Synthetic ventures inspired by biosynthetic hypotheses: the evolution of a method for the oxidative amidation of phenols

Article abstract of DOI:10.1016/j.tet.2006.01.111

We describe the development of a technique for the oxidative conversion of 4-alkyl phenols to derivatives of the corresponding 4-alkyl-4-amino-2,5-cyclohexanediones. This transformation, which was inspired by biogenetic considerations, constitutes a key s

Full text of DOI:10.1016/j.tet.2006.01.111

Tetrahedron 62 (2006) 5318–5337
Synthetic ventures inspired by biosynthetic hypotheses: the
evolution of a method for the oxidative amidation of phenols
b
b
b
Marco A. Ciufolini,a,b, Sylvain Canesi, Malika Ousmer and Norbert A. Braun
*
aDepartment of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
b
`
Laboratoire de Synthese et Methodologie Organiques, CNRS UM 5181, Universite Claude Bernard Lyon 1 and Ecole
Superieure de Chimie, Physique, Electronique de Lyon, 43, Bd. du 11 Novembre 1918, 69622 Villuerbanne, France
´
´
´
Received 23 December 2005; revised 8 January 2006; accepted 11 January 2006
Available online 24 April 2006
Abstract—We describe the development of a technique for the oxidative conversion of 4-alkyl phenols to derivatives of the corresponding
4-alkyl-4-amino-2,5-cyclohexanediones. This transformation, which was inspired by biogenetic considerations, constitutes a key step in the
total syntheses of FR-901483, TAN-1251C, and cylindricine C.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
new methodology. For instance, our work on pyridoacridine
alkaloids2 was inspired by the supposition that the ring sys-
tem of these substances, which are exemplified by structural
types 1–2 in Scheme 1, may result through oxidative conden-
sation of a molecule of tyramine (3, Z¼H, a product of deg-
radation of tyrosine, Z¼COOH) with one of kynurenin or
kynuramine (4, Z¼COOH or Z¼H), as outlined in Scheme 1.
This surmise, details of which may have been misconstrued
as embodying claims,3 led to the development of techniques
that accomplish the equivalent of bond-forming processes
a–c through a new pyridine-forming reaction (a–b)4 and a
Meth-Cohn nitrene insertion into a C–H bond (c). Scheme 2
The senior author of this article discovered the fascinating
world of biosynthesis through an elective course in bio-
organic chemistry that he attended as a graduate student.1
Since then, almost as a reflex, he has routinely engaged in
the exercise of imagining how an organism’s biosynthetic
machinery could possibly assemble the structure of an archi-
tecturally appealing natural product, even though he is not
involved in the study of biosynthesis per se.
Such an exercise does not constitute mere intellectual over-
kill. Indeed, biogenetic considerations often suggest interest-
ing strategies for the synthesis of structurally novel natural
products, and may even lead to the development of valuable
O
1. H2C=CHOEta
N
O
2. AcNHNab
ring
N3
MsO
N3
S
N
G
N
5
OEt
HN
N
HN
R
O
N
HN
CO-R
d
HO-NH2
O3
• HClc
Ar
Ar
Ar
Ar
2
1
Kuanoniamines, Dercitins: Cystodytins (G = H)
ring = thiazole
Diplamine (G = SMe)
6
7
AcHN
AcHN
Shermilamines:
ring = 1,4-thiazine-3-one
Z
N
N
OH
H2N
O
O
h
νe
a
[ ? ]
O
1-2
N3
N
R
b
H2N
NHAc
NHAc
H2N
Z
c
3
4
9 R = H
1 R = SMe
8
MeSHf
Scheme 2. (a) cat. Yb(fod)3, (CH2Cl)2, reflux, 99%; (b) NaH, DMF, 97%; (c)
MeCN, reflux, 62%; (d) O3, CH2Cl2/MeOH, ꢀ78 ꢁC, then Me2S, 67%; (e)
250 W sunlamp, PhCl, 110 ꢁC, then titration with DDQ, 30%; (f) 4:1CH2Cl2/
AcOH, then removal of volatiles and titration with DDQ in CH2Cl2, 94%.
Scheme 1.
* Corresponding author. Fax: +1 604 822 8710; e-mail: ciufi@chem.ubc.ca
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.111

M. A. Ciufolini et al. / Tetrahedron 62 (2006) 5318–5337
5319
HO
OMe
OH
O
Z
O
O
N
N
NH
N
H
O
N
O
X
O
N
O
N
Y
O
H
N
Y
N
O
N
O
X
O
N
HN
N
N
O
O
Z
O
OH
10 Luzopeptin E1: X = Y = Z = H
11 Luzopeptin C: X, Y = π bond; Z = OH
MeO
OH
OH
O
O
Y
Z
Z
O
O
COOH
N
NH
EDCI
N
H
O
N
O
O
N
N
N
O
N
Z
O
O
H
N
N
N
O
O
N
O
O
O
O
N
NH2
N
HN
HN
N
O
O
Y
O
Y
O
OH
12 Y = O-t-Bu, Z = H
13 Y = O-t-Bu, Z = OTBS
OH
14 Y = O-t-Bu, Z = H
15 Y = O-t-Bu, Z = OTBS
10
11
Scheme 3.
highlights these methods (5/7 and 8/9, respectively) in
might well emanate from biosynthetic precursor 20, which
is the product of oxidative spirolactamization of tyrosinyl-
tyrosine 21. If one could duplicate the conversion of 21 to
20 in the laboratory, then the synthesis of 16 would become
relatively straightforward, and it could be carried out using
enantiopure, inexpensivetyrosine, 22, as thestartingmaterial.
the context of the total synthesis of diplamine.5
Other times, the pursuit of a ‘biomimetic’ approach to a target
molecule may reveal unexpected chemical properties of an
advanced intermediate that greatly facilitate endgame plan-
ning. This is what happened during our synthesis of luzo-
peptins (Scheme 3). Our strategy was influenced by the
hypothesis that the macrocyclic portion of 10–11 is likely
to emerge upon enzymatic cyclodimerization of a pentapep-
tide of the type 12–13. It was ultimately discovered that
C-terminus activation of 12–13 themselves triggers sponta-
neous assembly of macrocycles 14–15. Yields are moderate
(25% and 26%, respectively), but comparable to those
observed in a stepwise sequence relying on preparation and
cyclization of a discrete linear decapeptide.6 Substances 14–
15 were elaborated to luzopeptins E1 and C, respectively.7
An analogous reaction might also facilitate the synthesis
of a group of fungal metabolites discovered at the Takeda
Pharmaceutical Co. in Japan, and christened the TAN-
1251 family of compounds.10 These substances appear to
share a common biogenetic precursor with 16 in the form of
a variant of aldehyde 19 wherein R¼prenyl. This material,
described in Scheme 5 as compound 24, may advance to
TAN-1251C, 23, via intramolecular enamine formation.
16
17
OMe
OMe
15
2. FR-901483 and TAN-1251: development of a novel
oxidative amidation of phenols
13
6
16'
14
5
15'
4
HO
O
HO
N
N
7
8
NHMe
3
Unique opportunities for the development of methodology
materialized in the mid-1990s with the discovery of a fungal
metabolite termed FR-901483, 16 (Scheme 4).8,9 This
remarkable compound displays potent immunosuppressive
activity, which is intimately associated with the presence of
the labile C-9 phosphate ester. Unfortunately, phosphatases
rapidly convert 16 to the corresponding diol 17, which is
inactive. Prospects for further development of 16 as
a drug, therefore, seem modest.
NHMe
O-R
1
2
H
10
9
11
18
O
Z
16 Z = P(O)(OH)2
17 Z = H
O-R
O
OHC
N
HOOC
O
N
NHMe
NH-R
O
19
20
Regardless, the structural novelty of 16 provided an irresist-
ible opportunity for biogenetic speculation, and the fact that
many nitrogenous natural products derive from aminoacids
led to the conclusion that FR-901483 must be a dimer of ty-
rosine. Indeed, if the oxygen atom anchoring the phosphate
ester were at some point part of a keto group, then the C-7–
C-8 bond in the hypothetical intermediate 18couldbe created
through a regio- and diastereoselective intramolecular aldol
cyclization of ketoaldehyde 19, R¼Me. The latter aldehyde
O-R
O
NHMe
HOOC
NH2
HOOC
HO
N
H
2
x
21
22
HO
Scheme 4.

5320
M. A. Ciufolini et al. / Tetrahedron 62 (2006) 5318–5337
interactions in 32 now promote accumulation of electronic
density on the nitrogen atom, which therefore becomes capa-
ble of expressing the desired nucleophilic reactivity.
Me
H
N
–H2O
N
O
It seemed to us that the same logic could be put to profit in our
case, provided that an iminoether-type functionality resistant
to the action of oxidants (e.g., DIB) could be identified.
Oxazolines ultimately emerged as suitable amide equivalents
in these transformations.14 Such heterocycles are prepared
by condensation of a phenolic carboxylic acid with a suitable
23
O
O
OHC
N
NHMe
1,2-aminoalcohol. The Vorbruggen oxazoline synthesis15
¨
24
proved to be especially effective for this purpose because,
contrary to other methods for oxazoline formation,16 it re-
quired no protection of the phenol. This removed the need
for a supplementary protection/deprotection sequence. An
initial version of the (formal) oxidative spirolactamization
of phenolic amides thus emerged as indicated in Scheme 8
for the conversion of 35 to 3817 under Kita-type18 conditions.
O
Scheme 5.
A search of the literature revealed that the oxidative cycliza-
tion of phenolic amides such as 21 to spirolactams of the
type 20 was unknown,11 even though the interest (and the
synthetic potential!) of this transformation had obviously
been recognized years earlier. For instance, in 1987 Kita
described the reaction of 25 with PhI(OAc)2 (‘DIB’), or
PhI(OCOCF3)2 (‘PIFA’).12 Perhaps the intent was to reach
spirolactams of the type 26. However, oxidative attack of
25 furnished only lactone 29, arguably through capture of
an electrophilic intermediate arising from the phenol, and
naively represented in Scheme 6 as 27, by the carbonyl
oxygen of the amide group. Hydrolysis of the intervening
iminolactone 28 during workup then produces 29.
O
R
R
HOOC
N
H2N
OH
PPh3, CCl4
Et3N, pyr.
HO
HO
34
35
R
O
R
O
PhI(OAc)2
N
N
CF3CH2OH
O
O
36
37
O
O
R
R-HN
N
DIB
O
R
Z–O
O
26
N
25
O
Ac2O
pyrid.
38 Z = H
39 Z = Ac
HO
DIB
O
Z
R
O
Scheme 8.
NH
O
Compounds of general structure 38 are prone to undergo
spontaneous Michael cyclization to morpholine derivatives.
The proclivity to cyclize appears to depend on structural
details, but the resulting morpholines always form in a highly
diastereoselective manner. For instance, compound 40
cyclized to give 41 exclusively (Scheme 9; structure ascer-
tained by X-ray crystallography). The stereoselective forma-
tion of 41 is attributable to the strong preference for the axial
orientation on the part of alkyl substituents flanking the ni-
trogen atom in N-acyl piperidines and related six-membered
heterocycles.19
28 Z = N-R
29 Z = O
27
O
H2O
Scheme 6.
Knapp encountered analogous difficulties during work on
the iodo-amidation of olefins.13 Thus, reaction of 30 with
I2 resulted in the formation of 31 instead of the desired 33
(Scheme 7). These observations, and Kita’s, are consistent
with the notion that resonance interactions between the N
atom and the carbonyl system in an amide promote accumu-
lation of electronic density on the oxygen atom, which there-
fore becomes nucleophilic at the expenses of the N atom.
Knapp circumvented such difficulties by the use of imi-
noethers 32 as substrates for iodolactamization. Resonance
O
O
Bn
HO
O
H
N
N
O
O
H
R–N
O
R–HN
"X+
"
O
40
41
X
X
30
31
Scheme 9.
R
N
N–R
"X+"
Morpholine formation is helpful in certain cases, because
it leads to fully stereocontrolled desymmetrization of the
‘locally symmetrical’ dienone segment of the primary prod-
ucts, in a manner that secures a specific configuration of the
now stereogenic spirocenter. This principle constitutes a
O
R'3SiO
32
33
Scheme 7.

M. A. Ciufolini et al. / Tetrahedron 62 (2006) 5318–5337
5321
Ar
pivotal point in the synthesis of cylindricines (vide infra). In
O
H
other instances, cyclization is problematic and must be sup-
pressed. Acetylation of the OH group in 38 prior to purifica-
tion readily accomplishes this objective. Overall yields of
acetates 39 are typically between 45–50%. Such moderate
yields must be weighed against the fact that the reaction
rapidly converts inexpensive aminoacid-derived substances
to valuable enantiopure intermediates.
N
OR
a
N
O
spirolactam
a
O
b
49
b
O
OR
N
byproducts
N
The opening moves of our syntheses of FR-901483 and TAN-
1251C appear in Scheme 10. The key oxazoline 44 was pre-
pared through the union of aminoalcohol 42 with acid 43,
both of which are readily available from (L)-tyrosine. Oxida-
tive spirocyclization and acetylation of the primary product
45, which was prone to Michael cyclization, provided 46.
The latter intermediate was uneventfully elaborated to 48,
at which stage the routes to TAN-1251C and FR-901483
diverged.
O
O
50
Ar
Scheme 11.
oxidative cyclization of phenolic amine 51 to spiropyrroli-
dine 52 (Scheme 12).9b,20 Significantly, a sulfonamido
protecting group was present on the spectator amino func-
tionality in 51. We presume that this choice was dictated
by the difficulties adumbrated in Scheme 12.
MeO
Z
OMe
PhI(OAc)2
(CF3)2CHOH
O
NH-P
NH-SO2Ar
NH-Ts
51% at 70%
conversion
a
R-O
MeOOC
HO
N
H
N
42 R = P = H,
Z = CH2OH
51
44
43 R = H, Z = COOH,
P = Ts
HO
OMe
O-R
Ar = 4-NO2C6H4–
R
O
d
MeOOC
N
1. H2
2. MeOHe
DIBb
NH-SO2Ar
R
O
N
N-Ts
52
O
Ac2Oc
45 R = H
46 R = Ac
O
MeO
Scheme 12.
O
The operations leading from 48 to fully synthetic TAN-
1251C21 are depicted in Scheme 13. Phenolic ether ex-
change and vigorous LAH reduction provided 54, which
G
HO
N
N-Ts
47 G = H
48 G = Me
MeIf
O
O
Scheme 10. (a) PPh3, CCl4, MeCN, pyridine, 25 ꢁC, Et3N, 73%; (b)
CF3CH2OH, 25 ꢁC; (c) pyridine, 4-DMAP, 25 ꢁC, 41% b–c; (d) PtO2,
EtOAc, 25 ꢁC, 96%; (e) K2CO3, 25 ꢁC, 79%; (f) K2CO3, Me2CO/DMF,
25 ꢁC, 97%.
O
a
1. BBr3
2. prenyl
bromideb
HO
48
N
NMeTs
53
A comment is in order regarding our choice of an N-tosyl
protecting group for 44. Initial experiments carried out
with variants of 44 displaying carbonyl-type N-protection
furnished complex mixtures containing only some of the de-
sired spirolactams. Byproducts were detected, the genesis of
which is consistent with the following mechanistic picture.
Oxidative activation of the phenol leads to an electrophilic
intermediate represented in Scheme 11 as cation 49. Capture
by the oxazoline (pathway a) leads to the desired spirolac-
tam. However, interception by the carbonyl group (pathway
b) competes effectively, causing formation of iminocarba-
mate 50, which then evolves to a variety of secondary prod-
ucts. It was necessary to subdue the nucleophilic aptitude of
the N-blocking group in order to maximize formation of 45.
The use of an N-sulfonamido group emerged as an eminently
effective solution.
O
O
Z
LAHc
TPAP
NMOe
HO
HO
N
N-Me
54 R = H
Troc-Cld
O
55 R = COOCH2CCl3
Cd/Pbf
O
N
23
NMe-Troc
56
O
Scheme 13. (a) CH2Cl2, ꢀ60 ꢁC, 87%; (b) Cs2CO3, Me2CO, 25 ꢁC, 98%;
(c) THF, 0 ꢁC to reflux, 48 h, 88%; (d) aq THF, NaHCO3, 25 ꢁC, 62%;
(e) CH2Cl2, 25 ꢁC, 1 h, 63%; (f) THF, NH4OAc buffer, 25 ꢁC, 79%.
A brief digression is appropriate at this juncture. The land-
mark Sorensen synthesis of 16 relied on an unprecedented

