Total synthesis of the eupomatilones

Article abstract of DOI:10.1021/jo701415m

(Chemical Equation Presented) Full details of the total syntheses of five members of the eupomatilone family of lignans are reported.

Full text of DOI:10.1021/jo701415m

Total Synthesis of the Eupomatilones
Soumya Mitra, Srinivas Reddy Gurrala, and Robert S. Coleman*
Department of Chemistry, The Ohio State UniVersity, 100 West 18th AVenue, Columbus, Ohio 43210
coleman@chemistry.ohio-state.edu
ReceiVed July 10, 2007
Full details of the total syntheses of five members of the eupomatilone family of lignans are reported.
Introduction
addition of thiol nucleophiles.4 This produces antigenic com-
pounds within the cell, which are a cause of chronic actinic
dermatitis (CAD). The moiety is also reported to form [2+2]
photoadducts with the DNA base thymine in the presence of
sunlight, and hence its photochemical role is strongly implicated
in CAD. The R-methylene-γ-lactone moiety has also been
shown to target the Iκâ kinase (IKK) in addition to the
transcription factor regulator nuclear factor-kappaB (NF-κB),
signifying their potential role in the cellular signaling process.5
The R-methylene lactone is presumably the biologically relevant
functionality of these natural products.6-8
Eupomatilones 1-7 (Figure 1) were isolated by Carroll and
Taylor in 1991 from the Australian shrub Eupomatia bennettii,
and were found to co-occur with a structurally diverse set of
related lignan natural products.1 Howarth defined lignan natural
products as cinnamic acid dimers, connected via the â-carbons.2
The aromatic rings are normally oxygenated and oftentimes
highly modified. This family of plant natural products is
distributed throughout the producing plants, including the roots,
stems, leaves, fruit, and seeds.
In the eupomatilone family of lignans, the dimeric â-cinnamic
acid carbon skeleton has undergone an unprecedented rear-
rangement that involves cleavage of a carbon-aryl bond. Carroll
and Taylor proposed that the spirocyclohexadienone skeleton
of eupodienone precursor 1 undergoes hemiketal formation to
afford 2, which fragments to lactone 3 (Figure 2).3 All six
carbons of the side chains of the cinnamic acid precursors end
up attached to one of the aromatic rings. The eupomatilones
equilibrate about the biaryl axis, which is stereogenic for
eupomatilones 5, 6, and 7. Two isomers are observed by both
1H and 13C NMR for eupomatilones 5, 6, and 7. The hydrogens
on the trimethoxyphenyl ring of eupomatilone 4 are diaste-
reotopic and slowly interconverting. The atropdiastereomers are
inseparable, and show a coalescence temperature between 97
and 102 °C.2
Herein, we will discuss two conceptually different strategies,
one of which is asymmetric, for the construction of the lactone
ring that is attached to the highly oxygenated biaryl system. It
is to be noted that the carbon that is incorporated as the carbonyl
of the lactone ring (Figure 3) for eupomatilones 4 and 6 is the
allylic carbon, adjacent to indium, which subsequently undergoes
a late stage oxygenation by hydroboration-oxidation reaction.
In the case of eupomatilones 1, 2, and 5, the lactone carbonyl
is directly incorporated from the existing carbomethoxy group
of the chiral crotylboronate reagent. The exo-methylene group
is formed from the allylic carbon of the boronate (Figure 3).
In our preliminary account of work on this family of natural
products, we detailed the total synthesis of eupomatilone 4 and
(4) Patel, B. B.; Waddell, T. G.; Pagni, R. M. Fitoterapia 2001, 72, 511.
(5) Huang, W.-C.; Chan, S.-T.; Yang, T.-L.; Tzeng, C.-C.; Chen, C.-C.
Carcinogenesis 2004, 25, 1925.
(6) Cassady, J. M.; Suffness, M. Anticancer Agents Based on Natural
Product Models; Acedemic: New York, 1980; Vol. 7, p 201.
(7) Kupchan, S. M.; Eakin, M. A.; Thomas, A. M. J. Med. Chem 1971,
14, 1147.
The R-methylene-γ-lactone found in eupomatilones 1, 2, and
5 readily forms covalent bonds to cellular proteins via Michael
(1) Carroll, A. R.; Taylor, W. C. Aust. J. Chem. 1991, 44, 1615.
(2) Ayers, D. C.; Loike, J. D. Lignans: Chemical, Biological and Clinical
Properties, University Press: Cambridge, UK, 1990.
(8) Kupchan, S. M.; Fessler, D. C.; Eakin, M. A.; Giacobbe, T. J. Science
1970, 168, 376.
(3) Carroll, A. R.; Taylor, W. C. Aust. J. Chem. 1991, 44, 1705.
10.1021/jo701415m CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/11/2007
8724
J. Org. Chem. 2007, 72, 8724-8736

Total Synthesis of the Eupomatilones
FIGURE 1. Structures of the eupomatilones.
FIGURE 5. Epimers and correct structure of eupomatilone 6.
FIGURE 2. Rearrangement of the dimeric lignan skeleton.3
synthetic approaches to eupomatilone 6, by McIntosh and co-
workers,11 who reported the synthesis of a bis-epimeric version
of eupomatilone 6, and by Gurjar and co-workers, who also
reported the total synthesis of 3-epi-eupomatilone 6.12 Hall and
co-workers have later reported the synthesis of eupomatilone 6
and its three unnatural diastereomers by acid catalyzed allylbo-
ration.13 We now report full details of the total synthesis of
eupomatilones 1, 2, 4, 5, and 6.
Results and Discussion
The initial synthetic plan for the synthesis of eupomatilones
bearing a cis-1,2-dimethyl-substitution pattern (eupomatilones
4 and 7, and what was assumed to be eupomatilone 6, as in
generic structure 5, Scheme 1) was based on the use of an
indium-based crotylation addition reaction that had been
developed as part of another study14 (Scheme 1). The combina-
tion of aryl aldehyde 8 and the (E)-2-methyl-2-butenylindium
reagent would install the 1-hydroxy-3-butenyl side chain of 7,
thereby introducing two of the three stereogenic elements of
the targets at C4 and C5 (eupomatilone numbering). The biaryl
bond of 7 would be formed either by Suzuki-Miyaura coupling
FIGURE 3. Lactone formation strategies.
FIGURE 4. Diastereoselective hydroboration.
the purported structure of eupomatilone 6 by a stereochemically
unambiguous route. In reality, the original structure reported
for eupomatilone 6 was incorrect, and we had synthesized 3-epi-
eupomatilone 6.9 Consequently, we revised the structure of the
natural product to possess a trans relationship of the C3 and
C4 methyl groups (cf. Figure 1).10 There have been reports of
(10) Coleman, R. S.; Gurrala, S. R. Org. Lett. 2004, 6, 4025.
(11) (a) Hutchison, J. M.; Hong, S.-P.; McIntosh, M. C. J. Org. Chem.
2004, 69, 4185. (b) Hong, S.-P.; McIntosh, M. C. Org. Lett. 2002, 4, 19.
(12) Gurjar, M. K.; Cherian, J.; Ramana, C. V. Org. Lett. 2004, 6, 317.
(13) Yu, S. H.; Ferguson, M. J.; McDonald, R.; Hall, D. G. J. Am. Chem.
Soc. 2005, 127, 12808.
(9) Nicolaou, K. C.; Snyder, S. A. Angew. Chem., Int. Ed. 2005, 44,
1012.
(14) Coleman, R. S.; Gurrala, S.; Mitra, S.; Raao, A. J. Org. Chem. 2005,
70, 8932.
J. Org. Chem, Vol. 72, No. 23, 2007 8725

Mitra et al.
SCHEME 1. First Generation Retrosynthetic Analysis
this system. We have employed this reaction in a stereocon-
trolled synthesis of the natural products calphostin A and
phleichrome18 and several members of the dibenzocycloocta-
diene lignan family.14
In the present case (Scheme 3), aryl bromide 13 was
converted to the aryllithium reagent 14 (t-BuLi, MeTHF,
-78 °C), and subsequently to the lower order cyanocuprate 15
(CuCN, MeTHF, -40 °C). Aryl bromide 16 was similarly
converted to aryllithium 17 (t-BuLi, MeTHF, -78 °C), which
was added to cyanocuprate 15 (-125 °C, 30 min) to form a
biarylcuprate species. Treatment with oxygen (-125 °C, 3 h)
affected conversion to the biaryl system 18, in modest yield.
Hydroboration of 18 (9-BBN, THF, 0-25 °C, 12 h) followed
by oxidation (NaOH, H2O2, 0-25 °C, 3 h) afforded the
corresponding primary alcohol in essentially quantitative yield,
with complete control of diastereoselectivity (Scheme 3).
Deprotection of the silyl ether (n-Bu4NF, THF, 25 °C, 3 h)
afforded diol 19. Selective oxidation of the primary alcohol of
19 (TEMPO, NCS, n-Bu4NI, CH2Cl2/1:1 0.05 M K2CO3/0.5 M
NaHCO3, 25 °C, 1 h)19 was accompanied by lactonization, and
afforded eupomatilone 4 (1d) in 92% yield for the two-step
sequence. Eupomatilone 4 was synthesized in eight steps from
known 16 and 10, in 33% overall yield. The 1H NMR spectrum
of synthetic eupomatilone 4 was identical with that reported
for the natural product.
SCHEME 2. Crotylation with Indium Reagent
of the bromide of 8 with the corresponding arylboronic acid 9
(X ) B(OH)2) or by using the Lipshutz oxidative cuprate biaryl
coupling with 9 (X ) Br). Hydroboration of the alkene of 7
would oxidize the terminal carbon of the butenyl chain and
introduce the third stereogenic center at C3 via A1,3-controlled
diastereofacial selectivity. Final C2 alcohol to carboxylic acid
oxidation of 6 with concomitant lactone formation would
provide the targeted natural products (5)
The origin of the diastereoselection in the hydroboration of
18 is due to A1,3 strain in the transition state (Figure 4). In the
lowest energy conformation (MM3) about the sp2-sp3 bond,
the allylic hydrogen is eclipsed with the alkene, thereby
minimizing A1,3 strain. The least sterically congested approach
by 9-BBN is from the side of the allylic methyl group, giving
the new stereogenic center wherein the methyl groups are anti.
This model has precedent in several related contexts.20
Total synthesis of what we believed to be eupomatilone 6
(bearing the cis-dimethyl-substitution pattern) proceeded from
aryl bromides 2021 and commercially available 23 (Scheme 4).
Cuprate coupling of the corresponding aryllithium reagents 21
and 24 under previously described conditions afforded biphenyl
25. Following reaction conditions used in the total synthesis of
eupomatilone 4, hydroboration/oxidation of the alkene of 25
afforded the corresponding primary alcohol (42% for two steps).
Fluoride-mediated desilylation and selective oxidation of the
primary alcohol afforded γ-lactone 26, supposedly eupomatilone
Initially, various methods were examined for crotylation.
Addition of (E)-2-methyl-2-buten-1-ylmagnesium bromide to
aldehyde 10 (THF, -78 °C, 1.5 h) provided a 1:1 mixture of
syn and anti adducts 11 and 12 in 95% yield (Scheme 2). This
reaction could be effected in an asymmetric fashion via the
corresponding diisopinocampheylborane reagent, albeit with no
diastereoselectivity due to equilibration of the Grignard precur-
sor.14 The undesired anti adduct 12 could be converted to the
desired syn adduct 11 by Mitsunobu inversion with p-nitroben-
zoic acid15 (Ph3P, DIAD, THF, 0-25 °C) and hydrolysis (K2-
CO3, MeOH, 25 °C), which resulted in an overall yield for
conversion of 10 to 11 of 73%. Most effectively with respect
to diastereoselection, 11 could be produced in racemic form as
a 95:5 syn/anti mixture in 92% yield by addition of the
corresponding indium reagent16 to aldehyde 10. The alcohol of
11 was protected as the tert-butyldimethylsilyl ether (t-BuMe2-
SiOTf, 2,6-lutidine, CH2Cl2, -78 °C, 20 min) to afford 13.
In this system, we implemented the methodology of Lipshutz
for biaryl coupling,17 which involves low-temperature formation
of a mixed biarylcuprate followed by oxidation of this species
to form a carbon-carbon biaryl bond. This reaction is essentially
insensitive to steric or electronic features of the aromatic systems
compared to palladium-mediated processes and worked well in
1
6. However, there were slight discrepancies in the H NMR
spectrum of synthetic 26 compared to the data published for
eupomatilone 6,3 present in the chemical shifts of and coupling
constants between C3-H and C4-H. Our spectral data matched
exactly that obtained by Gurjar and co-workers12 in their
synthesis of this putative structure of eupomatilone 6.
We had inadvertently synthesized the correct structure of
eupomatilone 6 during prior studies on the oxidation/lactone
(18) (a) Coleman, R. S.; Grant, E. B. J. Am. Chem. Soc. 1994, 116, 8795.
(b) Coleman, R. S.; Grant, E. B. J. Am. Chem. Soc. 1995, 117, 10889.
(19) (a) Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J.-L. J. Org. Chem.
1996, 61, 7452. (b) Kamal, A.; Sandbhor, M.; Shaik, A. A. Tetrahedron:
Asymmetry 2003, 14, 1575.
(15) (a) Dodge, J. A.; Trujillo, J. I.; Presnell, M. J. Org. Chem. 1994,
59, 234. (b) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
(16) Araki, S.; Ito, H.; Butsugan, Y. J. Org. Chem. 1988, 53, 1831.
(17) (a) Lipshutz, B. H.; Siegmann, K.; Garcia, E. J. Am. Chem. Soc.
1991, 113, 8161. (b) Lipshutz, B. H.; Siegmann, K.; Garcia, E.; Kayser, F.
J. Am. Chem. Soc. 1993, 115, 9276. (c) Lipshutz, B. H.; Kayser, F.; Maullin,
N. Tetrahedron Lett. 1994, 35, 815. (d) Lipshutz, B. H.; Liu, Z.-P.; Kayser,
F. Tetrahedron Lett. 1994, 35, 5567.
(20) (a) Hoffmann, R. W.; Dahmann, G.; Andersen, M. W. Synthesis
1984, 629. (b) Coutts, L. D.; Cywin, C. L.; Kallmerten, J. Synlett 1993,
696. (c) Bernsmann, H.; Fro¨hlich, R.; Metz, P. Tetrahedron Lett. 2000, 41,
4347. (d) Araki, K.; Suenaga, K.; Sengoku, T.; Uemura, D. Tetrahedron
2002, 58, 1983. (e) Herb, C.; Maier, M. E. J. Org. Chem. 2003, 68, 8129.
(21) Prepared from 2-bromo-3,4,5-trimethoxybenzaldehyde (cf.: Molan-
der, G. A.; George, K. M.; Monovich, L. G. J. Org. Chem. 2003, 68, 9533)
as described for the preparation of 13.
8726 J. Org. Chem., Vol. 72, No. 23, 2007

