Welwitindolinone C synthetic studies. Construction of the welwitindolinone carbon skeleton via a transannular nitrone cycloaddition

Article abstract of DOI:10.1016/j.tet.2010.04.131

Described is the construction of the N-methylwelwitindolinone C core via an efficient strategy that employs a sequential rhodium carbenoid-mediated O-H insertion, Claisen rearrangement and transannular [3+2] nitrone cycloaddition.

Full text of DOI:10.1016/j.tet.2010.04.131

Tetrahedron 66 (2010) 6647e6655
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Welwitindolinone C synthetic studies. Construction of the welwitindolinone
carbon skeleton via a transannular nitrone cycloaddition
David B. Freeman, Alexandra A. Holubec, Matthew W. Weiss, Julie A. Dixon, Akio Kakefuda,
Masami Ohtsuka, Munenori Inoue, Rishi G. Vaswani, Hidenori Ohki, Brian D. Doan,
Sarah E. Reisman, Brian M. Stoltz, Joshua J. Day, Ran N. Tao, Noah A. Dieterich, John L. Wood
*
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 March 2010
Received in revised form 21 April 2010
Accepted 29 April 2010
Available online 6 May 2010
Described is the construction of the N-methylwelwitindolinone C core via an efficient strategy that
employs a sequential rhodium carbenoid-mediated OeH insertion, Claisen rearrangement and trans-
annular [3þ2] nitrone cycloaddition.
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Professor Steven Ley, a friend
and inspirational leader in organic
chemistry
Keywords:
Welwitindolinone
[3þ2] Dipolar cycloaddition
Rhodium carbenoid
OeH insertion
Chloronium-ion semi-pinacol
1. Introduction
preparation of intermediate isoxazolidine 7 via a nitrone-mediated
transannular [3þ2] dipolar cycloaddition of olefin 6.22,23e26 Taking
Since their isolation in 1994 from the cyanobacteria Hapalosi-
phon welwitschii and Westiella intricata, the welwitindolinone al-
kaloids have received significant attention from the synthetic
community.1e18 Of biological relevance, it was found that
N-methylwelwitindolinone C isothiocyanate (1) was responsible
for the P-glycoprotein-mediated MDR-reversing and larvacidal ac-
tivities associated with the algae extracts.19,20 Intrigued by its
structural complexity and promising biological activity, we initi-
ated a program for the total synthesis of 1. Our initial attempt (Path
A, Scheme 1), reported in 1999, highlighted the utility of Mont-
morillonite K-10 clay in a rhodium-catalyzed CeH aryl insertion
maximum advantage of our prior efforts, olefin 6 was seen as
arising from the previously prepared diazoketone 4 by employing
a two-step sequence involving rhodium-catalyzed OeH insertion/
ring-opening to deliver enol ether
5 followed by Claisen
rearrangement.4,27,28
2. Results and discussions
As previously reported,4 diazoketone 4 was efficiently accessed
from isatin (8) as outlined in Scheme 2. In the event 8 was con-
verted to carboxylic acid 11 by a three-step sequence involving
Wittig olefination (8/9), phosphonium ylide-induced cyclo-
propanation/N-alkylation (9/10), and hydrolysis of the resultant
ethyl ester (10/11). Subsequent acid chloride formation and
treatment with trimethylsilyl diazomethane provided the desired
reaction that provided access to key a-diazoketone 4. Subsequent
OeH insertion chemistry produced enol ether 3, which was further
elaborated to the welwitindolinone core (2) in four steps. Un-
fortunately, numerous attempts to install the bridgehead nitrogen
failed21 thus an alternate strategy was devised. Herein we report
the details of this approach (Path B, Scheme. 1), which calls for the
a-diazoketone 12. After an extensive catalyst screen, it was found
that Rh2(TFA)4 in the presence of Montmorillonite K-10 clay opti-
mally promoted the aryl CeH insertion reaction to provide tetra-
cycle 13. Benzylic oxidation of ketone 13 and regioselective
diazotization afforded diazoketone 4.
* Corresponding author. Tel.: þ1 970 491 5703; fax: þ1 970 491 1801; e-mail
address: john.l.wood@colostate.edu (J.L. Wood).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.131

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D.B. Freeman et al. / Tetrahedron 66 (2010) 6647e6655
N2
O
O
OH
O
O
O
H
Rh2(OAc)4
CH2Cl2
H
H
H
O
O
O
N
N
N
3
4
14
O
O
1. H(OH)NMe•HCl
pyr., MeOH, 65 °C
N
O
xylenes, 145 °C
O
H
H
(65% yield, 2 steps)
2. imidazole•HCl
EtOH, 80 °C
(81% yield)
O
O
N
N
15
16
Scheme 3.
which were explored and found to either resist cycloaddition or give
large amounts of oxazole side-products via dehydration of the in-
termediate nitrone (i.e., 18).29,30 Eventually a more satisfactory so-
lution that allowed advancement of the N-methylhydroxylamine
adducts was implemented (vide infra).23e26,31
Scheme 1. Retrosynthetic analysis.
Scheme 4.
Turning to the issue of ring size, we targeted intermediate 21,
a compound that was both accessible via the developed OeH
insertion/ring-opening/Claisen rearrangement cascade and poised
for an olefin transposition that would set the stage for cycloaddition
to the requisite six-membered ring of 1 (Scheme 5). Implementa-
tion of this plan began with the combination of diazoketone 4 and
alcohol 19 in the presence of Rh2(OAc)4.32 The derived enol ether 20
Scheme 2.
With ready access to a-diazoketone (4) and taking inspiration
from early reports by Funk et al.,22 we turned toward the trans-
annular nitrone cycloaddition (Scheme 3). In initial studies we tar-
geted model substrate 15 and thus began with the Rh(II)-promoted
coupling of 4 with allyl alcohol. In the event, sequential OeH in-
sertion/cyclopropane ring-opening furnished known enol ether 3
via the intermediacy of 14.4 Subsequent Claisen rearrangement
under thermal conditions provided the desired diketone (15) as an
initial 1:1 mixture of diastereomers that underwent equilibration to
the illustrated single diastereomer upon silica gel chromatography.
Having installed the pendent olefin, we were poised for the pro-
posed cycloaddition and were delighted to find that exposure of 15 to
N-methylhydroxylamine and pyridine in methanol at reflux regio-
selectively furnishes a nitrone (observed but not isolated), which in
turn, undergoes [3þ2] cyloaddition to produce 16 in 81% yield. Al-
though this single-step procedure established the viability of the
transannular cycloaddition for installing the requisite bridgehead
nitrogen, issues of ring size, cleavage of the NeO bond, and nitrogen
deprotection remained. Regarding the latter, the use of N-benzylhy-
droxylamine (Scheme 4) is representative of several variations,
Scheme 5.
was subjected to thermally-induced Claisen rearrangement con-
ditions to provide acetate 21, which was isolated as a single isomer
after purification.33 Palladium-catalyzed allylic transposition of 21
to the contra-thermodynamic terminal alkene 22 was followed by
the key [3þ2] dipolar cycloaddition.34,35 To our delight, exposure of
diketone 22 to N-methylhydroxylamine in EtOH at reflux gave
isoxazolidine 23 as a complex mixture of diastereomers; thus,
completing assembly of the welwitindolinone core.36

D.B. Freeman et al. / Tetrahedron 66 (2010) 6647e6655
6649
Although success in accessing 23 further established the OeH
insertion/Claisen rearrangement sequence as quite general and il-
lustrated the feasibility of accessing both the bridgehead nitrogen
and six-membered ring, inefficiencies associated with the olefin
transposition led us to briefly explore alternatives. To this end, it
was envisioned that replacing 19 with alcohol 24 would allow us to
avoid the olefin transposition and provide a more functionalized
isoxazolidine (Scheme 6).37e39 As illustrated, exposure of diazo-
ketone 4 to alcohol 24 in the presence of Rh2(OAc)4 produced enol
ether 25, which was converted to diketone 26 upon heating.
However, subsequent treatment of diketone 26 to our established
cycloaddition conditions failed to provide desired cycloadduct 27.
Instead, cyclization of the intermediate nitrone (not shown) onto
the 1,1-disubstituted olefin converted diketone 26 exclusively to
adduct 28, the structure of which was confirmed by X-ray crystal-
lography.40 Attempts to modify the chemoselectivity of the cyclo-
addition by removal of the trimethylsilyl group or by olefin
functionalization were unsuccessful.
Scheme 7.
pioneered by Noyori et al.48 and modified more recently by Radinov
et al.49 Under the latter conditions, opening of vinyl epoxide 32 in
the presence of a fluorinated alcohol proceeded to furnish hemi-
acetals 33a and 33b as an inseparable mixture of diastereomers.
