Dearomatization applications of I(III) reagents and some unusual reactivity amongst resorcinol derived cyclohexadienones

Article abstract of DOI:10.1016/j.tet.2010.05.041

The oxidative dearomatization of resorcinol derivatives, which are outfitted with a lactic acid derived chiral tether, and mitigated by hypervalent iodine derivatives of PhIO, affords stable chiral cyclohexadienones as useful building blocks for the const

Full text of DOI:10.1016/j.tet.2010.05.041

Tetrahedron 66 (2010) 5873e5883
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Dearomatization applications of I(III) reagents and some unusual reactivity
amongst resorcinol derived cyclohexadienones
*
Todd A. Wenderski, Christophe Hoarau, Lupe Mejorado, Thomas R.R. Pettus
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106-9510, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The oxidative dearomatization of resorcinol derivatives, which are outfitted with a lactic acid derived
chiral tether, and mitigated by hypervalent iodine derivatives of PhIO, affords stable chiral cyclo-
hexadienones as useful building blocks for the construction of many highly functionalized chiral six and
seven-membered ring systems. Herein, we report a multitude of remarkable and unexpected diaster-
eoselective transformations stemming from these cyclohexadienone adducts.
Received 18 March 2010
Received in revised form 4 May 2010
Accepted 13 May 2010
Available online 19 May 2010
Published by Elsevier Ltd.
Keywords:
Dearomatization
Cyclohexadienone
Hypervalent iodine
Lactone
Vinylogous ester
1. Introduction
reactivity we have observed amongst the resulting cyclo-
hexadienone products.
Despite many advances in asymmetric organic reaction pro-
cesses, only a handful of chemical methods have emerged to pro-
vide enantiomerically enriched cyclohexadienones.1 Few are
catalytic. None are general. This is surprising because chiral cyclo-
hexadienones offer attractive entry points to a number of complex
non-racemic natural products. One needs to look no further than
the early racemic syntheses of ryanodol, calicheamicinone, and
ovalicin to be seduced by the utility of chiral cyclohexadienones.
However, after reflecting and studying the processes that deliver
these building blocks, we have come to appreciate the thorny issues
of product stability and utility, which have prevented real progress.
Any new dearomatization process should be judged just as much, if
not more so, in these realms as in their overall diastereomeric or
enantiomeric selectivity.
Diastereoselective dearomatization processes are inherently
useful. In total syntheses of epoxysorbicillinol,2 bisorbicillinol,2
rishirilide,3 and the cleroindicins,4 as well as for other puta-
tive natural products,5 we have confronted the issues of
cyclohexadienone stability and subsequent utility head-on.
Herein, we recount this diastereoselective dearomatization
process, and report for the first time some of the remarkable
2. The plan
Early on we speculated that a catalytic enantioselective method
offered limited synthetic potential because its efficient use would
be restricted by cyclohexadienone reactivity to circumstances
where the target molecule contained
a
single stereocenter.1
Therefore, our formulative ideas centered upon developing more
utilitarian diastereoselective dearomatization processes.6 We
imagined some hypervalent I(III) reagent prompted oxidative dear-
omatization involving an unprecedented ortho-cyclization of a lac-
tic acid derived tether should produce
a family of sturdy
cyclohexadienones capable of further regioselective and diaster-
eoselective reactions.7 Low yields (<70%) have long plagued the
synthesis of cyclohexadienones. This stems from the reactivity of
the reaction intermediates and the respective products. A work-
around solution, which we were resolved to not use, has been the
deployment of the oxidative dearomatization at a very early stage,
when starting material is overly abundant, or very near the end,
when the target compound can be easily reached. However, these
solutions fail to capitalize on the malleability intrinsic to the
cyclohexadienones product themselves. Fortunately, widespread
use of hypervalent iodine oxidants,8 particularly I(III) derivatives of
iodosyl benzene (PheI]O),9 have supplanted Pb(IV), Tl(III), and DDQ
as oxidants. These hypervalent iodine reagents have led to
* Corresponding author. E-mail address: pettus@chem.ucsb.edu (T.R.R. Pettus).
0040-4020/$ e see front matter Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.05.041

5874
T.A. Wenderski et al. / Tetrahedron 66 (2010) 5873e5883
improved yields, because these non-toxic I(III) reagents rarely par-
ticipate in undesirable side-reactions with the intermediate phe-
nonoxonium cation.10
CH3NO2 or in situ with aqueous LiOH at the conclusion of the
Mitsunobu reaction affords the respective non-racemic mono-
‘protected’ resorcinols 4 with enantiomeric excess of greater than
99%, demonstrated by chiral GC comparison of a derivative to a ra-
cemic standard.6a
We anticipated that the d-lactone formed by our proposed ox-
idation would further stabilize the cyclohexadienone so that the
enone, vinylogous ester, and ketone functionality could be manip-
ulated in both chemoselective and stereoselective manners to ad-
dress a number of natural products, in spite of the inescapable fact
that the cyclohexadienone product would display five trigonal sp2
carbon atoms. We therefore set out to build several of these scaf-
folds so that we might determine their subsequent reactivity,
which we expected to be nucleus dependent. For example, o-quinol
derivatives are susceptible to dimerization,1b,d whereas their p-
quinol counterparts succumb to single electron transfer reduction
and rearomatization.11 While none of these issues can be avoided
altogether, we imagined that some electronic and structural fea-
tures could be introduced into the phenol and tether functionalities
to dissuade some of undesired reactivities in the resulting cyclo-
hexadienone adduct. An added benefit of our plan was that the
oxygen atom, which would be installed during the dearomatization
reaction, would be already protected. This increased the efficiency
of any future synthetic plans by expanding the repertoire of ac-
cessible chemical transformations and obviating the need for sub-
sequent hydroxyl protection.
Oxidation of these substrates using various PhI(III) species afford
the corresponding lactones 5 as the major product (dr>12:1). In
some instances, where the R00 substituent is fairly small (R00¼eH),
a minor amount (<7%) of the lactones 6 can be observed. However,
this unwanted diastereomer is easily removed by column chro-
matography and it can even be re-introduced into the synthetic
stream by formation of the corresponding Weinreb amide followed
by the appropriate reduction. Given the structure of the major
product, we speculate that it arises from the compact, dipole sta-
bilized transition-state. From this transition-state, the Mee of the
lactate residue, and the R00CH2e substituent emerge on the same
face (syn) with respect to the newly forming 1,4-di-oxygenated
ring. On the other hand, for the minor diastereomer 6, the Mee and
the R00CH2e substituent emerge on the opposite face (anti). The X-
ray crystal structures for 5a and ent-5a have been previously
reported.4
After much experimentation with the oxidative dearomatiza-
tion of resorcinol 4d (R00¼e(CH2)2Ph), which can undergo either
ipso or ortho-cyclization (Scheme 1, inset shows the ipso product),
we believe that we have successfully ascertained the optimum
combination of reagents and substituents for the formation of the
desired 1,4-dioxan-2-one scaffold 5.3 Dilute conditions (0.05 M)
and very polar solvents, particularly nitromethane (CH3NO2),
proved best in most instances. A bromine or alkyl substituent at the
2-position of the resorcinol also appeared to facilitate the dear-
omatization process, and increase the diastereoselectivity. Re-
markably, the lactate tether motif not only resulted in
diastereoselection, it also improved yields and it provided a more
stable cyclohexadienone adduct than the corresponding glycolate
derived tethers. In addition, we found that the transformation can
be carried out at much higher concentrations (0.3 M) in methylene
chloride when the oxidation is carried out with either (1.1 equiv
PhIO, 0.1 equiv TMSOTf) or (1.1 equiv PhIO and 1.1 equiv TfOH).3,5
These oxidants, which are generated in situ, prevent any un-
desired participation of the ligand from the hypervalent iodine
species with the intermediate phenoxonium cation.14
3. Diastereoselective dearomatization with I(III) reagents; the
affects of reaction conditions and substrate substituents on
the overall yield and diastereoselectivity
Our studies have principally utilized two 2,4-dihydroxy-
benzaldehydes 1 (R0¼eMe, eBr, Scheme 1). Some time ago, we
reported a method for the straightforward conversion of these
kinds of aldehydes into their corresponding 2-bromo- and 2-
methyl-resorcinol derivatives 2 so as to display differing 4-alkyl
substituents (aeg).12 Before the development of our mild process,
which involves o-quinone methide (o-QM) generation and con-
sumption, these types of mono-protected 4-alkyl resorcinols were
relatively inaccessible. The unprotected phenol product partici-
pates in an SN2 reaction under Mitsunobu conditions with the
secondary alcohol within various amides 3, which are derived from
(S)-methyl lactate.13 Subsequent Boc deprotection with ZnBr2 in
ipso product
major
O
OBoc
Me
from 4d
R'
R'
O
O
O
O
OMe
R'
N
N
R'
O
O
CH3
H
O
O
OBoc
(S)
Me
syn
R"
CHO
1
(R)
PhI(OCOCF3)2 or [PhIOTMS(OTf)]
or [PhIOH(OTf)]
R"
O
Me
OH
compact
5
NaBH4, R"M
1-2 pots
dipole stabilized
ref. 12
O
d.r.>12:1, R" = -H, R' = -Br
R'
O
yields >70%
ref. 2-5
OBoc
OMe
N
(R)
R'
O
CH3
R" Me
Me
O
R'
O
O
R"
N
4
ref 2
a: R' = –Br, R" = -H
OH
ref. 6a
O
(R)
PPh3, DIAD, 3
ref 3
ref 4
ref 4
ref 5
b: R' = –Br, R" = -(CH2)5CH3
c: R' = –Br, R" = -CH2CH(CH3)2
d: R' = –Br, R" = -(CH2)2Ph
e: R' = –Br, R" = -(CH2)-O(CH2)2SiMe3
f: R' = –Me, R" = -H
H
R"
O–
2
R"
(R)
OH
O
R'
Me
Me
(S)
X
6
Me
O
O
anti
minor
3
O
non-compact
ref 3
g: R' = –Me, R" = -CH2CH(CH3)2
1) Me2AlNMe(OMe), 2) Zn / NH4Cl
Scheme 1. Diastereoselective dearomatization of resorcinol derivatives with [PhIOTMS(OTf)].

T.A. Wenderski et al. / Tetrahedron 66 (2010) 5873e5883
5875
4. Some surprising reactivity differences amongst epimeric
chiral cyclohexadienone adducts
epoxidation (t-BuOOH, DBU), whereas the enone 7b proves
unreactive.
