Oxidative spirocyclization of phenolic sulfonamides: Scope and applications

Article abstract of DOI:10.1002/chem.201001402

A full account of the oxidative dearomatization of para- and ortho-phenolic sulfonamides is provided together with an overview of the chemistry of the products and their elaboration to building blocks for spirocyclic alkaloids. A concise total synthesis of putative lepadiformine complements the discussion. Making building blocks: The oxidative dearomatization of para- and ortho-phenolic sulfonamides provides building blocks for spirocyclic alkaloids (see scheme). The chemistry of the products of this reaction and a concise total synthesis of putative lepadiformine is given.

Full text of DOI:10.1002/chem.201001402

DOI: 10.1002/chem.201001402
Oxidative Spirocyclization of Phenolic Sulfonamides: Scope and Applications
Huan Liang[a, b] and Marco A. Ciufolini*[a]
Abstract: A full account of the oxidative dearomatization of para- and ortho-phe-
nolic sulfonamides is provided together with an overview of the chemistry of the
products and their elaboration to building blocks for spirocyclic alkaloids. A con-
cise total synthesis of putative lepadiformine complements the discussion.
Keywords: alkaloids · dearomatiza-
tion · lepadiformine · phenols ·
sulfonamides
Introduction
workers.[8] Unfortunately, the high cost of TFE and, espe-
cially, of HFIP overshadows the usefulness of oxidative ami-
dation chemistry. Therefore, we have researched alternative
protocols that eschew the use of such media.
The oxidative amidation of phenols achieves the conversion
of substrates of type 1 into dienones 3 (Scheme 1).[1] The
Initial success in this domain was recorded recently in the
form of an improved procedure for the bimolecular oxida-
tive amidation of phenols in acetonitrile containing 1.3–
1.5 equivalents (relative to the substrate) of trifluoroacetic
acid (TFA).[9] This development encouraged us to explore
similar conditions for the oxidative cyclization of phenolic
sulfonamides, a technology that is central to some ongoing
efforts in our laboratory and that has resulted in the past in
what has been described as a “unique approach”[10] to cylin-
dricine alkaloids.[11] Herein, we disclose a solution to the
foregoing problem, illustrate the scope of the reaction, dis-
cuss aspects of the reactivity of the products thus obtained,
and demonstrate an application of the updated methodology
in the synthesis of the originally proposed,[12] and later cor-
rected,[13] structure of lepadiformine.[14,15]
Scheme 1. The oxidative amidation of phenols. DIB=PhIACTHNUTRGNEUNG(OAc)2.
process entails oxidative activation of the phenol with a hy-
pervalent iodine reagent[2] such as PhI
(OAc)2 (DIB) or oc-
casionally PhI(OCOCF3)2 (PIFA), followed by the capture
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
of the putative reactive intermediate 2 by an appropriate ni-
trogen nucleophile.[3] Intramolecular and bimolecular var-
iants of the reaction are known. In the intramolecular
regime, an oxazoline[4] or sulfonamide[5] serve to intercept
2.[6] In the bimolecular mode, acetonitrile discharges this
function.[7] In its original form, oxidative amidation chemis-
try necessitated the use of fluoro alcohol solvents, for exam-
ple, 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoro-
2-propanol (HFIP). These non-nucleophilic, polar solvents
are indeed the media of choice for many DIB- or PIFA-
mediated transformations, as determined by Kita and co-
Results and Discussion
An HFIP-free procedure for the oxidative cyclization of sul-
fonamides: The results that emanate from studies on bimo-
lecular reactions[9] induced us to examine the DIB-promoted
oxidative cyclization of test substrate 4a to spiropyrrolidine
5a in MeCN, CH2Cl2, or toluene containing TFA, or neat
TFA in the temperature range ꢀ78 to 258C (Table 1). Reac-
tions run at ambient temperature gave the best results. Thus,
portionwise addition of DIB (1.1 equiv) to a dilute solution
(10 mm) of 4a in an appropriate solvent containing TFA
(1.5 equiv) resulted in essentially quantitative conversion
into 5a. The reaction worked equally well in polar (MeCN),
moderately polar (CH2Cl2), and nonpolar (PhMe) solvents.
Only products of oxidative cyclization were detected in re-
[a] H. Liang, Prof. Dr. M. A. Ciufolini
Department of Chemistry, University of British Columbia
2036 Main Mall, Vancouver, BC V6T 1Z1 (Canada)
Fax : (+1)604-822-8710
E-mail: ciufi@chem.ubc.ca
[b] H. Liang
Current address: Department of Chemistry and Chemical Biology
Harvard University, 12 Oxford Street, Cambridge, MA 02138 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001402.
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FULL PAPER
Table 1. Oxidative cyclization of model substrate 4a.
Conditions[a]
Solvent
Yield [%][b]
A
A
A
B
MeCN
CH2Cl2
toluene
TFA
95
95
95
95
[a] Conditions A: A solution of DIB (1.1 equiv) and TFA (1.5 equiv) in
the indicated solvent were added at room temperature by syringe pump
to a solution of 4a (1 equiv) in the same volume of solvent (the final
formal concentration of 4a was 10 mm). Conditions B: A solution of DIB
(1.1 equiv) in TFA was added slowly at room temperature to a solution
of 4a in the same volume of TFA (the final formal concentration of 4a
was 0.3m). [b] After chromatography. TFA=trifluoroacetic acid.
Scheme 3. Presumed mechanism for the formation of 7 and 14.
actions carried out in MeCN: the bimolecular amidation[7]
did not compete. However, it transpired that the reaction
could be more conveniently carried out in neat TFA, a sol-
vent in which one could comfortably operate at a substrate
concentration of 0.3m (Table 1). Yields as high as those ob-
tained in more dilute reactions were thus achieved; further-
more, TFA did not seem to promote the dienone/phenol re-
arrangement[16] of 5a. The new protocol eliminated the need
for HFIP and other cosolvents.
NaHMDS) failed to promote cyclization to 14, which there-
fore must ensue from an intermediate such as 13.
Alkylsulfonamides 4b–f underwent oxidative cyclization
in uniformly good-to-excellent yields upon exposure to DIB
in TFA, and the resulting products were easily purified
(Table 2). The tert-butyl[19] and benzylsulfonamides (Table 2,
entries 2 and 4) afforded slightly lower yields relative to
methyl, trifluoromethyl, cyclopropyl, and CH2Ms sulfona-
mides. This outcome is presumably due to steric effects.
