A unified synthetic strategy toward oroidin-derived alkaloids premised on a biosynthetic proposal

Article abstract of DOI:10.1016/j.tet.2005.12.068

Details of the evolution of a synthetic strategy toward the spirocyclic chlorocyclopentane core of oroidin-derived alkaloids, including the axinellamines and potentially adaptable to palau'amine, are described. A proposed refinement of the Kinnel-Scheuer biosynthetic proposal for palau'amine is posited. Studies undertaken to improve the regioselectivity and efficiency of a key Diels-Alder reaction utilizing a novel protecting group strategy, microwave chemistry, and other strategies are described. Further insights regarding the suitability of different protecting groups during the epoxidation/chlorination/ring contraction sequence are disclosed. Several interesting by-products from this reaction sequence are reported. These studies have led to a unified synthetic strategy to the axinellamines and palau'amine.

Full text of DOI:10.1016/j.tet.2005.12.068

Tetrahedron 62 (2006) 5223–5247
A unified synthetic strategy toward oroidin-derived alkaloids
premised on a biosynthetic proposal*
y
z
*
Paul J. Dransfield, Anja S. Dilley, Shaohui Wang and Daniel Romo
Department of Chemistry, Texas A&M University, PO Box 30012, College Station TX 77843-3012, USA
Received 9 September 2005; revised 26 December 2005; accepted 27 December 2005
Available online 5 April 2006
Abstract—Details of the evolution of a synthetic strategy toward the spirocyclic chlorocyclopentane core of oroidin-derived alkaloids, in-
cluding the axinellamines and potentially adaptable to palau’amine, are described. A proposed refinement of the Kinnel–Scheuer biosynthetic
proposal for palau’amine is posited. Studies undertaken to improve the regioselectivity and efficiency of a key Diels–Alder reaction utilizing
a novel protecting group strategy, microwave chemistry, and other strategies are described. Further insights regarding the suitability of dif-
ferent protecting groups during the epoxidation/chlorination/ring contraction sequence are disclosed. Several interesting by-products from
this reaction sequence are reported. These studies have led to a unified synthetic strategy to the axinellamines and palau’amine.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
palau’amine contain a common structural feature, namely
a spirocyclic chlorocyclopentane ring. Several groups
have described synthetic approaches to these hexacyclic
oroidin-derived metabolites including those of Overman,3
Carreira,4 Lovely,5 Austin,6 and Harran.7 Our synthetic ap-
proach to this class of bisguanidine alkaloids is premised
on the biosynthetic hypothesis proposed by Kinnel and
Scheuer.8 Alternative biosynthetic proposals have been
posited by Al Mourabit and Potier9 and most recently by
Baran.10
Organisms produce a wide diversity of natural products, and
while a common view is that they are produced as a defense
mechanism against predators, the complexity of these struc-
tures, their ability to potently interact with mammalian pro-
teins, and the metabolic mechanisms and processes that are
known to produce them, raise a number of questions that
may only be answered by a more holistic approach to natural
products research. One such intriguing hypothesis named the
‘screening hypothesis’ seeks to overcome the inherent short-
comings of traditional evolutionary thought regarding the
incredible diversity of metabolites produced by a given
organism.1
Kinnel and Scheuer proposed that palau’amine originates
from a Diels–Alder reaction of dehydrophakellin (7a),
which has not been isolated, and a truncated oroidin
(AAPE, 5b), which has been isolated. This is followed by
a presumed chloroperoxidase-mediated chlorination initiat-
ing a 1,2-shift/ring contraction (Fig. 2), a process with
some precedent.11 In our synthetic studies of phakellstatin,12
we found that aminals 6a bearing a potential leaving group at
C10 were unstable likely due to acyliminium formation
while aminals 6b bearing a leaving group at C6 were quite
stable. The latter findings were in accord with concurrent
work by Evans demonstrating the utility of pyrrolocarbinol-
amines as aldehyde surrogates.13 These findings led to our
successful enantioselective synthesis of phakellstatin and
a proposed refinement of the biosynthetic proposal of Kinnel
and Scheuer. The initial idea that dehydrophakellin (7a)
could serve as a dienophile was unsettling as its reactivity
would be expected to be low in this regard. However, if
one considers the ring-opened form of dehydrophakellin
(7b) consisting of an allylic acyliminium species, which
may indeed be promoted in an enzyme active site, the ex-
pected high reactivity of the resulting acyliminium as
While classical synthetic routes toward these complex and
unusual architectures are possible, the convergent and effi-
cient construction of these intriguing metabolites, building
on knowledge garnered from consideration of possible bio-
synthetic origins, opens the possibility of discovering new
chemistry and testing theories regarding their biosynthesis.
In this regard, the oroidin family of marine alkaloids con-
tains a large number of biogenetically related molecules
that have inspired many to propose intriguing biosynthetic
hypotheses.2 The simple heterocyclic system, oroidin (5a),
is thought to be a common precursor to this alkaloid family
(Fig. 1). Among this family of alkaloids, axinellamine and
*
Taken in part from the Ph.D. Thesis of Anja S. Dilley (Texas A&M
University, 2003).
* Corresponding author. Tel.: +1 979 845 2011; fax: +1 979 845 4719;
e-mail: romo@mail.chem.tamu.edu
Present address: Amgen, San Francisco, CA, USA.
y
z
Present address: Wyeth Research, Princeton, NJ, USA.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.068

5224
P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
R2
R1
R2
R1
H
N
H2N
N
N
H2N
NH
HO
HN
N
N
HO
HN
H
HN
H
O
H2N
N
O
N
H2N
N
Cl
H
Cl
H
NH2
NH2
Palau'amine (2a, R1, R2 = H)
Monobromopalau'amine(2b, R1 = H, R2 = Br)
Dibromopalau'amine (2c, R1, R2 = Br)
Styloguanidine (1a, R1, R2 = H)
Monobromostyloguanidine (1b, R1, R2 = Br)
Dibromostyloguanidine(1c, R1, R2 = Br)
Br
HN
H2N
Br
Oroidin (5a, R =
)
NH
H
N
N
O
R
AAPE (5b, R = H)
NH
NH
NH
NH
HN
HN
H
HN
H
NH
OH
NH
OH
O
HN
HN
N
N
HN
NHR2
NHR2
HN
RO
HN
RO
NHR2
NHR2
N
H
HN
Cl
R2HN
Cl
R2HN
OH
Axinellamine C (4c, R = H)
Axinellamine D (4d, R = Me)
Axinellamine A (4a, R = H)
Axinellamine B (4b, R = Me)
Massadine (3)
Figure 1. Oroidin-derived natural products.
H2N
H2N
H2N
N
N
N
N
N
N
N
H2N
N
H
H
N
HN
H2N
HN
H
Diels-Alder
HO
R
N
H2N
N
HN
H
NH
6
O
O
10
N
N
N
N
O
N
O
H
H
NH2
7b
5b
6a
(R = NHC(O)NHBn, N3)
Cl
NH2
Cl
H2N
8
9
H2N
H2N
H2N
1,2-suprafacial
shift
"pinacol-like"
N
N
R
N
N
N
H2N
N
N
N
H2N
6
HN
H
H2O
H2NOC
N
10
HN
H
HN
N
N
O
N
O
HN
HO
N
O
O
HN
Cl
H
Cl
6b
H
7a (11,12-dehydrophakellin)
(R = NCBzOH,
NHOH, NHCBz)
NH2
2a (palau'amine)
NH2
10
Figure 2. Stable/unstable aminals and carbinolamines 6 and Kinnel and Scheuer’s proposed biosynthesis of palau’amine.
a dienophile is reminiscent of the allylic carbocations stud-
ied by Gassman and Singleton.14 Thus, we propose a refine-
ment to the Kinnel–Scheuer biosynthetic proposal that
proceeds through the ring-opened acyliminium species 7b
leading to Diels–Alder adduct 8. Chlorination initiates the
1,2-pinacol-like shift/ring contraction leading to cyclo-
pentane bearing the iminium species 10, which is trapped
with water to deliver palau’amine.
with its potent immunosuppressive activity. This parlayed
into our group’s interest in natural products displaying
potent, cell-specific, physiological properties and the struc-
turally distinct marine sponge isolate, pateamine A, is an
example.15 In the course of our studies toward palau’amine,
a unified strategy toward both axinellamine and palau’amine
evolved proceeding through a Diels–Alder reaction and then
diverging to either axinellamine or palau’amine by virtue of
either an inter- or intramolecular chlorination, respectively
(Fig. 3).
1.1. Overall synthetic strategy premised on a proposed
biosynthesis
This divergence addresses the proposed difference in rela-
tive stereochemistry between axinellamine and palau’amine
at the chlorine bearing carbon C1 and that of C3. The
Our initial interest in the oroidin alkaloids stemmed from the
unique architecture presented by palau’amine in conjunction

P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
5225
NH
NH
OH
H
Imidazolone
Annulation/
Cyclization
N
N
N
HN
H2N
N
H
Phakellin
Annulation
H
2
HN
H2N
HN
N
NH2
NH2
5
1
H2N
N
4
OH
N
O
5
1
5
H
4
HN
HO
HN
HO
4
3
H
HO
1
3
3
Cl
H
NHY
2
2
Cl
Cl
NH2
NH2
via inter- or intra-
molecular chlorination
via retention
or epimerization
NHY
11
Common
Core Structure
2a (palau'amine)
4a (axinellamine A)
OTIPS
O
O
O
OTIPS
OTIPS
NR
H
Epimerization
at C3
H
NR
NR
RN
RN
NTs
O
Retention at C3
RN
NTs
O
NHTs
3
HO
Cl
HO
Cl
Intermolecular
chlorination
H
Intramolecular
chlorination
CH=NOBn
3
H
RO
H2N
RO
14
13
12
Common Intermediate
Diels-Alder
O
H
N
TIPSO
Ts
HO2C
HO2C
OH
OH
RN
O
N
+
O
OH
HO
O
+
N
O
H2N
NH2
R
(R)-Pyroglutamic Acid
16
15
Figure 3. A unified synthetic strategy to the oroidin-derived alkaloids, axinellamine, and palau’amine.
anti-relationship between C1 and C2 found in axinellamine
could be accessed by intermolecular chlorination as a result
2. Results and discussion
of the topography of the tricyclic common intermediate 14.
This chlorination of enamine 8 would be expected to initiate
a pinacol-like, 1,2-shift of iminium 9 resulting in a ring con-
traction, as proposed by Kinnel and Scheuer.16
2.1. Studies of the Diels–Alder reaction toward common
intermediate 14
2.1.1. Synthesis of the dienophiles and dienes. A series of
dienophiles were prepared from L-(S)-pyroglutamic acid
(17), following modified literature procedures,17 to test their
reactivity in the Diels–Alder reaction. Esterification was fol-
lowed by reduction and protection of the resulting alcohol.
Initially a tert-butylcarbamate (Boc, 19a) was used to
protect the lactam nitrogen, however, low reactivity as a
dienophile subsequently led to the use of the p-toluene-
sulfonyl (Ts) protected lactam 19b. A two-step sequence
to introduce the unsaturation involving enolization with
LDA, selenation, and finally oxidation with H2O2 provided
enamides 15a,b efficiently on w1 g scale with no loss of
optical purity as determined by Mosher ester analysis of
the alcohol following TIPS deprotection. However, this reac-
tion was only reproducible and scaleable when LiHMDS
was used for enolization and ethyl acetate was used for the
oxidation–elimination. In this way, the enamide 15b could
be obtained in high and reproducible yield on a large scale
(w20 g) (Scheme 1).
Common intermediate 14 would be obtained by a Diels–
Alder reaction between the vinyl imidazolone 16 and a
dienophile 15 derived from pyroglutamic acid. The absolute
stereochemistry of axinellamine and palau’amine has not
been confirmed, however, based on similarities in the CD
spectra of palau’amine and dibromophakellin, the absolute
configuration has been proposed to be as shown.8 Based
on biosynthetic considerations, one might predict that axi-
nellamine will possess a related absolute configuration.
Thus, to obtain the natural configuration of these targets
would require the use of (R)-pyroglutamic acid and ulti-
mately all stereocenters in these natural products would be
derived from this single stereocenter. Due to cost consider-
ations, the (S) enantiomer has been utilized in initial studies.
The required diene is ultimately derived from urea and tarta-
ric acid. A subsequent epimerization at C3 via an imine
would be required to obtain the all anti-configuration about
the cyclopentane as found in axinellamine (i.e., 13). Sub-
sequent imidazolone annulation, guanidinylation, and an
oxidative cyclization are proposed to provide the final ring
and deliver axinellamine.
O
O
1) SOCl2, MeOH
2) NaBH4, EtOH
Boc2O, DMAP, Et3N, CH2Cl2
or NaHMDS, TsCl, THF
HN
TIPSO
HN
HO2C
3) TIPSCl, Im., DMF
(66%)
Toward palau’amine, an intramolecular chlorination would
be required to set the required stereochemistry between C1
and C2 (cf. 12). In this case, the Diels–Alder process sets
the required syn-stereochemistry at C3 and C4, thus epi-
merization is not required. Guanidinylation and annulation
of the phakellin substructure onto core structure 11 would
deliver palau’amine. Details of our synthetic studies in this
area culminating in a unified strategy toward the oroidin al-
kaloids, axinellamine, and palau’amine are described herein.
18
17
1) i) LiHMDS, THF, -78 °C
ii) PhSeBr, THF, -78 °C
O
O
RN
TIPSO
RN
2)H2O2, EtOAc, 0 °C
TIPSO
19a R = Boc (85%)
19b R = Ts (90%)
15a R = Boc (59%)
15b R = Ts (74%)
Scheme 1.

5226
P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
Formation of the diene commenced with imidazolone acid
20 prepared in one step from urea and tartaric acid.18 Again,
a number of different permutations of the diene were synthe-
sized. Perbenzylation of the acid, followed by diisobutyl-
aluminum hydride (DIBAl-H) reduction of the benzyl ester
gave alcohol 23a in good overall yield (Scheme 2 and Table
1). Oxidation with manganese dioxide followed by E selec-
tive olefination and reduction of the ester 25a furnished the
desired bis-benzylated diene 16a. A benzyloxymethylene
(BOM) protected diene 16b was synthesized in a similar
manner starting from the methyl ester 21.
homologation (entry 1, Table 1). Dienes successfully synthe-
sized in this manner include the Tse (p-tolylsulfonylethyl)/
DMB-protected diene 16d, Ts/PMB-protected diene 16e,
and the Ts/DMB (3,4-dimethoxybenzyl)-protected diene
16f (Scheme 3).
Boc
N
H
N
DIBAl-H
O
O
CH2Cl2, -78 °C
(99%)
OH
N
N
CO2Me
PMB
PMB
22c
26
Scheme 3.
R2
H
N
N
DIBAl-H
BnBr or BOMCl
O
O
CH2Cl2, -78 °C
The Tse group was installed using tosylethyl mesylate 29
(TseOMs) prepared in two steps from chloroethanol 27
on 100 g scale (Scheme 4). Importantly, the Tse/DMB-
protected diene 16d could be readily synthesized on 50–
60 g scale with no need for chromatographic purification
throughout the entire sequence.
CO2R1
NaH, DMF, 60 °C
N
N
H
CO2R
R2
SOCl2,
MeOH,
reflux
20 R = H
21 R = Me
22a R1 = R2 = Bn (41% from 20)
22b R1 = Me, R2 = BOM (31% from 21)
R
N
R
N
MnO2
(EtO)2P(O)CH2CO2Et
NaH, THF, 0 to 25 °C
O
O
OH
O
CH2Cl2
N
R
N
R
MsCl, Et3N,
-78 °C
TsNa, NaOH,
H2O
23a R = Bn (87%)
23b R = BOM (99%)
24a R = Bn (98%)
24b R = BOM (73%)
Ts
Cl
Ts
OH
OH
OMs
2h, (60% over
2 steps)
R
N
R
N
100 °C, 4h
DIBAl-H
27
Scheme 4.
28
29
O
O
CH2Cl2, -78 °C
N
R
N
R
OH
CO2Et
25a R = Bn (89%)
25b R = BOM (77%)
16a R = Bn (99%)
16b R = BOM (99%)
Dienes 16a–f displayed varied acid sensitivity due to the
presence of the allylic/benzylic alcohol and thus were typi-
cally prepared by DIBAl-H reduction and used directly in
the Diels–Alder reaction without purification. Those dienes
possessing an electron-withdrawing group (R1) were notably
more stable as expected. Protection of the hydroxyl moiety
of diene 16a as the tert-butyldimethylsilyl ether prior to
the cycloaddition was briefly investigated in efforts to in-
crease convergency (Scheme 5). While the silylation and
subsequent purification proceeded smoothly, the instability
of the silylated diene 30 appeared even more pronounced
than that of the parent alcohol.
Scheme 2.
All other dienes synthesized (i.e., 16c–f) incorporated
orthogonal protecting groups requiring two-step protection
but would allow for timed deprotection at later stages in
the synthesis (Table 1). The synthesis of these dienes
commenced from known methyl ester 21.18 Regioselective
nitrogen protection is readily achieved due to steric (ester
substituent) and electronic (increased acidity) properties of
ester 21.19 Subsequent homologation was achieved in a man-
ner similar to that described above for dienes 16a,b (Table 1).
While the Boc/p-methoxy (PMB) protected ester 22c could
be prepared, the acyl carbamate was not stable to DIBAl-H
reduction conditions leading to alcohol 26 precluding its
To further streamline the synthetic approach, incorporation
of the pendant amine functionality, eventually required for
Table 1. Synthesis of dienes 16c–f bearing orthogonal, nitrogen protecting groups
Nitrogen
Protection
Conditions
R1
N
R1
H
N
N
Homologation
O
(Scheme 2)
O
O
N
N
H
N
OH
CO2Me
CO2Me
R2
R2
21
22c-f
16c-f
Entry
Nitrogen protection
conditions (% yield, 22c–f)
R1
R2
Esters 22
Dienes 16c–f (% yield)
1
2
3
4
i) Boc2O, K2CO3, MeCN, 25 ꢀC (54)
ii) PMBBr, K2CO3, MeCN, 70 ꢀC (53)
i) TseOMs, NaHCO3, DMSO, 70 ꢀC (90)
ii) DMBCl, K2CO3, DMF, 65 ꢀC (100)
i) TsCl, NaH, DMF, 25 ꢀC (58)
Boc
Tse
Ts
PMB
DMB
PMB
DMB
22c
22d
22e
22f
16c (0)
16d (80)
16e (64)
16f (61)
ii) PMBBr, K2CO3, MeCN, 70 ꢀC (83)
i) TsCl, NaH, DMF, 25 ꢀC (58)
Ts
ii) DMBCl, K2CO3, MeCN, 50 ꢀC (64)

P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
5227
Bn
Bn
N
proceed, it required elevated temperatures providing cyclo-
adduct 34a in modest yields (28%, Table 2, entry 1). How-
ever, the expected initial Diels–Alder adduct 32a, was not
isolated, as the pseudoaromatic imidazolone was regener-
ated via double bond migration. Since the reactivity of the
Boc-protecteꢀd lactam 15a was low, requiring high tempera-
tures (w140 C) for cycloaddition, the synthesis and use of
a more reactive dienophile was warranted. The high reaction
temperatures also contributed to the rather rapid degradation
of diene 16a. When the tosylated dienophile 15b was used,
the reaction proceeded at lower temperatures and provided
higher yields (47%) of cycloadducts 34b. Subsequent re-
actions performed in benzene and in the presence of 2,6-
lutidine showed a marked improvement in yield (79%, Table
2, entry 3) suggestive of the acid instability of the dienes
previously observed. Two regioisomers were produced in
a w4.3:1 ratio and the major isomer was determined to be
the desired regioisomer based on extensive NMR studies in-
cluding NOE data for the major regioisomer (Fig. 4a). The
regioisomer 35b proved to be crystalline and suitable for
X-ray analysis providing further, albeit indirect, support
for the structural assignment of the desired regioisomer
(Fig. 4b).
N
TBSCl, DMAP
Et3N, CH2Cl2
(99%)
O
O
N
OTBS
N
OH
Bn
Bn
30
16a
Scheme 5.
the synthesis of palau’amine and axinellamine, into the
diene was studied (Scheme 6). This approach involved a
slight modification of the Horner–Wadsworth–Emmons ole-
fination previously employed allowing installation of a vinyl
cyanide, which was subsequently reduced to yield the amine
diene 31 in excellent overall yield.
1) (EtO)2P(O)CH2CN
Bn
N
Bn
N
NaH, THF, 0 to 25 o
C
O
O
O
2) i. DIBAl-H, Et2O, -78 o
C
ii. NaBH4, MeOH, -78 to 25 o
N
NH2
N
Bn
Bn
C
24a
31
(83%, 2 steps)
Scheme 6.
2.1.2. Facility and regioselectivity of the Diels–Alder
reaction: effects of dienophile electronics. Building on
precedence in the literature involving Diels–Alder reactions
of related pyroglutamic acid derived dienophiles, the
proposed cycloaddition was expected to proceed with high
facial selectivity and endo-selectivity.20 However, the regio-
selectivity was less certain given the fact that the diene is
substituted with two nitrogens and each was expected to di-
rect to opposite regioisomers (cf. diene 16). A slight prefer-
ence for the desired regiochemistry would be expected due
to the presence of the alkyl substituent at the terminus. We
recognized several possible strategies to overcome potential
regiochemical issues including the use of Lewis acids,
modifying the electronics of nitrogen protecting groups, and
templated reactions.21
Addition of Lewis acids to improve regioselectivity was
investigated briefly as this led to rapid decomposition of
diene 16a even at low temperature. An exception was
MgBr2$OEt2, which gave a slightly improved yield and re-
gioisomeric ratio but importantly using only 1 equiv of diene
(Table 2, entry 5 vs 6).
Other dienes were studied in efforts to facilitate protecting
group removal late in the synthesis and also to improve con-
vergency. The bis-BOM-protected diene 16b provided a sim-
ilar ratio of regioisomers in an unoptimized 36% yield (Table
2, entry 4). Cycloaddition of amino diene 31 and lactam 15b
was studied only briefly and provided low yields of the
amino-substituted Diels–Alder adduct (not shown) due to
extensive diene decomposition. Acylation or sulfonylation
of this diene will reduce basicity and increase stability pos-
sibly rendering it more useful in Diels–Alder reactions. The
Our initial studies began with the Boc-protected lactam 15a
and bis-benzyl diene 16a and while the cycloaddition did
Table 2. Diels–Alder reactions providing the tricyclic common intermediates 34a–f
R1
N
O
R1
N
R1
R1
N
TIPSO
N
O
O
O
TIPSO
TIPSO
+
HO
TIPSO
solvent
15a,b
+
OH
OH
OH
R2
O
R2
O
NR2
R2
O
N
N
N
NR3
34a-f
N
NR3
NR3
16a-e
O
R3
32a-f
35a-f
Entry
Dienophile
R1
Dienea
R2
R3
Reaction conditions
Products
% Yieldb
1
2
3
4
5
6
7
8
15a
15b
15b
15b
15b
15b
15b
15b
Boc
Ts
Ts
Ts
Ts
Ts
Ts
Ts
16a (1.1)
16a (2.5)
16a (1.41)
16b (0.9)
16d (2.5)
16d (1.0)
16e (1.0)
16f (1.45)
Bn
Bn
Bn
BOM
Tse
Tse
Ts
Bn
Bn
Bn
BOM
DMB
DMB
PMB
DMB
o-Xylene, 140 ꢀC, 14 h
34a
34b
28
47
o-Xylene, 2,6-lut. (1.2 equiv), 90 ꢀC, 28 h
PhH, 2,6-lut. (0.66 equiv), 95 ꢀC, 4 d
PhH, 2,6-lut. (0.57 equiv), 95 ꢀC, 24 h
PhH, 2,6-lut. (0.75 equiv), 95 ꢀC, 3 d
PhH, MgBr2$OEt2 (0.5 equiv), 100 ꢀC, 3 d
PhH, 2,6-lut. (0.55 equiv), 114 ꢀC, 4 d
PhH, 2,6-lut. (0.46 equiv), 110 ꢀC, 4 d
34b, 35b
34c, 35c
34d, 35d
34d, 35d
34e
64 (15)c
30 (6)c
54 (20)c
67 (12)c
59
Ts
34f
74
a
Equivalents of diene employed in parentheses.
Refers to isolated yields.
Yield for isolated regioisomers 35a–f given in parentheses.
b
c