The reactivity of the chiral cyclohexadienones 5 was next
studied. Remarkably, all attempts to epoxidize cyclohexadienones
resembling 5 under standard basic conditions failed.15 In our ex-
perience, we found that as long as the tertiary alcohol is protected,
then the resorcinol derived cyclohexadienones are quite stubborn
toward epoxidation.6 On the other hand, cyclohexadienones de-
rived from phenols usually undergo epoxidation, even if their ter-
tiary alcohol is protected.16 The conditions we used for the
attempted epoxidation, however, resulted in formation of the ent-6
5. Remarkable electrocylization discovered
Even more interesting is the stereospecific electrocyclization
that we observe upon treatment of the lactone 5 (0.1 M in THF) with
BnNþMeꢀ4 OH or DBU. We postulated this reaction, which resembles
a Favorskii rearrangement, proceeds through the anion shown to
afford the
g-lactone 9 (Scheme 3). Again, the transformation is
O
O–
epimer. Indeed, independent treatment of the syn-d-lactone 5a
(0.04 M in THF, 1.0 equiv DBU) caused rapid epimerization of the
tether methyl residue to produce, upon quenching with silica gel,
R'
O
R'
O
DBU
the corresponding anti-
d-lactone ent-6a (Scheme 2). We speculate
O
O
R"
R"
O
O–
O
O
5a,b
R'
R'
DBU
(S)
(S)
O–
O
O
O
O
SiO2 quench
(R)
(S)
O
O
R'
O
R'
O
R"
R"
O
O
ent-6a,b-anti
R"
R"
5a,b-syn
OR**
O
NAlMe2
CH2Cl2
O
NAlMe2
CH2Cl2
9a,b
faster
75%
slower
68%
0 °C
0 °C
O
O
R'
R'
KOTMS
THF
O
(S)
O
(S)
O
(R)
O
R"
R"
(S)
O
O
O
O
O
OH
N
OH
O
O
H
7a,b
O
N
8a,b
11
O
10
O
O
O
Scheme 3. An unexpected rearrangement.
somewhat structure dependant. In the case of 5b, where [R00¼
e(CH2)5CH3], the rearrangement product (R**¼H) emerges quite
cleanly (>85% yield). However, when R00¼eH as in 5a, compound 9
emerges (R**¼eH), along with a dimeric product where the tertiary
alcohol has participated in a stereoselective 1,4-addition with the
enone of the rearrangement product (1:3 ratio, monomeredimer).
Coincidently, this rearrangement does not readily occur with either
the thermodynamic diastereomer 6b, or the corresponding lac-
tones displaying a glycolate derived tether (not shown), suggesting
that the release of steric strain may play a role in the trans-
formation. Our observation of this rearrangement in other cores,
such as compound 10 and 18a, which converts to 11 with a variety
of bases,17 leads us to believe that neither an electron deficient R0
residue nor an enone are critical for this rearrangement process.
However, the vinylogous ester and the syn configured 1,4-dioxan-2-
one seem to be essential motifs.
Scheme 2. Epimers displaying different reactivity.
the axial hydrogen atom is unusually acidic because of the attached
vinylogous ester oxygen atom and its zwitterionic nature. More-
over, in the product 6a, both of the sp3 substituents in the 1,4-di-
oxan-2-one reside in a thermodynamically preferred anti 1,4-
diaxial orientation. This anti-arrangement thwarts further access to
the lactone carbonyl and many of the reactions that will be sub-
sequently described (Scheme 6) for type 5-system do not neces-
sarily apply to the corresponding 6-system. For example,
compounds 6a,b are a great deal less reactive with aluminum
amides than their corresponding diastereomer 5a,b. The relative
and absolute stereochemistry of the two pyrrolidine products have
been confirmed by X-ray analysis. In the case of the cyclo-
hexadienone 7b, the amide carbonyl is positioned in an eight-
6. Functional groups interconversion involving the lactone
and vinylogous ester moieties
Owing to the conjoined 1,4-dioxan-2-one and vinylogous ester,
compound 5 undergoes many other unusual functional group in-
terconversions, several of which prove diastereoselective. Some
time ago, we found that the glycolate lactone derivatives corre-
sponding to 5 (not shown) undergo saponification and diaster-
membered ring so as to form
a hydrogen bond with the
neighboring tertiary alcohol. In the cyclohexadienone 8b, however,
the carbonyl turns away from the tertiary alcohol. Again, this minor
structural difference profoundly influences the subsequent chem-
istry. The enone 8b smoothly undergoes syn selective anionic
eoselective lactonization to afford
saponification cleaves the spirolactone to reveal the carbonyl
a
spirolactone.2 Further

5876
T.A. Wenderski et al. / Tetrahedron 66 (2010) 5873e5883
moiety that was previously masked as the vinylogous ester and
thereby removes the tether. In the case of the lactic acid cyclo-
hexadienone derivatives, such as 5, however, the reaction is less
synthetically useful. Saponification and subsequent lactonization
O
O
O
Me
O
Br
O
N
N
H
H
OMe
now proceeds to a mixture of g-spirolactone adducts (14 and 15)
O
possessing dissimilar reactivity (2:1 ratio, 95% overall yield).
Compound 14, for example, undergoes an E2 elimination rather
than saponification upon treatment with aqueous base to return
the starting lactone 5, whereas compound 15 converts under sim-
16a
O
17g
O
OMe
SO2
[3+2]
[4+2]
CH2N2
76%
ilar conditions into the corresponding
b-diketone (not shown).
Compound 5 does, however, undergo a highly diastereoselective
transformation to afford the lactam 12 upon the addition of a pri-
mary amine (74% yield for 12a, Scheme 4). Amines R000¼eBn and
eBu have both been tested.15 The resulting spirocyclic lactam 12
forms as a single diastereomer and undergoes further stereo-
selective epoxidation to produce the anticipated syn-epoxy-alcohol
13 (85% yield). X-ray analysis of 13 has secured the stereochemistry
of the cyclization despite some variability throughout the lip-
ophyllic side chain. Yields are lower for cyclohexadienones when
the R0¼alkyl residues (12f) as opposed to R0¼eBr; it therefore ap-
pears that this lactamization is facilitated, at least some degree, by
an electron deficient R0 residue.
O
O
OMe
ZnO, 155 °C
R'
O
K2CO3
60%
R"
O
OEt
O
5
[Ph3PCuH]6
0 °C
O
O
Mg
1,4-additions
50%
O
O
O
Br
O
Br
R'
O
base
60%
EtO2C
OH
EtO2C
O
O
O
O
H3C(H2C)5
O
R'
O
O
[18a]
19a
20b
Scheme 5. Some stereoselective [3þ2] and [4þ2] additions and some 1,4-conjugate
additions to the enone of adduct 5.
O
R"
O
O
R'"NH2
74%
O
R'
O
5a,b,f
R'
H
O
O
diastereomer. However, 1,4-conjugated addition of alkyl and vinyl
cuprates is not as useful. In most instances the cyclohexadienone
succumbs to single electron transfer and elimination to return an
aromatic product (not shown). For example, addition of Stryker’s
reagent ([Ph3PCuH]6) to compound 5b affords the anticipated re-
duced product 20b (50% yield) along with about a 40% yield of
the corresponding 2-(R)-(2-bromo-6-heptyl-3-hydroxyphenoxy)-
propanoic acid (not shown). We therefore chose to next examine
other potentially chemoselective and stereoselective reduction
procedures to better understand and unleash the utility of this new
chiral building block.
O
HO
R"
1. LiOH, 1M
2. HCl, 3M
95%
R"
R"
O
N
OH
14a
CH3
R"'
12a,b,f
H
O
O
R'
O
DBU
HOOt-Bu
O
85%
OH
15a
O
O
Br
H
O
O
HO
H3C(H2C)6
N
CH3
13b
H
8. Reductions of the cyclohexadienone 5 and related scaffolds
Bu
O
Despite its structural enhancements and rigidity, type
5
Scheme 4. Remarkable functional group interconversions of the vinylogous ester in
type 5 cyclohexadienones.
cyclohexadienones still performed erratically in most transition
metal mediated procedures. Thus, most hydrogenation conditions
are accompanied with a fair amount of rearomatization.6a After
considerable experimentation and newly found appreciation of
Corey’s ovalicin work, we chose to subject the enone 5 (0.07 M in
CH3NO2) to a source of diimide, generated from potassium azo-
dicarboxylate by the addition of 3 equiv of acetic acid.21 The re-
duction smoothly afforded the vinylogous ester 20 (Scheme 6).
With one of the double bonds removed, the vinylogous ester
undergoes subsequent reduction with palladium/carbon and hy-
drogen to smoothly afford the ketone 21. In addition, the bromine
atom can be removed from 20 by standard conditions to afford its
hydrido counterpart 21. The vinylogous ester of 5 (0.1 M in tolu-
7. Reactions of the cyclohexadienone scaffold 5
Because of a pseudo equatorial arrangement of the CeO bond on
the cyclohexadienone, as opposed to a pseudo axial orientation, the
bicyclic compound 5 enjoys enhanced chemical and thermal sta-
bility as compared to a rudimentary p-quinol acetate cyclohexa-
2,5-dienone adduct. Compound 5 is far less susceptible to single
electron transfer and elimination. Moreover, because of the pseudo
axial eCH2R00 residue, many reactions of the bicyclic compound 5
prove stereoselective. For example, compound 5a undergoes a se-
lective [3þ2] cycloaddition with diazomethane at 0 ꢁC in diethyl
ether to afford the tetrahydro-3H-indazole 16a (76% yield,
Scheme 5).18 On the other hand, the enone 5g proceeds in a [4þ2]
cycloaddition at 155 ꢁC in a sealed tube containing toluene and the
masked DursteCharlton dimethide19 to afford the tricyclic ring
system 17g as a single diastereomer.17 Type 5 enones can also
participate in 1,4-conjugate additions. For example, addition of the
magnesium enolate20 to 5a followed by decarboxylation results in
the formation of the ester 18a, which under basic conditions un-
ene) at ꢀ78 ꢁC succumbs to
a diastereoselective reduction
with methylaluminum bis(2,6-di-tert-butyl-4-methylphenoxide)
(MAD) (2.2 equiv) and L-Selectride (1.1 equiv) to afford the trans
fused system 25 in 85% yield.22 Lower yields are obtained in
systems where R0¼eMe residue 25f, however the reaction is still
quite useful. The bromide in scaffolds, such as 25a can be re-
moved by treatment with TMSI (2 equiv) or PPh3 and methanol to
furnish the enone 26 in 98% yield.15 Hydrogenation of either
compound 20 or 25 affords the expected ketone 21. On the other
dergoes further rearrangement to afford 19a as
a single

T.A. Wenderski et al. / Tetrahedron 66 (2010) 5873e5883
5877
O
O
O
O
OH
Br
N
Br
O
NH
N
AlMe2
N
H
Br
O
1.