Scope of the para-oxidative cyclization of sulfonamides:
The scope of the reaction with respect to the sulfonamide
was explored with a number of substrates, including the un-
usual compound 4 f (Scheme 2). This substance was pre-
Table 2. Oxidative cyclization of phenolic alkylsulfonamides 4b–f.
Entry
R
Product
Yield [%][b]
1
2
3
4
5
CF3
5b
5c
5d
5e
5 f
94
85
90
89
92
tert-butyl
cyclopropyl
benzyl
ꢀ
CH3SO2CH2
Scheme 2. Preparation of 4 f. MsCl=methanesulfonyl chloride.
[a] These reactions were run under conditions
[b] After chromatography.
B
given in Table 1.
pared by O-deblocking of 7, which emerged fortuitously,
and in high yield when the mesylation of 6 was carried out
with excess MsCl and Et3N (3 and 4 equivalents, respective-
ly) in CH2Cl2 at room temperature. Essentially none of the
expected mesylamide was formed under these conditions.
The pathway that leads to 7 is likely to involve a reaction of
the amine with sulfene 9, thus arising through Et3N-promot-
ed elimination of HCl from MsCl.[17] N-Deprotonation of
zwitterion 10 yields 11, which probably undergoes C-mesyla-
tion by reaction with more MsCl, or possibly with a second
molecule of 9. The presumed intervention of the reactive
species 11 finds support in an observation recorded earlier
in our laboratory. Thus, the treatment of 2-aminobenzalde-
hydes 12 with MsCl and Et3N produced variable amounts of
heterocycle 14 in addition to the expected 15 (Scheme 3).[18]
Treatment of the latter with a base (Et3N, tBuOK, NaH,
All arylsulfonamides reacted efficiently. The yields were
largely insensitive to the nature of the arylsulfonyl group
(Table 3). Sterically hindered sulfonamides (i.e., triisopro-
pylsulfonamide; Table 3, entry 8) or those incorporating
electron-donating substituents on the aromatic ring (i.e., 4-
methoxysulfonamide; Table 3, entry 7) reacted less efficient-
ly, but still in more than 80% yield. All positional isomers
of nitrophenyl (nosyl) sulfonamides cyclized efficiently
(Table 3, entries 2–4).[20] The ortho- and para-nosyl products
are significant because the sulfonamide group can be re-
leased under mild conditions,[21] as detailed by Kan and Fu-
kuyama.[22]
Excellent results were also obtained with amino acid-de-
rived substrates. Derivatives 16 of l-homotyrosinol,[23] in
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M. A. Ciufolini and H. Liang
Table 3. Oxidative cyclization of phenolic arylsulfonamides 4g–o.
Entry
R
Product
Yield [%][b]
1
2
3
4
5
6
7
8
9
4-Me-C6H4
5g
5h
5i
5j
5k
5l
5m
5n
5o
94
95
95
96
93
93
85
83
91
2-O2N-C6H4
3-O2N-C6H4
4-O2N-C6H4
4-Br-C6H4
4-MeC(O)C6H4
4-MeO-C6H4
2,4,6-triisopropylphenyl
2-thienyl
Scheme 4. Oxidative cyclization of amino acid-derived sulfonamides. Ts=
4-toluenesulfonyl.
[a] These reactions were run under conditions
[b] After chromatography.
B
given in Table 1.
for such a decrease. Valine and alanine derivatives 22 and
23 cyclized in high yield, but the reaction failed with phenyl-
alanine-derived 24 (a complex mixture formed; no 27 was
detected).
which the primary OH group was either free or protected
with a group of modest steric demand (e.g, Me), cyclized in
nearly quantitative yield (Table 4). The free OH group in
16a did not compete with the sulfonamide moiety during
oxidative cyclization; that is, no spiropyran product was ob-
served. This result reaffirms that formation of a five-mem-
bered ring is kinetically much more favorable than a 6-mem-
The effect of substitution on the phenolic ring has yet to
be addressed in detail. One such example appears in
Scheme 5. Compound 28, obtained in high yield by iodina-
tion of 4a with bisACTHNUTRGNEUNG
(pyridine)iodonium tetrafluoroborate,[24]
cyclized in over 90% yield. The oxidative cyclization of
phosphoramides[25] was also efficient; for example, 30 ad-
vanced to 33 in 88% yield (Scheme 6). However, phosphina-
mides 31 and 32 produced no 34 or 35.
Table 4. Oxidative cyclization of amino acid-derived phenolic methane-
sulfonamides 16a–e.
Entry
R
Product
Yield [%][b]
1
2
3
4
5
CH2OH
CH2OMe
CHO
CH2OTBDPS
CH2OCPh3
17a
17b
17c
17d
17e
95
95
94
–
Scheme 5. Oxidative cyclization of iodophenol substrates.
–
[a] These reactions were run under conditions
B
given in Table 1.
[b] After chromatography. TBDPS=tert-butyldiphenylsilyl.
bered ring. Indeed, the formation of spiropyrans and espe-
cially spiropiperidines under these conditions tends to be
unsatisfactory. Furthermore, the emerging 17a[20] was config-
urationally homogeneous, as apparent from 19F NMR spec-
troscopic analysis of the corresponding Mosher derivative.
Even the homotyrosinal methanesulfonamide 16c cyclized
in excellent yield, thus indicating that a sensitive formyl
group is well tolerated during the reaction. On the other
hand, derivatives of 16a in which the OH group was
blocked with a sterically demanding protecting group, such
as TBDPS or trityl (Table 4, entries 4 and 5), failed to un-
dergo oxidative amidation and provided an intractable mix-
ture of products instead. Tyrosine derivatives 18 and 19 un-
derwent cyclization in diminished, but still good, yield
(about 80%; Scheme 4).[20] At this time, we can not account
Scheme 6. Behavior of phosphoramides and congeners in oxidative cycli-
zation.
The ortho-oxidative cyclization of sulfonamides: All the ex-
amples seen thus far involve what may be termed the para-
oxidative amidation of a phenol. However, an ortho-variant
of the reaction (i.e., 36 and 37; Table 5)[25] may provide in-
teresting opportunities because the resulting dienones dis-
play rich chemistry that can be harnessed meaningfully in a
synthetic context.[26] A study of the cyclization of 36 again
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Oxidative Cyclization of Phenolic Sulfonamides
FULL PAPER
Table 5. Oxidative ortho-cyclization of phenolic methanesulfonamide 36.
Table 7. Tandem oxidative ortho-cyclization IMDA reaction of sulfona-
mides 41.
