Development of a bio-inspired acyl-anion equivalent macrocyclization and synthesis of a trans-resorcylide precursor

Article abstract of DOI:10.1021/jo070676d

(Chemical Equation Presented) Studies on the macrocyclization of α,ω-dialdehydes have revealed a strong dependence on ring size with respect to the ultimate efficiency of the reaction. Strong catalyst dependence was observed, as thiazolium salts led to no detectable product formation, whereas electron-deficient triazolium salts served as precatalysts for the cyclization. Surprisingly, the N-pentafluorophenyl triazolium variant led to cyclization at room temperature within a short 90-min reaction time. These findings were applied to a range of substrates, including the synthesis of a key intermediate in a rapid synthesis of trans-resorcylide.

Full text of DOI:10.1021/jo070676d

Development of a Bio-Inspired Acyl-Anion Equivalent
Macrocyclization and Synthesis of a trans-Resorcylide Precursor
Steven M. Mennen and Scott J. Miller*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill,
Massachusetts 02467-3860, and Department of Chemistry, Yale UniVersity, P.O. Box 208107,
New HaVen, Connecticut 06520-8107
scott.miller@yale.edu
ReceiVed April 2, 2007
Studies on the macrocyclization of R,ω-dialdehydes have revealed a strong dependence on ring size with
respect to the ultimate efficiency of the reaction. Strong catalyst dependence was observed, as thiazolium
salts led to no detectable product formation, whereas electron-deficient triazolium salts served as
precatalysts for the cyclization. Surprisingly, the N-pentafluorophenyl triazolium variant led to cyclization
at room temperature within a short 90-min reaction time. These findings were applied to a range of
substrates, including the synthesis of a key intermediate in a rapid synthesis of trans-resorcylide.
CHART 1. Umpolung Catalysts
Introduction
The ability to access “umpolung” reactivity through the use
of catalysts has resulted in a resurgence of interest in chemistry
that proceeds through formal acyl-anion equivalents. With a rich
foundation in the classical mechanistic work of Breslow,1
synthetic catalysts that mimic the chemistry of the cofactor
thiamine diphosphate have led to the introduction of a range of
new synthetic transformations. Furthermore, striking examples
of asymmetric catalysis based on chiral heterozolium ylids
(Chart 1) have also been documented,2 establishing the basis
for a thriving and fast-moving subdiscipline in the area of
asymmetric catalysis. Highlights in the area have included
remarkable demonstrations of asymmetric Benzoin chemistry,3
Stetter cyclizations,4 syntheses through formal homoenolate,5
cyclizations through formal Diels-Alder reactions,6 nucleophilic
acylation,7 and an impressive array of heterozolium-based redox
processes.8
Within the subset of reactions based on benzoin reactions,
the cyclization of dialdehydes is particularly intriguing. Our own
interest in this area was stimulated by the existence of natural
(1) Breslow, R. J. Am. Chem. Soc. 1958, 60, 699-702.
(2) (a) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534-541.
(b) Zeitler, K. Angew. Chem., Int. Ed. 2005, 44, 7506-7510. (c) Johnson,
J. S. Angew. Chem., Int. Ed. 2004, 43, 1326-1328. (d) Marion, N.; D´ıez-
Gonza´lez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988-3000.
(e) Enders, D.; Balensiefer, T.; Niemeier, O.; Christmann, M. In Enanti-
oselectiVe Organocatalysis: Reactions and Experimental Procedures; Dalko,
P. I., Ed.; Wiley-VCH: Weinheim, 2007; pp 331-335.
(3) (a) Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743-
1745. (b) Enders, D.; Niemeier, O.; Balensiefer, T. Angew. Chem., Int. Ed.
2006, 45, 1463-1467. (c) Hachisu, Y.; Bode, J. W.; Suzuki, K.; J. Am.
Chem. Soc. 2003, 125, 8432-8433. (d) Takikawa, H.; Hachisu, Y.; Bode,
J. W.; Suzuki, K.; Angew. Chem., Int. Ed. 2006, 45, 3492-3494. (e) Linghu,
X.; Bausch, C. C.; Johnson, J. S. J. Am. Chem. Soc. 2006, 127, 1833-
1840.
10.1021/jo070676d CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/19/2007
5260
J. Org. Chem. 2007, 72, 5260-5269

Bio-Inspired Acyl-Anion EquiValent Macrocyclization
SCHEME 1. Synthesis of Acyloin Standards
CHART 2. Naturally Occurring Regioisomeric Acyloins
kinetic control via thiamine diphosphate-catalyzed retro-acyloin/
acyloin formation via an intermediate dialdehyde? Such a
mechanism would require an as-of-yet unreported macrocy-
clizations of dialdehydes via the acyloin mechanism. Moreover,
could acyloin-containing natural products undergo catalyst-
dependent reorganization upon exposure to synthetic catalysts
(or enzymes)? We examined model studies to see the likelihood
of the above mechanistic pathways. In a sense, since the catalytic
apparatus for acyloin chemistry is present in the milieu of
biosynthesis (and manifested in thiamine diphosphate-dependent
enzymes), we embarked upon the study of a potential biosyn-
thetically significant reaction.
products containing the “acyloin” substructure (i.e., an R-hy-
droxyketone). Among these, examples such as amphidinolide
T1 and T3 include representatives that constitute either of two
regioisomers (Chart 2). Could the existence of either regioisomer
in nature stem from (a) acid- or base-mediated interconversion
via an enediol structure or (b) retrocyclization-cyclization under
Results and Discussion
Our studies began with the synthesis of macrocycles 6 and 7
withthehypothesisthatinterconversionwouldproceedtoathermo-
dynamically favored benzylic ketone (7). The synthesis of key
macrolide regioisomers was accomplished in six straightforward
synthetic steps from commercially available 3-(2-bromophenyl)-
propionic acid (1, Scheme 1). The vinyl group was installed
with a Suzuki reaction,9 and saponification of the methyl ester
and esterification with 7-octene-1-ol afforded diene 4. Ring-
closing metathesis followed by ketohydroxylation with acidic
KMnO4 afforded a 1:1 mixture of separable acyloins 6 and 7.10
In our initial attempts to observe a catalyst-mediated inter-
conversion between regioisomers, we subjected both regioiso-
mers to a solution of either 1,2,2,6,6-pentamethylpiperidine
(PEMP) or thiazolium salt 8 and PEMP in a 1:1 mixture of
methanol/methylene chloride. Heating a solution of thiazolium
salt 8 and regioisomer 7 in a sealed tube at 60 °C for 16 h
allowed for 57% interconversion to regioisomer 6, whereas
heating PEMP and 7 allowed for 30% interconversion (Figure
1). Most surprisingly, we observed that the benzylic ketone
appeared to be the less stable isomer in this interconversion,
contrary to our hypothesis.
(4) (a) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. HelV. Chim. Acta
1996, 79, 1899-1902. (b) Kerr, M. S.; de Alaniz, J. R.; Rovis, T. J. Am.
Chem. Soc. 2002, 124, 10298-10299. (c) Mennen, S. M.; Blank, J. T.;
Tran-Dube´, M. B.; Imbriglio, J. E.; Miller, S. J. Chem. Commun. 2005,
195-197. (d) Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am.
Chem. Soc. 2004, 126, 2314-2315. (e) Matsumoto, Y.; Tomioka, K.
Tetrahedron Lett. 2006, 47, 5843-5846.