5228
P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
(a)
One strategy involved varying the electronics of protecting
TIPSO
nOe
Ts
N
groups on the nitrogen atoms of the diene imidazolone.
We reasoned that use of an electron-withdrawing group on
N1 while maintaining an electron-donating group on N2
would perturb the orbital coefficients of the diene leading
to improved regioselectivity (Fig. 5).
O
H
H
H
H
H
N
Ph
OH
N
O
Bn
34b
TIPSO
(b)
Ts
N
O
O
TIPSO
TIPSO
TsN
TsN
O
OH
OH
Ts
EDGN2
EDGN2
N
O
EWGN1
O
TIPSO
HO
OH
N1EWG
N1EWG
N2
EDG
O
O
NBn
Figure 5. Electronics of vinyl imidazolones as dienes.
N
O
Bn
35b
Indeed, initial studies employing the Ts/PMB diene 16e pro-
vided for the first time, the initial Diels–Alder adduct 32e
that had not undergone olefin isomerization. Continued heat-
ing for a further two days resulted in conversion to the iso-
merized cycloadduct (34e) and importantly as a single
regioisomer (59%, Table 2, entry 7). Further optimization
was performed with Ts/DMB diene 16f and ultimately led
to a highly stereo- and regioselective Diels–Alder reaction
providing adduct 34f in good yield (74%, Table 2, entry 8).
Figure 4. Regiochemical assignment of Diels–Alder adducts 34b and 35b.
(a) Key NOE correlations observed confirming regiochemistry. (b) POV-
chem rendering of the X-ray crystal structure of regioisomeric cycloadduct
35b (protecting groups removed for clarity).
use of Tse/DMB diene 16d was also studied for correlation
to a product obtained from a tosylvinyl (Tsv) protected diene
(16g, vide infra) and this gave diminished regioselectivity
(w2.7:1, Table 2, entry 5). The Tse group was also advanta-
geous from the standpoint of orthogonality with respect to
the lactam Ts group.
2.1.4. Development of an electronically adjustable tosyl-
vinyl (Tsv) nitrogen protecting group. In subsequent
studies, we determined that while the Ts/DMB diene 16f
produced only one regioisomer in the Diels–Alder reaction,
the resulting adduct and deprotected derivatives did not
participate in the chlorination/rearrangement process (vide
infra). Through our studies, we determined that an elec-
tron-withdrawing group (EWG) on N1 was required for
high regioselectivity in the Diels–Alder reaction while
successful chlorination/rearrangement required an electron-
donating group (EDG) on N1 (Fig. 6). A typical way to
address this issue would entail a protecting group switch,
however, we were attracted to the possibility of utilizing
a protecting group with readily adjusted electronics. This
led us to consider the use of a p-tolylsulfonylvinyl (Tsv)
group, which in a vinylogous manner provides the elec-
tron-withdrawing ability of the Ts group. However, reduc-
tion of the alkene provides the Tse group leading to an
EDG suitable for the chlorination/rearrangement sequence.
Erosion of optical purity of the dienophile 15b during the
Diels–Alder reaction was possible due to the potential for
pyrrole tautomer formation. Thus, the Mosher ester 36 of
alcohol 34b was prepared and integration of the diastereo-
meric methoxy protons by 1H NMR spectroscopy indicated
a diastereomeric excess of >95% for the cycloadduct (in
comparison to that prepared from racemic dienophile 15b).
This confirmed w2.5% epimerization of lactam 15b under
the Diels–Alder reaction conditions, which was >99% at
the outset of the reaction as determined by chiral HPLC
analysis (Scheme 7).
Ts
N
Ts
N
OMe
O
O
Ph
TIPSO
TIPSO
BnN
CF3
(S)-MTPA
OH
O
EDCI, CH2Cl2
(97%)
O
BnN
N
N
O
O
A range of electrophiles were studied to install the Tsv group
on imidazolone 21. The use of commercially available p-
toluenesulfonyl acetylene in the presence of a range of bases
resulted in disubstituted product 37. Similar methods were
used by Arjona and Vilarrasa to protect thiols with the Tsv
group (Scheme 8).22
Bn
Bn
36 (>95% de)
34b
Scheme 7.
Notably, in all Diels–Alder reactions, the majority of
unreacted dienophile 15b could be cleanly recovered
(w80–97% mass recovery) with minimal loss of optical
purity (chiral HPLC analysis) after the cycloadditions, while
the bis-alkylated dienes had decomposed.
Ultimately, only (Z)-1,2-di-p-toluenesulfonylethylene was
found to be useful to install the Tsv group via an addition–
elimination sequence using NaH as base.23 Subsequent
protection of the remaining nitrogen as the DMB amine pro-
vided ester 38. Attempted reduction of ester 38 with DIBAl-
H resulted in concomitant reduction of the Tsv group.
Chemoselective reduction was finally achieved by activation
of the acid functionality as either an acid chloride or a mixed
anhydride and reduction with lithium borohydride. Follow-
ing oxidation and olefination, this process was necessary
2.1.3. Regioselectivity of the Diels–Alder reaction: effects
of diene electronics. While Diels–Alder reactions employ-
ing bis-alkylated dienes 16a and 16b proceeded with high
facial and endo-selectivity as anticipated, we sought alterna-
tive means to improve the modest regioselectivity (w4:1).

P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
5229
TIPSO
TIPSO
Ts
Protecting group switch
or electronically tunable
protecting group
Ts
N
N
O
O
Diels-Alder
EWG-N1
O
EWG-N1
+
OH
OH
EDG-N2
N2
EDG
TIPSO
O
TIPSO
Ts
Ts
N
N
O
O
Epoxidation
EDG
O
N1
OR3
Chlorination
1,2-shift
EDG-N1
N2
OR3
EDG
N2
EDG
O
Cl
O
EWG = Electron withdrawing group
EDG = Electron donating group
Figure 6. Electronic requirements for the Diels–Alder reaction and chlorination/rearrangement sequence and possible solutions.
O
O
Use oꢀf the Tsv/DMB diene 16g in the Diels–Alder reaction
at 85 C under the previously described conditions gave ini-
tial Diels–Alder adduct 32g and regioisomer 34g (Scheme
Ts
Ts
NH
CO2Me
N
NH
CO2Me
HN
NaH, DMF, 20 °C
ꢀ
10). Upon increasing the reaction temperature to 95 C, ad-
Ts
duct 34g was obtained as a single isomer as determined by
1H NMR analysis of the crude reaction mixture (w20–30%
conversion). A by-product isolated from the reaction mix-
ture was derived from competing dimerization of the diene
at the Tsv group (not shown). Attempts to improve the yield
by the addition of multiple equivalents of diene at various
reaction time points were unsuccessful. Following alcohol
protection of adduct 34g, the Tsv group of silyl ether 42
was hydrogenated to give the reduced product in 93% yield.
This compound was correlated to the same cycloadduct (i.e.,
34d, Table 2) obtained by direct Diels–Alder reaction with
the Tse/DMB diene 16d and found to be identical thus
confirming its structure.
21
37
Scheme 8.
once again to prevent Tsv reduction. However, formation of
diene 16g by this route was possible without recourse to sil-
ica gel chromatography throughout the entire sequence on
large scale (Scheme 9).
1) TsCHCHTs,
DMB
LiBH4, THF
-78 °C,
NaH, DMF
COR
H
N
N
CO2Me
O
2) DMBCl, K2CO3,
DMF, 65 °C
(59%, 2 steps)
O
N
(96% over 3 steps)
N
H
21
Tsv
38 R = OMe
1) LiOH, THF/H2O
39 R = Cl
2) (COCl)2, THF, DMF
2.1.5. Microwave-assisted Diels–Alder reactions. The
long reaction times for several of the Diels–Alder reactions
described above, led us to consider the use of microwave
irradiation to accelerate these cycloadditions. Microwave
chemistry has developed into a very useful technique, and
has proven particularly useful for accelerating sluggish
cycloaddition reactions.24
1) MnO2, CH2Cl2
2) (EtO)2P(O)CH2CO2Et,
NaH, THF, 25 °C
DMB
N
DMB
N
R
OH
O
O
(72%, 2 steps)
N
N
Tsv
Tsv
1) LiOH, THF/H2O
2) ClCO2Me, Et3N, THF
3) LiBH4, THF, -78 °C,
(77%, 3 steps)
41 R = CO2Et
40
16g R = CH2OH
Initial studies into the Diels–Alder reaction of Tsv-diene 16g
with dienophile 15b under microwave conditions, employed
1 equiv of diene relative to dienophile and the crude reaction
Scheme 9.
TIPSO
15b
Ts
N
TIPSO
Ts
TIPSO
Ts
O
N
N
O
O
PhH, 2,6-lutidine
85 °C
Tsv
N
+
+
TsvN
O
TsvN
O
OR
O
OH
N
N
N
OH
DMB
DMB
DMB
TBDPSCl
Et3N, CH2Cl2
(48%, 2 steps)
34g: R = H
42: R = TBDPS
32g
16g
TIPSO
Ts
N
O
H2, Pd(OH)2/C, EtOAc
25 °C, 12h (93%)
42
Tse
N
OTBDPS
N
O
DMB
43
Scheme 10.

5230
P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
Table 3. Microwave-assisted Diels–Alder reactions
TIPSO
Ts
N
TIPSO
TIPSO
Ts
Ts
N
N
O
O
O
TIPSO
Ts
N
TIPSO
TIPSO
Ts
Ts
THF, 2,6-lutidine,
O
N
N
+
O
O
µW, 140 °C, 2h
15b
15b
NTse
TseN
O
Tse
conditions
2,6-lutidine
OR RO
68%
N
Tsv
N
+
+
N
N
O
TsvN
O
O
TsvN
O
DMB
DMB
OH
O
OH
32d:33d (1.4:1)
N
OH
N
N
DMB
N
OH
TBDPSCl, DMAP
Et3N, CH2Cl2
32d R = H
44 R = TBDPS
DMB
34g
DMB
16d
DMB
16g
32g
TIPSO
TIPSO
Ts
N
Ts
N
O
Entry Reagents and conditions
(with 0.6 equiv of 2,6-lutidine)
Ratio of
15b/32g/34g
O
PhH, 2,6-lutidine,
µW, 160 °C, 1h
+
NTse
PhH/H2O (1:4), 150 ꢀC, 1 h
1:0.07:0.18
1:0.07:0.44
1:0:1.38
TseN
O
1
2
3
4
5
99%
RO
OR
PhH/H2O (1:1), LiClO4, 170 ꢀC, 5 h
H2O, LiClO4, 170 ꢀC, 45 min
N
N
O
DMB
DMB
34d:35d (1.5:1)
H2O, LiClO4, 170 ꢀC, 45 min, 2 equiv of 16g 1:0:2
H2O, LiClO4, 170 ꢀC, 45 min, 3 equiv of 16g 1:0:6
TBDPSCl, DMAP
Et3N, CH2Cl2
34d R = H
43 R = TBDPS
Scheme 12.
mixture was analyzed (1H NMR) for the ratio of initial cy-
cloadduct 32g, isomerized cycloadduct 34g, and dienophile
15b (Table 3). In analogy to conventional thermal condi-
tions, the regioisomer of 34g was not observed under micro-
wave conditions. When aqueous benzene was used, some
degree of non-isomerized Diels–Alder adduct 32g was ob-
served (entry 1). Addition of LiClO4 led to further conver-
sion but only with extended reaction times (entry 2).
Ultimately, using only water as the heating medium resulted
in much shorter reaction times possibly due to hydrophobic
effects,25 and the initial cycloadduct 32g was not observed
(entry 3). As expected, increasing to 2.0 or 3.0 equiv of diene
16g further improved the resulting ratio of product to dieno-
phile 15b (entries 4 and 5).
with the weak Lewis acid, LiClO4, resulted in the formation
of isomerized adduct 34d as the major product along with
regioisomer 35d (2.4:1 ratio) in 87% overall yield using
only 1.1 equiv of diene (Scheme 13). This contrasts to
conventional heating, which required 2–2.5 equiv of diene
to achieve similar conversions. The addition of water to
the reaction medium had no effect on conversion or regio-
selectivity.
TIPSO
Ts
N
TIPSO
TIPSO
Ts
Ts
N
N
O
O
O
PhH, 2,6-lutidine,
LiClO4, 160 °C, 3h
+
15b
NTse
TseN
O
Tse
OH HO
Under optimal microwave conditions, the Diels–Alder reac-
tion of Tsv-diene 16g gave a maximum overall yield of 48%
yield after TBDPS protection (Scheme 11). Again the major
side product was determined to be the competing dimeriza-
tion of the Tsv-diene 16g. The competing dimerization
requiring excess diene to reach reaction completion has
limited the use of this substrate in our synthetic efforts
toward the axinellamines and palau’amine.
N
+
N
N
O
O
DMB
34d
DMB
N
OH
35d
DMB
16f
(87%, 2.4:1)
Scheme 13.
2.2. Attempted epoxidation/rearrangement of the Diels–
Alder adduct leading to serviceable allylic alcohols for
chlorination/rearrangement
TIPSO
Ts
N
TIPSO
Ts
O
N
O
1) H2O, LiClO4, 2,6-lutidine,
170 oC, 45 min,
2) TBDPSCl, Et3N, DMAP, CH2Cl2
Given that double bond isomerization of the initial Diels–
Alder adduct was observed, we proceeded to study the via-
bility of the proposed 1,2-shift/ring contraction sequence
to furnish a deschlorospirocycle (i.e., 49, Scheme 14). We
reasoned that highly facial selective epoxidation on the con-
vex face of the tricyclic imidazolone alkene would initiate
the desired rearrangement. Following epoxidation of the
electron-rich alkene of imidazolone 45 (cf. Scheme 15) or
direct formation of a hydroxy iminium species 47 via
enamine chemistry, carbinolurea 47 or 48 was expected to
undergo subsequent 1,2-shift/ring contraction to yield de-
schlorospirocycle 49. Importantly, it was inconsequential
which C–C bond participated in the 1,2-shift since both path-
ways (a and b) would ultimately deliver spirohydantoin 49
provided high facial selectivity was achieved in the initial
oxidation.
W
15b
Tsv
N
+
TsvN
O
O
OR
N
N
OH
16g (3 eq.)
DMB
DMB
42 R = TBDPS
(48%, 2 steps)
Scheme 11.
The cycloaddition of the Tse/DMB diene 16d was also in-
ꢀ
vestigated under microwave conditions in THF at 140 C
for 2 h and this gave exclusively the initial Diels–Alder ad-
duct 32d and regioisomer 33d (Scheme 12). Adduct 32d is
a useful substrate for direct chlorination and rearrangement
as originally proposed in our overall synthetic strategy.
These adducts could be converted to isomerized adducts
34d and 35d under microwave conditions in benzene in
the presence of 2,6-lutidine.
Toward deschlorospirocycle 49, silyl protection of alcohol
34b provided silyl ether 45, which was then treated with ex-
cess m-chloroperbenzoic acid (m-CPBA) furnishing what
Interestingly, conducting the Diels–Alder reaction of Tse/
DMB diene 16d in benzene under microwave conditions

P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
5231
Ts
Ts
N
Ts
N
O
N
HO
O
O
TIPSO
TIPSO
O
OSiMe2CPh3
[O]
a
b
4
BnN
O
BnN
45
O
BnN
N
O
O
OTBS
OTBS
Bn
OH
N
N
O
O
b
46
52
Bn
Bn
47
Figure 7. Structure of the derivatized over-oxidation product 52 and POV-
chem rendering of the X-ray crystal structure (protecting groups are re-
moved for clarity).
a
Ts
N
Ts
N
extremely facile transformation with m-CPBA. Indeed, use
of 1.0 equiv of m-CPBA led to 33% yield of 51 and 66%
recovered starting material.
O
O
TIPSO
TIPSO
O
BnN
O
BnN
O
OTBS
NBn
OTBS
N
O
The structure of this highly rearranged product could not be
confirmed despite extensive spectral analysis although we
recognized the presence of two acetal/aminal carbons and
a hydantoin. Consequently, we attempted preparation of
a crystalline derivative to confirm the proposed structure de-
rived from plausible mechanistic scenarios. Toward this end,
desilylation and mono-silylation with trityldimethylsilyl-
bromide, a protecting group known to frequently produce
crystalline derivatives,26 provided colorless needles suitable
for X-ray analysis. Thus, the structure of spirocycle 52 was
confirmed as the lactol hydantoin (Fig. 7) and retrospectively
the structure of the over-oxidation product was confirmed to
be lactol 51 following careful analysis of changes occurring
during the sequence leading to lactol 52 as described below
(Fig. 7).
Bn
48
49
Scheme 14.
Ts
N
Ts
N
O
O
TIPSO
BnN
TIPSO
m-CPBA
OR
OTBS
HO
BnN
CH2Cl2, 0 °C
(78%)
N
O
N
O
Bn
Bn
TBSCl, DMAP
50a
34b: R = H
45: R = TBS
Et3N, CH2Cl2 (85%)
Ts
N
Ts
N
O
O
1) TBAF, AcOH (20 mol%) HO
THF, 0 °C, (36%)
TIPSO
BnN
O
O
OTBS
BnN
4
4
2) Ph3CMe2SiBr, AgNO3,
DMF, (58%)
N
O
OSiMe2Tr
N
O
O
O
Bn
Bn
OH
The hydroxymethylene bearing center (C4) had epimerized
during the sequence and this was found to occur during the
desilylation step presumably via the aldehyde. The stereo-
chemistry at the spirocenter was unexpected for a suprafacial
1,2-shift, which was expected for this rearrangement. How-
ever, reasonable explanations for this inversion of stereo-
chemistry could be conceived when considering possible
mechanistic scenarios involved in the generation of this
over-oxidation product (Scheme 16). One possible mecha-
nism involves initial epoxidation of alkene 45 with
m-CPBA or direct iminium ion formation by oxidation (cf.
Scheme 14) followed by deprotonation to give alkene 50a.
A second epoxidation/ring opening sequence followed by
OH
51
52
Scheme 15.
we initially believed to be allylic alcohol 50a and not the re-
arranged spirohydantoin (Scheme 15). This structure was
quickly excluded, since mass spectrometric analysis of the
reaction product revealed incorporation of three oxygen
atoms rather than one. Notably, the formation of the major
reaction product was instantaneous at 0 C, and lowering
the reaction temperature appeared to have an effect on the
reaction rate but not the reaction outcome suggestive of an
ꢀ
TIPSO
TIPSO
TIPSO
TIPSO
Ts
N
Ts
N
Ts
N
Ts
N
O
O
O
O
m-CPBA
m-CPBA
m-CPBA
O
HO
O
CH2Cl2, 0 °C
BnN
BnN
BnN
BnN
O
OTBS
OTBS
OTBS
OTBS
N
N
N
N
O
O
O
OH
Bn
Bn
Bn
Bn
45
53
50a
54
TIPSO
H
TIPSO
TIPSO
TIPSO
Ts
N
Ts
N
Ts
Ts
N
TIPSO
BnN
Ts
N
O
O
O
N
O
O
O
HO
BnN
O
HO
BnN
HO
OTBS
Bn
4
N
BnN
1
O
OTBS
OTBS
OTBS
OTBS
O
H
N
N
O
O
N
N
O
N
O OH
OH
O
O OH
O
O
O OH
O
Bn
Bn
OH
Bn
Bn
Bn
H
O
Ar
Ar
Ar
58
51
O
O
O
56
55
57
Scheme 16.

