), 1.15 (3H, t, J ) 7.0 Hz), 0.79 (3H, s); 13C NMR (75
MHz, CDCl3) δ 175.3, 175.0, 135.1, 129.4, 99.4, 95.2, 77.7, 72.4,
60.8, 55.3, 51.8, 51.7, 51.6, 49.6, 48.5, 44.5, 37.2, 37.1, 36.4,
32.4, 31.4, 27.4, 24.3, 23.9, 19.3, 15.1; MS m/e 451 (M - OMe)+,
437 (M - MOM)+; HRMS calcd for C25H39O7 (M - OMe)+
451.2696, found 451.2689.
(75 MHz, CDCl3) δ 175.0, 145.1, 134.8, 132.3, 129.9, 129.7,
127.9, 95.3, 77.7, 69.7, 68.7, 55.4, 52.1, 51.6, 49.5, 44.7, 39.2,
37.0, 35.3, 34.2, 31.4, 30.1, 27.4, 23.9, 22.4, 21.6; MS m/e 504
(M - MeOH)+, 474 (M - MOM)+; HRMS calcd for C27H36O7S
(M - MeOH)+ 504.2182, found 504.2163.
(()-(1R,2R,5R,7R,10R,11S,12S)-5-H yd r oxym et h yl-11-
m eth oxyca r bon yl-12-m eth oxym eth oxy-1,5-d im eth yltr i-
cyclo[8.4.0.02,7]tetr a d ec-8-en e (28). To a solution of the
tosylate 27 (0.41 g, 0.08 mmol) in dimethyl sulfoxide (6 mL)
was added NaBH4 (0.04 g, 0.98 mmol). The resulting mixture
was stirred at 80 °C for 4 h, and the solution was cooled to 0
°C. A saturated aqueous solution of KHSO4 was added, and
the mixture was stirred for 1 h and extracted with ethyl
acetate. The organic phase was dried, filtered, and evaporated.
The crude product was purified by flash chromatography (ethyl
acetate-hexane, 30:70) to give compound 28 (260 mg, 93%)
as a yellow foam: Rf ) 0.51 (40% ethyl acetate-hexane); IR
(film) ν 3446, 2934, 1737, 1458, 1436, 1329, 1267, 1244, 1197,
To a solution of the ester (see above) (0.104 g, 0.22 mmol)
in tetrahydrofuran (20 mL) was added LiAlH4 (0.015 g, 0.39
mmol) at 0 °C. The mixture was stirred at 0 °C for 45 min,
and acetone (2 mL) was added followed by MgSO4‚10H2O. The
resulting mixture was stirred for 1 h at room temperature and
filtered through a silica pad, and the solvents were evaporated.
The crude product was purified by flash chromatography (ethyl
acetate-hexane, 1:1) to give the alcohol 26 (91 mg, 93%) as a
white foam: Rf ) 0.50 (50% ethyl acetate-hexane); IR (film)
ν 3496, 2935, 1738, 1437, 1378, 1196, 1134, 1100, 1042, 919
1
cm-1; H NMR (300 MHz, CDCl3) δ 5.69-5.58 (2H, m), 4.69
1173, 1099, 1040, 917 cm-1 1H NMR (300 MHz, CDCl3) δ
;
(1H, d, J ) 6.8 Hz), 4.68 (1H, m), 4.59 (1H, d, J ) 6.8 Hz),
3.81 (1H, td, J ) 10.2, 5.2 Hz), 3.73 (3H, s), 3.70-3.60 (3H,
m), 3.50-3.40 (2H, m), 3.32 (3H, s), 3.23 (1H, dd, J ) 8.9, 4.0
Hz), 2.75 (1H, dd, J ) 12.4, 10.4 Hz), 2.11-1.98 (2H, m), 1.85
(1H, m), 1.73-1.49 (6H, m), 1.32-1.20 (3H, m), 1.32 (3H, d, J
) 5.3 Hz), 1.25 (3H, t, J ) 7.1 Hz), 1.12-1.01 (2H, m), 0.82
(3H, s); MS m/e 423 (M - OMe)+; HRMS calcd for C24H39O6
(M - OMe)+ 423.2746, found 423.2753.