Total Synthesis of the Eupomatilones
SCHEME 3. Cuprate Coupling, Hydroboration, and Eupomatilone 4 Total Synthesis
SCHEME 4. Synthesis of the Putative Structure of
Eupomatilone 6
SCHEME 5. Eupomatilone 6 Total Synthesis
McIntosh and co-workers,11 whose reported synthesis of 5-epi-
eupomatilone 6 was now a synthesis of 3,5-bis-epi-eupomatilone
6 (29).
Our approach to the synthesis of eupomatilones 1, 2, and 5
relied on the development of an asymmetric crotylboration
strategy to directly assemble the R-methylene-γ-lactone moiety
with syn-stereochemistry at the C4 and C5 positions of the
lactone ring. Several crotylation strategies were explored to
construct the required R-methylene-γ-lactone moiety in an
asymmetric fashion.
There has been one report of a synthetic approach leading to
eupomatilones 2 and 5 by Kabalka,22 and Buchwald reported
an asymmetric approach to eupomatilone 3.23 Herein, we report
the first asymmetric total synthesis of eupomatilones 2 and 5.
An attempt at the asymmetric total synthesis of eupomatilone
1 will be discussed separately. A convergent synthetic strategy
was developed (Scheme 6) that was based on a Suzuki-Miyaura
cross coupling of 30 and 31 and an asymmetric carbomethoxy-
crotylation reaction protocol to directly install the R-methylene-
formation sequence (Scheme 5). Oxidation of alcohol 27 with
pyridinium dichromate (CH2Cl2, 25 °C, 3 h, 85%) afforded the
corresponding aldehyde, which cyclized to lactol 28 after
fluoride-mediated deprotection of the silyl ether (THF, 25 °C,
6 h). Compound 28 was produced as a mixture of diastereomers,
which were formed presumably by epimerization of the
intermediate aldehyde under basic silyl deprotection reaction
conditions, and which originally led to the abandonment of this
oxidation protocol. Lactol to lactone oxidation (CH2Cl2, 25 °C,
2 h, 90%) afforded a 1:3 mixture of 26 and its epimer 1f, which
could be separatedswith difficultysby preparative TLC. The
1H NMR spectrum of pure 1f proved identical with that
published for eupomatilone 6.3
Thus, our synthesis of 26 (Scheme 4) produced 3-epi-
eupomatilone 6, whereas the structure of the natural product
must possess a trans relationship of the C3 and C4 methyl
groups, as in 1f (Figure 5). This result changed the work of
(22) Kabalka, G. W.; Venkataiah, B. Tetrahedron Lett. 2005, 46, 7325.
(23) Rainka, M. P.; Milne, J. E.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2005, 44, 6177.
J. Org. Chem, Vol. 72, No. 23, 2007 8727

Mitra et al.
SCHEME 6. Retrosynthetic Analysis of Eupomatilone 5
SCHEME 8. Organosilicon Promoted Reaction with
Aldehydes30
SCHEME 9. Attempt with Brown’s
Chlorodiisopinocampheyl Borane Route
SCHEME 7. Attempt with Leighton’s Chiral Diamine
Route
Itoh.31 These workers used an unsubstituted allyl bromide 39
(Scheme 8), to form an alkylidene carbomethoxycrotyl trichlo-
rosilane intermediate 40, which was used in the construction
of an R-methylene-γ-lactone moiety. Problems of allylic
transposition observed in our work were nullified in their
approach due to the absence of the â-methyl substitution with
respect to the carbomethoxy group in 39. We faced a similar
problem in earlier work on dibenzocyclooctadiene lignan total
syntheses; at the time, there were no reports of crotyl metal
reagents that bore substituents that made them dissymmetric
with respect to allylic transposition.14
The unsuccessful attempts with organosilicon chemistry
directed our attention into organoboron chemistry. In our
asymmetric total synthesis of dibenzocyclooctadiene lignans,26
we had made a nonstereodefined tiglyl Grignard reagent (from
tiglyl bromide) at low temperature. After transmetallation from
magnesium to boron by treatment with (-)-(Ipc)2BCl, to form
Brown’s diisopinocampheylborane reagent,32 the resulting cro-
tylborane provided high levels of enantioselection in the addition
to aryl aldehydes, but no diastereoselection. We again examined
Brown’s chlorodiisopinocampheyl borane strategy in our quest
for making a chiral carbomethoxycrotyl reagent.
γ-lactone moiety onto the aldehyde 33. 1,3-Allylic rearrange-
ment of 34 would afford the carbomethoxycrotyl reagent 32 in
an efficient and stereocontrolled manner. A major challenge with
this strategy was how to make 32 stable and chiral, and how to
provide effective enantioselection in the addition to electron-
rich aryl aldehydes.
The initial attempt to synthesize a chiral carbomethoxycrotyl
reagent targeted silane 32, using Leighton’s chiral diamine
strategy.24,25 We had successfully applied this strategy in the
asymmetric total synthesis of dibenzocyclooctadiene lignans.26
The allyl alcohol 34 (Scheme 7) was synthesized in good yield
(85%) from acetaldehyde and methyl acrylate 38 with use of
DABCO (100 mol %),27 which was converted to the allylic
bromide 35 by using NBS.28,29 However, in this case, we
observed a 5:4 inseparable regioisomeric mixture of the car-
bomethoxycrotyl trichlorosilanes 36 and 37 upon reaction of
trichlorosilane with allylic bromide 35, as observed by 1H NMR
(Scheme 7), presumably formed via an allylic rearrangement
under the reaction conditions that required copper chloride as a
catalyst. Purification of the trichlorosilanes, using distillation
under reduced pressure, proved to be extremely difficult and
required a distillation temperature g200 °C, only to afford the
mixture of the trichlorosilanes. All attempts to preferentially
crystallize one of the regioisomers with Leighton’s chiral
diamine strategy were also an exercise in futility.
The allylic bromide 35 (Scheme 9) was treated with Knoch-
el’s reagent i-PrMgCl‚LiCl33,34 at -78 °C, and was gradually
warmed to -20 °C to form the Grignard reagent. (-)-(Ipc)2BCl
was added at -78 °C to form the desired diisopinocampheyl-
crotylborane reagent. Analysis of the crude reaction mixture
by 1H and 11B NMR revealed almost exclusive (>95%)
formation of the undesired 1,3-allylically rearranged car-
bomethoxycrotylborane species 42.
Inspired by contributions of Soderquist,35,36 we attempted to
synthesize the chiral (E)-carbomethoxycrotyl reagent 32. The
carbomethoxy allylic bromide 35 (Scheme 10) was treated with
i-PrMgCl‚LiCl under Knochel’s conditions,33,34 followed by
Carbomethoxycrotyl organosilicon reagents have been suc-
cessfully used for asymmetric crotylations by Kobayashi30 and
(30) Kobayashi, S.; Yasuda, M.; Nishio, K. Synlett 1996, 153.
(31) Nishiyama, H.; Yokoyama, H.; Narimatsu, S.; Itoh, K. Tetrahedron
Lett. 1982, 23, 1267.
(32) Brown, H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.; Racherla,
U. S. J. Am. Chem. Soc. 1990, 112, 2389.
(24) Kubota, K.; Leighton, J. L. Angew. Chem., Int. Ed. 2003, 42, 946.
(25) Hackman, B. M.; Lombardi, P. J.; Leighton, J. L. Org. Lett. 2004,
6, 4375.
(26) Coleman, R. S.; Gurrala, S. R.; Mitra, S.; Raao, A. J. Org. Chem.
2005, 70, 8932.
(27) Yu, C.; Liu, B.; Hu, L. J. Org. Chem. 2001, 66, 5413.
(28) Isaac, M. B.; Paquette, L. A. J. Org. Chem. 1997, 62, 5333.
(29) Buchholz, R.; Hoffmann, H. M. R. HelV. Chim. Acta 1991, 74, 1213.
(33) Liu, C.-Y.; Ren, H.; Knochel, P. Org. Lett. 2006, 8, 617.
(34) Sapountzis, I.; Dohle, W.; Knochel, P. Chem. Commun. 2001, 2068.
(35) Burgos, C. H.; Canales, E.; Matos, K.; Soderquist, J. A. J. Am. Chem.
Soc. 2005, 127, 8044.
(36) Hernandez, E.; Soderquist, J. A. Org. Lett. 2005, 7, 5397.
8728 J. Org. Chem., Vol. 72, No. 23, 2007