5232
P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
a Baeyer–Villiger type oxidation of the resulting iminium in-
termediate 54 yields oxepane 58. Notably, while transforma-
tions of this type have not been reported for iminium species,
analogous Baeyer–Villiger type oxidations of oxocarbenium
intermediates have been described previously.27 Consider-
ing this mechanistic proposal, the inverted stereochemistry
at the quaternary center may be rationalized by invoking
an acid-catalyzed epimerization of carbinolamine 55. The
epimerization may proceed via ketone 56 by reversible
ring cleavage and readdition of the urea from the convex
face. Subsequent 1,2-shift/ring contraction provides spiro-
cyclic hydantoin 51 containing a tetrahydropyran. Another
possible rationale for inversion at the quaternary center in-
volves epimerization at the stage of the final hydantoin 51
via ring-opened intermediates (not shown).
nOe
Ts
N
Ts
N
O
O
TIPSO
TIPSO
BnN
DMDO, MgSO4, CH2Cl2
-45 °C; Me2S
Hb OR
OR
HaO
BnN
N
N
O
O
Bn
Bn
50a: R = TBS (99%)
50b: R = H (98%)
45: R = TBS
34a: R = H
Ts
N
O
TIPSO
O
m-CPBA
50a
OTBS
BnN
CH2Cl2, 0 °C
(79%)
N
O
O
Bn
OH
51
Scheme 17.
While not useful toward the synthesis of the target core
structure of oroidin-derived alkaloids, the over-oxidation
product proved quite valuable. The formation of the spiro-
hydantoin 51 lent credence to our proposed 1,2-shift/ring
contraction. Furthermore, given the potential intermediacy
of allylic alcohol 50a, we recognized the utility of this
substrate for the projected chlorination/rearrangement se-
quence. The placement of the alkene moiety in carbinol
50a would facilitate the incorporation of a chlorine atom at
C5 by electrophilic addition. Furthermore, C]O bond for-
mation leading to a spirocyclic hydantoin as observed would
provide an added driving force for the 1,2-shift/ring contrac-
tion. Therefore, we examined other oxidants with the expec-
tation that milder conditions might allow isolation of alcohol
50a. While initial oxidations with DMDO28 gave complex
sequence (vide infra), synthesis of the corresponding carbi-
nolureas derived from bis-tosyl Diels–Alder adducts 59 and
60 were also investigated since these had been obtained as
single regioisomers in the cycloaddition. Not surprisingly,
oxidation of the imidazolone alkene, now rendered less elec-
tron rich due to the tosyl substituent, did not proceed but only
returned starting material (Table 4, entry 1). Increasing reac-
tion temperature only furnished starting material contami-
nated to a varying degree with unidentified oxidation
products (Table 4, entry 2). After unsuccessful oxidation at-
tempts with H2O2 (Table 4, entry 3) and m-CPBA (Table 4,
entry 4), the more reactive DMDO analog, methyl(trifluoro-
methyl)dioxirane30 was utilized and gratifyingly yielded the
desired allylic alcohol 50c in nearly quantitative yield (Table
4, entry 5). The same reaction conditions could be employed
to furnish the corresponding carbinolurea 50d derived from
the TBS-protected Diels–Alder adduct 60 (Table 4, entry 6).
ꢀ
reaction mixtures when performed at 22 C, we ultimately
generated allylic alcohol 50a in a highly diastereoselective
manner and in excellent yield by careful treatment of imida-
ꢀ
zolone 45 with DMDO at ꢁ45 C, followed by quenching of
excess DMDO with dimethylsulfide at low temperature.
While alcohol 50a could be purified by silica gel chromato-
graphy, substantial decomposition was observed. However,
it could be stored neatly in the freezer for several days and
it was of sufficient purity to be used directly in subsequent
reactions. The structural and stereochemical proof of carbi-
nolurea 50a was provided by detailed spectral analysis
including COSY and HMQC. Key data included the
presence of a carbinolurea carbon in the 13C NMR spectrum
(d 86.5, acetone-d6). This chemical shift correlated well with
that of known carbinolurea substructures found in related
natural products.29 In addition, a key NOE was observed be-
tween the hydroxyl proton Ha and the methine proton Hb
(Scheme 17). Interestingly, the hydroxyl proton Ha appeared
as a sharp singlet at d 5.57 but was exchangeable with D2O.
While these results were pleasing, the use of expensive and
volatile methyl(trifluoromethyl)dioxirane on large scale
would ultimately prevent the viability of this route. There-
fore, we explored the possibility of removing the electron-
withdrawing tosyl group prior to oxidation. Selective
Table 4. Oxidation of bis-sulfonylated Diels–Alder adducts
Ts
Ts
N
N
O
O
TIPSO
HO
TsN
TIPSO
TsN
[O]
OR2
OR2
CH2Cl2
N
N
O
O
R1
R1
TBSCl, DMAP
Et3N, CH2Cl2
34e R1 = PMB, R2 = H
59 R1 = PMB, R2 = TBS
60 R1 = DMB, R2 = TBS
61 R1 = PMB, R2 = H
50c R1 = PMB, R2 = TBS
50d R1 = DMB, R2 = TBS
(92%)
In support of the aforementioned mechanism for the gener-
ation of over-oxidation product 51, treatment of alcohol
50a with m-CPBA also led to the same oxepane 51 observed
using m-CPBA alone (Scheme 17). Notably, DMDO oxida-
tion of the unprotected Diels–Alder adduct 34a with a pen-
dant free hydroxyl furnished the analogous carbinolurea.
Alternative oxidants that were briefly investigated included
peracetic acid and hydrogen peroxide, which led to desilyl-
ation (ꢁTBS) and recovery of starting material, respectively.
Entry Imidazolone Reaction conditions
Reaction
outcome
1
2
34e
34e
DMDO, MgSO4, ꢁ45 ꢀC
No reaction
Mixture of
products
No reaction
Mixture of
products
DMDO, MgSO4, 22/41 ꢀC
3
4
34e
59
H2O2, 0 ꢀC
m-CPBA, 0 ꢀC
5
6
59
60
Methyl(trifluoromethyl)dioxirane, 50c (99%)
MgSO4, ꢁ45 ꢀC
Methyl(trifluoromethyl)dioxirane, 50d (99%)
MgSO4, ꢁ45 ꢀC
While the synthesis of allylic alcohol 50a enabled further
investigations toward the chlorination/ring contraction

P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
5233
Table 5. Chlorination/1,2-shift/ring contractions of allylic alcohols 50a,b
detosylation of Diels–Alder adduct 34e and its silylated an-
alog 59 proceeded smoothly with sodium naphthalenide at
low temperature (Scheme 18).
Ts
N
Ts
N
Ts
TIPSO
N
TIPSO
+
O
O
O
TIPSO
HO
BnN
O
BnN
O
BnN
Ts
H
OR
5
OR
NBn
Cl
N
N
O
OR
O
N
N
O
O
TIPSO
TsN
TIPSO
Na°, naphthalene
THF, -78 °C
Bn
Bn
50a, b
OR
OR
65a, b
66a, b
HN
Entry
Substrate
Reaction
conditions
65a,b
(% yield)
66a,b
(% yield)
N
N
O
O
PMB
PMB
34e R = H
59 R = TBS
62 R = H (87%)
63 R = TBS (86%)
1
2
50a (R¼TBS)
NCS, ꢁ12 ꢀC
ꢁ78/ꢁ45 ꢀC
NCS, C6H10
ꢁ78/ꢁ45 ꢀC
49
75
16
Trace
50a
NCS, C6H10
Scheme 18.
3
50b (R¼H)
78
Trace
Initial oxidation of these deprotected systems was conducted
with imidazolone 62 devoid of the silyl protecting group.
Treatment with DMDO did indeed produce a compound
tentatively assigned as the desired allylic alcohol 64, as
confirmed by mass spectrometry, albeit not reproducibly
(Scheme 19).
aromatic product 66a. To minimize the generation of these
side products, we employed cyclohexene as an acid buffer,
a technique utilized by Hoye to absorb HOCl.32 Pleasingly,
the addition of cyclohexene, in conjunction with lowering
the reaction temperature, furnished the desired spirocycle
in good yield with only trace amounts of the aromatized
by-product 66a. Subsequent rearrangements of allylic alco-
H
H
N
N
O
O
TIPSO
HN
DMDO, MgSO4 TIPSO
CH2Cl2, -45 °C
OH
OH
HO
HN
ꢀ
hol 50a were performed at ꢁ45 C, affording consistent
yields (75%) of spirocycle 65 (Table 5, entry 2). The se-
quence could also be performed on the unprotected allylic
alcohol 50b in similar yield (Table 5, entry 3).
N
N
O
O
PMB
PMB
62
64
Scheme 19.
Extensive NMR experiments were conducted to support the
proposed relative stereochemistry of the halogenated spiro-
hydantoins 65. Most diagnostic were NOE experiments,
which could be observed for chlorospirocycle 65 and its de-
silylated analog 67 (Fig. 8). Desilylation of the spirocycle 65
proved necessary since overlapping peaks precluded several
key NOE’s from being observed.
Ultimately, these attempted oxidation studies of N-unpro-
tected Diels–Alder adducts (cf. 62, 63) in conjunction with
findings made in subsequent chlorination studies (vide infra)
led us to conclude that efficient formation of spirocyclic sys-
tems mandated nitrogen protection.
2.3. Development of a chlorination/1,2-shift/ring con-
traction sequence: synthesis of the spirocyclic core
useful for axinellamine synthesis
The N-benzyl protons on the series of compounds including
the Diels–Alder adduct 34b, allylic alcohol 50a, and chloro-
cyclopentane 65 proved to be diagnostic markers for identi-
fying the nature of the tricyclic system (Fig. 9). As often
observed with benzyl protons in asymmetric environments,
differences in chemical shift between the diastereotopic
protons, h/h0 and i/i0, are reflective of the degree of steric
congestion (i.e., conformational mobility) about these
methylene groups. Thus, the benzylic protons are useful as
probes for the nature of the tricyclic system in these and
other systems in this series as the benzyl groups are readily
distinguished (confirmed by NOE experiments) based on the
Due to the ideal disposition of the double bond in allylic al-
cohol 50a and encouraged by the spirohydantoin formation
during the m-CPBA over-oxidation, we proceeded with in-
vestigation of the proposed halogenation/ring contraction
sequence. It was expected that treatment of the distinctly
cup-shaped carbinolurea 50a with a source of electrophilic
halogen would result in halide incorporation from the con-
vex face of the tricyclic system. Initial attempts to effect
the ring contraction by treatment of allylic alcohol 50a
ꢀ
with N-chlorosuccinimide (NCS) at ꢁ12 C pleasingly
gave a compound assigned as the desired spirohydantoin
65a (49%) but contaminated with a painfully obtained aro-
matic system 66a (loss of four stereocenters! Table 5, entry
1).31 The formation of spirohydantoin likely involves initial
chlorination, generating an iminium species, which subse-
quently undergoes a suprafacial 1,2-alkyl migration driven
by C]O bond formation to yield the desired ring contracted
spirocycle 65a,b (cf. Fig. 2).
OR1
Ts
N
O
H
H
O
OR2
BnN
O
N
H
Cl
Ph
65 R1 = TIPS, R2 = TBS
67 R1 = H, R2 = H
We postulated that acid-mediated eliminations of the car-
binolurea 50a may lead to cyclohexadiene intermediates,
which could then be oxidized further by NCS to give
Figure 8. Key NOE enhancements observed for chlorinated spirocycles 65
and 67.

5234
P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
h
i
i'
h'
TIPSO
h,h'
Ts
N
O
OH
Ph
N
N
O
i,i'
Ph
34b
5.3
5.2
5.1
5.0
4.9
4.8
4.7
4.6
4.5
4.4
4.3
ppm
TIPSO
h,h'
i'
Ts
N
h'
O
h
i
HO
N
OTBS
Ph
N
O
i,i'
50a
Ph
4.9
4.8
4.7
4.6
4.5
4.4
4.3
4.2
4.1
4.0
3.9
3.8
ppm
OTIPS
Ts
i
h
h'
i'
N
H
O
O
H
h,h'
N
Ph
OTBS
N
O
Cl H
Ph
i,i'
65
5.3 5.2 5.1 5.0 4.9 4.8 4.7 4.6 4.5 4.4 4.3
ppm
Figure 9. Benzyl protons of intermediates 34b, 50a, and 65 as diagnostic markers of steric congestion and structure.
Dd for these protons. For example, on conversion of the
allylic alcohol 50a to the spirocycle 65, one observes a
complete reversal in the Dd for protons h and i. Namely,
protons h of alcohol 50a, which are present in the bay region
of the tricycle have a large Dd relative to protons i since these
have greater conformational mobility. A complete reversal
in this effect is observed following rearrangement/ring con-
traction since protons i are situated in the concave face of the
spirocyclic system.
chlorination/rearrangement sequence (cf. Fig. 6). This added
further impetus to development of the Tsv/Tse protecting
group strategy described above. In further studies, it was
also found that the choice of protecting group for the alcohol
at C1 was also critical to this reaction (Scheme 21). Previous
studies toward the chlorocyclopentane ring had been con-
ducted using a TBS-protected alcohol, however, further
endeavors toward axinellamine required an acidic stable
protecting group. This led to the use of the pivaloate group,
however, conducting the rearrangement under conditions
previously utilized for the Tse/DMB-protected imidazolone
resulted in non-reproducible yields of the spirocycle 71.
In analogy to the oxidation sequence, we were again inter-
ested in applying the rearrangement to the bis-sulfonylated
Diels–Alder adducts (i.e., 61, 50c,d) as they were obtained
as single regioisomers. NCS, 2,3,4,5,6,6-hexachlorocyclo-
hexa-2,4-dien-1-one, sodium hypochlorite, chloramine-T,
and chlorine gas were all studied in attempts to effect the
rearrangement of allylic alcohol 50d. All these reaction
conditions furnished either starting allylic alcohol 50d or
produced only traces of the desired rearranged compound,
frequently only identifiable after mass spectrometric analy-
sis of the crude product. Attempted rearrangement of the
detosylated analog 64 led to the aromatized product even
DMDO,
MgSO4,
CH2Cl2
TIPSO
Ts
TIPSO
Ts
N
N
NCS, C6H10
CH2Cl2
O
O
HO
TseN
-45 °C-23 °C
1
-45 °C
TseN
O
OPiv
OR
N
N
O
DMB
70
DMB
PivCl, Et3N
CH2Cl2 (97%)
34d: R=H
69: R=Piv
ꢀ
TIPSO
at low (ꢁ95 C) temperature (Scheme 20).
Ts
N
TIPSO
Ts
N
TIPSO
DMB
Ts
N
O
O
O
DMB
+
+
H
H
N
N
N
N
TseN
O
O
O
O
O
TIPSO
HO
HN
TIPSO
HN
OPiv
NCS, cyclohexene
CH2Cl2, -95 °C
TseN
TseN
N
OH
OH
OPiv
Cl
OPiv
O
DMB
O
71 (42%)
72 (30%)
73 (17%)
N
N
O
O
PMB
PMB
Scheme 21.
64
68
Scheme 20.
The desired chlorocyclopentane 71 (42%) remained as the
major component and two by-products were identified as
the aromatized compound 72 (30%) and the deschlorospiro-
cycle 73 (17%). The presence of adventitious acid may lead
These results reinforced the need for electron-donating
groups on N1/N2 of the Diels–Alder adduct for the oxidation/

P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
5235
to protonation of enamine 69 rather than chlorination lead-
ing to deschlorocyclopentane 73 via iminium 74. Alterna-
tively, the acid presumably leads to the loss of the alcohol
and formation of an iminium intermediate, for example,
75. The increased amount of aromatized product 72 pro-
duced in this case compared to other protecting groups
studied leads us to speculate that the pivaloate group may
assist in diene formation by intramolecular deprotonation
via intermediate 75 (Scheme 22). Subsequent a-chlorination
and elimination or air oxidation of diene 76 may lead to the
aromatized adduct 72.
reactions of vinyl imidazolones provide adducts that have
undergone facile olefin isomerization, subsequent oxidation
provides a surprisingly stable allylic alcohol that serves as an
excellent substrate for the key halogenation/ring contraction
sequence. This involves a sequential chlorination/1,2-shift/
ring contraction sequence allowing rapid access to a tricyclic
spirocyclopentane (i.e., 78), which serves as a point of
departure for current synthetic studies toward the axinell-
amines. The requirement of imidazolone nitrogen protecting
groups with differing electronics led to the development
of several strategies for controlling regioselectivity in the
Diels–Alder process and promoting the chlorination/
rearrangement sequence. One strategy involved the develop-
ment of a Tsv/Tse protecting group strategy, which allows
for facile electronic tuning of this protecting group without
recourse to a protecting group switch. The described syn-
thetic studies have paved the way for our ongoing synthetic
approaches to several members of the oroidin family of bio-
active marine natural products that will ultimately enable
further study of their precise biological modes of action.
TIPSO
TIPSO
Ts
N
Ts
N
O
O
H
HO
OPiv
OPiv
HO
TseN
73
TseN
N
N
O
DMB
O
DMB
74
69
H
TIPSO
TIPSO
Ts
Ts
N
4. Experimental
4.1. General
N
O
O
72
OPiv
O
H2O
TseN
H
TseN
O
O
N
N
O
All non-aqueous reactions were carried out under a nitrogen
ꢀ
DMB
DMB
atmosphere in oven-dried (120 C) glassware unless noted
75
76
otherwise. Tetrahydrofuran (THF, EM Science) and diethyl
ether (Et2O, EM Science) were distilled immediately prior
to use from sodium metal/benzophenone ketyl. Methylene
chloride (CH2Cl2, EM Science) and benzene (PhH, EM
Science) were distilled from calcium hydride prior to use.
Methanol (MeOH, EM Science) was distilled from magne-
sium methoxide. N-Chlorosuccinimide (NCS) was recrys-
tallized from glacial acetic acid prior to use. Solutions
of dimethyldioxirane28 (DMDO) in acetone and methyl
(trifluoromethyl)dioxirane30 in 1,1,1-trifluoroacetone were
prepared according to literature procedures. All other com-
mercially available reagents were used as received unless
specified otherwise.
Scheme 22.
These findings led us to explore the more acid stable tert-
butydiphenylsilyl (TBDPS) protecting group at C1 and as
previously observed with the TBS ether, the chlorination/
rearrangement sequence proceeded without incident
(Scheme 23). However, while NCS gave isolable quantities
of the aromatized product, chloramine-T nearly eliminated
the formation of this by-product and gave highly reproduc-
ible yields of chlorocyclopentane 81 on gram scale (65–
70%, Scheme 23).
TIPSO
TIPSO
Ts
N
Ts
N
O
O
Infrared spectra were recorded with a Nicolet Impact 410
DMDO, MgSO4,
-50 oC, CH2Cl2
1
FTIR spectrometer. H NMR and 13C NMR spectra were
HO
TseN
TseN
O
obtained on a Varian Unity-500, Inova-500, Unity-300 or
VXR-300 spectrometer. Mass spectra were obtained on
a VG analytical 70S high resolution, double focusing, sec-
tored (EB) mass spectrometer (for FAB), an MDS Sciex
(Concord, Ontario, Canada) API Qstar Pulsar (for ESI) or
a ThermoFinnigan (San Jose, CA) LCQ Deca Mass Spec-
trometer (for APCI) at the Mass Spectrometry Application
and Collaboration Facility (Texas A&M University). Flash
OTBDPS
OTBDPS
(99%)
N
N
O
DMB
DMB
77
43
TIPSO
DMB
Ts
N
O
chloramine-T,
C6H10, CH2Cl2
N
OTBDPS
-50 °C to 25 °C
(65-70%)
O
˚
TseN
O
column chromatography was performed using 60 A Silica
Cl
Gel (EM Science, 230–400 mesh) as a stationary phase.
Enantiomeric excess (ee) was determined by HPLC analysis
(RAININ SD-200 with DYANMAX UV-C DETECTOR)
using a ChiralpakÒ AD column. Microwave reactions were
carried out in a CEMÒ ExplorerÔ/DiscoverÔ microwave
system.
78
Scheme 23.
3. Conclusion
We have developed a unified synthetic strategy to the oroidin
alkaloids that will allow access to several members of this
family of marine natural products. While Diels–Alder
4.1.1. General procedure for N-alkylation of imidazol-2-
one as described for 1,3-bis-(benzyl)-4-(benzyloxy-car-
bonyl)imidazol-2-one (22a). To a slurry of NaH (3.79 g,