Conditions[a]
Solvent
Temperature
Yield [%][b]
A
A
A
A
A
A
A
A
A
B
CH2Cl2
THF
toluene
toluene/MeCN (10:1)
toluene/MeCN (10:1)
toluene/MeCN (10:1)
toluene/MeCN (10:1)
toluene/MeCN (10:1)
toluene/MeCN (10:1)
TFA
ꢀ788C!rt
ꢀ788C!rt
ꢀ788C!rt
ꢀ788C!rt
ꢀ308C!rt
08C!rt
rt
608C
reflux
rt
50
45
51
59
52
50
50
45
45
60
Entry
R1
R2
Y
Product
Yield [%][b]
1
2
3
4
5
H
H
H
H
H
H
H
H
42a
42b
42c
42d
42e
40
31
43
34
27
Br
Me
H
ꢀ
CH2=CH
H
ꢀ
CH2=CH
H
[a] The oxidative cyclization step was carried out under conditions B
given in Table 5. Upon complete conversion of 40 into 41 (TLC), the
mixture was diluted with toluene (2 volumes) and heated to 1208C (oil-
bath temperature) until completion of the IMDA step. [b] After chroma-
tography.
[a] Conditions A: A solution of 36 in the stated solvent was added slowly
(syringe pump) at room temperature to a solution of DIB (1.1 equiv) and
TFA (1.5 equiv) in the same solvent (the final formal concentration of 36
was 10.0 mm). Conditions B: A solution of DIB (1.1 equiv) in TFA was
added at room temperature to a solution of 36 in the same volume of
TFA (the final formal concentration of 36 was 0.3m). [b] After chroma-
tography.
ed eliminative ring-opening of 3-sulfolene and trapping of
the intermediate sulfinate with N-chlorosuccinimide (NCS).
This affords a mixture of the two geometric isomers of the
product, which are, remarkably, separable by column chro-
matography, albeit in moderate overall yield. Oxidative cyc-
lization of 40 proceeded normally, but the primary products
41 resisted Diels–Alder cyclization at or near room temper-
ature. Furthermore, although 41 was readily detectable by
NMR spectroscopic analysis as the major component of the
crude reaction mixture, chromatographic purification pro-
ceeded with major loss of material. It proved expedient to
dilute the crude reaction mixture with toluene and heat the
resulting solution to 1208C to effect IMDA cyclization. Tet-
racyclic products 42 were thus isolated in 30–40% yield.[20]
Note that the diene moiety of 41d and 41e behaved exclu-
sively as the dienophilic component of the IMDA step.[30]
Related tandem processes initiated by para-oxidative cyc-
lization of dienic sulfonamides have also been demonstrat-
ed.[30] To wit, treatment of 43 with DIB in TFA, followed by
dilution with toluene and heating produced 45 in 39% yield
(Scheme 7). More importantly, the same reaction of 46 fur-
revealed that the reaction was best carried out in neat TFA
at room temperature and at a substrate concentration of
0.3m. However, the ortho-oxidative amidation was generally
less efficient than the para mode (Table 6). Substituents at
the phenolic para position, regardless of electronic character
(i.e., an electron-withdrawing Br atom in 38a versus an elec-
tron-donating Me group in 38b), resulted in lower yields.
The reaction failed altogether with 2-nosyl substrate 38c (a
mixture of products and no 39c were formed).
Table 6. Oxidative ortho-cyclization of various phenolic sulfonamides 38.
Entry
R1
R2
Conditions[a]
Product
Yield [%][b]
1
2
3
4
5
Br
Br
Me
Me
H
Me
Me
Me
Me
A
B
A
B
39a
39a
39b
39b
39c
30
29
51
47
–
ꢀ
2-O2N C6H4
A or B
[a] Conditions A and B are the same as in Table 5. [b] After chromatog-
raphy.
The fact that ortho-dienones such as 39 readily undergo
the Diels–Alder reaction[27] induced us to investigate a
tandem ortho-oxidative amidation/IMDA reaction[28] of vi-
nylsulfonamides 40 (Table 7).[25] Compounds 40a–c emerged
directly upon reaction of the corresponding free amines
with commercially available 2-chloroethylsulfonyl chloride.
Dienic substrates 40d and 40e were prepared by reaction of
the free amine with the trans and cis isomers of 1-(1,3-buta-
dien)ylsulfonyl chloride, respectively. The reported method
for the synthesis of this material[29] involves nBuLi-promot-
Scheme 7. Tandem para-oxidative amidation, that is, an IMDA reaction.
IMDA=intramolecular Diels–Alder reaction.
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M. A. Ciufolini and H. Liang
nished an 8:1 mixture of 47 and 48 (major and minor prod-
ucts, respectively), but in moderate yield. Note that the
latter compounds possess the trans-ring fusion of the deca-
line system.
The stereochemical outcome of the reaction that led to 47
may be rationalized as delineated in Scheme 8. The action
of DIB on the substrate initially yields azaspirane 49
advent of an improved procedure for the oxidative cycliza-
tion of sulfonamides provided an opportunity to revisit this
transformation and other aspects of the chemistry of spiro-
cyclic products that we had explored only briefly in the past.
These studies would lay the groundwork for future investi-
gations toward alkaloids such as polycitorol A (53)[33] and
lepadiformine (55)[12–15] (Scheme 9).
Scheme 9. Azaspirocyclic natural products of current interest.
Scheme 8. Mechanistic hypothesis for the oxidative amidation, that is, an
IMDA reaction of 43.
Foremost on our agenda was the optimization of the Mi-
chael cyclization of substrates 17, thus leading to compounds
58 (Scheme 10), which are key building blocks for the alka-
(Scheme 8; R=CH2OH), which can undergo IMDA cycliza-
tion either from conformer anti-49 or syn-49 (syn and anti
refer to the relative orientation of the sulfonyl and R
groups). Clearly, anti-49 is energetically preferred relative to
syn-49, which suffers from a greater degree of steric com-
pression between the SO2 and R moieties. The primary
IMDA adducts are undoubtedly the cis-decaline products 50
(minor) and 51. The TFA still present in the medium may
facilitate equilibration of the ketone with the corresponding
enol, thus leading to epimerization of cis-decaline to the
trans isomer.[31]
Desymmetrization of dienones obtained by para-oxidative
amidation of sulfonamides: It is recognized that the spiro
carbon atom in the transient 49 is not stereogenic, whereas
it is becomes stereogenic in 47. The IMDA step occurs se-
lectively at the pro-S double bond of 49, thereby desymme-
trizing the “locally symmetrical” dienone and selectively in-
ducing the S configuration of the spiro center in 47. The ste-
reocontrolled creation of stereogenic spirocenters through a
dienone desymmetrization strategy is central to a number of
our past and present synthetic endeavors. A recent review
highlights this principle and illustrates some key applications
in total synthesis.[32] It is also apparent from the above dis-
cussion that the sulfonyl segment, far from being merely a
modulator of the reactivity of the nitrogen atom (i.e., a pro-
tecting group), does indeed function as an integral compo-
nent of the target molecular architecture. Such a notion was
first explored during our synthesis of cylindricine C,[11] in
which a key step was the base-promoted stereoselective Mi-
chael cyclization of dienones of type 17 (see below). The
Scheme 10. Dienone desymmetrization through the Michael cyclization
of methanesulfonamides.