Total Synthesis of the Eupomatilones
SCHEME 10. Attempt with Soderquist’s Route
SCHEME 12. Synthesis of r-Methylene-γ-lactones with a
Chiral Carbomethoxycrotyl Boronate
SCHEME 11. Synthesis of r-Methylene-γ-lactones with
Achiral Crotylboronate
SCHEME 13. Asymmetric Crotylboration of Monoaryl
Aldehydes with the New Diborane Reagent 51
addition of Soderquist’s air-stable crystalline pseudoephedrine
borinic ester complexes of 10-trimethylsilyl-9-borabicyclo[3.3.2]-
decane. Unfortunately, the intermediate 43 obtained in this case
was almost exclusively the undesired 1,3-allylic rearranged
carbomethoxycrotylborane, which was confirmed by 1H and 11
NMR analysis of the crude reaction mixture.
B
The previously unsuccessful attempts with allylic bromides
led us to examine allylic acetates,37 to generate 44 from 34,
and use diboranes to generate boryl-copper species as inter-
mediates, as reported by Miyaura38,39 and Ramachandran.40 The
boryl-copper species is reportedly nucleophilic and undergoes
an allylic rearrangement via the acetate 44 to stereoselectively
generate 45 (E/Z ratio ) 95:5) (Scheme 11). Compound 45 was
further subjected to thermal crotylboration conditions under
argon in toluene for 3 days at 95-100 °C with 3,4,5-
trimethoxybromobenzaldehyde 33 to obtain 46, the top half of
eupomatilone 5, in good yield (82%). Synthesis of the car-
bomethoxycrotyl reagent 32 by an alternate strategy (achiral
version with boron) has also been reported by Hall and
Kennedy41 by tandem carbocupration of alkynoate esters fol-
lowed by electrophilic trapping with halomethyl boronates at
low temperature with HMPA as an additive. Hall and co-workers
have also reported 46 was synthesized under Lewis acid-
catalyzed conditions13 in their synthesis of eupomatilone 6.
On the basis of the success of the thermal crotylboration
reaction41,42 with 3,4,5-trimethoxybromobenzaldehyde 33, at-
tempts were directed toward developing a chiral carbomethoxy-
crotyl boronate for the asymmetric version of this reaction.
Bis[(()-pinanediolato]diboron was examined (Scheme 12) to
obtain the chiral crotylboronate 47 in an E/Z ratio of 95:5. A
one-pot thermal crotylboration was attempted with the aldehyde
33, which afforded 46 as a cis/trans mixture (6:1), although
surprisingly with no enantioselection (er ) 1:1).
On the basis of the above result it was realized that to enhance
the enantioselectivity in the thermal crotylborations, a more
effective chiral carbomethoxycrotyl boronate was required,
where we can efficiently direct the approach of the aldehyde in
the transition state. Villie´ras and co-workers43 and Hoffmann
(37) Cha, J. H.; Pae, A. N.; Choi, K.; Cho, Y. S.; Yun, H.-C.; Lee, J.;
Koh, H. Y.; Lee, E. Biotechnol. Lett. 2002, 24, 1695.
(38) Takahashi, K.; Ishiyama, T.; Miyaura, N. Chem. Lett. 2000, 982.
(39) Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Organomet. Chem. 2001,
625, 47.
(40) Ramachandran, P. V.; Pratihar, D.; Biswas, D.; Srivastava, A.;
Reddy, M. V. R. Org. Lett. 2004, 6, 481.
(42) Ramachandran, P. V.; Pratihar, D.; Biswas, D. Chem. Commun.
2005, 1988.
(43) Chataigner, I.; Lebreton, J.; Zammattio, F.; Villie´ras, J. Tetrahedron
Lett. 1997, 38, 3719.
(41) Kennedy, J. W. J.; Hall, D. G. J. Am. Chem. Soc. 2002, 124, 898.
J. Org. Chem, Vol. 72, No. 23, 2007 8729

Mitra et al.
SCHEME 14. Generation of the Crotylboronate via
Trifluoroborate and Trans-Esterification Route
FIGURE 6. A model for the stereoinduction based on a proposal by
Villieras et al.43
shutdown of the reaction. This observation corroborated the fact
that boryl-copper reactions are known to occur only in highly
polar solvents.38,39
The justification for a better stereoinduction via this auxiliary
(Figure 6) is adapted from the model proposed by Villie´ras and
co-workers.43 The aldehyde 33 is directed from one face of the
phenyl group, the orientation of which is likely governed by
stereoelectronics and steric hindrance in the system.
The transition state is also stabilized due to a possible
attractive interaction between the acidic aldehyde proton and
the coplanar oxygen attached to the electron-rich boron. In
addition to this, the boron-centered anomeric effect (n f s*
interactions) between the axial lone pairs of the ring oxygen of
the 6-membered cyclic transition state and the C-H single bond
of the B-OdCH-R system is also proposed to play some role
in the stereoinduction.
The poor yield of 52, however, led us to modify the route
(Scheme 14) and increase the efficiency of the process by
applying the chemistry of Molander48 and Hutton.49 The
pinacolylboronate 45 was converted to its corresponding trif-
luoroborate salt 54, which was recrystallized from hot acetone
and ether to afford 54 in g95:5 E/Z diastereomeric ratio. This
compound was subjected to hydrolysis with LiOH (1:2 H2O/
CH3CN, 20 h) and was trans-esterified in situ with a catalytic
amount of 1 N HCl and solid NH4Cl, with dropwise addition
of diol 49 in ether, to afford close to 70% overall yield of 52 in
three steps starting from the acetate 44.
The enantiomeric ratio of the product after the crotylation
with aldehyde 33 was found to be a modest 77:23 at 95 °C.
Lowering of the reaction temperature to 65 °C led to a slight
increase in the ratio to 83:17, implicating that the reaction
temperature had only a small effect on the difference of energies
of the transition states. The reaction rate was found to be
extremely slow at 65 °C (65% yield brsm, after 16 days).
Addition of Sc(OTf)3 as a Lewis acid to enhance the reaction
rate in the crotylboration reaction did not have any effect in
our system.50 Hence, our focus was shifted to increasing the
differences in energies of the diastereomeric transition states
by possible introduction of other noncovalent stabilizing factors.
It was envisioned that an “edge-to-face” CH-π interaction51
could perhaps make the transition state more stable and compact,
and enhance the enantioselectivity of the reaction. This was
based on extrapolation of the model proposed by Chataigner40
and co-workers as depicted below (Figure 7). Edge-to-face
FIGURE 7. Enhanced stability in the transition state due to edge-to-
face CH-π interaction.
and Herold44 reported one such boronic ester auxiliary, which
was used by Hall and co-workers45 in their study of enantiose-
lective additions with dual auxiliary allylboronates. Hence,
efforts were directed toward the synthesis of a new diborane
reagent 51 with the boronic ester auxiliary (Scheme 13). (+)-
(R)-Camphorquinone was reduced with L-selectride46 followed
by addition of the phenylcerium reagent generated in situ to
obtain the diol 49 in 60% yield. Diol 49 was subjected to
treatment with tetra(pyrrolidino)diborane 50 in benzene with
freshly prepared 3 M HCl in ether47 and was allowed to stir for
6 h at room temperature. Air stable colorless crystals of the
diborane reagent 51 were obtained, which were recrystallized
from hexane. This reagent was subjected to Miyaura’s boryl-
copper protocol to obtain the desired chiral carbomethoxycrotyl
boronate 52, although in low yield (25%). The low yield of 52
can be attributed to the fact that the oxidative insertion of copper
into the boron-boron bond during the formation of the boryl
copper intermediate is sterically hindered owing to the steric
bulk of the phenyl groups and the quaternary methyl groups in
the transition state. However, crotylation of this reagent with
aldehyde 33 resulted in a completely cis-selective reaction with
a modest enantiomeric ratio of 77:23 (reverse phase HPLC,
Chiralpak AD-RH, i-PrOH-H2O 1:1, flow rate ) 0.35 mL/
min, λ ) 254 nm, injection volume ) 20 µL) to afford 46. The
diborane reagent was found to be fairly insoluble in DMF and
would only dissolve gradually on gently heating the DMF
mixture. A 1:1 THF/DMF mixture was made in an attempt to
solubilize the diborane reagent, but that resulted in a complete
(44) Hoffmann, R. W.; Herold, T. Chem. Ber. 1981, 114, 375.
(45) Kennedy, J. W. J.; Hall, D. G. J. Org. Chem. 2004, 69, 4412.
(46) Lachance, H.; St-Onge, M.; Hall, D. G. J. Org. Chem. 2005, 70,
4180.
(47) Ali, H. A.; Goldberg, I.; Srebnik, M. Eur. J. Inorg. Chem. 2002,
73.
(48) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302.
(49) Yuen, A. K. L.; Hutton, C. A. Tetrahedron Lett. 2005, 46, 7899.
(50) Kennedy, J. W. J.; Hall, D. G. J. Am. Chem. Soc. 2002, 124, 11586.
(51) Matsushima, A; Fujita, T.; Nose, T.; Shimohigashi, Y. J. Biochem.
(Tokyo) 2000, 128 (2), 225.
8730 J. Org. Chem., Vol. 72, No. 23, 2007

