Enantioselective Halolactonization Reactions using BINOL-Derived Bifunctional Catalysts: Methodology, Diversification, and Applications

Article abstract of DOI:10.1021/acs.joc.8b00490

A general protocol is described for inducing enantioselective halolactonizations of unsaturated carboxylic acids using novel bifunctional organic catalysts derived from a chiral binaphthalene scaffold. Bromo- and iodolactonization reactions of diversely substituted, unsaturated carboxylic acids proceed with high degrees of enantioselectivity, regioselectivity, and diastereoselectivity. Notably, these BINOL-derived catalysts are the first to induce the bromo- and iodolactonizations of 5-alkyl-4(Z)-olefinic acids via 5-exo mode cyclizations to give lactones in which new carbon-halogen bonds are created at a stereogenic center with high diastereo- and enantioselectivities. Iodolactonizations of 6-substituted-5(Z)-olefinic acids also occur via 6-exo cyclizations to provide δ-lactones with excellent enantioselectivities. Several notable applications of this halolactonization methodology were developed for desymmetrization, kinetic resolution, and epoxidation of Z-alkenes. The utility of these reactions is demonstrated by their application to a synthesis of precursors of the F-ring subunit of kibdelone C and to the shortest catalytic, enantioselective synthesis of (+)-disparlure reported to date.

Full text of DOI:10.1021/acs.joc.8b00490

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Article
Enantioselective Halolactonization Reactions using BINOL-derived
Bifunctional Catalysts: Methodology, Diversification, and Applications
Daniel W. Klosowski, John Caleb Hethcox, Daniel H Paull, Chao Fang, James R.
Donald, Christopher Ryan Shugrue, Andrew David Pansick, and Stephen F. Martin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00490 • Publication Date (Web): 02 May 2018
Downloaded from http://pubs.acs.org on May 2, 2018
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The Journal of Organic Chemistry
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Enantioselective Halolactonization Reactions using BINOL-derived
Bifunctional Catalysts: Methodology, Diversification, and Applications
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Daniel W. Klosowski, J. Caleb Hethcox, Daniel H. Paull,a Chao Fang,b James R. Donald,c Christopher R.
Shugrue, Andrew D. Pansick, and Stephen F. Martin*
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Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712
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ABSTRACT: A general protocol is described for inducing enantioselective halolactonizations of
unsaturated carboxylic acids using novel bifunctional organic catalysts derived from a chiral
binaphthalene scaffold. Bromo- and iodolactonization reactions of diversely substituted, unsaturated
carboxylic acids proceed with high degrees of enantioselectivity, regioselectivity, and diastereoselectivity.
Notably, these BINOL-derived catalysts are the first to induce the bromo- and iodolactonizations of 5-
alkyl-4(Z)-olefinic acids via 5-exo mode cyclizations to give lactones in which new carbon–halogen bonds
are created at a stereogenic center with high diastereo- and enantioselectivities. Iodolactonizations of 6-
substituted-5(Z)-olefinic acids also occur via 6-exo cyclizations to provide δ-lactones with excellent
enantioselectivities. Several notable applications of this halolactonization methodology were developed
for desymmetrization, kinetic resolution, and epoxidation of Z-alkenes. The utility of these reactions is
demonstrated by their application to a synthesis of precursors of the F-ring subunit of kibdelone C and to
the shortest catalytic, enantioselective synthesis of (+)-disparlure reported to date.
INTRODUCTION
Cyclizations via halofunctionalization of olefins 1 represent an important class of reactions for the
construction of heterocyclic compounds with carbon-halogen bonds (C–X) outside (exo) or inside (endo)
the newly formed ring as in 2 and 3, respectively (Equation 1). Consequently, the development of catalytic,
enantioselective halocyclization reactions is a burgeoning field, and, although there have been a plethora
of advances over the past six years,1 significant gaps in the methodology remain.
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Enantioselective halocyclizations of α,ω-hydroxy alkenes 1 (Y = H2; Z = O)2 and α,ω-amino alkenes 1 (Y =
H2; Z = NR')3 have been reported, although the majority of the work in the area of enantioselective
halofunctionalizations of olefins has been focused on enantioselective halolactonization reactions (Y = O,
Z = OH).4–6 Borhan described the first highly enantioselective (up to 95:5 er) chlorolactonizations of a
series of 4-aryl-substituted-4-pentenoic acids to generate the corresponding chlorolactones using the
commercially-available, cinchona alkaloid derivative (DHQD)2PHAL (4) as the catalyst (Figure 1).4a There
have been only two other catalysts capable of effecting enantioselective chlorolactonizations. Tang
reported catalyst 5, which promoted chlorolactonizations 4-aryl-substituted-4-pentenoic acids,4b and
Zhou reported a cinchonine-squarimide catalyst that promotes chlorolactonizations of vinylbenzoic
acids.4d
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Enantioselective bromo- and iodolactonization reactions have attracted greater attention than any other
cyclization involving halofunctionalization of olefins. For example, the C3-symmetric trisimidazoline
catalyst 6 was first reported to induce 6-exo bromolactonizations of 5-aryl-substituted-5-hexenoic acids to
deliver δ-lactones,5f and it has since been shown to work equally well with tri- and tetrasubstituted olefinic
acids.5g In 2010 Yeung showed that the quinidine-derived thiocarbamate 7 catalyzed enantioselective
bromolactonizations of 4-aryl-substituted-4-pentenoic acids,5b and by making slight changes in the
quinidine catalyst, he was able to induce the enantioselective bromolactonizations of a variety of other
substrates.5c–e Yeung later developed several proline derived catalysts 8 for the enantioselective
bromolactonizations of 4-substituted-4-pentenoic acids and 5-substituted-5-hexenoic acids, but each
substrate class required catalyst optimization.
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Figure 1. Halolactonization catalysts.