Although the intermediacy of the hemiacetals was expected, the
effect of the altered electronics on the subsequent cycloaddition
was uncertain (cf., 26 and 33). Unfortunately, exposure of 33
33 to N-methylhydroxylamine under forcing conditions did not
produce any of the desired cycloadduct 34.
a and
b
In addition to our efforts with the more advanced cycloaddition
substrates illustrated in Schemes 6 and 7, we had continued ex-
ploring cycloadduct 23 as a potential intermediate (Scheme 8). In
these more fruitful studies, recent results from our synthetic ap-
proach to welwitindolinone A (35) were most influential and we
targeted allylic alcohol 38 as an eventual substrate for a chloro-
nium-ion induced semi-pinacol rearrangement that was envi-
sioned as giving rise to the desired quaternary center and requisite
neopentyl chlorine.11,13,50
Scheme 6.
Although the selectivity observed in the cycloaddition of 26 was
disappointing we were encouraged by our ability to stereo-
selectively forge the fully-substituted quaternary carbon adjacent
to the bridgehead nitrogen and thus began pursuing an alternative
wherein the requisite [4.3.1] bicyclic backbone and C12 quaternary
center would be produced in a single step (Scheme 7). The designed
cyclization substrate in this scenario (33) was prepared in a se-
quence that began with cross metathesis of diketone 15 and silyl
ether 29 followed by silyl deprotection.41,42 The derived alcohol
(30) was isolated as an inconsequential mixture of E/Z di-
astereomers (2:1, respectively). Selenenylation of 30 via the
method of Grieco [o-(NO2)C6H4eSeCN and P(n-Bu)3] furnished
selenide 31, which43e45 upon oxidation with DMDO provided the
corresponding epoxy selenoxide. As expected the latter was un-
stable and upon work-up underwent clean elimination to deliver
vinyl epoxide 32 in good yield.46,47
Scheme 8.
Having accessed 32, attention was turned to opening the ep-
oxide and delivering the cycloaddition substrate (33). After con-
siderable fruitless experimentation with several Lewis acids we
eventually explored a palladium-catalyzed isomerization approach
As illustrated in Scheme 9, isoxazolidine 23 was advanced by
first rearranging to the corresponding aminal (39).26,51 Subsequent
treatment of 39 with hydroxylamine hydrochloride produced

6650
D.B. Freeman et al. / Tetrahedron 66 (2010) 6647e6655
amino-alcohol 40 in 95% yield. To set the stage for eventual in-
troduction of the bridgehead isonitrile, 40 was bis-fomylated.52,53
Selective deformylation of the derived formate produced alcohol
41, which in a three-step process involving oxidation with Dess/
Martin periodinane (DMP),54 base-induced elimination to the enal,
and addition of methyl magnesium bromide, was converted to
secondary alcohol 42 as an inconsequential mixture of di-
astereomers. In practice, the instability to silica gel of the
intermediates produced in this three-step sequence required that it
be performed without purification. Finally, oxidation of alcohol 42
to enone 43, followed by addition of methyl magnesium bromide,
provided desired tertiary allylic alcohol 38, albeit in low yield
(Scheme 10).
chlorination. Given our success in applying this type of semi-
pinacol in the welwitindolinone A synthesis (Scheme 8) we were
both surprised and dissappointed.11,13 In recent efforts to overcome
this problem, preliminary studies wherein the stoichiometry of the
oxidant is limited have revealed that in substrate 38 the aromatic
system reacts first. Thus, as is often the case with synthetic en-
deavors, the absence of a simple solution has inspired further ef-
forts and the completion of 1 continues to challenge our resolve
(Scheme 11).
Scheme 11.
3. Conclusion
In summary, we have developed a novel approach toward the
synthesis of N-methylwelwitindolinone C isothiocyanate (1) that
employs a sequential OeH insertion/Claisen rearrangement fol-
lowed by a transannular [3þ2] nitrone cycloaddition to efficiently
deliver a heavily functionalized carbocyclic welwitindolinone core
(23). Further advancement of 23 via a chloronium-ion induced
semi-pinacol rearrangement allows installation of the requisite
quaternary center; however, over functionalization in this process
has to-date thwarted efforts to complete the synthesis. The
exploration of alternative strategies for accessing 1 as well as
optimization studies on reactions leading to 23 is currently
underway.
Scheme 9.
4. Experimental
4.1. General
Unless otherwise stated, reactions were magnetically stirred in
flame-dried glassware under an atmosphere of nitrogen. Triethyl-
amine (Et3N) and methanol were dried over calcium hydride.
Benzene, tetrahydrofuran, dichloromethane, toluene, and diethyl
ether were dried using a solvent purification system manufactured
by SG Water U.S.A., LLC. All other commercially available reagents
were used as received.
Unless otherwise stated, all reactions were monitored by thin-
layer chromatography (TLC) using Silicycle glass-backed extra hard
ꢀ
layer, 60 A plates (indicator F-254, 250
m
m). Column or flash
chromatography was performed with the indicated solvents using
Silicycle SiliaFlashÒ P60 (230e400 mesh) silica gel as the stationary
phase. Chromatography was conducted in accordance with the
guidelines reported by Still et al.55 All melting points were obtained
on a Gallenkamp capillary melting point apparatus and are
uncorrected.
Scheme 10.
Infrared spectra were obtained using a Midac M1200 FTIR or
a Nicolet Avatar 320 FTIR. 1H and 13C NMR spectra were recorded on
a Bruker AM-500, Bruker Avance DPX-500, Bruker Avance DPX-
Despite its poor overall yield, the unoptimized synthetic
sequence leading to 38 provided sufficient material to explore the
proposed halonium ion induced semi-pinacol rearrangement. In
the event, exposure of 38 to CeCl3$7H2O and NaOCl was found to
produce 44. Extensive NMR analysis indicated that chloronium-ion
activation resulting in rearrangement had occurred from what
appeared to be the desired and sterically more demanding face.
However this transformation was accompanied by over-
400, or Varian Inova 400 spectrometer. Chemical shifts (d) are
reported in parts per million (ppm) relative to internal residual
solvent peaks from indicated deuterated solvents. High-resolution
mass spectra were performed at the University of Illinois Mass
Spectrometry Center or by Donald L. Dick of Colorado State Uni-
versity. Single-crystal X-ray analyses were performed by Susan
DeGala of Yale University.

D.B. Freeman et al. / Tetrahedron 66 (2010) 6647e6655
6651
4.1.1. Diketone 15. To
2.36 mmol, 1.0 equiv) and allyl alcohol (161
a
solution of diazoketone
4
(630 mg,
15.6 Hz, 1H), 3.21 (s, 3H), 2.66 (dd, J¼10.0, 14.4 Hz, 1H), 2.45 (d,
J¼8.5 Hz, 1H), 2.03 (ddd, J¼8.6, 8.6, 14.4 Hz, 1H), 1.62 (s, 3H),
mL, 2.36 mmol,
1.0 equiv) in CH2Cl2 (24 mL) was added Rh2(OAc)4 (10.4 mg,
0.024 mmol, 0.01 equiv). Gas evolution was observed and the
reaction turned dark brown. After stirring at room temperature
for 20 min, the mixture was concentrated to afford a dark brown
oil, which was subsequently dissolved in xylenes (35 mL) and
heated at reflux for 1 h. After cooling to room temperature, the
reaction was concentrated and purified by silica gel column
chromatography (30% hexane/EtOAc) to afford diketone 15 as
yellow crystals (596 mg, 85% yield). Mp 196e197 ꢀC; FTIR (thin
film/NaCl) 3079, 2895, 1706, 1597, 1467, 1408, 1368, 1337, 1295,
0.82 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 213.4, 175.1, 144.6,
139.4, 135.0, 129.1, 128.4, 127.5, 126.9, 123.7, 117.4, 106.9, 76.6,
73.6, 65.1, 55.3, 51.9, 51.7, 42.2, 28.9, 26.3, 25.1, 21.5; HRMS (FAB)
m/z 403.2022 [calcd for C25H27N2O3 (Mþ1) 403.2022].Compound
18: mp 156e157 ꢀC; FTIR (thin film/NaCl) 2930, 1707, 1618, 1600,
1464, 1372, 1337, 1299, 1083, 915, 784 cmꢁ1
CDCl3)
;
1H NMR (500 MHz,
8.09 (m, J¼1.7, 8.0 Hz, 2H), 7.91 (d, J¼7.5 Hz, 1H),
d
7.51e7.47 (m, 3H), 7.41 (t, J¼7.9 Hz, 1H), 6.78 (d, J¼7.5 Hz, 1H),
5.91 (dddd, J¼6.3, 8.4, 10.3, 16.8 Hz, 1H), 5.10e5.03 (m, 2H), 3.74
(s, 1H), 3.25 (s, 3H), 3.00 (dd, J¼4.2, 7.4 Hz, 1H), 2.90 (m, 1H),
2.49 (ddd, J¼7.4, 7.6, 14.7 Hz, 1H), 1.68 (s, 3H), 0.77 (s, 3H); 13C
1269, 1187, 1161, 1140, 1019 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d
7.68 (d, J¼7.6 Hz, 1H), 7.50 (t, J¼8.0 Hz, 1H), 7.12 (d, J¼7.6 Hz,
NMR (125 MHz, CDCl3) d 175.2, 160.0, 150.6, 143.8, 136.3, 133.5,
1H), 5.59 (dddd, J¼6.7, 6.7, 10.3, 17.0 Hz, 1H), 5.02e4.98 (m, 2H),
3.36 (s, 1H), 3.25 (s, 3H), 2.93 (dd, J¼2.4, 11.6 Hz, 1H), 2.74 (ddd,
J¼6.9, 12.2, 13.2 Hz, 1H), 2.18 (ddd, J¼1.0, 6.4, 14.0 Hz, 1H), 1.50
130.2, 128.8, 128.2, 128.1, 127.5, 126.3, 122.7, 119.1, 116.9, 106.6,
50.4, 50.1, 38.2, 34.2, 26.4, 25.9, 24.9; HRMS (EI) m/z 384.1839
[calcd for C25H24N2O2 (Mþ) 384.1838].