R"
O
O
20a
O
2. TBSOTf,
Et3N
21a-c
22a
23a
OTBS
O
OH
O
27a
64%
DIBAL
Pd/C, H2,
KOAc
NaBH4, THF,
69% yield
98% yield
O
H2O, 76% yield
O
CO2K
N
O
O
O
N
Br
O
R'
Br
NaBH4,
O
OH
CeCl3, MeOH
KO2C
O
OH
R"
O
R"
O
O
O
30a
28a
85% yield
HOAc,
CH3NO2
O
O
CH2I2
DIBAL; MnO2;
Me2NNH2 ; TFA
51%
>90% yield
20a-c
5a-f
24a
O
O
OH
Et2Zn
71%
MAD,
26a,b
L-Selectride
85% yield
1. RhCl(PPh3)3
Et3SiH, C6H6
2. DMDO
CuBr•Me2S
MgBr
O
O
R'
89%
TMSCl,
70%
NaI
25a,b
(R' = –Br)
R"
25a,b,e,f
O
R"
O
O
OSiEt3
O
O
98% yield
O
26a,b
O
O
O
O
H3C(H2C)6
Scheme 6. Unexpected reductions in rigid cyclohexadienones.
O
O
O
O
29b
hand, we found that addition of DIBAL (2 equiv) to 5a (0.04 M in
toluene at ꢀ78 ꢁC) results in the lactol 22a in 69% yield. Pre-
sumably, this transformation proceeds by sequential stereo-
selective reduction of the vinylogous ester, followed by the
lactone. Surprisingly, the use of sodium borohydride (10 equiv)
with 5a (0.04 M in THF/H2O at 0 ꢁC) reduces the vinylogous ester,
followed by 1,2-reduction of the enone to thereby afford com-
pound 23a in >75% yield. More remarkably still, compound 5a
(0.04 M in MeOH at ꢀ78 ꢁC) in the presence of cerium trichloride
(1.2 equiv) undergoes reduction of the lactone with sodium bo-
rohydride (2 equiv) to produce the lactol 24a. This outcome was
certainly not anticipated from Luche reduction conditions.
31a
CO2Et
25a
Bu3Sn
Br2; Et3N
56%
AIBN
81%
O
O
CO2Et
Br
Br
O
O
O
O
32a
33a
O
O
9. Other useful transformations of scaffolds derived from the
cyclohexadienone 5
O
O
O
CH2N2
52%
m-CPBA
We have developed several methods for removal of the tether,
that is, derived from methyl lactate and directs the stereochemical
formation of the tertiary alcohol in the cyclohexa-2,5-dienone. The
simplest is treatment of fused compounds, such as 21, with KOTMS.
21a
65%
O
O
O
O
O
O
34a
35a
Saponification of the lactone causes a ring flip and concomitant b-
elimination of the lactate derived functionality.6a However, we have
also developed processes that enables us to retain the oxygen atom
by severing the CeO bond from both the lactone and its corre-
sponding hemiketal by formation of various hydrazone de-
rivatives.3,4 For example, treatment of 20a (0.05 M in CH2Cl2 at 0 ꢁC)
with excess Me2AlNHNMe2 (3 equiv) affords a single vinylogous
hydrazide. Subsequent silylation facilitating isolation as compound
27a. Reduction of the enone carbonyl and lactone functionalities in
26a, followed by allylic MnO2 oxidation and treatment of the cor-
responding lactol with H2NNMe2 followed by TFA affords the diol
28a by a similar CeO fragmentation mechanism.
The rigid enone 26 also participates in many other selective
transformations. For example, it undergoes 1,4-addition of hydride
mediated by rhodium to afford the corresponding silyl enol ether.
Further epoxidation with DMDO affords compound 29b. The enone
in 26 also undergoes stereoselective cyclopropanation under Fur-
ukawa modified SimmonseSmith conditions to produce compound
30a (Scheme 7). The conjugate addition of homo-allyl cuprate
Scheme 7. Some other useful transformations.
(0.04 M in THF at ꢀ78 ꢁC) to afford 31a is similarly diaster-
eoselective. We speculated that the outstanding stereoselectivity in
all of these reactions is due to the steric encumbrance of the angular
eCH2R000 residue.
The equatorial bromide compound 25, formed by L-Selectride
reduction, also undergoes selective reactions. For example, bro-
mination (1 equiv of Br2; 1.5 equiv Et3N) of enone 25 (0.05 M in
CH2Cl2 at 0 ꢁC) proceeds as expected to produce the vinyl bromide
32a. On the other hand, treatment of 25a (0.02 M in benzene at
80 ꢁC) with AIBN and the allyl tin species shown (2 equiv) affords
a single diastereomer of the unsaturated ester 33a in greater than
80% yield.
The fully reduced scaffold 21 also undergoes some unexpectedly
reactions. For example, in the presence of CH2N2, 21a affords the
spiroepoxide 34a, rather than the intended ring expanded product
(not shown). Surprisingly, migration proceeds in only one direction

5878
T.A. Wenderski et al. / Tetrahedron 66 (2010) 5873e5883
upon treatment of 21a with m-CPBA, to afford the seven-membered
lactone 35a as a single regioisomer. This selective ring expansion
further illustrates the remarkable and unexpected selectivity of
these cylcohexadienones and their derivatives.
HRMS (ESI) calcd for C12H16NO4BrNaþ: 340.0154, found 340.0159;
mp¼127e128 ꢁC.
11.2.2. Compound 4f. Yield 75%. 1H NMR (500 MHz)
d (multiplicity,
J (Hz), integration): 6.83 (d, 8.2, 1H), 6.55 (d, 8.1, 1H), 5.54 (s, 1H),
4.88 (br q, 6.0, 1H), 3.49 (s, 3H), 3.2 (s, 3H), 2.21 (s, 3H), 2.19 (s, 3H),
10. Conclusion
1.49 (d, 6.6, 3H); 13C NMR
d: 155.8, 153.4, 128.3, 122.9, 118.0, 111.0,
74.5, 61.5, 32.5, 18.2, 16.8, 10.1.
In closing, we believe that the dearomatization process, that is,
mitigated by hypervalent iodine derivatives of PhIO, that afford
chiral cyclohexadienones, such as 5 from the corresponding methyl
lactate 3 and the resorcinol 2 compounds, displays tremendous
potential. The cyclohexadienone 5, that is, formed is a useful
building block for both six and seven-membered rings as well as for
acyclic arrays. Moreover, its epimer 6 is expected to afford a very
different reactivity profile because its lactone carbonyl is better
protected by the anti-3,5-alkyl substituents of the corresponding
1,4-dioxan-2-one. We therefore believe that the 5-pot protocol
used to construct 5 in either optical antipode with various hyper-
valent iodine reagents might indeed find many good applications in
future enantioselective syntheses.
11.3. Scaffold 5
A solution of 4a (0.363 g, 1.33 mmol) previously dried under
vacuum (48 h at 0.07 mmHg), in CH3NO2 (12 mL) was cooled to 0 ꢁC
and [bis(trifluoroacetoxy)iodo]benzene (0.738 g, 1.72 mmol) was
added in one portion. The reaction mixture was stirred at 0 ꢁC for
15 min, and gradually turned light yellow. Deionized water (20 mL)
was added followed by CH2Cl2 (20 mL) and it was stirred vigorously
at 0 ꢁC for 15 min. Upon initial addition of water the solution turned
dark green, then faded to yellow after several minutes. The aqueous
layer was extracted with CH2Cl2 four times and the combined or-
ganic layers were washed with brine, dried (Na2SO4), and con-
centrated. The crude product was purified by flash chromatography
(30% EtOAcehexanes) to afford 5a (0.224 g, 75% yield) as an off-
white solid.
11. Experimental procedures and spectral data for
representative scaffolds 2e9, 11, 19e36
11.3.1. Compound 5a. 1H NMR
6.84 (d, 10.0, 1H), 6.36 (d, 10.0, 1H), 4.99 (q, 7.2, 1H), 1.88 (d, 7.2, 3H),
1.85 (s, 3H); 13C NMR
: 179.4, 166.5, 162.1, 143.1, 127.1, 107.0, 76.6,
74.4, 29.9, 19.5; IR (thin film): 2924, 1759, 1668, 1607, 1261,
d (multiplicity, J (Hz), integration):
11.1. General techniques
d
In reactions, where water was not present as solvent, reagent, or
by-product, vessels were flame-dried under a slow nitrogen flow. A
slight positive pressure of dry nitrogen was maintained via rubber
septum seal during the course of the reaction. Diethyl ether, tet-
rahydrofuran, benzene, and toluene were distilled from sodium and
benzophenone. Dichloromethane and nitromethane were distilled
from calcium hydride. 1H NMR and 13C NMR spectra were recorded
at 400 MHz and 100 MHz, respectively, and in CDCl3 unless other-
wise noted. Chromatography purification was performed using
1049 cmꢀ1
;
HRMS (EI) calcd for C10H9BrOþ4 271.9684, found
271.9689; mp¼111e114 ꢁC.
11.3.2. Compound 5bed. See Ref. 6a.
11.3.3. Compound 5e. See Ref. 4.
11.3.4. Compound 5f. Yield 70%. 1H NMR (500 MHz)
d (multiplicity,
40e63
mm silica gel.