loids in Scheme 9. This step establishes the configuration of
the spiro center through a selective 1,4-addition of the anion
of the sulfonamide to one of the diastereotopic double
bonds of the enone, thereby desymmetrizing that “locally
symmetrical” moiety. In its original form,[11] this operation
was carried out by treatment of protected variants of 17a
(i.e., 17b, 17d, and 56) with KHMDS at ꢀ1008C. It will be
recalled that 17d is unavailable by direct cyclization of 16d
(Table 4). Indeed, 17d and substrate 56 were prepared by
protection of the OH group in 17a with the appropriate silyl
chloride. The diastereoselectivity observed in the cyclization
step seemed to correlate with the steric demand of the O-
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Oxidative Cyclization of Phenolic Sulfonamides
FULL PAPER
protecting group, thus attaining a maximal level with sub-
strate 17d (7:1 in favor of the desired 58a). This outcome is
consistent with a preferential reaction from conformer anti-
57 of the metalated sulfonamide, which experiences a lesser
degree of steric compression relative to syn-57.
ties were easier to determine at the stage in which 58a and
59a resulted (a summary appears in Table 9). A higher level
of stereocontrol was indeed achieved; however, contrary to
Table 9. Effect of bases and temperature on the Michael cyclization of
17a.
A more detailed study of the reaction was undertaken to
improve the diastereoselectivity further. It soon transpired
that the temperature and mode of addition are the primary
determinants of stereocontrol (Table 8). Thus, highest selec-
tivity was observed when the base was added to the sub-
strate at ꢀ1008C. On the other hand, no set of conditions
improved the diastereomeric ratio beyond 7:1 in favor of
58a.
Entry[a]
Base
T [8C]
Yield [%][b]
58a/59a
1
2
3
4
5
LiHMDS
LiHMDS
LiHMDS+CuCN
NaHMDS
KHMDS
ꢀ78
67
78
78
77
79
6:1
ꢀ100
ꢀ100
ꢀ100
ꢀ100
14:1
14:1
8:1
Table 8. Effect of bases and temperature on the Michael cyclization of
17d.
7:1
[a] Base was added to a solution of the substrate. [b] Overall yield of 58a
from 17a over two steps and after chromatography.
Entry Mode of
addition[a]
T [8C] Base
Yield [%][b] 58a/59a
what would be predicted based on the model of Scheme 11,
the selectivity increased with the Lewis acidity of the metal
counterion. Thus, the best results (14:1 in favor of 58a)
were attained with LiHMDS, whereas Na and K bases af-
forded the same selectivity as with the O-TBDPS substrate.
We rationalize this result by invoking cyclization through a
rigid chelate of the initially formed lithium alkoxide with
the sulfonamido nitrogen atom (refer to 63; Scheme 12).
1
2
3
4
5
6
A
A
A
A
A
B
ꢀ78
KHMDS
72
81
77
80
3:1
7:1
7:1
ꢀ100
ꢀ100
ꢀ100
ꢀ100
ꢀ100
KHMDS
NaHMDS
LiHMDS
7:1
LiHMDS+CuCN 79
LiHMDS 58
7:1
1.5:1
[a] A: Base was added to the substrate. B: Substrate was added to the
base. [b] After chromatography. HMDS=bis(trimethylsilyl)amide.
A search for alternative factors that could influence prod-
uct distribution led to the appealing surmise that electrostat-
ic forces might amplify the steric repulsion between the sul-
fonyl and hydroxymethyl groups if the cyclization were car-
ried out with the dianion of 17a (Scheme 11). Experiments
designed to probe this hypothesis revealed that it was con-
venient to O-protect the primary product of the Michael
cyclization step, that is, the mixture of 61 and 62, as the
TBDPS derivative prior to purification. Yields and selectivi-
Scheme 12. Mechanistic hypothesis for the cyclization of the dilithio
derivative of 17a.
The justification for this hypothesis rests upon the observa-
tion that the NH group in a secondary sulfonamide displays
reactivity similar to that of an alcohol.[5] It segues that the
nitrogen atom of a tertiary sulfonamide is likely to be ether-
like in character and consequently capable of ligating suita-
bly Lewis acidic metal ions.
Reductive chemistry of ketones of the type 58a: A second
aspect of this study pertained to the reductive chemistry of
ketones of the type 58a (Scheme 13). The synthesis of cylin-
dricine alkaloids involves the reduction of 58a to 69. In the
past, we had reached 69 from 71, the triple thiophenol
adduct of 56, through desulfurization by using RaNi.[11]
When this reaction was carried out on multigram scales, the
desired 69 was accompanied by an unidentified byproduct
that was difficult to separate. Fortunately, desulfurization of
thioketals 67 and 68 with the NiCl2/NaBH4 system in a mix-
Scheme 11. Mechanistic hypothesis for the cyclization of the dianion of
17a.
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M. A. Ciufolini and H. Liang
of 52, we envisioned that 75 would derive from 69 by elabo-
ration into 76 and desulfonylative fragmentation of the
latter.
The sequence that led to 75 appears in Scheme 15. Alky-
lation of the anion of 69 with 1-octene oxide followed by
Dess–Martin oxidation yielded 76, which upon treatment
Scheme 13. Reductive chemistry of ketones 58a and 64. a) Pd(C), H2
(1 atm), EtOH (65: 87, 66: 85%); b) PhSH, BF3OEt2, CH2Cl2 (67: 84, 68:
86%); c) NiCl2, NaBH4, MeOH/EtOH (69: 71, 70: 70%); d) the same as
(b) but with PhSH (20 equiv; 71: 77, 72: 75%); e) RaNi, EtOH (71!69:
77%).[11] TBDPS=tert-butyldiphenylsilyl.
ture of MeOH and EtOH[34] proceeded without byproduct
formation. It should be noted that anhydrous NiCl2 gave su-
perior results in this step relative to hydrated NiCl2. The thi-
oketals were prepared in the customary fashion from ke-
tones 65 and 66 obtained by hydrogenation over Pd(C) of
58a and 64 (the latter was made in racemic form by the
base-promoted cyclization of 5a).