5322
M. A. Ciufolini et al. / Tetrahedron 62 (2006) 5318–5337
for ease of processing was N-blocked as the Troc derivative.
Subsequent Ley oxidation22 furnished ketoaldehyde 55.
Release of the free amino function with Cd/Pb couple23 pre-
cipitated instant enamine formation leading to 23. The yield
of 23 from tyrosine was 4% over 16 steps.24
stereogenic center at the a-position of the aldehyde, aldol
cyclization from the incorrect regioisomer of the cyclohexa-
none enolate, 58, forces the 4-methoxybenzyl substituent
into an axial orientation in transition states such as 59. This
generates severe compression against a methylene group of
the enolate ring (dashed semicircles). No such problems
subsist in regioisomeric transition state 62, wherein the sub-
stituent in question is pseudoequatorial in the developing
ring. This should favor selective formation of the correct
regioisomer of the aldol product, both on kinetic and on ther-
modynamic grounds. However, a potential complication
loomed if substituent Z were a carbonyl group. The ring sys-
tem emerging from the aldol reaction is now an N-acyl piper-
idine. As mentioned earlier, substituents at the a-position of
the nitrogen atom in such structures prefer the axial orienta-
tion.18 The incorrect aldol regioisomer would then be
favored under thermodynamic conditions, and possibly even
under kinetic conditions, if the transition state for the aldol
cyclization were product-like. Avoiding entanglement with
these complications entailed execution of the aldol step
with substrates in which substituent Z is a pair of H atoms;
i.e., with a variant of 19. This is the pathway that Sorensen
chose.9b On the other hand, a sequence proceeding through
direct aldol closure of 57 would be shorter than the one
requiring prior elaboration to a protected form of 19.
The synthesis of FR-901483 presented the complex issue of
the aldol cyclization of ketoaldehyde 57, prepared from 48 as
detailed in Scheme 14, or of one of the type 19. The success
of this step is subordinate to the occurrence of the following
sequence of events: the substrate must undergo chemoselec-
tive enolization of the cyclohexanone segment, leading
to regioselective formation of enolate 61 (Z¼H, H or O;
P¼prot. group), which must add diastereoselectively to
the Si-face of the aldehyde to yield 65. Superficially, any
hope to entice 57/19 to behave as required may seem overly
optimistic. A careful analysis leads to a more favorable
prognosis.
MeO
O
TPAP
O
Me
48
N
NMO
77%
N-Ts
57
O
A computational simulation (MM+) carried out with simpli-
fied variants of transition state structures 59 and 62, in which
R¼H, Z¼O, and the distance between enolate and formyl
57 or 19
base
Ar
N
Ar
Z
Z
˚
carbons (dashed bonds) was arbitrarily fixed at 2.3 A, sug-
OHC
OHC
N
gested that 62 would still be less energetic than 59 by about
0.8 kcal/mol. This value is below the confidence level of the
calculation; still, it engendered measured optimism concern-
ing the feasibility of the aldol step in the desired regiochem-
ical mode. The question of diastereoselectivity constituted
a more delicate issue. Indeed, MM+ revealed that transition
state models 62 and 64, which reflect the desired (cf. 63) and
undesired (cf. 65) epimers of the aldol product, are essen-
tially isoenergetic, as are 63 and 65 themselves. This inti-
mated that no substrate-directed diasterocontrol could be
exerted during the aldol step in the absence of external influ-
ences.
R
R
58
61
O
O
Z
Ar
Z
axial
H
O
equatorial
R
R
N
O
H
Ar
N
H
O
59
62
O
Ar
Ar
N
Z
Z
HO
O
N
HO
R
R
In an attempt to reach a tricyclic intermediate, compound 57
was treated with DBU in CH2Cl2 (Scheme 15). This led to
the stereoselective formation of a compound (accompanied
by diastereomeric products) that was ultimately shown to
be 66 by comparison with analogs of secure constitution.
60
63
O
Z
Ar
Ar
Z
equatorial
R
HO
O
N
H
H
N
O
R
The sole structural parameter initially available to us was
the magnitude of the vicinal coupling constant, JH-6,H-7
3
¼
O
64
65
8.8 Hz (FR-901483 numbering), for acetate ester 67. This
suggested a trans-diaxial arrangement of the H’s in question,
i.e., formation of the incorrect aldol diastereomer. Still, it
was apparent that the use of a weak base indeed promotes
kinetically faster enolization of the cyclohexanone.
Scheme 14.
Important work by Myers indicates that the kinetics of
enolization of protected a-amino aldehydes are not as rapid
as one might expect.25 This principle has been incorporated
in a number of brilliant syntheses.26 If this were true for 57/
19, then selective enolization of the cyclohexanone may be
possible under gently basic conditions. Exposure to mild
bases would promote reversible, non-regioselective forma-
tion of the ketone enolate and prime the molecule for aldol
cyclization via isomeric chair-like transition states.27
Scheme 14 illustrates that for a fixed (S)-configuration of the
It did not escape our attention that the formation of 66 was
consistent with the so-called Seebach rule.28 This reactivity
model holds for nonprotic solvents and it may break down
in protic ones, leading to an erosion, or even a reversal, of di-
astereoselectivity, that may be ascribed to solvation of reac-
tivespecies through H-bonding. One might hope that conduct
of the reaction in a protic medium could afford reasonable

M. A. Ciufolini et al. / Tetrahedron 62 (2006) 5318–5337
5323
JH-6, H-7 = 8.8 Hz
Ar
H
mined that a methanolic solution of 57 remained homoge-
neous upon dilution with up to 10 vol % of water. Addition
of solid NaOMe triggered rapid aldol cyclization and dia-
stereoselective formation of 71 in 44% chromatographed
yield. It is tempting to speculate that if the biosynthetic path-
way leading to 16 indeed involves aldol cyclization of a spe-
cies akin to 19, then the occurrence of this event within an
enzyme with a hydrophilic active site hosting numerous
water molecules could facilitate formation of the ‘good’
diastereomer.
O
H
R–O
6
N
DBU
7
NMeTs
57
CH2Cl2
O
Ac2O
66 R = H
67 R = Ac
Ar
W
O
N
X
Ar = 4-MeOC6H4
O
68 W = O; X = H
69 W = O; X = NMe–BOC
70 W = H, H; X = NMe–BOC
With a reliable avenue to 71 in hand, the synthesis was com-
pleted rapidly and without incident (Scheme 16). Vigorous
LAH reduction of 71 produced 73 (82%) plus a small amount
of what appeared to be the epimeric alcohol. Compound 73
may also be obtained with complete diastereoselectivity
(within the limits of 500 MHz 1H NMR) by reduction of 71
with L-SelectrideÒ and converted to fully synthetic 1631 by
the Snider method.9a A more rapid endgame relied on regio-
Ar
JH-6, H-7 = 1.5 Hz
O
H
H
N
R–O
6
7
NMeTs
solvent
base
57
O
71 R = H
72 R = Ac
Ac2O
`
selective Mitsunobu reaction of 73 with dibenzylphosphate a
la Sorensen.9b The emerging 74 was extremely polar and dif-
ficult to purify. To palliate such difficulties, we installed an
N-CBZ group prior to purification. Hydrogenolysis of pure
75 yielded totally synthetic FR-901483, the bis-hydrochlo-
ride salt of which was found to be identical to that of natural
16.24,32 The longest linear sequence in this synthesis is 17
steps from tyrosine, and the overall yield approaches 1.5%.
• 3:1 tBuOH/THF; tBuOK: 21 %
• 9:1 MeOH/H2O; MeONa: 44 %
Scheme 15.
quantities of the desired aldol diastereomer. Indeed, pioneer-
ing work by Snider appearing in the literature at this juncture
proved that model system 689g as well as ‘real’substrate 69,9a
which differs from 57 only at the level of the N-protecting
group (BOC in lieu of a tosylamide), cyclize diastereoselec-
tively to the correct aldol isomer upon reaction with t-BuOK
in t-BuOH. The same outcome obtained upon treatment of
70 with MeONa/MeOH, as reported shortly thereafter by
Sorensen.9b Interestingly, Snider had determined that the
aldol cyclization of 69 proceed with slightly lower diastereo-
selectivity in MeOH/NaOMe,9a suggesting that optimal con-
ditions for this step are intimately dependent on structural
details.
Ar
H
H
N
HO
HO
LAHa
Mitsunobub
71
NHMe
73
H
Ar
H
H
HO
O
d
H2
N
NMe–R
16
(BnO)2P
O
74 R = H
75 R = Cbz
Cbz-Clc
Ketoaldehyde 57 did not perform well under Snider-type
conditions. First, the compound was poorly soluble in plain
t-BuOH, necessitating the use of a 3:1 mixture of t-BuOH/
THF to effect aldol cyclization (t-BuOK). This reaction fur-
nished 71 as a significant component of a mixture of dia-
stereomeric aldol products in 21% chromatographed yield:
unacceptable in terms of both yield and diastereoselectivity.
The structural assignment of 71 initially rested on the cou-
Scheme 16. (a) THF, ꢀ78 ꢁC to reflux, 12 h, 91%; (b) DIAD, (BnO)2
P(O)OH, (4-ClC6H4)3P; (c) Cbz/Cl, aq THF, NaHCO3, 25 ꢁC, 26% a–c;
(d) Pd(C), MeOH, HCl, 25 ꢁC, 3 h, 94%.
3. Second-generation methodology: oxidative cycliza-
tion of phenolic sulfonamides
3
pling constant, JH-6–H-7¼1.5 Hz, measured for acetate 72,
implying a cis relative configuration, and it was ultimately
confirmed by an X-ray study of a derivative. Efforts to
improve this step led us to examine alternative alcohol/
alkoxide combinations. The reaction became increasingly
more efficient as we switched to EtOH/EtONa and then to
MeOH/MeONa. This again contrasted with the behavior of
the Snider substrate, but it was consonant with Sorensen’s
choice of conditions.
We rapidly realized that a generic oxidative amidation of
phenols holds considerable potential in the chemical synthe-
sis of nitrogenous spirocycles. The biosynthetically inspired
hypotheses that led to the chemistry of Scheme 8 thus stim-
ulated the evolution of the methodology in a direction that no
longer paralleled biomimetic pathways. A case in point is
that of the cylindricines,33 exemplified in Scheme 17 by (ꢀ)-
cylindricine C, 76.34 These moderately cytotoxic, but struc-
turally unique, secondary metabolites of the ascidian,
Clavelina cylindrica, have engendered considerable interest
in the synthetic community.35 An approach to 76 based on
oxazoline technology envisions annulation of the piperidi-
none ring onto spirodienone 77 (Scheme 17) with concomi-
tant differentiation of the pair of diastereotopic olefins
present in the substrate. Compound 77 is available through
The fact that 57 produced more of the desired 71 in media of
higher polarity29 and/or of higher hydrogen bonding abil-
ity30 crystallized an interesting question: how could one
render methanol even more polar and more apt to establish
strong hydrogen bonds? A plausible answer was to add
some water to the methanolic medium. We rapidly deter-

5324
M. A. Ciufolini et al. / Tetrahedron 62 (2006) 5318–5337
oxidative cyclization of oxazoline 79, which in turn derives
from homotyrosine, 80.36
significant in this regard is the work of Zhou,37 who observed
that furylsulfonamides (86, Z¼NHTs; Scheme 19) undergo
aza-Achmatowicz reaction38 as efficiently as furylcarbinols
(the original substrates for Achmatowicz reactions; 86,
Z¼OH). This stands in sharp contrast to furylamides and fur-
ylcarbamates, which are poor substrates for this transforma-
tion. Sulfonamides 88 might well be competent substrates
for the desired transformation.
O
O
C6H13-n
H
4
5
10
O
2
H
1
N
N
C6H13-n
OH
13
77
12
OH
14
76
O
O
R
R
R
*
H
O
O
MCPBA
N
R
*
O
N
Z
Z
86
87
OH
OH
HO
78
79
Z = OH or Z = NHTs: good yield
Z = NHCOR or NHCOOR: no 87
H
H2N
COOH
R-O2S
1
3
R-SO2
N
H
G
80
HO
G
2
N
DIB
Scheme 17.
(CF3)2CHOH
80-95 %
O
HO
A number of technical difficulties conspired to render the
above strategy entirely impractical. First of all, and contrary
to previous cases, oxazoline 79 was difficult to purify due to
its propensity to retain debris of reagents used in its prepara-
tion. Second, oxidative cyclization to 78 was low yielding
(25–30%). Third, deacylation of the pyrrolidine nitrogen at
the stage of 78, in preparation for piperidone ring assem-
blage, was problematic and low yielding. Finally, free
aminodienone 77 was prone to polymerization, presumably
through cascade Michael-type reactions.
89
88
G = H, 1-COOMe, 1-CH2OH, 1-CH2Br,
1-CH2OMe, 1-CH2OTBS, 2-NHTs
R = Me, Et, 4-Tol, 2-NO2C6H4, 4-NO2C6H4,
2,4-(NO2)2C6H3
Scheme 19.
It was most pleasing to discover that contrary to the case of
oxazolines, which rarely afford yields of spirocycles greater
than 50%, the oxidative cyclization of sulfonamides is nearly
quantitative. The reaction tolerates awide range offunctional
groups and it proceeds very cleanly: in most cases, there is no
need for subsequent purification of products 89.39 Applica-
tion of Fukuyama nitrobenzenesulfonamide technology40
in this reaction yields materials that may be N-deblocked
under gentle conditions. The resulting N-unprotected spiro-
dienones are formal products of cyclization of primary
amines. We have already alluded to the poor stability of
such educts, which we prefer to avoid. Fortunately, an appro-
priate sulfonamide can function not only as a modulator
of the reactivity of the nitrogen atom during oxidative spiro-
cyclization, but also as a potential nucleophilic handle for
elaboration of products 89 to advanced intermediates. This
adds an interesting new dimension to the newly devised
methodology.
Some of the foregoing obstacles could have been circum-
vented through direct oxidative cyclization of an N-unpro-
tected homoalaninol derivative. Such reactions proceed
reasonably well with phenolic secondary amines9b,19 but
not so with primary ones. Thus, in our hands 81 never af-
forded the desired 82 in more than 6% yield (Scheme 18).
A corrective measure for this unpleasant behavior could in-
volve derivatization of the primary amine with a suitable
group Z that modulates the reactivity of the nitrogen center
(cf. 83). Unit Z could then be removed at an opportune post-
oxidation stage (cf. 84/85). Kita had established that
phenolic 3-arylpropanols cyclize efficiently to spirotetrahy-
drofurans upon oxidative attack with DIB.11,17 If group Z in
83 imparted alcohol-like reactivity to the primary amino
function, i.e., moderate nucleophilicity and low basicity,
then conversion to 84 might become efficient.
In the context of the synthesis of 76 (Scheme 20),41
a
methanesulfonamide, was effectively employed as a car-
bonyl anion equivalent. To illustrate, oxidative cyclization
of homotyrosine-derived 90 proceeded with no interference
from the free alcohol. The highly polar spirodienone thus
obtained was O-protected with a sterically demanding silyl
ether, which directed a subsequent Michael-type cyclization
regioselectively to the pro-S double bond of 91 (dr¼7),42
thereby exerting stereocontrol at the emerging spiro-stereo-
genic center through desymmetrization of the dienone. This
technique for stereoselective spirocenter formation was in-
spired by the results of Scheme 9. Unusual in the realm of
synthetic endeavoring, compound 93 contained surplus
functionality relative to the required cylindricine inter-
mediate 95. Conversion to 95, therefore, continued with
H
H
O-R
DIB
O-R
Z–HN
Z–N
O
HO
81 R = Me; Z = H
83 R = prot. group.;
Z = modulator of
N-reactivity
82 R = Me; Z = H
84 R = prot. grp.;
Z = modul. of
N-react.
"– Z"
85 R = prot. grp.;
Z = H
Scheme 18.
Recent literature precedents indicate that the reactivity of
sulfonamides is comparable to that of alcohols. Especially