(s, 3H), 0.93 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 204.7, 192.5,
174.3, 145.1, 134.8, 129.6, 129.1, 128.6, 120.7, 117.6, 113.3, 57.2,
53.0, 38.4, 29.9, 26.4, 22.7, 20.9; HRMS (EI) m/z 297.1364 [calcd
for C18H19NO3 (Mþ) 297.1365].
4.1.4. Acetate 21. To
a
solution of diazoketone
4
(6.00 g,
22.4 mmol, 1.0 equiv) and allylic alcohol 19 (3.50 g, 26.9 mmol,
1.2 equiv) in CH2Cl2 (224 mL) at room temperature was added
Rh2(OAc)4 (250 mg, 0.56 mmol, 0.02 equiv). As soon as gas evo-
lution ceased (ca. 1 min), Et3N (15.6 mL, 112 mmol, 5.0 equiv)
was quickly added at once via syringe. The mixture was con-
centrated to afford a dark purple oil, which was subsequently
dissolved in xylenes (224 mL) and heated at reflux for 45 min.
After cooling to room temperature, the reaction was concen-
trated and purified by silica gel column chromatography (20%
acetone/hexanes) to afford diketone 21 as a yellow solid (5.36 g,
65% yield). Mp 170e172 ꢀC; FTIR (thin film/NaCl) 2971, 2939,
4.1.2. Isoxazolidine 16. To a solution of diketone 15 (386 mg,
1.30 mmol 1.0 equiv) in MeOH (15 mL) was added N-methylhy-
droxylamine hydrochloride (543 mg, 6.50 mmol, 5.0 equiv) fol-
lowed by pyridine (736 mL, 9.10 mmol, 7.0 equiv). The reaction
mixture was heated at reflux for 15 h and was concentrated after
cooling to room temperature. The residual pyridine was removed
in vacuo and the crude white solid was redissolved in EtOH
(18 mL) and imidazole hydrochloride was added (272 mg,
2.60 mmol, 2.0 equiv). The mixture was heated at reflux for an
additional 14 h. After cooling to room temperature, the reaction
was concentrated and purified by silica gel column chromatogra-
phy (30% hexane/EtOAc) to furnish cycloadduct 16 as white crys-
tals (342 mg, 81% yield). Mp 206e207 ꢀC; FTIR (thin film/NaCl)
2964, 2928, 2872, 1709, 1593, 1588, 1468, 1368, 1334, 1300, 1210,
2885, 1716, 1603, 1472, 1372, 1339, 1300, 1268, 1233 cmꢁ1
NMR (500 MHz, acetone-d6)
J¼7.9 Hz, 1H), 7.10 (d, J¼7.7 Hz, 1H), 5.55e5.46 (m, 2H), 4.40 (dd,
J¼3.6, 27.0 Hz, 1H), 4.37 (dd, J¼4.7, 27.0 Hz, 1H), 3.30 (s, 1H), 3.22
(s, 3H), 2.89 (dd, J¼2.3, 11.5 Hz, 1H), 2.72 (m, 1H), 2.17e2.13 (m,
1H), 2.00 (s, 3H), 1.45 (s, 3H), 0.89 (s, 3H); 13C NMR (125 MHz,
;
1H
7.63 (d, J¼7.9 Hz, 1H), 7.48 (t,
d
1169, 1146, 1115, 1077, 1008 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
7.33
CDCl3) d 205.2, 193.3, 174.9, 170.6, 146.5, 132.6, 130.4, 130.0,
(t, J¼8.2 Hz, 1H), 7.02 (d, J¼8.0 Hz, 1H), 6.72 (d, J¼8.1 Hz, 1H), 3.99
(dd, J¼6.5, 8.7 Hz, 1H), 3.77 (d, J¼8.8 Hz, 1H), 3.49 (s, 1H), 3.28 (m,
1H), 3.23 (s, 3H), 3.19 (s, 3H), 2.61 (dd, J¼9.7, 14.1 Hz, 1H), 2.38 (d,
J¼8.3 Hz, 1H), 1.97 (ddd, J¼8.7, 8.7, 14.1 Hz, 1H), 1.58 (s, 3H), 0.77 (s,
129.8, 127.9, 120.6, 114.4, 64.7, 57.9, 53.6, 263, 38.9, 29.1, 26.5,
22.9, 21.1, 20.7; HRMS (EI) m/z 369.1571 [calcd for C21H23NO5
(Mþ) 369.1576].
3H); 13C NMR (125 MHz, CDCl3)
d
212.8, 175.0, 144.5, 135.1, 128.9,
4.1.5. Acetates 22. To a solution of a acetate 21 (4.25 g,
123.6, 117.3, 106.8, 76.4, 73.1, 65.3, 52.4, 51.7, 42.2, 39.7, 28.8, 26.3,
25.1, 21.4; HRMS (EI) m/z 326.1627 [calcd for C19H22N2O3 (Mþ)
326.1630].
11.5 mmol, 1.0 equiv) in THF (115 mL) was added PdCl2(MeCN)2
(119 mg, 0.46 mmol, 0.04 equiv) and the reaction was warmed to
50 ꢀC. After stirring for 2 h, the reaction was cooled to room
temperature, concentrated, adsorbed onto SiO2 and subjected to
flash chromatography (30% EtOAc/hexanes) to provide a 1:1.4
ratio of diastereomers of olefins 22a and 22b (1.20 g, 28% yield,
96% yield based on recovered starting material) and recovered
acetate 21 (3.00 g, 71% yield). Compound 22a: Although the
mixture will be carried on in the next step, separation of the
minor diastereomer (22a) can be affected via recrystallization
from EtOAc/hexanes: mp 194e195 ꢀC; FTIR (thin film/NaCl) 2974,
4.1.3. Isoxazolidine 17 and Oxazole 18. To a solution of diketone 15
(96 mg, 0.32 mmol, 1.0 equiv) in MeOH (5 mL) was added N-
benzylhydroxylamine
hydrochloride
(258 mg,
1.62 mmol,
5.0 equiv) followed by pyridine (131
mL, 1.62 mmol, 5.0 equiv).