Total Synthesis of the Eupomatilones
SCHEME 15. Asymmetric Thermal Crotylboration of Biaryl Aldehydes
SCHEME 16. Suzuki-Miyaura Biaryl Cross Coupling with
aromatic interactions and CH-π interactions52 have been
invoked previously in stabilizing certain protein folding motifs
in literature.53
Buchwald Conditions54
Having this preconceived notion in mind, the asymmetric
thermal crotylboration was attempted on electron-rich biaryl
aldehydes that were direct precursors to eupomatilones 2 and
5, which afforded good enantioselectivity (88:12 and 87:13
enantiomeric ratios, respectively) for the natural products
(Scheme 15). The 1H NMR spectrum of synthetic eupomatilones
2 and 5 were identical with that reported for the natural product.
This level of enantioselection was the maximum observed in
this work.
Optimization of the Suzuki-Miyaura Biaryl Cross-
Coupling Reaction. After optimization of the crotylation
reaction, the focus was on optimizing the Suzuki-Miyaura
biaryl cross-coupling reaction. Several variations of Suzuki
conditions were attempted on two electron-rich boronic acids
55 and 56 with aryl bromide 33, the results of which are given
in Table 1.
SCHEME 17. Suzuki-Miyaura Coupling with Itami,
Yoshido Conditions55
Buchwald conditions54,23 (entries 7 and 8) were found to work
best for our system. On the basis of the above optimization we
examined Suzuki conditions on 46 in a sealed tube that was
preflushed with argon. All the reaction materials were weighed
in a glovebox before the reaction vessel was sealed and heated
for 22 h at 95 °C. The reaction mixture was then passed through
a short pad of Celite and chromatographic purification afforded
eupomatilone 5 (1e) in excellent yield (90%) with an enantio-
meric ratio of 83:17 (Scheme 16).
SCHEME 18. Synthesis of Eupomatilone 1
After successful application of our asymmetric biaryl croty-
lboration strategy to the synthesis of eupomatilones 2 and 5,
we thought of extending it to the asymmetric synthesis of
eupomatilone 1. Buchwald’s Suzuki-Miyaura conditions54,23
were found to be ineffective for synthesizing this biaryl subunit
59 with a methylenedioxy group (Scheme 17). We subsequently
tried Itami, Yoshido conditions55 using bis(tri-tert-butylphos-
phine)palladium (which proved to be successful in the total
synthesis of strobilurin B by Coleman and Lu56) in our system,
and it worked fine affording 59, with no impurities, in a decent
isolated yield (55%).
Quite interestingly, when this methylenedioxy biaryl aldehyde
59 was subjected to standard thermal carbomethoxycrotylbo-
ration conditions with reagent 52, the reaction was extremely
sluggish and afforded eupomatilone 1 (1e) (30%) after heating
at 80-85 °C for 8 days, albeit with poor diastereoselectivity,
as an inseparable mixture of cis (1a) and trans (60) isomers
(52) Kim, E.-i.; Paliwal, S.; Wilcox, C. S. J. Am. Chem. Soc. 1998, 120,
11192.
(53) (a) Burley, S. K.; Petsko, G. A. Science 1985, 229, 23. (b) Burley,
S. K.; Petsko, G. A. AdV. Protein Chem. 1988, 39, 125. (c) Burley, S. K.;
Petsko, G. A. Trends Biotechnol. 1989, 7, 354.
(54) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871.
(55) Itami, K.; Kamei, T.; Yoshida, J.-I. J. Am. Chem. Soc. 2003, 125,
14670.
(56) Coleman, R. S.; Lu, X. Chem. Commun. 2006, 423.
J. Org. Chem, Vol. 72, No. 23, 2007 8731

Mitra et al.
TABLE 1. Optimization of the Suzuki-Miyaura Cross Coupling Reaction
equiv of 55
or 56
equiv of
Aryl-Br
yield
(%)
no.
Suzuki-Miyaura coupling conditions
1
2
3
4
5
6
7
8
1.4 (55)
1.2 (55)
1.0 (55)
1.2 (55)
1.2 (56)
1.2 (56)
2.0 (56)
2.0 (55)
1.0
1.0
2.0
1.0
1.0
1.0
1.0
1.0
Pd(OAc)2 (1 mol %), DABCO (2 mol %), K2CO3 (3.0 equiv), acetone, 90 °C, 10 h
Pd(OAc)2 (1 mol %), DABCO (2 mol %), K2CO3 (3.0 equiv), NMP, 80 °C, 22 h
Pd[(PPh)3]4 (5 mol %), 85 °C, 21 h toluene/ethanol/2 M Na2CO3 (3:2:1.5)
Pd[(PPh)3]4 (3 mol %), Cs2CO3 (1.5 equiv), DMF, 80 °C, 18 h
Pd[(PPh)3]4 (8 mol %), PPh3 (10 mol %), Cs2CO3 (1.5 equiv), DMF, 75 °C, 15 h
Pd[(PPh)3]4 (8 mol %), PPh3 (12 mol %), Cs2CO3 (2.0 equiv), DMF, 75 °C, 24 h
Pd2(dba)3 (4 mol %), S-Phos (8 mol %), K3PO4 (3.0 equiv), toluene, 95 °C, 6 h
Pd2(dba)3 (4 mol %), S-Phos (8 mol %), K3PO4 (3.0 equiv), toluene, 100 °C, 6 h
50
41
59
76
81
82
90
351.0202, found 351.0208. Anti isomer (12): 1H NMR (CDCl3,
500 MHz) δ 6.76 (s, 1H), 5.98 (ABq, 2H, J ) 1.5 Hz, ∆ν ) 4.6
Hz), 5.04 (dd, 1H, J ) 9.1, 2.5 Hz), 4.97 (app t, 1H, J ) 1.8 Hz),
4.96 (s, 1H), 4.03 (s, 3H), 2.47 (qd, 1H, J ) 8.0, 7.1 Hz), 2.23 (d,
1H, J ) 2.5 Hz), 1.79 (s, 3H), 0.91 (d, 3H J ) 7.1 Hz); 13C NMR
(CDCl3, 125 MHz) δ 149.1, 147.2, 139.7, 137.0, 136.2, 1140.,
109.0, 102.3, 101.7, 74.0, 60.2, 50.4, 19.0, 15.5; IR (neat) νmax 3448,
(3:1, Scheme 18). HPLC analysis showed that the er was 94:6
for the natural cis isomer 1a, and 8:1 for the unnatural trans
isomer 60. On the basis of our assumption of possible leakage
from the transition state at temperatures above 80 °C, the thermal
crotylboration was examined at 60 °C for 18 days in toluene,
with no improvement in diastereoselection. This indicated that
temperature does not play any significant role in the transition
state in this case. The role of electronic effect, if any, of the
methylenedioxy group in the enantioselectivity of the thermal
crotylboration reactions needs further scrutiny.
2969, 1642, 1474, 1402, 1272, 1210, 1082, 1048, 959, 895 cm-1
;
HRMS (ESI), m/z calcd for C14H17BrO4Na 351.0202, found
351.0214.
Biaryl 18. A solution of 13 (0.20 g, 0.45 mmol) in MeTHF (15
mL) was treated with t-BuLi (2.3 M, 0.39 mL, 0.90 mmol) at
-78 °C under argon. After 30 min, the aryllithium was transferred
via cannula to a flask containing CuCN (40.0 mg, 0.45 mmol) in
MeTHF (15 mL) at -78 °C under argon. The heterogeneous
mixture was allowed to warm to -40 °C over 1 h and was stirred
until it became homogeneous. The resulting solution was cooled
to -125 °C. In a separate flask, a solution of 1,2,3-trimethoxy-5-
bromobenzene (16, 0.11 g, 0.45 mmol) in MeTHF (15 mL) was
treated with t-BuLi (2.3 M, 0.39 mL 0.90 mmol) at -78 °C for 15
min. This aryllithium was transferred via cannula dropwise to the
previously prepared arylcuprate at -125 °C over 30 min, and the
resulting mixture was allowed to stir for 10 min at this temperature.
Oxygen was bubbled through the reaction mixture via a fine-fritted
gas dispersion tube at -125 °C for 2 h, as the solution turned from
red to brown. The oxygen was removed in vacuo, and the reaction
mixture was quenched by the addition of saturated aqueous NH4-
Cl (20 mL) at this temperature. The reaction mixture was allowed
to warm to 25 °C, diluted with EtOAc (50 mL), and washed with
water and saturated aqueous NH4Cl. The organic layer was dried
(Na2SO4) and concentrated, and the residue was purified by flash
chromatography (5% EtOAc/hexane) to afford 18 (0.12 g, 51%)
as a syrup: 1H NMR (CDCl3, 500 MHz) δ 6.87 (s, 1H), 6.41 (d,
1H, J ) 1.7 Hz), 6.40 (d, 1H, J ) 1.7 Hz), 5.98 (ABq, 2H, J ) 1.5
Hz, ∆ν ) 14.6 Hz), 4.74 (d, 1H, J ) 1.9 Hz), 4.67 (s, 1H), 4.53
(s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.84 (s, 3H), 1.95
(q, 1H, J ) 6.9 Hz), 1.20 (s, 3H), 0.89 (d, 3H, J ) 6.8 Hz), 0.88
(s, 9H), -0.09 (s, 3H), -0.14 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ 153.2 (2 C), 147.9, 147.3, 140.5, 137.8, 137.2, 135.3, 132.0, 125.5,
111.1, 108.9, 106.5, 102.5, 100.9, 71.5, 60.9, 60.0, 56.2, 56.0, 46.3,
25.9, 21.8, 18.3, 10.4, -4.5, -5.0; IR (neat) νmax 2933, 2855, 1615,
1583, 1552, 1499, 1472, 1422, 1409, 1236, 1128, 1080, 1048, 1009,
887, 834, 774 cm-1; HRMS (ESI) m/z calcd for C29H42O7SiNa
553.2592, found 553.2583.
Conclusion
In conclusion, we have demonstrated a successful strategy
for the synthesis of members of the eupomatilone family. The
total synthesis of eupomatilones 4 and 6 rectified the previous
incorrect stereochemical assignments. The asymmetric total
synthesis of eupomatilones 2 and 5 was completed in five linear
steps in close to 55% overall yield. The key to the success of
the sequence was a highly efficient Suzuki-Miyaura biaryl
cross-coupling reaction and an efficient asymmetric carbomethox-
ycrotylboration reaction. The edge-to-face effect observed in
the aryl-aryl interaction exemplified the importance of weak
noncovalent electrostatic components in stabilizing transition
states. In the process of developing a chiral carbomethoxycro-
tylboration reagent, a new air-stable diborane reagent was
prepared. Although its solubility in DMF posed a problem, other
solvent systems need to be examined to achieve optimized
conditions for the asymmetric crotylboration reaction with this
reagent. The optimized conditions for the Suzuki-Miyaura
biaryl cross-coupling reaction would be useful for the synthesis
of other electron-rich biaryl coupling partners.
Experimental Section
5-((1S*,2R*)-1-Hydroxy-2,3-dimethyl-3-butenyl)-6-bromo-7-
methoxy benzo[d][1,3]dioxole (11). A solution of (E)-2-methyl-
2-butene-1-ylmagnesium bromide in THF (0.3 M, 21 mL, 6.3
mmol) was added dropwise by syringe over 20 min to a solution
of 8 (1.5 g, 5.8 mmol) in THF at -78 °C. The reaction mixture
was stirred for 30 min at -78 °C and was quenched by the addition
of saturated aqueous NH4Cl (10 mL). The volatiles were removed
and the residue was dissolved in EtOAc (100 mL) and washed with
water and saturated aqueous NaCl. The organic layer was dried
(Na2SO4) and concentrated, and the residue was purified by flash
chromatography (silica, 10% EtOAc/hexane) to afford a 1:1 mixture
Diol 19. A solution of 17 (0.10 g, 0.19 mmol) in THF (2 mL)
was cooled to 0 °C, and a solution of 9-BBN in THF (0.5 M, 0.68
mL, 0.34 mmol) was added dropwise by syringe over 30 min at
this temperature. The reaction mixture was allowed to warm to
25 °C over 3 h, then was stirred at this temperature for 6 h. The
resulting mixture was cooled to 0 °C, and aqueous NaOH (45 mg,
1.13 mmol), aqueous 30% H2O2 (0.13 mL, 1.13 mmol), and EtOH
(0.4 mL) were added dropwise, then the reaction mixture was
allowed to warm to 25 °C. After 3 h at this temperature, the volatiles
were removed, and the residue was diluted with EtOAc (25 mL)
and washed with water and saturated aqueous NaCl. The organic
layer was dried (Na2SO4) and concentrated, and the residue was
1
of syn/anti isomers (1.8 g, 95%). Syn isomer (11): H NMR (CDCl3,
500 MHz) 6.85 (s 1H), 5.97 (s, 2H), 5.10 (d, 1H, J ) 3.4 Hz),
4.95 (app t, 1H, J ) 1.4 Hz), 4.88 (s, 1H), 4.03 (s, 3H), 2.69 (qd,
1H, J ) 3.4, 7.0 Hz), 1.95 (br s, 1H), 1.92 (s, 3H), 0.87 (d, 3H, J
) 7.0 Hz); 13C NMR (CDCl3, 125 MHz) δ 148.5, 148.0, 140.0,
136.4, 135.0, 111.7, 106.4, 102.9, 101.6, 72.6, 60.1, 43.9, 22.2,
11.4; IR (neat) νmax 3442, 3054, 2986, 1642, 1474, 1421, 1264,
1080, 1046, 895 cm-1; HRMS (ESI), m/z calcd for C14H17BrO4Na
8732 J. Org. Chem., Vol. 72, No. 23, 2007