Scheme 15. Elaboration of 69 into 75 and reductive chemistry thereof.
a) tBuLi, ꢀ788C, 1-octene oxide, BF3OEt2; b) Dess–Martin periodinane
(89% from 69); c) DBU, DMF, 10 min (93%). DBU=1,8-diazabicyclo-
AHCTUNGTREG[NNUN 5.4.0]undec-7-ene.
with DBU in DMF provided 75 in 93% yield. Other amine
bases (Et3N, iPr2NEt) were less satisfactory. The crucial re-
duction of 75 to 74 proved to be difficult. Thus, hydrogena-
tion over Pd(C) or reaction with Et3SiH in the presence of
the Wilkinson catalyst, CuH (Stryker reagent)[35] with or
without TMSCl, NaTeH,[36] and other agents[37] gave mix-
tures of desired 74 accompanied by the tricyclic product of
intramolecular reductive amination. The latter consisted of
an inseparable mixture of 78 and 79. Substance 79 is recog-
nized as the O-TBDPS derivative of putative lepadiformine
54.
A final objective was to achieve the chemoselective re-
duction of N-unprotected enones of the type 75 to 74
(Scheme 14), without concomitant intramolecular reductive
A more efficient transformation was the conversion of 75
into 79 by hydrogenation over the Adams catalyst
(Scheme 16). Product 79 emerged as a single diastereomer
1
within the limits of 300 MHz H NMR spectroscopic analy-
sis. Subsequent deprotection furnished 54, namely, the origi-
nally proposed – but incorrect – structure of lepadiformine
(Scheme 9). A more efficient conversion of 77 into 54 was
achieved by TBAF-induced desilylation/SO2 extrusion fol-
lowed by hydrogenation of the transient 80 over the Adams
catalyst. In this manner, 54 emerged in 31% yield from 17a
over eight steps.[38] The structure of 54 was confirmed by an
X-ray crystallographic study of its HCl salt.[20]
Scheme 14. Strategy for polycitorol-type natural products.
amination. This goal was perceived as an important step
toward to a possible total synthesis of polycitorol-type[32]
natural products. Such an effort would rest on principles de-
veloped earlier during the synthesis of 52,[11] a key step in
which the directed reduction of an iminium species with
NaBHACHTUNGTRENNUNG(OAc)3 (i.e., 73) ensued upon cyclization of a ketone
akin to 74. In contrast, premature reductive cyclization of
the nascent 74 during reduction of 75 would lead to tricyclic
intermediates that displayed the incorrect configuration of
the butyl side chain. By retracing the logic of the synthesis
Scheme 16. Synthesis of putative lepadiformine. a) H2, PtO2, EtOAc
(80%); b) TBAF (96%); c) TBAF, THF, then H2, PtO2 (92%). TBAF=
tetrabutylammonium fluoride.
13268
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 13262 – 13270

Oxidative Cyclization of Phenolic Sulfonamides
FULL PAPER
HRMS (ESI): m/z: calcd for C10H13NO3S: 250.0514 [M+Na]+; found
250.0512.
Conclusion
General procedure for the tandem ortho-cyclization/intramolecular
Diels–Alder reaction of phenolic vinylsulfonamides (preparation of 42c):
A solution of DIB (177 mg, 0.55 mmol) in TFA (0.5 mL) was added
This report has provided an overview of the para- and
ortho-oxidative cyclization of phenolic sulfonamides and of
aspects of the chemistry of the resulting products. The latter
are essentially unavailable by any other means. Further-
more, they are demonstrably useful building blocks for the
synthesis of nitrogenous compounds, including spirocyclic al-
kaloids and possibly also substances of interest in medicinal
chemistry. Applications of the findings described herein are
actively being pursued and additional results in this area
shall be reported in due course.
slowly at room temperature to
a stirred solution of 40c (128 mg,
0.5 mmol) in TFA (0.5 mL). The final formal substrate concentration was
0.3m. Upon consumption of the starting material (15 min, TLC), the mix-
ture was diluted with twice the volume of toluene (2 mL) and heated to
reflux. Upon completion of the reaction (5 h, TLC), the mixture was
evaporated to dryness under reduced pressure and the residue was puri-
fied by flash chromatography (EtOAc/hexane 1:2) to afford the spirocy-
clic product 42c as a colorless foam (54 mg, 43% yield). Small crystals
formed over time, thus enabling an X-ray crystallographic study to be
conducted. 1H NMR (300 MHz, CDCl3, 258C, TMS): d=6.09 (dt, 3J1 =
3J2 =6.9, 4J=1.6 Hz, 1H), 3.76–3.66 (m, 1H), 3.47–3.40 (m, 2H), 3.37–
2
3
3.30 (m, 1H), 3.02–2.91 (m, 1H), 2.83 (dt, J=14.5, J1 =3J2 =2.3 Hz, 1H),
2.31–2.18 (m, 1H), 2.17–2.05 (m, 1H), 2.05–1.92 (m, 2H), 1.94 (d, 3J=
1.6 Hz, 3H), 1.63–1.54 ppm (m, 1H); 13C NMR (75 MHz, CDCl3, 258C,
TMS): d=202.4, 139.8, 125.8, 71.3, 56.6, 48.8, 45.7, 44.7, 29.6, 27.3, 27.1,
21.7 ppm; IR (film): n˜ =1731 (C=O) cmꢀ1; HRMS (ESI): m/z: calcd for
C12H15NO3S: 276.0670 [M+Na]+; found 276.0664.
Experimental Section
Representative procedure for the para-oxidative cyclization of phenolic
sulfonamides (preparation of 17a):
A solution of DIB (354 mg,
1.1 mmol) in TFA (1.7 mL) was added slowly at room temperature to a
stirred solution of 16a (212 mg, 1.0 mmol) in TFA (1.7 mL). The final
formal substrate concentration was 0.3m. Upon completion of the reac-
tion (10 min, TLC), the mixture was evaporated to dryness under re-
duced pressure and the residue was purified by flash chromatography
(1% MeOH in EtOAc) to afford the spirocyclic product 17a as a light
yellow foam (245 mg, 95%). Small crystals formed over time, thus ena-
bling an X-ray crystallographic study to be conducted. [a]D22 =ꢀ20.38
(c=1.1 in acetone); 1H NMR (300 MHz, [D6]acetone, 258C, TMS): d=
Acknowledgements
We thank the University of British Columbia, the Canada Research
Chair Program, CFI, BCKDF, NSERC, CIHR, and MerckFrosst Canada
for support of our program. H.L. is the recipient of the UGF Fellowship
and the G.E. Laird Research Fellowship.