M. A. Ciufolini et al. / Tetrahedron 62 (2006) 5318–5337
5325
HO
n-Hex
Z
OTBDPS
TBDPS-O
O2
S
N
O
O
t-BuLi,
Ms-HN
S
1. DIBa
DBU
c
( )-1-octene
Me
N
95
2.O-prot.b
oxide,
- 100%
BF3OEt2
HO
O
91
90
Dess-Martin,
88 % from 95
96 Z = H, OH
97 Z = O
O2
OTBDPS
d
S
OTBDPS
+
n-Hex
O
CO-Hex-n
N
H
N
SO2
H
O
H
H
N
H
O
G
H
NH
92
93
OP
1
:
7
front (Si-face)
OP
attack favored
99
OTBDPS
98
O2
S
OTBDPS
O2
S
n-Hex
H
O
N
RaNie
"H–"
H
N
G
PhS
G
H
N
H
N
SPh
94
SPh
95
Hex-n
H
PO
OP
100
101
Scheme 20. (a) (CF3)2CHOH, 25 ꢁC, 30 min; (b) DMF, imidazole, t-BuPh2-
SiCl, 3 h, 87% a–b; (c) KHMDS/toluene, THF, ꢀ100 ꢁC, 3 h, 89%; (d)
PhSH, BF3OEt2, CH2Cl2, 25 ꢁC, 12 h, 77%; (e) 2:1 EtOAc/EtOH, 25 ꢁC,
3 h, 77%.
H
O
H
H
G
76
N
N
Hex-n
Hex-n
elaboration to trisulfide 94 and RaNi desulfurization.43 It is
worthy of note that the desilylated analog of 94 was crystal-
line and it was characterized by X-ray diffractometry. This
confirmed the regiochemical outcome of the sulfonamide
Michael cyclization, as well as the R-configuration of the
sulfenylated stereogenic carbon. This configuration was ex-
pected based on an anti-selective conjugate addition of thio-
phenol directed by the spirosulfonamide nitrogen through
a Felkin–Anh-type effect.44
H
H
PO
PO
102
103
Scheme 21.
uct was a 1:1 mixture of alcohol epimers, due to the racemic
nature of the epoxide. However, Dess–Martin oxidation48 of
this mixture afforded stereochemically homogeneous ketone
97 (88% from 95), which upon exposure to DBU ex-
perienced retro-Michael extrusion of SO2 to furnish 98.
Unpleasant difficulties could be anticipated with the 1,4-
addition of an actual oxygen nucleophile to 98. Besides,
one may foresee mediocre levels of conformational control
if group G in 100 were an alcohol or a derivative thereof.
Exploratory work aiming to reach ketones of the type 103,
therefore, relied on intermediates derived from racemic
model enone 104 (Scheme 22) through conjugate addition
Extensive model work aiming to define the best approach for
the installation of the piperidinone ring on compound 95 re-
vealed an optimal endgame strategy in the form of an intra-
molecular reductive amination of ketone 100 (Scheme 21).
Group G in 100 stands for an appropriate precursor to the
keto function of cylindricine C (cf. 102/76). The steric de-
mand of G must be sufficiently large to enforce a significant
preference for conformer 101 of the iminium ion involved in
the reductive amination step. Nucleophilic addition to such
species tends to occur under stereoelectronic control in the
axial mode;45 therefore, reduction of 101 was expected to
produce the correct (S)-configuration at C-2 in 102 (cylindri-
cine numbering). Substituent G could be introduced by dia-
stereoselective conjugate addition to enone 98, which may
be anticipated to react in the correct stereochemical sense
on the basis of well documented conformational properties
of a C(sp2)–C(sp3) junction. Minimization of A1,3-interac-
tions would strongly favor conformer 99. Consequently,
a nucleophilic form of G should selectively add to the
more exposed Si-face of the enone p bond.
Me
O
H
H
H
H
H
1. "G–"
H
N
H
G
2. NaBH3CN
AcOH
N
Me
105
104
H
H
H
H
H
H
H
H
H
bases
Z
Z
N
N
Me
Me
106 Z = CN
109
107 Z = SPh
108 Z = SO2Ph
Oxone®
The conversion of 95 to 98 again relied on transformations
orchestrated by the sulfonamide unit, which therefore played
a triple role during the synthesis: modulator of N-atom reac-
tivity, agent for the desymmetrization of the ‘locally sym-
metrical’ dienone, and now implement for the annulation
of the piperidinone segment. Deprotonation of 95 with
t-BuLi46 and reaction with (ꢂ)-1-octene oxide activated by
X
S
H
H
N
H
N
O2
H
Me
Z
Me
110
111 X = Li
112 X = N3
47
BF3OEt2 resulted in fully diastereoselective (300 MHz
1H NMR) a-face alkylation to yield 96. Of course, this prod-
Scheme 22.

5326
M. A. Ciufolini et al. / Tetrahedron 62 (2006) 5318–5337
of a cyano or a phenylsulfenyl group, either one of which can
function as a precursor to a carbonyl.
B(OR)2
H
Cu
R
H
DBU,
86%
N
97
O-P
O
H
Nagata cyanation49 of 104 took place in the anticipated
sense, but with a modest 4:1 facial selectivity. The subse-
quent reductive amination likewise proceeded with moder-
ate diastereocontrol. Conjugate addition of thiophenoxide
ion fared much better, occurring with essentially complete
stereoselectivity. The bulkier phenylsulfenyl substituent also
performed exceptionally well as an element of stereocontrol
during the subsequent reductive amination. However, to our
utter dismay, the emerging tricyclic intermediates 106–108
resisted conversion to the corresponding ketone. Thus, fail-
ure was the result of attempted a-chlorination (PCl5) of
nitrile 106, or deprotonation (cf. anion 109, Z¼CN)/oxida-
tion, e.g., with the Davis oxaziridine. The same fate awaited
attempts to induce Pummerer-type reactions of 107, via the
corresponding sulfoxide or through an S-halosulfonium ion,
or to deprotonate sulfone 10850 as a prelude to oxygenation
of anion 109 (Z¼SO2Ph). We imputed this string of failures
to the conformational rigidity of structures 106–108, which
exist exclusively as the depicted conformers (NMR). The
proton that must be abstracted in the course of the foregoing,
unsuccessful reactions is inaccessible to external bases,
situated as it is at an axial position and between the pair
of axial protons on the second cyclohexane ring of the cis-
decaline-type system. Interconversion of 106–108 with
conformer 110, in which the proton in question, being equa-
torial, would be more readily accessible, might facilitate
deprotonation. However, a triad of problematic 1,3-diaxial
interactions, especially severe if Z¼SO2Ph, all but precludes
access to 110. Even intramolecular reactions requiring
abstraction of the recalcitrant proton were unfruitful. For
instance, treatment of 108 with t-BuLi promoted ortho-
lithiation to 111. A solution of 111 was warmed to just above
rt, in the hope to induce intramolecular proton transfer from
the aliphatic C–H bond, and formation of a more stable
anion. This only resulted in decomposition. Interception
of 111 with trisyl azide furnished 112 (90%). Photochem-
ical activation of the azido group was expected to form
Miyaura
(text)
H
H
113
n-Hex
O
O
B
O
H
H
H
N
OTBDPS
114
Scheme 23.
at the B atom, or at both) promotes directed delivery to the
Re face of the alkene (cf. 113).53
The stereochemical outcome of the Miyaura borylation
created an interesting problem at the stage of the subsequent
reductive amination step. As shown in Scheme 24, the
boronic ester segment favors conformer 115 of the inter-
mediate iminium ion. Axial delivery of hydride44 upon
NaBH3CN/AcOH reduction produced the unnatural 2-(R)-
configuration of tricyclic intermediate 116. The latter was
not isolated, but it was converted in situ to alcohol 117, which
was uneventfully elaborated to (ꢀ)-2-epi-cylindricine, 119.
Our synthetic material [a]2D5 ꢀ39 (c 0.5, CH2Cl2), was thus
obtained in 15 steps and 18% overall yield from homotyro-
sine, and it was spectrally identical to the racemic 119
described by Weinreb.35h
OR
O
NaBH3CNa
N
H
B
114
O
n-Hex
H
115
H-BH2CN
O
N
Z
H
H
c
a triplet nitrenoid that might undergo insertion into the
`
H
H
51
aliphatic C–H bond a la Meth-Cohn: hydrolytic cleavage
Hex-n
N
Hex-n
of the resultant would produce the target ketone. None of
the desired product was obtained upon any form of azide
activation.
H
OH
H
OTBDPS
116 Z = α-B(OCMe2)2; β-H
117 Z = α-OH; β-H
118 Z = O
119
a
b
At this juncture, we turned our attention to a bulky boronic
ester as an alternative for group G in 100, and we were not
to regret this choice. The recently developed Miyaura conju-
gate borylation of enones52 allowed us to subject 97 to an un-
precedented transformation involving treatment with DBU,
CuCl, KOAc, and bis-pinacolyldiboronate, leading directly
to 114 in 86% yield (Scheme 23). Isolable enone 98 forms
transiently through the action of DBU on 97, the other
reagents convert it to 114 in situ.
Scheme 24. (a) MeOH, cat. AcOH, 0 ꢁC, 3 h, then aq NaOH, 30% H2O2,
0 ꢁC, 30 min, 80%; (b) Dess–Martin periodinane, CH2Cl2, 1 h, 94%;
(c) TBAF, THF, 25 ꢁC, 3 h, 96%.
A computational simulation revealed that natural cylindri-
cine contains at least 2.8 kcal/mol less steric energy than
2-epi-cylindricine. Furthermore, aspects of recorded synthe-
ses of cylindricines may lead one to infer that it should be
possible to induce isomerization of 119 to 76 through revers-
ible opening of the piperidinone ring, either in a retro-
Michael mode (cf. 120, Scheme 25) or in a retro-Mannich
sense (cf. 121)—with a caveat. Observations recorded by
Weinreb35h cast doubt on this surmise. We must go with
Weinreb on this issue: extensive experimentation aiming to
promote the desired isomerization, in the interest of reaching
the natural product, was entirely unfruitful.
This second step, the Miyaura borylation proper, took place
at an unusually fast rate (10 min instead of the normal 15 h
or longer) and it occurred with complete reversal of facial
selectivity at the level of 98. Experiment determined that
kinetic and stereochemical aspects of the reaction may be as-
cribed to the directing effect of the nitrogen atom: coordina-
tion of the Miyaura borylcopper complex (at the Cu atom,

M. A. Ciufolini et al. / Tetrahedron 62 (2006) 5318–5337
5327
O
oxidative cyclization of 127 or 129 (Scheme 27) produced
spiropiperidines 128 and 130 in a disheartening 10–15%
yield. Spiranes 128–130 are synthetically valuable building
blocks for many alkaloids: a more efficient avenue to these
materials seemed highly desirable.
H
OH
[ ? ]
N
n-Hex
NH Hex-n
O
H
H
OH
119
120
[ ? ]
[ ? ]
OH
Bn
H
O
H
[ ? ]
Bn
O
O
N
N
AcO
O
1. DIB
2. Ac2O
N
Hex-n
Hex-n
76
N
H
OH
121
OH
17%
chrom.
+
∆E ² –2.8 kcal/mol (MM )
HO
128
127
Scheme 25.
MsHN
Ms
DIB
N
A felicitous development allowed us to exert complete rever-
sal of facial selectivity in the reductive amination step,
permitting access to intermediates displaying the natural
C-2-(S)-configuration. Thus, ketone 114 was desilylated and
treated with NaBH(OAc)3 and AcOH. Analogy with the
presumed course of the Evans directed carbonyl reduction54
crystallized the idea that the reductant should rapidly anchor
itself to the now free hydroxymethyl group of the substrate.
Intramolecular hydride transfer from the resultant complex
122 (Scheme 26) would secure the correct C-2 configura-
tion. The fact that such a hydride transfer must occur through
a seven-centered cyclic transition state was a potential obsta-
cle, but inspection of a molecular model of 122 allayed our
concerns. Indeed, the borohydride agent is perfectly posi-
tioned to deliver Hꢀ to the iminium ion with the correct ori-
entation. Experiment vindicated this hypothesis: compound
123 emerged from the reaction as essentially the sole prod-
uct. We are not aware of literature precedent for this type of
directed iminium ion reduction. The synthesis of (ꢀ)-cylin-
dricine C was thus completed as shown in Scheme 26.55
10-15%
(NMR)
O
HO
130
129
Scheme 27.
Efforts to correct the problem led to a ‘third generation’
method of oxidative amidation of phenols in the bimolecular
regime. The genesis of the new process is rooted in the
hypothesis sketched in Scheme 28. Oxidative activation
of a 4-substituted phenol 131 (L¼leaving group) and capture
of the electrophilic intermediate, perhaps 132, with the
equivalent of a primary amine would surrender 133, which
upon nucleophilic displacement of L should produce the
desired 134.
L
L
[O]
131
132
HO
O
L
AcO
OAc
R
R
N
NH
B
O
"R-NH2"
[ ? ]
- L
1. TBAFa
2. [ H ]b
H
114
O
[ ? ]
N
H
O
O
134
133
B
O
n-Hex
H
Scheme 28.
122
O
Z
H
H
It must be stressed that a bimolecular variant of the oxidative
amidation of phenols is problematic for several reasons. First
of all, it is difficult to identify a competent nitrogen nucleo-
phile that is also resistant to the action of oxidants such as
DIB. Second, the kinetics of capture of the electrophilic re-
sultant of phenol activation (cf. hypothetical cation 132) by
an external nitrogen nucleophile are generally unfavorable.
Thus, all attempts to intercept the electrophilic agent pro-
duced through DIB activation of the phenol with amines
(primary or secondary), pyridine, imidazole, and primary
sulfonamides,57 were entirely unsuccessful. Indeed, phenols
131 are customarily converted to products 133 through reac-
tion with electrophilic nitrogen species,58 but until recently,
consensus had it that it was not possible to effect the same
transformation with a nucleophilic nitrogenous agent.
f
H
H
N
Hex-n
H
OH
N
Hex-n
H
O-R
76
123 Z = α-B(OCMe2)2, β-H; R = H
c
d
e
124 Z = α-B(OCMe2)2, β-H; R = TBDPS
125 Z = α-OH, β-H; R = TBDPS
126 Z = O; R = TBDPS
Scheme 26. (a) THF, 25 ꢁC, 3 h, 95%; (b) NaBH(OAc)3, cat. AcOH,
CH2Cl2, ꢀ78ꢁ to 25 ꢁC, 12 h, 73%; (c) t-BuPh2SiCl, imidazole, DMF,
25 ꢁC, 95%; (d) aq NaOH, 30% H2O2, 0 ꢁC, 30 min, 97%; (e) Dess–Martin
periodinane, CH2Cl2, 1 h, 94%; (f) TBAF, THF, 25 ꢁC, 3 h, 96%.
4. Third generation oxidative amidation of phenols: the
bimolecular reaction
An interesting result disclosed by Wood (Scheme 29)59 sug-
gested a possible way to attain our objective. Thus, phenol
135 reacted with PIFA in MeCN to furnish products pre-
sumed to originate from nitrilium ion 137, which forms
Oxazoline- and sulfonamide-based techniques of oxidative
amidation of phenols suffer from a major limitation: forma-
tion of six-membered rings is problematic.56 To illustrate,