5.66-5.60 (2H, m), 4.69 (1H, d, J ) 6.9 Hz), 4.58 (1H, d, J )
6.9 Hz), 3.81 (1H, td, J ) 10.5, 5.1 Hz), 3.72 (3H, s), 3.32 (3H,
s), 3.29 (2H, s), 2.74 (1H, dd, J ) 12.4, 10.4 Hz), 2.10-2.02
(2H, m), 1.88 (1H, m), 1.66-1.19 (9H, m), 0.93 (3H, s), 0.81
(3H, s), 0.72 (1H, m); 13C NMR (75 MHz, CDCl3) δ 175.2, 135.8,
129.4, 95.3, 77.8, 74.4, 55.4, 52.5, 51.6, 49.7, 44.8, 39.9, 37.2,
35.63, 34.7, 31.6, 27.5, 23.9, 22.8, 19.9; MS m/e 351 (M - Me)+,
335 (M - OMe)+; HRMS calcd for C20H31O4 (M - OMe)+
335.2222, found 335.2227.
(()-(1R,2R,5S,7R,10R,11S,12S)-5-H yd r oxym et h yl-11-
m e t h oxyca r b on yl-12-m e t h oxym e t h oxy-1-m e t h yl-5-p -
t olu en esu lfon yloxym et h ylt r icyclo[8.4.0.02,7]t et r a d ec-8-
en e (27). To a solution of the alcohol 26 (0.36 g, 0.80 mmol)
in dichloromethane (50 mL) were added triethylamine (0.33
mL, 2.41 mmol) and 4-(dimethylamino)pyridine (0.3 g, 2.4
mmol) followed by p-toluenesulfonyl chloride (0.31 g, 1.61
mmol). The mixture was heated at reflux for 5 h and was
cooled to room temperature. Water was added, and the
aqueous phase was extracted with dichloromethane. The
organic phases were dried, filtered, and evaporated. The crude
product was purified by flash chromatography (ethyl acetate-
hexane, 30:70) to give the corresponding tosylate (424 mg, 88%)
as a white foam: Rf ) 0.77 (50% ethyl acetate-hexane); IR
(film) ν 3018, 2980, 2951, 1730, 1437, 1362, 1224, 1176, 1134,
1098, 1040, 966, 846, 666 cm-1; 1H NMR (300 MHz, CDCl3) δ
7.79 (2H, d, J ) 8.3 Hz), 7.36 (2H, d, J ) 8.0 Hz), 5.59-5.49
(2H, m), 4.69 (1H, d, J ) 6.9 Hz), 4.66-4.53 (2H, m), 4.04 (1H,
d, J ) 9.4 Hz), 3.94 (1H, d, J ) 9.4 Hz), 3.74 (1H, m), 3.73
(3H, s), 3.56 (1H, m), 3.40 (1H, m), 3.33 (3H, s), 3.26 (1H, t, J
) 8.2 Hz), 3.11 (1H, t, J ) 10.8 Hz), 2.69 (1H, dd, J ) 12.3,
10.4 Hz), 2.46 (3H, s), 2.05 (1H, m), 1.87-1.43 (8H, m), 1.36-
1.04 (9H, m), 0.78 (3H, s), 0.71 (1H, m); 13C NMR (75 MHz,
C6D6) δ 174.5, 144.3, 135.2, 133.6, 129.6, 127.8, 127.5, 99.8,
95.1, 77.4, 70.6 70.5, 69.5, 60.9, 60.8, 54.9, 51.9, 50.8, 49.6,
44.8, 38.1, 36.8, 35.9, 35.7, 34.1, 34.0, 31.2, 30.6, 30.4, 27.5,
23.6, 22.2, 22.1, 20.9, 19.6, 15.4; MS m/e 593 (M - Me)+, 576
(M - MeOH)•+, 563 (M - MOM)+; HRMS calcd for C31H44O8S
(M - MeOH)+ 576.2757, found 576.2744.