(5) (a) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004,
126, 14370-14371. (b) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed.
2004, 43, 6205-6208. (c) He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131-
3134. (d) Nair, V.; Vellalath, S.; Poonoth, M.; Suresh, E. J. Am. Chem.
Soc. 2006, 128, 8736-8737. (e) Nair, V.; Vellalath, S.; Poonoth, M.; Mohan,
R.; Suresh, E. Org. Lett. 2006, 8, 507-509.
(6) (a) He, M.; Struble, J. R.; Bode, J. J. Am. Chem. Soc. 2006, 128,
8418-8420. (b) He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006,
128, 15088-15089.
(7) (a) Mennen, S. M.; Gipson, J. D.; Kim, Y. R.; Miller, S. J. J. Am.
Chem. Soc. 2005, 127, 1654-1655. For examples of alkylation of umploung
nucleophiles, see: (b) Fischer, C.; Smith, S. W.; Powell, D. A.; Fu, G. C.
J. Am. Chem. Soc. 2006, 128, 1472-1473. (c) He, J.; Zheng, J.; Liu, J.;
She, X.; Pan, X. Org. Lett. 2006, 8, 4637-4640. For examples of acylation/
transesterification, see: (d) Movassaghi, M.; Schmidt, M. Org. Lett. 2005,
7, 2453-2456. (e) Thompson, J. E.; Rix, K.; Smith, A. D. Org. Lett. 2006,
8, 3785-3788. For examples of azirididine opening, see: (f) Liu, Y.-K.;
Li, R.; Yue, L.; Li, B.-J.; Chen, Y.-C.; Wu, Y.; Ding, L.-S. Org. Lett. 2006,
8, 1521-1544. (g) Sun, X.; Ye, S.; Wu, J. Eur. J. Org. Chem. 2006, 4787-
4790. (h) Wu, J.; Sun, X.; Ye, S.; Sun, W. Tetrahedron Lett. 2006, 4813-
4816.
Since we observed interconversion in the control reaction,
as well as in the reaction containing a thiazolium catalyst, we
(8) (a) Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126-
8127. (b) Reynolds, N. T.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc.
2004, 126, 9518-9519. (c) Reynolds, N. T.; Rovis, T. J. Am. Chem. Soc.
2005, 127, 16406-16407. (d) Zeitler, K. Org. Lett. 2006, 8, 637-640. (e)
Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905-908. (f) Chan, A.; Scheidt,
K. A. J. Am. Chem. Soc. 2006, 128, 4558-4559.
(9) Kerins, F.; O’Shea, D. F. J. Org. Chem. 2002, 67, 4968-4971.
(10) (a) For a streamlined strategy, see: Scholte, A. A.; An, M. H.;
Snapper, M. L. Org. Lett. 2006, 8, 4759-4762. (b) Scholl, S.; Ding, S.;
Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953. For recent reviews, see:
(c) Fuerstner, A. Angew. Chem. Int Ed. 2000, 39, 312. (d) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
J. Org. Chem, Vol. 72, No. 14, 2007 5261

Mennen and Miller
FIGURE 1. Interconversion of macrocyclic acyloins.
TABLE 1. Initial Development of a Macrocyclization Reaction
a Reaction was performed in toluene.
could not discount the possibility of interconversion through
an enediol mechanism. However, we did observe trace aldehyde
in the crude 1H NMR of the reaction mixture. The presence of
an aldehyde could be the result of our proposed retro-benzoin
reaction (Figure 1) or the product of a base-mediated acyloin
rearrangement.11 Intrigued by the former possibility, we wanted
to validate the possibility that our proposed dialdehyde inter-
mediate (9) could indeed be cyclized to macrolide 6.
The development of an N-heterocyclic carbene (NHC)-
mediated macrocyclization began with the examination of
different solvent systems, using DBU to deprotonate the
precatalyst salt. When reactions were performed in toluene or
tetrahydrofuran, no products were observed. In a mixture of
methylene chloride and tert-butanol,12 we observed macrolide
6 by thin layer chromatography when using triazolium catalyst
11 (Table 1, entry 3). Encouraged by this empirical observation,
we suspected that, as with many macrocyclization reactions,
an increase in the reaction temperature might lead to a more
efficient reaction. Heating a 2.5:1 mixture of methylene chloride/
tert-butanol to reflux for 20 h allowed for macrolide 6 to be
isolated in 21% yield as the sole regioisomer (entry 4). With
potassium tert-butoxide, triazolium salt 11 provided 16% yield
(entry 5), whereas lithium hexamethyldisilazide at 56 °C in
toluene afforded a 9% yield of 6 (entry 6). Diluting a 2.5:1
mixture of methylene chloride/tert-butanol from 0.01 to 0.0025
M and utilizing DBU provided 6 in 30% yield after a 36 h
reaction time (entry 7).
Different ring systems affected the cyclization. When the loca-
tion of the ester was moved, as in benzoate 9b, no desired prod-
uct was observable under our macrocyclization conditions (eq
1). Independent synthesis of 6b ensured that this compound was
stable toward isolation. We suspected that the proximity of the
aldehyde and the benzoate could induce a triazolium-mediated
Cannizzaro reduction of the benzoate. Recent and fascinating
studies in the literature have documented similar behavior that
(11) Gelin, S.; Gelin, R. J. Org. Chem. 1979, 44, 808-810.
(12) Using tert-butanol as a solvent has proven successful for the
development of intramolecular ketone Benzoin reactions; see: (a) Hachisu,
Y.; Bode, J. W.; Suzuki, K. J. Am. Chem. Soc. 2003, 125, 8432-8433. (b)
Enders, D.; Niemeier, O. Synlett 2004, 2111-2114.
5262 J. Org. Chem., Vol. 72, No. 14, 2007

Bio-Inspired Acyl-Anion EquiValent Macrocyclization
supports the possibility of an intramolecular reduction (eq 2).8f
We speculated that the incorporation of an electron-withdrawing
group on the triazolium salt would lower the basicity of the
NHC and serve to bypass this nonproductive pathway.
TABLE 2. Influence of Concentration and Base
entry
base
DBU
DBU
DBU
DBU
DBU
DBU
time (min) temp (°C) conc (µM)
yield (%)
1
2
3
4
5
6
7
8
9
17
25
30
90
45
90
30
30
30
22
0
250
250
250
250
100
50
250
250
250
39
31
33
-10
-15
22
22
0
21
42a
48a
t-BuMgBr
KHMDS
PEMP
decomposition
starting material
26
0
0
1
a Conversion by H NMR based on internal bromoform standard.
When precatalyst 1613 was allowed to react at reflux for 40
h in a 2.5:1 mixture of methylene chloride/tert-butanol, our
desired product was produced in 34% yield (eq 3). Given our
previous results in acyloin equilibration, we moved to examine
if the product formed would be stable to the reaction conditions
under which it was formed. By resubjecting macrolide 6 to a
refluxing solution of triazolium and DBU for 20 h in a 2.5:1
mixture of methylene chloride/tert-butanol, 6 was recovered in
30% yield (eq 4). We postulated that the refluxing temperatures
might contribute to product degradation and that pentafluo-
rophenyl triazolium precatalyst 16 would allow for cyclization
at lower temperatures.
FIGURE 2. Product stability.