Total Synthesis of the Eupomatilones
purified by flash chromatography (30% EtOAc/hexane) to afford
the corresponding primary alcohol (0.10 g, 98%) as a syrup: 1H
NMR (CDCl3, 500 MHz) δ 6.82 (s, 1H), 6.40 (d, 1H, J ) 1.7 Hz),
6.36 (d, 1H, J ) 1.7 Hz), 5.97 (ABq, 2H, J ) 1.4 Hz, ∆ν ) 14.6
Hz), 4.78 (d, 1H, J ) 1.5 Hz), 3.85 (s, 3H), 3.84 (s, 3H), 3.83 (s,
3H), 3.82 (s, 3H), 3.42 (ABX, 2H, JAB ) 10.7 Hz, JAX ) 4.0 Hz,
JBX ) 5.9 Hz, ∆ν ) 57.7 Hz), 1.57-1.38 (m, 1H), 1.31-1.26 (m,
2H), 0.92 (s, 9H), 0.81 (d, 3H, J ) 6.9 Hz), 0.47 (d, 3H, J ) 6.9
Hz), -0.08 (s, 3H), -0.15 (s, 3H); 13C NMR (CDCl3, 125 MHz)
δ 153.2, 153.1, 147.8, 140.6, 137.8, 137.3, 135.3, 132.0, 125.6,
108.9, 106.5, 102.8, 100.9, 71.5, 66.1, 60.9, 60.0, 56.2, 56.1, 42.4,
37.6, 26.0, 18.2, 14.9, 9.1, -3.9, -4.7; IR (neat) νmax 3436, 2931,
1618, 1583, 1508, 1472, 1423, 1409, 1306, 1234, 1127, 1080, 1047,
834, 773, 736 cm-1; HRMS (ESI, m/z calcd for C29H44O8SiNa
571.2697, found 571.2722.
A solution of n-Bu4NF (12 mg, 0.04 mmol) in THF (2 mL) was
added to a solution of the above primary alcohol (25 mg, 0.04
mmol) in THF at 25 °C and the reaction mixture was stirred for
2 h at this temperature. The volatiles were removed and the residue
was dissolved in EtOAc (10 mL), and then washed with water and
saturated aqueous NaCl. The organic layer was dried (Na2SO4) and
concentrated, and the residue was purified by flash chromatography
(40% EtOAc/hexane) to afford the diol 19 (18 mg, 94%): 1H NMR
(CDCl3, 500 MHz) δ 6.91 (s, 1H), 6.44 (d, 1H, J ) 1.7 Hz), 6.36
(d, 1H, J ) 1.7 Hz), 5.97 (s, 2H), 4.69 (d, 1H, J ) 2.2 Hz), 3.89
(s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.35 (ABX, 2H,
JAB ) 10.9 Hz, JAX ) 9.1 Hz, JBX ) 4.7 Hz, ∆ν ) 29.8 Hz), 2.92
(br s, 1H), 1.64-1.59 (m, 2H), 1.49-1.46 (m, 1H), 0.79 (d, 3H, J
) 7.2 Hz), 0.66 (d, 3H, J ) 7.2 Hz); 13C NMR (CDCl3, 125 MHz)
δ 153.1, 152.9, 148.3, 140.9, 137.2, 137.0, 135.7, 132.0, 126.4,
108.3, 106.9, 101.3, 101.1, 73.7, 64.2, 60.9, 60.1, 56.2, 56.1, 43.7,
39.9, 16.9, 5.7; IR (neat) νmax 3354, 2962, 1617, 1583, 1507, 1469,
1409, 1305, 1271, 1236, 1169, 1126, 1080, 1050, 1008, 972, 930,
844, 736 cm-1; HRMS (ESI), m/z calcd for C23H30O8Na 457.1832,
found 457.1824.
Eupomatilone 4 (1d). A solution of diol 19 (12 mg, 0.03 mmol),
TEMPO (1.0 mg), and n-Bu4NI (15 mg, 0.04 mmol) in CH2Cl2 (2
mL) and 2 mL of 0.5 M aqueous NaHCO3 and 0.05 M K2CO3
(1:1) was vigorously stirred at room temperature for 5 min.
N-Chlorosuccinimide (10 mg, 0.08 mmol) was added and the
reaction mixture was stirred for 1 h at this temperature. The reaction
mixture was diluted with CH2Cl2 (10 mL) and washed with water
and saturated aqueous NaCl. The organic layer was dried (Na2-
SO4) and concentrated, and the residue was purified by flash
chromatography (30% EtOAc/hexane) to afford eupomatilone 4 (1d,
11.8 mg, 98%): 1H NMR (CDCl3, 500 MHz) δ 6.76 (s, 1H), 6.43
(d, 1H, J ) 1.7 Hz), 6.30 (d, 1H, J ) 1.7 Hz), 6.00 (s, 2H), 5.28
(d, 1H, J ) 5.0 Hz), 3.93 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.83
(s, 3H), 2.71 (app quintet, 1H, J ) 7.3 Hz), 2.18 (qd, 1H, J ) 7.3,
5.2 Hz), 1.11 (d, 3H, J ) 7.3 Hz), 0.59 (d, 3H, J ) 7.3 Hz); 13C
NMR (CDCl3, 125 MHz) δ 178.5, 153.3, 153.1, 148.8, 141.0, 137.3,
136.3, 131.2, 129.0, 126.2, 107.7, 106.3, 101.3, 101.1, 80.4, 60.9,
60.0, 56.3, 56.2, 40.6, 39.1, 9.9, 9.8; IR (neat) νmax 2972, 2940,
2837, 1773, 1618, 1582, 1505, 1477, 1425, 1410, 1378, 1338, 1310,
1278, 1239, 1172, 1126, 1093, 1061, 1022, 975, 929, 839, 733
cm-1; HRMS (ESI) m/z calcd for C23H26O8Na 453.1519, found
453.1519.
1-((1S*,2R*)-1-(tert-Butyldimethylsilyl)oxy-2,3-dimethyl-3-
butenyl)-2-bromo-3,4,5-trimethoxybenzene (20). Following the
procedure for the preparation of 11, to a solution of (E)-2-methyl-
2-butene-1-ylmagnesium bromide in THF (0.3 M, 28 mL, 8.5
mmol) was added o-bromotrimethoxybenzaldehyde (1.91 g, 7.7
mmol) to afford syn and anti isomers (1:1) (2.4 g, 90%) as a syrup.
Syn isomer: 1H NMR (CDCl3, 500 MHz) δ 6.97 (s, 1H), 5.12 (app
t, 1H, J ) 2.4 Hz), 4.98 (s, 1H), 4.89 (s, 1H), 3.90 (s, 3H), 3.89 (s,
3H), 3.88 (s, 3H), 2.75-2.70 (m, 1H), 1.99 (d, 1H, J ) 2.1 Hz),
1.95 (s, 3H), 0.90 (d, 3H, J ) 7.1 Hz); 13C NMR (CDCl3, 125
MHz) δ 152.5, 150.5, 148.1, 142.1, 136.9, 111.7, 107.9, 107.2,
72.4, 61.1, 61.0, 56.1, 43.8, 22.3, 11.3; IR (neat) νmax 3472, 2969,
2937, 1642, 1568, 1481, 1448, 1426, 1394, 1324, 1194, 1162, 1105,
1037, 1009, 893, 817, 738 cm-1; HRMS (ESI) m/z calcd for C15H21-
BrO4Na 367.0521, found 367.0512. Anti isomer: 1H NMR (CDCl3,
500 MHz) δ 6.87 (s, 1H), 5.05 (d, 1H, J ) 9.1 Hz), 4.99 (s, 2H),
3.89 (s, 9H), 2.50 (qd, 1H, J ) 7.1, 9.0 Hz), 2.27 (br s, 1H), 1.80
(s, 3H), 0.92 (d, 3H, J ) 7.1 Hz); 13C NMR (CDCl3, 125 MHz) δ
153.2, 150.3, 147.2, 142.6, 137.4, 113.7, 110.5, 106.6, 73.7, 61.1,
61.0, 56.2, 50.5, 18.8, 15.6; IR (neat) νmax 3421, 2966, 2941, 1642,
1482, 1394, 1324, 1238, 1195, 1162, 1104, 1011, 886, 824 cm-1
;
HRMS (ESI) m/z calcd for C15H21BrO4Na 367.0521, found
367.0553.
Following the procedure for the preparation of 13, 2,6-lutidine
(0.3 mL, 2.6 mmol) and BuMe2SiOTf (0.44 mL, 1.9 mmol) were
added to a solution of the preceding syn isomer (0.6 g, 1.7 mmol)
to afford 20: 1H NMR (CDCl3, 500 MHz) δ 6.93 (s, 1H), 5.07 (d,
1H, J) 3.1 Hz), 4.82 (s, 1H), 4.77 (s, 1H), 3.89 (s, 3H), 3.88 (s,
3H), 3.85 (s, 3H), 2.40-2.35 (m, 1H), 1.86 (s, 3H), 0.97 (d, 3H, J
) 6.9 Hz), 0.89 (s, 9H), 0.03 (s, 3H), -0.21 (s, 3H); 13C NMR
(CDCl3, 500 MHz) δ 152.1, 150.0, 147.2, 141.8, 139.2, 111.8,
108.0, 107.9, 74.7, 61.1, 61.0, 56.0, 45.7, 25.9, 22.2, 18.2, 12.0,
-4.8, -5.2; IR (neat) νmax 3053, 2985, 2856, 1480, 1422, 1395,
1324, 1265, 1195, 1162, 1106, 1039, 1010, 895, 737, 704 cm-1
;
HRMS (ESI) m/z calcd for C21H35BrO4SiNa 481.1386, found
481.1360.
3-epi-Eupomatilone 6 (26). Following the previously described
procedure for the preparation of the eupomatilone 4 diol 19, a
solution of n-Bu4NF (18 mg, 0.07 mmol) in THF (2 mL) was added
to a solution of alcohol (30 mg, 0.06 mmol) to afford the
corresponding diol (22 mg, 95%): 1H NMR (CDCl3, 500 MHz) δ
6.99 (s, 2H), 6.87 (d, 1H, J ) 7.6 Hz), 6.86 (d, 1H, J ) 7.9 Hz),
6.72 (d, 2H, J ) 1.5 Hz), 6.70 (d, 1H, J ) 1.5 Hz), 6.68 (br s, 3H),
6.62 (dd, 1H, J ) 7.9, 1.5 Hz), 6.02 (d, 2H, J ) 1.3 Hz), 6.00 (br
s, 2H), 4.81 (d, 1H, J ) 2.0 Hz), 4.74 (d, 1H, J ) 2.0 Hz), 3.93 (s,
6H), 3.90 (s, 3H), 3.89 (s, 3H), 3.64 (s, 3H), 3.63 (s, 3H), 3.42 (td,
1H, J ) 2.1, 10.9 Hz), 3.35 (dd, 1H, J ) 4.5, 10.9 Hz), 2.32 (br,
2H), 1.67-1.60 (m, 2H), 1.55-1.50 (m, 2H), 1.30-1.22 (m, 2H),
0.81 (d, 3H, J ) 7.3 Hz), 0.79 (d, 3H, J ) 7.3 Hz), 0.69 (d, 6H,
J ) 7.1 Hz); IR (neat) νmax 3355, 2935, 1597, 1571, 1479, 1401,
1321, 1267, 1230, 1125, 1081, 1038, 935, 810, 737 cm-1; HRMS
(ESI) m/z calcd for C22H28O7SiNa 427.1733, found 427.1734.
Following the procedure for the preparation of eupomatilone 4,
N-chlorosuccinimide (10 mg) was added to a solution of the
preceding diol (15 mg, 0.04 mmol), TEMPO (1.0 mg), and n-Bu4-
NI (19 mg, 0.05 mmol) in CH2Cl2 (2 mL) and 2 mL of 0.5 M
aqueous NaHCO3 and 0.05 M K2CO3 (1:1) to afford 26 (two
atropisomers) (14 mg, 93%): 1H NMR (CDCl3, 500 MHz) δ 6.88
(d, 1H, J ) 7.9 Hz), 6.87 (d, 1H, J ) 7.9 Hz), 6.83 (s, 1H), 6.82
(s, 1H), 6.73 (d, 1H, J ) 1.4 Hz), 6.70 (dd, 1H, J ) 1.4, 7.9 Hz),
6.62 (d, 1H, J ) 1.4 Hz), 6.57 (dd, 1H, J ) 1.4, 7.9 Hz), 6.05 (dd,
2H, J ) 1.1, 4.3 Hz), 6.03 (m, 2H), 5.40 (d, 1H, J ) 4.9 Hz), 5.32
(d, 1H, J ) 4.9 Hz), 3.91 (s, 6H), 3.90 (s, 6H), 3.66 (s, 3H), 3.65
(s, 3H), 2.74 (app sextet, 2H, J ) 7.0 Hz), 2.20-2.10 (m, 2H),
1.12 (d, 6H, J ) 7.3 Hz), 0.56 (d, 3H, J ) 7.3 Hz), 0.54 (d, 3H,
J ) 7.3 Hz); 13C NMR (CDCl3, 125 MHz) δ 178.7, 152.9, 151.5,
147.7, 147.6, 147.0, 146.9, 141.6, 130.2, 129.2, 129.1, 126.3, 126.2,
123.5, 122.4, 110.6, 109.6, 108.5, 108.2, 105.0, 104.9, 101.2, 101.1,
80.6, 80.5, 61.2, 61.1, 60.8, 56.2, 40.7, 38.9, 38.6, 29.7, 9.9, 9.8,
9.7; IR (neat) νmax 2972, 2938, 1775, 1598, 1482, 1458, 1436, 1402,
1360, 1340, 1323, 1273, 1226, 1173, 1127, 1092, 1057, 1038, 1006,
970, 934, 910, 859, 810, 734 cm-1; HRMS (ESI) m/z calcd for
C22H24O7Na 423.1420, found 423.1416.
Eupomatilone 6 (1f). Pyridinium dichromate (15 mg, 0.07
mmol) was added to a solution of alcohol 27 (30 mg, 0.06 mmol)
in CH2Cl2 (1 mL) at 25 °C. The reaction mixture was stirred at
this temperature for 2 h, diluted with Et2O (15 mL), and washed
with water and saturated aqueous NaCl. The organic layer was dried
(Na2SO4) and concentrated to afford corresponding aldehyde (25
mg, 85%), which was used without further purification.
J. Org. Chem, Vol. 72, No. 23, 2007 8733