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Jacobsen’s tertiary aminourea catalyst 9 promoted enantioselective iodolactonizations of 5-substituted-
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5-hexenoic acids with moderate to excellent selectivities.6a Subsequently, Hansen disclosed that the
squarimide variant 10 also induced iodolactonization reactions, although the selectivities were lower than
with 9.6b The catalyst 11, which was developed by Johnston, effected the iodolactonizations of 5-
substituted-5-hexenoic acids with generally high enantioselectivities.6c Ishihara reported that
iodolactonizations of benzyl-substituted-4-pentenoic acids in the presence of the binaphthyl 12 formed γ-
butyrolactones with good enantioselectivities.6h
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The first example of a catalytic, enantioselective fluorolactonization was reported by Rueping, who
utilized a combination of (DHQ)2PHAL (4) and Selectfluor® to generate a fluorinated isobenzofuran in
modest yield (50%) and with low enantioselectivity (27% ee).7a The only catalytic, highly enantioselective
fluorolactonization using an electrophilic fluorine source reported thus far was achieved using the
binaphthyl derivative 13, although the substrate scope was somewhat limited.7b The methylene spacer
between the naphthol and hydroxyl group was found to be critical because the naphthol based catalyst
gave racemic product. Jacobsen recently reported a method for asymmetric fluorolactonization using a
chiral aryl iodide catalyst and a nucleophilic fluoride source that delivered fluorinated isochromanones
with generally high enantioselectivity.7c
Several chiral Lewis acid-derived catalysts have also been used to promote enantioselective
halolactonizations,6e,f,g but these catalysts have some notable limitations. Specifically, halolactonizations
of olefinic acids bearing an alkyl group on the double bond often led to lower enantioselectivities
compared to aryl-substituted olefinic acids, and most catalytic systems appear to be limited to a specific
halogen atom.
Despite the many advances in catalysts that have been developed to promote enantioselective
halolactonizations, the substrate scope of each is typically limited, especially for chloro- and
iodolactonizations. Although there were several gaps in the methodology when we initiated our work, a
major deficiency in the contemporaneous art was the lack of any example of a halolactonization that
proceeded via an exo mode of ring closure to give a lactone bearing a new C–X bond at a stereogenic
secondary carbon atom (e.g., 2, R = alkyl, aryl; Z = Y = O). This was somewhat surprising because several
examples of the corresponding exo halocyclizations of hydroxy alkenes 1 (R = alkyl or aryl; Y = H2, Z = O)
to furnish the corresponding tetrahydrofurans were known.2a–d The sole example of a halolactonization
that created a stereogenic carbon atom bearing a halogen atom involved an endo cyclization mode.5c It
should be noted that during the course of our studies, Yeung reported the use of 4 to catalyze the
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bromolactonization of several 5-substituted-4(Z)-pentenoic acids in an exo fashion to give stereogenic C–X
bonds at secondary carbons.5d Herein we report the details of our methodological studies directed toward
the design and development of novel organic catalysts for enantioselective bromo- and
iodolactonizations,8 as well as the applications of these enantioselective halolactonizations to solving
several synthetic problems in this account.9
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RESULTS AND DISCUSSION
Catalyst Design and Conditions: Bromolactonizations. The difficulty associated with developing an
enantioselective bromocyclization reaction arises, in part, from the reversibility of bromonium ion
formation and its propensity to transfer Br+ to another olefin prior to intramolecular capture by a pendant
nucleophile.10 In order to address this problem, most successful known catalysts are bifunctional
containing both Lewis/Brønsted acid and Lewis/Brønsted base functionalities (Figure 1). This critical
attribute enables the catalyst to coordinate with the substrate as well as with the brominating reagent or
bromonium ion. When we began designing a catalyst for bromolactonizations, we envisioned that
established bifunctional motifs found in some of the known catalysts (e.g., 4–9, Figure 1) could be
mounted on a chiral binaphthyl backbone, which despite its near ubiquity in the field of enantioselective
reactions had not yet been applied to halocyclization reactions.
The initial goal was to develop analogs of the bifunctional catalyst 17, which bear amidine and
thiocarbamate groups as the requisite Lewis base and acid motifs appended to a BINOL-derived scaffold.
An amidine group was selected rather than a tertiary amine because bromine was well-known to rapidly
oxidize benzylic tertiary amines.11 Having a phenyl group at the 3-position of 17 was designed to increase
steric bulk around the proposed catalophore, a tactic known to enhance the enantioselectivity of reactions
catalyzed by BINOL derivatives.12
Toward the synthesis of 17, the known (R)-BINOL 1413 was first converted into 15 by monotriflation
followed by nickel-mediated cross-coupling with potassium cyanide (Scheme 1). Reduction of the nitrile
and amidine formation provided 16. Unfortunately, all of our efforts to convert the phenol moiety into the
thiocarbamate 17 were unsuccessful.
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Scheme 1. Attempted synthesis of catalyst 17
The initial disappointment notwithstanding, we queried whether 16, which has an acidic phenolic
hydroxyl group, might itself serve as a suitable catalyst for bromolactonizations.8a The first step toward
testing this hypothesis involved identifying reaction conditions that gave minimal amounts of background
reaction. In our initial screenings, we discovered that stirring solutions of 5-phenyl-4(E)-pentenoic acid
(18) in PhMe/CH2Cl2 (1:1) containing 2,4,4,6-tetrabromobenzo-quinone (TBCO) at temperatures less than
–40 °C for 14 h gave negligible amounts of racemic lactones 19a and 19b.