5236
P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
158 mmol) in anhydrous DMF (90 mL) was added imidazo-
lone carboxylic acid 20 (4.01 g, 31.2 mmol) at 0 C. The ice
the crude mesylate. Recrystallization from ethyl acetate/
hexane gave mesylate 29 (81.0 g, 52%) as a colorless solid:
ꢀ
bath was removed and the reaction was allowed to warm to
ꢀ
mp 89–91 C; Rf¼0.38 (hexanes/EtOAc, 6:4); IR (thin film)
22 C. After stirring for 30 min, benzyl bromide (19.0 mL,
1593 cmꢁ1
;
1H NMR (300 MHz, CDCl3) d 7.82 (d,
ꢀ
160 mmol) was added and the reaction was stirred for an ad-
ditional 10 h at 22 C. Water was added and the mixture was
J¼8.1 Hz, 2H), 7.40 (d, J¼8.1 Hz, 2H), 4.55 (t, J¼6.0 Hz,
2H), 3.53 (t, J¼6.0 Hz, 2H), 2.98 (s, 3H), 2.48 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 145.8, 136.3, 130.4, 128.4, 62.2,
55.5, 38.0, 22.0; LRMS (APCI) Calcd for C10H15S2O5
[M+H]: 279. Found: 279.
ꢀ
extracted with Et2O. The combined organic layers were
washed with water and brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. Purification by flash
chromatography on SiO2 eluting with hexanes/EtOAc
(9:1/1:9) gave benzyl ester 22a (5.1 g, 41%) as a light yel-
low solid: Rf¼0.30 (hexanes/EtOAc, 7:3); IR (thin film)
4.1.5. Synthesis of 2-oxo-1-[2-(toluene-4-sulfonyl)-ethyl]-
2,3-dihydro-1H-imidazole-4-carboxylic acid methyl
1724, 1695 cmꢁ1
;
1H NMR (300 MHz, CDCl3) d 7.36–
ester (Tse-21).
A
solution of ꢀimidazolone (45.0 g,
7.25 (m, 15H), 7.01 (s, 1H), 5.25 (s, 2H), 5.15 (s, 2H),
4.86 (s, 2H); 13C NMR (75 MHz, CDCl3) d 159.0, 153.5,
137.8, 135.7, 135.4, 129.0, 128.4, 128.36, 128.3, 128.2,
128.0, 127.9, 127.8, 127.3, 120.5, 113.6, 66.1, 47.6, 45.6;
HRMS (FAB) Calcd for C25H23N2O3 [M+H]: 399.1781.
Found: 399.1726.
317 mmol) in 900 mL DMSO at 25 C was treated with so-
dium hydrogen carbonate (53.2 g, 634 mmol). After 10 min
ꢀ
at 70 C, TseOMs (88.1 g, 317 mmol) was added to the re-
sulting solution. The reaction was further stirred for 12 h,
and poured onto ice (300 g). The resulting solution was fil-
tered to give a brown solid. The crude solid was purified
by dissolution of impurities in ethyl acetate and the solid res-
idue was filtered to afford Tse-21 (>95% purity, 78.0 g,
76%) as a tan solid. Rf¼0.34 (EtOAc); 1H NMR
(500 MHz, CDCl3) d 8.24 (br s, 1H), 7.76 (AB, J¼8.5 Hz,
2H), 7.35 (AB, J¼8.5 Hz, 2H), 7.03 (d, J¼2.0 Hz, 1H),
4.16 (t, J¼6.5 Hz, 2H), 3.84 (s, 3H), 3.55 (t, J¼6.5 Hz,
2H), 2.45 (s, 3H); 13C NMR (125 MHz, CDCl3) d 159.4,
152.2, 145.3, 136.0, 130.1, 127.8, 120.1, 113.1, 54.1, 51.9,
38.5, 21.6; MS (ESI) 331 [M+Li], 325 [M+H]. HRMS
(ESI) Calcd for C14H16N2O5SLi [M+Li]: 331.0940. Found:
331.0942.
4.1.2. 1,3-Bis(benzyloxymethyl)-4-(methoxycarbonyl)-
imidazol-2-one (22b). Rf¼0.40 (hexanes/EtOAc, 7:3); IR
(thin film) 1731, 1593 cmꢁ1; 1H NMR (300 MHz, acetone-
d6) d 7.49 (s, 1H), 7.38–7.21 (m, 10H), 5.49 (s, 2H), 5.19
(s, 2H), 4.60 (s, 2H), 4.59 (s, 2H), 3.79 (s, 3H); 13C NMR
(125 MHz, acetone-d6) d 160.1, 154.5, 139.2, 138.5, 129.0,
128.9, 128.5, 128.4, 128.2, 128.17, 122.3, 114.4, 73.5,
71.8, 71.4, 71.3, 51.8; HRMS (FAB) Calcd for
C21H23N2O5 [M+H]: 383.1607. Found: 383.1597.
4.1.3. 1-tert-Butoxycarbonyl-4-(methoxycarbonyl)imida-
zol-2-one (Boc-21). To a slurry of imidazolone methyl ester
21 (943 mg, 6.64 mmol) in 50 mL CH3CN was added
K2CO3 (873 mg, 6.32 mmol) and Boc2O (1.42 g,
6.50 mmol). Upon completion of the reaction as monitored
by TLC the reaction mixture was concentrated in vacuo
and purified by flash chromatography on SiO2 eluting with
CH2Cl2/MeOH (10:0/9.5:0.5) to yield the Boc-protected
imidazolone methyl ester Boc-21 (872 mg, 54%) as an off-
white solid. In a separate reaction the crude product was
found to be sufficiently pure for alkylation: Rf¼0.43
(MeOH/CH2Cl2, 1:9); IR (thin film) 1796, 1753,
4.1.6. Synthesis of 2-oxo-1,5-bis-[2-(toluene-4-sulfonyl)-
vinyl]-2,3-dihydro-1H-imidazole-4-carboxylic acid
methyl ester (37). A solution of imidazolone 21 (25.0 mg,
ꢀ
0.18 mmol) in 3 mL DMF at 0 C was treated with potas-
sium carbonate (1.20 mg, 0.0087 mmol). A solution of
1-ethynesulfonyl-4-methylbenzene (32 mg, 0.18 mmol) in
2 mL DMF was added to the stirred solution dropwise
over the period of an hour. The mixture was allowed to
warm to room temperature over 12 h. Solvents were re-
moved in vacuo and the crude solid was purified by flash
chromatography (SiO2, EtOAc/hexane, 4:6) to afford 37
1
1738 cmꢁ1; H NMR (300 MHz, acetone-d6) d 9.90 (br s,
(29.0 mg, 66%) as a colorless solid: mp 160–165 C (dec);
ꢀ
1H), 7.35 (s, 1H), 3.81 (s, 3H), 1.57 (s, 9H); 13C NMR
(75 MHz, acetone-d6) d 160.0, 150.2, 147.9, 116.4, 115.9,
84.9, 52.3, 27.9; HRMS (ESI) Calcd for C10H15N2O5
[M+H]: 243.0981. Found: 243.0889.
Rf¼0.60 (EtOAc/hexane, 2:3); IR (thin film) 3587, 1721,
1703, 1633 cmꢁ1 1H NMR (500 MHz, CDCl3) d 7.82–
;
7.78 (m, 5H), 7.35 (d, J¼8.0 Hz, 2H), 7.32 (d, J¼8.0 Hz,
2H), 7.23 (s, 1H), 6.86 (d, J¼8.5 Hz, 1H), 6.83 (d,
J¼13.5.5 Hz, 1H), 6.40 (d, J¼8.5 Hz, 1H), 3.85 (s, 3H),
2.44 (s, 3H), 2.43 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 158.8, 149.1, 145.3, 144.9, 137.8, 137.0, 132.3, 130.2,
130.0, 128.6, 128.3, 123.2, 127.8, 18.4, 117.3, 116.6, 52.7,
21.82, 21.77; MS (ESI) 509 [M+Li]. HRMS (ESI) Calcd
for C23H22N2O7S2Li [M+Li]: 509.1028. Found: 509.1016.
4.1.4. Methanesulfonic acid 2-(toluene-4-sulfonyl)-ethyl
ester (29). To a stirred solution of the sodium salt of toluene
sulfinic acid (100 g, 561 mmol) and sodium hydroxide (45 g,
1.12 mol) in water (1000 mL) was added chloroethanol
ꢀ
(75.0 mL, 1.12 mol) at 100 C and stirring continued for
5 h. The reaction was cooled to room temperature and ex-
tracted with ethyl acetate (3ꢂ500 mL). The combined or-
ganic layers were dried over anhydrous MgSO4. Solvents
were removed in vacuo and the crude alcohol isolated as
an orange oil. Triethylamine (69.6 mL, 499 mmol) was
added to a stirred solutionꢀof the crude alcohol in dichloro-
methane (1000 mL) at 0 C, followed by the addition of
MsCl (38.6 mL, 499 mmol) and stirring continued for
30 min. The organic layer was washed with water and dried
over anhydrous MgSO4 and concentrated in vacuo to give
4.1.7. 1-Toluenesulfonyl-4-(methoxycarbonyl)imidazol-
2-one (Ts-21). To a stirred solution of NaH (219 mg,
9.14 mmol) in 50 mL anhydrous DMF at 0 C was added
imidazolone methyl ester 21 (1.29 g, 9.06 mmol) followed
ꢀ
by TsCl (1.74 g, 9.12 mmol). The reaction mixture was
ꢀ
heated at 65 C for 19 h, diluted with pH 7 buffer and
extracted with EtOAc. The combined organic layers were
washed with H2O and brine, dried over anhydrous
Na2SO4. Solvents were removed in vacuo and the crude solid

P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
5237
was purified by flash chromatography on SiO2, eluting with
CH2Cl2/MeOH (10:0/9:1) to furnish tosylated methyl
esterꢀTs-21 (1.55 g, 58%) as an off-white solid: mp 191–
192 C (EtOAc/hexanes); Rf¼0.40 (hexanes/EtOAc, 6:4);
IR (thin film) 1724 cmꢁ1; 1H NMR (500 MHz, acetone-d6)
d 10.06 (br s, 1H), 8.01 (d, J¼8.5 Hz, 2H), 7.50 (d,
J¼8.5 Hz, 2H), 7.46 (s, 1H), 3.86 (s, 3H), 2.46 (s, 3H);
13C NMR (125 MHz, acetone-d6) d 159.6, 149.7, 147.2,
134.9, 130.8, 117.0, 116.1, 52.4, 21.6; HRMS (ESI) Calcd
for C12H13N2O5S [M+H]: 297.0539. Found: 297.0560.
acetone-d6) d 159.8, 150.3, 150.1, 149.8, 147.5, 134.6,
130.8, 130.7, 130.6, 129.4, 120.9, 117.0, 112.4, 112.3,
55.9, 55.8, 52.4, 45.7, 21.6; HRMS (ESI) Calcd for
C21H23N2O7S [M+H]: 447.1226. Found: 447.1205.
4.1.12. General procedure for DIBAl-H reduction of
imidazolone ester as described for 1,3-bis(benzyl)-4-
(hydroxymethylene)imidazol-2-one (23a). To a cooled
ꢀ
(ꢁ78 C) solution of benzyl ester 22a (8.61 g, 21.6 mmol)
in 165 mL CH2Cl2 was added a 0.99 M solution of DIBAl-
H in CH2Cl2 (54.6 mL, 53.8 mmol). The reaction was stirred
ꢀ
(11.0 mL, 1.0 M, 11.2 mmol). After 4 h MeOH (40 mL)
4.1.8. General procedure for the N-alkylation of the acyl-
ated or sulfonylated imidazol-2-one as described for
1-tert-butoxycarbonyl-3-(4-methoxybenzyl)-4-(methoxy-
carbonyl)imidazol-2-one (22c). To crude Boc imidazolone
methyl ester Boc-21 (3.41 g, 14.1 mmol) in 100 mL acetoni-
trile was added K2CO3 (6.15 g, 44.5 mmol) and PMBBr
(4.00 mL, 28.7 mmol). The reaction mixture was heated to
reflux for 16 h, diluted with pH 7 buffer, and extracted
with CH2Cl2. The combined organic layers were dried
over anhydrous Na2SO4 and concentrated in vacuo. Purifica-
tion by flash chromatography on SiO2 eluting with hexanes/
EtOAc (10:0/7:3) gave PMB-protected imidazolone 22c
(2.69 g, 53%) as a light yellow solid: Rf¼0.52 (hexanes/
for 3 h at ꢁ78 C and additional DIBAl-H was added
ꢀ
salt and the heterogeneous mixture was allowed to warm
to 22 C overnight. The layers were separated and the aque-
was added at ꢁ78 C followed by a solution of Rochelle’s
ꢀ
ous layer was extracted with CH2Cl2. The combined
organics were washed with brine, dried over Na2SO4, and
concentrated in vacuo. Purification by flash chromatography
on SiO2 eluting with hexanes/EtOAc (9:1/1:9) afforded al-
cohol 23a (5.55 g, 87%) as an off-white solid: Rf¼0.28 (hex-
anes/EtOAc, 3:7); IR (thin film) 3360, 1687 cmꢁ1; 1H NMR
(300 MHz, CDCl3) d 7.35–7.20 (m, 10H), 6.01 (s, 1H), 4.95
(s, 2H), 4.73 (s, 2H), 4.15 (s, 2H), 2.92 (br s, 1H); 13C NMR
(125 MHz, CDCl3) d 153.8, 137.6, 136.7, 128.8, 128.7,
128.0, 127.9, 127.5, 127.2, 122.3, 109.0, 55.3, 47.1, 44.9;
HRMS (ESI) Calcd for C18H19N2O2 [M+H]: 295.1497.
Found: 295.1584.
1
EtOAc, 6:4); IR (thin film) 1796, 1753, 1724 cmꢁ1; H
NMR (500 MHz, acetone-d6) d 7.36 (s, 1H), 7.31 (d,
J¼8.5 Hz, 2H), 6.77 (d, J¼8.5 Hz, 2H), 5.08 (s, 2H), 3.77
(s, 3H), 3.72 (s, 3H), 1.56 (s, 9H); 13C NMR (125 MHz,
acetone-d6) d 159.3, 158.9, 150.9, 146.7, 129.5, 129.3, 116.5,
115.1, 113.6, 85.3, 55.0, 51.8, 44.6, 27.3; HRMS (ESI)
Calcd for C18H23N2O6 [M+H]: 363.1556. Found: 363.1454.
4.1.13. 1,3-Bis(benzyloxymethyl)-4-(hydroxymethyl-
ene)imidazol-2-one (23b). Rf¼0.09 (hexanes/EtOAc, 6:4);
1
IR (thin film) 3491, 1702 cmꢁ1; H NMR (500 MHz, ace-
4.1.9. 3-(3,4-Dimethoxybenzyl)-2-oxo-1-[2-(toluene-4-
sulfonyl)-ethyl]-2,3-dihydro-1H-imidazole-4-carboxylic
acid methyl ester (22d). Rf¼0.50 (EtOAc); IR (neat) 1721,
1692 cmꢁ1; 1H NMR (500 MHz, C6D6) d 7.59 (d, J¼8.0 Hz,
2H), 7.23 (m, 2H), 6.66 (d, J¼8.0 Hz, 2H), 6.56 (m, 2H),
5.19 (s, 2H), 3.63 (t, J¼7.0, 5.5 Hz, 2H), 3.52 (s, 3H),
3.334 (s, 3H), 3.332 (s, 3H), 3.11 (t, J¼7.0, 5.5 Hz, 2H),
1.85 (s, 3H); 13C NMR (125 MHz, C6D6) d 159.8, 153.0,
150.1, 149.7, 144.4, 137.3, 131.3, 129.8, 128.0, 121.2,
121.1, 113.3, 113.1, 112.3, 55.6, 55.5, 53.7, 50.8, 45.3,
38.7, 21.1; HRMS (ESI) Calcd for C23H27N2O7S [M+H]:
475.1539. Found: 475.1529.
tone-d6) d 7.37–7.25 (m, 9H), 7.13–7.07 (m, 1H), 6.54
(s, 1H), 5.30 (s, 2H), 5.09 (s, 2H), 4.59 (s, 2H), 4.56
(s, 2H), 4.51 (s, 2H); 13C NMR (125 MHz, acetone-d6)
d 154.8, 138.8, 138.7, 130.1, 128.94, 128.93, 128.43,
128.41, 128.25, 128.23, 126.5, 124.1, 109.8, 72.9, 71.2,
70.9, 70.8, 55.0; HRMS (FAB) Calcd for C20H23N2O4
[M+H]: 355.1650. Found: 355.1658.
4.1.14. 3-(3,4-Dimethoxybenzyl)-4-hydroxymethyl-1-[2-
(toluene-4-sulfonyl)-ethyl]-1,3-dihydro-imidazol-2-one
1
(23d). Rf¼0.15 (EtOAc); IR (film) 3367, 1670 cmꢁ1; H
NMR (500 MHz, C6D6) d 7.75 (d, J¼8.0 Hz, 2H), 7.32 (d,
J¼8.0 Hz, 2H), 6.85 (s, 1H), 6.78 (m, 2H), 6.22 (s, 1H),
4.80 (s, 2H), 4.22 (s, 2H), 4.01 (t, J¼6.5 Hz, 2H), 3.83 (s,
3H), 3.82 (s, 3H), 3.50 (t, J¼7.0, 6.5 Hz, 2H), 2.42 (s,
3H), 2.32 (br s, 1H); 13C NMR (125 MHz, C6D6) d 153.2,
149.1, 148.5, 145.1, 136.0, 130.0, 129.8, 127.8, 122.5,
119.6, 111.1, 110.8, 109.6, 55.9, 55.8, 55.1, 54.3, 44.6,
38.0, 21.6; HRMS (ESI) Calcd for C22H27N2O6S [M+H]:
453.1672. Found: 453.1647.
4.1.10. 1-Toluenesulfonyl-3-(4-methoxybenzyl)-4-
(methoxycarbonyl)imidazol-2-one (22e). Rf¼0.32 (hex-
anes/EtOAc, 7:3); IR (thin film) 1726 cmꢁ1 1H NMR
;
(500 MHz, acetone-d6) d 8.01 (d, J¼8.5 Hz, 2H), 7.55 (s,
1H), 7.52 (d, J¼8.5 Hz, 2H), 7.12 (d, J¼9.0 Hz, 2H), 6.79
(d, J¼9.0 Hz, 2H), 4.98 (s, 2H), 3.80 (s, 3H), 3.74 (s, 3H),
2.48 (s, 3H); 13C NMR (125 MHz, acetone-d6) d 160.1,
159.9, 150.4, 147.5, 134.6, 130.9, 130.1, 129.9, 129.4,
117.1, 114.6, 55.4, 52.4, 45.5, 21.6; HRMS (ESI) Calcd
for C20H21N2O6S [M+H]: 417.1120. Found: 417.1078.
4.1.15. 3-(4-Methoxybenzyl)-1-toluenesulfonyl-4-(hy-
droxymethylene)imidazol-2-one (23e). Rf¼0.07 (hexanes/
1
EtOAc, 7:3); IR (thin film) 3411, 1709 cmꢁ1; H NMR
4.1.11. 1-Toluenesulfonyl-3-(3,4-dimethoxybenzyl)-
4-(methoxycarbonyl)imidazol-2-one (22f). Rf¼0.36 (hex-
(500 MHz, acetone-d6) d 7.95 (d, J¼8.5 Hz, 2H), 7.46 (d,
J¼8.5 Hz, 2H), 7.10 (d, J¼8.5 Hz, 2H), 6.81 (d, J¼8.5 Hz,
2H), 6.77 (s, 1H), 4.74 (s, 2H), 4.29 (s, 2H), 3.75 (s, 3H),
2.45 (s, 3H); 13C NMR (125 MHz, acetone-d6) d 160.1,
151.3, 146.6, 135.6, 130.6, 129.9, 129.4, 128.8, 114.7,
105.9, 55.4, 55.2, 44.7, 21.5; HRMS (ESI) Calcd for
C19H20N2O5SLi [M+Li]: 395.1253. Found: 395.1234.
anes/EtOAc, 6:4); IR (thin film) 1731, 1724 cmꢁ1 1H
;
NMR (500 MHz, acetone-d6) d 8.03 (d, J¼8.5 Hz, 2H),
7.56 (s, 1H), 7.51 (d, J¼8.5 Hz, 2H), 6.78 (m, 1H), 6.77
(s, 1H), 6.71 (m, 1H), 4.98 (s, 2H), 3.80 (s, 3H), 3.74
(s, 3H), 3.61 (s, 3H), 2.48 (s, 3H); 13C NMR (125 MHz,

5238
P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
4.1.16. 3-(3,4-Dimethoxybenzyl)-1-toluenesulfonyl-
4-(hydroxymethylene)imidazol-2-one (23f). Mp 135–
(ESI) Calcd for C19H18N2O5SLi [M+Li]: 393.1096.
Found: 393.1081.
ꢀ
136 C (EtOAc/hexanes); Rf¼0.09 (hexanes/EtOAc, 6:4);
1
IR (thin film) 3418, 1716 cmꢁ1; H NMR (500 MHz, ace-
4.1.21. 3-(3,4-Dimethoxybenzyl)-1-toluenesulfonyl-
4-(carboxaldehyde)imidazol-2-one (24f). Rf¼0.23 (hex-
tone-d6) d 7.96 (d, J¼8.5 Hz, 2H), 7.48 (d, J¼8.5 Hz, 2H),
6.81 (d, J¼7.5 Hz, 1H), 6.77 (app t, J¼1.5 Hz, 1H), 6.68
(dd, J¼7.5, 1.5 Hz, 1H), 4.74 (s, 2H), 4.29 (d, J¼5.5 Hz,
2H), 3.75 (s, 3H), 3.62 (s, 3H), 2.47 (s, 3H); 13C NMR
(125 MHz, acetone-d6) d 150.7, 149.8, 149.2, 146.0, 135.1,
130.9, 129.9, 128.3, 126.9, 119.7, 112.0, 111.3, 105.2,
55.4, 55.2, 54.6, 44.4, 20.9; HRMS (ESI) Calcd for
C20H23N2O6S [M+H]: 419.1277. Found: 419.1189.
anes/EtOAc, 6:4); IR (thin film) 2836, 1731, 1673 cmꢁ1
;
1H NMR (300 MHz, acetone-d6) d 9.42 (s, 1H), 8.01 (d,
J¼8.4 Hz, 2H), 7.98 (s, 1H), 7.51 (d, J¼8.4 Hz, 2H),
6.82–6.74 (m, 3H), 4.96 (s, 2H), 3.73 (s, 3H), 3.62 (s, 3H),
2.47 (s, 3H); 13C NMR (125 MHz, acetone-d6) d 180.0,
150.21, 150.17, 150.0, 147.7, 134.4, 130.9, 130.5, 129.5,
125.5, 124.7, 121.1, 112.6, 112.5, 56.0, 55.8, 46.0, 21.6;
HRMS (ESI) Calcd for C20H21N2O6S [M+H]: 417.1120.
Found: 417.1089.
4.1.17. General procedure for oxidation of 4-(hydroxy-
methylene)imidazol-2-one as described for 1,3-bis
(benzyl)4-(carboxaldehyde)imidazol-2-one (24a). To acti-
vated MnO2 (13.1 g, 151 mmol) was added alcohol 23a
(5.55 g, 18.9 mmol) in 40 mL CH2Cl2, rinsing twice with
20 mL CH2Cl2 to complete the transfer. After stirring for
10 h at ambient temperature the reaction mixture was filtered
through Celite and concentrated in vacuo to yield aldehyde
24a (5.38g, 98%) as a yellow viscous oil. No further purifi-
cation was required: Rf¼0.67 (hexanes/EtOAc, 3:7); IR (thin
film) 1702, 1658 cmꢁ1; 1H NMR (500 MHz, CDCl3) d 9.14
(s, 1H), 7.43–7.23 (m, 10H), 6.89 (s, 1H), 5.23 (s, 2H), 4.87
(s, 2H); 13C NMR (75 MHz, CDCl3) d 176.5, 153.3, 137.4,
135.1, 129.1, 128.5, 128.4, 128.2, 127.6, 127.2, 47.8, 45.9;
HRMS (FAB) Calcd for C18H17N2O2 [M+H]: 293.1290.
Found: 293.1279.
4.1.22. General procedure for Horner–Wadsworth–
Emmons reaction as described for 1,3-bis(benzyl)-4-
(ethylpropenoate)imidazol-2-one (25a). To a cooled
ꢀ
(0 C) suspension of NaH (11.8 mg, 0.49 mmol) in 2.5 mL
THF was slowly added triethylphosphonoacetate (98.0 mL,
ꢀ
0.49 mmol). After stirring the reaction at 0 C for 5 min
theꢀice bath was removed and the mixture was stirred at
22 C for 1 h. Aldehyde 24a (131 mg, 0.45 mmol) was
added at ambient temperature in 2 mL THF. After 2 h pH 4
buffer was added and the layers were separated. The aqueous
layer was extracted with Et2O and the combined organics
were dried over anhydrous Na2SO4 and concentrated
in vacuo to give a mixture of product and starting material.
The crude reaction mixture was resubjected to the reaction
conditions and furnished upon purification by flash chroma-
tography on SiO2 eluting with hexanes/EtOAc (9:1/4:6)
ester 25a (44.7 mg, 89%) as a light yellow solid: Rf¼0.34
4.1.18. 1,3-Bis(benzyloxymethyl)-4-(carboxaldehyde)-
imidazol-2-one (24b). Rf¼0.25 (hexanes/EtOAc, 6:4); IR
(thin film) 1731, 1673 cmꢁ1; 1H NMR (500 MHz, acetone-
d6) d 9.36 (s, 1H), 7.72 (s, 1H), 7.36–7.28 (m, 10H), 5.49
(s, 2H), 5.23 (s, 2H), 4.62 (br s, 4H); 13C NMR (125 MHz,
acetone-d6) d 178.3, 156.3, 139.1, 138.3, 129.7, 129.0,
128.9, 128.5, 128.4, 128.16, 128.13, 124.0, 73.6, 72.1,
71.5, 71.3; HRMS (FAB) Calcd for C20H21N2O4 [M+H]:
353.1501. Found: 353.1507.
1
(hexanes/EtOAc, 6:4); IR (thin film) 1687, 1629 cmꢁ1; H
NMR (300 MHz, CDCl3) d 7.36–7.20 (m, 10H), 7.14 (d,
J¼15.9 Hz, 1H), 6.57 (s, 1H), 5.90 (d, J¼15.9 Hz, 1H),
5.02 (s, 2H), 4.86 (s, 2H), 4.12 (q, J¼7.2 Hz, 2H), 1.22 (t,
J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 166.5,
153.5, 136.5, 135.9, 129.8, 128.8, 128.7, 128.0, 127.9,
127.5, 126.6, 120.1, 114.4, 114.2, 60.2, 47.3, 45.1, 14.1;
HRMS (FAB) Calcd for C22H23N2O2 [M+H]: 363.1709.
Found: 363.1691. Generally, the HWE olefination pro-
ceeded smoothly and all the aldehyde was consumed, such
that the crude reaction mixture did not have to be resub-
jected.
4.1.19. 3-(3,4-Dimethoxybenzyl)-2-oxo-1-(2-tosylethyl)-
2,3-dihydro-1H-imidazole-4-carbaldehyde (24d). Mp
ꢀ
150–152 C; Rf¼0.39 (EtOAc); IR (KBr) 2837, 1708,
1660 cmꢁ1
;
1H NMR (500 MHz, CDCl3) 9.21 (s, 1H),
7.72 (d, J¼8.5 Hz, 2H), 7.29 (d, J¼8.5 Hz, 2H), 7.14 (s,
1H), 7.02 (d, J¼2.0 Hz, 1H), 6.97 (dd, J¼8.0, 2.0 Hz, 1H),
6.77 (d, J¼8.0 Hz, 1H), 5.04 (s, 2H), 4.19 (t, J¼6.5,
5.5 Hz, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.56 (t, J¼6.5,
5.5 Hz, 2H), 2.43 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 176.8, 152.6, 148.8, 148.6, 145.4, 136.0, 130.1, 129.8,
128.3, 127.6, 122.8, 121.0, 111.9, 110.9, 55.8, 53.7, 45.6,
38.9, 21.6; HRMS (ESI) Calcd for C22H24N2O6SLi
[M+Li]: 451.1515. Found: 451.1496.
4.1.23. 1,3-Bis(benzyloxymethyl)-4-(ethylpropenoate)-
imidazol-2-one (25b). Rf¼0.40 (hexanes/EtOAc, 6:4); IR
(thin film) 1702, 1636 cmꢁ1; 1H NMR (500 MHz, acetone-
d6) d 7.39–7.25 (m, 12H), 6.39 (d, J¼16.0 Hz, 1H), 5.31
(s, 2H), 5.17 (s, 2H), 4.62 (s, 2H), 4.59 (s, 2H), 4.18 (q,
J¼7.0 Hz, 2H), 1.26 (t, J¼7.0 Hz, 3H); 13C NMR
(125 MHz, acetone-d6) d 167.2, 154.8, 138.6, 138.56,
131.0, 129.0, 128.6, 128.5, 128.3, 121.4, 118.0, 115.8,
73.3, 71.7, 71.3, 70.9, 66.6, 14.6; HRMS (FAB) Calcd for
C24H27N2O5 [M+H]: 423.1920. Found: 423.1922.
4.1.20. 3-(4-Methoxybenzyl)-1-toluenesulfonyl-4-
(carboxaldehyde)imidazol-2-one (24e). Rf¼0.31 (hex-
anes/EtOAc, 7:3); IR (thin film) 2836, 1731, 1673 cmꢁ1
;
4.1.24. 3-{3-(3,4-Dimethoxybenzyl)-2-oxo-1-[2-(toluene-
4-sulfonyl)-ethyl]-2,3-dihydro-1H-imidazol-4-yl}-acrylic
acid ethyl ester (25d). A solution of triethylphosphono-
acetate (10.3 mL, 52.0 mmol) in 100 mL THF was cooled
1H NMR (500 MHz, acetone-d6) d 9.45 (s, 1H), 8.02 (d,
J¼8.5 Hz, 2H), 7.99 (s, 1H), 7.52 (d, J¼8.5 Hz, 2H),
7.17 (d, J¼8.5 Hz, 2H), 6.80 (d, J¼8.5 Hz, 2H), 4.97
(s, 2H), 3.74 (s, 3H), 2.47 (s, 3H); 13C NMR (125 MHz,
acetone-d6) d 179.9, 159.6, 149.6, 147.1, 133.8, 130.3,
129.5, 128.9, 124.1, 113.9, 54.8, 45.2, 21.0; HRMS
ꢀ
to 0 C and treated witꢀh 80% NaH (1.43 g, 49.5 mmol),
allowed to warm to 25 C and further stirred for 40 min.
To the resulting solution was added dropwise a solution of