J (Hz), integration): 6.79 (d, 10.0, 1H), 6.24 (d, 10.0, 1H), 4.79 (q, 7.0,
1H), 1.87 (s, 3H), 1.81 (d, 7.0, 3H), 1.79 (s, 3H); 13C NMR (125 MHz)
186.5, 167.6, 160.0, 143.0, 128.1, 119.2, 75.5, 73.9, 29.4, 19.4, 7.6.
d:
11.2. Scaffold 4
11.3.5. Compound 5g. See Ref. 3.
To a stirred solution of triphenyl phosphine (6.49 g, 24.8 mmol)
in THF (60 mL) at 0 ꢁC was added diisopropyl azodicarboxylate
(4.9 mL, 24.9 mmol), dropwise over 1 min. The resulting suspen-
sion was stirred from 0 ꢁC to rt for 1 h. The mixture was re-cooled to
0 ꢁC, and a solution of 3 (5.01 g, 16.5 mmol) in THF (40 mL) was
added via a cannula, followed by a solution of 2a (2.20 g,
16.5 mmol) in THF (25 mL). The reaction was stirred at 0 ꢁC to rt for
12 h. It was concentrated under reduced pressure and crude resi-
due was purified by column chromatography (20% EtOAcehexanes)
to afford a light yellow oil.
The above product was redissolved in CH3NO2 (125 mL) and
ZnBr2 (14.3 g, 63.4 mmol) was added. The reaction was stirred at rt
for 5 h, then quenched with 1 M aq HCl and diluted with EtOAc. The
organic layer was washed twice with 1 M citric acid, twice with
deionized water, once with brine, and dried (Na2SO4). The mixture
was filtered, concentrated, and the crude residue was purified by
chromatography (30% EtOAcehexanes) to afford 4a as a white solid
(4.11 g, 78% yield over two steps).
11.4. Scaffold 6
This minor diastereomer formed during the synthesis of 5 was
isolated by chromatography (30% EtOAcehexanes). Alternatively,
ent-6a can be obtained from the following procedure: to a solution
of 5a (0.020 g, 0.073 mmol) in THF (2 mL) at 0 ꢁC was added DBU
(0.012 mL, 0.079 mmol). The reaction was stirred for 30 s, quenched
with silica gel, and immediately concentrated under reduced
pressure and purified by flash chromatography (30%
EtOAcehexanes) to afford ent-6a (0.018 g, 90% yield) as a light
yellow oil.
11.4.1. Compound 6a. 1H NMR
6.80 (d, 10.0, 1H), 6.30 (d, 10.0, 1H), 5.20 (q, 6.5, 1H), 1.88 (s, 3H), 1.78
(d, 6.7, 3H); 13C NMR
: 179.2, 166.3, 162.6, 142.3, 126.7, 102.2, 77.0,
73.1, 27.0, 18.3; IR (thin film): 2923, 1767, 1666, 1603, 1286, 1248.
1055 cmꢀ1; HRMS (EI) calcd for C10H9BrOþ4 : 271.9684, found:
271.9693.
d (multiplicity, J (Hz), integration):
d
11.2.1. Compound 4a. 1H NMR
7.02 (d, 8.5, 1H), 6.74 (d, 8.4, 1H), 5.55 (s, 1H), 5.14 (d, 6.4, 1H), 3.59
(s, 3H), 3.23 (s, 3H), 2.28 (s, 3H), 1.55 (d, 6.6, 3H); 13C NMR
172.4,
153.6, 152.1, 130.4, 124.7, 111.7, 105.9, 75.6, 61.6, 32.5, 18.1, 16.7; IR
(thin film): 3242, 2934, 1651, 1423, 1177, 1076, 1038, 987 cmꢀ1
d (multiplicity, J (Hz), integration):
11.5. Scaffold 7
d
To a solution of pyrrolidine (0.0034 mL, 0.041 mmol) in CH2Cl2
(0.5 mL) cooled to 0 ꢁC was added AlMe3 (0.0175 mL, 0.040 mmol,
;

T.A. Wenderski et al. / Tetrahedron 66 (2010) 5873e5883
5879
2.3 M in hexanes), and the resulting solution was stirred at 0 ꢁC for
25 min. A solution of dienenone 5a (0.010 g, 0.036 mmol) in CH2Cl2
(0.5 mL) was added to the aluminum amide. The reaction was
allowed to slowly warm to rt and was stirred for 2.5 h. It was
quenched with aq 1 M Rochelle’s salt, diluted with CH2Cl2, and
stirred vigorously for 30 min. The aqueous layer was extracted four
times with CH2Cl2. The combined organic layers were dried
(Na2SO4), concentrated, and the crude residue was purified by
chromatography (40% EtOAcehexanes) to afford 7a as a light yel-
low oil (0.009 g, 75% yield).
2.21 (m, 1H), 2.0 (m, 1H), 1.98 (s, 3H), 1.38e1.17 (m, 10H), 0.86 (t,
6.8, 3H).
11.7.3. Compound 9c (R**¼H). Yield 80%. 1H NMR
d (multiplicity, J
(Hz), integration): 7.18 (d, 9.9, 1H), 6.44 (d, 9.9, 1H), 2.71 (s, 1H), 2.21
(dt, 4.5, 13.4, 1H), 2.01 (dt, 4.8, 12.4, 1H), 1.97 (s, 3H), 1.51 (sep, 6.7,
1H), 1.20 (m, 1H), 1.13 (m, 1H), 0.85 (t, 6.7, 6H).
11.8. Scaffold 11
To a solution of 1017 (0.012 g, 0.038 mmol) in THF (1 mL) was
added KOTMS (0.0072 g, 0.057 mmol) and the resulting orange
slurry was stirred for 25 min. The reaction was quenched with TFA
(one drop), concentrated, and purified by column chromatography
(20% EtOAcehexanes) to afford 11 (0.009 g, 75% yield).
11.5.1. Compound 7a. 1H NMR
d (multiplicity, J (Hz), integration):
6.84 (d, 9.9, 1H), 6.48 (s, 1H), 6.17 (d, 9.9, 1H), 6.08 (q, 6.7, 1H),
3.61e3.48 (m, 2H), 3.44e3.34 (m, 2H), 2.01 (quintet, 6.4, 2H), 1.87
(m, 6.4, 2H), 1.65 (d, 6.7, 3H), 1.58 (s, 3H); 13C NMR
d: 181.2, 174.0,
170.1, 151.2, 123.6, 106.8, 75.5, 71.8, 46.9, 46.5, 27.0, 26.3, 23.9, 18.6;
IR (thin film): 3252, 2977, 1664, 1630, 1583, 1458, 1186, 1026; HRMS
(EI) calcd for C14H18BrNO4þ: 343.0419, found: 343.0423.
11.8.1. Compound 11. 1H NMR
7.38 (dd, 9.8, 15.2, 1H), 6.41e6.21 (m, 3H), 3.96 (s, 1H), 2.05 (s, 3H),
d (multiplicity, J (Hz), integration):
1.90 (d, 6.8, 3H), 1.78 (s, 3H), 1.73 (s, 3H).
11.5.2. Compound 7b. Yield 72%. 1H NMR
d (multiplicity, J (Hz),
integration): 6.76 (d, 10.1, 1H), 6.54 (s, 1H), 6.24 (d, 9.9, 1H), 6.03
(q, 6.8, 1H), 3.60e3.48 (m, 2H), 3.44e3.33 (m, 2H), 2.07e1.98 (m,
2H), 1.89e1.78 (m, 2H), 1.65 (d, 6.6, 3H), 1.30e1.00 (m, 12H), 0.87
(t, 6.8, 3H).
11.9. Scaffold 12
To a solution of 5a (0.0500 g, 0.183 mmol) in CH2Cl2 (3 mL)
cooled to 0 ꢁC was added BnNH2 (0.022 mL, 0.201 mmol). The so-
lution was stirred at 0 ꢁC to rt for 14 h, concentrated and purified by
chromatography (40% EtOAcehexanes) to afford 12a (0.026 g, 74%
yield based on consumed starting) and recovered 5a (0.025 g, 50%
recovery).
11.6. Scaffold 8
The procedure for scaffold 7 was used, except the reaction was
allowed to stir for 6 h following the addition of dienone 6. The
reaction generally and gave slightly lower yields (68%).
11.9.1. Compound 12a (R’’’¼Bn). 1H NMR
d (multiplicity, J (Hz), in-
tegration): 7.38 (m, 5H), 6.58 (d, 10.0, 1H), 6.18 (d, 10.0, 3H), 5.71 (s,
1H), 5.20 (d, 15.3, 1H), 4.77 (q, 6.8, 1H), 4.02 (d, 15.3, 1H), 1.46 (d, 6.8,
11.6.1. Compound 8a. 1H NMR
d
(multiplicity, J (Hz), integration):
3H), 1.27 (s, 3H); 13C NMR
d: 188.6, 175.6, 148.9, 137.5, 129.3, 128.7,
6.84 (d, 10.0, 1H), 6.25 (d, 10.0, 1H), 5.66 (q, 6.8, 1H), 3.70e3.41 (m,
4H), 2.05 (quin, 6.7, 2H), 1.93 (quin, 6.7, 2H), 1.59 (s, 3H), 1.53 (d,
6.8, 3H).
128.3, 127.6, 99.8, 75.8, 73.9, 60.9, 47.0, 23.6, 18.4; IR (thin film):
3380, 2924, 1697, 1095, 703; HRMS (ESI): calcd for
C17H18NO4BrNaþ: 402.0311, found: 402.0300.
11.6.2. Compound 8b. Yield 64%. 1H NMR
d
(multiplicity, J (Hz),
11.9.2. Compound 12b (R000¼Bu). This compound was characterized
as is epoxide derivative 13b.
integration): 6.77 (d, 9.8, 1H), 6.32 (d, 9.8, 1H), 6.19 (s, 1H), 5.54 (q,
6.83, 1H), 3.70e3.40 (m, 4H), 2.10e1.78 (m, 2H), 1.71e1.56 (m, 2H),
1.53 (d, 6.84, 3H), 1.34e1.17 (m, 12H), 0.86 (t, 6.83, 3H); IR (thin
Compound 12f (R000¼Bn): 48% yield. 1H NMR
d (multiplicity, J
(Hz), integration): 7.44e7.32 (m, 5H), 6.54 (d,10.0,1H), 6.06 (d,10.0,
1H), 5.11 (d, 14.6, 1H), 4.54 (q, 6.8, 1H), 4.20 (d, 14.8, 1H), 3.52 (q, 7.0,
1H), 1.46 (d, 6.7, 3H), 1.24 (s, 3H), 1.01 (d, 6.8, 3H).
film): 3254, 2929, 1665, 1631, 1584, 1187 cmꢀ1
.