Mass Balance and Product Stability Studies. By using the
more reactive pentafluorophenyl triazolium salt, we were able
to execute the macrocyclization at ambient temperature. Our
previous experiments demonstrated that the product of the
reaction is slowly decomposed upon extended exposure to the
reaction conditions; therefore, under milder conditions, we were
hopeful that this undesirable pathway would be prevented. By
resubjecting macrolide 6 to a 50 µM solution of pentafluo-
rophenyl triazolium precatalyst 16 and DBU for 90 min, we
were able to reisolate only 47% of our starting macrolide along
with 40% of a material that has mass spectrum signals indicating
one or more dimeric products (Figure 2).
Thin layer chromatography of the macrocyclization reaction
shows clean conversion from dialdehyde 9 to macrolide 6 along
with baseline material. Although DBU‚HBF4 and triazolium
NHC are expected to reside on the baseline, flushing the silica
gel column with increasingly polar solvents allows for the
isolation of a complex mixture of at least six products, which,
by mass spectrometry analysis, indicates possible variable
Surprisingly, at 22 °C pentafluorophenyl triazolium catalyst
16 cyclized dialdehyde 9 in only 17 min, providing 6 in 39%
yield (Table 2, entry 1). At 0 °C, 6 was isolated in 31% yield
after 25 min (entry 2). Further lowering the temperature to -10
°C allowed for 33% yield in 30 min (entry 3). At -15 °C, a
21% yield was obtained after 90 min (entry 4). Concentration
played a key role in the efficiency of the reaction (entries 1, 5,
and 6). Use of tert-butyl magnesium bromide as our base
completely decomposed the starting material, potassium hex-
amethyldisilazide provided only recovered starting material, and
PEMP produced the desired product in 26% yield (entries 7-9).
1
dimeric materials. H NMR analysis of the isolable baseline
compounds indicates the presence of the aliphatic chain as well
as aromatic functionality present in the starting material. Because
of the complexity, no definite assignments of the baseline
mixture could be made, but the two experiments show that the
products are being consumed by the reaction conditions under
which they are formed and that it is likely this is occurring by
dimerization processes (cross-benzoin, aldol, aldol-dehydration,
Cannizzaro reduction, acyloin rearrangement, etc.). Nonetheless,
we are pleased to document facile macrocyclization under NHC
conditions. These experiments have established this approach
(13) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Org. Chem. 2005, 70,
5725-5728.
J. Org. Chem, Vol. 72, No. 14, 2007 5263

Mennen and Miller
observed. Heating the reaction containing only DBU to reflux
did, however, allow for 33% interconversion of 7 to 6 in 30
min (eq 6). Since the macrocyclization reaction is performed
at ambient temperature, the lack of interconversion under the
reaction conditions led us to conclude that 6 is the kinetic
product. Additionally, on the basis of the slow interconversion
with DBU, presumably via the enediol (19), we found that 6 is
also more stable than 7.
The experimental observations reported above indicate that
the productive acyl-anion formation occurs at the aliphatic
aldehyde, not the aromatic aldehyde. We decided to design an
experiment in which we could examine two possible contribut-
ing factors: the conformational constraints for the macrocy-
clization and the steric hindrance of the ortho-substituted
benzaldehyde. Reaction of hexanal and ortho-tolualdehyde under
the macrocyclization conditions afforded 22 as the only isolable
compound after silica gel chromatography (eq 7). The cross-
coupling of benzaldehyde and hexanal shows that, in the absence
of an ortho substituent, a mixture of 24/25/26 in a 1:4:3 ratio is
isolated (eq 8). These results indicate that sterics may preclude
triazolium catalyst 16 from generation of the acyl-anion at the
ortho-substituted benzaldehyde. We cannot exclude the pos-
sibility that the conformational constraints are also an additive
effect, especially considering the data that suggest that 6 is more
stable than 7.
FIGURE 3. Possible mechanisms for the interconversion of 7 to 6.
(Enamine double bond geometries for 17 and 18 are not known. An
arbitrary configuration is drawn for clarity.)
as a potential disconnection in chemical synthesis and a possible
process in biosynthesis.
Interconversion and Selectivity Studies. The exclusive
regioselectivity in the macrocyclization led us to question
whether the selectivity was dictated by thermodynamic or kinetic
control and the possible underlying factors that influence the
selectivity. As with our preliminary studies, we hypothesized
two possible scenarios for the interconversion: first, NHC-
mediated retro-benzoin reaction, followed by catalyst dissocia-
tion and thermodynamically controlled macrocyclization (Figure
3, Path A) and second, enolization to enediol (19) followed by
protonation (Path B).
Subjection of 7 to a mixture of triazolium salt 16 and DBU
in methylene chloride at room temperature for 30 min allowed
for the recovery of 7. Under otherwise identical conditions,
heating to reflux for 30 min allowed for trace conversion to 6
(<1%) as determined by 1H NMR (eq 5). When 7 was allowed
to react with only DBU for 30 min, 5% interconversion was
r-Phenylketone Stereoelectronic Effect. Our interconver-
sion studies supported that regioisomer 6 is more stable than 7
and that the steric effect of the ortho substituent is, to some
degree, responsible for the product distribution. Nevertheless,
we were still curious why the benzylic carbonyl (7) was less
favored. Independent synthesis demonstrated the benzylic car-
bonyl (7) is isolable, indicating that there is not a conformational
restriction preventing the formation of 7. We speculated that
benzylic ketone 7 may contain an inherent entropic penalty
resulting from conjugation that would not be present in benzylic
alcohol 6. A less obvious possibility was the potential existence
of a subtle stereoelectronic effect that may be stabilizing 6.
R-Phenylcarbonyl compounds are believed to possess a
stabilizing interaction wherein the π face of the carbonyl and
the π face of the aryl ring are orthogonally aligned (I, Figure
4).14-17 This interaction can be observed by UV-vis spectros-
copy by the presence of a band at 290 nm which displays an
unusually high extinction coefficient (ꢀ g 100). Kumler and
co-workers have studied numerous R-phenylcarbonyl com-
pounds, and they have suggested that this particular stereoelec-
tronic effect is on the order of magnitude of 3-5 kcal.15
Cookson and co-workers later proposed that the π-orbitals of
the carbonyl and the π-system were directed approximately
toward each other.16 This interaction is not observable with
2-phenylcyclohexanone (27), indicating that the interaction is
5264 J. Org. Chem., Vol. 72, No. 14, 2007

Bio-Inspired Acyl-Anion EquiValent Macrocyclization
FIGURE 4. Examples of an R-phenylketone stereoelectronic effect.
not strong enough to overcome the equatorial preference of a
phenyl group. However, when a phenyl group is fixed in the
axial position, as in 2,2-diphenylcyclohexanone (28), the ap-
propriate geometry is readily achieved.16 A particularly note-
worthy example is the high extinction coefficient observed with
2-methyl-2-phenylcyclohexanone (29).17 The phenyl group
would be predicted to preferentially adopt an equatorial
geometry; however, an almost 1:1 mixture of the axial vs
equatorial phenyl is observed.
Analysis of our 12-membered macrocycle 6d by single-crystal
X-ray analysis provides an alluring depiction of this R-phenyl-
carbonyl stereoelectronic effect (Figure 5). Macrolide 6d
disposes the plane of the carbonyl and the face of the aryl ring
in an orthogonal arrangement in agreement with Cookson et
al.’s proposal. Additionally, X-ray analysis indicates that the
acyloin is involved in a hydrogen-bonding arrangement. The
hydrogen bond may lower the carbonyl LUMO and serve to
enhance the R-phenylcarbonyl stereoelectronic effect. This
analysis suggests that an intriguing R-phenylcarbonyl stereo-
electronic effect could be at the heart of our observed macro-
cyclization regiochemistry.