Having discovered conditions under which a background reaction was insignificant, a solvent screen was
performed for the bromolactonization of the olefinic acid 18 promoted by TBCO in the presence of 16 (10
mol %) (Table 1) to identify conditions that provided 19a with high regioselectivity and enantiomeric ratio
(er). Although reactions in pure toluene or THF proceeded with low conversion and regioselectivity (Table
1, entries 1 and 2), use of CH2Cl2 led to furnished 19a in good yield and with good enantioselectivity (Table
1, entry 3). We then examined mixtures of toluene and CH2Cl2 (Table 1, entries 4–6) and discovered that a
mixture (2:1) of toluene and CH2Cl2 provided 19a with excellent regioselectivity (15:1) and a high
enantioselectivity (97:3 er) (Table 1, entry 5). Notably, similar combinations of a polar solvent (CH2Cl2 or
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CHCl3) and a nonpolar solvent (toluene or hexane) have been used in a number of other enantioselective
halolactonizations.5,6
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Table 1. Solvent Screening for Bromolactonizationa
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O
O
16 (10 mol %)
TBCO (1.2 equiv)
Ph
O
O
OH
H
Ph
solvent
–40 °C, 14 h
O
Br
Ph
Br
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19a
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Entry
Solvent
Yield (%)b 19a:19b erd
1
PhMe
THF
trace
ca. 20
64
4:1
ND
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3
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5
6
1:1
ND
CH2Cl2
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15:1
15:1
15:1
91:9
96:4
97:3
97:3
PhMe/CH2Cl2 (1:1) 75
PhMe/CH2Cl2 (2:1) 95
PhMe/CH2Cl2 (4:1) 50
aReactions run on 0.1 mmol scale. Yield of mixture of
b
c
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19a,b. Regioselectivity determined by H NMR spectra of
d
the crude reaction mixtures. er determined by chiral
HPLC; absolute stereochemistry of 19a was assigned based
upon correlation of optical rotation with reported value;5c
the absolute stereochemistry of 19b was assigned based
upon working model (vide infra); ND = not determined.
Subsequent to these exploratory studies, we found that N-bromosuccinimide (NBS) and 1,3-dibromo-
5,5-dimethylhydantoin (DBDMH) could also be employed as brominating agents to furnish 19a with
similarly high enantioselectivities and yields. The fact that the enantioselectivity of bromolactonization
with catalyst 16 is independent of the brominating reagent is unlike what is observed with other organic
catalysts.5 Moreover, this observation has mechanistic implications and suggests that the intermediate
bromonium ion might be formed by delivery of Br+ from an N-bromo amidine that is generated in situ
rather than directly from the original brominating reagent (vide infra).14 When we sought to recover 16 for
reuse, we were somewhat surprised to isolate the 6-bromo analog 20 rather than the original catalyst 16.
Because 16 underwent facile bromination to give 20 under the conditions for bromolactonization, we
believe that 20 is the dominant active catalyst in bromolactonization reactions. This fortuitous finding led
to the identification of 20 as an effective organic catalyst to promote enantioselective brominations,
although we rarely prepared and used it for this purpose, and iodolactonizations (vide infra).8b
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Modification of Original Catalyst Design. Although we established that 16 catalyzed the
bromolactonization of 18 to give 19a with high regio- and enantioselectivity, we found that it promoted the
bromolactonization of 21, a common test substrate for bromolactonizations,5 to give 22 with reduced
enantioselectivity (86:14 er) (Table 2, entry 1). Perhaps not surprisingly, we also showed that preformed 20
catalyzed the bromolactonization of 21 with the same enantioselectivity as 16 (Table 2, entry 2). In order to
identify analogs of 16 and 20 that might be superior catalysts, we prepared the series of analogs 23a–i
(Figure 2), and surveyed their suitability for promoting the enantioselective bromolactonization of 21.
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Figure 2. General design for analogs of catalyst 16.
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Table 2. Effects of Catalyst Modificationsa
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Entry
Cat.
R1
R2
R3
R4
R5
erb
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16
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1
16
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Ph
H
H
H
H
H
H
Ph
H
H
H
H
H
86:14
86:14
NR
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20
Br
NO2
H
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5
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23b
23c
23d
23e
23f
23g
23h
23i
84:16
74:26
50:50
85:15
82:18
87:13
62:38
50:50
Ph3Si
TRIPd
Ph
Ph
H
H
6
7
H
H
8
9
10
11
H
Ph
H
H
t-Bu
Me
H
H
H
aReactions run on 0.1 mmol scale, and all reactions gave >90% conversion. er determined by chiral
b
HPLC; the absolute stereochemistry of 22 was assigned based upon correlations of optical rotation with
those previously reported values.5b,6a cNR = no reaction. dTRIP: 2,4,6-triisopropylphenyl.
We first evaluated the effect of placing an electron withdrawing group on the binaphthyl scaffold, and
we found that 23a, the 6-nitro analog of 16, did not catalyze the bromolactonization of 21 (Table 2, entry
3). We then probed the consequence of varying the steric requirements of substituents at the 3- and 3'-
positions of the binaphthyl moiety as well as on the amidine group (Figure 2). In our initial design of
catalyst 16, the phenyl ring was incorporated at C3 to help create a sterically biased catalytic pocket, which
we believed would be important for obtaining high enantioselectivities. However, we discovered that
bromolactonization of 21 with 23b (R1 = H, Table 2, entry 4), which lacks the phenyl group at the 3-
position, gave 22 with nearly identical selectivity as 16 (84:16 er vs. 86:14 er) (Table 2, entry 3). On the other
hand, increasing the size of the R1 substituent to triphenylsilyl (23c, Table 2, entry 5) or 2,4,6-
triisopropylphenyl (23d, Table 2, entry 6) led to a significant erosion of enantioselectivity. Introducing a
phenyl group at the 3-position adjacent to the amidine group led to 23e, which catalyzed the
bromolactonization of 21 with selectivities comparable to that of the parent catalyst 16 (Table 2, entry 7)
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We also briefly examined the effects of altering the substituent R3 on the amidine group upon the
bromolactonization of 21. Although replacing the methyl group in 16 (Table 2, entry 8) and 23b (Table 2,
entry 9) with a phenyl group did not significantly affect the enantioselectivities, the presence of a tert-
butyl group 23h (R3 = t-Bu) led to significant drop in selectivity (62:38 er, Table 1, entry 10). In order to
assess whether the bifunctional nature of the catalyst was critical for inducing enantioselectivity, the
acidic phenolic group in 23b was methylated to give 23i. This modification led to complete loss of
enantioselectivity (Table 2, entry 11), an observation that suggests that the acidic proton in the catalyst is
imperative for enantioselectivity. Although screening a number of analogs of 16 led to several catalysts that
promote the bromolactonization of 21 with comparable enantioselectivities, there were instances where 16
was superior, so it was used uniformly in subsequent experiments.