P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
5239
aldehyde 49 (22.0 g, 49.5 mmol) in 300 mL THF and then
stirring was continued for 2 h. The reaction was quenched
with 100 mL of pH 4 buffer solution. THF was removed
in vacuo and the aqueous phase was extracted with EtOAc
(3ꢂ300 mL). The organic layers were combined and dried
(MgSO4). Solvents were removed in vacuo and the crude
ester 50 was isolated as a yellow oil. The ester was generally
used without purification.
1H), 6.14 (dt, J¼5.0, 16.0 Hz, 1H), 5.03 (s, 2H), 4.93 (s,
2H), 4.42 (s, 2H), 4.39 (s, 2H), 4.05 (br s, 2H); 13C NMR
(125 MHz, acetone-d6) d 154.7, 138.8, 138.7, 136.9, 131.3,
130.2, 128.94, 128.93, 128.4, 128.3, 126.5, 123.2, 116.2,
109.1, 73.2, 71.3, 70.9, 70.8, 62.9; HRMS (FAB) Calcd for
C22H25N2O4 [M+H]: 381.1814. Found: 381.1800.
4.1.29. 3-(3,4-Dimethoxybenzyl)-4-(3-hydroxypropenyl)-
1-[2-(toluene-4-sulfonyl)-ethyl]-1,3-dihydro-imidazol-
ꢀ
4.1.25. 3-(4-Methoxybenzyl)-1-toluenesulfonyl-4-(ethyl-
propenoate)imidazol-2-one (25e). Rf¼0.25 (hexanes/
2-one (16d). Mp 81–83 C (EtOAc/hexanes); Rf¼0.16
1
(EtOAc); IR (film) 3432, 1713 cmꢁ1; H NMR (500 MHz,
1
EtOAc, 7:3); IR (thin film) 1724, 1716 cmꢁ1; H NMR
C6D6) d 7.70 (d, J¼8.0 Hz, 2H), 6.90 (d, J¼2.0 Hz, 1H),
6.82 (dd, J¼8.0, 2.0 Hz, 1H), 6.73 (d, J¼8.0 Hz, 2H), 6.54
(d, J¼8.0 Hz, 1H), 6.09 (d, J¼16.0 Hz, 1H), 5.90 (s, 1H),
5.78 (dt, J¼16.0, 5.5 Hz, 1H), 4.73 (s, 2H), 3.86 (br s,
2H), 3.86 (t, J¼6.5, 6.0 Hz, 2H), 3.50 (s, 3H), 3.33 (s,
3H), 3.21 (t, J¼6.5, 6.0 Hz, 2H), 1.86 (s, 3H); 13C NMR
(125 MHz, C6D6) d 153.4, 150.4, 149.6, 137.5, 130.6,
129.8, 129.4, 128.3, 127.9, 122.1, 119.7, 116.6, 112.4,
111.9, 108.1, 62.9, 55.7, 55.5, 54.4, 44.8, 38.2, 21.1;
HRMS (ESI) Calcd for C24H28N2O6SNa [M+Na]:
473.1746. Found: 473.1704.
(500 MHz, acetone-d6) d 7.99 (d, J¼8.5 Hz, 2H), 7.56 (s,
1H), 7.51 (d, J¼8.5 Hz, 2H), 7.22 (d, J¼16.5 Hz, 1H),
7.04 (d, J¼8.5 Hz, 2H), 6.84 (d, J¼8.5 Hz, 2H), 6.36 (d,
J¼16.5 Hz, 1H), 4.87 (s, 2H), 4.14 (q, J¼7.0 Hz, 2H),
3.75 (s, 3H), 2.48 (s, 3H), 1.23 (t, J¼7.0 Hz, 3H); 13C
NMR (125 MHz, acetone-d6) d 166.3, 160.2, 150.9, 147.1,
135.1, 130.8, 129.9, 129.3, 129.1, 128.9, 123.7, 119.9,
115.0, 110.7, 61.0, 55.5, 44.8, 21.6, 14.5; HRMS (ESI)
Calcd for C23H24N2O6S [M+H]: 457.1433. Found:
457.1415.
4.1.26. 3-(3,4-Dimethoxybenzyl)-1-toluenesulfonyl-
4-(ethylpropenoate)imidazol-2-one (25f). Rf¼0.25 (hex-
4.1.30. 3-(4-Methoxybenzyl)-1-toluenesulfonyl-4-(3-
hydroxypropenyl)imidazol-2-one (16e). Rf¼0.36 (hexanes/
anes/EtOAc, 6:4); IR (thin film) 1724, 1716 cmꢁ1
;
1H
EtOAc, 3:7); IR (thin film) 3491, 1709 cmꢁ1 1H NMR
;
NMR (500 MHz, acetone-d6) d 8.01 (d, J¼8.5 Hz, 2H),
7.57 (app t, J¼0.5 Hz, 1H), 7.51 (d, J¼8.5 Hz, 2H), 7.25
(dd, J¼16.0, 0.5 Hz, 1H), 6.83 (d, J¼8.0 Hz, 1H), 6.73 (d,
J¼2.0 Hz, 1H), 6.62 (dd, J¼8.0, 2.0 Hz, 1H), 6.37 (dd,
J¼16.0, 0.5 Hz, 1H), 4.87 (s, 2H), 4.14 (q, J¼7.0 Hz, 2H),
3.75 (s, 3H), 3.63 (s, 3H), 2.48 (s, 3H), 1.22 (t, J¼7.0 Hz,
3H); 13C NMR (125 MHz, acetone-d6) d 166.3, 150.8,
150.5, 149.9, 147.1, 135.1, 130.8, 129.9, 129.8, 129.2,
123.7, 119.9, 119.8, 112.8, 111.5, 110.6, 61.0, 56.0, 55.8,
45.1, 21.6, 14.8; HRMS (ESI) Calcd for C24H27N2O7S
[M+H]: 487.1539. Found: 487.1568.
(500 MHz, acetone-d6) d 7.96 (d, J¼8.5 Hz, 2H), 7.48 (d,
J¼8.5 Hz, 2H), 7.02 (d, J¼8.5 Hz, 2H), 6.95 (s, 1H), 6.80
(d, J¼8.5 Hz, 2H), 6.33 (dt, J¼4.0, 16.5 Hz, 1H), 6.24 (m,
1H), 4.71 (s, 2H), 4.14 (m, 2H), 3.75 (s, 3H), 2.47 (s, 3H);
13C NMR (125 MHz, acetone-d6) d 160.0, 151.0, 146.6,
135.5, 135.3, 130.6, 129.7, 129.0, 128.9, 126.3, 114.7,
114.6, 104.0, 62.3, 55.4, 44.5; HRMS (ESI) Calcd for
C21H23N2O5S [M+H]: 415.1328. Found: 415.1297.
4.1.31. 3-(3,4-Dimethoxybenzyl)-1-toluenesulfonyl-4-
(3-hydroxypropenyl)imidazol-2-one (16f). Rf¼0.24 (hex-
anes/EtOAc, 3:7); IR (thin film) 3433, 1716 cmꢁ1 1H
;
4.1.27. General procedure for preparation of diene as
described for 1,3-bis(benzyl)-4-(3-hydrꢀoxypropenyl)-
imidazol-2-one (16a). To a cooled (ꢁ78 C) solution of
a,b-unsaturated ester 25a (1.10 g, 3.05 mmol) was added
a 1.0 M solution of DIBAl-H in CH2Cl2 (9.15 mL,
9.15 mmol). After 2 h, MeOH (15 mL) was added followed
by Rochelle’s salt solution. Upon stirring for 8 h the layers
were separated and the aqueous layer was extracted with
CH2Cl2. The combined organics were dried over anhydrous
Na2SO4 and concentrated in vacuo to give diene 16a
(977 mg, 99%) as a yellow foam. No further purification
was required: Rf¼0.17 (hexanes/EtOAc, 3:7); IR (thin
NMR (500 MHz, acetone-d6) d 7.77 (d, J¼8.5 Hz, 2H),
7.48 (d, J¼8.5 Hz, 2H), 6.95 (s, 1H) 6.79 (d, J¼8.0 Hz,
1H), 6.72 (d, J¼2.0 Hz, 1H), 6.62 (dd, J¼8.0, 2.0 Hz, 1H),
6.33 (dt, J¼16.0, 4.0 Hz, 1H), 6.27 (m, 1H), 4.71 (s, 2H),
4.18 (br s, 2H), 3.75 (s, 3H), 3.62 (s, 3H), 2.46 (s, 3H);
13C NMR (125 MHz, acetone-d6) d 151.0, 150.4, 149.8,
146.6, 135.6, 135.3, 130.6, 130.3, 128.9, 126.3, 120.0,
114.7, 112.7, 111.7, 103.9, 62.4, 56.0, 55.8, 44.8, 21.5;
HRMS (ESI) Calcd for C22H25N2O6S [M+H]: 445.1433.
Found: 445.1452.
4.1.32. Diels–Alder adduct 34a. A heterogeneous mixture
of diene 16a (33.9 mg, 0.11 mmol) and dienophile 15a
(36.3 mg, 0.10 mmol) in 500 mL o-xylene was heated to
1
film) 3404, 1673 cmꢁ1; H NMR (500 MHz, acetone-d6)
d 7.39–7.25 (m, 10H), 6.64 (s, 1H), 6.24 (d, J¼15.5 Hz,
1H), 6.04 (dt, J¼5.5, 15.5 Hz, 1H), 4.96 (s, 2H), 4.85 (s,
2H), 4.07 (app t, J¼5.5 Hz, 2H); 13C NMR (125 MHz, ace-
tone-d6) d 154.3, 139.3, 139.0, 130.3, 129.4, 129.3, 128.5,
128.3, 128.0, 127.6, 122.7, 116.5, 108.3, 62.8, 47.3, 45.1;
HRMS (ESI) Calcd for C20H21N2O2 [M+H]: 321.1603.
Found: 321.1595.
ꢀ
140 C for 24 h. The reaction mixture was concentrated
in vacuo and purification by flash chromatography on SiO2
eluting with hexanes/EtOAc (7:3/3:7) furnished Diels–
Alder adduct 34a (19.1 mg, 28%) as a light yellow solid:
Rf¼0.54 (hexanes/EtOAc, 3:7); [a]2D5 ꢁ55.3ꢀ (c 1.64,
1
CH2Cl2); IR (thin film) 3418, 1724, 1680, 1651 cmꢁ1; H
NMR (300 MHz, CDCl3) d 7.34–7.22 (m, 8H), 7.12 (m,
2H), 5.16 (d, J¼16.2 Hz, 1H), 4.93 (d, J¼15.9 Hz, 1H),
4.69 (d, J¼15.9 Hz, 1H), 4.65 (d, J¼16.2 Hz, 1H), 3.96–
3.85 (m, 4H), 3.69 (dd, J¼6.3, 14.4 Hz, 1H), 3.43 (dd,
J¼3.6, 7.5 Hz, 1H), 3.14 (d, J¼7.5 Hz, 1H), 2.50 (ddd,
4.1.28. 1,3-Bis(benzyloxymethyl)-4-(3-hydroxypropenyl)
imidazol-2-one (16b). Rf¼0.31 (hexanes/EtOAc, 3:7); IR
(thin film) 3404, 1687 cmꢁ1; 1H NMR (500 MHz, acetone-
d6) 7.20–7.09 (m, 10H), 6.51 (s, 1H), 6.23 (d, J¼16.0 Hz,

5240
P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
J¼2.7, 12.0, 15.9 Hz, 1H), 2.22 (m, 1H), 2.03–1.95 (m, 1H),
1.40 (s, 9H), 0.98–0.95 (m, 21H); 13C NMR (75 MHz,
CDCl3) d 175.0, 154.7, 149.4, 137.3, 137.1, 128.9, 128.8,
127.7, 127.6, 127.3, 126.6, 120.5, 114.7, 88.7, 64.5, 63.7,
62.0, 46.1, 45.4, 44.9, 36.8, 33.9, 27.9, 19.2, 17.9, 11.8;
HRMS (ESI) Calcd for C39H56N3O6Si [M+H]: 690.3938.
Found: 690.3939.
J¼12.5 Hz, 1H), 4.74 (app t, J¼4.0 Hz, 1H), 4.71 (d,
J¼12.5 Hz, 1H), 4.50 (d, J¼12.0 Hz, 1H), 4.43 (d,
J¼12.0 Hz, 1H), 4.17 (d, J¼4.0 Hz, 2H), 3.90–3.80 (m,
2H), 3.65 (dd, J¼3.0, 7.0 Hz, 1H), 3.60 (m, 1H), 2.41
(ddd, J¼1.0, 4.5, 15.5 Hz, 1H), 1.99–1.91 (m, 1H), 1.71
(ddd, J¼3.0, 11.5, 15.5 Hz, 1H), 1.14–1.12 (m, 21H); 13C
NMR (125 MHz, acetone-d6) d 174.6, 155.2, 145.6, 138.8,
138.7, 136.4, 130.0, 129.0, 128.9, 128.6, 128.5, 128.4,
128.3, 128.2, 121.1, 115.9, 71.7, 71.4, 70.9, 70.8, 65.8,
64.2, 63.3, 42.4, 38.1, 35.6, 21.5, 19.6, 18.4, 12.6; HRMS
(MALDI) Calcd for C43H58N3O8SSi [M+H]: 804.3708.
Found: 804.3698.
4.1.33. Diels–Alder adduct 34b. To a solution of dienophile
15b (2.77 g, 6.55 mmol) in 50 mL PhH was added diene 16a
(2.81 g, 6.52 mmol) and 2,6-lutidine (450 mL, 3.95 mmol).
ꢀ
The reaction mixture was heated to 95 C in a sealed tube
for three days. Upon cooling additional diene 16a
ꢀ
(891 mg, 2.79 mmol) was added. After stirring at 95 C for
4.1.35. Diels–Alder adduct 34e. To dienophile 15b
(663 mg, 1.57 mmol) and diene 16e (650 mg, 1.57 mmol)
was added 7 mL PhH and 2,6-lutidine (100 mL,
an additional 24 h, the reaction was concentrated in vacuo.
Purification by flash chromatography on SiO2 eluting with
hexanes/EtOAc (8:2/1:9) gave 3.09 g (64%) Diels–Alder
adduct 34b as a yellow foam along with 714.1 mg (15%)
of regioisomer 35b. 34b: Rf¼0.69 (hexanes/EtOAc, 3:7);
[a]2D5 ꢁ53.0ꢀ (c 2.53, CH2Cl2); IR (thin film) 3475, 1738,
ꢀ
0.86 mmol). The reaction mixture was heated to 114 C in
a sealed vial for 19 h, concentrated in vacuo and purified
by flash chromatography on SiO2 eluting with hexanes/
EtOAc (9:1/1:1) to furnish 494 mg (59%) Diels–Alder ad-
duct 34e as a single regioisomer: Rf¼0.25 (hexanes/EtOAc,
1680 cmꢁ1
;
1H NMR (300 MHz, CDCl3) d 7.55 (d,
1
J¼8.1 Hz, 2H), 7.34–7.10 (m, 12H), 5.23 (d, J¼16.2 Hz,
1H), 4.91 (d, J¼16.2 Hz, 1H), 4.62 (d, J¼16.2 Hz, 1H),
4.32 (d, J¼16.2 Hz, 1H), 4.21 (dd, J¼2.7, 5.1 Hz, 1H),
4.04 (dd, J¼5.1, 10.5 Hz, 1H), 3.92 (dd, J¼2.7, 10.5 Hz,
1H), 3.74 (app t, J¼3.9 Hz, 2H), 3.41 (dd, J¼3.0, 6.9 Hz,
1H), 3.18 (app br d, J¼6.9 Hz, 1H), 2.40 (s, 3H), 2.00–
1.90 (m, 2H), 1.88–1.80 (m, 1H), 1.05–0.95 (m, 21H); 13C
NMR (75 MHz, CDCl3) d 174.6, 154.6, 145.1, 137.03,
137.0, 135.0, 129.4, 128.9, 128.8, 128.5, 128.4, 127.9,
127.6, 127.1, 127.0, 120.8, 114.0, 65.2, 64.3, 64.1, 45.6,
45.0, 44.7, 36.4, 35.5, 21.7, 18.9, 17.9, 11.8; HRMS (FAB)
Calcd for C41H53N3O6SSiNa [M+Na]: 766.3322. Found:
766.3314. 35b: Rf¼0.42 (hexanes/EtOAc, 3:7); [a]D25
6:4); IR (thin film) 3476, 1731 cmꢁ1; H NMR (500 MHz,
acetone-d6) d 7.94 (d, J¼8.0 Hz, 2H), 7.62 (d, J¼8.5 Hz,
2H), 7.51 (d, J¼8.0 Hz, 2H), 7.31 (d, J¼8.5 Hz, 2H), 6.67
(s, 4H), 4.66 (d, J¼16.0 Hz, 1H), 4.41 (t, J¼2.0 Hz, 1H),
4.36 (dd, J¼2.5, 6.0 Hz, 2H), 4.05 (d, J¼16.0 Hz, 1H),
3.87 (m, 1H), 3.81–3.75 (m, 2H), 3.73 (s, 3H), 3.71 (m,
1H), 2.51 (s, 3H), 2.46 (s, 3H), 2.01 (br s, 1H), 2.00–1.96
(m, 1H), 1.72 (m, 1H), 1.14–1.11 (m, 21H); 13C NMR
(125 MHz, acetone-d6) d 175.0, 159.9, 152.6, 146.7, 146.0,
138.6, 135.1, 130.6, 130.5, 129.1, 129.0, 128.6, 127.9,
127.8, 114.7, 114.6, 67.2, 66.0, 63.2, 55.4, 44.1, 43.8,
39.0, 37.0, 21.7, 21.6, 20.5, 18.4, 12.6; HRMS (ESI) Calcd
for C42H56N3O9S2Si [M+H]: 838.3227. Found: 838.3303.
ꢀ
ꢁ24.1ꢀ (c 1.85, CH2Cl2); mp 76.0–78.0 C; IR (thin film)
1
3385, 1737, 1690 cmꢁ1; H NMR (500 MHz, acetone-d6)
4.1.36. Diels–Alder adduct 34f. Rf¼0.44 (hexanes/EtOAc,
3:7); [a]2D5 ꢁ71.9ꢀ (c 1.66, CH2Cl2); IR (thin film) 3440,
d 7.91 (d, J¼8.0 Hz, 2H), 7.36–7.26 (m, 10H), 7.10 (d, J¼
8.0 Hz, 2H), 5.09 (d, J¼16.5 Hz, 1H), 5.01 (d, J¼16.5 Hz,
1H), 4.91 (d, J¼16.0 Hz, 1H), 4.71 (d, J¼16.0 Hz, 1H),
4.36 (br s, 1H), 4.25 (dd, J¼3.5, 11.0 Hz, 1H), 4.02 (m,
1H), 3.85 (m, 1H), 3.62 (d, J¼7.5 Hz, 1H), 3.52–3.49 (m,
1H), 3.22 (m, 1H), 3.00–2.97 (m, 1H), 2.69 (dd, J¼4.0,
16.5, 1H), 2.42 (s, 3H), 2.34 (ddd, J¼2.5, 4.0, 16.5 Hz,
1H), 2.27–2.22 (m, 1H), 0.94–0.93 (m, 21H); 13C NMR
(125 MHz, acetone-d6) d 172.4, 154.7, 146.1, 139.4, 139.1,
136.5, 130.2, 129.3, 129.2, 128.9, 128.0, 127.9, 127.7,
127.1, 118.8, 111.2, 66.1, 63.1, 60.6, 45.2, 44.9, 40.2,
39.2, 37.5, 21.5, 20.8, 18.2, 12.5; HRMS (FAB) Calcd for
C41H54N3O6SSi [M+H]: 744.3503. Found: 744.3508.
1724 cmꢁ1 1H NMR (500 MHz, acetone-d6) d 7.96 (d,
;
J¼8.5 Hz, 2H), 7.63 (d, J¼8.5 Hz, 2H), 7.49 (d, J¼7.5 Hz,
2H), 7.32 (d, J¼7.5 Hz, 2H), 6.66 (d, J¼8.0 Hz, 1H), 6.57
(d, J¼2.0 Hz, 1H), 6.23 (dd, J¼8.0, 2.0 Hz, 1H), 4.68 (d,
J¼16.0 Hz, 1H), 4.42 (s, 1H), 4.37 (m, 2H), 4.03 (d,
J¼16.0 Hz, 1H), 3.87 (m, 1H), 3.82–3.75 (m, 2H), 3.76–
3.71 (m, 2H), 3.74 (s, 3H), 3.58 (s, 3H), 2.49 (s, 3H), 2.47
(s, 3H), 2.10 (m, 1H), 2.01–1.95 (m, 1H), 1.74 (m, 1H),
1.14–1.23 (m, 21H); 13C NMR (125 MHz, acetone-d6)
d 175.0, 152.3, 150.4, 149.8, 146.8, 146.0, 136.6, 135.8,
130.6, 130.5, 129.7, 129.2, 127.9, 127.5, 119.6, 114.8,
112.4, 111.5, 67.3, 66.1, 63.2, 56.0, 55.9, 44.2, 44.1, 39.0,
37.1, 21.7, 21.6, 20.5, 18.41, 18.40, 12.7; HRMS (ESI)
Calcd for C43H57N3O10S2SiNa [M+Na]: 890.3152. Found:
890.3201.
4.1.34. Diels–Alder adduct 34c. To dienophile 15b
(275 mg, 0.65 mmol) and diene 16b (230 mg, 0.61 mmol)
was added 5 mL PhH and 2,6-lutidine (40.ꢀ0 mL,
0.34 mmol). The reaction mixture was heated to 95 C in
a sealed vial for 17 h, concentrated in vacuo, and purified
by flash chromatography on SiO2 eluting with hexanes/
EtOAc (9:1/1:1) to furnish 148 mg (30%) Diels–Alder ad-
duct 34c along with the 31.1 mg presumed regioisomer:
Rf¼0.62 (hexanes/EtOAc, 3:7); IR (thin film) 3476,
4.1.37. 3-(3,4-Dimethoxybenzyl)-2-oxo-1-[2-(toluene-4-
sulfonyl)-vinyl]-2,3-dihydro-1H-imidazole-4-carboxylic
acid methyl ester (38). To a stirred solution of 21 (3.80 g,
ꢀ
26.7 mmol) in 200 mL of DMF at 25 C was added 80% so-
dium hydride (722 mg, 24.1 mmol), the resulting mixture
was stirred for 15 min. To the slurry was added dropwise
a solution of cis-1,2-di-p-toluenesulfonylethylene (6.30 g,
18.7 mmol) in 100 mL of DMF. Stirring was continued for
1738 cmꢁ1 1H NMR (500 MHz, acetone-d6) d 7.64 (d,
;
J¼8.5 Hz, 2H), 7.48 (d, J¼8.5 Hz, 2H), 7.37–7.24 (m, 10
H), 5.15 (d, J¼11.0 Hz, 1H), 5.11 (d, J¼11.0 Hz, 1H),
5.09 (d, J¼11.0 Hz, 1H), 5.05 (d, J¼11.0 Hz, 1H), 4.80 (d,
ꢀ
13 h, the reaction was cooled to 0 C and then ethyl acetate
(200 mL) and water (200 mL) were added to quench the