FIGURE 5. X-ray analysis of an R-phenylketone stereoelectronic
effect.
1-4). Remote stereocenters (entries 5 and 6) helped the
cyclization, affording 6f and 6g in 42 and 47% yield, respec-
tively. Of particular interest was the cyclization of compound
9b. During our initial examination with catalyst 11, carboxy-
benzaldehyde derivative 9b afforded no conversion to our
desired product. We reasoned that the more basic carbene may
promote an intramolecular Cannizzaro reduction and that
reducing the basicity of the carbene by employing pentafluo-
rophenyl triazolium salt 16 would minimize this pathway.
Indeed, the solution to our hypothesis allowed for 9b to be
cyclized under the macrocyclization conditions to afford mac-
rolide 6b (entry 7). This exciting result ultimately served as
the springboard toward applying this methodology in a synthesis
of the natural product trans-resorcylide.
Synthesis of trans-Resorcylide. trans-Resorcylide is a 12-
membered macrocycle belonging to a family of naturally
occurring benzoic acid-derived macrolide plant growth inhibitors
isolated from the species Penicillium sp.18 This family of natural
products19 has received attention from the laboratories of
Danishefsky,20 De Brabander,21 Fu¨rstner,22 Porco,23 Snider,24
Tsuji,25 as well as Couladouros,26 who recently completed the
first total synthesis of both cis- and trans-resorcylide. Our
acyloin synthetic disconnection affords a direct opportunity to
test the possibility of using in situ acyl-anion equivalents as a
Macrocyclization Substrate Scope. An examination of the
scope of this macrocyclization provided valuable data on the
current limits of this methodology. The 14-membered ring (6)
served as the starting point for this analysis. As shown in Table
3, entry 1, reducing the concentration to 50 µM allowed for the
product to be isolated in 43% yield in only 90 min. The yield
of the macrocyclization reaction decreased as the ring size
decreased, presumably as a result of greater ring strain (entries
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2311. (b) Birnbaum, H.; Cookson, R. C.; Lewin, N. J. Chem. Soc. 1961,
1224-1228.
(17) (a) Colard, P.; Elphimoff-Felkin, I.; Verrier, M. Bull. Soc. Chim.
Fr. 1961, 516-520. (b) Elphimoff-Felkin, I.; Verrier, M. Bull. Soc. Chim.
Fr. 1967, 1047-1052.
(23) Wang, X.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 6040-
6041.
(24) Snider, B. B.; Song, F. Org. Lett. 2001, 3, 1817-1820.
(25) Takahashi, T.; Minami, I.; Tsuji, J. Tetrahedron Lett. 1981, 22,
2651-2654.
J. Org. Chem, Vol. 72, No. 14, 2007 5265

Mennen and Miller
TABLE 3. Substrate Scope
a Reactions were conducted at a concentration of 50 µM in CH2Cl2 under an argon atmosphere at 22 °C for 90 min and employed 1 equiv of 16 and 2
equiv of DBU. b Yield refers to the mass isolated after silica gel chromatography. c Diastereomeric mixtures were deoxygenated for characterization.
scribed by Tsuji and Mandai.28 Coupling of the congested o,o-
disubstituted chlorobenzoic acid 35 to secondary alcohol 33 was
accomplished by a Mitsunobu protocol to provide chloroacetate
38 in 60% yield (Scheme 2).26 After experimenting with several
modifications of the Kornblum oxidation,29 we found that by
allowing 38 to react with silver(I) tosylate, followed by the
addition of 10 equiv of tri-n-propylamine (BP ) 156 °C) and
heating to 110 °C in dimethylsulfoxide for 2 h we could isolate
aldehyde 39 in 44% yield. However, subjecting 39 to several
hydrolysis conditions hydrolyzed the benzoate within 30 min.
Suspecting that the electron-withdrawing benzaldehyde was
activating the benzoate (vinylogous glyoxylate) toward hydroly-
sis, we speculated that changing the order of steps would allow
access to the desired dialdehyde (Scheme 3). Hydrolyzing
chloroacetate 38 with K2CO3 at 0 °C for 2 h (81% yield)
followed by isolation and immediate oxidation with Dess-
Martin periodinane (DMP) provided R,â-unsaturated aldehyde
42 in 83% yield. Kornblum oxidation with silver(I) tosylate
followed by the addition of 10 equiv of tri-n-propylamine and
heating to 110 °C in dimethylsulfoxide for 2 h allowed for the
isolation of dialdehyde 32 in 16% yield. The Kornblum
procedure produced an extremely complex mixture of com-
FIGURE 6. Retrosynthetic analysis of trans-resorcylide.
novel method for macrocyclization in natural product synthesis,
as depicted in Figure 6.
Synthesis of Dialdehyde 32. The synthesis of benzoic acid
34 was accomplished as described by Couladouros and co-
workers.26,27 Alcohol 33 was synthesized from commercially
available alcohol 37 by acylation with acetic anhydride (Ac2O),
followed by Wacker oxidation and NaBH4 reduction as de-
(28) Tsuji, J.; Mandai, T. Tetrahedron Lett. 1978, 19, 1817-1820.
(29) (a) Kornblum, N.; Powers, J. W.; Anderson, G. J.; Jones, W. J.;
Larson, H. O.; Levand, O.; Weaver, W. M. J. Am. Chem. Soc. 1957, 79,
6562. (b) Kornblum, N.; Jones, W. J.; Anderson, G. J. J. Am. Chem. Soc.
1959, 81, 4113-4114.
(26) Couladouros, E. A.; Mihou, A.; Bouzas, E. A. Org. Lett. 2004, 6,
977-980.
(27) Venkatachalam, T. K.; Huang, H.; Yu, G.; Uckun, F. M. Synth.
Commun. 2004, 34, 1489-1497.
5266 J. Org. Chem., Vol. 72, No. 14, 2007

Bio-Inspired Acyl-Anion EquiValent Macrocyclization
SCHEME 2. Synthesis of trans-Resorcylide
compound was poised for the crucial macrocyclization, and our
optimized conditions for macrocyclization afforded 43 as an
inconsequential mixture of diastereomers in 21% yield. Acyl-
ation of the acyloin followed by immediate deoxygenation with
SmI2 provided 44 in 51% yield.31 Sulfide 44 was oxidized with
meta-chloroperoxybenzoic acid (m-CPBA) to the sulfone (76%
yield), which was immediately eliminated with DBU to afford
trans-dibenzylresorcylide (45) in 88% yield. Compound 45 was
converted to trans-resorcylide by Couladouros et al.,26 and thus,
the present route constitutes a formal synthesis of trans-
resorcylide.
Conclusions
In summary, stimulated by ruminations about biosynthetic
possibilities for natural products containing the acyloin sub-
structure, we have explored the utility of N-heterocyclic carbene
catalysts for the macrocyclization of R,ω-dienes. In the process,
we have discovered a remarkably fast cyclization protocol for
several large rings, including one of relevance to the synthesis
of trans-resorcylide. While reaction yields are modest in many
cases, it appears that this drawback may be due to product
stability, rather than inherent limitations associated with the
catalytic cyclization strategy. Moreover, we find that there are
striking issues of macrocycle structure that dictate thermody-
namic stability of products and kinetic facility of ring formation
of various regioisomers. The plausibility of thiamine diphosphate
participation in the biosynthesis of acyloin-containing natural
products remains to be determined. Yet, it appears that specula-
tion about biosynthesis, in terms of both biosynthesis pathways
and the potential role of various enzymes and cofactors, remains
a fruitful avenue for the conception of intriguing new synthetic
chemistry and for the discovery of unanticipated chemical
behavior.