11.7. Scaffold 9
11.10. Scaffold 13
To a solution of 5a (0.020 g, 0.073 mmol) in THF (2 mL) at 0 ꢁC
was added DBU (0.012 mL, 0.079 mmol). The reaction was stirred
for 30 min, then concentrated under reduced pressure and purified
by flash chromatography (30% EtOAcehexanes) to afford 9a as
a light yellow oil (0.017 g, 88% yield). For the synthesis of 9b,
BnNMe3OH (40% wt in methanol, 1.0 equiv) was used instead of
DBU, and the reaction was quenched with silica gel upon comple-
tion by TLC analysis.
To a solution of 12b (0.0047 g, 0.019 mmol) in CH2Cl2 (0.5 mL)
was added t-BuOOH (0.0040 mL, 0.038 mmol) and DBU (cat.). The
solution was stirred at rt for 45 h, concentrated, and purified by
chromatography (40% EtOAcehexanes) to afford 13b (0.0041 g, 85%
yield).
11.10.1. Compound 13b. 1H NMR (500 MHz)
d (multiplicity, J (Hz),
integration): 4.67 (d, 1.7, 1H), 4.34 (q, 6.9, 1H), 3.75 (m, 1H), 3.63 (m,
2H), 3.55 (d, 3.7, 1H), 1.97 (m, 1H), 1.85 (m, 1H), 1.75 (m, 1H),
1.50e1.70 (m, 4H), 1.45e1.23 (m, 12H), 0.97 (t, 7.2, 3H), 0.90 (t, 6.8,
11.7.1. Compound 9a (dimer). 1H NMR (500 MHz)
d (multiplicity, J
(Hz), integration): 6.80 (d, 10.3, 1H), 6.14 (d, 10.3, 1H), 5.15 (s, 1H),
4.24 (d, 10.1, 1H), 2.95 (d, 9.9, 1H), 2.65 (s, 1H), 1.93 (s, 3H), 1.81 (s,
3H); 13C NMR (125 MHz)
d: 197.6, 172.6, 102.9, 94.6, 91.7, 74.3, 54.4,
51.7, 42.3, 31.8, 31.6, 31.0, 29.2, 29.2, 22.8, 22.1, 20.6, 18.4, 14.3, 13.9;
IR (thin film): 2930, 1718, 1413, 1374 cmꢀ1; HRMS (EI) calcd for
C20H32NO5Brþ: 446.1542, found: 446.1559.
3H), 1.79 (s, 3H), 1.68 (s, 3H); 13C NMR (125 MHz)
d: 188.0, 185.2,
173.6, 167.6, 152.6, 145.7, 130.2, 120.0, 89.2, 85.9, 85.5, 81.2, 74.4,
58.5, 55.3, 54.1, 32.2, 27.4, 20.9, 20.5; IR (thin film): 3464, 2925,
1794, 1757, 1695, 1380, 1120, 1072; HRMS (ESI) calcd for
C20H18O8Br2Naþ: 566.9260, found: 566.9257.
11.11. Scaffold 14,15
To a solution of 5a (0.0730 g, 0.267 mmol) in THF was added
LiOH (0.30 mL, 0.30 mmol, 1 M in H2O). The solution was stirred for
10 min, then HCl (0.30 mL, 0.90 mmol, 3 M in H2O) was added
11.7.2. Compound 9b (R**¼H). Yield 79%. 1H NMR
d (multiplicity, J
(Hz), integration): 7.2 (d, 10.0, 1H), 6.42 (d, 10.0, 1H), 2.61 (s, 1H),

5880
T.A. Wenderski et al. / Tetrahedron 66 (2010) 5873e5883
stirring was continued for 1 h. The THF was removed under re-
duced pressure; the aq solution was further diluted and extracted
five times with EtOAc. The combined organic layers were washed
with brine, dried (Na2SO4), and concentrated. The crude residue
was a 2:1 mixture of 14a and 15a (0.0690 g, 95% NMR yield).
Chromatography generally gave some separation and low isolated
yields, however an analytically pure sample was obtained by flash
chromatography (50% EtOAcehexanes) to afford 14a and a mixture
of 14a and 15a (0.0140 g, 20% isolated yield).
with 1 M aq HCl and diluted with Et2O. The organic layer was
washed twice with water, once with brine, dried (Na2SO4), and
concentrated. The crude material was purified by chromatography
(30% EtOAcehexanes) to afford 19a as a colorless oil (0.0039 g, 60%
yield).
11.14.1. Compound 19a. 1H NMR
d (multiplicity, J (Hz), integration):
4.14 (q, 7.0, 1H), 3.13 (m, 1H), 2.95 (m, 3H), 2.74 (s, 1H), 2.57 (dd,
15.8, 5.4, 1H), 2.20 (dd, 15.8, 9.0, 1H), 1.95 (s, 3H), 1.82 (s, 3H).
11.11.1. Compound 14a. 1H NMR
6.87 (d, 10.3, 1H), 6.18 (d, 10.3, 1H), 5.01 (s, 1H), 4.90 (q, 6.8, 1H),
1.583 (s, 3H), 1.580 (d, 6.8, 1H); 13C NMR
: 187.0, 172.5, 152.2, 126.2,
111.1, 74.1, 73.3, 60.5, 22.6, 17.9; IR (thin film): 3461, 2925, 1803,
1697, 1271, 1204, 1003; HRMS (ESI) calcd for C10H11O5BrNaþ
312.9692, found 312.9694.
d
(multiplicity, J (Hz), integration):
11.15. Scaffold 20
d
To a solution of dienone 5a (0.199 g, 0.729 mmol) in CH3NO2
(10 mL) at 0 ꢁC was added potassium azodicarboxylate (1.706 g,
8.78 mmol). Acetic acid (1.50 mL, 26.2 mmol) was added dropwise
via a syringe pump over 4 h while the temperature was maintained
at 0 ꢁC. The reaction mixture was immediately diluted with EtOAc,
filtered through Celite, and washed successively with satd aq
NaHCO3, water, and brine. The organic layer was dried (Na2SO4),
and concentrated. It was occasionally necessary to re-subject the
crude material to additional potassium azodicarboxylate (1.137 g,
5.85 mmol) and acetic acid (1.00 mL,17.5 mmol). The crude product
was purified by crystallization from EtOAcehexanes to afford 20a
(0.190 g, 95% yield). The diimide reduction proved superior over
previously reported use of [Ph3PCuH]6 for 20b,17 and Rhealumina
hydrogenation to afford 20c.6a
11.11.2. Compound 15a. 1H NMR
d (multiplicity, J (Hz), integration):
6.85 (d, 10.3, 1H), 6.20 (d, 10.3, 1H), 5.05 (s, 1H), 4.70 (q, 6.84, 1H),
1.60 (s, 3H), 1.59 (d, 6.8, 3H).
11.12. Scaffold 16
To a solution of 5a (0.0050 g, 0.018 mmol) in ether (1 mL) at 0 ꢁC
was added diazomethane (0.27 M in Et2O, 1.0 mL, 0.27 mmol) and
the resulting solution was stirred for 12 h, gradually turning col-
orless. The reaction was concentrated and purified by crystalliza-
tion from CH2Cl2ehexanes to afford 16a (0.0043 g, 76% yield).
11.15.1. Compound 20a. 1H NMR
d (multiplicity, J (Hz), integration):
5.09 (q, 7.3, 1H), 2.88 (ddd, 2.4, 4.8, 17.5, 1H), 2.56 (ddd, 5.7, 8.3, 17.7,
1H), 2.40 (dt, 4.1, 13.1, 1H), 2.53 (ddd, 2.1, 5.6, 12.8, 1H), 1.87 (d, 7.3,
11.12.1. Compound 16a. 1H NMR (500 MHz)
d (multiplicity, J (Hz),
integration): 5.86 (dd, 2.5, 9.4, 1H), 5.24 (dd, 9.5, 18.5, 1H), 5.12 (q,
7.4, 1H), 4.41 (ddd, 2.5, 9.7, 18.4, 1H), 2.98 (q, 9.4, 1H), 1.94 (s, 3H),
3H), 1.83 (s, 3H); 13C NMR
d: 188.9, 166.7, 164.5, 105.6, 79.7, 73.4,
34.3, 34.0, 19.7; IR (thin film) 2941, 1751, 1670, 1600, 1274, 1188,
1038 cmꢀ1; HRMS (EI) calcd for C10H11BrOþ4 : 273.9841, found:
273.9832; mp¼116e118 ꢁC.
1.86 (d, 7.4, 3H); 13C NMR (125 MHz)
d: 177.8, 165.6, 162.2, 103.6,
92.0, 81.0, 80.5, 72.8, 41.0, 33.4, 19.6; IR (thin film): 2988, 2942,
1759, 1672, 1597, 1273, 1211, 1035 cmꢀ1; HRMS (ESI) calcd for
C11H11N2O4NaBrþ: 336.9800, found: 336.9798.
11.16. Scaffold 21
11.13. Scaffold 17
To a solution of enone 20a (0.057 g, 0.207 mmol) in EtOAc
(3 mL) in 50 mL flask was added Pd/C (10%, 0.011 g, 0.010 mmol)
followed by KOAc (0.034 g, 0.313 mmol). The flask was purged with
H2 for several minutes, then stirred under a H2 balloon for 4 h. The
reaction mixture was filtered through a pad of Celite, and concen-
trated. The crude material was purified by chromatography (30%
A mixture of dienone 5g (0.080 g, 0.30 mmol), sulfone (0.87 g,
0.38 mmol), zinc oxide (0.081 g, 1.0 mmol), and K2CO3 (0.138 g,
1.00 mmol), in toluene (4 mL) was heated in a sealed tube to 155 ꢁC
for 8e10 h. The reaction was worked up with 2 M aq HCl and
extracted with EtOAc. The combined organic layers were washed
with water, brine, dried (Na2SO4), and concentrated.
EtOAcehexanes) to afford 21a as
a colorless oil (0.040 g,
0.203 mmol, 98% yield).
The crude material was taken up in CHCl3 and treated with TFA
(0.0093 mL, 0.125 mmol). The solution was stirred at rt for 4 h,
11.16.1. Compound 21a. 1H NMR
d (multiplicity, J (Hz), integration):
concentrated
and
purified
by
chromatography
(20%
4.46 (q, 7.0,1H), 3.84 (dd,10.2,1H), 2.79 (ddd,15.8, 5.6, 2.3,1H), 2.56
(dd,16.7, 5.1,1H), 2.43 (dd,13.1,15.4,1H), 2.38 (dd,14.0, 7.3,1H), 2.17
(ddd, 13.4, 8.8, 1.9, 1H), 1.93 (dd, 13.9, 5.6, 1H), 1.62 (s, 3H), 1.61 (d,
EtOAcehexanes) to afford 17g as a light yellow oil (0.067 g, 60%
yield).