The reaction mixture was heated at reflux for 15 h and was
concentrated after cooling to room temperature. The residual
pyridine was removed in vacuo and the crude white solid was
redissolved in EtOH (8 mL) and imidazole hydrochloride was
added (34 mg, 0.32 mmol, 1.0 equiv). The mixture was heated at
reflux for an additional 18 h. After cooling to room temperature,
the reaction was concentrated and purified by silica gel column
chromatography (30% hexane/EtOAc) to afford oxazole 18 as
a white solid (50 mg, 40% yield) and cycloadduct 17 as a white
solid (62 mg 48% yield). Compound 17: mp >243 ꢀC; FTIR (thin
film/NaCl) 2969, 2924, 2873, 1739, 1697, 1608, 1592, 1470, 1368,
2938, 1716, 1603, 1473, 1372, 1339, 1299, 1271, 1234, 1018 cmꢁ1
;
1H NMR (500 MHz, CDCl3)
d
7.65 (d, J¼8.0 Hz, 1H), 7.51 (dd,
J¼7.9 Hz, 1H), 7.13 (d, J¼7.8 Hz, 1H), 5.66 (ddd, J¼6.3, 10.6,
17.1 Hz, 1H), 5.19e5.14 (m, 2H), 5.04 (ddd, J¼4.8, 4.8, 9.4 Hz, 1H),
3.34 (s, 1H), 3.25 (s, 3H), 2.83 (d, J¼10.6 Hz, 1H), 2.46 (ddd,
J¼10.0, 10.0, 14.2 Hz, 1H), 2.06 (s, 3H), 1.76 (dd, J¼4.1, 14.2 Hz,
1H), 1.47 (s, 3H), 0.89 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
204.0, 192.4, 174.3, 170.5, 145.0, 135.4, 129.7, 129.1, 128.3, 120.6,
1341, 1304, 1149, 1080, 1012, 986, 910, 774, 728, 699 cmꢁ1
NMR (500 MHz, CDCl3)
2H), 7.30 (m, 2H), 7.06 (d, J¼7.9 Hz, 1H), 6.74 (d, J¼7.6 Hz, 1H),
4.89 (d, J¼16.4 Hz, 1H), 4.52 (d, J¼16.5 Hz, 1H), 4.02 (dd, J¼6.8,
8.6 Hz, 1H), 3.78 (d, J¼8.6 Hz, 1H), 3.55 (s, 1H), 3.32 (dd, J¼9.0,
;
1H
117.6, 113.3, 74.1, 53.9, 52.7, 38.5, 30.9, 26.4, 22.5, 21.2, 20.5;
HRMS (EI) m/z 369.1586 [calcd for C21H23NO5 (Mþ) 369.1576].
Compound 22b: mp 97e99 ꢀC (wax); FTIR (thin film/NaCl) 2972,
d
7.56 (d, J¼7.7 Hz, 2H), 7.40 (t, J¼7.6 Hz,
2939, 1717, 1603, 1472, 1373, 1339, 1299, 1271, 1233, 1022 cmꢁ1
;
1H NMR (500 MHz, CDCl3)
d
7.69 (d, J¼8.0 Hz, 1H), 7.52 (t,

6652
D.B. Freeman et al. / Tetrahedron 66 (2010) 6647e6655
J¼7.9 Hz, 1H), 7.12 (d, J¼7.8 Hz, 1H), 5.58 (m, 1H), 5.29 (m, 1H),
5.12e5.09 (m, 2H), 3.35 (s, 1H), 3.25 (s, 3H), 2.93 (d, J¼11.1 Hz,
1H), 2.55 (ddd, J¼5.7, 11.2, 14.1 Hz, 1H), 2.07 (s, 3H), 1.67 (dd,
J¼4.0, 14.1 Hz, 1H), 1.45 (s, 3H), 0.86 (s, 3H); 13C NMR (125 MHz,
33.2, 26.4, 22.4, 20.9, ꢁ0.3; HRMS (EI) m/z 393.1756 [calcd for
23H27NO3Si (Mþ) 393.1760].
C
4.1.8. Isoxazolidine 28. To a solution of diketone 26 (118 mg,
0.30 mmol, 1.0 equiv) in MeOH (6 mL) was added N-methylhy-
droxylamine hydrochloride (126 mg, 1.50 mmol, 5.0 equiv) fol-
CDCl3)
d 204.2, 192.0, 174.4, 170.0, 144.9, 134.9, 129.6, 129.3,
128.2, 120.5, 117.3, 113.2, 71.9, 52.7, 51.6, 38.2, 30.0, 26.4, 22.4,
20.8, 20.5; HRMS (EI) m/z 369.1575 [calcd for C21H23NO5 (Mþ)
369.1576].
lowed by pyridine (171 mL, 2.10 mmol, 7.0 equiv). The reaction
mixture was heated at reflux for 15 h and was concentrated after
cooling to room temperature. The residual pyridine was removed
in vacuo and the crude white solid was redissolved in EtOH
(12 mL) and imidazole hydrochloride was added (63 mg,
0.60 mmol, 2.0 equiv). The mixture was heated at reflux for an
additional 14 h. After cooling to room temperature, the reaction
was concentrated and purified by silica gel column chromatog-
raphy (25% EtOAc/hexane) to furnish cycloadduct 28 as white
crystals (89 mg, 70% yield). Mp 210e211 ꢀC; FTIR (thin film/NaCl)
2967, 2928, 2873, 2172, 1736, 1708, 1606, 1589, 1467, 1386, 1338,
4.1.6. Isoxazolidines 23. N-Methylhydroxylamine hydrochloride
(3.35 g, 40.1 mmol, 10.0 equiv) was dissolved in EtOH (200 mL) via
gentle heating with a heat gun. NaOMe (3.38 g, 40.5 mmol,
10.1 equiv) was added, which resulted in immediate salt formation.
The mixture was stirred for 2 h and was then filtered into a round
bottom flask containing acetates 22 (1.48 g, 4.01 mmol, 1.0 equiv).
The reaction was heated at reflux for 18.5 h, which resulted in
a complex mixture of products as visualized by NMR. After cooling
to room temperature, the reaction was concentrated in vacuo,
adsorbed onto SiO2, and subjected to flash chromatography
(30e75% EtOAc/hexanes). Three diastereomers were isolated and
characterized as follows: 23a and 23b: (865 mg, 54% yield); FTIR
(thin film/NaCl) 2968, 2933, 2878, 1744, 1708, 1603, 1592, 1464,
1299, 1250, 1214, 1172, 1106, 1084 cmꢁ1
CDCl3)
;
1H NMR (500 MHz,
7.30 (t, J¼7.8 Hz, 1H), 6.95 (d, J¼8.0 Hz, 1H), 6.72 (d,
d
J¼7.6 Hz, 1H), 4.09 (d, J¼8.3 Hz, 1H), 4.00 (d, J¼8.2 Hz, 1H), 3.96
(s, 1H), 3.28 (s, 3H), 3.16 (s, 3H), 2.71 (d, J¼14.4 Hz, 1H),
2.46e2.38 (m, 2H), 1.56 (s, 3H), 0.81 (s, 3H), ꢁ0.25 (s, 9H); 13C
1368, 1339, 1300, 1235, 1143, 1118, 1037 cmꢁ1
;
1H NMR (400 MHz,
7.58 (d, J¼8.0 Hz, 1H), 7.41 (t, J¼8.0 Hz, 1H), 7.35e7.26 (m,
NMR (125 MHz, CDCl3) d 213.1, 175.0, 144.2, 132.1, 128.6, 125.0,
CDCl3)
d
118.6, 107.2, 107.1, 90.7, 81.8, 64.4, 54.2, 52.8, 41.0, 39.3, 37.4, 26.1,
25.1, 21.8, 0.0; HRMS (EI) m/z 422.2018 [calcd for C24H30N2O3Si
(Mþ) 422.2026].