SCHEME 3. Synthesis of trans-Resorcylide Precursor
Experimental Section
General Procedure for Macrocyclization. Preparation of
Acyloin 6. To a 1-L Schlenk flask was added methylene chloride
(500 mL) directly from a Seca Solvent System under an atmosphere
of argon. Dialdehyde 9 (80.9 mg, 0.279 mmol) in CH2Cl2 (30 mL)
was added by cannula, followed by the addition of DBU (0.083
mL, 0.558 mmol). Then, a vigorously stirred suspension of
pentafluorophenyl triazolium salt 16 (101 mg, 0.279 mmol) in
CH2Cl2 (25 mL) was added by cannula over 10 min. The reaction
was stirred at 22 °C for 90 min, at which time the reaction turned
from a colorless solution to a resilient yellow solution. At 90 min,
the contents of the reaction vessel were filtered through a plug of
silica gel (100 cm3) followed by eluting the plug with 400 mL of
EtOAc. The filtrate was concentrated under reduced pressure to
yield crude 6, which was purified by silica gel chromatography
(12% EtOAc/hexane, 35.1 mg, 43% yield). 1H NMR (CDCl3, 500
MHz): δ 7.32-7.22 (m, 4H), 5.32 (d, J ) 3.6 Hz, 1H), 4.07 (m,
1H), 3.95 (m, 1H), 3.35 (m, 1H), 3.00-2.77 (m, 3H), 2.52 (m,
1H), 2.27 (dt, J ) 16.0 Hz, J ) 2.3 Hz, 1H), 1.62 (p, J ) 6.9 Hz,
1H), 1.49-1.40 (m, 2H), 1.33 (m, 1H), 1.23-1.12 (m, 2H), 1.05-
0.99 (m, 2H); 13C NMR (CDCl3, 125 MHz): δ 209.9, 172.3, 138.5,
135.1, 129.6, 128.9, 127.3, 126.6, 78.9, 64.7, 36.2, 32.9, 26.5, 26.3,
25.9, 23.7, 22.1; IR (film, cm-1): 3454, 2934, 2862, 1726; TLC
Rf 0.29 (25% EtOAc/hexane); HRMS [C17H22O4 + Na] requires
m/z 313.1416. Found 313.1411 (ESI).
pounds, which made isolation of pure dialdehyde exceedingly
difficult. Thus, substituting the Kornblum oxidation with a
modification known as the Ganem oxidation30 (i.e., a tertiary
amine-N-oxide is the oxidant) provided an operationally more
appealing protocol. Oxidation of benzylic chloride 32 with 5
equiv of N-methylmorpholine-N-oxide in a solution of dimeth-
ylsulfoxide at 50 °C for 1 h allowed for the smooth isolation of
dialdehyde 32 in 32% yield.
The R,â-unsaturated aldehyde was first converted to the
â-thioether to prevent homoenolate formation.5 Subjection of
R,â-unsaturated aldehyde 32 to benzenethiol with catalytic
triethylamine afforded the â-thioether in 78% yield. This
Preparation of Acyloin 6c. Acyloin 6c was prepared in a manner
analogous to that described for acyloin 6, employing dialdehyde
9c (62.7 mg, 0.227 mmol), pentafluorophenyl triazolium salt 16
(30) (a) Godfrey, A.; Ganem, B. Tetrahedron Lett. 1990, 31, 4825-
4826. (b) Griffith, W. P.; Jolliffe, J. M.; Ley, S. V.; Springhorn, K. F.;
Tiffin, P. D. Synth. Commun. 1992, 22, 1967.
(31) Molander, G.; Hahn, G. J. Org. Chem. 1986, 51, 1135-1138.
J. Org. Chem, Vol. 72, No. 14, 2007 5267

Mennen and Miller
(82.4 mg, 0.227 mmol), DBU (68 µL, 0.454 mmol), and CH2Cl2
(454 mL), which afforded acyloin 6c, which was purified by silica
gel chromatography (12% EtOAc/hexane, 21.9 mg, 35% yield).
1H NMR (CDCl3, 500 MHz): δ 7.36-7.30 (m, 2H), 7.23 (t, J )
7.6 Hz, 1H), 7.18 (d, J ) 6.3 Hz, 1H), 5.27 (d, J ) 2.6 Hz, 1H),
4.23 (d, J ) 3.2 Hz, 1H), 4.12 (m, 1H), 3.79 (dt, J ) 9.1 Hz, J )
2.2 Hz, 1H), 3.25 (m, 1H), 2.95 (m, 1H), 2.89-2.82 (m, 2H), 2.58
(m, 1H), 2.22 (m, 1H), 1.54-1.47 (m, 2H), 1.45-1.37 (m, 2H),
1.33-1.25 (m, 2H); 13C NMR (CDCl3, 125 MHz): δ 210.8, 171.8,
138.0, 135.8, 130.0, 129.0, 127.0, 126.7, 79.2, 64.3, 36.4, 32.6,
26.0, 25.5, 24.7, 22.5; IR (film, cm-1): 3453, 2952, 2925, 2854,
1730, 1717, 1256; TLC Rf 0.20 (25% EtOAc/hexane); HRMS
[C16H20O4 + Na] requires m/z 299.1259. Found 299.1262 (ESI).
MHz): δ 7.33 (d, J ) 7.6 Hz, 1H), 7.28 (t, J ) 6.9 Hz, 1H), 7.19
(t, J ) 7.2 Hz, 1H), 7.05 (d, J ) 7.6 Hz, 1H), 4.74 (m, 1H), 3.89
(d, J ) 16.4 Hz, 1H), 3.50 (d, J ) 16.4 Hz, 1H), 3.04 (m, 1H),
2.87-2.73 (m, 3H), 2.36 (m, 1H), 2.25 (m, 1H), 1.83-1.75 (m,
2H), 1.46 (m, 2H), 1.13 (d, J ) 6.3 Hz, 3H); 13C NMR (CDCl3,
125 MHz): δ 209.5, 171.6, 138.2, 133.4, 131.2, 128.4, 127.8, 126.7,
72.3, 48.8, 39.1, 35.6, 32.2, 26.1, 20.4, 20.1; IR (film, cm-1): 2974,
2929, 2852, 1724, 1716, 1255; TLC Rf 0.45 (25% EtOAc/hexane);
HRMS [C16H21O3 + H] requires m/z 261.1491. Found 261.1496
(ESI).