7.26 (dd, 3J
2A
3J (H,H)=3.0 Hz, 1H), 6.16 (dd, 3J
6.10 (dd, J
C
R
1ACHTUNGTRENN(UNG H,H)=9.9,
C
E
CHTUNGTRENNUNG
3
3
(m, 1H), 3.82–3.72 (m, 2H), 3.00 (s, 3H), 2.61–2.33 (m, 2H), 2.24–2.13
(m, 1H), 1.99–1.89 ppm (m, 1H); 13C NMR (75 MHz, [D6]acetone, 258C,
TMS): d=184.4, 152.7, 148.7, 127.7, 127.3, 64.2, 63.9, 63.1, 39.3, 37.7,
[1] Review: a) M. A. Ciufolini, N. A. Braun, S. Canesi, M. Ousmer, J.
Chang, D. Chai, Synthesis 2007, 3759–3772; b) M. A. Ciufolini, S.
Canesi, M. Ousmer, N. A. Braun, Tetrahedron 2006, 62, 5318–5337;
c) M. A. Ciufolini, H. Liang in Biomimetic Organic Synthesis (Eds.:
E. Poupon, B. Nay), Wiley-VCH, Weinheim, 2010.
26.5 ppm; IR (film): n˜ =3417 (OH), 2929, 1667 (C=O), 1328 cmꢀ1
;
HRMS (ESI): m/z: calcd for C11H15NO4SNa: 280.0619 [M+Na]+; found
280.0619.
Representative procedure for the oxidative cyclization of phenolic phos-
phoramides (preparation of 33): A solution of DIB (425 mg, 1.3 mmol) in
TFA (2.1 mL) was added slowly at room temperature to a stirred solution
of 30 (310 mg, 1.2 mmol) in TFA (2.1 mL). The final formal substrate
concentration was 0.3m. Upon completion of the reaction (10 min, TLC),
the mixture was evaporated to dryness under reduced pressure and the
residue was purified by flash chromatography (6% MeOH in EtOAc) to
afford the spirocyclic product 33 as a light yellow oil (270 mg, 88%).
1H NMR (300 MHz, CDCl3, 258C, TMS): d=6.84 (d, 3J=10.1 Hz, 2H),
6.16 (d, 3J=10.1 Hz, 2H), 3.66 (s, 3H), 3.62 (s, 3H), 3.54–3.47 (m, 2H),
2.09–2.01 ppm (m, 4H); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=
185.3, 151.5, 127.1, 61.99 (61.93), 53.43 (53.36), 48.94 (48.87), 40.39
[2] Reviews: a) R. M. Moriarty, J. Org. Chem. 2005, 70, 2893–2903;
b) T. Wirth, Angew. Chem. 2005, 117, 3722–3731; Angew. Chem. Int.
Ed. 2005, 44, 3656–3665; c) H. Hamamoto, G. Anilkumar, H.
Tohma, Y. Kita, Chem. Eur. J. 2002, 8, 5377–5383; d) V. Zhdankin
P. J. Stang, Chem. Rev. 2002, 102, 2523–2584; e) R. M. Moriarty, O.
Prakash, Org. React. 2001, 57, 327–415; f) P. J. Stang, V. Zhdankin,
Chem. Rev. 1996, 96, 1123–1178; g) A. Varvoglis, Hypervalent
Iodine in Organic Synthesis, Academic Press, San Diego, 1997.
[3] For a more thorough mechanistic discussion of the oxidative dearo-
matization of phenols promoted by hypervalent iodine reagents, see:
L. Pouysꢁgu, D. Deffieux, S. Quideau, Tetrahedron 2010, 66, 2235–
2261.
[4] a) N. A. Braun, M. A. Ciufolini, K. Peters, E.-M. Peters, Tetrahedron
Lett. 1998, 39, 4667–4670; b) N. A. Braun, M. Ousmer, J. D. Bray,
D. Bouchu, K. Peters, E.-M. Peters, M. A. Ciufolini, J. Org. Chem.
2000, 65, 4397–4408; c) M. Ousmer, N. A. Braun, C. Bavoux, M.
Perrin, M. A. Ciufolini, J. Am. Chem. Soc. 2001, 123, 7534–7538.
[5] a) S. Canesi, P. Belmont, D. Bouchu, L. Rousset, M. A. Ciufolini,
Tetrahedron Lett. 2002, 43, 5193–5195; b) S. Canesi, PhD Thesis,
Universitꢁ Claude Bernard Lyon 1 (France), 2004.
(40.25), 25.14 (25.01) ppm; IR (film): n˜ =1662 (C=O), 1251, 1016 cmꢀ1
;
HRMS (EI, 70 eV): m/z: calcd for C11H16NO4P: 257.0817; found
257.0821.
Representative procedure for the ortho-oxidative cyclization of phenolic
sulfonamides (preparation of 37): A solution of DIB (354 mg, 1.1 mmol)
in TFA (1.7 mL) was added slowly at room temperature to a stirred solu-
tion of 36 (230 mg, 1.0 mmol) in TFA (1.7 mL). The final formal sub-
strate concentration was 0.3m. Upon completion of the reaction (10 min,
TLC), the mixture was evaporated to dryness under reduced pressure
and the residue was purified by flash chromatography (EtOAc/hexane
2:1) to afford the spirocyclic product 37 as a light-yellow oil (136 mg,
60%). 1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.01 (ddd, 3J1 =9.8,
3J2 =5.8, 4J=0.7 Hz, 1H), 6.55 (dd, 3J=9.6, 4J=0.8 Hz, 1H), 6.16 (ddd,
3J1 =9.6, 3J2 =5.8, 4J=0.9 Hz, 1H), 6.05 (dd, 3J1 =9.8, 4J=0.8 Hz, 1H),
3.78–3.57 (m, 2H), 2.96 (s, 3H), 2.27–1.97 ppm (m, 4H); 13C NMR
(75 MHz, CDCl3, 258C, TMS): d=201.6, 146.1, 142.0, 124.9, 119.8, 73.2,
[6] For related reactions in which a secondary amine functions at the
nucleophilic trap, see: a) G. Scheffler, H. Seike, E. J. Sorensen,
Angew. Chem. 2000, 112, 4783–4785; Angew. Chem. Int. Ed. 2000,
39, 4593–4596; b) H. Seike, E. J. Sorensen, Synlett 2008, 695–701;
c) H. Mizutani, J. Takayama, Y. Soeda, T. Honda, Tetrahedron Lett.