2H), 6.79 (d, J¼8.0 Hz, 1H), 6.75 (d, J¼7.6 Hz, 1H), 5.15 (m, 1H), 4.67
(ddd, J¼2.4, 10.0, 12.2 Hz, 1H), 4.27e4.09 (m, 3H), 3.83 (s, 1H), 3.74
(dd, J¼8.4, 8.4 Hz, 1H), 3.43 (dd, J¼8.2, 17.8 Hz, 1H), 3.28 (s, 1H),
3.24e3.17 (m, 4H), 3.21 (s, 3H), 3.20 (s, 3H), 3.02 (s, 3H), 2.73 (dd,
J¼8.8, 12.4 Hz, 1H), 2.64e2.58 (m, 3H), 2.24e2.16 (m, 1H), 2.11 (s,
3H), 2.02 (s, 3H), 1.86 (dd, J¼12.6, 25.0 Hz, 1H), 1.70 (s, 3H), 1.49 (s,
4.1.9. Diketone 30. Diketone 15 (187 mg, 0.63, 1.0 equiv) and olefin
29 (882 mg, 4.40 mmol, 7.0 equiv) were diluted in CH2Cl2
(15.7 mL) and stirred for 10 min. Grubbs second generation cata-
lyst (54 mg, 0.063 mmol, 0.1 equiv) was then added and the re-
action was stirred at reflux overnight (approx. 12 h). Upon
completion as indicated by TLC, the reaction was concentrated and
immediately purified via column chromatography (20% EtOAc/
hexanes) to give the resulting coupled adduct (193 mg,
0.411 mmol). The coupled adduct was taken up in MeOH (41 mL)
before pyridinium p-toluenesulfonate (21 mg, 0.082 mmol,
0.2 equiv) was added. The reaction was stirred at room tempera-
ture over 12 h whereupon TLC indicated the consumption of
starting material. The reaction was concentrated, re-dissolved in
EtOAc, washed with saturated NaHCO3, brine, and dried over
Na2SO4. Purification of the concentrated mixture by flash chro-
matography (50% EtOAc/hexanes) gave diketone product 30
(104 mg, E/Z: 2:1, 47% yield, two steps) as a yellow oil. FTIR (thin
film/NaCl) 3420, 2935, 1715, 1604, 1473, 1372, 1339, 1300,
3H), 0.82 (s, 3H), 0.64 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 210.0,
202.7, 174.8, 174.4, 170.3, 170.0, 144.5, 144.4, 136.4, 135.0, 129.1,
128.9, 124.1, 122.8, 122.2, 120.3, 107.4, 107.3, 80.3, 72.1, 71.6, 70.7,
69.6, 63.5, 61.5, 56.9, 54.9, 52.1, 49.0, 43.9, 40.0, 38.2, 38.1, 31.0, 30.2,
29.9, 26.4, 26.2, 24.6, 21.3, 21.0, 21.0, 19.4; HRMS (EI) m/z 398.1840
[calcd for C22H26N2O5 (Mþ) 398.1842]. Compound 23c: (171 mg,11%
yield); FTIR (thin film/NaCl) 2967, 2882, 1738, 1713, 1603, 1462,
1370, 1340, 1308, 1233, 1054, 917, 787, 732 cmꢁ1
(500 MHz, CDCl3)
;
1H NMR
d
7.36 (t, J¼8.0 Hz, 1H), 7.21 (d, J¼8.1 Hz, 1H), 6.76
(d, J¼7.6 Hz, 1H), 5.23 (t, J¼4.7 Hz, 1H), 4.10 (t, J¼8.1 Hz, 1H), 3.69 (t,
J¼9.1 Hz, 1H), 3.52 (ddd, J¼5.1, 8.0, 9.3 Hz, 1H), 3.34 (s, 1H), 3.18 (s,
3H), 2.71 (dd, J¼8.0, 12.1 Hz, 1H), 2.58 (s, 3H), 2.31 (ddd, J¼5.3, 8.2,
13.8 Hz, 1H), 2.07 (s, 3H), 1.81 (dd, J¼13.2, 13.2 Hz, 1H), 1.72 (s, 3H),
0.80 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 209.6, 174.5, 170.2, 144.5,
135.8, 128.7, 123.9, 122.0, 107.1, 74.6, 66.5, 66.4, 63.8, 53.7, 52.5, 39.1,
36.9, 30.4, 29.7, 26.1, 20.8, 19.3; HRMS (EI) m/z 398.1851 [calcd for
C22H26N2O5 (Mþ) 398.1842].
1272 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.70 (d, J¼8.0 Hz, 1H), 7.69
(d, J¼8.0 Hz, 1H), 7.49 (t, J¼8.0 Hz, 2H), 7.29 (d, J¼7.6 Hz, 2H),
5.04e4.98 (m, 2H), 3.68e3.57 (m, 4H), 3.37 (s, 1H), 3.36 (s, 1H),
3.24 (s, 6H), 2.90e2.86 (m, 2H), 2.82e2.74 (m, 2H), 2.37e2.25 (m,
2H), 2.22e2.05 (m, 6H), 1.64 (s, 6H), 1.52 (s, 3H), 1.5 (s, 3H), 0.93 (s,
4.1.7. Diketone 26. To
a solution of diazoketone 4 (115 mg,
0.43 mmol, 1.0 equiv) and allylic alcohol 24 (66 mg, 0.43 mmol,
1.0 equiv) in CH2Cl2 (5 mL) was added Rh2(OAc)4 (1.9 mg,
0.004 mmol, 0.01 equiv). Gas evolution was observed and the re-
action turned dark brown. After stirring at room temperature for
30 min, the mixture was concentrated to afford a dark brown oil,
which was subsequently dissolved in xylenes (8 mL) and heated at
reflux for 20 min. After cooling to room temperature, the reaction
was concentrated and purified by silica gel column chromatogra-
phy (30% hexane/EtOAc) to afford diketone 26 as yellow crystals
(103 mg, 60% yield). Mp 137e139 ꢀC; FTIR (thin film/NaCl) 2966,
2900, 1705, 1599, 1469, 1411, 1370, 1338, 1295, 1268, 1251, 1082,
6H); 13C NMR (100 MHz, CDCl3)
d 205.9, 193.6, 174.5, 145.3, 135.2,
129.7, 129.0, 128.9, 124.2, 123.9, 120.92, 120.87, 113.5, 113.4, 60.6,
60.2, 58.3, 58.2, 53.4, 53.2, 43.0, 38.6, 38.3, 35.1, 26.6, 24.6, 24.5,
23.4, 23.0, 22.9, 21.3, 21.2, 15.9; HRMS (EI) m/z 356.1862 [calcd for
C21H26NO4 (Mþ) 356.1856].
4.1.10. Selenide 31. A solution of alcohol 30 (60 mg, 0.17 mmol,
1.0 equiv) in THF (1.69 mL) was treated with o-nitro-
phenylselenocyanate (46 mg, 0.20 mmol, 1.2 equiv) at room
temperature. The mixture was stirred for 10 min before tri-n-
1022 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
7.71 (d, J¼7.8 Hz, 1H), 7.52
butylphosphine (50.5 mL, 0.20, 1.2 equiv) was added. Upon com-
(t, J¼7.8 Hz, 1H), 7.13 (d, J¼7.7 Hz, 1H), 5.36 (s, 1H), 5.28 (s, 1H), 3.39
(s, 1H), 3.32 (dd, J¼2.2, 11.0 Hz, 1H), 3.27 (s, 3H), 2.87 (dd, J¼11.2,
13.8 Hz, 1H), 2.27 (d, J¼14.1 Hz,1H), 1.50 (s, 3H), 0.95 (s, 3H), 0.07 (s,
pletion as indicated by TLC (approx. 2 h) an aliquot of saturated
NH4Cl was added. The resulting brown mixture was extracted
with Et2O, washed with brine, dried over MgSO4, and concen-
trated in vacuo. Purification of the concentrated mixture by flash
chromatography (30% EtOAc/hexanes) gave selenide 31 (49 mg,
9H); 13C NMR (125 MHz, CDCl3)
d 203.7, 191.7, 174.4, 145.0, 129.6,
129.4, 128.3, 128.2, 124.4, 120.8, 113.1, 104.1, 96.4, 56.0, 53.0, 38.4,

D.B. Freeman et al. / Tetrahedron 66 (2010) 6647e6655
6653
54% yield) as a yellow oil. The major diastereomer was charac-
a reflux condenser was charged with p-TSA (85 mg, 0.44 mmol,
1.0 equiv) and benzene (150 mL). The resulting suspension was
then heated at reflux for 1 h before isoxazolidine 23 (175 mg,
0.44 mmol, 1.0 equiv) was introduced as a solid in one portion.
The resulting suspension was immersed into an oil bath and
heated at 110 ꢀC for 48 h to provide a dark brown reaction
mixture containing a small amount of a brown precipitate. The
terized as follows: FTIR (thin film/NaCl) 2970, 2930, 1716, 1604,
1513, 1473, 1332, 1303, 1271 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
8.30 (d, J¼8.4 Hz, 1H), 7.71 (d, J¼8.0 Hz, 1H), 7.58e7.49 (m, 3H),
7.31 (t, J¼8.0 Hz, 1H), 7.13 (d, J¼7.6 Hz, 1H), 5.02 (t, J¼7.2 Hz, 1H),
3.39 (s, 1H), 3.26 (s, 3H), 2.99e2.88 (m, 3H), 2.81 (ddd, J¼8.0,
13.2, 13.2 Hz, 1H), 2.39e2.35 (m, 2H), 2.15 (dd, J¼6.0, 13.6 Hz,
1H), 1.70 (s, 3H), 1.53 (s, 3H), 0.96 (s, 3H); 13C NMR (100 MHz,
reaction was cooled to 0 ꢀC and treated with Et3N (61
mL,
CDCl3)
d
205.6, 192.8, 174.5, 147.0, 145.2, 136.9, 133.8, 129.8,
0.44 mmol, 1.0 equiv). Concentration provided a brown foam that
was purified by silica gel chromatography (50e100% EtOAc/
hexanes) to afford recovered starting material 23 (11 mg, 11%)
and aminal 39 (94 mg, 54% yield, 65% BORSM) as a white solid.
Mp 251e254 ꢀC; FTIR (thin film/NaCl) 2967, 1711, 1606, 1457,
129.3, 128.8, 126.6, 125.4, 122.9, 120.9, 113.4, 58.1, 53.3, 38.6,
38.2, 26.6, 24.6, 23.0, 21.2, 16.0; HRMS (EI) m/z 563.1060 [calcd
for C27H28N2NaO5Se (Mþ) 563.1056].
4.1.11. Vinyl epoxide 32. In a flask open to air, selenide 31 (49 mg,
0.09, 1.0 equiv) was diluted with CH2Cl2 (7 mL) and cooled to
ꢁ78 ꢀC. Freshly made dimethyldioxirane in acetone (7 mL, approx.