7.0, 3H); 13C NMR
d: 205.14, 170.1, 81.63, 75.16, 73.15, 43.85, 37.74,
11.13.1. Compound 17g. 1H NMR
d
(multiplicity, J (Hz), integration):
31.67, 18.59, 18.38; IR (thin film) 2988, 2943, 2880, 1731, 1373, 1257.
7.65 (d, 2.9, 1H), 7.20 (t, 7.7, 1H), 7.00 (d, 7.4, 1H), 6.95 (d, 7.4, 1H),
4.87 (q, 7.1, 1H), 3.88 (s, 3H), 3.46 (m, 1H), 3.27 (m, 1H), 2.67 (t, 16.6,
1H), 2.12 (m, 1H) 1.98 (s, 3H), 1.96 (m, 1H), 1.84 (d, 7.1, 3H), 1.53 (sep,
6.6, 1H), 0.88 (m, 6H).
1124 cmꢀ1
199.0968.
;
HRMS (CI) calcd for C10H15Oþ4 : 199.0970, found:
11.16.2. Compound 21c. Please see Ref. 6a.
11.14. Scaffold 18,19
11.17. Scaffold 22
To
a
cooled solution of mono-ethylmalonate (0.0043 mL,
To a solution of dienone 5a (0.0500 g, 0.183 mmol) in toluene
(5 mL) cooled to ꢀ78 ꢁC was added DIBAL (1 M in hexanes,
0.366 mL, 0.366 mmol). The solution was stirred at ꢀ78 ꢁC for
15 min. It was quenched with 1 M aq Rochelle’s salt, diluted in
EtOAc, quickly warmed to rt and stirred vigorously for 30 min. The
aqueous layer was extracted with EtOAc. The combined organic
layers were washed with brine, dried (Na2SO4), and concentrated.
0.036 mmol) in THF (0.5 mL) at 0 ꢁC was added t-BuMgCl (0.83 M in
THF, 0.089 mL, 0.072 mmol). The solution was stirred at 0 ꢁC to rt
for 10 h, and the residual solvent was removed by evaporation
under a gentle flow of N2. A solution of dienone 5a (0.0050 g,
0.018 mmol) in DMF (0.5 mL) was added to the malonate salt and
the solution was stirred at 60 ꢁC for 2 h. The reaction was quenched

T.A. Wenderski et al. / Tetrahedron 66 (2010) 5873e5883
5881
The residue was purified by flash chromatography (30%
EtOAcehexanes) to yield 22a as a colorless oil (0.035 g, 0.127 mmol,
69% yield).
The reaction mixture was quenched with 1 M Rochelle’s salt
(10 mL), diluted with EtOAc (20 mL), and quickly warmed by hand
to rt. It was stirred vigorously for 1 h. The aqueous layer was
extracted with EtOAc four times and the combined organic layers
were washed with brine (5 mL), dried (Na2SO4), and concentrated.
The crude material was purified by flash chromatography (100%
hexanes to 30% EtOAcehexanes) to give 25a as white solid (0.410 g,
1.49 mmol, 77% yield).
11.17.1. Compound 22a. 1H NMR
d (multiplicity, J (Hz), integration):
7.04 (d, 10.0, 1H), 6.05 (d, 10.1, 1H), 4.89 (t, 8.0, 1H), 4.41 (d, 12.4, 1H),
3.92 (d, 12.4 Hz, 1H), 3.46 (dq, 6.2, 8.2, 1H), 2.76 (d, 8.0, 1H), 1.56 (s,
3H), 1.39 (d, 6.2, 3H); 13C NMR
d: 190.4, 153.6, 126.6, 94.0, 82.5, 78.7,
76.0, 51.7, 19.1, 16.7; IR (thin film) 3450, 2980, 2935, 1691, 1105,
1080 cmꢀ1; HRMS (ESI) calcd for C10H13BrO4Naþ: 300.9868, found:
300.9879.
11.20.1. Compound 25a. 1H NMR
7.08 (d, 10.2, 1H), 6.17 (d, J¼10.0 Hz, 1H), 4.63 (q, 7.0, 1H), 4.50 (d,
11.9, 1H), 4.13 (d, 11.9, 1H), 1.69 (d, 7.0, 3H), 1.66 (s, 3H); 13C NMR
d (multiplicity, J (Hz), integration):
d
:
11.18. Scaffold 23
188.7, 168.9, 149.6, 127.6, 80.8, 79.8, 74.6, 50.4, 22.5, 18.4; IR (thin
film) 2923, 1747, 1693, 1271, 1225, 1182, 1070 cmꢀ1; HRMS (EI) calcd
for C10H11BrO4Naþ: 296.9732, found: 296.9737.
Dienone 5a (0.021 g, 0.077 mmol) was dissolved in THFeH2O (5/
1, 1.8 mL) and cooled to 0 ꢁC. NaBH4 (0.0029 g, 0.77 mmol) was
allowed to stand in air for several minutes until it appeared slightly
moist, at which time it was added to the dienone solution. Addition
of dry NaBH4 generally resulted in a mixture of products, including
over-reduction. The reaction was stirred for 5 min at 0 ꢁC, quenched
with saturated NH4Cl, and diluted in EtOAc. The aqueous layer was
extracted with EtOAc. The combined organic layers were washed
with brine, dried (Na2SO4), and concentrated. The crude material
was purified by flash chromatography (40% EtOAcehexanes) to give
23a as colorless oil (0.016 g, 0.059 mmol, 76% yield).
11.20.2. Compound 25b. Yield 85%. 1H NMR
d (multiplicity, J (Hz),
integration): 7.10 (d, 10.1, 1H), 6.18 (dd, 10.1, 0.8, 1H), 4.60 (q, 6.6,
1H), 4.58 (d, 11.8, 1H), 4.14 (d, 11.8, 1H), 2.13 (t, 9.8, 3H), 1.66 (d, 7.1,
3H), 1.4e1.2 (m, 11H), 0.87 (t, 6.9, 3H). 13C NMR
d: 188.6, 169.1, 149.6,
127.9, 83.0, 80.5, 74.5, 50.0, 37.2, 31.8, 30.1, 29.1, 22.8, 22.7, 18.4, 14.2.
11.20.3. Compound 25e. See Ref. 4.
11.20.4. Compound 25f. Yield 62%. 1H NMR (500 MHz)
d (multi-
plicity, J (Hz), integration): 6.96 (d, 10.1, 1H), 6.01 (d, 10.1, 1H), 4.52
11.18.1. Compound 23a. 1H NMR (500 MHz)
d
(multiplicity, J (Hz),
(q, 7.0, 1H), 3.75 (d, 12.1, 1H), 2.41 (dq, 12.5, 6.4, 1H), 1.64 (d, 7.0, 3H),
integration): 5.90 (dd, 2.3, 10.2, 1H), 5.73 (dd, 2.7, 10.3, 1H), 4.65 (m,
1H), 4.49 (q, 7.0, 1H), 3.96 (dd, 8.0, 12.0, 1H), 3.82 (d, 12.0, 1H), 2.65
1.63 (s, 3H), 1.31 (d, 6.7, 3H); 13C NMR (125 MHz)
148.7, 128.8, 81.0, 79.9, 74.3, 44.6, 22.1, 18.5, 11.1.
d: 197.8, 169.9,
(d, 4.5, 1H), 1.66 (d, 7.0, 3H), 1.55 (s, 3H); 13C NMR (125 MHz)
d:
170.1,130.7,128.8, 81.6, 75.6, 75.1, 67.5, 54.2, 24.2,18.6; IR (thin film)
3435, 2986, 2938, 2872, 1744, 1275, 1227, 1047 cmꢀ1; HRMS (ESI)
calcd for C10H13BrO4Naþ: 298.9889, found: 298.9894.
11.21. Scaffold 26
To a solution of bromide 25a (0.230 g, 0.842 mmol) in CH3CN
(15 mL) was added a solution of NaI (0.379 g, 2.53 mmol) in CH3CN
(5 mL), followed by TMSCl (0.215 mL, 1.68 mmol). The resulting
orange solution was stirred at rt for 3 h then quenched with satu-
rated aq Na2S2O3. The colorless solution was diluted with EtOAc,
and the aqueous layer was extracted with EtOAc three times. The
combined organic layers were washed with brine, dried (Na2SO4),
and concentrated. The crude material was purified by flash chro-
matography (30% EtOAcehexanes) to afford 26a as a colorless oil
(0.162 g, 98% yield).
11.19. Scaffold 24
A suspension of anhydrous CeCl3 (0.010 g, 0.046 mmol) and
MeOH (1 mL) was cooled to ꢀ78 ꢁC. Dienone 5a (0.01 g,
0.037 mmol) was added, followed by NaBH4 (0.0018 g,
0.048 mmol). The temperature was maintained at ꢀ78 ꢁC and ad-
ditional NaBH4 (0.0018 g, 0.048 mmol) was added every hour until
the reaction was complete by TLC. The reaction was normally
completed within 2e3 h. The reaction was quenched with satd aq
NH4Cl, and diluted in EtOAc. The aqueous layer was extracted with
EtOAc. The combined organic layers were washed with brine, dried
(Na2SO4), and concentrated. The crude material was purified by
flash chromatography (30% EtOAcehexanes) to give 24a as color-
less oil (0.009 g, 85% yield).
11.21.1. Compound 26a. 1H NMR
d (multiplicity, J (Hz), integration):
7.01 (d, 10.0, 1H), 6.02 (d, 10.0, 1H), 4.54 (q, 7.0, 1H), 4.17 (dd, 5.6,
13.1, 1H), 2.91 (dd, 5.6, 17.5, 1H), 2.49 (dd, 13.1, 17.5, 1H), 1.61 (m,
6H); 13C NMR
d 149.6, 129.3, 80.8, 74.6, 40.3, 21.7, 18.5; IR (thin film)
2981, 2934, 1747, 1688, 1273, 1111; HRMS (CI) calcd for C10H13Oþ4 :
197.0813, found: 197.0810.