Preparation of Acyloin 6g and Deoxy-6g. Acyloin 6g was
prepared in a manner analogous to that described for acyloin 6,
employing dialdehyde 9g (83.6 mg, 0.303 mmol), pentafluorophenyl
triazolium salt 16 (110 mg, 0.303 mmol), DBU (90 µL, 0.606
mmol), and CH2Cl2 (605 mL), which afforded acyloin 6g as a
mixture of diastereomers, which was purified by silica gel chro-
matography (12% EtOAc/hexane, 39.4 mg, 47% yield). Acyloin
6g (32.4 mg, 0.117 mmol) was deoxygenated in a manner analogous
to that described for compound deoxy-6f, employing DMAP (21
mg, 0.176 mmol), CH2Cl2 (1.7 mL), and acetic anhydride (17 µL,
0.176 mmol) followed by 9:1 THF/CH3OH (351 µL) and SmI2 (2.3
mL, 0.234 mmol, 0.1 M), which afforded deoxy-6g, which was
purified by silica gel chromatography (10% EtOAc/hexane, 15.6
Preparation of Acyloin 6d. Acyloin 6d was prepared in a
manner analogous to that described for acyloin 6, employing
dialdehyde 9d (65.5 mg, 0.250 mmol), pentafluorophenyl triazolium
salt 16 (91 mg, 0.250 mmol), DBU (75 µL, 0.50 mmol), and CH2-
Cl2 (500 mL), which afforded acyloin 6d, which was purified by
silica gel chromatography (12% EtOAc/hexane, 21.5 mg, 33%
1
yield). H NMR (DMSO-d6, 500 MHz): δ 7.37 (d, J ) 7.8 Hz,
1H), 7.31-7.26 (m, 2H), 7.20 (t, J ) 7.3 Hz, 1H), 5.76 (d, J ) 3.8
Hz, 1H), 5.17 (d, J ) 3.5 Hz, 1H), 3.87 (m, 1H), 3.79 (m, 1H),
2.99 (m, 1H), 2.83-2.77 (m, 2H), 2.72 (m, 1H), 2.46 (m, 1H),
2.30 (m, 1H), 1.73 (m, 1H), 1.63-1.49 (m, 3H); 13C NMR (DMSO-
d6, 125 MHz): δ 209.5, 171.3, 138.7, 138.1, 128.4, 127.9, 125.9,
64.6, 35.8, 34.5, 25.3, 25.1, 20.6; IR (film, cm-1): 3455, 2961,
2923, 2852, 1724, 1257; TLC Rf 0.53 (50% EtOAc/hexane); HRMS
[C15H18O4+] requires m/z 262.1205. Found 262.1202 (EI). X-ray:
crystal obtained by slow evaporation from EtOAc/hexane.
1
mg, 52% yield). H NMR (CDCl3, 500 MHz): δ 7.22-7.19 (m,
2H), 7.15-7.10 (m, 2H), 3.94 (m, 1H), 3.85 (m, 1H), 3.67 (d, J )
16.1 Hz, 1H), 3.58 (d, J ) 16.1 Hz, 1H), 2.90 (m, 1H), 2.83-2.70
(m, 3H), 2.32 (dd, J ) 10.1 Hz, J ) 8.2 Hz, 1H), 2.18-2.11 (m,
2H), 1.88 (m, 1H), 1.42 (m, 1H), 0.84 (d, J ) 6.9 Hz, 3H); 13C
NMR (CDCl3, 125 MHz): δ 208.1, 171.7, 138.4, 133.4, 131.7,
128.2, 127.7, 126.6, 63.0, 48.9, 47.0, 35.3, 33.3, 26.5, 25.5, 21.3;
IR (film, cm-1): 2926, 2896, 1720, 1707, 1269; TLC Rf 0.40 (25%
EtOAc/hexane); HRMS [C16H21O3 + H] requires m/z 261.1491.
Found 261.1495 (ESI).
Preparation of Acyloin 6e. Acyloin 6e was prepared in a manner
analogous to that described for acyloin 6, employing dialdehyde
9e (62.8 mg, 0.253 mmol), pentafluorophenyl triazolium salt 16
(91.8 mg, 0.253 mmol), and DBU (76 µL, 0.506 mmol) in CH2Cl2
(506 mL), which afforded acyloin 6e, which was purified by silica
gel chromatography (12% EtOAc/hexane, 10.0 mg, 16% yield).
1H NMR (DMSO-d6, 400 MHz, T ) 55 °C): δ 7.47 (d, J ) 7.6
Hz, 1H), 7.32-7.20 (m, 3H), 5.49 (bs, 1H), 5.16 (d, J ) 3.3 Hz,
1H), 3.73 (dt, J ) 10.9 Hz, J ) 4.6 Hz, 1H), 3.46 (td, J ) 10.4
Hz, J ) 3.6 Hz, 1H), 2.96 (m, 1H), 2.75-2.62 (m, 3H), 2.33-
2.12 (m, 3H), 1.69 (m, 1H); 13C NMR (DMSO-d6, 125 MHz): δ
208.0, 170.8, 137.6, 128.8, 128.0, 126.0, 63.7, 34.4, 25.0, 21.2; IR
(film, cm-1): 3451, 2957, 2920, 2852, 1733, 1715, 1252; TLC Rf
0.17 (25% EtOAc/hexane); HRMS [C14H16O4 + Na] requires m/z
271.0946. Found 271.0951 (ESI).
Preparation of Acyloin 6b. Acyloin 6b was prepared in a
manner analogous to that described for acyloin 6, employing
dialdehyde 9b (39.1 mg, 0.150 mmol), pentafluorotriazolium salt
16 (54.0 mg, 0.150 mmol), and DBU (45 µL, 0.30 mmol) in CH2Cl2
(300 mL), which afforded acyloin 6b, which was purified by silica
gel chromatography (12% EtOAc/hexane, 14.1 mg, 36% yield).
1H NMR (DMSO-d6, 500 MHz): δ 7.78 (d, J ) 7.7 Hz, 1H), 7.62
(d, J ) 7.9 Hz, 1H), 7.57 (t, J ) 7.7 Hz, 1H), 7.40 (t, J ) 7.4 Hz,
1H), 6.49 (bd, J ) 4.5 Hz, 1H), 5.83 (bs, 1H), 4.39 (m, 1H), 4.12
(m, 1H), 4.12 (m, 1H), 2.84 (m, 1H), 2.47 (m, 1H), 1.79-1.73 (m,
2H), 1.68-1.55 (m, 2H), 1.49-1.30 (m, 4H); 13C NMR (DMSO-
d6, 125 MHz): δ 209.1, 167.6, 139.3, 131.3, 130.1, 129.7, 127.4,
127.0, 74.5, 65.2, 37.1, 25.4, 25.0, 23.4, 21.1; IR (film, cm-1):
3447, 2940, 1713, 1283; TLC Rf 0.30 (5% acetone/toluene); HRMS
[C15H18O4 + Na] requires m/z 285.1103. Found 285.1088 (ESI).
Synthesis of trans-Resorcylide.
Preparation of Dialdehyde 32. To a stirred solution of 42 (429
mg, 0.846 mmol) in DMSO (1.69 mL) under an atmosphere of
argon was added N-methylmorpholine-N-oxide (497 mg, 4.23
mmol) and heated to 50 °C for 1 h. The reaction mixture was cooled
to 22 °C and partitioned with 1:1 H2O/brine (200 mL), extracted
with EtOAc (4 × 50 mL), and dried over Na2SO4. The solution
was then concentrated and purified by silica gel chromatography
(10% EtOAc/hexane) to afford dialdehyde 32 as a clear oil (133
mg, 32% yield). 1H NMR (CDCl3, 500 MHz): δ 9.96 (s, 1H), 9.43
(d, J ) 7.9 Hz, 1H), 7.42-7.32 (m, 10H), 7.06 (d, J ) 2.2 Hz,
1H), 6.83 (d, J ) 2.2 Hz, 1H), 6.68 (dt, J ) 15.6 Hz, J ) 6.8 Hz,
1H), 6.05 (dd, J ) 15.6 Hz, J ) 7.8 Hz, 1H), 5.23 (m, 1H), 5.11
(s, 2H), 5.07 (d, J ) 2.3 Hz, 2H), 2.27-2.21 (m, 2H), 1.71-1.63
(m, 1H), 1.60-1.48 (m, 3H), 1.29 (d, J ) 6.3 Hz, 3H); 13C NMR
(CDCl3, 125 MHz): δ 193.9, 189.8, 166.0, 160.7, 158.0, 157.2,
135.8, 135.7, 135.3, 133.1, 128.8, 128.6, 128.4, 128.3, 127.5, 127.4,
119.0, 106.7, 106.4, 72.1, 71.0, 70.6, 35.3, 32.3, 23.6, 19.9; IR
(film, cm-1): 2927, 2852, 2737, 1725, 1718, 1684, 1600, 1577;
TLC Rf 0.26 (25% EtOAc/hexane); HRMS [C30H30O6 + H] requires
m/z 487.2121. Found 487.2134 (ESI).