5328
M. A. Ciufolini et al. / Tetrahedron 62 (2006) 5318–5337
upon Ritter-type addition of MeCN to 136. This induced us
to study the oxidative amidation of 4-substituted phenols in
the presence of nitriles, with the expectation that these might
play the role of agent ‘R–NH2’ of Scheme 28.
of ‘biomimetic chemistry,’ ultimately spawned research that
retains little of the original ‘biomimetic’ flavor. Venturing
into the terra incognita of the reactions of Schemes 19 and
30, however, produced a great deal of new chemistry. Bio-
synthetic considerations are undeniably a major source of
Me
´
inspiration: the marriage thereof with the elan toward ever
HOOC
C
N
shorter avenues to molecular architectures that only synthe-
sis can engender is a powerful motor to drive the progress of
organic chemical technology.
HOOC
PhI(OCOCF3)3
MeCN
OH
135
Me
O
136
products
HOOC
5. Experimental
H
N
5.1. Experimental protocols
137
O
Unless otherwise noted, NMR spectra were recorded in
CDCl3 at 300 MHz for H and 75 MHz for 13C. Chemical
1
Scheme 29.
shift (d) are in parts per million, and coupling constants (J)
are in Hertz. Multiplicities are reported as: ‘s’ (singlet), ‘d’
(doublet), ‘dd’ (doublet of doublets), ‘t’ (triplet), ‘q’ (quar-
tet), ‘m’ (multiplet), ‘c’ (complex), ‘br’ broad. IR spectra
(cmꢀ1) were measured on a Perkin Elmer 1720-X FTIR
from CHCl3 solutions. Low- and high-resolution mass spec-
tra (m/e) were obtained in the CI (isobutane), EI (70 eV),
LSIMS (Cs+), or ESI mode, as specified. Optical rotations
were measured in CHCl3, with concentrations (c) expressed
in g/100 mL. All reactions were run under argon, and
monitored by TLC. Reagents and solvents were commercial
products and were used as received, including trifluoro-
ethanol (TFE) and hexafluoroisopropanol (HFIP), except
THF (freshly distd Na/benzophenone); CH2Cl2, Et3N (distd
Oxidative attack of several 4-substituted phenols with PIFA
in MeCN resulted in the formation of complex mixtures of
products, whereas treatment of the same substrates with
DIB in MeCN induced no reaction. However, acetamides
139 were obtained in fair to good yield upon DIB oxidation
of phenols138inamixtureofMeCNandHFIP(Scheme 30).60
Nitrilesolvents other than MeCN may be used in the reaction,
which also tolerate a range of useful functionality on the side
chain of the substrates. Halogenated substrates performed
quite well and afforded the expected products without inci-
dent. This is especially relevant to the present discussion:
as seen in Scheme 31, exposure of, e.g., 140, to NaH triggered
cyclization to 141 in excellent yield, thereby circumventing
the limitation alluded to earlier.
˚
CaH2). Ground 4 A molecular sieves used for TPAP–NMO
oxidations were activated at 120 ꢁC under vacuum.
NHAc
R
R
DIB
5.2. General procedure for the oxidative cyclization of
phenolic oxazoline
MeCN
HFIP
OH
O
138
139
A solution of DIB (0.4 g, 1.2 mmol) in TFE (5 mL) was
added dropwise at rt over 5 min to a solution of a phenolic
oxazoline (1.0 mmol) in TFE (5 mL), and the mixture was
stirred for 30 min (argon). Solid NaHCO3 (0.3 g) was added
and after brief stirring the resulting suspension was filtered
over glass wool and concentrated. The crude product
was immediately taken up in anhydrous pyridine (0.8 g,
10.0 mmol) and treated with Ac2O (1.0 g, 10.0 mmol) and
DMAP (6.1 mg, 50 mmol) at rt for 12 h with good stirring.
Finally, the mixture was evaporated and the residue was
purified by chromatography and/or recrystallization.
yielda
%
yielda
%
R
R
Me
Pr-n
Pr-i
CH2COOMe
(CH2)2NHTs
(CH2)3OPiv
56
54
62
58
53
67
(CH2)nCN
67 (n=2)
71 (n=3)
71 (n=4)
42 (n=3)
49 (n=4)
65 (n=3)
72 (n=4)
(CH2)nN3
(CH2)nBr
(CH2)3CO2TFE 57
achromatographed
Scheme 30.
5.2.1. Oxazoline 44. A solution of PPh3 (8 g, 30 mmol) in
1:1 acetonitrile/pyridine (20 mL, warming necessary to
completely dissolve PPh3) was added dropwise at rt over
3 h to a solution of 42 (1.81 g, 10 mmol), 43 (3.35 g,
10 mmol), NEt3 (3.05 g, 30 mmol), and CCl4 (6.22 g,
40 mmol) in 1:1 MeCN/pyridine (20 mL) at 30 ꢁC. Stirring
was continued for 24 h at 30 ꢁC (thermostat). Aqueous
0.5 M NaOH (200 mL) was added with good stirring and
the organic layer was discarded. The aqueous layer was
successively washed with Et2O (2ꢃ50 mL) and CH2Cl2
(2ꢃ50 mL). These extracts were also discarded, then EtOAc
(50 mL) was added to the aqueous layer and the mixture was
carefully acidified to pH 6 with solid NH4Cl. The layers
were separated and the aqueous phase was extracted with
Br
NHAc
NAc
NaH
91%
O
O
141
140
Scheme 31.
The bimolecular oxidative amidation of phenols is the cen-
terpiece of a number of ongoing synthetic efforts, disclosure
of which is premature at this point. We find it interesting
that a hypothesis formulated in connection with our effort
toward 16 and 23, and that falls squarely under the rubric

M. A. Ciufolini et al. / Tetrahedron 62 (2006) 5318–5337
5329
more EtOAc (4ꢃ50 mL). The combined extracts were dried
(MgSO4) and evaporated to yield 3.5 g (73%) of 44, orange
foam, [a]2D5 +13.3 (c 1.00, EtOH). 1H: 7.73 (2H, d, J¼8.5),
7.26 (2H, d, J¼8.5), 6.92 (2H, d, J¼8.5), 6.83 (2H, d,
J¼8.5), 6.76 (2H, d, J¼8.5), 6.44 (2H, d, J¼8.5), 5.51
(1H, d, J¼9.6, NH), 4.40–4.25 (1H, m), 4.15–4.00 (2H,
m), 3.87–3.80 (1H, m), 3.73 (3H, s), 2.93 (2H, d, J¼5.5),
2.60 (1H, dd, J¼13.8, 5.5), 2.39 (3H, s), 2.10 (1H, dd,
J¼13.8, 7.7). 13C: 166.2, 158.4, 155.5, 143.4, 137.3,
130.5, 129.9, 129.5, 129.1, 127.4, 125.7, 115.4, 114.0,
72.5, 66.7, 55.2, 52.2, 40.2, 38.9, 21.5. IR: 3260, 1515,
1445, 1340, 1305. MS (CI): 481 (MH+). HRMS (CI): calcd
for C26H28N2O5S (MH+) 481.1797; found: 481.1770.
was extracted with more EtOAc (2ꢃ30 mL). The combined
EtOAc extracts were washed with brine (30 mL) and dried
(MgSO4). Concentration afforded 0.360 g (79%) of 47, yel-
1
low foam, [a]2D5 +2.7 (c 1.1). H: 7.80 (2H, d, J¼8.5), 7.32
(2H, d, J¼8.5), 7.02 (2H, d, J¼8.5), 6.79 (2H, d, J¼8.5),
5.84 (1H, s, NH), 3.98 (1H, dd, J¼11.1, 7.0), 3.87–3.72
(1H, m), 3.75 (3H, s), 3.69 (1H, dd, J¼11.1, 3.3), 3.28–
3.16 (1H, m), 3.11 (1H, dd, J¼14.0, 8.1), 2.98 (1H, dd,
J¼14.0, 6.6), 2.88 (1H, dd, J¼13.2, 8.1), 2.53–2.15 (4H,
m), 2.43 (3H, s), 2.13–1.91 (1H, m), 1.90–1.56 (3H, m),
0.81–0.65 (1H, m). 13C: 208.1, 171.8, 158.5, 144.0, 135.9,
130.4, 130.0, 129.9, 127.2, 114.0, 62.8, 61.5, 58.3, 55.2,
52.4, 38.0, 37.6, 37.1, 35.1, 33.8, 32.9, 21.5. IR: 3261,
1715, 1682. MS (CI): 501 (MH+). HRMS (CI): calcd for
C26H32N2O6S (MH+) 501.2059; found: 501.2058.
5.2.2. Spirolactam 46. A solution of DIB (0.74 g, 2.3 mmol)
in TFE (10 mL) was added dropwise over 5 min to a solution
of oxazoline 44 (0.96 g, 2 mmol) in TFE (10 mL). The mix-
ture was stirred for 30 min at rt; then solid NaHCO3 (0.50 g,
6 mmol) was added. The suspension was filtered through
glass wool and evaporated under reduced pressure. Crude
45 thus obtained was redissolved in pyridine (1.58 g,
20 mmol) and treated with Ac2O (2.03 g, 20 mmol) and
DMAP (24.4 mg, 0.2 mmol) at rt. After stirring overnight,
the solution was diluted with EtOAc and washed with satd
aq NH4Cl (3ꢃ15 mL). The organic layer was dried (MgSO4)
and concentrated. Chromatography of the residue (10%/
60% EtOAc/hexane) afforded 0.48 g (41%) of 46, yellow
5.2.4. Compound 48. Iodomethane (caution: suspect car-
cinogen, corrosive, poison; 0.68 g, 4.8 mmol;) was added
to a solution of 47 (0.785 g, 1.60 mmol) in acetone/DMF
(14 mL/2 mL) containing K2CO3 (0.261 g, 1.92 mmol). Af-
ter stirring for 12 h, the solution was concentrated and the
residue was diluted with EtOAc (40 mL) and washed with
1 M HCl (20 mL) and brine (20 mL). The organic layer
was dried (MgSO4) and concentrated to yield 0.780 g
1
(97%) of 48, yellow foam, [a]2D5 ꢀ76.0 (c 1.0). H: 7.84
(2H, d, J¼8.5), 7.31 (2H, d, J¼8.5), 7.02 (2H, d, J¼8.5),
6.75 (2H, d, J¼8.5), 5.03 (1H, dd, J¼10.7, 9.2), 4.12 (1H,
dd, J¼11.2, 7.2), 3.74 (3H, s), 3.72 (1H, dd, J¼11.2, 3.3),
3.31–3.19 (1H, m), 3.13 (1H, dd, J¼13.6, 8.8), 2.98 (1H,
dd, J¼13.6, 5.9), 2.76 (3H, s), 2.57 (1H, dd, J¼12.7, 9.2);
2.45–2.35 (2H, m), 2.42 (3H, s), 2.21–2.09 (2H, m), 2.02–
1.91 (2H, m), 1.74–1.63 (1H, m), 1.56 (1H, dd, J¼12.7,
10.7), 0.68–0.57 (1H, m). 13C: 208.4, 171.4, 158.5, 143.8,
136.1, 130.6, 130.4, 129.8, 127.6, 113.8, 63.1, 60.2, 58.5,
57.2, 55.3, 38.2, 37.2, 35.7, 34.1, 32.9, 31.8, 29.8, 21.6.
IR: 3415, 1703. MS (CI): 515 (MH+). HRMS (CI): calcd
for C27H34N2O6S (MH+) 515.2216; found: 515.2215.
1
foam, [a]2D5 ꢀ22.7 (c 1.21). H: 8.04 (2H, d, J¼8.1), 7.42
(2H, d, J¼8.1), 7.10 (2H, d, J¼8.5), 6.83 (3H, m), 6.24
(1H, dd, J¼9.9, 1.8), 6.17 (1H, dd, J¼10.3, 2.8), 6.07 (1H,
dd, J¼10.3, 1.8), 5.24 (1H, t, J¼8.8), 4.57 (1H, dd, J¼11.3,
8.3), 4.28 (1H, dd, J¼11.3, 4.4), 3.78 (3H, s), 3.18 (1H, dd,
J¼12.1, 7.0), 3.23–3.05 (1H, m), 3.00 (1H, dd, J¼12.1,
5.5), 2.54 (1H, dd, J¼13.2, 5.5), 2.47 (3H, s), 2.42 (1H, dd,
J¼13.2, 5.2), 2.28 (3H, s), 2.03 (3H, s). 13C: 184.1, 170.3,
169.8, 169.6, 158.6, 149.0, 148.6, 145.5, 136.2, 130.8,
130.2, 130.1, 129.6, 128.9, 127.6, 113.9, 62.5, 60.0, 57.5,
55.2, 34.7, 34.4, 25.1, 21. 7, 20.9. IR: 1745, 1705, 1675.
MS (EI): 580 (M+), 375, 323, 206 (100), 163, 147, 121, 91,
43. HRMS (EI): calcd for C26H28N2O5S (M+) 580.1879;
found: 580.1884.
5.2.5. Prenyl ether 53. Commercial 1 M BBr3 in CH2Cl2
(2.45 mL, 2.45 mmol) was added dropwise to a cold
(ꢀ60 ꢁC) solution of 48 (0.360 g, 0.7 mmol) in CH2Cl2
(2.3 mL). The mixture was stirred for 30 min, then it was
warmed to 0 ꢁC and stirring was continued for another
30 min. Aqueous 10% HCl solution (5 mL) was added and
the layers were separated. The aqueous layer was extracted
with EtOAc (2ꢃ5 mL) and the combined extracts were dried
(MgSO4) and concentrated. Purification by column chro-
matography (silica gel, EtOAc/hexane: 70:30/90:10) af-
forded 0.306 g (87%) of the free phenol, yellow foam,
[a]2D5 ꢀ76.5 (c 0.65). 1H: 8.26 (1H, s), 7.86 (2H, d, J¼8.3),
7.40 (2H, d, J¼8.3), 7.02 (2H, d, J¼8.7), 6.73 (2H, d,
J¼8.7), 4.99 (1H, dd, J¼10.7, 9.0), 3.99 (1H, dd, J¼11.3,
6.9), 3.72 (1H, dd, J¼11.3, 5.1), 3.48–3.35 (1H, m), 3.11
(1H, dd, J¼13.4, 9.0), 2.97 (1H, dd, J¼13.4, 6.0), 2.78
(3H, s), 2.69 (1H, dd, J¼13.0, 9.0), 2.68–2.53 (1H, m),
2.41 (3H, s), 2.32 (1H, dd, J¼14.7, 9.0), 2.31–2.16 (1H,
m), 2.11–1.92 (3H, m), 1.81 (1H, ddd, J¼17.8, 14, 4.4),
1.70 (1H, t, J¼11.7), 0.79–0.69 (1H, m). 13C: 208.9,
171.8, 157.3, 144.5, 138.4, 131.9, 131.1, 130.8, 128.8,
116.3, 63.0, 61.1, 59.7, 58.5, 39.0, 38.1, 36.6, 35.2, 33.9,
32.5, 30.6, 21.9. IR: 3372, 1681. MS (CI): 501 (MH+).
HRMS (CI): calcd for C26H32N2O6S (MH+) 501.2059;
found: 501.2049. A solution of this compound (0.354 g,
5.2.3. Cyclohexanone 47. A solution of 46 (0.548 g,
0.95 mmol) and PtO2 (22 mg) in EtOAc (5 mL) was stirred
at rt under 1 atm of H2 overnight. Filtration (Celite) and con-
centration afforded 0.530 g (96%) of the corresponding sat-
1
urated ketone, white foam, [a]2D5 ꢀ53.2 (c 1.25). H: 8.07
(2H, d, J¼8.1), 7.42 (2H, d, J¼8.1), 7.15 (2H, d, J¼8.5),
6.82 (2H, d, J¼8.5), 5.20–5.06 (1H, m), 4.66 (1H, dd,
J¼11.0, 8.1), 4.31 (1H, dd, J¼11.0, 5.5), 3.77 (3H, s),
3.41–3.28 (1H, m), 3.14 (2H, dd, J¼7.0, 3.3), 2.79 (1H,
dd, J¼12.3, 10.1), 2.56–2.20 (5H, m), 2.46 (3H, s), 2.27
(3H, s), 2.18–2.07 (1H, m), 1.99 (3H, s), 1.89–1.54 (3H,
m). 13C: 208.3, 169.7, 169.6, 158.4, 145.3, 130.6, 130.4,
130.2, 127.6, 127.3, 114.0, 62.9, 60.2, 57.4, 55.4, 55.2,
38.0, 37.2, 35.2, 35.0, 33.9, 33.7, 25.2, 21.7, 20.9. IR:
3377, 1715, 1695. MS (CI): 585 (MH+). HRMS (CI): calcd
for C30H36N2O8S (MH+) 585.2271; found: 585.2285. A
mixture of this material (0.530 g, 0.91 mmol) and K2CO3
(0.025 g, 0.18 mmol) in MeOH (18 mL) was stirred over-
night, and then it was concentrated. The residue was taken
up with EtOAc (30 mL) and acidified with 1 M HCl
(20 mL). The layers were separated and the aqueous layer