Mitra et al.
The preceding aldehyde was treated with n-Bu4NF (25 mg, 0.1
mmol) in THF (1 mL) at 25 °C and the reaction mixture was stirred
at this temperature for 1 h, and then diluted with EtOAc (10 mL)
and washed with water and saturated aqueous NaCl. The organic
layer was dried (Na2SO4) and concentrated, and the residue was
passed through a bed of silica to afford corresponding lactol 28
(13 mg, 71%), which was used without further purification.
Pyridinium dichromate (1.5 mg, 0.07 mmol) was added to a
solution of lactol 28 (14 mg, 0.03 mmol) in CH2Cl2 (1 mL) at
25 °C and the reaction mixture was stirred at this temperature for
2 h, diluted with Et2O (10 mL), and washed with water and saturated
aqueous NaCl. The organic layer was dried (Na2SO4) and concen-
trated to afford a mixture of 26 and 1f (1:3) (10 mg, 90%). An
analytically pure sample of 1f was obtained by preparative TLC
(20% EtOAc/hexane; multiple developments) as a mixture of
interconverting atropdiastereomers: 1H NMR (CDCl3, 500 MHz)
δ 6.88 (d, 1H, J ) 7.9 Hz), 6.87 (d, 1H, J ) 7.9 Hz), 6.73 (d, 1H,
J ) 1.5 Hz), 6.70 (dd, 1H, J ) 1.6, 7.9 Hz), 6.68 (s, 1H), 6.67 (s,
1H), 6.66 (d, 1H, J ) 1.5 Hz), 6.59 (dd, 1H, J ) 1.6, 7.9 Hz), 6.03
(ABq, 2H, J ) 1.3 Hz, ∆ν ) 8.7 Hz), 5.65 (d, 1H, J ) 6.9 Hz),
5.54 (d, 1H, J ) 6.9 Hz), 3.91 (s, 6H), 3.89 (s, 6H), 3.65 (s, 3H),
3.64 (s, 3H), 2.37 (sextet, 2H, J ) 7.2 Hz), 2.05-1.96 (m, 2H),
2.20 (d, 3H, J ) 7.4 Hz), 1.19 (d, 3H, J ) 7.4 Hz), 0.73 (d, 3H,
J ) 7.1 Hz), 0.70 (d, 3H, J ) 7.1 Hz); 13C NMR (CDCl3, 125
MHz) δ 179.8, 153.0, 151.8, 148.0, 147.8, 147.1, 147.0., 142.0,
130.5, 129.3, 129.2, 127.4, 127.3, 124.0, 122.9, 111.2, 110.1, 108.5,
108.3, 105.0, 104.9, 101.4, 101.3, 80.1, 80.0, 61.3, 61.2, 61.0, 56.3,
42.9, 42.7, 41.7, 41.4, 15.7, 15.5, 15.1, 15.0; IR (neat) νmax 2972,
2931, 1774, 1599, 1482, 1458, 1440, 1406, 1325, 1225, 1154, 1173,
1127, 1038, 1004, 971, 933, 810, 733 cm-1; HRMS (ESI) m/z calcd
for C22H24O7Na 423.1420, found 423.1383.
to afford 46 as a colorless syrup (240 mg, 78%): 1H NMR (CDCl3,
500 MHz) δ 6.72 (s, 1H), 6.35 (d, 1H, J ) 2.5 Hz), 5.85 (d, 1H,
J ) 7.5 Hz), 5.68 (d, 1H, J ) 2.0 Hz), 3.92 (s, 3H), 3.91 (s, 3H),
3.86 (s, 3H), 3.70 (m, 1H), 0.80 (d, 3H, J ) 7.5 Hz); 13C NMR
(CDCl3, 100 MHz) δ 170.0, 153.1, 150.8, 142.7, 140.5, 131.4,
122.9, 107.4, 106.0, 80.9, 61.1, 56.3, 37.3, 16.9; IR (thin film) νmax
2926, 2853, 1772, 1570, 1484, 1452, 1397, 1360, 1324, 1267, 1244,
1148, 1108, 1004, 972, 813 cm-1; HRMS (ESI) m/z calcd for
C15H17BrO5Na 379.0157, found 379.0161; er 77:23 (HPLC, chiral-
pak AD-RH column, i-PrOH-H2O 1:1, flow rate ) 0.35 mL/min,
λ ) 254 nm, injection volume ) 20 µL).
(E)-iso-Pinanecamphenyl Crotylboronate (47). An oven-dried
round-bottomed flask was charged with CuCl (143.5 mg, 1.45
mmol) and LiCl (61.5 mg, 1.45 mmol). DMF (3 mL) was added
and the mixture was stirred for 1 h at 25 °C under argon when the
solution became brownish-yellow. A solution of bis((()-pinanediola-
to)diboron (465 mg, 1.30 mmol) in DMF (5 mL) was added via
cannula to the reaction mixture over 5 min. Dry KOAc (140 mg,
1.45 mmol) was added to the reaction mixture in one portion, and
the reaction mixture turned blackish-brown. A solution of allyl
acetate 44 (178 mg, 1.03 mmol) in DMF (2 mL) was added
dropwise. The reaction mixture was stirred for 5 h at 25 °C, during
which time the color of the reaction mixture gradually faded to
light pink and finally turned blue. The reaction mixture was
quenched by the addition of water (4 mL). The mixture was
extracted with ether (2 × 10 mL) and the aqueous layer was re-
extracted with ether (2 × 10 mL). The combined organic extracts
were washed with saturated aqueous NaCl (2 × 20 mL), dried (Na2-
SO4), and concentrated. The residue was quickly purified by flash
chromatography (silica, 5% EtOAc/hexane) to afford boronate 47
(95:5 ) E/Z) as a colorless oil (180 mg, 86% brsm): 1H NMR
(CDCl3, 500 MHz) δ 6.84 (q, 1H, J ) 7.0 Hz), 4.27 (dd, 1H, J )
9.0, 2.0 Hz), 3.72 (s, 3H), 2.32 (m, 1H), 2.21 (m, 1H), 2.05 (t, J )
5.7 Hz, 1H), 1.82 (m, 1H), 1.90 (m, 3H), 1.79 (d, J ) 7 Hz, 3H),
1.38 (s, 3H), 1.29 (s, 3H), 1.22 (d, J ) 10.9 Hz, 1H), 0.84 (s, 3H);
13C NMR (CDCl3, 125 MHz) δ 168.5, 135.7, 130.1, 85.7, 77.9,
51.6, 51.3, 39.5, 38.2, 35.5, 29.7, 28.6, 27.1, 26.3, 24.0, 14.5; 11B
NMR (CDCl3, 80 MHz) δ 32.06; IR (thin film) νmax 2922, 1712,
(E)-Methyl-2-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
methyl)but-2-enoate (45). A flame-dried round-bottomed flask was
charged with CuCl (257.4 mg, 2.60 mmol) and LiCl (110.2 mg,
2.60 mmol). DMF (3 mL) was added and the mixture was stirred
for 30 min at 25 °C under argon. A solution of bis-pinacolatodi-
boron (660 mg, 2.60 mmol) in DMF (2 mL) was cannulated into
the reaction mixture, which was stirred for 5 min. Dried KOAc
(255.2 mg, 2.60 mmol) was added to the reaction mixture in one
portion, and the reaction mixture turned blackish-brown. A solution
of acetate 44 in DMF (1 mL) was added dropwise. The reaction
mixture was stirred for 6.5 h at 25 °C during which the color of
the reaction mixture turned blue. The reaction mixture was quenched
by the addition of water (4 mL). The mixture was extracted with
ether (3 × 10 mL) and the combined organic extracts were washed
with saturated aqueous NaCl (2 × 10 mL), dried (Na2SO4), and
concentrated. The residue was quickly purified by flash chroma-
tography (silica, 10% ether/hexane) to afford 45 as a colorless oil
1649, 1440, 1380, 1344, 1279, 1191, 1160, 1123, 1028, 755 cm-1
;
HRMS (ESI) m/z calcd for C16H25O4BNa 315.1744, found 315.1736.
Diboron Reagent 51. A solution of tetra(pyrrolidino)diborane
(50, 61.3 mg, 0.20 mmol) in freshly distilled benzene (0.5 mL)
was added to a vigorously stirred solution of diol 49 (100 mg, 0.41
mmol) in benzene (0.2 mL) at 25 °C. A solution of 3 M HCl in
ether (0.5 mL) was added to the resulting mixture. After 6 h of
vigorous stirring, the reaction mixture was filtered and benzene
was removed under vacuum to afford the crude product as a yellow
oil that was purified by flash chromatography (silica, 10% Et2O/
hexane) to obtain the desired diborane reagent 51 (82 mg, 78%) as
colorless crystals, which were found to be air-stable for several
days: 1H NMR (CDCl3, 500 MHz) δ 7.42 (s, 1H), 7.41 (s, 1H),
7.31-7.22 (m, 3H), 4.72 (s, 1H), 2.21 (d, 1H, J ) 5 Hz), 1.83 (m,
1H), 1.27 (s, 3H), 1.20-1.14 (m, 2H), 1.03-0.95 (m, 1H), 0.99
(s, 3H), 0.91 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 141.5, 127.4,
127.2, 126.7, 96.0, 88.4, 52.2, 50.5, 48.8, 29.6, 24.9, 23.7, 20.7,
9.5; 11B NMR (CDCl3, 80 MHz) δ 31.90; IR (film) νmax 2958, 1485,
1445, 1369, 1265, 1244, 1145, 992, 956, 749, 703 cm-1; HRMS
(ESI) m/z calcd for C32H40B2O4Na 533.3010, found 533.2998.
Carbomethoxycrotyl Potassium Trifluoroborate Salt 54. An
aqueous solution of KHF2 (4.5 M, 1.7 mL) was added dropwise
under nitrogen to a solution of carbomethoxy pinacolylcrotylbor-
onate 45 (520 mg, 2.17 mmol) in MeOH (10 mL). The reaction
mixture was stirred for 25 min at 25 °C then concentrated in vacuo,
and the residue was dissolved in hot acetone. The reaction mixture
was filtered and the filtrate was concentrated and recrystallized from
a minimum volume of hot acetone and a few drops of ether several
times to obtain the required (E)-diastereomer of the potassium
trifluoroborate salt 54 (380 mg, 80%) as a colorless needle-like
crystalline solid: 1H NMR (acetone-d6, 400 MHz) δ 6.40 (q, 1H,
1
(437 mg, 91%) that was found to be a 93:7 E/Z mixture by H
NMR. The major Z diastereomer was characterized: 1H NMR
(CDCl3, 500 MHz) δ 6.83 (tq, 1H, J ) 7.5, 1.0 Hz), 3.71 (s, 3H),
1.86 (s, 2H), 1.78 (d, 3H, J ) 7.0 Hz), 1.24 (s, 12H); 13C NMR
(CDCl3, 125 MHz) δ 168.6, 135.7, 130.0, 83.3, 83.2, 51.6, 24.9,
24.7 (4C), 14.5; IR (thin film) νmax 2979, 2950, 1712, 1650, 1436,
1354, 1324, 1271, 1195, 1163, 1146, 1124, 1051, 968, 884, 847,
756, 675, 542 cm-1; HRMS (ESI) m/z calcd for C12H21BO4Na
263.1431, found 263.1426.
(4S,5S)-5-(2-Bromo-3,4,5-trimethoxyphenyl)dihydro-4-meth-
yl-3-methylenefuran-2(3H)-one (46). A solution of trimethoxy-
bromoaldehyde 33 (212 mg, 0.77 mmol) in toluene (2 mL) was
added to a solution of carbomethoxycrotyl boronate 52 (318 mg,
0.86 mmol) in toluene (3 mL) under argon. The reaction vessel
was sealed with Teflon and the reaction mixture was warmed at
95 °C for 72 h. The reaction mixture was quenched by the addition
of water (2 mL). The mixture was diluted with ether (5 mL) and
the aqueous layer was re-extracted with ether (2 × 5 mL). The
combined organic extracts were washed with saturated aqueous
NaCl (2 × 10 mL), dried (Na2SO4), and concentrated. The residue
was purified by flash chromatography (silica, 10% Et2O/hexane)
8734 J. Org. Chem., Vol. 72, No. 23, 2007