Preparation of Acyloin 6f and Deoxy-6f. Acyloin 6f was
prepared in a manner analogous to that described for acyloin 6,
employing dialdehyde 9f (69.4 mg, 0.251 mmol), pentafluorotria-
zolium salt 16 (91.0 mg, 0.251 mmol), DBU (75 µL, 0.502 mmol),
and CH2Cl2 (502 mL), which afforded acyloin 6f as a mixture of
diastereomers, which was purified by silica gel chromatography
(12% EtOAc/hexane, 29.4 mg, 42% yield). To a stirred solution of
acyloin 6f (19.9 mg, 0.071 mmol) and DMAP (13.5 mg, 0.107
mmol) in CH2Cl2 (0.50 mL) was added acetic anhydride (10 µL,
0.107 mmol) in one portion. The reaction mixture was stirred at
22 °C for 1 h, followed by filtering the crude reaction mixture
through a short plug of silica gel and eluting with 50% EtOAc/
hexane. The filtrate was concentrated under reduced pressure and
dissolved in 9:1 THF/CH3OH (211 µL) and added over 5 min to a
-78 °C solution of freshly prepared SmI2 (1.78 mL, 0.178 mmol,
0.1 M). The resulting blue solution was stirred at -78 °C for 10
min and then allowed to warm to 22 °C. The reaction mixture was
quenched by addition of 10 mL of saturated K2CO3, extracted with
diethyl ether (3 × 10 mL), dried over MgSO4, and concentrated to
afford deoxy-6f, which was purified by silica gel chromatography
(10% EtOAc/hexane, 14.3 mg, 77% yield). 1H NMR (CDCl3, 500
5268 J. Org. Chem., Vol. 72, No. 14, 2007

Bio-Inspired Acyl-Anion EquiValent Macrocyclization
Preparation of Resorcylide Acyloin 43. To a stirred solution
of dialdehyde 32 (104 mg, 0.215 mmol) in CH2Cl2 (2.2 mL) under
an atmosphere of argon was added benzenethiol (0.0242 mL, 0.236
mmol) and Et3N (0.0015 mL, 0.0107 mmol). The reaction was
stirred at 22 °C for 14 h, concentrated under reduced pressure, and
quickly purified by silica gel chromatography (12% EtOAc/hexane)
to afford â-thioether 32a as a clear oil (100 mg, 78% yield), which
126.7, 118.4, 117.8, 109.2, 109.1, 100.0, 99.6, 72.1, 71.3, 70.7,
70.4, 70.2, 48.8, 47.9, 47.1, 47.1, 43.2, 41.8, 36.6, 34.1, 33.5, 32.3,
31.8, 24.6, 23.3, 22.6, 20.7, 19.9, 19.4; IR (film, cm-1): 2931, 1717,
1603; TLC Rf 0.52 (25% EtOAc/hexane); HRMS [C36H36O5S +
H] requires m/z 581.2362. Found 581.2365 (ESI).
Preparation of trans-Dibenzylresorcylide (45). To a stirred
solution of sulfide 44 (5.0 mg, 0.0086 mmol) in CH2Cl2 (500 mL)
was added m-CPBA (7.4 mg, 0.043 mmol) in one portion. The
reaction was stirred for 1 h at 22 °C, partitioned with saturated
NaHCO3 (15 mL), extracted with CH2Cl2 (4 × 10 mL), and dried
over Na2SO4. The organic solution was concentrated under reduced
pressure and was purified by silica gel chromatography (10-25%
EtOAc/hexane), which afforded sulfone 44a (4.0 mg, 76% yield
as an approximately 1.8:1 mixture of diastereomers), which was
immediately carried forward.
1
was immediately used for the next step. H NMR (CDCl3, 400
MHz): δ 9.97 (d, J ) 0.8 Hz, 1H), 9.69 (m, 1H), 7.42-7.25 (m,
15H), 7.06 (d, J ) 2.2 Hz, 1H), 6.81 (d, J ) 2.2 Hz, 1H), 5.20 (m,
1H), 5.11-5.08 (m, 4H), 3.44 (m, 1H), 2.54 (m, 2H), 1.67-1.46
(m, 6H), 1.29-1.27 (m, 3H); TLC Rf 0.31 (25% EtOAc/hexane).
A Schlenk flask containing a stirred solution of â-thioether 32a
(100 mg, 0.167 mmol) and pentafluorophenyl triazolium salt 16
(61.0 mg, 0.167 mmol) in CH2Cl2 (35 mL) was cannulated to a
Schlenk flask containing CH2Cl2 (300 mL). Then, DBU (0.050 mL,
0.334 mmol) was added by syringe, and the reaction turned from
a colorless solution to a resilient yellow solution. At 90 min, the
now bright red reaction mixture was filtered through a plug of silica
gel (100 cm-1) followed by eluting the plug with 300 mL of EtOAc.
The filtrate was concentrated under reduced pressure and purified
by silica gel chromatography (12% EtOAc/hexane) to afford
resorcylide acyloin 43 (21.1 mg, 21% yield as an approximately
To a conical vial containing sulfone 44a (4.0 mg, 0.0065 mmol)
was added a stock solution of toluene (0.650 mL) containing DBU
(1.06 µL, 0.0072 mmol) and stirred at 22 °C for 40 min. The
reaction mixture was concentrated under reduced pressure and
purified by silica gel chromatography (10% EtOAc/hexane) to
afford trans-dibenzylresorcylide (45) as a white foam (2.7 mg, 88%
yield) that is in agreement with the literature characterization data.26
Data for Sulfone 44a: 1H NMR (CDCl3, 400 MHz): δ 7.90
(d, J ) 7.2 Hz, 2H), 7.69-7.65 (m, 1H), 7.57 (t, J ) 7.5 Hz, 2H),
7.44-7.28 (m, 10H), 6.55 (d, J ) 2.0 Hz, 0.65H), 6.54 (d, J ) 2.0
Hz, 0.35H), 6.37 (d, J ) 2.0 Hz, 0.65 Hz), 6.33 (d, J ) 2.0 Hz,
0.35H), 5.21-5.10 (m, 1H), 5.07-4.97 (m, 4H), 4.24 (d, J ) 18.1
Hz, 0.35H), 4.00 (d, J ) 17.8 Hz, 0.65H), 3.85 (d, J ) 17.8 Hz,
0.65H), 3.78-3.70 (m, 1H), 3.55 (d, J ) 18.3 Hz, 0.35H), 2.97-
2.84 (m, 1.35H), 2.73 (dd, J ) 13.5 Hz, J ) 2.7 Hz, 0.65H), 1.93-
1.42 (m, 4H), 1.14-1.10 (m, 3H); TLC Rf 0.28 (33% EtOAc/
hexane).