P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
5241
reaction. The organic layer was washed with water
(6ꢂ100 mL) and dried (MgSO4). Solvents were removed
in vacuo and the crude solid was purified by dissolution of
impurities in ethyl acetate and filtering the residue to afford
the Tsv-protected imidazolone ester Tsv-21 (>95% puriꢀty,
3.41 g, 56%) as a light yellow solid (mp 239–241 C
(EtOAc/hexanes)). To a solution of Tsv-21 (13.4 g,
2.0 Hz, 1H), 6.77 (d, J¼8.0 Hz, 1H), 6.46 (d, J¼14.0 Hz,
1H), 6.31 (s, 1H), 4.87 (s, 2H), 4.29 (s, 2H), 3.827 (s, 3H),
3.825 (s, 3H), 2.50 (br s, 1H), 2.42 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 152.2, 149.5, 149.0, 144.6, 138.5,
133.9, 130.2, 129.0, 127.5, 127.4, 120.1, 113.2, 111.4,
111.1, 105.4, 56.2, 56.1, 55.3, 45.2, 21.8; HRMS (ESI)
Calcd for C22H25N2O6S [M+H]: 445.1407. Found:
445.1407.
ꢀ
41.4 mmol) in 300 mL of DMF at 25 C was added potas-
sium carbonate (6.30 g, 45.6 mmol) followed by DMBCl
ꢀ
stirring continued for 16 h. On cooling to 25 C the reaction
(8.10 g, 43.5 mmol). The reaction was heated to 60 C and
ꢀ
4.1.39. 3-{3-(3,4-Dimethoxybenzyl)-2-oxo-1-[2-(toluene-
4-sulfonyl)-vinyl]-2,3-dihydro-1H-imidazol-4-yl}-acrylic
acid ethyl ester (41). To a slurry of activated manganese
dioxide (heated with a heat gun under vacuum) (32.4 g,
was diluted with 200 mL of ethyl acetate and washed with
water (6ꢂ100 mL). The organic layer was dried (MgSO4).
Solvents were removed in vacuo to afford the ester 38
(19.6 g, 99%), which was of sufficient purity to be taken
onto the next step without purification. A small sample of
crude 38 was taken and purified by flash chromatography
for analysis on SiO2, eluting with EtOAc/hexanes (2:5)
affording ester 38 as a colorless foam: Rf¼0.31 (EtOAc/
ꢀ
373 mmol) in 60 mL of dichloromethane at 25 C was
added a solution of 40 (13.8 g, 31.0 mmol) in 400 mL of di-
chloromethane. The resulting solution was stirred for 12 h
and filtered through a pad of CeliteÒ. Solvents were removed
in vacuo and the crude aldehydeꢀ(9.90 g, 72%) was isolated
as a yellow solid (mp 150–152 C). A solution of triethyl-
phosphonoacetate (4.78 ꢀmL, 24.1 mmol) in 100 mL of
THF was cooled to 0 C and treated with 80% NaH
1
hexanes, 2:5); IR (neat) 1716 cmꢁ1; H NMR (500 MHz,
CDCl3) d 7.79 (d, J¼14.0 Hz, 1H), 7.77 (d, J¼8.0 Hz,
2H), 7.32 (d, J¼8.0 Hz, 2H), 7.12 (s, 1H), 6.97 (d,
J¼2.0 Hz, 1H), 6.91 (dd, J¼8.5, 2.0 Hz, 1H), 6.85 (d,
J¼14.0 Hz, 1H), 6.76 (d, J¼8.5 Hz, 1H), 5.13 (s, 2H),
3.84 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H), 2.43 (s, 3H); 13C
NMR (125 MHz, CDCl3) d 159.1, 151.3, 148.8, 148.6,
144.5, 137.8, 132.9, 130.0, 129.3, 127.5, 120.8, 117.0,
116.6, 115.8, 111.7, 110.9, 55.9, 55.8, 52.1, 45.4, 21.6;
HRMS (ESI) Calcd for C23H25N2O7S [M+H]: 473.1382.
Found: 473.1410.
ꢀ
(658 mg, 21.9 mmol), after warming to 25 C and stirring
for an additional 40 min. The resulting solution was added
dropwise to a solution of the crude aldehyde (9.70 g,
21.9 mmol) in 300 mL of THF and stirring was continued
for 30 min. The reaction was quenched with 50 mL of pH
4 buffer solution. THF was removed in vacuo and the aque-
ous phase was extracted with EtOAc (3ꢂ300 mL). The or-
ganic layers were combined and dried (MgSO4). Solvents
were removed in vacuo and the crude ester 41 isolated as
a yellow oil (13.2 g). A small amount of the crude ester
was taken and purified by flash chromatography for analysis
on SiO2, eluting with EtOAc/hexanes (2:3) to afford ester 41
as a colorless foam: Rf¼0.41 (EtOAc/hexanes, 2:3); IR
4.1.38. 3-(3,4-Dimethoxybenzyl)-4-hydroxymethyl-1-[2-
(toluene-4-sulfonyl)-vinyl]-1,3-dihydro-imidazol-2-one
(40). To a stirred solution of crude ester 38 (19.6ꢀg,
41.4 mmol) in 400 mL of THF/H2O (v/v; 3:1) at 25 C
was added LiOH (1.14 g, 47.5 mmol) and stirred continu-
ously for 2 h and then the THF was removed in vacuo.
EtOAc (400 mL) was added and the mixture was extracted
(the organic phase was discarded). HCl (1 M, 500 mL) was
added to the aqueous phase and extracted with EtOAc
(3ꢂ500 mL). Organic layers were combined and dried
(MgSO4). Solvents were removed in vacuo to yield the crude
acid as a yellow foam (18.2 g, 96%). The crude acid (18.1 g,
39.5 mmol) was dissolved in 400 mL of THF and 0.5 mL of
1
(film) 1712 cmꢁ1; H NMR (500 MHz, CDCl3) d 7.87 (d,
J¼14.0 Hz, 1H), 7.79 (d, J¼8.5 Hz, 2H), 7.33 (d,
J¼8.5 Hz, 2H), 7.22 (d, J¼16.0 Hz, 1H), 6.80–6.76 (m,
4H), 6.67 (d, J¼14.0 Hz, 1H), 6.14 (d, J¼16.0 Hz, 1H),
4.89 (s, 2H), 4.20 (q, J¼7.0 Hz, 2H), 3.85 (s, 3H), 3.84 (s,
3H), 2.43 (s, 3H), 1.28 (t, J¼7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 166.1, 151.8, 149.6, 149.1, 144.7,
138.7, 133.2, 130.2, 128.8, 128.3, 127.7, 124.3, 119.74,
119.69, 115.3, 111.5, 110.6, 108.5, 61.2, 56.2, 56.1, 45.5,
21.9, 14.4; HRMS (ESI) Calcd for C26H29N2O7S [M+H]:
513.1695. Found: 513.1692.
ꢀ
DMF at 25 C, oxalyl chloride (3.70 mL, 43.4 mmol) was
added dropwise to the solution, and the mixture wasꢀstirred
for 1 h. The reaction mixture was cooled to ꢁ78 C and
LiBH4 in THF (2 M, 59.2 mL, 118 mmol) was added drop-
wise. The reaction mixture was stirred for 2 h, 100 mL of
H2O was added to quench the reaction, and then THF was
removed in vacuo. HCl (1 M, 500 mL) was added to the
aqueous phase and extracted with EtOAc (3ꢂ500 mL). Or-
ganic layers were combined and dried (MgSO4). Solvents
were removed in vacuo and the crude alcohol 40 (17.1 g,
97%) isolated as a yellow solid, which was of sufficient pu-
rity to be taken onto the next step without purification. A
small amount was taken and purified by flash chromatogra-
phy for analysis on SiO2 eluting with EtOAc/hexanes (2:5)
4.1.40. 3-(3,4-Dimethoxybenzyl)-4-(3-hydroxypropenyl)-
1-[2-(toluene-4-sulfonyl)-vinyl]-1,3-dihydro-imidazol-
2-one (16g). To a stirred solution of crude 41 (13.2ꢀg,
25.8 mmol) in 400 mL of THF/H2O (v/v; 3:1) at 25 C
was added LiOH (788 mg, 32.9 mmol) and stirring was con-
tinued for 12 h and then THF was removed in vacuo. EtOAc
(150 mL) was added and the mixture extracted, the organic
phase was discarded. HCl (1 M, 150 mL) was added to the
aqueous phase and extracted with EtOAc (3ꢂ300 mL). Or-
ganic layers were combined and dried (MgSO4). Solvents
were removed in vacuo and the crude acꢀid was isolated
(8.10 g, 76%) as a yellow solid (mp 99–102 C (EtOAc/hex-
anes)). Due to the instability of the diene, a portion of the
acid ꢀ(1.00 g, 2.06 mmol) was dissolved in 100 mL of THF
at 0 C. To the solution was added triethylamine (288 mL,
2.06 mmol), followed by methyl chloroformate (174 mL,
2.06 mmol), and the mixture was stirred for 15 min or until
ꢀ
to afford alcohol 40 as a yellow solid: mp 138–140 C
(EtOAc/hexanes); Rf¼0.14 (EtOAc/hexanes, 4:1); IR (film)
1
3466, 1711 cmꢁ1; H NMR (500 MHz, CDCl3) d 7.80 (d,
J¼14.0 Hz, 1H), 7.75 (d, J¼8.0 Hz, 2H), 7.30 (d,
J¼8.0 Hz, 2H), 6.85 (d, J¼2.0, 1H), 6.81 (dd, J¼8.0,

5242
P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
TLC indicated complete formation of the mixed anhydride.
ꢀ
Pd(OH)2/C (spatula tip). The reaction was placed under an
atmosphere of hydrogen and the reaction stirred for 24 h.
The reaction mixture was filtered through a pad of CeliteÒ
and solvents were removed in vacuo to afford a yellow oil.
Purification by flash chromatography on SiO2, eluting with
EtOAc/hexanes (3:2) afforded Tse-protected Diels–Alder
adduct 43 (52.0 mg, 93%) as a colorless oil. Rf¼0.40
The reaction mixture was cooled to ꢁ78 C and LiBH4 in
THF (2 M, 2.06 mL, 4.13 mmol) was added dropwise. The
reaction mixture was stirred for 15 min, after which 50 mL
of H2O was added to quench the reaction and the solvents
were removed in vacuo. HCl (1 M, 100 mL) was added to
the aqueous phase and extracted with CH2Cl2
(3ꢂ200 mL). The organic layers were combined and dried
(MgSO4) and solvents were removed in vacuo and the crude
alcohol 16g (972 mg, 99%) was isolated as a yellow foam:
(EtOAc/hexanes, 2:5); IR (film) 1738 cmꢁ1 1H NMR
;
(500 MHz, C6D6) d 7.79 (d, J¼8.0 Hz, 2H), 7.73–7.70 (m,
4H), 7.63 (d, J¼8.0 Hz, 2H), 7.25–7.20 (m, 6H), 6.97 (d,
J¼1.5 Hz, 1H), 6.78 (dd, J¼8.0, 1.5 Hz, 1H), 6.72 (d,
J¼8.0 Hz, 2H), 6.66 (d, J¼8.0 Hz, 2H), 6.61 (d, J¼8.0 Hz,
1H), 4.79 (d, J¼15.5 Hz, 1H), 4.39 (m, 2H), 4.24 (app t,
J¼7.5 Hz, 1H), 4.20–4.16 (m, 2H), 4.14–4.07 (m, 2H),
3.99 (d, J¼15.5 Hz, 1H), 3.97–3.91 (m, 2H), 3.82 (br d,
J¼6.0 Hz, 1H), 3.56 (s, 3H), 3.39 (s, 3H), 3.25 (dd, J¼6.0,
2.5 Hz, 1H), 2.95 (m, 1H), 2.23 (m, 1H), 1.98 (m, 1H),
1.86 (m, 1H), 1.84 (s, 3H), 1.22–1.07 (m, 30H); 13C NMR
(125 MHz, C6D6) d 173.1, 153.9, 150.7, 149.7, 144.6,
144.1, 137.9, 136.2, 135.9, 133.94, 133.92, 130.4, 130.1,
130.0, 129.7, 129.5, 127.9, 120.4, 119.6, 114.7, 112.3,
111.7, 65.2, 65.1, 64.6, 55.8, 55.6, 53.3, 53.0, 44.4, 41.9,
37.8, 36.5, 35.0, 27.1, 21.3, 21.1, 20.1, 19.4, 18.30, 18.28,
12.2; HRMS (ESI) Calcd for C61H80N3O10S2Si2 [M+H]:
1134.4824. Found: 1134.4818.
1
Rf¼0.16 (EtOAc); IR (film) 3391, 1721 cmꢁ1; H NMR
(500 MHz, C6D6) d 8.11 (d, J¼14.0 Hz, 1H), 7.82 (d,
J¼8.0 Hz, 2H), 6.80 (d, J¼2.0 Hz, 1H), 6.77–6.73 (m,
4H), 6.48 (d, J¼8.0 Hz, 1H), 6.02 (m, 1H), 5.74 (dt,
J¼16.0, 2.0 Hz, 1H), 5.45 (s, 1H), 4.55 (s, 2H), 3.77 (dd,
J¼4.5, 2.0 Hz, 2H), 3.40 (s, 3H), 3.30 (s, 3H), 1.86 (s,
3H); 13C NMR (125 MHz, C6D6) d 151.7, 150.3, 149.8,
143.3, 140.1, 133.6, 132.7, 129.8, 129.75, 129.71, 125.9,
119.8, 114.9, 113.9, 112.1, 111.8, 102.9, 62.3, 55.5, 55.4,
44.7, 21.0; HRMS (ESI) Calcd for C24H27N2O6S [M+H]:
471.1590. Found: 471.1609.
4.1.41. TBDPS-protected Diels–Alder adduct 42. To a so-
lution of crude ꢀdiene 16g (10.0 mg, 0.02 mmol) in 1 mL of
benzene at 25 C in a sealed tube was added dienophile
15b (9.0 mg, 0.02 mmol), followed by 2,6-lutidine
(1.85 mL, 0.02 mmol). The resulting solution was stirred
4.1.43. Typical procedure for microwave-assisted Diels–
Alder reactions. To a specially designed reaction tube
equipped with a magnetic stirrer was added dienophile
15b (122 mg, 0.29 mmol), Tse-diene 16d (204 mg,
0.43 mmol), and lithium perchlorate (3.0 mg, 0.03 mmol)
sequentially, followed by benzene (2.0 mL) and 2,6-lutidine
(20 mL, 0.17 mmol). The reaction vessel was sealed and
heated under microwave conditions. The temperature was
ꢀ
for 24 h at 95 C. Another portion (10.0 mg, 0.02 mmol)
of diene 16g was added every 24 h until 4.0 equiv had
been added. Solvents were removed in vacuo and the crude
oil was purified by passing through a plug of SiO2, eluting
with EtOAc to afford recovered dienophile 15b (5.0 mg),
and a single Diels–Alder regioisomer as a colorless oil
(w80% purity). A solution of the Diels–Alder adduct in
ꢀ
ꢀ
3 mL of dichloromethane at 25 C was treated with
set to 160 C and the reaction time was 3 h. After 3 h, the re-
TBDPSCl (3.20 mL, 0.01 mmol), followed by triethylamine
(1.7 mL, 0.01 mmol) and DMAP (catalytic). After 24 h at
25 C, solvents were removed in vacuo and the crude oil
action mixture was cooled down and concentrated in vacuo.
Flash chromatography (75% EtOAc/hexanes to 90% EtOAc/
hexanes) afforded isomerized Diels–Alder adduct 34d along
with its regioisomer (224 mg, 87%) as light yellow foam.
The regioisomeric ratio was 2.4:1 in favor of 34d based on
1H NMR integration. Compound 34d can be separated
from its regioisomer by automated MPLC purification.
ꢀ
was purified by flash chromatography on SiO2, eluting
with EtOAc/hexanes (7:3) to afford silyl ether 42
(11.5 mg, 48%) as a clear oil: Rf¼0.73 (EtOAc/hexanes,
2:3); IR (film) 1723 cmꢁ1 1H NMR (500 MHz, C6D6)
;
d 7.93 (d, J¼8.5 Hz, 2H), 7.79 (s, 2H), 7.76–7.73 (m, 4H),
7.65 (d, J¼8.5 Hz, 2H), 7.27–7.24 (m, 6H), 6.88 (d,
J¼2.0 Hz, 1H), 6.85 (d, J¼8.5 Hz, 2H), 6.71 (dd, J¼8.0,
2.0 Hz, 1H), 6.61 (d, J¼8.5 Hz, 2H), 6.55 (d, J¼8.0 Hz,
1H), 4.68 (d, J¼15.0 Hz, 1H), 4.27 (dd, J¼10.5, 3.5 Hz,
1H), 4.23 (dd, J¼7.0, 3.5 Hz, 1H), 4.19 (app d, J¼8.0 Hz,
2H), 3.97 (dd, J¼10.5, 7.0 Hz, 1H), 3.68 (d, J¼15.0 Hz,
1H), 3.43 (s, 3H), 3.36 (s, 3H), 3.29 (dd, J¼6.0, 3.5 Hz,
1H), 3.20 (m, 1H), 2.13 (m, 1H), 1.95 (s, 3H), 1.88 (m,
1H), 1.84 (s, 3H), 1.71 (m, 1H), 1.17–1.13 (m, 30H); 13C
NMR (125 MHz, C6D6) d 172.4, 151.9, 150.5, 150.1,
145.0, 143.6, 140.0, 135.8, 135.4, 133.7, 133.6, 132.4,
130.1, 130.0, 129.5, 129.2, 128.1, 127.5, 127.4, 123.9,
120.3, 116.6, 112.14, 112.09, 112.07, 64.8, 64.5, 62.4,
55.6, 55.5, 44.5, 41.4, 36.7, 34.3, 27.0, 21.3, 21.0, 19.8,
19.3, 18.3, 18.2, 12.0; HRMS (ESI) Calcd for
C61H78N3O10S2Si2 [M+H]: 1132.4667. Found: 1132.4666.
4.1.44. Initial Diels–Alder adduct 32d and TBDPS-pro-
tected adduct 44. To a microwave reaction tube equipped
with a magnetic stirrer was added dienophile 15b (12 mg,
0.028 mmol) and Tse-diene 16d (16 mg, 0.034 mmol), fol-
lowed by anhydrous THF (0.3 mL) and 2,6-lutidine (2 mL,
ꢀ
0.017 mmol). The reaction mixture was heated to 140 C
under microwave for 2 h. Then the reaction mixture was
cooled down and concentrated. Silica gel flash chromatogra-
phy (50% EtOAc/hexanes to 75% EtOAc/hexanes) gave ini-
tial Diels–Alder adduct 32d and its regioisomer 33d (17 mg,
68%) as off-white foam. The regioisomeric ratio was 1.4:1 in
favor of 32d based on NMR integration. Compound 32d
cannot be separated from its regioisomer at this stage.
They have same Rf values (0.34, 60% EtOAc/hexanes).
The mixture was subjected to TBDPS protection. To a solu-
tion of 32d and its regioisomer (33.0 mg, 0.037 mmol) in
CH2Cl2 (0.50 mL) was added Et3N (20 mL, 0.142 mmol)
at room temperature, followed by TBDPSCl (11 mL,
0.041 mmol) and catalytic amount of DMAP. The reaction
mixture was stirred at ambient temperature for 24 h. The
4.1.42. TBDPS-protected Diels–Alder adduct (43). To
a stirred solution of Tsv-protected adduct 42 (56.0 mg,
ꢀ
0.05 mmol) in 3 mL of EtOAc at 25 C was added