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Application to Other Halolactonizations. At the time of our investigations, no catalyst was known to
promote enantioselective halolactonizations with more than one halogen. We were thus inspired to
ascertain whether 16 might catalyze other enantioselective halolactonizations. Chlorolactonization of 21
was first examined using 16 and 20 with N-chlorosuccinimide (NCS) and 1,3-dichloro-5,5-
dimethylhydantoin (DCDMH) in a variety of solvents. However, consistent with other literature reports,
the reactions proceeded with low conversions and poor enantioselectivities.5b,d Owing to the poor
enantioselectivity in these preliminary experiments, we did not further pursue chlorolactonizations.
We then turned our attention to iodolactonizations, and gratifyingly we discovered that the
iodolactonization of 21 with N-iodosuccinimide (NIS) in the presence of 16 in a mixture (2:1) of toluene
and CH2Cl2 at –40 °C delivered the iodolactone 24 (93:7 er). Although this reaction was sluggish, we found
that the corresponding reaction with the brominated catalyst 20 was somewhat faster (Table 3, entry 1).
Because of the operational advantage associated with using 20 as the catalyst, we screened several
temperatures and conditions to identify a standard set of reaction parameters to establish the scope of this
process. We discovered that iodolactonizations of 21 with NIS in the presence of 20 proceeded with
comparable yields and enantioselectivities at temperatures between –10 and –40 °C, but there was a slight
erosion in enantioselectivity when the reaction was performed at 0 °C (Table 3, entries 1–4). Not
surprisingly, reaction times decreased significantly with increasing temperature. Because Jacobsen had
reported that use of iodine as an additive had a beneficial effect on iodolactonizations using 9 as the
catalyst,6a we tested the effects of adding catalytic amounts of iodine. However, the presence of iodine(1 or
10 mol %) had little effect on the enantioselectivity of the iodolactonization of 21 (Table 3, entries 6 and 7).
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The Journal of Organic Chemistry
It is notable, however, that the effect of iodine as an additive was not consistent, and some reactions
benefited from the addition of iodine.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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Table 3. Optimization of Iodolactonizationa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry
Time (h) Yield (%) erb
Temp (°C)
1
–40
–20
–10
0
38
14
89
86
87
87
99
86
93:7
93:7
92:8
90:10
92:8
93:7
2
3
1.5
0.75
14
4
5c
6c
–20
–20
14
aReactions run on 0.1 mmol scale. er determined
by chiral HPLC; absolute stereochemistry of
iodolactone 24 was assigned by correlation of optical
rotation with previously reported values.5b,6a cResults
obtained with 10 mol % I2.
b
Substrate Scope of Halolactonizations. Having established that 16 and/or 20 catalyze highly regio-
and enantioselective bromo- and iodolactonizations, we elucidated the scope of these reactions. 4-
Substituted-4-pentenoic acids are commonly employed as test substrates to demonstrate the efficacy of
enantioselective halolactonizations,5,6 so we examined the bromo- and iodolactonizations, respectively, of
21 and 25a–e (Table 4). Notably, the enantioselectivities obtained in these reactions with our new BINOL-
derived catalysts are comparable to those obtained with other catalysts.5b,6a Although we did not fully
evaluate electronic effects, the presence of an electron-withdrawing group on the aromatic ring appears to
lead to a slight increase in enantioselectivity in bromolactonizations (Table 4, entries 1, 3, and 5); however,
this effect was not observed for iodolactonizations (Table 4, entries 2 and 4). On the other hand, an
electron-donating group (R = p-MeO-Ph, 25c) led to a significant reduction in enantioselectivity of the
iodolactonization (Table 4, entry 6). This finding is consistent with literature reports that
chlorolactonization4a and bromolactonization5b of 25c are even less enantioselective. In contrast to what
we observed in the iodolactonization of 21 (vide supra) but consistent with the observations of Jacobsen,6a
cyclization of 25c proceeded with somewhat higher enantioselectivity (er = 82:18) in the presence of iodine
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The Journal of Organic Chemistry
(Table 4, entry 6). This 4-Alkyl-4-pentenoic acids also underwent facile iodolactonizations, but steric
effects are important, and the enantioselectivity is better for larger alkyl groups (Table 4, entries 7 and 8).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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Table 4. Halolactonization of 4-Substituted-4-Pentenoic Acidsa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry Acids R
Product Yield (%) erb
1
21
Ph
22
99
89
92
73
86:14
93:7
2
3
21
Ph
24
25a
25a
25b
25c
25d
25e
p-NC-Ph
p-NC-Ph
26a
27a
94:6
90:10
91:9
4
5
6c
7
8
m-NC-Ph 26b
p-MeO-Ph 27c
89
90
96
91
74:26
65:35
83:17
Me
27d
27e
t-Bu
aReactions run on 0.10 mmol scale. Conditions for
bromolactonization: 10 mol % 16, 1.2 equiv TBCO in
PhMe/CH2Cl2 (2:1) at −50 °C. Conditions for
iodolactonization: 10 mol % 20, 1.2 equiv NIS in
b
PhMe/CH2Cl2 (2:1) at −20 °C. er determined by chiral
HPLC; absolute stereochemistry of 22 and 24 were
assigned by correlation of optical rotations with
previously reported values,5b,6a and other assignments are
c
based upon analogy. Results obtained with 10 mol % I2,
93% yield, 82:18 er.
The next set of substrates examined was a small collection of 5-substituted-5-hexenoic acid derivatives
that cyclize via 6-exo cyclizations to give δ-lactones (Table 5). Under the standard conditions,
bromolactonization of 5-phenyl-5-hexenoic acid (28a) proceeded with 75% yield and 62:38 er (Table 5,
entry 1), whereas the iodolactone 30a was obtained from 28a in slightly better enantioselectivity (76:24 er,
Table 5, entry 2). Consistent with findings of Jacobsen,6a addition of iodine (10 mol %) led to a modest
increase in enantioselectivity (85:15 er) to provide 30a. It should be noted at this juncture, however, that
the presence of iodine did not always increase the selectivity of iodolactonizations catalyzed by 20 (vide
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The Journal of Organic Chemistry
infra). Although Jacobsen observed that the 6-exo cyclization of 28a and the 5-exo cyclization of 21 with 9
proceeded with opposite facial selectivities,6a use of 20 as a catalyst for these cyclizations gave products 24
and 30a that have the same absolute configuration. The 6-exo bromo- and iodolactonization of 28b
delivered the bromolactone 29b and iodolactone 30b in 82:18 and 79:21 er, respectively (Table 5, entries 3
and 4); addition of iodine had little effect on the enantioselectivity of the iodolactonization.