(()-(1R,2R,5R,7R,10R,11S,12S)-12-Hyd r oxy-5-h yd r oxy-
methyl-11-methoxycarbonyl-1,5-dimethyltricyclo[8.4.0.02,7]-
tetr a d ec-8-en e (41). To a stirred solution of the alcohol 28
(0.1 g, 0.3 mmol) in methanol (25 mL) was added concentrated
HCl (4 drops). The mixture was stirred at 60 °C for 2 h and
was cooled to room temperature. An aqueous solution of
NaHCO3 was added, methanol was evaporated, and the
residue was extracted with ethyl acetate. The combined
organic phases were dried, filtered, and evaporated. The crude
product was purified by flash chromatography (ethyl acetate-
hexane, 1:1) to give the diol 41 (78 mg, 90%) as a white foam:
Rf ) 0.37 (50% ethyl acetate-hexane); IR (film) ν 3996, 2936,
2869, 1732, 1462, 1435, 1377, 1333, 1372, 1198, 1173, 1035,
912, 731 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.63 (2H, s), 3.85
(1H, m), 3.73 (3H, s), 3.28 (2H, s), 2.63 (1H, dd, J ) 12.4, 10.4
Hz), 2.05-1.83 (3H, m), 1.70-1.18 (10H, m), 0.92 (3H, s), 0.81
(3H, s), 0.72 (1H, m); 13C NMR (75 MHz, CDCl3) δ 175.4, 135.7,
129.5, 74.4, 72.3, 52.5, 51.8, 51.2, 44.3, 39.9, 37.2, 35.6, 34.7,
34.6, 31.7, 30.4, 23.9, 22.8, 19.9; MS m/e 322 M•+, 307 (M -
Me)+, 304 (M - H2O)•+; HRMS calcd for C19H28O3 (M - H2O)
304.2038, found 304.2033.
(()-(1R,2R,5R,7R,8R,9R,10R,11S,12S)-8-Acetoxy-9-br o-
m o-12-h yd r oxy-5-h yd r oxym et h yl-11-m et h oxyca r b on yl-
1,5-dim eth yltr icyclo[8.4.0.02,7]tetr adecan e (42). To a stirred
solution of the diol 41 (0.20 mg, 0.06 mmol) in acetic acid (20
mL) was added N-bromoacetamide (9 mg, 0.06 mmol), followed
by silver acetate (10 mg, 0.06 mmol). The mixture was stirred
overnight at room temperature and was filtered through a
silica pad. Solvents were removed, and the crude product was
purified by flash chromatography (ethyl acetate-hexane, 1:1)
to give bromoacetate 42 (22 mg, 75%) as a white foam: Rf )
0.14 (50% ethyl acetate-hexane); IR (film) ν 3426, 2929, 2856,
1738, 1434, 1371, 1330, 1286, 1228, 1040 cm-1; 1H NMR (300
MHz, CDCl3) δ 5.19 (1H, s), 3.96 (1H, d, J ) 10.0 Hz), 3.82
(1H, td, J ) 10.5, 4.8 Hz), 3.72 (3H, s), 3.26 (2H, s), 2.50 (1H,
t, J ) 11.0 Hz), 2.13 (1H, t, J ) 10.3 Hz), 2.09 (3H, s), 1.86
(1H, m), 1.72 (1H, m), 1.66-1.13 (9H, m), 1.12 (3H, s), 0.93
(3H, s); 13C NMR (75 MHz, CDCl3) δ 174.9, 170.0, 81.2, 73.9,
72.1, 54.1, 52.7, 52.4, 48.3, 45.9, 37.5, 36.7, 35.6, 34.3, 33.8,
33.0, 29.1, 23.6, 22.9, 21.0, 20.3; MS m/e 429 (M - OMe)+;
HRMS calcd for C20H30O5Br (M - OMe)+ 429.1276, found
429.1284.