11.19.1. Compound 24a. 1H NMR (500 MHz)
d (multiplicity, J (Hz),
integration): 6.82 (d, 9.9, 1H), 6.25 (d, 9.9, 1H), 5.19 (m, 1H), 4.01 (q,
11.21.2. Compound 26b. Yield 98%. 1H NMR (500 MHz)
d (multi-
6.5, 1H), 2.96 (s, 1H), 1.71 (s, 3H), 1.59 (d, 6.5, 3H); 13C NMR
plicity, J (Hz), integration): 7.03 (d, 10.1, 1H), 6.03 (dd, 10.1, 0.9, 1H),
4.52 (q, 7.1, 1H), 4.20 (dd, 12.9, 5.7, 1H), 2.89 (ddd, 17.5, 5.7, 0.9, 1H),
2.58 (dd, 17.5, 12.9, 1H), 2.03 (t, 12.3, 1H), 1.76 (t, 13.2, 1H), 1.61 (d,
6.9, 3H), 1.40e1.20 (m, 10H), 0.88 (t, 6.8, 3H); 13C NMR (125 MHz.
(125 MHz. CDCl3) d: 180.6, 168.9, 147.0, 125.9, 105.5, 92.7, 80.0, 73.6,
27.2, 17.1; IR (thin film) 3398, 2986, 2935, 1659, 1591, 1027, 1055;
HRMS (ESI) calcd for C10H11BrO4Naþ: 296.9732, found: 296.9737.
CDCl3) d: 195.1, 169.9, 149.6, 129.6, 82.8, 75.2, 73.9, 39.9, 36.3, 31.9,
11.20. Scaffold 25
30.2, 29.2, 22.9, 22.8, 18.5, 14.3.
A solution of BHT (1.88 g, 8.54 mmol) in toluene (15 mL) was
cooled to 0 ꢁC and AlMe3 (25% in hexanes, 1.85 mL, 4.26 mmol) was
added. The resulting mixture of MAD was stirred at 0 ꢁC to rt for 1 h,
then cooled to ꢀ78 ꢁC. In a separate flask, dienone 5a was dissolved
in toluene (5 mL), and the solution was added via cannula to the
MAD at ꢀ78 ꢁC, immediately turning deep purple. The reaction was
stirred for 5 min, then L-Selectride (1 M in THF, 2.1 mL, 2.1 mmol)
was added and the solution was stirred for another 5 min at ꢀ78 ꢁC.
11.22. Scaffold 27
A solution of N,N-dimethylhydrazine (0.021 mL, 0.27 mmol) in
CH2Cl2 (1.0 mL) was cooled to 0 ꢁC and AlMe3 (25% in hexanes,
0.110 mL, 0.253 mmol) was added dropwise. The solution was
stirred and allowed to slowly warm to rt for 1 h. The solution was
cooled to 0 ꢁC, and to it was added the vinylogous ester 20a
(0.023 g, 0.084 mmol) as a solution in CH2Cl2 (0.5 mL). The reaction

5882
T.A. Wenderski et al. / Tetrahedron 66 (2010) 5873e5883
was stirred from 0 ꢁC to rt for 4 h. The reaction was quenched with
1 M aq Rochelle’s salt, diluted with EtOAc and stirred vigorously for
1 h. The aqueous layer was extracted four times with EtOAc, and the
combined organic layers were washed with brine, dried (Na2SO4),
and concentrated. To facilitate isolation, the product was derivat-
ized as the silyl ether.
The crude product was dissolved in CH2Cl2 (1.5 mL) and Et3N
(0.105 mL, 0.753 mmol) was added, followed by TBSOTf (0.115 mL,
0.501 mmol). Stirring was continued at rt for 40 min, then the re-
action was quenched with satd aq NaHCO3 and diluted in CH2Cl2.
The aqueous layer was extracted four times with CH2Cl2 and the
combined organics were washed with brine, dried (Na2SO4), and
concentrated. The residue was purified by flash chromatography
(20% EtOAcehexanes) to afford 27a as a colorless oil (0.020 g, 64%
yield over two steps).
(0.04 M in acetone, 3 mL, 0.62 mmol) was added and the reaction
was stirred at 0 ꢁC for 1 h. The reaction mixture was dried (Na2SO4)
and concentrated. The residue was purified by alumina chroma-
tography (5% EtOAcepet. ether) to afford of 29b (0.0598 g, 70%
yield).
11.24.1. Compound 29b. 1H NMR
d (multiplicity, J (Hz), integration):
4.28 (q, 6.9, 1H), 3.62 (dd, 5.8, 11.1, 1H), 3.14 (dd, 1.1, 5.5, 1H), 2.59
(dd, 1H, 5.8, 14.1, 1H), 2.46 (dd, 1H, 5.7, 15.4, 1H), 2.08 (dd, 11.1, 14.1,
1H), 1.93 (t, 9.5, 3H), 1.79 (dd, 1.8, 15.4, 1H), 1.4e1.2 (m, 18H), 0.96
(m, 9H), 0.89 (t, 7.1, 3H), 0.63 (m, 6H).
11.25. Scaffold 30
To a solution of enone 26a (0.0050 g, 0.025 mmol) in toluene
(1.0 mL) at 0 ꢁC was added Et2Zn (1 M in hexanes, 0.052 mL,
0.052 mmol) followed by CH2I2 (0.0045 mL, 0.050 mmol). The re-
action was stirred at 0 ꢁC to rt for 40 h. Pyridine (0.050 mL) was
added and the solution was stirred for 10 min, then diluted with
EtOAc and worked up with H2O. The aqueous layer was extracted
four times with EtOAc. The combined organic layers were washed
with brine, dried (Na2SO4), and concentrated. The crude product
was purified by chromatography (30% EtOAcehexanes) to afford
30a as a colorless oil (0.0038 g, 71% yield).
11.22.1. Compound 27a. 1H NMR
d (multiplicity, J (Hz), integration):
5.70 (s, 1H), 2.66e2.57 (m, 1H), 2.32 (dt, 17.5, 4.9, 1H), 1.81 (m, 7H),
1.49e1.43 (m, 1H), 1.39 (s, 3H), 1.00 (s, 9H), 0.24 (s, 3H), 0.30 (s, 3H);
13C NMR
d: 187.9, 159.5, 92.4, 75.9, 48.1, 36.8, 26.5, 25.7, 24.4, 19.0,
ꢀ2.1, ꢀ3.1; IR (thin film) 2926, 2971, 2854, 1581, 1387 cmꢀ1; HRMS
(ESI) calcd for C15H29BrN2O2Siþ: 399.1073, found: 399.1090.
11.23. Scaffold 28
To a solution of 26a (0.098 g, 0.499 mmol) in toluene (7 mL)
cooled to ꢀ78 ꢁC was added DIBAL (1 M in hexanes, 2.50 mL,
2.50 mmol) and the solution was stirred for 1 h. The reaction
mixture was quenched with 1 M aq Rochelle’s salt, diluted with
EtOAc, quickly warmed to rt and stirred vigorously for 45 min. The
aqueous layer was extracted with EtOAc four times. The combined
organic layers were washed with brine, dried (Na2SO4), and con-
centrated. The crude reaction material was sufficiently pure for
subsequent chemistry.
To a solution of the above crude product in CH2Cl2 (10 mL) was
added active precipitated MnO2 (1.063 g, 12.2 mmol) and the so-
lution was stirred at rt for 16 h. The reaction mixture was filtered
through Celite and concentrated. The crude material was suffi-
ciently pure for subsequent chemistry.
To a solution of the crude reaction material in CH2Cl2 (5 mL) was
added H2NNMe2 (0.025 mL, 0.549 mmol). The solution was stirred
at rt for 4 h, and concentrated under reduced pressure to afford the
hydrazone, which was taken on crude in the following sequence.
The hydrazone (0.064 g, 0.566 mmol) was dissolved in CHCl3
(5 mL). TFA (five drops) was added and the reaction was stirred at rt
for 9 h. It was concentrated and the residue was purified by chro-
matography (5% MeOHeCH2Cl2) to provide 28a as a colorless oil
(0.036 g, 51% yield over four steps).
11.25.1. Compound 30a. 1H NMR
d (multiplicity, J (Hz), integration):
4.46 (q, 7.0, 1H), 4.44 (dd, 10.8, 7.2, 1H), 3.77 (d, 4.1, 1H), 3.49 (d, 4.2,
1H), 2.90 (dd, 19.4, 7.2, 3H), 2.29 (dd, 19.3, 10.8, 3H), 1.58 (d, 7.0, 3H),
1.29 (m, 2H).
11.26. Scaffold 31
Freshly
prepared
homoallylic
magnesium
bromide
(0.153 mmol) in THF (0.5 mL) was added to CuBr$Me2S (0.12 g,
0.058 mmol), instantly forming a dark purple solution. HMPA
(0.054 mL, 0.31 mmol) was added to the cuprate and the solution
was cooled to ꢀ78 ꢁC. In a separate flask, enone 26a (0.0080 g,
0.041 mmol) was dissolved in THF (0.5 mL) and TMSCl (0.032 mL,
0.25 mmol) was added. The enone solution was added via a cannula
to the cuprate solution and the reaction was stirred at ꢀ78 ꢁC for
1.5 h. Et3N (0.035 mL, 0.25 mmol) was added to the solution, and it
was warmed to rt, diluted with Et2O, and worked up with H2O. The
organic layer washed twice with water, once with brine, dried
(Na2SO4), and concentrated. It was purified by chromatography
(20% EtOAcehexanes) to afford 31a (0.0080 g, 89% yield).
11.26.1. Compound 31a. 1H NMR
d (multiplicity, J (Hz), integration):
5.73 (m, 1H), 5.01 (m, 2H), 4.43 (q, 7.0, 1H), 3.99 (dd, 5.8, 12.6, 1H),
2.79 (dd, 5.8,15.4, 1H), 2.54 (d, 4.3, 2H), 2.46 (dd, 12.5,15.4, 1H), 2.16
(m, 2H), 1.96 (m, 2H), 1.68 (s, 3H), 1.60 (d, 7.0, 3H).
11.23.1. Compound 28a. 1H NMR
d (multiplicity, J (Hz), integration):
6.85 (d, 10.1, 1H), 5.94 (d, 10.2, 1H), 4.14 (dd, 5.1, 12.1, 1H), 2.83 (dd,
5.1, 17.0, 1H), 2.45 (dd, 12.1, 16.9, 1H), 1.9 (br s, 2H), 1.43 (s, 3H); 13C
NMR d: 197.5, 154.6, 128.4, 73.8, 73.4, 43.3, 20.7; IR (thin film) 3409,
2954, 2921, 1666, 1047 cmꢀ1; HRMS calcd for C7H11Oþ3 : 143.0708,
found: 143.0705.