Halolactonization of 28c occurred to give bromo- and iododioxanones in 85:15 and 84:16 er, respectively,
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
with a slight increase in selectivity being observed when iodine was present (Table 5, entries 5 and 6).
Table 5. Halolactonization of 5-Substituted-5-Hexenoic Acidsa
Entry Acids R
X
Product Yield (%) erb
1
2c
28a
28a
28b
28b
28c
28c
Ph CH2 29a
Ph CH2 30a
Me CH2 29b
Me CH2 30b
78
98
90
89
94
91
62:38
76:24
82:18
79:21
85:15
84:16
3
4d
5
6e
Ph
Ph
O
O
29c
30c
aReactions run on 0.10 mmol scale. Conditions for
bromolactonization: 10 mol % 16, 1.2 equiv TBCO in
PhMe/CH2Cl2 (2:1) at −50 °C. Conditions for
iodolactonization: 10 mol % 20, 1.2 equiv NIS in
b
PhMe/CH2Cl2 (2:1) at −20 °C. er determined by chiral
HPLC; absolute stereochemistry of 30a was assigned by
correlation of optical rotation with previously reported
value,6a and the other assignments are based upon
c
analogy. Results obtained with 10 mol % I2, 95% yield,
d
85:15 er. Results obtained with 10 mol % I2, 90% yield,
e
80:20 er. Results obtained with 10 mol % I2, 89% yield,
90:10 er.
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In our initial exploratory studies, we discovered that 16 promoted the highly enantioselective cyclization
of 18 to give 19a (Table 1). Although 19a contains a new stereocenter bearing a bromo group, the
formation of similar chiral alkyl bromides via a 6-endo cyclization mode was known.5c However,
enantioselective halolactonizations in which a new C–X bond is produced at a secondary carbon atom via a
5-exo cyclization was unprecedented. It is thus notable that the bromo- and iodolactonizations of a
representative selection of 5-alkyl-4(Z)-pentenoic acids 31a–e catalyzed by 16 and 20 proceeded via a 5-exo
cyclization to furnish the corresponding γ-lactones 32a–e and 33b–e in generally high yields and
enantioselectivities (≥95:5 er) (Table 6, entries 1–9). The unsaturated acid 31a (R = Et, Table 6, entry 1) was
the only substrate tested that cyclized with a modest er (85:15), suggesting that branching on the carbon
atom attached directly to the double bond might play a role in determining selectivity. The γ-lactones 32a–
e and 33b–e contain two contiguous stereogenic centers, one of which bears a carbon-halogen bond. The
Z-olefin geometry appears to be an important prerequisite for high enantioselectivity because the
corresponding 5-alkyl substituted-4(E)-pentenoic acids cyclized with only 50:50 to 78:22 er. The set of 5-
aryl-4(Z)-pentenoic acids 31f–i also underwent facile iodolactonization via a 5-exo cyclization pathway to
form γ-iodolactones 33f–i with high enantioselectivity (er ≥98:2) (Table 6, entries 10–13). Collectively, the
cyclizations of 31a–i represent the first examples halolactonizations that occur via a 5-exo mode of ring
closure to give products in which new C–O and C–X bonds are formed at contiguous stereogenic centers.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
One might anticipate that the Z-alkenes 31f–i, like the E-alkene 18, would be electronically biased to
cyclize via a 6-endo mode. However, the observation that cis-aryl olefinic acids 31f–i underwent selective
exo cyclizations is consistent with the transition state 35 that is favored relative to 34, because the
unfavorable steric interaction depicted in 34 prevents benzylic stabilization of the putative iodonium ion,
or the nascent carbocation, by the π electrons of the aryl group (Figure 3).15 Cyclization of conformer 35
through the 5-exo mode is thus favored for steric and entropic reasons. The regiochemical outcome in
d,f
these cyclizations are consistent with those observed by Denmark in related bromoetherifications.2
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1
2
3
4
Table 6. Halolactonization of 5-Substituted-4(Z)-Pentenoic Acidsa
5
6
7
8
9
O
O
R
conditions
O
O
OH
or
H
R
H
R
O
I
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Br
31a
–
i
32a–e
33b–i
¨
Entry Acids R
Product Yield (%) erb
1
31a
31b
31b
31c
31c
31d
31d
31e
31e
31f
Et
32a
32b
33b
32c
33c
32d
33d
32e
33e
33f
90
94
93
87
94
97
99
94
97
93
95
89
94
85:15
97:3
2
i-Pr
i-Pr
i-Bu
i-Bu
t-Bu
t-Bu
Cy
3
97:3
4
5
95:5
98:2
97:3
6
7
97:3
8
9
10
11
12
13
98.5:1.5
98:2
98.5:1.5
99:1
Cy
Ph
31g
31h
31i
p-NC-Ph 33g
p-Cl-Ph 33h
98:2
98:2
2-Np
33i
aReactions run on 0.10 mmol scale. Conditions for
bromolactonization: 10 mol % 16, 1.2 equiv TBCO in
PhMe/CH2Cl2 (2:1) at −50 °C. Conditions for
iodolactonization: 10 mol % 20, 1.2 equiv NIS in
b
PhMe/CH2Cl2 (2:1) at −20 °C. er determined by chiral
HPLC; absolute stereochemistry of 32d, 33d, and 33f were
determined by X-ray crystallography, and other assignments
are based upon analogy.