P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
5243
solvent was removed in vacuo and purified by flash chroma-
tography on SiO2 (20% / 40% EtOAc/hexanes) afforded
the silyl-protected adduct 44 as a colorless film (25.0 mg,
60%). Rf¼0.74 (60% EtOAc/hexanes); 1H NMR
(500 MHz, C6D6) d 8.02 (d, J¼8.5 Hz, 2H), 7.82 (m, 2H),
7.75 (m, 4H), 7.16–7.29 (m, 6H), 6.98 (d, J¼2.0 Hz, 1H),
6.81 (dd, J¼8.0, 2.0 Hz, 1H), 6.78 (d, J¼8.5 Hz, 2H), 6.75
(d, J¼8.5 Hz, 2H), 6.59 (d, J¼8.0 Hz, 1H), 4.93 (d,
J¼15.0 Hz, 1H), 4.49 (dd, J¼8.5, 10.0 Hz, 1H), 4.39 (t,
J¼3.5 Hz, 1H), 4.36 (m, 1H), 4.05–4.16 (m, 5H), 3.58 (s,
3H), 3.52 (m, 1H), 3.48 (d, J¼15.0 Hz, 1H), 3.38 (m, 1H),
3.32 (s, 3H), 3.22 (dd, J¼3.5, 9.0 Hz, 1H), 2.97–3.04
(m, 2H), 2.31 (m, 1H), 1.86 (s, 3H), 1.85 (s, 3H), 1.17
(s, 9H), 1.12–1.16 (m, 21H); 13C NMR (125 MHz, C6D6)
d 172.9, 158.4, 150.6, 149.7, 144.5, 144.2, 137.17, 137.11,
137.0, 136.0, 135.87, 135.83, 134.1, 134.0, 129.9, 129.88,
129.87, 129.6, 129.14, 128.61, 128.23, 119.7, 112.4,
111.5, 93.22, 66.42, 63.78, 59.23, 55.7, 55.5, 54.0, 52.39,
44.70, 42.36, 39.52, 36.57, 36.32, 27.06, 21.04, 19.4,
18.23, 18.21, 18.2, 12.2; IR (thin film) 2940, 2858, 1726,
1680, 1255, 1117 cmꢁ1; HRMS (ESI) calculated for
10H), 7.10 (m, 2H), 5.15 (d, J¼15.9 Hz, 1H), 4.93 (d,
J¼15.6 Hz, 1H), 4.71 (d, J¼15.9 Hz, 1H), 4.25 (d,
J¼15.6 Hz, 1H), 4.21 (dd, J¼3.6, 6.0 Hz, 1H), 4.02–3.95
(m, 2H), 3.87 (dd, J¼6.9, 9.6 Hz, 1H), 3.75 (dd, J¼7.2,
9.6 Hz, 1H), 3.31–3.24 (m, 2H), 2.44 (s, 3H), 2.06 (dd,
J¼3.9, 15.0 Hz, 1H), 1.89–1.78 (m, 1H), 1.67 (m, 1H),
1.04–1.02 (m, 21H), 0.80 (s, 9H), 0.00 (s, 3H), ꢁ0.04 (s,
3H); 13C NMR (75 MHz, CDCl3) d 173.1, 154.5, 144.8,
137.2, 137.0, 135.3, 129.3, 128.8, 128.7, 127.9, 127.6,
127.5, 127.3, 127.0, 120.6, 114.5, 64.7, 63.6, 63.4, 45.4,
44.6, 41.3, 37.6, 34.8, 25.8, 21.7, 19.6, 17.9, 11.8, ꢁ5.5;
HRMS (FAB) Calcd for C47H68N3O6SSi2 [M+H]:
858.4367. Found: 858.4355.
4.1.47. tert-Butyldimethylsilyl ether 59. Rf¼0.68 (hex-
anes/EtOAc, 6:4); [a]2D5 +25.3ꢀ (c 0.95, CH2Cl2); IR (thin
1
film) 1726 cmꢁ1; H NMR (500 MHz, acetone-d6) d 7.96
(d, J¼8.5 Hz, 2H), 7.62 (d, J¼8.5 Hz, 2H), 7.51 (d,
J¼8.0 Hz, 2H), 7.31 (d, J¼8.0 Hz, 2H), 6.66 (s, 4H), 4.69
(d, J¼15.5 Hz, 1H), 4.38 (m, 3H), 4.03 (d, J¼15.5 Hz,
1H), 3.89 (d, J¼7.5 Hz, 1H), 3.73 (s, 3H), 3.60 (dd, J¼3.0,
7.5 Hz, 1H), 2.51 (s, 3H), 2.46 (s, 3H), 2.03–2.02 (m, 1H),
1.99–1.95 (m, 1H), 1.67 (ddd, J¼3.0, 11.0, 16.0 Hz, 1H),
1.44–1.12 (m, 21H), 0.82 (s, 9H), 0.00 (s, 3H), ꢁ0.01 (s,
3H); 13C NMR (125 MHz, acetone-d6) d 174.1, 159.3,
151.9, 146.1, 145.4, 136.0, 134.5, 130.0, 129.9, 128.54,
128.51, 128.0, 127.2, 126.8, 114.2, 114.1, 66.6, 65.4, 63.7,
54.8, 43.3, 42.9, 38.2, 36.6, 25.6, 21.1, 17.8, 12.1, ꢁ5.8,
ꢁ5.9; HRMS (ESI) Calcd for C48H70N3O9S2Si2 [M+H]:
952.4092. Found: 952.4079.
C61H79N3O10S2Si2Li
1140.4898.
[M+Li]:
1140.4905.
Found:
4.1.45. Mosher ester 36. To a solution of (S)-MTPA
(58.2 mg, 0.25 mmol) and EDCI (68.3 mg, 0.36 mmol) in
500 mL CH2Cl2 was added Diels–Alder adduct 34b
(8.80 mg, 0.01 mmol) in 500 mL CH2Cl2. The reaction mix-
ture was stirred for 18 h, washed with H2O, brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. Purification
by flash chromatography on SiO2 eluting with hexanes/
EtOAc (9:1/7:3) gave 11.0 mg (97%) ester 36 as an off-
white solid: Rf¼0.37 (hexanes/EtOAc, 6:4); [a]2D5 ꢁ27.7ꢀ
ꢀ
4.1.48. Lactol 51. To a cooled (0 C) solution of silylated
Diels–Alder adduct 45 (16.7 mg, 0.02 mmol) in 250 mL
CH2Cl2 was added m-CPBA (4.50 mg, 0.03 mmol). Addi-
tional m-CPBA (5.0 mg, 4.8 mg) was added after 1.5 and
3.5 h, respectively. Following the addition of m-CPBA the
reaction was stirred for 1.5 h and diluted with saturated
NaHCO3 (2.0 mL). The layers were separated and the aque-
ous layer was extracted with CH2Cl2. The combined organic
extracts were washed with NaHCO3 and brine, dried over
Na2SO4, and concentrated in vacuo. Purification by flash
chromatography on SiO2 eluting with hexanes/EtOAc
(9:1/6:4) furnished 13.7 mg (78%) lactol 51 as a light yel-
low solid: Rf¼0.30 (hexanes/EtOAc, 8:2); [a]2D5 ꢁ52.0ꢀ (c
(c 1.26, CH2Cl2); IR (thin film) 1745, 1702, 1658 cmꢁ1
;
1H NMR (300 MHz, acetone-d6) d 7.58 (d, J¼8.7 Hz, 2H),
7.45–7.24 (m, 15H), 7.11 (m, 2H), 5.09 (d, J¼15.9 Hz,
1H), 4.87 (d, J¼15.9 Hz, 1H), 4.81 (d, J¼15.9 Hz, 1H),
4.73 (d, J¼10.5 Hz, 1H), 4.54 (dd, J¼5.4, 10.5 Hz, 1H),
4.34 (d, J¼15.9 Hz, 1H), 4.25 (dd, J¼3.3, 6.0 Hz, 1H),
4.13–4.09 (m, 1H), 3.49 (m, 1H), 3.45 (m, 1H), 3.35 (s,
3H), 2.50 (s, 3H), 2.41 (m, 1H), 2.26–2.14 (m, 1H), 1.78
(m, 1H), 1.07–1.05 (m, 21H); 13C NMR (125 MHz, ace-
tone-d6) d 173.9, 166.7, 155.2, 146.2, 139.0, 138.8, 136.2,
133.0, 130.6, 130.4, 129.5, 129.4, 129.3, 128.4, 128.2,
128.1, 128.0, 127.7, 120.2, 114.9, 68.0, 65.8, 64.7, 55.8,
45.6, 44.7, 43.0, 35.7, 34.4, 21.7, 20.6, 18.32, 18.31, 12.6;
HRMS (ESI) Calcd for C51H61F3N3O8SSi [M+H]:
960.3901. Found: 960.3988.
1
0.34, CH2Cl2); IR (thin film) 3476, 1789, 1724 cmꢁ1; H
NMR (500 MHz, CDCl3) d 7.85 (d, J¼8.0 Hz, 2H), 7.40–
7.25 (m, 12H), 5.69 (dd, J¼2.5, 8.5 Hz, 1H), 4.92 (d,
J¼17.0 Hz, 1H), 4.69 (d, J¼15.0 Hz, 1H), 4.54 (d,
J¼15.0 Hz, 1H), 4.43 (d, J¼2.5 Hz, 1H), 4.35 (dd, J¼9.5,
11.0 Hz, 1H), 4.28 (d, J¼17.0 Hz, 1H), 3.98 (app d,
J¼11.0 Hz, 1H), 3.97 (dd, J¼6.0, 11.0 Hz, 1H), 3.62 (br s,
1H), 3.55 (dd, J¼7.0, 8.5 Hz, 1H), 2.68 (dd, J¼1.5,
11.0 Hz, 1H), 2.51 (d, J¼8.5 Hz, 1H), 2.41 (s, 3H), 1.98–
1.91 (m, 1H), 0.87–0.84 (m, 30H), 0.06 (s, 3H), 0.05 (s,
3H); 13C NMR (75 MHz, CDCl3) d 170.9, 167.8, 156.9,
144.8, 137.8, 135.8, 135.1, 129.3, 129.0, 128.8, 128.7,
128.6, 128.1, 127.9, 127.2, 94.2, 87.7, 65.3, 61.3, 59.6,
42.55, 42.47, 42.1, 41.1, 38.7, 25.8, 21.6, 17.8, 11.6, ꢁ5.5,
ꢁ5.6; HRMS (FAB) Calcd for C47H68N3O9SSi2 [M+H]:
906.4215. Found: 906.4207.
4.1.46. General procedure for the silylation of Diels–
Alder adducts as described for tert-butyldimethylsilyl
ether 45. To a solution of Diels–Alder adduct 34b
(24.8 mg, 0.03 mmol) in 400 mL CH2Cl2 was added
DMAP (catalytic), Et3N (35.0 mL, 0.25 mmol), and TBSCl
(26.3 mg, 0.18 mmol). The reaction was stirred at ambient
temperature for 8 h, diluted with CH2Cl2, and washed with
H2O and brine. The organic layer was dried over MgSO4
and concentrated in vacuo. Purification by flash chromatog-
raphy on SiO2 eluting with hexanes/EtOAc (9:1/7:3) gave
27.5 mg (96%) silylated Diels–Alder adduct 45 as an off-
white foam: Rf¼0.73 (hexanes/EtOAc, 3:7); [a]2D5 +8.7ꢀ (c
1.0, CH2Cl2); IR (thin film) 1695 cmꢁ1
;
1H NMR
4.1.49. Trityldimethylsilyl ether 52. To a cooled (0 C) so-
ꢀ
lution of lactol 51 (303 mg, 0.34 mmol) in 3.0 mL THF was
(300 MHz, CDCl3) d 7.53 (d, 8.4 Hz, 2H), 7.34–7.20 (m,

5244
P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
added a solution of TBAF containing 20 mol % AcOH in
THF (3.5 mL). After 1 h pH 7 buffer was added and the
layers were separated. The aqueous layer was extracted
with Et2O and the combined organic layers were dried
over Na2SO4 and concentrated. Purification by flash chroma-
tography on SiO2 eluting with hexanes/EtOAc (7:3/0:1)
gave 75.4 mg (36%) desilylated triol as a white solid:
Rf¼0.28 (hexanes/EtOAc, 3:7); [a]2D5 ꢁ23.1ꢀ (c 3.67,
11.0 Hz, 1H), 3.20 (dd, J¼4.5, 9.0 Hz, 1H), 3.09–3.03 (m,
1H), 2.89 (d, J¼9.0 Hz, 1H), 2.56 (d, J¼11.0 Hz, 1H),
2.50 (s, 3H), 0.99–0.97 (m, 21H), 0.90 (s, 9H), ꢁ0.05 (s,
6H); 13C NMR (75 MHz, acetone-d6) d 173.9, 158.8,
145.8, 141.1, 139.7, 137.7, 130.6, 129.8, 129.4, 128.8,
128.2, 127.6, 98.2, 86.4, 66.0, 63.8, 62.5, 62.1, 46.5, 45.2,
44.6, 43.8, 38.4, 26.3, 21.7, 18.5, 13.6, ꢁ5.0; HRMS
(FAB) Calcd for C47H67N3O7SSi2Na [M+Na]: 896.4136.
Found: 896.4139.
CH2Cl2); IR (thin film) 3437, 1726 cmꢁ1
;
1H NMR
(300 MHz, CDCl3) d 7.76 (d, J¼8.1 Hz, 2H), 7.45–7.26
(m, 12H), 5.39 (d, J¼1.8 Hz, 1H), 4.91 (d, J¼15.6 Hz,
1H), 4.65 (d, J¼14.7 Hz, 1H), 5.54 (d, J¼14.7 Hz, 1H),
4.20 (d, J¼15.6 Hz, 1H), 3.80 (d, J¼5.1 Hz, 2H), 3.64 (dd,
J¼2.1, 12.0 Hz, 1H), 3.50 (br s, 1H), 3.22–3.12 (m, 2H),
2.70–2.62 (m, 3H), 2.41 (s, 3H), 1.82 (dd, J¼1.2, 12.0 Hz,
1H); 13C NMR (125 MHz, CDCl3) d 175.4, 170.0, 156.7,
145.4, 138.4, 135.3, 134.6, 129.4, 129.1, 128.9, 128.8,
128.7, 128.2, 128.1, 94.1, 87.5, 63.3, 62.2, 60.9, 42.5,
42.3, 39.8, 37.1, 36.0, 21.7; HRMS (ESI) Calcd for
C32H34N3O9S [M+H]: 636.2016. Found: 636.2078.
4.1.51. Allylic alcohol 50b. Rf¼0.55 (hexanes/EtOAc, 6:4);
[a]2D5 ꢁ38.7ꢀ (c 2.08, CH2Cl2); IR (thin film) 3396, 1721,
1680 cmꢁ1 1H NMR (500 MHz, acetone-d6) d 7.78 (d,
;
J¼8.5 Hz, 2H), 7.53 (d, J¼7.5 Hz, 2H), 7.47 (d, J¼8.5 Hz,
2H), 7.41 (app t, J¼7.5 Hz, 2H), 7.35–7.24 (m, 6H), 5.54
(s, 1H), 4.79 (d, J¼16.0 Hz, 1H), 4.74 (d, J¼15.5 Hz, 1H),
4.59 (d, J¼3.5 Hz, 1H), 4.51 (d, J¼15.5 Hz, 1H), 4.00–
3.98 (dd, J¼1.5, 2.5 Hz, 1H), 3.85 (d, J¼16.0 Hz, 1H),
3.82–3.78 (m, 1H), 3.76–3.71 (m, 1H), 3.58 (app t,
J¼6.0 Hz, 1H), 3.55 (dd, J¼2.5, 10.5 Hz, 1H), 3.21 (dd,
J¼4.5, 9.0 Hz, 1H), 3.06–3.02 (ddd, J¼3.5, 7.5, 11.0 Hz,
1H), 2.93 (d, J¼9.0 Hz, 1H), 2.63 (dd, J¼1.5, 10.5 Hz,
1H), 2.49 (s, 3H), 1.01–0.97 (m, 21H); 13C NMR
(125 MHz, acetone-d6) d 174.4, 158.8, 145.8, 141.1, 139.7,
137.8, 137.5, 130.5, 129.7, 129.5, 129.3, 128.8, 128.3,
128.0, 127.9, 98.6, 86.3, 65.9, 63.3, 62.3, 46.2, 45.8, 45.1,
43.9, 38.1, 21.6, 18.4, 18.3, 12.5; HRMS (ESI) Calcd for
C41H53N3O7SSiLi [M+Li]: 766.3534. Found: 766.3632.
To a solution of the desilylated triol obtained above
(10.5 mg, 0.02 mmol) in 220 mL anhydrous DMF was added
Ph3CSiMe2Br (34.0 mg, 0.09 mmol) and AgNO3 (17.5 mg,
0.10 mmol). The reaction was stirred in the dark for 20 h
and filtered through cotton. The filtrate was diluted with
Et2O and washed with H2O and brine, dried over Na2SO4,
and concentrated in vacuo. Purification by flash chromato-
graphy on SiO2 eluting with hexanes/EtOAc (8:2/6:4)
gave monosilylated lactol 52 (9.0 mg, 58%) as an off-white
film, which was recrystallized from hexanes/Et2O/EtOAc:
Rf¼0.65 (hexanes/EtOAc, 6:4); [a]2D5 ꢁ40.0ꢀ (c 1.43,
ꢀ
4.1.52. Allylic alcohol 50c. To a cooled (ꢁ40 C) slurry of
silylated Diels–Alder adduct 59 (83.3 mg, 0.09 mmol) and
MgSO4 was added 0.7 M methyl(trifluoromethyl)dioxirane
(450 mL, 0.32 mmol) via Teflon cannula. Me2S was added
after 5 h and the mixture was filtered through cotton and con-
centrated in vacuo to give 84.6 mg (99%) allylic alcohol 50c
as a light orange residue: Rf¼0.25 (hexanes/EtOAc, 8:2);
[a]2D5 ꢁ12.4ꢀ (c 1.80, CH2Cl2); IR (thin film) 3432, 1731,
ꢀ
CH2Cl2); mp 98.0–100.0 C; IR (thin film) 3426, 1726,
1
1680 cmꢁ1; H NMR (500 MHz, CDCl3) d 7.74 (d, J¼
8.5 Hz, 2H), 7.41–7.16 (m, 25H), 6.99 (m, 2H), 4.94 (d, J¼
2.0 Hz, 1H), 4.86 (d, J¼15.5 Hz, 1H), 4.63 (d, J¼14.5 Hz,
1H), 4.54 (d, J¼14.5 Hz, 1H), 4.12 (d, J¼15.5 Hz, 1H),
3.86 (dd, J¼3.5, 10.0 Hz, 1H), 3.75 (dd, J¼6.5, 10.0 Hz,
1H), 3.63 (dd, J¼2.0, 12.0 Hz, 1H), 3.45 (br s, 1H), 2.95
(d, J¼10.0 Hz, 1H), 2.86 (t, J¼10.0 Hz, 1H), 2.60–2.54
(m, 1H), 2.41 (s, 3H), 1.82 (d, J¼12.0 Hz, 1H), 0.22 (s,
6H); 13C NMR (125 MHz, CDCl3) d 174.1, 169.8, 156.8,
145.4, 145.2, 138.6, 135.4, 134.9, 130.1, 129.3, 129.0,
128.89, 128.86, 128.8, 128.21, 128.19, 128.15, 128.11,
128.0, 125.7, 94.5, 87.6, 63.8, 62.3, 60.3, 54.8, 42.5, 42.2,
39.4, 36.0, 35.6, 29.7, 21.7, 0.3, ꢁ0.7; LRMS (ESI) Calcd
for C53H54N3O9SSi [M+H]: 935. Found [M+HꢁTr]: 692.
1650 cmꢁ1 1H NMR (500 MHz, acetone-d6) d 8.06 (d,
;
J¼8.5 Hz, 2H), 7.83 (d, J¼8.5 Hz, 2H), 7.45 (d, J¼8.5 Hz,
2H), 7.42 (d, J¼8.5 Hz, 2H), 7.03 (d, J¼8.5 Hz, 2H), 6.77
(d, J¼8.5 Hz, 2H), 4.68 (d, J¼8.5 Hz, 1H), 4.56 (br s, 1H),
4.53 (d, J¼16.0 Hz, 1H), 4.33 (br s, 2H), 4.12 (dd, J¼8.0,
9.5 Hz, 1H), 3.77 (d, J¼16.0 Hz, 1H), 3.72 (s, 3H), 3.65
(dd, J¼1.5, 9.0 Hz, 1H), 3.36 (dd, J¼4.5, 9.0 Hz, 1H),
3.00–2.95 (m, 1H), 2.48 (s, 3H), 2.45 (s, 3H), 1.10–1.08
(m, 21H), 0.84 (s, 9H), 0.01 (s, 3H), 0.01 (s, 3H); 13C
NMR (125 MHz, acetone-d6) d 173.6, 160.0, 152.1, 145.8,
145.7, 138.2, 137.4, 137.2, 130.6, 130.02, 129.96, 129.4,
128.6, 128.0, 114.7, 101.3, 89.1, 66.6, 63.5, 63.4, 55.4,
48.0, 44.6, 44.4, 37.9, 26.2, 21.57, 21.51, 18.4, 18.3, 12.7,
ꢁ5.2, ꢁ5.3; LRMS (ESI) Calcd for C48H70N3O10S2Si2
[M+H]: 968. Found: 968.
ꢀ
4.1.50. Allylic alcohol 50a. To a cooled (ꢁ45 C) solution
of silylated Diels–Alder adduct 45 (87.3 mg, 0.10 mmol)
in 1.1 mL CH2Cl2 was added a 0.09 M solution of DMDO
(1.15 mL, 0.103 mmol). After 4 h the reaction was quenched
with Me2S, filtered through cotton, and concentrated
in vacuo to give 88.9 mg (99%) allylic alcohol 50a as an
off-white foam: Rf¼0.75 (hexanes/EtOAc, 6:4); [a]D25
ꢁ115.4ꢀ (c 1.41, CH2Cl2); IR (thin film) 3273, 1731,
4.1.53. Allylic alcohol 50d. Rf¼0.26 (hexanes/EtOAc, 7:3);
[a]2D5 +3.8ꢀ (c 2.12, CH2Cl2); IR (thin film) 3426, 1724,
1690 cmꢁ1 1H NMR (500 MHz, acetone-d6) d 8.10 (d,
;
1680 cmꢁ1
;
1H NMR (500 MHz, acetone-d6) d 7.80 (d,
J¼8.0 Hz, 2H), 7.80 (d, J¼8.0 Hz, 2H), 7.66 (dd, J¼8.0,
1.5 Hz, 2H), 7.65 (dd, J¼8.0, 1.5 Hz, 2H), 7.46–7.38 (m,
10H), 6.71 (d, J¼8.5 Hz, 1H), 6.65 (dd, J¼8.5, 2.0 Hz,
1H), 6.52 (d, J¼2.0 Hz, 1H), 5.61 (s, 1H), 4.71 (d,
J¼4.0 Hz, 1H), 4.58 (app d, J¼1.5, 1H), 4.54 (d,
J¼16.0 Hz, 1H), 4.35 (d, J¼1.5 Hz, 2H), 4.23 (dd, J¼9.5,
8.0 Hz, 1H), 3.80 (dd, J¼9.5, 8.0 Hz, 1H), 3.70 (s, 3H),
J¼8.5 Hz, 2H), 7.54 (d, J¼7.5 Hz, 2H), 7.48 (d, J¼8.0 Hz,
2H), 7.42 (app t, J¼7.5 Hz, 2H), 7.36–7.22 (m, 6H), 5.57
(s, 1H), 4.83 (d, J¼15.5 Hz, 1H), 4.76 (d, J¼15.5 Hz, 1H),
4.50 (d, J¼16.0 Hz, 1H), 4.47 (d, J¼3.3 Hz, 1H), 4.10 (dd,
J¼8.0, 9.5 Hz, 1H), 3.97 (app s, 1H), 3.76 (d, J¼16.0 Hz,
1H), 3.72 (dd, J¼8.0, 9.5 Hz, 1H), 3.53 (dd, J¼2.5,