2002, 43, 2411–2414; d) H. Mizutani, J. Takayama, Y. Soeda, T.
Honda, Heterocycles 2004, 62, 343–355; e) H. Mizutani, J. Takaya-
ma, T. Honda, Synlett 2005, 328–330.
49.4, 39.7, 39.5, 22.8 ppm; IR (film): n˜ =1655 (C=O); 1318, 1147 cmꢀ1
;
[7] S. Canesi, D. Bouchu, M. A. Ciufolini, Org. Lett. 2005, 7, 175–177.
Chem. Eur. J. 2010, 16, 13262 – 13270
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13269

M. A. Ciufolini and H. Liang
[8] a) Y. Tamura, T, Yakura, J. Haruta, Y. Kita, J. Org. Chem. 1987,
52, 3927–3930; b) Y. Kita, H. Tohma, K. Kikuchi, M. Inagaki, T.
Yakura, J. Org. Chem. 1991, 56, 435–438; c) Y. Kita, H. Fujioka,
Pure Appl. Chem. 2007, 79, 701–716.
[9] H. Liang, M. A. Ciufolini, J. Org. Chem. 2008, 73, 4299–4301.
[10] S. M. Weinreb, Chem. Rev. 2006, 106, 2531–2549.
[19] The preparation of 4c involved an oxidation of the corresponding
tert-butyl sulfinamide with meta-chloroperoxybenzoic acid
(MCPBA), as dictated by the instability of the tert-butylsulfonyl
chloride derivative; a) P. Sun, S. M. Weinreb, M. Shang, J. Org.
Chem. 1997, 62, 8604–8608; b) J. F. King, J. Y. L. Lam, V. Dave, J.
Org. Chem. 1995, 60, 2831–2834; the tert-butylsulfinamide com-
pound itself proved to be a poor substrate for oxidative cyclization
(as a result of the formation of a mixture of products).
[11] S. Canesi, D. Bouchu, M. A. Ciufolini, Angew. Chem. 2004, 116,
4436–4438; Angew. Chem. Int. Ed. 2004, 43, 4336–4338.
[20] The X-ray structures of compounds 5i, 5j, 17a, 21, 42a (H. Liang, S.
Canesi, B. O. Patrick, M. A. Ciufolini, Z. Kristallogr. New Cryst.
Struct. 2009, 224, 83–84), 42b, 42c, and the hydrochloride salt of 54
are provided in the Supporting Information.
[12] J. F. Biard, S. Guyot, C. Roussakis, J. F. Verbist, J. Vercauteren, J. F.
Weber, K. Boukef, Tetrahedron Lett. 1994, 35, 2691–2694.
[13] a) H. Abe, S. Aoyagi, C. Kibayashi, J. Am. Chem. Soc. 2000, 122,
4583–4592; b) P. Sun, C. Sun, S. M. Weinreb, Org. Lett. 2001, 3,
3507–3510; c) T. J. Greshock, R. L. Funk, Org. Lett. 2001, 3, 3511–
3514; d) H. Abe, S. Aoyagi, C. Kibayashi, Angew. Chem. 2002, 114,
3143–3146; Angew. Chem. Int. Ed. 2002, 41, 3017–3020; e) P. Sun,
C. Sun, S. M. Weinreb, J. Org. Chem. 2002, 67, 4337–4345; f) H.
Abe, S. Aoyagi, C. Kibayashi, J. Am. Chem. Soc. 2005, 127, 1473–
1480; g) review: S. M. Weinreb, Acc. Chem. Res. 2003, 36, 59–65.
[14] For the total syntheses of lepadiformine, see references [10] and
[13]; a) J. Liu, R. P. Hsung, S. D. Peters, Org. Lett. 2004, 6, 3989–
3992; b) P. Schꢂr, P. Renaud, Org. Lett. 2006, 8, 1569–1571; c) J. J.
Caldwell, D. Craig, Angew. Chem. 2007, 119, 2685–2688; Angew.
Chem. Int. Ed. 2007, 46, 2631–2634; d) B. Lygo, E. H. M. Kirton, C.
Lumley, Org. Biomol. Chem. 2008, 6, 3085–3090; e) P. Vital, M.
Hosseini, M. S. Shanmugham, C. H. Gotfredsen, P. Harris, D.
Tanner, Chem. Commun. 2009, 1888–1890; f) A. M. Meyer, C. E.
Katz, S.-W. Li, D. Vander Velde, J. Aube, Org. Lett. 2010, 12, 1244–
1247; g) S.-L. Mei, G. Zhao, Eur. J. Org. Chem. 2010, 1660–1668;
h) M. Fujitani, M. Tsuchiya, K. Okano, K. Takasu, M. Ihara, H. To-
kuyama, Synlett 2010, 822–826; synthetic studies: i) W. H. Pearson,
N. S. Barta, J. W. Kamp, Tetrahedron Lett. 1997, 38, 3369–3372;
j) W. Oppolzer, C. G. Bochet, Tetrahedron: Asymmetry 2000, 11,
4761–4770; k) R. Hunter, P. Richards, Synlett 2003, 271–273; l) E.
Miyazawa, T. Sakamoto, Y. Kikugawa, J. Org. Chem. 2003, 68,
5429–5432; m) F. Diaba, E. Ricou, J. Bonjoch, Tetrahedron: Asym-
metry 2006, 17, 1437–1443; n) M. Lee, T. Lee, E.-Y. Kim, H. Ko, D.
Kim, S. Kim, Org. Lett. 2006, 8, 745–748; o) H. Mihara, T, Shibu-
guchi, A. Kuramochi, T. Ohshima, M. Shibasaki, Heterocycles 2007,
72, 421–438; biological activity: p) M. Juge, N. Grimaud, J.-F. Biard,
M.-P. Sauviat, M. Nabil, J.-F. Verbist, J.-Y. Petit, Toxicon 2001, 39,
1231–1237; q) M. P. Sauviat, J. Vercauteren, N. Grimaud, M. Juge,
M. Nabil, J.-Y. Petit, J.-F. Biard, J. Nat. Prod. 2006, 69, 558–562.
[15] Reviews: see references [10] and [13g]; a) G. Dake, Tetrahedron
2006, 62, 3467–3492; b) C. Kibayashi, S. Aoyagi, H. Abe, Yuki
Gosei Kagaku Kyokaishi 2007, 65, 805–819; c) P. Schꢂr, S. Cren, P.