5330
M. A. Ciufolini et al. / Tetrahedron 62 (2006) 5318–5337
708 mmol), Cs2CO3 (0.346 g, 106 mmol), and 1-bromo-3-
methyl-but-2-ene (122 mL, 106 mmol) in acetone (10 mL)
was stirred at 50 ꢁC for 2 h. After cooling to 25 ꢁC, the mix-
ture was filtered through Celite with additional CH2Cl2
(2ꢃ10 mL). The filtrates were concentrated and the residue
was purified by column chromatography (silica gel, EtOAc/
hexane: 60:40) to yield 0.394 g (98%) of 53, colorless foam,
5.2.8. Aldehyde 56. A solution of 55 (65 mg, 112 mmol),
4-methylmorpholine-N-oxide (52 mg, 448 mmol), and
Pr4NRuO4 (4 mg, 11.2 mmol) in CH2Cl2 (2.2 mL) contain-
˚
ing suspended powdered 4 A molecular sieves (56 mg,
0.5 g/mmol) was stirred at rt for 1 h. Filtration over silica
gel (EtOAc) and concentration afforded 40 mg (63%) of
1
56, colorless foam, [a]2D5 ꢀ38.6 (c 0.95). H: 9.66 (1H, s),
1
[a]2D5 ꢀ75.0 (c 1.00). H: 7.81 (2H, d, J¼8.3), 7.32 (2H, d,
7.06 (2H, d, J¼8.6), 6.81 (2H, d, J¼8.6), 5.52–4.41 (1H,
m), 4.92–4.70 (3H, m), 4.47 (2H, J¼6.7), 3.84 (1H, t,
J¼8.8), 3.44–3.39 (2H, m), 3.00 (3H, s), 2.67–2.57 (3H,
m), 2.43–2.29 (2H, m), 2.26–2.18 (2H, m), 1.93–1.67 (3H,
m), 1.78 (3H, s), 1.73 (3H, s), 1.51–1.40 (2H, m). 13C:
210.6, 201.4, 157.9, 154.9, 138.5, 131.3, 130.8, 120.1,
114.9, 96.0, 75.7, 71.2, 65.2, 62.4, 59.6, 59.1, 41.3, 36.6,
39.1, 38.4, 30.4, 26.2, 18.6. IR: 3411, 1716. MS (CI): 579
(weak), 577, 575, 573 (MH+, Cl cluster). HRMS (CI): calcd
for C27H34N2O355Cl3 (MH+) 573.1690; found: 573.1690.
J¼8.3), 7.02 (2H, d, J¼8.5), 6.77 (2H, d, J¼8.5), 5.44
(1H, br t, J¼6.7), 5.03 (1H, dd, J¼10.6, 9.1), 4.44 (2H, d,
J¼7.0), 4.12 (1H, dd, J¼11.8, 7.0), 3.73 (1H, dd, J¼11.8,
3.2), 3.30–3.19 (1H, m), 3.13 (1H, dd, J¼13.5, 9.7), 2.98
(1H, dd, J¼13.5, 6.0), 2.77 (3H, s), 2.57 (1H, dd, J¼12.7,
8.9), 2.45–2.35 (2H, m), 2.42 (3H, s), 2.25–2.09 (2H, m),
2.03–1.92 (2H, m), 1.77 (3H, s), 1.71 (3H, s), 1.70–1.59
(1H, m), 1.56 (1H, t, J¼12.0), 0.60 (1H, d, J¼12.8). 13C:
209.3, 171.6, 158.0, 144.1, 138.6, 136.4, 130.9, 130.8, 130.2,
127.9, 119.9, 114.9, 65.2, 62.9, 60.5, 58.9, 57.5, 38.6, 37.6,
36.0, 34.3, 33.2, 31.4, 30.2, 26.3, 21.9, 18.6. IR: 3434, 1716,
1686. MS (CI): 569 (MH+). HRMS (CI): calcd for
C31H40N2O6S (MH+) 569.2685; found: 569.2682.
5.2.9. Synthetic TAN-1251C, 23. A mixture of 56 (50 mg,
87 mmol), THF (0.4 mL), aq 1 M NH4OAc solution
(0.4 mL), and 10% Cd/Pb couple (435 mmol of Cd) was
vigorously stirred at rt for 1 h. The solid was filtered off
and rinsed with EtOAc. The filtrate was basified (aq
NaOH) and the product was extracted with EtOAc. Concen-
tration and purification of the residue by preparative TLC
(100% EtOAc) afforded 26 mg (79%) of TAN-1251C, pale
yellow oil, [a]2D5 +23.4 (c 0.48, MeOH) (lit. [a]2D5 +24 (c
5.2.6. Compound 54. Commercial 1 M LiAlH4 in THF
(1.8 mL, 1.76 mmol) was added dropwise to a cold
(ꢀ78 ꢁC) solution of 53 (0.20 g, 352 mmol) in THF
(3.5 mL). The mixture was warmed to 0 ꢁC, stirred for an ad-
ditional 15 min and then heated at reflux for 2 days. After
cooling to 0 ꢁC EtOAc was added (caution: vigorous reac-
tion) followed by H2O (30 mL), 15% NaOH (30 mL), and
H2O (90 mL). The precipitate was filtered through Celite
and rinsed with EtOAc. The filtrates were concentrated to
1
0.44, MeOH), Refs. 10 and 21b). H: 7.08 (2H, d, J¼8.7),
6.82 (2H, d, J¼8.7), 5.53–5.46 (1H, m), 5.22 (1H, d,
J¼1.1), 4.47 (2H, d, J¼6.7), 3.42–3.37 (1H, m), 3.22 (2H,
s), 3.21 (1H, dd, J¼11.5, 2.8), 2.80 (1H, dd, J¼11.5, 1.9),
2.61–2.56 (1H, m), 2.51 (3H, s), 2.50–2.44 (1H, m), 2.41–
2.17 (4H, m), 2.00 (1H, ddd, J¼13.6, 10.7, 5.4), 1.89 (1H,
J¼13.6, 5.4), 1.86–1.81 (2H, m), 1.79 (3H, s, CH3); 1.73
(3H, s, CH3). 13C: 212.0, 157.5, 138.4, 132.2, 130.2,
128.5, 128.2, 120.2, 114.8, 71.9, 65.1, 59.4, 52.5, 43.2,
41.8, 40.7, 39.9, 38.2, 37.6, 35.0, 26.2, 18.6. IR: 3393,
1716. MS (CI): 381 (MH+). HRMS (CI): calcd for
C24H33N2O2 (MH+) 381.2542; found: 381.2543.
1
yield 0.124 g of crude 54, colorless foam. H: 7.00 (2H, d,
J¼8.6), 6.81 (2H, d, J¼8.6), 5.47 (1H, t, J¼6.7), 4.46 (2H,
J¼6.8), 3.57–3.46 (1H, m), 3.29 (1H, dd, J¼9.8, 4.9),
3.19–3.05 (3H, m), 3.04–2.80 (2H, m), 2.62 (1H, br t,
J¼7.9), 2.43 (3H, s), 2.47–2.38 (1H, m), 2.2 (1H, ddd,
J¼14.3, 10.9, 2.9), 1.98–1.85 (3H, m), 1.77 (3H, s), 1.72
(3H, s), 1.67–1.19 (5H, m). 13C: 157.8, 138.5, 131.2, 130.0,
120.1, 115.1, 70.2, 65.2, 62.9, 60.9, 57.8, 56.7, 49.4, 43.0,
36.6 (two resonances), 35.3, 34.1, 32.9 (two resonances),
26.2, 18.6. IR: 3379. MS (LSI): 403 (MH+). HRMS (LSI):
calcd for C24H38N2O3 (MH+) 403.2961; found: 403.2959.
5.2.10. Aldehyde 57. A solution of 48 (0.340g, 0.66 mmol),
4-methylmorpholine-N-oxide (0.154 g, 1.32 mmol), and
Pr4NRuO4 (23 mg, 66 mmol) in CH2Cl2 (13.2 mL) contain-
˚
5.2.7. Carbamate 55. Trichloroethyl chloroformate
(0.142 g, 0.67 mmol) was added to a solution of 54
(0.245 g, 0.61 mmol) and NaHCO3 (0.154 g, 1.83 mmol)
in THF/H2O (3 mL/3 mL). After stirring at rt overnight the
mixture was extracted with EtOAc (2ꢃ10 mL). The com-
bined extracts were dried (MgSO4) and concentrated. Filtra-
tion of the residue through silica gel (EtOAc/hexane: 70:30)
afforded 0.22 g (62%) of 55, white foam, [a]2D5 ꢀ8.8 (c
ing suspended powdered 4 A molecular sieves (330 mg,
0.5 g/mmol), was stirred at rt for 15 min, then it was filtered
over silica gel (EtOAc) and concentrated to afford 0.263 g
(77%) of 57, colorless foam, [a]2D5 ꢀ56.6 (c 1.25). 1H:
9.57 (1H, s), 7.84 (2H, d, J¼8.1), 7.32 (2H, d, J¼8.1);
7.01 (2H, d, J¼8.6), 6.75 (2H, d, J¼8.6), 5.01 (1H, dd,
J¼11.0, 9.2), 3.76 (3H, s), 3.56–3.45 (1H, m), 3.36 (1H, d,
J¼7.7), 2.77 (3H, s), 2.75–3.70 (1H, m), 2.47–2.37 (2H,
m), 2.42 (3H, s), 2.31–1.65 (5H, m), 1.47–1.33 (1H, m),
0.60–0.46 (1H, m). 13C: 207.6, 197.6, 170.4, 158.8, 143.8,
136.0, 132.3, 130.6, 129.8, 127.7, 114.1, 63.2, 59.2, 57.0,
55.4, 37.9, 37.1, 35.6, 32.9, 32.9, 32.7, 29.9, 21.7. IR:
1736, 1717, 1698. MS (CI): 513 (MH+). HRMS (CI): calcd
for C27H32N2O6S (MH+) 513.2059; found: 513.2054.
1
1.05). H: 7.01 (2H, d, J¼8.4), 6.82 (2H, d, J¼8.4), 5.47
(1H, t, J¼6.7), 4.75 (2H, s), 4.66–4.54 (1H, m), 4.47 (2H,
J¼6.7), 3.64–3.52 (1H, m), 3.33 (1H, dd, J¼10.1, 4.4);
3.16 (1H, t, J¼10.1), 3.05–2.92 (3H, m), 2.95 (3H, s), 2.88
(1H, dd, J¼13.5, 2.9), 2.44 (1H, t, J¼13.5), 1.99–1.91
(2H, m), 1.78 (3H, s), 1.73 (3H, s), 1.76–1.54 (6H, m),
1.44–1.27 (2H, m). 13C: 157.8, 155.0, 138.6, 130.9, 130.0,
120.1, 115.2, 96.0, 75.6, 70.1, 65.2, 62.7, 61.1, 57.1, 54.3,
45.0, 36.6, 36.1, 34.0, 33.3, 33.1, 32.7, 30.6, 26.2, 18.6.
IR: 3410, 1712. MS (CI): 583 (w), 581, 579, 577 (MH+, Cl
cluster). HRMS (CI): calcd for C27H39N2O355Cl3 (MH+)
577.2003; found: 577.2006.
5.2.11. Tricyclic intermediate 71. Commercial sodium
methoxide (42 mg, 780 mmol) was added to a solution of
57 (200 mg, 390 mmol) in MeOH/H2O (7.2 mL/0.8 mL),
and the mixture was stirred at rt for 30 min. The solution
was concentrated and the residue was diluted with EtOAc