To a solution of the tosylate (see above) (0.05 g, 0.08 mmol)
in tetrahydrofuran (30 mL) was added 0.5 M aqueous HCl (1.5
mL). The mixture was stirred for 4 h at room temperature,
and a saturated aqueous solution of NaHCO3 was added. The
solvent was evaporated, and the mixture was extracted with
ethyl acetate. The organic phase was dried, filtered, and
evaporated. The crude product was purified by flash chroma-
tography (ethyl acetate-hexane, 1:1) to give the alcohol 27
(39 mg, 90%) as a white foam: Rf ) 0.49 (50% ethyl acetate-
hexane); IR (film) ν 3480, 2945, 2948, 1738, 1598, 1436, 1360,
1244, 1188, 1176, 1098, 1039, 964, 822, 814 cm-1 1H NMR
;
(300 MHz, CDCl3) δ 7.77 (2H, d, J ) 8.3 Hz), 7.35 (2H, d, J )
8.2 Hz), 5.60-5.47 (2H, m), 4.65 (1H, d, J ) 6.9 Hz), 4.54 (1H,
d, J ) 6.9 Hz), 4.02 (1H, d, J ) 10.1 Hz), 3.95 (1H, d, J ) 10.1
Hz), 3.75 (1H, m), 3.69 (3H, s), 3.33 (2H, s), 3.29 (3H, s), 2.68
(1H, dd, J ) 12.3, 10.4 Hz), 2.43 (3H, s), 2.14-1.95 (2H, m),
1.86-1.22 (9H, m), 1.13-0.88 (3H, m), 0.75 (3H, s); 13C NMR
(()-(1R,2R,5R,7R,8R,9R,10R,11S)-8-Acetoxy-9-br om o-5-
for m yl-11-m eth oxycar bon yl-1,5-dim eth yltr icyclo[8.4.0.02,7]-
J . Org. Chem, Vol. 67, No. 15, 2002 5277

Germain and Deslongchamps
tetr a d eca n -12-on e (43). To a stirred solution of diol 42 (0.03
g, 0.08 mmol) in dichloromethane (30 mL) at 0 °C was added
Dess-Martin periodinane (0.08 g, 0.19 mmol). The mixture
was stirred at room temperature for 1 h, and 1 M aqueous
solution of Na2S2O3 was added followed by a saturated aqueous
solution of NaHCO3. Layers were separated, and the aqueous
phase was extracted with dichloromethane. The combined
organic phases were dried, filtered, and evaporated. The
residue was purified by flash chromatography (ethyl acetate-
hexane, 1:1) to give aldehyde 43 (25 mg, 83%) as a white
foam: Rf ) 0.61 (50% ethyl acetate-hexane); IR (film) ν 2951,
2932, 2873, 1744, 1732, 1722, 1714, 1462, 1434, 1372, 1274,
1.03 (3H, s); 13C NMR (75 MHz, CDCl3) δ 210.7, 170.6, 149.9,
109.5, 77.0, 67.6, 50.1, 44.1, 41.4, 40.9, 37.9, 37.3, 36.6, 35.9,
32.0, 23.8, 23.3, 22.5; MS m/e 318 M•+, 300 (M - H2O)+; HRMS
calcd for C19H26O4 (M+) 318.1831, found 318.1836.
(()-7â-Hydr oxy-8r-h ydr om om ilacton e A (45). To a stirred
solution of the lactone 44 (5 mg, 15.6 µmol) in acetonitrile (2
mL) was added iodomethane (5 µL, 78.1 µmol) followed by
cesium carbonate (25 mg, 78.1 µmol). The mixture was stirred
for 1.5 h at room temperature and was filtered through a Celite
pad. The solvent was evaporated to give â-ketolactone 45 (4.6
mg, 89%) as a white solid: Rf ) 0.42 (20% ethyl acetate-
dichloromethane); mp 240 °C dec (ethyl acetate, methanol, and
hexane); IR (CHCl3) ν 3692, 3602, 2961, 2926, 1788, 1706,
1602, 1460, 1391, 1375, 1265, 1232, 1200, 1111, 1100, 1071,
1
1228, 1159, 1116, 1054, 1023, 916 cm-1; H NMR (300 MHz,
CDCl3) δ 9.37 (1H, s), 5.48 (1H, t, J ) 5.4 Hz), 3.98 (1H, dd, J
) 12.3, 5.6 Hz), 3.72 (3H, s), 3.28 (1H, dd, J ) 10.8, 0.9 Hz),
2.97 (1H, dd, J ) 12.2, 11.0 Hz), 2.69 (1H, m), 2.50 (1H, m),
2.20 (1H, m), 2.13 (3H, s), 2.01 (1H, m), 1.76-1.63 (2H, m),
1.59-1.28 (6H, m), 1.13 (3H, s), 1.02 (3H, s); 13C NMR (75
MHz, CDCl3) δ 205.4, 204.9, 170.0, 169.7, 79.3, 60.2, 54.6, 53.1,
45.5, 45.3, 43.4, 36.9, 35.2, 32.8, 31.8, 31.1, 30.3, 21.0, 20.8,
20.7, 16.9; MS m/e 444; HRMS calcd for C20H29O6Br 444.1147,
found 444.1153.