0.07e0.09 M) was added rapidly. The solution was stirred at ꢁ78 ꢀC
for 30 min and then gradually warmed to room temperature. The
reaction was then concentrated in vacuo and subsequently purified
by flash chromatography (20% EtOAc/hexanes eluent) to give di-
astereomeric vinyl epoxide 32 (23 mg, 72% yield) as a pale yellow
solid. The mixture of diastereomers was characterized as follows:
FTIR (thin film/NaCl) 2970, 1716, 1604, 1473, 1373, 1339, 1300,
1237 cmꢁ1
;
1H NMR (500 MHz, CDCl3)
d
7.49 (t, J¼8.1 Hz, 1H),
7.32 (d, J¼8.1 Hz, 1H), 6.83 (d, J¼7.7 Hz, 1H), 4.60 (d, J¼10.7 Hz,
1H), 4.52 (d, J¼10.3 Hz, 1H), 4.34 (ddd, J¼5.0, 6.9, 12.5 Hz, 1H),
4.17 (dd, J¼5.5, 11.9 Hz, 1H), 3.35 (t, J¼12.1 Hz, 1H), 3.32 (s, 1H),
3.19 (s, 3H), 3.12e3.07 (m, 1H), 2.52 (dd, J¼7.6, 12.6 Hz, 1H), 2.16
(br s, 1H), 2.00 (s, 3H), 1.89e1.75 (m, 2H), 1.67 (s, 3H), 0.79 (s,
3H); 13C NMR (100 MHz, CDCl3)
d 211.1, 174.5, 170.3, 144.7, 139.6,
130.2, 123.6, 119.2, 107.8, 77.4, 69.9, 68.1, 66.1, 54.9, 51.3, 45.3,
39.2, 29.7, 28.8, 26.2, 21.1, 19.8; HRMS (EI) m/z 398.1839 [calcd
for C22H26N2O5 (Mþ) 398.1842].
1272 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.72 (d, J¼8.0 Hz, 2H), 7.52
(t, J¼8.0 Hz, 2H), 7.13 (d, J¼8.0 Hz, 2H), 5.82 (dd, J¼11.2, 17.6 Hz,1H),
5.61 (dd, J¼10.8, 17.6 Hz, 1H), 5.29 (d, J¼17.2 Hz, 2H), 5.17 (d,
J¼10.8 Hz, 2H), 3.39 (s, 1H), 3.38 (s, 1H), 3.25 (s, 6H), 3.14e3.10 (m,
2H), 2.70 (dd, J¼3.6, 8.4 Hz, 1H), 2.59 (dd, J¼4.0, 7.6 Hz, 1H), 2.47
(ddd, J¼4.0, 11.6, 13.6 Hz, 1H), 2.36 (ddd, J¼3.6, 11.6, 14.0 Hz, 1H),
1.59e1.53 (m, 2H), 1.49 (s, 3H), 1.45 (s, 3H), 1.37 (s, 3H), 1.36 (s, 3H),
4.1.14. Amino-alcohol 40. A solution of aminal 39 (610 mg,
1.53 mmol, 1.0 equiv) in MeOH (100 mL) was treated with
hydroxylamine hydrochloride (1.06 g, 15.33 mmol, 10.0 equiv). The
solution that resulted was heated at reflux for 30 min before being
cooled, concentrated, taken up in EtOAc (200 mL) and quenched
with saturated NaHCO3 (250 mL). Separation of the layers and
extraction of the aqueous layer with EtOAc was followed by
washing with brine, drying over Na2SO4, and concentration under
reduced pressure. The resulting residue was purified using silica
gel chromatography (30e100% EtOAc/hexanes) to furnish amino-
alcohol 40 (577 mg, 98% yield) as a white solid. Mp dec >205 ꢀC;
FTIR (thin film/NaCl) 3260, 2968, 1715, 1608, 1465, 1240,
0.93 (s, 3H), 0.88 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 204.7, 192.1,
174.5, 145.2, 140.0, 135.5, 129.9, 129.3, 128.7, 121.1, 118.0, 116.5, 113.5,
63.4, 63.1, 62.1, 60.8, 54.7, 53.1, 38.8, 26.6, 25.4, 24.9, 22.8, 21.8, 21.1,
15.3; HRMS (EI) m/z 376.1526 [calcd for C21H23NNaO4 (Mþ)
376.1519].
4.1.12. Hemiacetals 33. Triphenylphosphine (20.0 mg, 75.0
0.5 equiv) and tris(dibenzylideneacetone)-dipalladium(0)-chloro-
form (7.0 mg, 7.5 mol, 0.05 equiv) were combined and diluted
with toluene (0.8 mL). The deep purple mixture changed to
a deep yellow after 1 h. 1,1,1,3,3,3-Hexafluoro-2-phenyl-2-prop-
mmol,
1019 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
7.47 (t, J¼7.8 Hz, 1H), 7.34
(d, J¼8.0 Hz, 1H), 6.79 (d, J¼7.6 Hz, 1H), 4.32e4.27 (m, 1H),
3.58e3.47 (m, 2H), 3.18 (s, 3H), 3.16 (s, 2H), 2.63 (dd, J¼7.4,
12.0 Hz, 1H), 2.00 (s, 3H), 1.92e1.78 (m, 2H), 1.65 (s, 3H), 0.82 (s,
m
3H); 13C NMR (100 MHz, CDCl3)
d 212.0, 174.2, 170.4, 144.3, 141.1,
anol (25.3
m
L, 0.15 mmol, 1.0 equiv) was then added. After 10 min
130.2, 121.7, 120.8, 107.4, 68.8, 67.2, 62.1, 54.9, 54.6, 51.3, 38.6, 29.3,
29.2, 26.1, 21.0, 19.6; HRMS (EI) m/z 386.1834 [calcd for
C21H26N2O5 (Mþ) 386.1842].
the mixture turned a deep red-orange and was added via can-
nula into a vial containing vinyl epoxide 32 (53.0 mg, 0.15 mmol,
1.0 equiv) The reaction was then submerged in a 35 ꢀC oil bath
and left overnight (approx. 12 h) to react. After completion as
indicated by TLC, the reaction was rapidly concentrated and
immediately purified by flash chromatography (20% EtOAc/hex-
anes) to give diastereomeric acetals 33 (31 mg, 58% yield) as an
off white solid. The mixture of diastereomers was characterized
as follows: FTIR (thin film/NaCl) 3377, 2926, 1699, 1604, 1372,
4.1.15. Alcohol 41. A solution of amino-alcohol 40 (53 mg,
0.14 mmol, 1.0 equiv) in THF (3.4 mL) at 0 ꢀC was treated with
freshly prepared acetic formic anhydride [0.52 mL, prepared by
heating equal amounts of acetic anhydride (0.26 mL) and formic
acid (0.26 mL) at 60 ꢀC for 1 h]. Stirring was continued for 5 min at
this temperature and then at room temperature for 30 min. The
reaction was then concentrated under reduced pressure. The crude
mixture was then diluted in MeOH (3.4 mL) at room temperature
and was treated with Et3N (0.19 mL, 1.37 mmol, 10.0 equiv). The
solution was allowed to stir for 10 min, at which point TLC indicated
complete consumption of starting material. Concentration in vacuo
and purification by flash chromatography (100% EtOAc) furnished
1339, 1298, 1216 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 7.64 (d,
J¼8.0 Hz, 2H), 7.43 (t, J¼8.0 Hz, 2H), 7.04 (d, J¼8.0 Hz, 2H), 6.46
(dd, J¼11.2, 18.0 Hz, 1H), 6.34 (dd, J¼11.6, 18.4 Hz, 1H), 5.45 (s,
1H), 5.3e5.02 (m, 8H), 4.72 (m, 1H), 4.14 (s, 1H), 4.08 (s, 1H),
3.24 (s, 3H), 3.23 (s, 3H), 3.03 (d, J¼11.6 Hz, 2H), 2.78 (m, 1H),
2.33e2.15 (m, 4H), 1.96e1.91 (m, 1H), 1.67 (s, 3H), 1.63 (s, 3H),
0.85 (s, 3H), 0.77 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
196.6,
alcohol 41 (52 mg, 91% yield) as
181e184 ꢀC; FTIR (thin film/NaCl) 3300, 1730, 1694, 1609, 1466,
1236 cmꢁ1 1H NMR (400 MHz, CDCl3)
8.07 (m, 2H), 7.49 (d,
a pale yellow foam. Mp
196.5, 175.9, 146.1, 145.9, 144.8, 136.5, 136.1, 131.3, 131.1, 129.0,
128.9, 127.9, 127.8, 122.2, 121.9, 114.7, 114.4, 114.2, 112.2, 112.1,
103.2, 102.6, 78.0, 75.9, 53.6, 52.7, 52.6, 50.5, 35.4, 35.2, 33.3,
31.1, 26.4, 25.3, 25.2, 23.8, 23.7; HRMS (EI) m/z 376.1519 [calcd
for C21H23NNaO4 (Mþ) 376.1519].