Total Synthesis of the Eupomatilones
J ) 6.8 Hz), 3.59 (s, 3H), 1.69 (d, 3H, J ) 6.8 Hz), 1.38 (br s,
2H); 13C NMR (DMSO-d6, 125 MHz) δ 169.9, 137.1, 128.9, 51.2,
14.5; 11B NMR (acetone-d6, 80 MHz) δ 4.07 (q, J ) 60 Hz); IR
(film) νmax 2947, 2916, 1698, 1438, 1283, 1239, 1200, 1125, 1056,
1020, 935, 765 cm-1; HRMS (ESI) m/z calcd for C6H9BF3O2K
258.9919, found 258.9918.
1482, 1464, 1401, 1316, 1252, 1238, 1196, 1127, 1102, 1007, 929
cm-1; HRMS (ESI) m/z calcd for C19H22O7Na 385.1263, found
385.1263.
7-Methoxy-6-(3,4,5-trimethoxyphenyl)benzo[d][1,3]dioxole-5-
carbaldehyde (59). Pd[P(t-Bu)3]2 (10 mg, 0.019 mmol) and
6-bromo-7-methoxybenzo[d][1,3]dioxole-5-carbaldehyde (100 mg,
0.386 mmol) were added to an oven-dried conical vial in a
glovebox. The vial was taken out of the glovebox and flushed with
argon. THF (2 mL) was added to the mixture, which was then stirred
for about 8 min. 3,4,5-Trimethoxyphenylboronic acid (164 mg,
0.772 mmol) in THF (2 mL) was added by cannula to the reaction
mixture (THF wash, 1 mL). Finely powdered NaOH (46.3 mg, 1.16
mmol) was quickly added to the reaction mixture in one portion
followed by dropwise addition of d-H2O (22 µL, 1.16 mmol) by a
microsyringe. The reaction mixture was heated at 60 °C for 22 h.
It was then quenched by the addition of water (10 mL) and diluted
with ether (10 mL). The aqueous phase was extracted with ether
(3 × 10 mL). The combined organic extracts were collected, washed
with saturated aqueous NaCl (2 × 10 mL), and dried (Na2SO4).
Concentration of the filtrate and purification of the residue by flash
chromatography (silica, 5% to 10% EtOAc/hexane) afforded 59
(73 mg, 55%) as a colorless crystalline solid: 1H NMR (CDCl3,
500 MHz) δ 9.56 (s, 1H), 7.21 (s, 1H), 6.49 (s, 2H), 6.01 (s, 2H),
3.91 (s, 3H), 3.86 (s, 3H), 3.85 (s, 6H); 13C NMR (CDCl3, 125
MHz) δ 190.8, 153.4, 152.8, 149.1, 142.2, 140.7, 137.8, 135.4,
129.9, 128.3, 108.4, 104.7, 102.2, 101.0, 60.9, 60.2, 56.3, 56.2; IR
(film) νmax 2936, 1679, 1606, 1582, 1509, 1462, 1411, 1362, 1285,
1243, 1126 cm-1; HRMS (ESI) m/z calcd for C18H18O7Na 369.0950,
found 369.0947.
Carbomethoxycrotyl Boronate 52. Trifluoroborate 54 (226 mg,
1.03 mmol) was dissolved in a mixture of acetonitrile and water (9
mL, 2:1), and LiOH (74 mg, 3.09 mmol) was added in one portion.
The reaction mixture was stirred for 20 h at 25 °C. Solid NH4Cl
(70 mg, 1.31 mmol) was added to the reaction mixture followed
by diol 49 (266 mg, 1.08 mmol) and a solution of 1 N HCl (0.05
mL) was added dropwise by syringe. After vigorous stirring for
4 h, the reaction mixture was separated, the aqueous layer was
extracted with ether (3 × 10 mL), and the combined organic extracts
were washed with water (3 × 10 mL) and saturated aqueous NaCl
(2 × 10 mL), dried (Na2SO4), and concentrated. Purification of
the residue by flash chromatography (silica, 10% Et2O/hexane)
afforded boronate 52 (367 mg, 97%) as a colorless oil (g95% (E)-
isomer by NMR): 1H NMR (CDCl3, 400 MHz) δ 7.40 (m, 2H),
7.33 (m, 3H), 6.82 (q, 1H, J ) 7.2 Hz), 4.73 (s, 1H), 3.41 (s, 3H),
2.14 (d, 1H, J ) 5.2 Hz), 1.88 (d, 2H, J ) 2.0 Hz), 1.83 (m, 1H),
1.72 (d, 3H, J ) 7.2 Hz), 1.57 (s, 1H), 1.23 (s, 3H), 1.18 (m, 2H),
1.05 (m, 1H), 0.94 (s, 3H), 0.93 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 168.4, 141.8, 135.8, 129.6, 127.4, 127.2, 126.7, 95.7, 88.9,
88.4, 52.0, 51.3, 50.2, 48.8, 29.6, 24.9, 24.7, 23.6, 20.8, 14.5, 9.4,
9.3; 11B NMR (CDCl3, 80 MHz) δ 34.23; IR (film) νmax 3448, 2956,
2365, 1718, 1648, 1341, 1270, 1156, 1012 cm-1; HRMS (ESI) m/z
calcd for C22H29BO4Na 391.2057, found 391.2051.
Eupomatilone 2 (1b). A solution of 58 (36.3 mg, 0.10 mmol)
in toluene (1 mL) was added to a solution of the carbomethoxycrotyl
boronate 52 (39 mg, 0.106 mmol) in toluene (1 mL) via a syringe.
The reaction vessel was flushed with Argon, then sealed with Teflon
and heated at 75 °C for 9 days. The reaction mixture was quenched
by the addition of water (2 mL). The aqueous layer was washed
with ether (2 × 10 mL). The combined organic extracts were
washed with saturated aqueous NaCl (2 × 10 mL), dried (Na2-
SO4), and concentrated. Purification of the residue by flash
chromatography (silica, 10-50% Et2O/hexane) afforded eupoma-
tilone 2 (1b, 34 mg, 74%) as a colorless syrup, in an 88:12
enantiomeric ratio (chiralpak AD-RH, i-PrOH/H2O ) 50:50,
flowrate ) 0.35 mL/min, injection volume ) 20 µL, λ ) 254 nm);
1H NMR (CDCl3, 500 MHz) δ 6.69 (s, 1H), 6.46 (d, 1H, J ) 1.5
Hz), 6.37 (d, 1H, J ) 2.0 Hz), 6.26 (d, 1H, J ) 2.5 Hz), 5.55 (d,
1H, J ) 2.0 Hz), 5.52 (d, 1H, J ) 7.0 Hz), 3.92 (s, 6H), 3.89 (s,
3H), 3.87 (s, 3H), 3.85 (s, 3H), 3.70 (s, 3H), 2.88 (app tp, 1H, J )
7.5, 2.0 Hz), 0.87 (dd, 3H, J ) 4.0, 2.5 Hz); 13C NMR (CDCl3,
125 MHz) δ 170.2, 153.3, 153.1, 153.0, 151.3, 141.9, 140.9, 137.3,
131.1, 129.9, 127.7, 122.2, 107.4, 106.4, 104.9, 79.3, 61.4, 61.0,
60.9, 56.3, 56.2, 56.1, 38.3, 16.9; IR (film) νmax 2965, 2935, 2836,
1767, 1583, 1489, 1463, 1404, 1363, 1313, 1247, 1127, 1103, 1002,
974 cm-1; HRMS (ESI) m/z calcd for C24H28O8Na 467.1682, found
467.1675.
Eupomatilone 5 (1e): Method A. Suzuki-Miyaura. Aryl
bromide 46 (17 mg, 0.048 mmol), 3,4-(methylenedioxy)phenylbo-
ronic acid (20.4 mg, 0.096 mmol), Pd2(dba)3 (2.0 mg, 0.002 mmol),
S-Phos (1.6 mg, 0.004 mmol), and finely powdered K3PO4 (30.6
mg, 0.144 mmol) were added to an oven-dried round-bottomed flask
in a glovebox. The reaction vessel was taken out of the glovebox
and flushed with argon. Toluene (2 mL) was added, and the reaction
mixture was warmed at 95 °C for 22 h. The reaction mixture was
cooled to 25 °C and passed through a short pad of Celite, then the
filtrate was diluted with ether (5 mL), washed with water (2 × 5
mL) and saturated aqueous NaCl (2 × 5 mL), dried (Na2SO4), and
concentrated. Purification of the residue by flash chromatography
(silica, 10-20% Et2O/hexane) afforded eupomatilone 5 (1e, 18 mg,
95%) as a colorless oil: 83:17 enantiomeric ratio (chiralpak AD-
RH, i-PrOH/H2O ) 50:50, flowrate ) 0.35 mL/min, injection
volume ) 20 µL, λ ) 254 nm).
2-(Benzo[d][1,3]dioxol-6-yl)-3,4,5-trimethoxybenzaldehyde (57).
2-Bromo-3,4,5-trimethoxybenzaldehyde (33) (200 mg, 0.73 mmol),
3,4-(methylenedioxy)phenylboronic acid (55, 241.3 mg, 1.45
mmol), Pd2(dba)3 (26.6 mg, 0.03 mmol), S-Phos (23.8 mg, 0.06
mmol), and anhydrous K3PO4 (462.8 mg, 2.18 mmol) were added
to an oven-dried conical vial in a glovebox. The vial was taken
out of the glovebox and flushed with argon. Toluene (3 mL) was
added and the conical vial was sealed with a Teflon cap and heated
at 100 °C for 6 h. After cooling to 25 °C, the reaction mixture was
passed through a short pad of Celite (ether wash, 20 mL).
Concentration of the filtrate and purification of the residue by flash
chromatography (silica, 5-10% EtOAc/hexane) afforded 57 (216
mg, 90%): 1H NMR (CDCl3, 500 MHz) 9.70 (s, 1H), 7.34 (s, 1H),
6.89 (d, 1H, J ) 7.88 Hz), 6.85 (s, 1H), 6.74 (d, 1H, J ) 7.84 Hz),
6.05 (s, 2H), 4.00 (s, 3H), 3.96 (s, 3H), 3.65 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 191.3, 153.1, 151.2, 147.6, 147.5, 134.0,
130.0, 126.3, 124.8, 111.3, 107.9, 105.2, 101.3, 61.1 (2C), 56.1,
29.7; IR (film) νmax 2937, 1681, 1587, 1504, 1480, 1461, 1438,
1390, 1325, 1288, 1235, 1197, 1159, 1129, 1083, 1039, 1005, 929,
860, 810, 757 cm-1; HRMS (ESI) m/z calcd for C17H16O6Na
339.0845, found 339.0845.
2-(3,4,5-Trimethoxyphenyl)-3,4,5-trimethoxybenzaldehyde (58).
2-Bromo-3,4,5-trimethoxybenzaldehyde (33) (100 mg, 0.36 mmol),
3,4,5-trimethoxyphenylboronic acid (56, 154.4 mg, 0.73 mmol),
finely powdered K3PO4 (231.8 mg, 1.09 mmol), Pd2(dba)3 (14 mg,
0.015 mmol), and S-Phos (11.9 mg, 0.03 mmol) were added to an
oven-dried conical vial in a glovebox. The vial was taken out of
the glovebox and flushed with argon. Toluene (3 mL) was added
and the conical vial was sealed with a Teflon screw-cap and heated
at 100 °C for 8 h. After cooling to 25 °C, the reaction mixture was
passed through a short pad of Celite (ether wash, 20 mL). The
filtrate was evaporated and the residue was purified by flash
chromatography (silica, 10% EtOAc/hexane) to afford 58 (108 mg,
82%): 1H NMR (CDCl3, 400 MHz) δ 9.69 (s, 1H), 7.35 (s, 1H),
6.54 (s, 2H), 4.01 (s, 3H), 3.96 (s, 3H), 3.92 (s, 3H), 3.86 (s, 6H),
3.69 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 191.3, 153.2, 152.8,
151.1, 147.6, 137.8, 134.3, 129.8, 128.3, 108.4, 105.1, 61.3, 61.1,
61.0, 60.4, 56.3, 56.2, 21.0, 14.2; IR (film) νmax 2940, 1682, 1584,
J. Org. Chem, Vol. 72, No. 23, 2007 8735