M. A. Ciufolini et al. / Tetrahedron 62 (2006) 5318–5337
5331
(40 mL). This organic phase was sequentially washed with
1 M HCl (20 mL) and brine (20 mL), dried (MgSO4) and
concentrated, and the residue was purified by preparative
TLC (EtOAc/hexane: 60:40) to afford 90 mg (44%) of 71,
The mixture was stirred at rt for 1 h then it was concentrated.
The residue was taken up with EtOAc, and the solution was
washed (H2O, then brine), dried (MgSO4), and concentrated.
The highly polar, crude Mitsunobu product was converted,
taken up in CH2Cl2 (1 mL) and treated with NEt3 (30 mL,
208 mmol), and benzyl chloroformate (20 mL, 135 mmol).
After stirring at rt until TLC showed complete conversion,
the solution was concentrated and the residue was purified
by preparative TLC (10% MeOH in CH2Cl2) to afford
75 in an overall 26% yield from compound 73. Aqueous
3 M HCl (6 mL) was added to a solution of 75 (13 mg,
17.5 mmol) in MeOH (1 mL). The mixture was concentrated
and the residue was redissolved in MeOH (0.2 mL), treated
with 10% Pd/C (5 mg) and stirred at rt under 1 atm of H2
(balloon) for 3 h. Filtration through Celite and concentration
yielded 7.6 mg (94%) of FR-901483 bis-hydrochloride, [a]D25
+4.0 (c 0.35, MeOH, lit. [Ref. 9a] +5, rotation very sensitive
to the amount of water and of residual HCl). 1H (500 MHz,
CD3OD): 7.35 (2H, d, J¼8.6), 6.92 (2H, d, J¼8.6), 4.52
(1H, dd, J¼13.6, 9.9), 4.36 (1H, br d, J¼7.7), 4.33–4.26
(1H, m), 3.97 (1H, dd, J¼13.6, 2.9), 3.93–3.88 (1H, m),
3.80 (3H, s), 3.67 (1H, br s), 3.34 (1H, m), 3.10 (1H, dd,
J¼12.4, 3.6), 2.81 (3H, s), 2.65 (1H, dd, J¼14.0, 8.9), 2.48
(1H, br s), 2.35–2.07 (6H, m), 1.93 (1H, br d, J¼14.2). 13C
(125 MHz, CD3OD): 159.5, 130.7, 127.4, 114.3, 71.4, 67.9,
63.9, 61.0, 54.7, 54.1, 50.9, 41.8, 40.7, 33.0, 31.4, 27.2,
26.6, 21.7. MS (LSI): 427 (MH+). HRMS (LSI): calcd for
C31H38N2O8S (MH+) 427.1998; found: 427.2000.
1
colorless foam, [a]2D5 ꢀ10.6 (c 1.41, EtOH). H: 7.86 (2H,
d, J¼8.1), 7.31 (2H, d, J¼8.1), 7.10 (2H, d, J¼8.8), 6.76
(2H, d, J¼8.8), 5.00 (1H, dd, J¼11.0, 8.8), 3.81–3.69 (2H,
m), 3.75 (3H, s), 3.38 (1H, dd, J¼14.0, 8.8), 3.32–3.25
(1H, m), 2.82–2.76 (1H, m), 2.65–2.37 (3H, m), 2.61 (3H,
s), 2.41 (3H, s), 2.29 (1H, dd, J¼12.9, 8.8), 2.25–1.90 (2H,
m), 1.80 (1H, dd, J¼13.6, 3.3), 1.72 (1H, dd, J¼12.9,
11.0). 13C: 211.8, 171.5, 158.1, 143.5, 136.3, 130.7, 129.9,
129.8, 127.6, 113.9, 68.5, 59.8, 58.4, 57.2, 55.2, 50.7,
36.9, 35.61, 33.1, 32.3, 29.6, 28.3, 21.6. IR: 3428, 1702.
MS (CI): 513 (MH+). HRMS (CI): calcd for C27H32N2O6S
(MH+) 513.2059; found: 513.2061.
5.2.12. Acetate 72. A solution of 71 (0.140 g, 0.27 mmol),
pyridine (0.064 g, 0.81 mmol), acetic anhydride (0.033 g,
0.33 mmol), and DMAP (catalytic amount) in CH2Cl2
(2.7 mL) was stirred at rt for 3 h. The mixture was concen-
trated and the residue was purified by preparative TLC
(EtOAc/hexane: 60:40) to afford 0.140 g (93%) of 72, color-
1
less foam, [a]2D5 ꢀ27.8 (c 1.41). H: 7.82 (2H, d, J¼8.1),
7.30 (2H, d, J¼8.1), 7.02 (2H, d, J¼8.8), 6.74 (2H, d,
J¼8.8), 4.94–4.85 (2H, m), 3.80 (1H, dd, J¼14.0, 7.4),
3.73 (3H, s), 3.41–3.32 (1H, m), 3.05 (1H, dd, J¼14.0,
7.4), 2.92–2.86 (1H, m), 2.65–2.97 (2H, m), 2.57 (3H, s),
2.41 (3H, s), 2.30 (1H, dd, J¼12.8, 8.8), 2.19 (3H, s),
2.04–1.84 (2H, m), 1.77 (1H, dd, J¼12.8, 11.0). 13C:
209.5, 170.4, 169.7, 158.3, 143.5, 136.3, 130.1, 129.7,
127.6, 113.9, 68.9, 58.3, 58.1, 56.6, 55.2, 47.5, 36.9, 35.2,
33.2, 32.1, 29.5, 28.9, 21.6, 21.0. IR: 3405, 1742, 1708.
MS (CI): 555 (MH+). HRMS (CI): calcd for C29H34N2O7S
(MH+) 555.2165; found: 555.2163.
5.3. General procedure for oxidative cyclization of
phenolic sulfonamides 88
A solution of DIB (2.2 mmol) in HFIP (3.5 mL) was added
to a solution of a phenolic sulfonamide (2 mmol) in HFIP
(5 mL) during 5 min. After 30–60 min, a color change
from yellow to green occurred and TLC showed complete
conversion. The mixture was concentrated in vacuo and the
residue was chromatographed (silica gel, typically 60:40
EtOAc/cyclohexane) to furnish the product, which is often
obtained as a foam.
5.2.13. Diol 73. Commercial 1 M LAH in THF (0.96 mL,
0.96 mmol) was added dropwise to a cold (ꢀ78 ꢁC) solution
of compound 71 (98 mg, 191 mmol) in THF (2 mL). The
mixture was warmed to 0 ꢁC and stirred for 15 min, then it
was refluxed overnight. The reaction was cooled to 0 ꢁC
and quenched with EtOAc (caution: vigorous reaction), fol-
lowed by H2O (30 mL), 15% NaOH (30 mL), and H2O
(50 mL). The precipitate was filtered through Celite and
rinsed with EtOAc. The filtrate was concentrated to yield
60 mg of 73 (contaminated with some of its diastereomer)
as a yellow foam. The two isomers were not separated at
5.3.1. Spirodienone 91. A 1 M solution of PhI(OAc)2
(‘DIB’) in hexafluoroisopropanol (‘HFIP’, 4.05 mL,
1.05 equiv of DIB) was added dropwise to a well stirred
solution of (D)-(ꢀ)-N-methanesulfonyl-homotyrosinol
(1.0 g, 3.86 mmol) in HFIP (15 mL) at rt. A color change
from yellow to green occurred and no starting material
was apparent (TLC) after 30 min. The volatiles were re-
moved and the highly polar, crude product, tan foam, was
used directly in the next step. [a]2D5 +10 (c 0.5, acetone) 1H
(acetone-d6): 7.26 (1H, dd, J¼9.8, 3.0), 7.03 (1H, dd,
J¼10.2, 3.0), 6.16 (1H, dd, J¼10.2, 2.3), 6.10 (1H, dd,
J¼10.2, 2.3), 4.07 (1H, m), 3.76 (2H, m), 3.01 (3H, s),
2.52 (1H, m), 2.48 (1H, m), 2.18 (1H, m), 1.92 (1H, m).
13C (acetone-d6): 185.4, 153.7, 149.6, 128.6, 128.2, 65.2,
64.8, 63.9, 40.2, 38.6, 27.3. IR: 3414, 1666. HRMS (CI):
calcd for C11H15NO4S (MH+): 258.0800; found 258.0801.
A solution of this material (0.9 g), imidazole (1 g, 4 equiv),
and TBDPSCl (1.10 g, 1.1 equiv) in DMF (15 mL) was
stirred at rt for 3 h, then it was diluted with EtOAc
(20 mL) and washed with brine (15 mL). The organic phase
was separated and the aqueous layer was extracted with
more EtOAc (10 mL). The combined extracts were washed
1
this point. H: 7.17 (2H, d, J¼8.6), 6.77 (2H, d, J¼8.6),
3.93–3.81 (1H, m), 3.73 (3H, s), 3.65–3.39 (3H, m), 3.16–
3.05 (1H, m), 2.77 (2H, d, J¼5.0), 2.50 (1H, dd, J¼9.4,
5.0), 2.29 (3H, s), 2.23–2.07 (2H, m), 2.01–1.87 (2H, m),
1.82 (1H, dd, J¼12.7, 9.0), 1.73–1.64 (1H, m), 1.34 (1H,
dd, J¼12.7, 5.6), 1.29–1.19 (2H, m). 13C: 156.7, 130.2,
129.3, 112.6, 68.8, 63.2, 60.2, 57.8, 55.3, 54.2, 53.6, 45.0,
43.1, 34.8, 33.7, 30.4, 29.8, 29.0. IR: 3384. MS (CI): 347
(MH+). HRMS (CI): calcd for C20H30N2O3 (MH+)
347.2335; found: 347.2338.
5.2.14. Synthetic FR-901483 bis-hydrochloride:16$2HCl.
Dibenzylphosphate (145 mg, 520 mmol), tris(4-chloro-
phenyl)phosphine (98 mg, 270 mmol), DIAD (54 mL,
270 mmol), and Et3N (0.121 mL, 0.87 mmol) were added
to a solution of 73 (30 mg, 86.7 mmol) in THF (1.7 mL).

5332
M. A. Ciufolini et al. / Tetrahedron 62 (2006) 5318–5337
with brine (4ꢃ15 mL), and then they were concentrated.
Silica gel chromatography of the residue (1:1:0.1, EtOAc/
hexanes/NEt3) afforded pure 91 (pale yellow foam, 1.56 g,
3.17 mmol, 82% from homotyrosinol mesylamide). [a]D25
+8 (c 0.5, acetone). 1H (acetone-d6): 7.74 (m, 4H), 7.47 (m,
6H), 7.27 (1H, dd, J¼10.2, 3.0), 6.94 (1H, dd, J¼9.8, 3.0),
6.20 (1H, dd, J¼10.2, 1.9), 6.09 (1H, dd, J¼10.2, 2.3), 4.17
(1H, m), 4.03 (1H, dd, J¼10.2, 3.8), 3.93 (1H, dd, J¼10.2,
7.5), 2.95 (3H, s), 2.48 (2H, m), 2.30 (1H, m), 1.93
(1H, m), 1.10 (9H, s). 13C (acetone-d6): 185.2, 153.7,
148.7, 136.4, 134.0, 130.8, 129.1, 128.7, 128.2, 66.7, 65.3,
63.3, 39.6, 38.3, 27.3, 27.1, 19.8. IR: 1668. HRMS (CI):
calcd for C27H33NO4SSi (MH+): 496.1978; found: 496.1972.
a wet metallic powder, 15 g) was stirred at rt for 4 h, then
it was carefully filtered over Celite (caution: RaNi is pyro-
phoric when dry). The metallic residue was washed with
more EtOAc (3ꢃ30 mL), and the combined organic phases
were concentrated. Silica gel chromatography (1:9 EtOAc/
hexanes) of the residue afforded pure 95 (pale yellow
foam, 623 mg, 1.29 mmol, 77%), uncontaminated by the re-
gioisomer formed during cyclization of 91. [a]2D5 ꢀ13 (c 0.5,
CH2Cl2) 1H: 7.69 (4H, m), 7.39 (6H, m), 4.13 (1H, m), 3.65
(1H, dd, J¼10.2, 4.9), 3.53 (1H, dd, J¼10.2, 6.8), 3.48 (3H,
t, J¼13.2), 3.25 (1H, dd, J¼13.2, 7.5), 2.50 (1H, m), 2.10–
1.00 (12H, m), 1.08 (9H, s). 13C: 135.6, 133.2, 129.6,
127.6, 73.8, 66.3, 59.5, 53.1, 40.8, 35.5, 35.1, 27.9, 26.8,
24.6, 23.4, 19.6, 19.2. IR: 1307. HRMS (CI): calcd for
C27H37NO3SSi (MH+): 484.2342; found: 484.2349.
5.3.2. Compounds 92 and 93. A 0.5 M solution of KHMDS
in toluene (8 mL, 4 mmol, 1.3 equiv) was added to a cold
(ꢀ100 ꢁC), stirred solution of 91 (1.5 g, 3.00 mmol) in dry
THF (100 mL), under argon. The reaction was allowed to
warm up to 0 ꢁC during 3 h, then it was quenched with aq
satd NH4Cl (50 mL) and diluted with EtOAc (50 mL). The
aqueous phase was discarded and the organic layer was
washed with brine (50 mL) and concentrated. A proton NMR
spectrum of the crude product revealed that 93 was the
major product of a 7:1 mixture of regioisomers (de¼75%).
Silica gel chromatography (3:7:0.1, EtOAc/hexanes/NEt3)
afforded an inseparable mixture of 93 and its regioisomer
(1.33 g, 2.70 mmol, 89%). Separation was effected at the
stage of compound 95. [a]2D5 +30 (c 0.5, CH2Cl2). 1H: 7.67
(4H, m), 7.40 (6H, m), 6.62 (1H, dd, J¼10.2, 1.9), 6.03
(1H, d, 10.2), 4.27 (1H, m), 3.67 (1H, dd, J¼10.5, 4.9),
3.62 (1H, dd, J¼7.6, 2.3), 3.43 (1H, dd, J¼13.2, 7.9), 3.25
(1H, t, 12.4), 3.00 (1H, m), 2.70 (1H, dd, J¼17.3, 5.3),
2.63 (1H, dd, J¼16.2, 2.3), 2.14 (4H, m), 1.07 (9H, s).
13C: 194.5, 150.2, 135.5, 134.7, 132.8, 129.8, 127.7, 71.1,
66.3, 61.1, 53.3, 40.6, 36.7, 34.8, 27.2, 26.8, 19.1. IR:
1682. HRMS (CI): calcd for C27H33NO4SSi (MH+):
496.1978; found: 496.1975.
5.3.5. Compounds 96. A 1.5 M pentane solution of t-BuLi
(0.5 mL, 0.75 mmol, 1.1 equiv) was added to a cold
(ꢀ78 ꢁC), stirred solution of 95 (345 mg, 0.71 mmol) in THF
(5 mL) under argon. After 15 min, BF3$Et2O (100 mg,
1.1 equiv) was added, followed 5 min later by (ꢂ)-octene
oxide (120 mg, 1.3 equiv). The mixture was stirred for 3 h,
during which time it was allowed to warm to 0 ꢁC, then it was
quenched with aq satd NH4Cl (10 mL) and diluted with
EtOAc (10 mL). The organic layer was separated, washed
with brine (10 mL), and concentrated. Crude 97, foam, mix-
ture of diastereomers, was advanced to the next step without
further purification. IR: 3479, 1428, 1301. HRMS (CI): calcd
for C35H53NO4SSi (MH+): 612.3543; found: 612.3547.
5.3.6. Ketone 97. A 0.5 M solution of Dess–Martin period-
inane in CH2Cl2 (Acros, 2.1 mL, 1.5 equiv) was added at rt
to a solution of crude 96 (430 mg) in CH2Cl2 (4 mL) and the
mixture was stirred for 2 h. The solution was diluted with
EtOAc (15 mL) and washed with a 1:1 mixture of aq satd
K2CO3 and aq satd Na2S2O3 (3ꢃ10 mL), and then it was
concentrated. Crude 97 (yellow foam, 381 mg, 0.62 mmol,
88% from 95) required no further purification. [a]2D5 +3 (c
1
5.3.3. Thiophenol adduct 94 and regioisomer. A cold
(0 ꢁC) solution of the 7:1 mixture of regioisomers 92 and
93 (1.30 g, 2.62 mmol,), BF3Et2O (20 mol %, 70 mg), and
thiophenol (1.8 g, 6 equiv) in CH2Cl2 (40 mL) was stirred
overnight, during which time it was allowed to warm to rt.
The reaction was quenched with aq satd K2CO3 (40 mL)
and diluted with EtOAc (80 mL). The aqueous layer was
separated and extracted with more EtOAc (30 mL). The
combined extracts were washed with brine (50 mL) and con-
centrated. Silica gel chromatography (15:85, EtOAc/
hexanes) of the residue provided 94 (1.63 g, 2.02 mmol,
77%, 7:1 mixture of regioisomers) as a foam. [a]2D5 +12 (c
0.5 CH2Cl2) 1H: 7.80–7.00 (15H, m), 4.41 (1H, t, J¼12.8),
4.25 (1H, m), 3.90 (2H, m), 3.65 (1H, t, J¼8.3), 3.31 (1H,
dd, J¼13.2, 8.3), 2.59 (1H, m), 2.32 (1H, d, J¼14.7), 2.24–
1.23 (7H, m), 1.06 (9H, s). 13C: 137.1, 136.3, 135.6, 134.6,
133.5, 133.4, 133.1, 130.8, 129.7, 129.5, 129.4, 129.0,
128.9, 128.7, 127.5, 127.4, 76.2, 65.5, 62.0, 61.0, 53.5,
51.9, 42.9, 42.2, 35.0, 30.9, 27.2, 26.7, 19.2. IR: 1474,
1436, 1307. MS (LSI): 808 (MH+) for C45H45NO4S4Si.
0.5, CH2Cl2). H: 7.69 (4H, m), 7.39 (6H, m), 4.13 (2H,
m), 3.69 (1H, dd, J¼10.2, 4.9), 3.51 (1H, dd, J¼10.2, 3.0),
3.12 (1H, dd, J¼18.5, 5.7), 2.60 (1H, dd, J¼18.5, 6.4),
2.50 (2H, m), 2.38 (3H, t, 7.5), 2.07–1.49 (11H, m), 1.28
(8H, m), 1.09 (9H, s), 0.90 (3H, t, J¼5.4). 13C: 206.2,
135.6, 134.7, 129.6, 127.6, 71.8, 66.2, 59.6, 56.9, 54.8,
47.5, 45.0, 42.9, 40.8, 35.9, 34.9, 31.4, 30.2, 28.7, 27.7,
26.6, 23.6, 22.4, 19.1, 13.9. IR: 1720, 1462, 1428, 1305.
HRMS (CI): calcd for C35H51NO4SSi (MH+): 610.3386;
found: 610.3386.
5.3.7. Borylketone 114. A stirred solution of 97 (370 mg,
0.61 mmol) in dry DMF (5 mL) under argon was treated
with DBU (100 mg, 1.05 equiv), followed, after 10 min,
by bis(pinacolyl)diboronate (175 mg, 1.1 equiv), CuCl
(70 mg, 1.1 equiv), and KOAc (70 mg, 1.1 equiv). Stirring
was continued for 20 min, then the mixture was diluted
with EtOAc (10 mL), sequentially washed with aq concd
NH4OH (2ꢃ5 mL) and brine (3ꢃ10 mL), and concentrated.
Silica gel chromatography (1:9:0.1, EtOAc/hexanes/NEt3)
of the residue afforded pure 144 (pale yellow oil, 352 mg,
0.52 mmol, 86%). [a]D25 +10 (c 0.5, CH2Cl2). 1H: 7.59 (4H,
m), 7.39 (6H, m), 4.01 (1H, dd, J¼10.5, 2.6), 3.68 (1H, d,
J¼10.5), 3.51 (2H, br m), 2.62 (1H, dd, J¼15.8, 3.0), 2.40
(2H, m), 2.30 (1H, dd, J¼13.9, 3.4), 2.12–1.12 (15H, m),
5.3.4. Sulfonamide 95. A solution of 94 (1.35 g, 1.67 mmol,
7:1 mixture of regioisomers) in a 1:3 mixture of EtOAc/
EtOH (100 mL) containing suspended activated Raney
nickel (50% slurry in water, Acros, decanted and added as