1
4:1 mixture of diastereomers). H NMR (CDCl3, 500 MHz): δ
7.42-7.20 (m, 15H), 6.51-6.47 (m, 2H), 5.60 (d, J ) 4.4 Hz,
0.8H), 5.32 (d, J ) 11.1 Hz, 0.2H), 5.26 (m, 0.2H), 5.06 (m, 0.8H),
4.97-4.87 (m, 4H), 4.65 (d, J ) 11.1 Hz, 0.2H), 4.09 (d, J ) 4.4
Hz, 0.8H), 3.73 (m, 0.2H), 3.53 (dd, J ) 10.5 Hz, J ) 8.1 Hz,
0.2H), 3.20 (m, 0.8H), 2.90 (dd, J ) 9.8 Hz, J ) 3.6 Hz, 0.8H),
2.59 (d, J ) 18.6 Hz, 0.2H), 2.13 (t, J ) 12.5 Hz, 0.8H), 1.80-
1.37 (m, 6H), 1.07 (d, J ) 6.3 Hz, 2.4H), 0.91 (d, J ) 6.3 Hz,
0.6H); 13C NMR (CDCl3, 125 MHz): δ 212.2, 207.0, 204.2, 171.0,
170.4, 167.3, 167.0, 166.0, 161.6, 160.9, 159.1, 158.7, 157.5, 148.2,
142.9, 138.5, 136.0, 136.0, 135.9, 135.8, 135.5, 135.3, 135.1, 134.6,
134.0, 132.5, 131.7, 131.1, 129.0, 129.0, 128.9, 128.7, 128.7, 128.6,
128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 127.9, 127.7, 127.6, 127.5,
127.3, 126.7, 126.7, 117.0, 113.5, 110.5, 106.0, 103.5, 102.3, 100.9,
100.7, 99.6, 82.8, 82.2, 73.1, 72.1, 71.5, 71.1, 70.9, 70.7, 70.6, 70.3,
70.3, 67.7, 60.3, 44.6, 44.3, 43.5, 43.1, 42.8, 40.9, 38.7, 36.6, 34.8,
34.7, 34.3, 33.5, 33.1, 24.6, 23.4, 22.8, 22.0, 21.0, 20.5, 19.4, 19.3,
14.1; IR (film, cm-1): 3449, 2932, 1770, 1717, 1603; TLC Rf 0.39
(25% EtOAc/hexane); HRMS [C36H36O6S + H] requires m/z
597.2311. Found 597.2334 (ESI).
1
Data for trans-Dibenzylresorcylide (45): H NMR (CDCl3, 500
MHz): δ 7.44-7.29 (m, 10H), 6.91 (ddd, J ) 16.1 Hz, J ) 9.6
Hz, J ) 5.2 Hz, 1H), 6.66 (d, J ) 2.2 Hz, 1H), 6.49 (d, J ) 2.2
Hz, 1H), 5.94 (d, J ) 16.2 Hz, 1H), 5.15-5.09 (m, 1H), 5.04 (dd,
J ) 11.4 Hz, J ) 2.9 Hz, 1H), 4.98 (dd, J ) 11.4 Hz, J ) 8.7 Hz,
1H), 4.62 (d, J ) 12.2 Hz, 1H), 3.30 (d, J ) 12.2 Hz, 1H), 2.35-
2.27 (m, 1H), 2.26-2.19 (m, 1H), 1.88-1.79 (m, 2H), 1.77-1.71
(m, 1H), 1.69-1.60 (m, 1H), 1.11 (d, J ) 6.3 Hz, 3H); 13C NMR
(CDCl3, 125 MHz): δ 199.0, 168.6, 160.5, 157.4, 150.1, 136.3,
136.2, 134.8, 130.8, 128.6, 128.3, 128.1, 128.0, 127.6, 117.9, 107.7,
99.7, 72.2, 70.6, 70.2, 42.8, 34.0, 31.6, 24.6, 20.2; IR (film, cm-1):
3063, 3032, 2973, 2934, 2872, 1708, 1668, 1602, 1581, 1456,
1433, 1379, 1284, 1165, 1062, 740, 697; TLC Rf 0.53 (33% EtOAc/
hexane); HRMS [C30H30O5 + Na] requires m/z 493.1991. Found
493.1993 (ESI).
Preparation of Sulfide 44. Deoxygenation of resorcylide acyloin
43 was performed in a manner analogous to that described for
acyloin 6f, employing resorcylide acyloin 43 (20.0 mg, 0.034
mmol). The reaction mixture was quenched by addition of 10 mL
of saturated NaHCO3, extracted with diethyl ether (3 × 10 mL),
dried over Na2SO4, and concentrated to afford sulfide 44 after
purification by silica gel chromatography (5% EtOAc/hexane, 10.2
mg, 52% yield as an approximately 1.8:1 mixture of diastereomers).
1H NMR (CDCl3, 500 MHz): δ 7.44-7.22 (m, 15H), 6.54 (d, J )
2.1 Hz, 1H), 6.38 (d, J ) 2.1 Hz, 0.65H), 6.35 (d, J ) 2.1, 0.35H),
5.25 (m, 0.65H), 5.17 (m, 0.35H), 5.04-4.99 (m, 4H), 4.14 (d, J
) 18.0 Hz, 0.35H), 4.07 (d, J ) 17.0 Hz, 0.65H), 3.89 (m, 0.35H),
3.75 (m, 0.65H), 3.55 (d, J ) 17.1 Hz, 0.65H), 3.52 (d, J ) 18.0
Hz, 0.35H), 2.85 (dd, J ) 10.7 Hz, J ) 5.0 Hz, 0.35H), 2.76 (dd,
J ) 9.5 Hz, J ) 5.3 Hz, 0.65H), 2.64 (dd, J ) 13.3 Hz, J ) 2.3
Hz, 0.35H), 2.51 (dd, J ) 9.9 Hz, J ) 4.9 Hz, 0.35H), 1.93-1.24
(m, 6H), 1.17-1.14 (m, 3H); 13C NMR (CDCl3, 125 MHz): δ
205.4, 205.2, 168.0, 167.3, 160.5, 160.3, 157.8, 156.9, 136.4, 136.4,
136.3, 134.9, 133.9, 133.9, 133.2, 132.3, 130.7, 129.0, 128.6, 128.4,
128.3, 128.1, 128.1, 127.9, 127.8, 127.5, 127.5, 127.3, 127.3, 127.2,
Acknowledgment. This research was supported by the
National Science Foundation (CHE-0639069). We thank Profes-
sor Glenn Micalizio for helpful discussions, Ms. Stephanie Ng
for X-ray assistance, and Dr. Gorka Peris for helpful suggestions
in the preparation of this manuscript. S.M.M. thanks the ACS
Division of Organic Chemistry for a fellowship sponsored by
Abbott Laboratories.
Supporting Information Available: Experimental procedures,
characterization data, 1H and 13C NMR spectra for compounds 1a,
3, 4, 4a, 6, 7, 9-9g, 22, 25, 38, 38a, 39, and 42, and X-ray
crystallographic data for compound 6d (CIF). This material is free
of charge via the Internet at http://pubs.acs.org.
JO070676D
J. Org. Chem, Vol. 72, No. 14, 2007 5269