1049 cm-1 1H NMR (300 MHz, CDCl3) δ 5.82 (1H, dd, J )
;
17.5, 10.7 Hz), 4.96 (1H, dd, J ) 17.5, 1.2 Hz), 4.89 (1H, dd, J
) 10.7, 1.2 Hz), 4.63 (1H, dd, J ) 7.2, 6.3 Hz), 4.15 (1H, dd, J
) 7.4, 1.3 Hz), 2.59-2.54 (2H, m), 2.37 (1H, d, J ) 6.2 Hz),
2.09 (1H, s), 1.95-1.69 (4H, m), 1.52 (3H, s), 1.42-1.23 (5H,
m), 1.17 (3H, s), 1.03 (3H, s); 13C NMR (75 MHz, CDCl3) δ
205.8, 174.1, 149.5, 109.5, 75.4, 67.6, 52.2, 48.7, 44.1, 40.9, 37.8,
37.0, 36.6, 34.3, 32.2, 31.9, 23.9, 23.8, 22.5, 22.2; MS m/e 332
M+, 314 (M - H2O)+; HRMS calcd for C20H28O4 (M+) 332.1987,
found 332.1996.
(()-4-Desm et h yl-4r,8r-d ih yd r o-7â-h yd r oxym om ila c-
ton e A (44). To a suspension of methyltriphenylphosphonium
bromide (20 mg, 0.06 mmol) in THF (10 mL) was added
KHMDS (0.5 M in toluene, 100 µL, 0.06 mmol). The mixture
was stirred for 15 min and was cooled to -78 °C. A solution of
the aldehyde 43 (12 mg, 0.02 mmol) in tetrahydrofuran (1.5
mL) was added. The resulting mixture was stirred at -78 °C
for 15 min, warmed to 0 °C, and stirred for 45 min. An aqueous
solution of NH4Cl was added, and the mixture was extracted
with ethyl acetate. Layers were separated, and the combined
organic phases were dried, filtered, and evaporated. The
residue was quickly purified by flash chromatography (ethyl
acetate-hexane, 30:70) to give the vinylic compound: Rf ) 0.89
(50% ethyl acetate-hexane); IR (CHCl3) ν 2955, 2928, 2855,
(()-Mom ila cton e A (1). To a solution of hydroxymomilac-
tone A 45 (12 mg, 0.04 mmol) in toluene was added Burgess
reagent (19 mg, 0.08 mmol). The mixture was heated at reflux
for 12 h and was cooled to room temperature. Solvent was
evaporated, and the residue was purified by flash chromatog-
raphy (ethyl acetate-dichloromethane, 20:80) to give momi-
lactone A as a white solid (4.5 mg, 40-50%): Rf ) 0.83 (20%
ethyl acetate-dichloromethane); mp 150-154 °C (ethanol and
dichloromethane); IR (CHCl3) ν 2937, 1770, 1702, 1602, 1458,
1
1378, 1331, 1184, 1137, 1038, 991 cm-1; H NMR (300 MHz,
CDCl3) δ 5.85 (1H, dd, J ) 17.3, 10.7 Hz, CHdCHH), 5.71 (1H,
d, J ) 5.2 Hz, H7), 4.98 (1H, dd, J ) 17.0, 0.9 Hz, CHd
CHHtrans), 4.94 (1H, dd, J ) 10.7, 0.9 Hz, CHdCHcisH), 4.84
(1H, t, J ) 5.2 Hz, H6), 2.66-2.58 (2H, m, H2), 2.32 (1H, d, J
) 4.9 Hz, H5), 2.21 (1H, d, J ) 11.8 Hz), 2.06 (1H, d, J ) 12.1
Hz), 1.98-1.70 (3H, m), 1.66-1.50 (3H, m), 1.52 (3H, s, CH3
at C4), 1.32 (1H, m), 1.00 (3H, s, CH3 at C10), 0.90 (3H, s,
CH3 at C13); 13C NMR (75 MHz, CDCl3) δ 205.2, 174.3, 148.9,
148.0, 114.0, 110.2, 73.1, 53.5, 50.1, 47.5, 46.4, 40.1, 37.2, 34.9,
32.4, 31.2, 23.9, 21.9, 21.8, 21.4; MS m/e 314 M+; HRMS calcd
for C20H26O3 (M+) 314.1882, found 314.1886.