11.27. Scaffold 32
To a solution of 25a (0.0740 g, 0.269 mmol) in CH2Cl2 (4.0 mL) at
0 ꢁC was added a solution of Br2 (0.043 g, 0.269 mmol) in CH2Cl2
(1.0 mL) dropwise over 1 h using a syringe pump. The solution was
stirred for an additional 1 h and allowed to gradually warm to rt, as
the solution turned from light orange to colorless. The solution was
re-cooled to 0 ꢁC and Et3N was added (0.056 mL, 0.40 mmol). The
reaction was stirred for an additional 30 min and quenched with
1 M aq HCl. The aqueous layer was extracted with CH2Cl2 four
times. The combined organic layers were dried (Na2SO4) and con-
centrated. The crude product was purified by chromatography (10%
EtOAcehexanes) to afford 32a (0.053 g, 56% yield).
11.24. Scaffold 29
To a solution of 26b (57.9 mg, 0.207 mmol) in degassed benzene
(4 mL, 0.05 M) was added triethylsilane (0.33 mL, 2.07 mmol) and
RhCl(PPh3)3 (19.0 mg, 0.0207 mmol) and the solution was stirred
for 2 h. The solvent was removed by evaporation under a gentle
flow of N2 and the residue was taken up in hexanes. The catalyst
was removed by filtration through a cotton pad and the solution
was concentrated under reduced pressure. The crude oil was dis-
solved in CH2Cl2 (0.5 mL) and cooled to 0 ꢁC. A solution of DMDO

T.A. Wenderski et al. / Tetrahedron 66 (2010) 5873e5883
5883
11.27.1. Compound 32a. 1H NMR
d
(multiplicity, J (Hz), integration):
11.30.1. Compound 35a. 1H NMR
d
(multiplicity, J (Hz), integration):
7.52 (s, 1H), 4.64 (q, 7.0, 1H), 4.58 (d, 12.0, 1H), 4.16 (d, 12.0, 1H), 1.68
(m, 6H).
4.47 (q, 7.0, 1H), 4.35 (ddd, 2.6, 5.1, 13.9, 1H), 4.18 (dd, 10.7, 13.8, 1H),
3.83 (5.1, 8.6, 1H), 2.85 (m, 2H), 2.17 (m, 2H), 1.58 (m, 6H); 13C NMR
d
: 170.2, 169.4, 83.5, 77.4, 73.9, 63.9, 38.8, 36.7, 19.1, 18.3; IR (thin
11.28. Scaffold 33
film): 2923, 1734, 1286, 1258, 1143, 1086 cmꢀ1; HRMS (EI): calcd for
C10H15Oþ5 : 215.0919, found: 215.0914.
To a solution of enone 25a (0.0050 g, 0.018 mmol) and ethyl 2-
((tributylstannyl)methyl)acrylate (0.015 g, 0.037 mmol) in benzene
(1.0 mL) was added AIBN (0.00060 g, 3.6 mmol) and the mixture
Acknowledgements
was heated to 80 ꢁC for 12 h. The solvent was removed under re-
duced pressure and the residue was purified by chromatography
(30% EtOAcehexanes) to afford 34a (0.0045 g, 81% yield).
The National Institutes of Health (R01-GM064831-09) is ac-
knowledged for their support of oxidative dearomatization chem-
istry and their role in society is and appreciated.
11.28.1. Compound 33a. 1H NMR
d (multiplicity, J (Hz), integration):
6.96 (d, 10.2, 1H), 6.20 (d, 1.1, 1H), 6.00 (d, 10.2, 1H), 5.64 (d, 1.1, 1H),
4.36 (q, 7.0, 1H), 4.22 (m, 2H), 3.90 (d, 11.6, 1H), 3.01 (m, 1H), 2.74
(m, 2H), 1.61 (m, 6H), 1.32 (t, 7.2, 3H).
References and notes
1. (a) Zhu, J.; Grigoriadis, N. P.; Lee, J. P.; Porco, J. A., Jr. J. Am. Chem. Soc. 2005, 127,
9342; (b) Dong, S.; Zhu, J.; Porco, J. A., Jr. J. Am. Chem. Soc. 2008, 130, 2738; (c)
Dohi, T.; Maruyama, A.; Takenaga, N.; Senami, K,; Minamitsuju, Y.; Fujioka, H.;
Caemmerer, S. B.; Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 3787; (d) Quideau, S.;
Lyvinec, G.; Marguerit, M.; Bathany, K.; Ozanne-Beaudenon, A.; Buffeteau, T.;
Cavagnat, D.; Chénedé, A. Angew. Chem., Int. Ed. 2009, 48, 4605; (e) Uyanik, M.;
Yasui, T.; Ishihara, K. Angew. Chem., Int. Ed. 2010, 49, 2175.
2. Pettus, L. H.; Van De Water, R. W.; Pettus, T. R. R. Org. Lett. 2001, 6, 905.
3. Mejorado, L. H.; Pettus, T. R. R. J. Am. Chem. Soc. 2006, 128, 15625.
4. Wenderski, T. A.; Huang, S.; Pettus, T. R. R. J. Org. Chem. 2009, 74, 4104.
5. Hoarau, C.; Pettus, T. R. R. Org. Lett. 2006, 8, 2843.
6. (a) Mejorado, L. H.; Hoarau, C.; Pettus, T. R. R. Org. Lett. 2004, 6, 1535; (b) Cha, J.
Y.; Huang, Y.; Pettus, T. R. R. Angew. Chem., Int. Ed. 2009, 48, 9519.
7. Magdziak, D.; Meek, S.; Pettus, T. R. R. Chem. Rev. 2004, 104, 1383.
8. (a) Kita, Y.; Takada, T.; Tohma, H. Pure Appl. Chem. 1996, 68, 627; (b) Varvoglis, A.
Synthesis 1984, 709; (c) Moriarty, R. M.; Prakash, O. Acc. Chem. Res. 1986, 19, 244.
9. (a) Takada, T.; Tajima, R.; Ando, W. J. Org. Chem. 1983, 48, 4764; (b) Fox, A. R.;
Pausacker, K. H. J. Chem. Soc. 1957, 295.
10. Tamura, Y.; Takura, T.; Haruta, J.; Kita, Y. J. Org. Chem. 1987, 52, 3927.
11. Braun, N. A.; Ciufolini, M. A.; Peters, K.; Peters, E.-M. Tetrahedron Lett. 1998, 39,
4667.
11.29. Scaffold 34
Compound 21a (0.00236 g, 0.0119 mmol) was dissolved in a so-
lution of CH2N2 (0.27 M in ether, 1 mL, 0.27 mmol). The mixture
was stirred at 0 ꢁC to rt for 4 h, or until the yellow solution turned
colorless. Additional CH2N2 solution (1 mL) was added and the
process was repeated twice. After the third portion of CH2N2 had
turned colorless, the solution was concentrated and the residue was
purified by chromatography to afford 34a as a colorless oil
(0.00131 g, 52% yield).
11.29.1. Compound 34a. 1H NMR
d (multiplicity, J (Hz), integration):
4.45 (q, 7.0, 1H), 3.90 (dd, 12.4, 4.8, 1H), 2.71 (m, 2H), 1.96 (m, 4H),
1.56 (m, 5H), 1.46 (s, 3H); 13C NMR (125 MHz)
73.9, 56.9, 52.6, 35.7, 33.0, 29.8, 18.7, 18.5.
d: 170.8, 82.6, 76.1,
12. (a) Van De Water, R. W.; Magdziak, D. J.; Chau, J. N.; Pettus, T. R. R. J. Am. Chem.
Soc. 2000, 122, 6502; (b) Jones, R. M.; Van De Water, R. W.; Lindsey, C. C.; Pettus,
T. R. R. J. Org. Chem. 2001, 66, 3435; (c) Hoarau, C.; Pettus, T. R. R. Synlett 2003,
127.
13. (a) Patterson, I.; Wallace, D. J.; Cowden, C. J. Synthesis 1998, 639; (b) Less, S. L.;
Leadlay, P. F.; Dutton, C. J.; Staunton, J. Tetrahedron Lett. 1996, 37, 3519.
14. Van De Water, R. W.; Hoarau, C.; Pettus, T. R. R. Tetrahedron Lett. 2003, 44, 5109.
15. Hoarau, C. Ph.D. Dissertation, University of California, Santa Barbara, CA, 2005.
16. For an example, see: Wipf, P.; Kim, Y.; Jahn, H. Synthesis 1995, 1549.
17. Mejorado, L.H. Ph.D. Dissertation, University of California, Santa Barbara, CA,
2006.
18. Rosenstock, B.; Gais, H.-J.; Herrmann, E.; Raabe, G.; Binger, P.; Freud, A.; We-
demann, P.; Krüger, C.; Lindner, H. J. Eur. J. Chem. 1998, 257.
19. (a) Durst, T.; Kozma, E. C.; Charlton, J. L. J. Org. Chem. 1985, 50, 4829; (b) Wang,
J.; Pettus, T. R. R. Tetrahedron Lett. 2004, 45, 5895.
20. Bohlmann, F.; Suding, H. Liebigs Ann. Chem. 1985, 160.
11.30. Scaffold 35
To a solution of 21a (0.00570 g, 0.0289 mmol) in CH2Cl2 (1.0 mL)
was added m-CPBA (0.0200 g, 0.111 mmol) followed by NaHCO3
(0.0045 g, 0.054 mmol). The solution was stirred at rt for 2 days.
Additional m-CPBA (0.030 g, 0.174 mmol) and NaHCO3 (0.0060 g,
0.072 mmol) were added and stirring was continued for 24 h. The
reaction was quenched with satd aq Na2S2O3 and diluted with
CH2Cl2. The organic layer was washed with aq NaHCO3 and the
aqueous layer was extracted with CH2Cl2 four times. The combined
organic layers were dried (Na2SO4) and concentrated. The crude
material was purified by chromatography (40% EtOAcehexanes) to
afford 35a (0.00401 g, 65% yield).
21. Hamersma, J. W.; Snyder, E. I. J. Org. Chem. 1965, 30, 3985.
22. Doty, B. J.; Morrow, G. W. Tetrahedron Lett. 1990, 43, 6125.