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‡
O
I
δꢀ
O
O
1
O
2
3
4
Ph
δ+ I
5
34
36
6
7
8
9
‡
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
δꢀ
O
O
H
Ph
I
δ+
I
35
37
Figure 3. The 6-endo product 36 is disfavored
because the phenyl ring in 34 cannot adopt a
conformation that stabilizes the transition state
leading to 36, thereby leading preferentially to
the formation of the 5-exo product 37.
In a closely related set of experiments, we examined the iodolactonizations of 6-substituted-5(Z)-
hexenoic acids 38a–d and found that the corresponding iodo δ-lactones 39a–d were produced in high
yields and enantioselectivities of ≥98:2 (Table 7). These cyclizations are also notable in that two adjacent
stereogenic centers, one of which is a C–I bond, are generated.
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1
2
3
Table 7. Iodolactonization of 6-Substituted-5(Z)-Hexenoic Acidsa
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry Acids
R
Product Yield (%) erb
1
38a
38b
38c
38d
Ph
39a
89
88
93
98
99:1
2
p-NC-Ph 39b
99:1
3c
4c
2-Np
39c
39d
98.5:1.5
98:2
t-Bu
aReactions run on 0.10 mmol scale. er determined by
chiral HPLC; absolute stereochemistry assigned based on
analogy with 33d and 33f. cResults obtained after 38 h at –20
°C.
b
We then investigated halolactonizations of a set of 5-aryl-4(E)-pentenoic acids comprising 18 and 40a–
d. Unsaturated acids 18, 40a, and 40b underwent bromolactonizations in the presence of 16 and TBCO by
6-endo cyclizations to form the δ-lactones 19a, 41a, and 41b with high yields and enantioselectivities
(Table 8, entries 1–3). On the other hand, iodolactonization of 18 afforded an inseparable mixture (1:1.3) of
6-endo and 5-exo products 42a and 43a, respectively (Table 8, entry 4). Iodolactonization of 40c (Ar = p-
MeO-Ph) selectively gave the 6-endo product 42c (>20:1) with moderate enantioselectivity (86.5:13.5 er,
Table 8, entry 5), whereas iodolactonization of 40d (Ar = p-NC-Ph) afforded the 5-exo product 43d with
poor enantioselectivity (Table 8, entry 6). With the exception of the iodolactonization of 18, the preferred
regioselectivity in these cyclizations is consistent with electronic effects.
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1
2
3
Table 8. Halolactonization of 5-Aryl-4(E)-Pentenoic Acidsa
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry Acids Ar
Product Yield (%) erb
1
18
Ph
19a
41a
41b
94d
97
98:2
96:4
94:6
95:5e
87:13
58:42
2
3
4
5
6f
40a
40b
18
2-Np
2-thienyl
Ph
92
42a+43a 89e
40c
40d
p-MeO-Ph 42c
p-NC-Ph 43d
89
94
aReactions run on 0.10 mmol scale. Conditions for
bromolactonization: 10 mol % 16, 1.2 equiv TBCO in
PhMe/CH2Cl2
(2:1)
at
−50
°C.
Conditions
for
iodolactonization: 10 mol % 20, 1.2 equiv NIS in
PhMe/CH2Cl2 (2:1) at −20 °C. ber determined by chiral HPLC;
absolute stereochemistry of 19a, 41a, and 41b were assigned
by correlation of optical rotations with previously reported
values,5c whereas absolute stereochemistry of iodolactones
c
assigned based on analogy. The absolute stereochemistry of
43a and 43d (major enantiomer) were assigned based upon
working model (vide infra). dReaction run at −60 °C.
eCombined yield; ratio of 1.0:1.3 for 42a/43a based upon H
1
NMR analysis; er shown in parentheses is for 42a, and er for
f
43a is 52:48. Reaction performed for 14 h at –20 °C and 48 h
at –10 °C in CH2Cl2/PhMe (1:1).
Inducing enantioselective halolactonizations of tri-substituted olefinic acids presents some significant
challenges relative to 1,1- and 1,2-disubstituted substrates with only one report of a highly selective
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The Journal of Organic Chemistry
bromolactonization to date.5g For example, subjection of 44 and 46 to standard bromo- and
iodolactonization conditions furnished the corresponding bromo- and iodolactones 45 (X = Br and I) and
47 (X = Br and I) in very good yields but with only moderate enantioselectivities (Equations 3 and 4). The
enantioselectivity of the 6-exo cyclizations of 46 are slightly better than the 5-exo cyclizations of 44. The
addition of 10 mol % iodine also led to modest increases in the enantioselectivities of the
iodolactonizations of 44 and 46. The absolute stereochemistry of 45 and 47 is tentatively assigned based
upon analogy with the cyclizations of other 4,4- and 5,5-disubsitituted olefinic acids (see Tables 4,5).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Working Model. It is evident from the foregoing discussions that we have established 16 and 20 as novel
bifunctional catalysts to promote bromo- and iodolactonizations of a rather diverse set of substituted
olefinic acids 48 to give the respective lactones 49–51, typically with excellent regio- and stereoselectivity
(Scheme 2). Based on these results coupled with previous mechanistic proposals,1h,2f we have developed a
tentative working model to rationalize the stereochemical outcomes for these processes.