;
d
J¼7.8 Hz,1H), 7.41 (t, J¼8.0 Hz, 1H), 6.79 (d, J¼7.2 Hz, 1H), 4.62 (ddd,
J¼5.5, 7.6, 12.5 Hz, 1H), 3.79e3.71 (m, 2H), 3.65 (s, 1H), 3.42 (dt,
J¼3.0, 7.3 Hz, 1H), 3.18 (s, 3H), 2.60 (dd, J¼7.9, 12.1 Hz, 1H), 2.49 (t,
J¼3.7 Hz, 1H), 2.01 (s, 3H), 1.90e1.78 (m, 2H), 1.67 (s, 3H), 0.83 (s,
4.1.13. Aminal 39. A 500 mL flask equipped with an addition
funnel (containing 30 g 4 A molecular sieves) and connected to
3H); 13C NMR (125 MHz, CDCl3)
d 206.8, 175.1, 170.3, 160.2, 143.4,
ꢀ
138.0, 129.1, 124.9, 121.1, 107.3, 68.8, 68.6, 61.7, 55.1, 51.8, 51.7, 38.4,

6654
D.B. Freeman et al. / Tetrahedron 66 (2010) 6647e6655
29.2, 28.8, 26.1, 21.0, 20.0; HRMS (EI) m/z 414.1782 [calcd for
at 0 ꢀC. Cerium(III) chloride heptahydrate (149 mg, 0.40 mmol,
3.0 equiv) was added followed by addition of a 0.1 M aqueous
solution of sodium hypochlorite (10.7 mL, 1.07 mmol, 8.0 equiv).
The reaction was stirred from 0 ꢀC to room temperature over 9 h
whereupon TLC indicated consumption of starting material. The
reaction was cooled to 0 ꢀC before saturated sodium sulfite
(10 mL) was added and stirred for 10 min. Chloroform was
added and the layers were separated. The aqueous layer was
extracted twice more with chloroform and the organic partitions
were combine, washed with brine, and dried over Na2SO4. Pu-
rification of the filtrate by flash chromatography (33% EtOAc/
hexanes) furnished chlorinated product 44 (49 mg, 71% yield) as
C22H26N2O6 (Mþ) 414.1791].
4.1.16. Alcohol 42. A solution of alcohol 41 (207 mg, 0.5 mmol,
1.0 equiv) in CH2Cl2 (10 mL) was treated with Dess/Martin period-
inane (319 mg, 0.75 mmol, 1.5 equiv) and stirred at room temper-
ature for 30 min, at which point TLC indicated the reaction
complete. The reaction was cooled to 0 ꢀC before saturated NaHSO3
(5 mL) and saturated NaHCO3 (5 mL) were added. The two layers
were separated and the organic extract was washed with brine,
dried over Na2SO4, filtered, and concentrated. The crude reaction
mixture was diluted in CH2Cl2 (10 mL) and stirred at 0 ꢀC before
triethylamine (77
mL, 0.55 mmol,1.1 equiv) was added. After 30 min
a colorless foam. 1H NMR (400 MHz, CDCl3)
d 8.05 (s, 1H) 7.41 (s,
acetic acid (31 L, 0.55 mmol, 1.1 equiv) was added and the reaction
m
1H), 5.03e4.98 (dd, J¼9.2, 11.6 Hz, 1H), 3.54 (s, 3H), 3.02 (s, 1H),
2.63e2.57 (dd, J¼9.6, 10.4 Hz, 1H), 2.53e2.45 (ddd, J¼8.8, 10.8,
14.0 Hz, 1H), 2.27 (s, 3H), 2.0 (s, 3H), 1.85e1.76 (ddd, J¼9.2, 11.4,
14.0 1H), 1.71 (s, 3H), 0.80 (s, 3H); 13C NMR (125 MHz, CDCl3)
was partitioned between CH2Cl2 (20 mL) and saturated NaHCO3
(20 mL). The organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated. The crude reaction mixture,
diluted in THF (10 mL) was cooled to 0 ꢀC. A 3.0 M solution of
methyl magnesium bromide in Et2O (0.37 mL, 1.11 mmol, 3.0 equiv)
was added and the reaction was stirred for 30 min. Upon con-
sumption of starting material, the reaction was quenched with 1 M
NH4Cl, extracted with EtOAc, washed with brine, and dried over
Na2SO4. The resulting mixture was purified by flash chromatogra-
phy (90% EtOAc/hexanes) to give secondary alcohol 42 as a mixture
of diastereomers (134 mg, 73% yield, three steps). The complex
mixture was carried through the next step and characterized.
d
206.5, 175.7, 171.7, 160.0, 140.3, 132.7, 132.6, 128.2, 127.4, 117.3,
90.3, 75.8, 60.8, 58.0, 54.4, 52.4, 40.6, 34.0, 30.1, 29.9, 26.8, 26.4,
26.0, 22.0, 21.4, 14.6, 14.5; HRMS (EI) m/z 541.0233 [calcd for
C22H22Cl4N2NaO4 (Mþ) 541.0226].
Acknowledgements
Funding from the NIH (1 RO1 CA 93591), Astellas (formerly
Yamanouchi), Daiichi, and Fujisawa are gratefully acknowledged.
MI thanks the University of Tokyo School of Agricultural Sciences.
JLW thanks Amgen, Merck, Bristol-Myers Squibb, GlaxoSmithKline
and Pfizer for research support. RNT would like to acknowledge the
Jack and June Richardson Honors Scholarship Fund and the CSU
CNS Undergraduate Scholarship Fund for financial support. Dr.
Chris Incarvito, Dr. Chris Rithner, Don Heyse and Don Dick are ac-
knowledged for their assistance with X-ray crystallography and
instrumentation.
4.1.17. Enone 43. A solution of alcohol 42 (20 mg, 0.05 mmol,
1.0 equiv) in CH2Cl2 (1.9 mL) was treated with DesseMartin peri-
odinane (73 mg, 0.17 mmol, 3.0 equiv) and stirred at room tem-
perature for 8 h, at which point TLC indicated the reaction
complete. The reaction was cooled to 0 ꢀC before saturated NaHSO3
(2 mL) and saturated NaHCO3 (2 mL) were added. The two layers
were separated and the organic extract was washed with brine,
dried over Na2SO4, filtered, and concentrated. Purification by flash
chromatography (75% EtOAc/hexanes) gave enone 43 (7 mg, 35%
yield) as a pale yellow oil. FTIR (thin film/NaCl) 3329, 3055, 2970,
2917, 1731, 1698, 1609, 1465, 1368, 1340, 1266, 1243 cmꢁ1; 1H NMR
References and notes
(400 MHz, CDCl3)
d
8.14 (d, J¼1.2 Hz, 1H), 7.25 (t, J¼8.0 Hz, 1H),
7.04e7.02 (m, 1H), 6.9 (s, 1H), 6.70 (d, J¼8.0 Hz, 1H), 3.88 (s, 1H),
3.15 (s, 3H), 2.58e2.49 (m, 2H), 2.45 (s, 3H), 2.36e2.28 (m, 1H), 1.68
1. Stratmann, K.; Moore, R. E.; Bonjouklian, R.; Deeter, J. B.; Patterson, G. M. L.;
Shaffer, S.; Smith, C. D.; Smitka, T. A. J. Am. Chem. Soc. 1994, 116, 9935e9942.
2. Jimenez, J. I.; Huber, U.; Moore, R. E.; Patterson, G. M. L. J. Nat. Prod. 1999, 62,
569e572.
(s, 3H), 0.94 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 201.1, 174.9, 160.1,
142.8,134.6,129.5,126.0,120.9,107.2, 69.9, 51.8, 51.7, 37.7, 29.2, 27.8,
27.4, 26.3, 20.6; HRMS (EI) m/z 389.1480 [cacld for C21H22N2NaO4
(Mþ) 389.1472].
3. Jimenez, J. L.; Huber, U.; Moore, R. E.; Patterson, G. M. L. J. Nat. Prod. 1999, 62,
940.
4. Wood, J. L.; Holubec, A. A.; Stoltz, B. M.; Weiss, M. M.; Dixon, J. A.; Doan, B.
D.; Shamji, M. F.; Chen, J. M.; Heffron, T. P. J. Am. Chem. Soc. 1999, 121,
6326e6327.