1742, 1713, 1460, 1436, 1376, 1275, 1275, 1236, 1162 cm-1
;
1H NMR (300 MHz, CDCl3) δ 5.75 (1H, dd, J ) 17.5, 10.8 Hz),
5.47 (1H, t, J ) 5.6 Hz), 4.93 (1H, dd, J ) 17.4, 1.1 Hz), 4.89
(1H, dd, J ) 10.6, 1.1 Hz), 3.99 (1H, dd, J ) 12.4, 5.8 Hz),
3.74 (3H, s), 3.31 (1H, dd, J ) 11.0, 1.2 Hz), 2.97 (1H, dd, J )
12.3, 11.1 Hz), 2.69 (1H, m), 2.49 (1H, m), 2.21 (1H, dd, J )
9.5, 4.2 Hz), 2.12 (3H, s), 2.05 (1H, m), 1.73-1.08 (8H, m), 1.01
(3H, s), 1.00 (3H, s); MS m/e 426 (M - MeOH)•+; HRMS calcd
for C21H32O4Br (M - MeOH)+ 426.1406, found 426.1412.
A solution of residue (see above) in a mixture of acetic acid-
water (10 mL - 1 mL) was heated overnight at 90 °C. The
solution was cooled to room temperature, and solvents were
evaporated. The residue was extracted with ethyl acetate, and
solvent was evaporated. The mixture of hydroxyacetates was
dissolved in methanol, and solid K2CO3 (15 mg, 0.10 mmol)
was added. The mixture was stirred at room temperature for
1 h, and an aqueous saturated solution of NH4Cl was added.
Methanol was evaporated, and the aqueous phase was ex-
tracted with ethyl acetate. The combined organic phases were
dried, filtered, and evaporated. The crude product was purified
by flash chromatography (ethyl acetate-dichloromethane, 20:
80) to give lactone 44 (5 mg, 65% for the last two steps) as an
oil: Rf ) 0.36 (20% ethyl acetate-dichloromethane); IR (CHCl3)
ν 3686, 3605, 2958, 2927, 1791, 1748, 1710, 1672, 1638, 1602,
Ack n ow led gm en t. This research was supported by
the Natural Sciences and Engineering Research Council
of Canada (NSERCC), Ministe`re de l’Enseignement
Supe´rieur et de la Science (FCAR, Que´bec). J . Germain
gratefully acknowledges Universite´ de Sherbrooke for
financial support. We are also thankful to Marc Drouin,
Universite´ de Sherbrooke, for carrying out the X-ray
structural determination of hydroxymomilactone A (45)
as well as Gaston Boulay, Universite´ de Sherbrooke, for
MS analyses.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for compounds 4, 5, 7, 10-
1
1462, 1376, 1230, 1122, 1100, 1048, 925 cm-1; H NMR (300
1
17, 22, 23, 29, 31-35, and 37-40; copies of H NMR spectra
MHz, CDCl3) δ 5.82 (1H, dd, J ) 17.5, 10.8 Hz), 4.96 (1H, dd,
J ) 17.5, 1.2 Hz), 4.89 (1H, dd, J ) 10.7, 1.2 Hz), 4.53 (1H,
dd, J ) 7.1, 6.3 Hz), 4.14 (1H, d, J ) 7.2 Hz), 3.34 (1H, d, J )
8.1 Hz), 2.79 (1H, dd, J ) 8.1, 6.2 Hz), 2.67-2.52 (2H, m), 2.10
(1H, s), 1.90-1.72 (4H, m), 1.64-1.31 (5H, m), 1.20 (3H, s),
of compounds 1, 2, 4, 5, 18-29, 31-35, and 37-45 and 13C
NMR of 1; X-ray crystal structure of 45. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O025873L
5278 J . Org. Chem., Vol. 67, No. 15, 2002