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Scheme 2. Summary of enantioselective halolactonizations catalyzed by 16 and 20
1
2
3
4
5
6
7
8
As a starting point, we recognize that the bridged halonium ion intermediate could be stabilized by a
Lewis acid/base interaction with either the basic amidine moiety or the naphthalenoxide ion of the
catalyst 16 or 20. However, we are aware of no models for catalytic halocyclizations in which the halonium
ion is stabilized by a phenoxide ion, whereas there are a number of mechanistic models wherein this ion is
stabilized by a basic nitrogen atom. Indeed, amidines are known to transfer bromine from NBS to olefins.14
Accordingly, we presently prefer a model for halolactonizations catalyzed by 16 or 20 in which the
halonium ion is stabilized by the amidine moiety, and there is a Brønsted acid/base interaction between
the carboxylate group of the olefinic acid and the naphthol moiety. Assuming that these are the key ionic
interactions in the transition states for the halolactonization, one may envision the competing transition
states for the enantioselective cyclizations that deliver 49–51 as those shown in Figure 4A–C, respectively.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A
B
C
O
O
H
O
H
H
H
H
O
O
O
H
O
H
O
O
H
O
O
O
O
O
O
R1
H
O
R3
H
H
H
O
O
Ar
H
n( )
vs
n( )
vs
vs
R3
( )n
R1
n( )
H
N
H
Ar
H
H
H
N
X
X
X
N
N
N
N
X
X
X
Me2N
Me2N
Me
Me
Me
NMe2
Me2N
Me
Me
NMe2
Me
NMe2
52
53
54
55
56
57
disfavored
favored
favored
disfavored
favored
disfavored
O
O
O
O
X
O
O
O
O
O
O
O
O
( )n
X
( )n
X
( )n
X
( )n
X
R3
R3
H
H
Ar
Ar
R1
R1
X
ent-49
49
50
ent-50
51
ent-51
Figure 4. Tentative working stereochemical model for halolactonization reactions of 48 (see Scheme 2)
catalyzed by 16 and 20 showing adverse steric interactions (red double headed arrow) in disfavored
transition states. (A) Competing transition states for halolactonizations of acids 48 (n = 1,2; R1 = R2 = H).
(B) Competing transition states for halolactonizations of acids 48 (n = 1,2; R2 = R3 = H). (C) Competing
transition states for halolactonizations of acids 48 (n=1; R1 = R3 = H).
An inspection of models of these transition states reveals dominating steric interactions between the
benzylic methyene group that is attached to the amidine substituent and either the olefinic R3 group (e.g.,
52, Figure 4A) or the allylic methylene group in the chain linking the double bond with the carboxylic acid
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moiety (e.g., 55 and 57, Figure 4B, C) in the disfavored transition states. The transition states 53, 54, and 56
leading to the observed products do not suffer such unfavorable steric interactions. In a recent study of
bromocycloetherifications of 5-aryl-4(E/Z)-pentenols, Denmark noted that the catalyst directed the
electrophilic bromine ion to one face of the olefin, irrespective of olefin geometry.2d,f Similarly, we find that
the electrophilic bromo or iodo species is preferentially delivered from the same face of the olefin in all
cyclizations of unsaturated pentenoic and hexenoic acids that lack a substituent on the olefinic carbon
atom proximal to the carboxyl group (i.e., 48, n = 1,2 and R3 = H) (see Tables 6–8 and Figure 4B,C). When
the internal carbon atom of the olefin is geminally substituted (i.e., 48, n = 1,2 and R3 = alkyl, aryl) (see
Tables 4,5), however, attack of the electrophilic halogen moiety is from the opposite face.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Applications to Methodological Problems. At the outset of our studies, we identified a number of
synthetic challenges that needed to be addressed in the context of enantioselective halolactonizations.
The first of these was to induce transformations that created new C–Br of C–I at stereogenic centers exo to
a ring; we had now achieved that goal. However, other problems that needed to be solved involved
desymmetrization of prochiral substrates and kinetic resolution of racemic substrates, although there have
been several reports of alternative solutions since we completed our own work.16
The potential of 16 as a catalyst to induce desymmetrization reactions is exemplified by the
bromolactonization of 1,4-dihydrobenzoic acid (58) in the presence of 16 to furnish lactone 59 in 73:27 er
(Equation 5). Although the enantioselectivity in this reaction was modest, the enantiopurity of 59 was
easily improved to 99:1 er after a single recrystallization. This process was then applied in the syntheses of
several synthons of the F ring subunit of the natural product kibdelone C (vide infra).9a Iodolactonization
of 58 could be effected using catalyst 20, but the resultant iodolactone was unstable. On the other hand,
the utility of 20 as a catalyst to promote kinetic resolutions of racemic olefinic acids is illustrated by the
iodolactonizations of 60 and 62 to deliver the corresponding bicyclic iodolactones 61 and 63 in 83:17 er and
78:22 er, respectively (Equations 6 and 7). Both 61 and 63 are important intermediates for the syntheses of
several natural products,17 including sieboldine A17b and phyllanthocin.17d
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O
16 (10 mol %)
CO2H
1
2
3
4
5
6
TBCO (1.2 equiv)
O
(5)
PhMe/CH2Cl2 (1:1)
–50 °C, 4 d
72%, 73:27 er
Br
58
59
99:1 er after one recrystallization
7
8
9
O
O
20 (10 mol %)
NIS (0.5 equiv)
HO
O
(6)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
PhMe/CH2Cl2 (2:1)
–50 °C, 2 d
44%, 83:17 er
I
60
61
O
20 (10 mol %)
NIS (0.5 equiv)
O
HO2C
(7)
PhMe/CH2Cl2 (2:1)
–50 °C, 2 d
43%, 78:22 er
I
62
63
Another important extension of our halolactonization methodology is to the synthesis of
enantioenriched cis-1,2-disubstituted epoxides. The direct epoxidation of Z-disubstituted olefins without
directing groups remains a significant challenge,18 but we discovered that 4(Z)-alkenoic acids can be
readily converted into the corresponding epoxides by a facile two-step process. For example, iodolactone
33e, which was obtained from the cis-disubstituted olefinic acid 32e (Table 6, entry 9), was converted to
cis-epoxide 64 with no loss of enantiopurity simply upon treatment with Cs2CO3 in MeOH (Equation 8). A
similar iodolactonization-epoxidation sequence was utilized in our concise enantioselective synthesis of
(+)-disparlure (vide infra).9b
O
O
Cs2CO3, MeOH
O
OMe
(8)
O
H
rt, 38 h
87%
Cy
64
Cy
I
no loss of optical purity
33e
Application to Natural Product Synthesis: F-Ring Fragments of Kibdelone C.