P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
5245
3.67 (dd, J¼9.0, 1.5 Hz, 1H), 3.61 (d, J¼16.0 Hz, 1H), 3.47
(s, 3H), 3.45 (dd, J¼9.0, 4.0 Hz, 1H), 3.12–3.08 (m, 1H),
2.46 (s, 3H), 2.45 (s, 3H), 1.16–1.02 (m, 21H), 0.91 (s,
9H); 13C NMR (125 MHz, acetone-d6) d 173.6, 152.2,
145.9, 145.7, 138.1, 137.5, 137.3, 136.2, 134.3, 130.6,
130.5, 130.1, 130.0, 128.6, 128.5, 120.7, 112.3, 111.7,
101.2, 89.1, 66.9, 64.5, 63.5, 56.0, 55.5, 48.3, 44.8, 44.3,
37.9, 27.2, 21.6, 21.5, 19.7, 18.42, 18.39, 17.8, 12.7;
HRMS (ESI) Calcd for C59H75N3O11S2SiNa [M+Na]:
1144.4279. Found: 1144. 4290.
65.7, 61.3, 60.6, 59.7, 48.7, 47.7, 46.9, 46.3, 43.4, 41.0,
26.4, 18.4, 18.3, 12.7, ꢁ5.2; HRMS (FAB) Calcd for
C47H66ClN3O7SSi2Na
930.3785. An aromatic side product 66a was also isolated
[M+Na]:
930.3746.
Found:
in this reaction: Rf¼0.35 (hexanes/EtOAc, 8:2); [a]D25
1
ꢁ24.5ꢀ (c 0.44, CH2Cl2); IR (thin film) 1711; H NMR
(300 MHz, acetone-d6) d 7.82 (d, J¼7.8 Hz, 2H), 7.43–
7.31 (m, 12H), 5.63 (d, J¼16.2 Hz, 1H), 5.36 (d,
J¼15.9 Hz, 1H), 5.30 (dd, J¼1.5, 3.0 Hz, 1H), 5.25 (d,
J¼15.9 Hz, 1H), 5.16 (d, J¼16.2, 1H), 5.07 (br s, 2H),
4.30 (dd, J¼3.0, 10.8 Hz, 1H), 4.03 (dd, J¼1.5, 10.8 Hz,
1H), 2.39 (s, 3H), 0.90 (s, 9H), 0.68–0.64 (m, 21H), 0.04
(s, 3H), 0.02 (s, 3H); 13C NMR (125 MHz, acetone-d6)
d 166.8, 156.2, 145.6, 138.1, 138.0, 137.7, 137.2, 135.0,
130.3, 129.9, 129.6, 128.7, 128.6, 128.5, 128.0, 127.4,
126.3, 122.9, 121.0, 107.0, 65.4, 62.4, 61.4, 46.8, 45.6,
26.3, 18.8, 17.9, 17.8, 12.3, ꢁ5.3; HRMS (ESI) Calcd for
C47H64N3O6SSi2 [M+H]: 854.4054. Found: 854.3971.
ꢀ
4.1.54. Lactam 63. To a cooled (ꢁ78 C) solution of sily-
lated Diels–Alder adduct 59 (50.3 mg, 0.53 mmol) in
1 mL THF was added a 0.27 M solution of sodium naphtha-
lenide in THF (1.0 mL, 0.27 mmol). After stirring the result-
ing yellow solution for 3.5 h pH 7 buffer was added and the
mixture was diluted with CH2Cl2. The layers were separated
and the aqueous layer was extracted with CH2Cl2. The com-
bined organic extracts were dried over Na2SO4 and con-
centrated in vacuo. Purification by flash chromatography
on SiO2 eluting with hexanes/EtOAc (8:2/0:10) gave
29.1 mg (86%) detosylated cycloadduct 63 as an off-white
residue: Rf¼0.14 (hexanes/EtOAc, 3:7); [a]2D5 +14.4ꢀ (c
4.1.56. Chlorospirohydantoin 65b. Rf¼0.39 (hexanes/
EtOAc, 7:3); [a]2D5 ꢁ16.8ꢀ (c 2.13, CH2Cl2), IR (thin film)
1
3454, 1716 cmꢁ1; H NMR (500 MHz, acetone-d6) d 8.05
(d, J¼8.5 Hz, 2H), 7.49 (d, J¼8.5 Hz, 2H), 7.43 (d,
J¼7.0 Hz, 2H), 7.38 (d, J¼7.5 Hz, 2H), 7.34–7.26 (m,
6H), 5.23 (d, J¼16.0 Hz, 1H), 4.71 (d, J¼15.0 Hz, 1H),
4.66 (d, J¼15.0 Hz, 1H), 4.63 (br s, 1H), 4.39 (d,
J¼16.0 Hz, 1H), 4.25 (d, J¼12.5 Hz, 1H), 4.02 (dd,
J¼3.5, 11.0 Hz, 1H), 3.84 (dd, J¼2.0, 11.0 Hz, 1H), 3.78–
3.72 (m, 2H), 3.52 (app t, J¼9.0 Hz, 1H), 3.36 (d,
J¼9.0 Hz, 1H), 3.30 (m, 1H), 3.08 (m, 1H), 2.46 (s, 3H),
0.98–0.90 (m, 21H); 13C NMR (125 MHz, acetone-d6)
d 174.0, 173.6, 157.8, 146.8, 138.2, 137.1, 136.4, 130.7,
129.4, 129.3, 129.2, 129.0, 128.7, 128.6, 128.4, 76.6, 65.2,
61.6, 60.0, 58.6, 48.2, 47.5, 46.8, 46.2, 43.2, 21.5, 18.2,
18.1, 12.5; HRMS (ESI) Calcd for C41H53ClN3O7SSi
[M+H]: 794.3062. Found: 794.2923.
1.55, CH2Cl2); IR (thin film) 1685 cmꢁ1
;
1H NMR
(500 MHz, acetone-d6) d 10.00 (br s, 1H), 7.23 (d,
J¼8.5 Hz, 2H), 6.86 (d, J¼8.5 Hz, 2H), 6.76 (br s, 1H),
4.74 (d, J¼15.5 Hz, 1H), 4.66 (d, J¼15.5 Hz, 1H), 4.08 (d,
J¼6.5 Hz, 2H), 3.88 (d, J¼5.0 Hz, 2H), 3.76 (s, 3H), 3.63
(m, 1H), 3.34 (d, J¼7.0 Hz, 1H), 3.16 (dd, J¼2.5, 7.0 Hz,
1H), 2.46 (d, J¼11.5 Hz, 1H), 2.08–2.01 (m, 2H), 1.08–
1.07 (m, 21H), 0.89 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H); 13C
NMR (acetone-d6) d 176.9, 159.9, 155.6, 131.4, 129.5,
119.8, 115.7, 114.7, 66.7, 65.2, 59.2, 55.4, 43.8, 40.7,
38.8, 37.0, 26.3, 21.1, 18.3, 12.6, ꢁ5.2; LRMS (ESI) Calcd
for C34H58N3O5Si2 [M+H]: 644. Found: 644.
ꢀ
4.1.55. Chlorospirohydantoin 65a. To a cooled (ꢁ45 C)
solution of allylic alcohol 50a (19.0 mg, 0.02 mmol)
in 200 mL CH2Cl2 was added cyclohexene (11.0 mL,
4.1.57. Chlorocyclopentane 71 and deschlorocyclopen-
tane 73. A solution of 69 (320 mg, 0.33 mmol) and magne-
sium sulꢀfate (30 mg) in 10 mL dichloromethane was cooled
to ꢁ60 C and treated with dimethyldioxirane (0.09 M in
acetone, 3.99 mL, 0.36 mmol) over 2 h. Stirring continued
for a further 2 h, after which the reaction was quenched
with 100 mL of methyl sulfide. Solvents were removed
in vacuo to afford crude allylic alcohol 40 (320 mg, 99%)
as a colorless foam. A solution of crude allylic alcohol
(150 mg, ꢀ0.15 mmol) in 10 mL dichloromethane was cooled
to ꢁ50 C and treated with cyclohexene (76.0 mL,
0.75 mmol) and sodium hydrogen carbonate (25.3 mg,
0.30 mmol) followed by NCS (50.0 mg, 0.38ꢀmmol). The re-
action mixture was allowed to warm to 25 C, and further
stirred for a total of 26 h. The reaction was quenched with
2 mL of pH 7 buffer. The aqueous layer was extracted
with CH2Cl2 (3ꢂ5 mL). The combined organic layers
were dried (MgSO4). Solvents were removed in vacuo and
the crude oil was purified by flash chromatography (SiO2,
EtOAc/hexane, 4:6) to afford a mixture of the chlorospiro-
cyclic pentane 71 and the aromatic compound 72
(52.0 mg, 50%). These were further purified to obtain ana-
lytically pure samples. Chlorocyclopentane 71: Rf¼0.47
ꢀ
0.11 mmol). A cooled (ꢁ45 C) solution of N-chlorosucci-
nimide (9.60 mg, 0.07 mmol) in 100 mL CH2Cl2 was added
and the resulting reaction mixture was stirred at ambient
temperature overnight. Water was added and the layers
were separated. The aqueous layer was extracted with
CH2Cl2 and the combined organic layers were dried over an-
hydrous MgSO4 and concentrated in vacuo. The crude resi-
due was purified by flash chromatography on SiO2 eluting
with hexanes/EtOAc (9:1/8:2) and gave 14.7 mg (75%)
spirohydantoin 65a as a white foam: Rf¼0.47 (hexanes/
EtOAc, 8:2); [a]D25 ꢁ8.4ꢀ (c 0.75, CH2Cl2), IR (thin film)
1
1782, 1745, 1716 cmꢁ1; H NMR (500 MHz, acetone-d6)
d 8.08 (d, J¼8.5 Hz, 2H), 7.49 (d, J¼8.5 Hz, 2H), 7.43 (d,
J¼8.0 Hz, 2H), 7.38 (d, J¼8.5 Hz, 2H), 7.34–7.30 (m,
6H), 5.32 (d, J¼16.0 Hz, 1H), 4.70 (d, J¼15.0 Hz, 1H),
4.65 (d, J¼15.0 Hz, 1H), 4.63 (m, 1H), 4.37 (d,
J¼16.0 Hz, 1H), 4.10 (d, J¼12.5 Hz, 1H), 4.09 (dd,
J¼3.5, 10.5 Hz, 1H), 4.05 (dd, J¼8.5, 10.0 Hz, 1H), 3.92
(dd, J¼1.5, 10.5 Hz, 1H), 3.79 (dd, J¼4.0, 10.0 Hz, 1H),
3.48 (t, J¼8.5 Hz, 1H), 3.29 (d, J¼8.5 Hz, 1H), 3.15–
3.07 (m, 1H), 2.44 (s, 3H), 0.98–0.83 (m, 30H), 0.07
(s, 3H), 0.07 (s, 3H); 13C NMR (75 MHz, acetone-d6)
d 173.8, 171.9, 157.8, 146.8, 138.4, 137.3, 136.9, 130.8,
129.5, 129.44, 129.39, 129.2, 128.8, 128.7, 128.6, 76.8,
1
(EtOAc/hexane, 2:3); H NMR (500 MHz, C6D6) d 8.19
(d, J¼8.5 Hz, 2H), 7.87 (d, J¼8.5 Hz, 2H), 7.47 (d, J¼2.0,
1H), 7.39 (dd, J¼8.5, 2.0 Hz, 1H), 6.86 (d, J¼8.5 Hz, 2H),

5246
P. J. Dransfield et al. / Tetrahedron 62 (2006) 5223–5247
6.74 (d, J¼8.5, 2H), 6.53 (d, J¼8.5 Hz, 1H), 5.83 (d,
J¼15.5, 1H), 4.88 (s, 1H), 4.79 (dd, J¼11.0, 9.5 Hz, 1H),
4.71 (d, J¼15.5 Hz, 1H), 4.58 (d, J¼12.0 Hz, 1H), 4.55
(dd, J¼11.0, 4.0 Hz, 1H), 4.20 (dd, J¼11.0, 2.5 Hz, 1H),
4.08 (dd, J¼11.0, 1.3 Hz, 1H), 3.75 (m, 3H), 3.66 (s, 3H),
3.55 (ddd, J¼15.0, 9.0, 3.0 Hz, 1H), 3.38 (ddd, J¼16.0,
7.0, 3.0 Hz, 1H), 3.33 (s, 3H), 3.22 (ddd, J¼15.0, 9.0,
3.0 Hz, 1H), 2.91 (ddd, J¼16.0, 7.0, 2.5 Hz, 1H), 1.87 (s,
3H), 1.82 (s, 3H), 1.19 (s, 9H), 0.96–0.88 (m, 21H); 13C
NMR (125 MHz, C6D6) d 177.1, 173.2, 171.4, 156.8,
150.5, 150.1, 145.1, 144.8, 136.3, 135.8, 129.9, 129.7,
129.1, 127.6, 127.4, 127.2, 121.5, 113.2, 112.3, 76.6, 65.5,
61.3, 60.3, 55.8, 55.4, 50.5, 48.3, 47.5, 46.1, 45.4, 38.8,
33.4, 27.3, 21.2, 21.1, 18.2, 12.2; HRMS (ESI) Calcd for
C50H68N3O12S2SiClLi [M+Li]: 1036.3862. Found:
1036.3912. Further elution gave the deschloro spirocyclic
pentane 73: Rf¼0.38 (EtOAc/hexane, 2:3); IR (thin film)
4.55 (t, J¼10.0 Hz, 1H), 4.50 (d, J¼12.5 Hz, 1H), 4.23
(dd, J¼10.0, 2.0 Hz, 1H), 4.11 (m, 2H), 3.96 (t, J¼8.0 Hz,
1H), 3.80 (d, J¼8.0 Hz, 1H), 3.79–3.73 (m, 1H), 3.62 (s,
3H), 3.58–3.53 (ddd, J¼15.0, 9.0, 3.0 Hz, 1H), 3.39–3.34
(ddd, J¼15.5, 7.0, 3.0 Hz, 1H), 3.27 (s, 3H) 3.26–3.21
(ddd, J¼15.0, 9.0, 3.0 Hz, 1H), 2.95–2.90 (ddd, J¼15.5,
7.0, 3.0 Hz, 1H), 1.87 (s, 3H), 1.84 (s, 3H), 1.20 (s, 9H),
0.98–0.90 (m, 21H); 13C NMR (125 MHz, C6D6) d 173.3,
171.8, 156.8, 150.3, 149.9, 145.0, 144.8, 136.5, 136.3,
136.0, 135.9, 133.9, 133.7, 129.91, 129.88, 129.8, 129.6,
129.14, 129.12, 128.0, 121.5, 113.1, 112.2, 76.8, 65.5,
61.2, 60.6, 60.0, 55.8, 55.3, 50.6, 49.1, 48.6, 47.2, 46.0,
33.4, 27.1, 21.2, 21.1, 19.5, 18.18, 18.15, 18.11, 12.2;
HRMS (ESI) Calcd for C61H78N3O11S2Si2ClLi [M+Li]:
1190.4465. Found: 1190.4366.
1713 cmꢁ1
;
1H NMR (500 MHz, C6D6) d 8.22 (d,
Acknowledgments
J¼8.5 Hz, 2H), 7.88 (d, J¼8.5 Hz, 2H), 7.27 (d, J¼2.0 Hz,
1H), 7.15 (dd, J¼8.5, 2.0 Hz, 1H), 6.86 (d, J¼8.5 Hz, 2H),
6.76 (d, J¼8.5, 2H), 6.53 (d, J¼8.5 Hz, 1H), 5.83 (d,
J¼16.0, 1H), 4.87 (s, 1H), 4.69 (d, J¼16.0 Hz, 1H), 4.66
(dd, J¼11.0, 8.5 Hz, 1H), 4.28 (dd, J¼11.0, 6.5 Hz, 1H),
4.18 (dd, J¼11.0, 2.5 Hz, 1H), 4.09 (dd, J¼11.0, 2.5 Hz,
1H), 3.62 (m, 3H), 3.60–3.50 (m, 3H), 3.43–3.37 (m, 5H),
3.36 (s, 3H), 3.27 (ddd, J¼15.0, 8.5, 3.0 Hz, 1H), 3.04
(ddd, J¼15.0, 7.0, 3.0 Hz, 1H), 2.12 (app t, J¼13.5 Hz,
1H), 1.87 (m, 2H), 1.86 (s, 3H), 1.82 (s, 3H), 1.13 (s, 9H),
0.97–0.90 (m, 21H); 13C NMR (125 MHz, C6D6) d 177.2,
177.0, 172.5, 156.4, 150.5, 149.8, 144.9, 144.8, 136.4,
135.9, 130.7, 129.9, 129.6, 129.2, 128.3, 128.1, 127.9,
120.4, 112.5, 112.4, 71.9, 65.5, 63.3, 61.6, 55.8, 55.5,
50.9, 50.3, 49.6, 45.8, 40.4, 38.7, 35.7, 33.1, 27.2, 21.14,
21.08, 18.2, 18.1 12.2; MS (ESI) 1002 [M+Li]. HRMS
(ESI) Calcd for C50H69N3O12S2SiLi [M+Li]: 1002.4252.
Found: 1002.4262.
We thank the NIH (NIGMS 52964), the Welch Foundation
(A-1280), Pfizer, and Eisai for support of these investiga-
tions. The NSF (CHE-0077917) provided funds for purchase
of NMR instrumentation.
References and notes
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ꢀ
dichloromethane was cooled to ꢁ50 C and treated with di-
methyldioxirane (w0.06 M in acetone, 8.1 mL, 0.48 mmol).
After 3 h, the reaction was quenched with 100 mL of methyl
Ò
ꢀ
sulfide at ꢁ50 C, filtered through a pad of Celite and con-
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1718 cmꢁ1
;
1H NMR (500 MHz, C6D6) d 8.26 (d, J¼
8.5 Hz, 2H), 7.96–7.94 (m, 2H), 7.88 (d, J¼8.5 Hz, 2H),
7.81–7.79 (m, 2H), 7.46 (d, J¼2.0 Hz, 1H), 7.39 (dd,
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(d, J¼16.0 Hz, 1H), 4.90 (s, 1H), 4.74 (d, J¼16.0 Hz, 1H),

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