M. A. Ciufolini et al. / Tetrahedron 62 (2006) 5318–5337
5333
1.09 (21H, s), 0.90 (3H, t, J¼6.4). 13C: 214.9, 135.6, 130.0,
127.7, 127.6, 72.1, 63.9, 58.0, 47.5, 45.1, 42.1, 34.5, 32.7,
31.5, 28.9, 26.9, 26.7, 24.5, 24.0, 23.7, 22.4, 19.5, 19.0,
13.9. HRMS (ESI): calcd for C41H64NO4BSi (MH+):
674.4784; found: 674.4792.
residue was quickly chromatographed (silica gel) by sequen-
tial elution with 1:9:0.1 EtOAc/hexanes/NEt3 (silicon-
containing byproducts) and 95:5 EtOAc/NEt3 (elution of
desilylated 123). The spectra of the product (pale yellow
oil, 75 mg, 0.17 mmol, 95%) suggest that it exists largely
as the open-chain, instead of the hemiaminal, tautomer.
1
5.3.8. Tricyclic intermediate 117. A cold (0 ꢁC) solution of
114 (35 mg, 0.052 mmol), AcOH (1 drop), and NaBH3CN
(10 mg, 3 equiv) in dry MeOH (3 mL) was stirred under
argon for 4 h, then it was treated with aq 2 N NaOH
(0.3 mL) and aq 35% H2O2 (0.2 mL) and stirred at 0 ꢁC
for another 30 min. The mixture was diluted with EtOAc
(10 mL). The aqueous layer was separated and washed
with more EtOAc (5 mL), and the combined organic phases
were washed with brine (10 mL) and concentrated. Silica gel
chromatography (1:9:0.1, EtOAc/hexanes/NEt3) of the resi-
due yielded pure 117 (pale yellow oil, 23 mg, 0.042 mmol,
[a]2D5 +11 (c 0.5, CH2Cl2). H: 3.90 (1H, d, J¼9.4), 3.61
(2H, m), 3.04 (1H, d, J¼8.7), 2.71 (1H, dd, J¼16.2, 3.8),
2.40 (2H, m), 2.31 (1H, dd, J¼13.2, 3.8), 2.20–1.20 (21H,
m), 1.15 (12H, d, J¼12.4), 0.87 (3H, t, J¼6.5). 13C: 214.9,
79.3, 72.9, 63.3, 59.5, 47.2, 46.3, 42.3, 34.0, 32.7, 31.5,
28.9, 27.4, 26.8, 26.0, 24.9, 24.4, 24.0, 23.6, 22.4, 19.5,
14.0. IR: 3253, 1704. MS (ESI): 436 (MH+) for
C25H46NO4B. A cold (ꢀ78 ꢁC) solution of this material
(70 mg, 0.16 mmol), AcOH (two drops), and NaBH(OAc)3
(50 mg, 1.5 equiv) in CH2Cl2 (4 mL) was stirred under argon
overnight, during which time it was allowed to warm up to rt.
The mixture was diluted with EtOAc (10 mL) and washed
with aq satd K2CO3 (10 mL). The organic phase was further
washed with brine (10 mL) and concentrated. Silica gel
chromatography of the residue (2:8:0.1 EtOAc/hexanes/
NEt3) provided pure 123 (49 mg, 0.12 mmol, 73%) as a
1
80%). [a]2D5 +6 (c 0.5, CH2Cl2). H: 7.69 (4H, m), 7.39
(6H, m), 4.14 (1H, m), 3.65 (1H, br), 3.41 (1H, br), 3.0
(1H, br), 2.48 (1H, br), 2.15–1.10 (25H, m), 1.08 (9H, s),
0.86 (3H, t, J¼6.8). 13C: 135.6, 129.5, 127.6, 127.5, 71.3,
66.9, 68.6, 63.8, 57.0, 39.7, 38.6, 37.4, 36.2, 33.6, 31.9,
31.8, 29.4, 26.9, 26.8, 26.5, 25.6, 23.7, 22.6, 19.2, 14.1.
IR: 3417. HRMS (CI): calcd for C35H53NO2Si (MH+):
548.3929; found: 548.3928.
1
pale yellow oil, [a]D25 ꢀ22 (c 0.5, CH2Cl2). H: 3.44–3.22
(4H, m), 2.28 (1H, dt, J¼12.8; 4.1), 2.22–1.90 (3H, m),
1.80–1.20 (22H, m), 1.25 (12H, s), 0.87 (3H, t, J¼6.5).
13C: 82.7, 66.3, 66.2, 56.1, 51.0, 37.0, 36.7, 35.4, 34.0,
31.9, 30.0, 29.7, 29.4, 28.9, 27.1, 24.9, 24.0, 22.7, 21.7,
19.0, 14.1. IR: 3409. MS (ESI): 420 (MH+) for C25H46NO3B.
5.3.9. Piperidinone 118. A 0.5 M solution of Dess–Martin
periodinane in CH2Cl2 (Acros, 0.15 mL, 2.0 equiv) was
added to a solution of 117 (20 mg, 0.036 mmol) in CH2Cl2
(1 mL) at rt. The mixture was stirred for 2 h, then it was di-
luted with EtOAc (5 mL), washed with a 1:1 mixture of aq
satd K2CO3 and aq satd Na2S2O3 (3ꢃ5 mL), and concen-
trated. Silica gel chromatography of the residue (1:9:0.1,
EtOAc/hexane/NEt3) delivered pure 118 (pale yellow oil,
5.3.12. Compound 124. A solution of 123 (42 mg,
0.10 mmol), imidazole (25 mg, 4 equiv), and TBDPSCl
(28 mg, 1.1 equiv) in DMF (2 mL) was stirred at rt for 3 h,
then it was diluted with EtOAc (5 mL) and brine (5 mL).
The aqueous layer was removed and washed with more
EtOAc (5 mL). The combined organic phases were washed
with brine (4ꢃ15 mL) and concentrated. Silica gel chroma-
tography of the residue (1:9:0.1 EtOAc/hexanes/NEt3)
yielded pure 22 (pale yellow oil, 0.63 mg, 0.095 mmol,
1
19 mg, 0.034 mmol, 94%). [a]2D5 +3 (c 0.5, CH2Cl2). H:
7.69 (4H, m), 7.39 (6H, m), 3.60 (1H, dd, J¼10.2, 4.5),
3.40 (1H, t, J¼8.7), 3.13 (1H, m), 3.00 (1H, m), 2.51 (1H,
dd, J¼15.4, 5.3), 2.44 (1H, br), 2.24 (1H, d, J¼10.5), 2.10
(1H, dd, J¼15.8, 7.2), 2.05–1.00 (16H, m), 1.08 (9H, s),
0.85 (3H, t, J¼7.2). 13C: 212.6, 135.6, 134.8, 129.6, 127.7,
127.6, 68.1, 68.0, 66.2, 58.5, 50.9, 43.0, 40.5, 36.9, 36.2,
31.8, 29.2, 26.9, 26.5, 26.0, 24.3, 23.1, 22.6, 21.6, 19.2,
14.1. IR: 1707. HRMS (CI): calcd for C35H51NO2Si
(MH+): 546.3767; found: 546.3768.
1
95%). [a]2D5 +9 (c 0.5, CH2Cl2). H: 7.70 (4H, m), 7.39
(6H, m), 3.52 (1H, br), 3.15 (3H, br), 2.20–1.00 (25H, m),
1.25 (12H, s), 1.06 (9H, s), 0.87 (3H, t, J¼6.5). 13C: 135.6,
129.4, 127.5, 82.6, 69.3, 65.3, 57.8, 50.7, 37.3, 35.6, 35.3,
34.2, 31.9, 29.7, 29.3, 27.1, 26.9, 26.4, 24.9, 24.8,
24.2, 22.6, 21.6, 19.2, 14.1. MS (ESI): 658 (MH+) for
C41H64NO3SiB.
5.3.10. Synthetic (L)-2-epicylindricine C, 119. A solution
of 118 (18 mg, 33 mmol) and TBAF (32 mg, 3 equiv) in THF
(1 mL) was stirred at rt for 4 h. Concentration and chroma-
tography of the residue (1:9:0.1, EtOAc/hexanes/NEt3) af-
forded pure (ꢀ)-119 (pale yellow oil, 10 mg, 0.032 mmol,
96%), whose 1H NMR spectra were superimposable to those
published by Weinreb (Ref. 35h). [a]2D5 ꢀ39 (c 0.5, CH2Cl2).
1H: 3.53 (1H, dd, J¼10.5, 4.1), 3.40–3.20 (3H, m), 2.63 (1H,
dd, J¼15.3, 5.7), 2.52 (1H, br), 2.27 (1H, m), 2.19 (1H, dd,
J¼15.4, 6.0), 2.03 (2H, m), 1.83 (2H, m), 1.70–1.20 (19H,
m), 0.87 (3H, t, J¼6.5). 13C: 211.5, 68.9, 64.6, 63.7, 57.9,
50.9, 42.7, 39.4, 36.9, 36.7, 31.7, 29.7, 29.2, 26.6, 26.2,
24.3, 22.6, 22.6, 14.1. IR: 3445, 1707. HRMS (CI): calcd
for C19H33NO2 (MH+): 308.2589; found: 308.2587.
5.3.13. Alcohol 125. A cold (0 ꢁC) solution of 124 (56 mg,
0.085 mmol), 2 N aq NaOH (0.5 mL), and aq 35% H2O2
(0.3 mL) in THF (2 mL) was stirred for 30 min, and then it
was diluted with EtOAc (5 mL). The aqueous layer was
discarded and the organic phase was washed with
brine (3ꢃ3 mL) and concentrated. Crude 125 (45 mg,
0.083 mmol, 97%), pale yellow oil, was used without further
purification. [a]2D5 +6 (c 0.5, CH2Cl2). 1H: 7.66 (4H, m), 7.37
(6H, m), 4.14, (1H, br), 3.57 (1H, br), 3.16 (3H, br), 2.15–
1.00 (25H, m), 1.08 (9H, s), 0.84 (3H, t, J¼6.5). 13C:
135.6, 134.3, 134.0, 129.4, 127.5, 73.6, 68.9, 65.1, 57.5,
46.9, 37.8, 36.2, 35.1, 35.0, 33.8, 31.8, 29.3, 27.2, 26.9,
26.2, 24.4, 23.1, 22.6, 19.2, 14.0. IR: 3417. HRMS (CI):
calcd for C35H53NO2Si (MH+): 548.3929; found: 548.3929.
5.3.11. Boronic ester 123. A solution of 114 (122 mg,
0.18 mmol) and TBAF (175 mg, 3 equiv) in THF (4 mL)
was stirred at rt for 5 h, and then it was concentrated. The
5.3.14. Protected cylindricine C, 126. A 0.5 M CH2Cl2
solution of Dess–Martin periodinane (Acros, 0.5 mL,