First isolated in 2007 by Capon and coworkers, kibdelone C (65) is a member of a novel family of
polycyclic xanthone natural products that is produced by Kibdelosporangium sp, a rare soil actinomycete.19
Collectively, compounds belonging to this class possess an array of potentially useful biological activities
that include low nanomolar GI50’s against a panel of human cancer cell lines as well as potent antibacterial
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The Journal of Organic Chemistry
and nematocidal properties. The promising biological activity of 65 coupled with its complex polycyclic
architecture sparked considerable interest in the synthetic community, culminating in two successful
enantioselective syntheses, (+)-kibdelone C completed by Porco,20 and (–)-kibdelone C completed by
Ready.21 A key challenge for both groups was the synthesis of the chiral polyhydroxylated F ring (Scheme
3). Toward this end, for his synthesis of (+)-kibdelone C, Porco utilized 66a, which was prepared in 13 steps
and 15% overall yield.20 Hudlicky subsequently reported an enzymatic approach that provided the related
F ring precursor 66b in three steps, albeit in only 2.2% overall yield.22 Ready’s approach to (–)-kibdelone C
required the use of fragment 67, which was in prepared in seven steps and 30% overall yield.21
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H3C
CH3
N
A
O
OH
OH
Cl
O
O
OH
OH
HO
F
OCH3
OH
65: (+)ꢀkibdelone C
I
CO2Me
O
OH
X
F
or
F
TBSO
OTBS
O
HO
67
Porco
Ready
7 steps (30%)
66a: X = I, 13 steps (15%)
Hudlicky
66b: X = Br, 3 steps (2.2%)
Scheme 3. Fꢀring fragments of kibdelone C used by Porco and Ready
With the view of developing a short entry to cyclohexene derivatives related to 66a,b and 67, we
envisioned that the lactone ent-59 might be a viable intermediate (Scheme 4). Drawing from earlier work
directed toward developing modified catalysts (vide supra), we initially queried whether the simplified
catalyst ent-23b might deliver ent-59 with selectivity comparable to that of ent-16 (see Equation 5).
However, desymmetrization of 58 using ent-23b afforded ent-59 with slightly diminished
enantioselectivity (63:37 er), so we were relegated to using ent-16. In our initial experiments to
desymmetrize 58 via an enantioselective bromolactonization using ent-16, the reaction was performed on
a relatively small scale (100 mg) at low concentrations (0.03 M). However, we found this reaction was
readily scalable to multigram quantities (2.5 g) at higher concentrations (0.1 M). Moreover, we discovered
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that the less expensive brominating agent N-bromosuccinimide (NBS) gave ent-59 in comparable yield
1
2
3
and enantioselectivity to TBCO.
4
5
6
7
8
O
CO2H
citric acid, NMO
K2OsO4—2H2O
ent-16 (10 mol %)
NBS (1.2 equiv)
O
9
PhMe/CH2Cl2 (1:1)
⎼50 °C
after single recrystallization
45%, (>99:1 er)
tꢀBuOH/H2O (1:1)
0 °C
60%, (>20:1 dr)
Br
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
58
ent-59
O
CO2Me
OH
CO2Me
O
OH
OH
OH
K2CO3
MeOH
O
Br
OH
HO
OH
68
69
70
CO2Me
O
2,2ꢀdimethoxy
propane
MOMCl, iꢀPr2NEt
CSA, 4 Å sieves
CH2Cl2, reflux
75% from 68
CH2Cl2, reflux
95%
O
HO
71
S
N
CO2Me
O
CO2H
ONa
75
O
O
LiOH
6
H2O/CH3CN
87%
EDCI—HCl
CH2Cl2
O
MOMO
MOMO
72
74
S
N
O
O
Br
Cl3CBr
O
O
O
O
150 W flood lamp
55% from 70
MOMO
MOMO
76
77
Scheme 4. Synthesis of F-ring fragments of kibdelone C
Our initial foray to induce dihydroxylation of ent-59 was problematic because ent-59 was unstable in
the basic media typical of standard Sharpless or Upjohn reaction conditions,23 so 68 was isolated in <35%
yield and only <4:1 dr. After screening a variety of conditions, we discovered that dihydroxylation of ent-59
in the presence of citric acid proceeded with high selectivity from the less hindered face to deliver 68 in
60% yield (>20:1 dr).24 Treating the lactone 68 with methanol and potassium carbonate initiated a
multistep cascade of reactions involving sequential transesterification and formation of the epoxide 69
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that underwent spontaneous β-elimination to deliver triol 70, which was used without further
purification. Formation of the acetonide moiety of the vicinal diol in 70 then gave 71, and subsequent
protection of the distal hydroxyl group furnished 72 in 71% yield over three steps. Although we did not
pursue the possibility, it is notable that 71, which is available in only four steps and 19% overall yield from
1,4-dihydrobenzoic acid (58) is also a potential F-ring precursor of (+)-kibdelone C.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Our initial plan was to directly install a halogen atom at the β-position of the enoate 72 to provide 73
(Equation 9), but numerous attempts to induce this transformation were unavailing. For example,
treatment of 72 with a variety of reagents such as Br2 and triethylamine,25 NBS, NIS, or I(coll)2PF6 gave no
detectable amounts of the desired product 73. Another approach to prepare 73 was inspired by Bartlett’s
synthesis of (–)-2-chloroshikimic acid,26 but preliminary efforts to apply this procedure to the problem at
hand were unsuccessful. A change of plan was needed, and we turned our attention to the synthesis of 77,
a putative F-ring fragment similar to 67.
CO2Me
O
CO2Me
O
X
(9)
O
O
MOMO
MOMO
X = Cl, Br, I
72
73
In the event, the methyl ester moiety of 72 was saponified to deliver the carboxylic acid 74 in 87% yield
(Scheme 4). The use of CH3CN as solvent in this reaction proved to be critical, because when aqueous
solvent mixtures of THF or MeOH were used, unavoidable epimerization of the C6 stereocenter was
observed. Carbodiimide mediated coupling 74 with 75 afforded the intermediate thiohydroxamate ester 76
that was immediately subjected to a Barton–Hunsdiecker27 halodecarboxylation by irradiation in
bromotrichloromethane to provide vinyl bromide 77 in 55% overall yield from 74. We thus completed a
short synthesis of 77, an alternate F-ring synthon of kibdelone C, in eight steps and 9% overall yield from
1,4-dihydrobenzoic acid (58).
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