5. Ready, J. M.; Reisman, S. E.; Hirata, M.; Weiss, M. M.; Tamaki, K.; Ovaska, T. V.;
Wood, J. L. Angew. Chem., Int. Ed. 2004, 43, 1270e1272.
4.1.18. Allylic Alcohol 38. A solution of enone 43 (66 mg,
0.18 mmol, 1.0 equiv) in THF (8 mL) was cooled to 0 ꢀC. A 3.0 M
solution of methyl magnesium bromide in Et2O (0.30 mL,
0.90 mmol, 5.0 equiv) was added and the reaction was stirred for
7 h. Upon consumption of starting material, the reaction was
quenched with 1 M NH4Cl, extracted with EtOAc, washed with
brine, and dried over Na2SO4. The resulting mixture was purified
by flash chromatography (2% MeOH/CHCl3) to give allylic alcohol
38 (26 mg, 26% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-
6. Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005, 127, 15394e15396.
7. Baudoux, J.; Blake, A. J.; Simpkins, N. S. Org. Lett. 2005, 7, 4087e4089.
8. MacKay, J. A.; Bishop, R. L.; Rawal, V. H. Org. Lett. 2005, 7, 3421e3424.
9. Greshock, T. J.; Funk, R. L. Org. Lett. 2006, 8, 2643e2645.
10. Lauchli, R.; Shea, K. J. Org. Lett. 2006, 8, 5287e5289.
11. Reisman, S. E.; Ready, J. M.; Hasuoka, A.; Smith, C. J.; Wood, J. L. J. Am. Chem. Soc.
2006, 128, 1448e1449.
12. Baran, P.S.; Maimone, T.J.; Richter, J.M. Nature 2007, 446, 404e408.
13. Reisman, S. E.; Ready, J. M.; Weiss, M. M.; Hasuoka, A.; Hirata, M.; Tamaki,
K.; Ovaska, T. V.; Smith, C. J.; Wood, J. L. J. Am. Chem. Soc. 2008, 130,
2087e2100.
14. Richter, J. M.; Ishihara, Y.; Masuda, T.; Whitefield, B. W.; Llamas, T.; Pohjakallio,
A.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 17938e17954.
15. Boissel, V.; Simpkins, N. S.; Bhalay, G. Tetrahedron Lett. 2009, 50, 3283e3286.
16. Brailsford, J. A.; Lauchli, R.; Shea, K. J. Org. Lett. 2009, 11, 5330e5333.
17. Tian, X.; Huters, A. D.; Douglas, C. J.; Garg, N. K. Org. Lett. 2009, 11, 2349e2351.
18. Trost, B. M.; McDougall, P. J. Org. Lett. 2009, 11, 3782e3785.
19. Smith, C. D.; Zilfou, J. T.; Stratmann, K.; Patterson, G. M. L.; Moore, R. E. Mol.
Pharmacol. 1995, 47, 241e247.
d6)
d
9.42 (s, 1H), 8.02 (s, 1H), 7.27 (t, J¼8.0 Hz, 1H), 7.18 (d,
J¼8.0 Hz, 1H), 6.85 (d, J¼7.6 Hz, 1H), 6.06 (s, 1H), 5.81e5.79 (m,
1H), 3.80 (s, 1H), 3.10 (s, 3H), 2.31e2.18 (m, 2H), 1.79e1.73 (m, 1H),
1.55 (s, 3H), 1.47 (s, 3H), 1.35 (s, 3H), 0.76 (s, 3H); 13C NMR
(100 MHz, DMSO-d6)
d 201.7, 174.5, 160.1, 147.3, 141.5, 136.4, 128.6,
125.3, 124.4, 121.1, 106.5, 73.0, 70.9, 51.3, 51.2, 36.5, 31.4, 30.2, 28.5,
25.8, 25.2, 19.8; HRMS (EI) m/z 405.1789 [calcd for C22H26N2NaO4
(Mþ) 405.1785].
20. Zhang, X. Q.; Smith, C. D. Mol. Pharmacol. 1996, 49, 288e294.
21. Chen, H. G.; Goel, O. P.; Kesten, S.; Knobelsdorf, J. Tetrahedron Lett. 1996, 37,
8129e8132.
22. Funk, R. L.; Horcher, L. H. M.; Daggett, J. U.; Hansen, M. M. J. Org. Chem. 1983, 48,
2632e2634.
4.1.19. Chlorinated product 44. Tertiary allylic alcohol 38 (51 mg,
0.133 mmol, 1.0 equiv) was diluted in CH3CN (10 mL) and stirred

D.B. Freeman et al. / Tetrahedron 66 (2010) 6647e6655
6655
23. Falb, E.; Bechor, Y.; Nudelman, A.; Hassner, A.; Albeck, A.; Gottlieb, H. E. J. Org.
Chem. 1999, 64, 498e506.
illustrated below. Lebel, N. A.; Post, M. E.; Hwang, D. J. Org. Chem. 1979, 44,
1819e1823.
24. Katagiri, N.; Okada, M.; Morishita, Y.; Kaneko, C. Tetrahedron1997, 53, 5725e5746.
25. Palmisano, G.; Danieli, B.; Lesma, G.; Trupiano, F.; Pilati, T. J. Org. Chem. 1988, 53,
1056e1064.
26. Rajkovic, M.; Lorenc, L.; Petrovic, I.; Milovanovic, A.; Mihailovic, M. L. Tetrahe-
dron Lett. 1991, 32, 7605e7608.
27. Wood, J. L.; Moniz, G. A. Org. Lett. 1999, 1, 371e374.
28. Wood, J. L.; Moniz, G. A.; Pflum, D. A.; Stoltz, B. M.; Holubec, A. A.; Dietrich, H. J.
J. Am. Chem. Soc. 1999, 121, 1748e1749.
29. Ooi, N. S.; Wilson, D. A. J. Chem. Res., Synop. 1980, 366e367.
30. Sevastyanova, T. K.; Volodarskii, L. B. Zh. Org. Khim. 1971, 7, 1687e1692.
31. Lebel, N. A.; Post, M. E.; Hwang, D. J. Org. Chem. 1979, 44, 1819e1823.
32. Nicolaou, K. C.; Koide, K. Tetrahedron Lett. 1997, 38, 3667e3670.
33. Uemura, S.; Kito, R.; Ichikawa, K. Nippon Kagaku Zasshi 1966, 87, 986.
34. Overman, L. E. Angew. Chem., Int. Ed. 1984, 23, 579e586.
35. Overman, L. E.; Campbell, C. B.; Knoll, F. M. J. Am. Chem. Soc. 1978, 100,
4822e4834.
36. These alternative conditions were employed due to the base-lability of the
allylic acetate moiety within diketone 22.
37. Huisgen, R. Angew. Chem., Int. Ed. 1963, 2, 565e598.
38. Lebel, N. A.; Banucci, E. J. Am. Chem. Soc. 1970, 92, 5278e5280.
39. Padwa, A. Angew. Chem., Int. Ed. 1976, 15, 123e136.
40. Crystallographic data (excluding structure factors) for the structures in this
paper have been deposited with the Cambridge Crystallographic Data Center as
supplementary publication nos. CCDC 763861.
41. Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360e11370.
42. Yan, J. B.; Herndon, J. W. J. Org. Chem. 1998, 63, 2325e2331.
43. Grieco, P. A.; Masaki, Y.; Boxler, D. J. Am. Chem. Soc. 1975, 97, 1597e1599.
44. Grieco, P. A.; Noguez, J. A.; Masaki, Y. Tetrahedron Lett. 1975, 16, 4213e4216.
45. Nicolaou, K. C.; Zhang, H.; Ortiz, A.; Dagneau, P. Angew. Chem., Int. Ed. 2008, 47,
8605e8610.
46. Murray, R. W. S. M. Org. Synth. 1998, 9, 288e293.
47. Other oxidants were screened but produced BaeyereVilliger side products.
48. Suzuki, M.; Oda, Y.; Noyori, R. J. Am. Chem. Soc. 1979, 101, 1623e1625.
49. Kabat, M. M.; Garofalo, L. M.; Daniewski, A. R.; Hutchings, S. D.; Liu, W.; Okabe,
M.; Radinov, R.; Zhou, Y. F. J. Org. Chem. 2001, 66, 6141e6150.
50. Wang, B. M.; Song, Z. L.; Fan, C. A.; Tu, Y. Q.; Chen, W. M. Synlett 2003,1497e1499.
51. For oxidative NeO bond cleavage see Altenative methods for NeO bond
cleavage were pursued via ketone i, however all ultimately failed as
52. Obrecht, R.; Herrmann, R.; Ugi, I. Synthesis 1985, 400e402.
53. Porcheddu, A.; Giacomelli, G.; Salaris, M. J. Org. Chem. 2005, 70, 2361e2363.
54. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277e7287.
55. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923e2925.