Renaud, Chimia 2006, 60, 131–141; d) J. Liu, R. P. Hsung, Chem-
tracts 2005, 18, 321–330; e) C. Kibayashi, Chem. Pharm. Bull. 2005,
53, 1375–1386; f) C. Kibayashi, S. Aoyagi, H. Abe, Bull. Chem. Soc.
Jpn. 2003, 76, 2059–2074; g) W. H. Pearson, Pure Appl. Chem. 2002,
74, 1339–1358.
[21] Some examples are provided in references [5b].
[22] T. Kan, T. Fukuyama, Chem. Commun. 2004, 353–359.
[23] A practical route to these substances is described in H. Liang, Y.
Zhou, M. Ciufolini, Synthesis 2010, 2515–2520.
[24] a) J. Barluenga, J. M. Gonzꢃlez, P. J. Campos, G. Asensio, Angew.
Chem. 1985, 97, 341–342; Angew. Chem. Int. Ed. Engl. 1985, 24,
319–320; b) J. Barluenga, J. M. Gonzꢃlez, P. J. Campos, G. Asensio,
Tetrahedron Lett. 1986, 27, 1715–1718; c) K. Muniz, Synlett 1999,
1679. This reagent was superior to NIS or I2.
[25] This transformation was first achieved in our laboratory by S.
Canesi using a HFIP-based procedure; see reference [5b].
[26] See, for example: a) I. Drutu, J. Njardson, J. Wood, Org. Lett. 2002,
4, 493–496; b) A. Bꢁrubꢁ, I. Drutu, J. L. Wood, Org. Lett. 2006, 8,
5421–5424.
[27] See Reference [26] as well as: a) M. Breuning, E. J. Corey, Org.
Lett. 2001, 3, 1559–1562; b) M. Yu, S. J. Danishefsky, J. Am. Chem.
Soc. 2008, 130, 2783–2785; c) A. E. Hayden, J. DeChancie, A. H
George, M. Dai, M. Yu, S. J. Danishefsky, K. N. Houk, J. Org.
Chem. 2009, 74, 6770–6776; d) Y. L. Dory, A.-L. Roy, P. Soucy, P.
Deslongchamps, Org. Lett. 2009, 11, 1197–1200; e) P.-H. Lu, C.-S.
Yang, B. Devendar, C.-C. Liao, Org. Lett. 2010, 12, 2642–2645.
[28] Review: E. Ciganek, Org. React. 1984, 32, 1–374.
[29] Y. S. Lee, E. K. Ryu, K.-Y. Yun, Y. H. Kim, Synlett 1996, 247–248.
[30] H. Liang, M. A. Ciufolini, Org. Lett. 2010, 12, 1760–1763.
[31] It remains unclear why isomerization occurred in the cases of 50
and 51, but not with 45.
[32] H. Liang, M. A. Ciufolini, Tetrahedron 2010, 66, 5884–5892.
[33] H. H. Issa, J. Tanaka, R. Rachmat, A. Setiawan, A. Trianto, T. Higa,
Mar. Drugs 2005, 3, 78–83.
[34] a) T. G. Back, D. L. Baron, K. Yang, J. Org. Chem. 1993, 58, 2407–
2413; b) J. M. Khurana, G. Kukreja, Synth. Commun. 2002, 32,
1265–1269.
[35] a) W. S. Mahoney, D. M. Brestensky, J. M. Stryker, J. Am. Chem.
Soc. 1988, 110, 291–293; J. M. Stryker, J. Am. Chem. Soc. 1988, 110,
291–293; b) D. W. Lee, J. Yun, Tetrahedron Lett. 2005, 46, 2037–
2039.
[36] a) M. Yamashita, Y. Kato, R. Suemitsu, Chem. Lett. 1980, 847–848;
b) M. Yamashita, Y. Tanaka, A. Arita, M. Nishida, J. Org. Chem.
1994, 59, 3500–3502; c) V. Bargues, G. Blay, L. Cardona, B. Garcia,
J. R. Pedro, Tetrahedron 1998, 54, 1845–1852.
[37] H. Ito, T. Ishizuka, K. Arimoto, K. Miura, A. Hosomi, Tetrahedron
Lett. 1997, 38, 8887–8890.
[38] Previous syntheses of putative lepadiformine: a) K. M. Werner, J. M.
De Los Santos, S. M. Weinreb, M. Shang, J. Org. Chem. 1999, 64,
686–687; b) W. H. Pearson, Y. Ren, J. Org. Chem. 1999, 64, 688–
689; c) K. M. Werner, J. M. De Los Santos, S. M. Weinreb, M.
Shang, J. Org. Chem. 1999, 64, 4865–4873; d) H. Abe, S. Aoyagi, C.
Kibayashi, Tetrahedron Lett. 2000, 41, 1205–1208; e) J. Wang, J. J.
Swidorski, N. Sydorenko, R. P. Hsung, H. A. Coverdale, J. M.
Kuyava, J. Liu, Heterocycles 2006, 70, 423–459.
[16] Reviews: a) B. Miller, Acc. Chem. Res. 1975, 8, 245–256; b) D. A.
Whiting in Comprehensive Organic Synthesis; Vol. 3 (Eds.: B. M.
Trost, I. Fleming), Pergamon, Oxford, 1991, pp. 803 ff.; recent exam-
ples: c) Y. Wada, K. Otani, N. Endo, Y. Kita, H. Fujioka, Chem.
Commun. 2010, 46, 797–799; d) I. Kim, K. Kim, J. Choi, J. Org.
Chem. 2009, 74, 8492–8495; e) H. Shigehisa, T. Honda, Heterocycles
2008, 75, 1233–1239; f) A. M. Sauer, W. E. Crowe, G. Henderson,
R. A. Laine, Tetrahedron Lett. 2007, 48, 6590–6593.
[17] a) G. Opitz Angew. Chem. 1967, 79, 161–177; Angew. Chem. Int. Ed.
Engl. 1967, 6, 107–123; Angew. Chem. Int. Ed. Engl. 1967, 6, 107–
123; b) W. E. Truce, K. Liu, Mech. React. Sulfur Comp. 1969, 4, 145–
154; c) J. F. King, Acc. Chem. Res. 1975, 8, 10–17.
[18] S. Bennabi, PhD Thesis, Universitꢁ Claude Bernard Lyon
1
Received: May 21, 2010
(France), 2000.
Published online: October 7, 2010
13270
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 13262 – 13270