Mitra et al.
Method B. Crotylboration. An oven-dried round-bottomed flask
(5 mL) was charged with carbomethoxycrotyl boronate 52 (30.2
mg, 0.082 mmol) in toluene (1.0 mL) under argon. A solution of
biaryl aldehyde 57 (23.4 mg, 0.074 mmol) in toluene (0.75 mL)
was added via a syringe. The reaction mixture was vigorously stirred
at 75 °C for 7 days and then quenched by the addition of water
(2 mL) and diluted with ether (5 mL). The water layer was extracted
with ether (2 × 5 mL). The combined organic extracts were washed
with saturated aqueous NaCl (2 × 5 mL), dried (Na2SO4), and
concentrated. The residue was purified by flash chromatography
(silica, 10-20% Et2O/hexane) to afford eupomatilone 5 (1e, 17
mg, 65%) as a colorless oil: 87:13 enantiomeric ratio (chiralpak
AD-RH, i-PrOH/H2O ) 50:50, flow rate ) 0.35 mL/min, injection
at 85 °C for 8 days. It was quenched by the addition of water (1
mL) and diluted with ether (5 mL). The water layer was extracted
with ether (2 × 2 mL). The combined organic extracts were washed
with saturated aqueous NaCl (2 × 5 mL), dried (Na2SO4), and
concentrated. The residue was purified by chromatography (silica,
10-40% ether/hexane) to afford eupomatilone 1 (1a) (9.2 mg, 32%)
as a colorless oil: 3.3:1 inseparable diastereomeric cis:trans mixture
1a and 60: 1H NMR (CDCl3, 400 MHz) δ 6.56 (s, 1H), 6.44 (d,
1H, J ) 2.0 Hz), 6.33 (d, 1H, J ) 2.0 Hz), 6.25 (d, 1H, J ) 2.8
Hz), 6.00 (s, 2 H), 5.53 (d, 1H, J ) 2.4 Hz), 5.44 (d, 1H, J ) 7.6
Hz), 3.91 (s, 3H), 3.856 (s, 3H), 3.852 (s, 3H), 3.846 (s, 3H), 2.93
(m, 1H), 0.88 (d, 3H, J ) 7.2 Hz); 13C NMR (CDCl3, 100 MHz)
δ 170.1, 153.3, 153.0, 148.8, 140.7, 137.3, 136.6, 131.0, 128.9,
127.4, 121.9, 107.7, 106.7, 101.4, 100.8, 79.3, 60.9, 60.0, 56.2,
56.1, 29.7, 22.7, 14.1; IR (thin film) νmax 2922, 2851, 2361, 2340,
1764, 1581, 1464, 1410, 1237, 1127, 1089, 1055, 974 cm-1; HRMS
(ESI) m/z calcd for C23H24O8Na 451.1369, found 451.1366;
enantiomeric ratio, er 94:6 for the cis-isomer, er 8:1 for trans isomer
[Chiralpak-AD-RH column; λ ) 254 nm; flow rate ) 0.25 mL/
min; injection volume ) 20 µL; i-PrOH:H2O ) 50:50].
1
volume ) 20 µL, λ ) 254 nm); H NMR (CDCl3, 500 MHz) δ
6.88 (d, 2H, J ) 8 Hz), 6.73 (dd, 2H, J ) 5.6, 1.6 Hz), 6.69 (s,
2H), 6.65 (d, 1H, J ) 1.2 Hz), 6.60 (dd, 1H, J ) 8.0, 1.2 Hz), 6.24
(d, 2H, J ) 2 Hz), 6.03 (ABq, 4H, J ) 1.0 Hz, ∆ν ) 8.7 Hz), 5.54
(d, 3H, J ) 7.2 Hz), 5.45 (d, 1H, J ) 7.2 Hz), 3.91 (s, 6H), 3.88
(s, 6H), 3.66 (s, 3H), 3.65 (s, 3H), 2.87 (dq, 2H, J ) 5.0, 2.5 Hz),
0.83 (d, 3H, J ) 7.6 Hz), 0.80 (d, 3H, J ) 7.6 Hz); 13C NMR
(CDCl3, 125 MHz) δ 170.2, 152.9, 151.5, 147.7, 147.1, 141.9,
141.2, 130.1, 129.0, 127.2, 123.4, 122.8, 122.0, 110.6, 110.0, 108.6,
108.2, 104.8, 101.2, 79.4, 61.2, 60.9, 56.2, 38.4, 38.2, 17.3, 17.1;
IR (film) νmax 2929, 2853, 2253, 1766, 1598, 1482, 1459, 1403,
1362, 1325, 1266, 1236, 1196, 1156, 1128, 1089, 1038, 1002, 971,
936, 912, 811, 733 cm-1; HRMS (ESI) m/z calcd for C22H22O7Na
421.1263, found 421.1265.
Acknowledgment. This work was supported by a grant from
the National Cancer Institute (NIH R01 CA91904). S.M. thanks
Dr. Dennis Bong (Ohio State University) for helpful discussions.
Supporting Information Available: Experimental procedures
and copies of 1H and 13C NMR spectra of intermediates and
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
Eupomatilone 1. An oven-dried round-bottomed flask (5 mL)
was charged with carbomethoxycrotyl boronate 52 (27 mg, 0.073
mmol) in toluene (0.5 mL) under argon. A solution of biaryl
aldehyde 59 (23 mg, 0.067 mmol) in toluene (1 mL) was added
via a syringe. The resulting reaction mixture was vigorously stirred
JO701415M
8736 J. Org. Chem., Vol. 72, No. 23, 2007