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M. A. Ciufolini et al. / Tetrahedron 62 (2006) 5318–5337
1.5 equiv) was added to a solution of 125 (41 mg,
0.075 mmol) in CH2Cl2 (2 mL). The mixture was stirred at
rt for 2 h, then it was diluted with EtOAc (5 mL), washed
with a 1:1 mixture of aq satd K2CO3 and aq satd Na2S2O3
(3ꢃ5 mL), and concentrated. Silica gel chromatography of
the residue (1:9:0.1 EtOAc/hexanes/NEt3) afforded pure
126 (38 mg, 0.070 mmol, 94%) as a (pale yellow oil, [a]D25
129.3, 58.9, 34.7, 23.3, 16.9. HRMS (CI): calcd for
C11H16O2N1 (MH+): 194.1181; found: 194.1181.
1
R¼CH2COOMe. Yield¼58%. H: 6.95 (2H, d, J¼10.2),
6.80 (1H, br s), 6.29 (2H, d, J¼10.2), 3.72 (3H, s), 2.76
(2H, s), 1.97 (3H, s). 13C: 184.7, 170.2, 170.1, 148.4,
128.8, 53.2, 52.3, 42.2, 23.5.
1
ꢀ6 (c 0.5, CH2Cl2). H: 7.68 (4H, m), 7.39 (6H, m), 3.63,
(1H, dd, J¼6.4, 1.9), 3.32 (1H, m), 3.29 (1H, t, J¼9.0),
3.09 (1H, m), 2.30–2.00 (7H, m), 1.70–1.00 (18H, m),
1.08 (9H, s), 0.84 (3H, t, J¼7.2). 13C: 211.4, 135.6, 134.0,
133.8, 129.6, 127.6, 70.2, 68.4, 57.7, 55.3, 50.1, 42.9,
35.8, 34.9, 34.8, 31.7, 29.7, 29.0, 26.9, 25.9, 24.4, 22.9,
22.5, 21.9, 19.2, 14.0. IR: 1707. HRMS (CI): calcd for
C35H51NO2Si (MH+): 546.3767; found: 546.3768.
R¼(CH2)2NHTs. Yield¼53%. 1H: 7.62 (2H, d, J¼7.9), 7.24
(2H, d, J¼7.9), 6.98 (1H, br s), 6.84 (2H, d, J¼9.8), 6.21 (2H,
d, J¼9.8), 5.83 (1H, br s), 2.83 (2H, br m), 2.38 (3H, s), 2.03
(2H, br m), 1.91 (3H, s). 13C: 185.6, 170.8, 150.4, 143.8,
136.1, 129.8, 128.9, 126.9, 54.8, 38.2, 37.7, 23.3, 21.5.
R¼(CH2)3OPiv. Yield¼67%. 1H: 6.80 (2H, d, J¼10.2), 6.30
(2H, d, J¼10.2), 6.21 (1H, br s), 3.99 (2H, t, J¼6.0), 1.95
(3H, s), 1.88 (2H, m), 1.53 (2H, m), 1.16 (9H, s). 13C:
185.4, 178.4, 169.9, 150.1, 129.1, 63.3, 55.5, 38.6, 34.2,
27.0, 23.3, 22.6. HRMS (CI): calcd for C16H24O4N1
(MH+): 294.1705; found 294.1705.
5.3.15. Synthetic (L)-cylindricine C, 76. A solution of 126
(29 mg, 0.053 mmol) and TBAF (50 mg, 3 equiv) in THF
(1 mL) was stirred at rt for 4 h, and then it was concentrated.
Silica gel chromatography of the residue (1:9:0.1 EtOAc/
hexanes/NEt3) provided pure (ꢀ)-76 (pale yellow oil,
1
16 mg, 0.051 mmol, 96%), whose H NMR spectra were
R¼(CH2)3CO2TFE. Yield¼57%. 1H: 6.84 (2H, d, J¼10.2),
6.43 (1H, br s), 6.28 (2H, d, J¼10.2), 4.47 (2H, q, J¼8.3),
2.41 (2H, t, J¼6.8), 1.94 (3H, s), 1.83 (2H, m), 1.62 (2H,
m). 13C: 185.4, 171.4, 170.0, 150.0, 129.2, 60.5 (q), 55.6,
37.2, 32.7, 23.4, 18.4.
superimposable to those published by Molander (Ref. 35a).
The optical rotation measured for 3, [a]2D5 ꢀ66 (c 0.5,
CH2Cl2), matched that reported by Molander for (ꢀ)-cylin-
dricine C, [a]2D5 ꢀ64 (c 0.2, CH2Cl2), and, in absolute value,
that reported by Trost (Ref. 35b) for (+)-cylindricine C, [a]D25
+61 (c 0.4, CH2Cl2). 1H: 3.52, (2H, m), 3.44 (1H, m), 3.29
(1H, m), 2.86 (1H, br m), 2.30–2.07 (5H, m), 1.83 (1H, m),
1.77–1.20 (19H, m), 0.88 (3H, t, J¼7.2). 13C: 210.4, 70.6,
66.3, 56.5, 55.3, 50.2, 42.5, 36.4, 35.9, 35.2, 31.7, 29.2,
28.7, 27.1, 24.2, 22.7, 22.5, 21.8, 14.0. IR: 3445, 1707.
HRMS (CI): calcd for C19H33NO2 (MH+): 308.2589; found:
308.2589.
1
R¼(CH2)2CN. Yield¼67%. H: 6.89 (2H, d, J¼10.2), 6.70
(1H, br s), 6.31 (2H, d, J¼10.2), 2.26 (4H, br), 1.91 (3H, s).
13C: 184.7, 170.5, 148.0, 130.0, 118.7, 55.0, 32.4, 23.4,
11.9.
R¼(CH2)3CN. Yield¼71%. 1H: 6.91 (1H, br s), 6.82 (2H, d,
J¼10.2), 6.26 (2H, d, J¼10.2), 2.31 (2H, t, J¼6.8), 1.97 (2H,
m), 1.89 (3H, s), 1.52 (2H, m). 13C: 185.3, 170.2, 149.9,
129.1, 118.8, 55.3, 36.1, 23.2, 19.2, 16.8.
5.4. General procedure for bimolecular oxidative
amidation of phenols
1
R¼(CH2)4CN. Yield¼71%. H: 6.86 (2H, d, J¼10.2), 6.60
A solution of PhI(OAc)2 (‘DIB’, 232.0 mg, 0.7 mmol,
1.2 equiv) in (CF3)2CHOH (‘HFIP’, 0.5 mL) was added
dropwise over 30 s to a vigorously stirred solution of a
phenol (0.6 mmol, 1 equiv) in MeCN (2.0 mL) and HFIP
(1.5 mL) kept at 15 ꢁC (bath temperature). The mixture
was stirred for 20 min, and then it was concentrated. Silica
gel chromatography of the residue, first with 1:1 AcOEt/
Hexanes (removal of gross contaminants), and then with
5–10% MeOH in CH2Cl2, provided the pure product.
(1H, br s), 6.26 (2H, d, J¼10.2), 2.31 (2H, t, J¼7.2), 1.92
(3H, s), 1.87 (2H, m), 1.60 (2H, q, J¼7.2), 1.35 (2H, m).
13C: 185.4, 170.1, 150.2, 129.0, 119.2, 55.7, 36.9, 25.0,
23.4, 22.4, 16.8.
1
R¼(CH2)3N3. Yield¼42%. H: 6.82 (2H, d, J¼10.2), 6.29
(2H, d, J¼10.2), 5.89. (1H, br s), 3.31 (2H, t, J¼6.4), 1.98
(2H, m, 3H, overlapping a s), 1.47 (2H, m). 13C: 185.4,
170.1, 150.0, 129.2, 55.6, 50.9, 34.9, 23.4, 22.9.
1
1
5.4.1. Amidodienones 139. R¼CH3. Yield¼56%. H: 6.82
R¼(CH2)4N3. Yield¼49%. H: 6.79 (2H, d, J¼10.2), 6.25
(2H, d, J¼10.2), 6.31 (1H, br s), 6.19 (2H, d, J¼10.2),
1.91 (3H, s), 1.43 (3H, s). 13C: 185.5, 170.3, 152.5, 127.6,
52.5, 26.1, 23.1. HRMS (CI): calcd for C9H12O2N1
(MH+): 166.0868; found:166.0871.
(1H, br s), 6.24 (2H, d, J¼10.2), 3.20 (2H, t, J¼7.0), 1.91
(3H, s), 1.78 (2H, m), 1.47 (2H, quintuplet, J¼7.0), 1.25
(2H, m). 13C: 185.6, 170.2, 150.7, 128.8, 55.8, 50.8, 37.4,
28.4, 23.2, 20.4.
1
R¼(CH2)2CH3. Yield¼54%. 1H: 6.77 (2H, d, J¼10.2), 6.67
(1H, br s), 6.24 (2H, d, J¼10.2), 1.96 (3H, s), 1.69 (2H, m),
1.22 (2H, m), 0.84 (3H, t, J¼7.2). 13C: 185.8, 170.0, 151.3,
128.6, 55.9, 40.4, 23.2, 16.4, 13.9. HRMS (CI): calcd for
C11H16O2N1 (MH+): 194.1181; found: 194.1182.
R¼(CH2)3Br. Yield¼65%. H: 6.81 (2H, d, J¼10.2), 6.37
(1H, br s), 6.30 (2H, d, J¼10.2), 3.35 (2H, t, J¼6.0), 2.01
(2H, m), 1.96 (3H, s), 1.73 (2H, m). 13C 185.3, 170.0,
149.9, 129.4, 55.5, 36.4, 32.8, 26.3, 23.5.
1
R¼(CH2)4Br. Yield¼72%. H: 6.84 (2H, d, J¼10.2), 6.68
1
R¼CH(CH3)2. Yield¼62%. H: 6.81 (2H, d, J¼10.2), 6.31
(1H, br s), 6.26 (2H, d, J¼10.2), 3.32 (2H, t, J¼6.8), 1.91
(3H, s), 1.80 (4H, m), 1.37 (2H, m). 13C: 185.6, 170.1,
150.6, 128.9, 55.8, 37.0, 32.9, 32.1, 23.3, 21.7.
(1H, br s), 6.26 (2H, d, J¼10.2), 2.21 (1H, h, J¼7.0), 1.91
(3H, s), 0.89 (6H, d, J¼7.0). 13C: 185.8, 170.1, 149.8,

M. A. Ciufolini et al. / Tetrahedron 62 (2006) 5318–5337
5335
9. Enantiocontrolled total syntheses: (a) Snider, B. B.; Lin, H.
J. Am. Chem. Soc. 1999, 121, 7778; (b) Scheffler, G.; Seike,
H.; Sorensen, E. J. Angew. Chem., Int. Ed. 2000, 39, 4593; Syn-
theses of the racemate: (c) Maeng, J.-H.; Funk, R. L. Org. Lett.
2001, 3, 1125; (d) Kan, T.; Fujimoto, T.; Ieda, S.; Asoh, Y.;
Kitaoka, H.; Fukuyama, T. Org. Lett. 2004, 6, 2729; Synthetic
studies: (e) Quirante, J.; Escolano, C.; Massot, M.; Bonjoch,
J. Tetrahedron 1997, 53, 1391; (f) Yamazaki, N.; Suzuki,
H.; Kibayashi, C. J. Org. Chem. 1997, 62, 8280; (g) Snider,
B. B.; Lin, H.; Foxman, B. M. J. Org. Chem. 1998, 63,
6442; (h) Kropf, J. E.; Weinreb, S. M. Abstracts of Papers,
222nd National Meeting of the American Chemical Society,
Chicago, IL, Aug 26–30, 2001; American Chemical Society:
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Puigbo, E.; Sole, D.; Segarra, V.; Santamaria, L.; Beleta, J.;
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H.; Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 2001, 42,
3013; (m) Puigbo, G.; Diaba, F.; Bonjoch, J. Tetrahedron
2003, 59, 2657; (n) Bonjoch, J.; Diaba, F.; Puigbo, E.; Sole,
D. Tetrahedron Lett. 2003, 44, 8387; (o) Panchaud, P.; Olliv-
ier, C.; Renaud, P.; Zigmantas, S. J. Org. Chem. 2004, 69,
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5.4.2. Spirane 141. A solution of 140 (0.2 mmol) in dry THF
(2.0 mL) was treated with solid NaH (1.1 equiv) and stirred at
rt (Ar). After 1 h, TLC showed complete conversion. Satd aq
NH4Cl solution (two drops) was added and the mixture was
concentrated. The residue was taken up with CHCl3
(3ꢃ2 mL). Filtration and concentration provided essentially
1
pure 141 (91%) as a slightly yellow oil. H: 7.01 (2H, d,
J¼10.2), 6.19 (2H, d, J¼10.2), 3.58 (2H, app t, J¼5.7),
2.08 (3H, s), 1.80 (2H, m), 1.63 (4H, m). 13C: 185.3, 171.8,
152.0, 125.9, 56.8, 38.2, 23.9, 23.2 (two overlapping signals),
19.5.
Note added in proof
A noteworthy synthesis of (ꢀ)-cylindricine has recently
been disclosed by Swidorski, J. J.; Wang, J.; Sung, R. P.
Org. Lett. 2006, 8, 777.
Acknowledgment
´
ˆ
We thank MENRT, CNRS, and the Region Rhone Alpes
(France), as well as the University of British Columbia,
the Canada Research Chair Program, and NSERC (Canada)
for financial support of our research.
10. Shirafuji, H.; Tsubotani, S.; Ishimaru, T.; Harada, S. (Takeda
Chemical Industries, Ltd.) WO91/13887, 1991
11. Implicit in the formulation of Scheme 4 is the notion that 21
will advance to spirolactam 20 through oxidative conversion
of the phenol to an electrophilic species, perhaps a cationic
agent of the type 27 (cf. Scheme 6), which is then captured
by the nitrogen atom of the amide. The N atom thus expresses
nucleophilic character in this transformation. Complementary
reactions also leading to spirolactams, but involving reaction
of an electron-rich aromatic ring with an electrophilic N
atom, were known prior to our work. Notable in this regard is
the chemistry of N-alkoxy-acylnitrenium species (cf. (a)
Glover, S. A.; Goosen, A.; McCleland, C. W.; Schoonraad,
J. L. J. Chem. Soc., Perkin Trans. 1 1984, 2255; (b) Kiku-
gawa, Y.; Kawase, M. J. Am. Chem. Soc. 1984, 106, 5728;
(c) Kawase, M.; Kitamura, T.; Kikugawa, Y. J. Org. Chem.
1989, 54, 3394; (d) Glover, S. A.; Scott, A. P. Tetrahedron
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1990, 581; (f) Kikugawa, Y.; Shimada, M.; Matsumoto, K.
Heterocycles 1994, 37, 293), which in recent years has
revealed its full synthetic potential thanks to the work of
Wardrop; For leading references see: (g) Wardrop, D. J.;
Burge, M. S. J. Org. Chem. 2005, 70, 10271; (h) Wardrop,
D. J.; Burge, M. S. Chem. Commun. 2004, 1230; (i) Wardrop,
D. J.; Landrie, C. L.; Ortiz, J. A. Synlett 2003, 1352; (j) War-
drop, D. J.; Burge, M. S.; Zhang, W.; Ortiz, J. A. Tetrahedron
Lett. 2003, 44, 2587. See also Refs. 9k, 21g and 35v.
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29. Dielectric constants at 25 ꢁC (CRC Handbook of Chemistry
and Physics, 59th Ed.): t-BuOH¼10.9; EtOH¼24.3;
MeOH¼32.6.
30. The OH group is more accessible in the less sterically hindered
MeOH and EtOH relative to the more sterically encumbered
t-BuOH. This should result in stronger H-bonds.
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765.
18. This entails conduct of the reaction in fluorinated alcohol sol-
vents such as hexafluoro-2-propanol (HFIP) or trifluoroethanol
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32. We are grateful to the Fujisawa Co. for a sample of nature FR-
901483.
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´
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34. The absolute configuration of natural cylindricines remains un-
known. We focused on (ꢀ)-cylindricine C, 76, only because we
intended to compare our ultimate product with that described
by Molander (Ref. 35a), who at the onset of our investigations
was the sole author to have achieved the enantiocontrolled syn-
thesis of a cylindricine.
20. For additional applications of this transformation, which one
may rightfully describe as the Sorensen reaction, see, e.g.:
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41. In principle, all cylindricines may be obtained by appropriate
manipulations of cylindricine C, which therefore is a privileged
target for chemical synthesis.

M. A. Ciufolini et al. / Tetrahedron 62 (2006) 5318–5337
5337
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