Reagent control of [1,2]-Wagner-Meerwein shift chemoselectivity following the nazarov cyclization: Application to the total synthesis of enokipodin B

Article abstract of DOI:10.1002/chem.201203395

An approach toward the carbon framework of various sesquiterpenes from the herbertane and cuparane families is described, including the concise total synthesis of enokipodin B. The key step is the construction of the vicinal quarter- ACHTUNGTRENUNGnary centers of the skeleton through a tandem Nazarov cyclization/WagnerMeerwein rearrangement mediated by a copper(II) complex. During this study, it was also found that changing the ligand architecture on the copper(II) promoter improved the chemoselectivity of the cationic rearrangement.

Full text of DOI:10.1002/chem.201203395

FULL PAPER
DOI: 10.1002/chem.201203395
Reagent Control of [1,2]-Wagner–Meerwein Shift Chemoselectivity
Following the Nazarov Cyclization: Application to the Total Synthesis of
Enokipodin B
David Lebœuf, Christopher M. Wright, and Alison J. Frontier*[a]
Abstract: An approach toward the carbon framework of various sesquiterpenes
from the herbertane and cuparane families is described, including the concise total
synthesis of enokipodin B. The key step is the construction of the vicinal quarter-
ACHTUNGTRENNUNGnary centers of the skeleton through a tandem Nazarov cyclization/Wagner–Meer-
wein rearrangement mediated by a copper(II) complex. During this study, it was
also found that changing the ligand architecture on the copper(II) promoter im-
proved the chemoselectivity of the cationic rearrangement.
Keywords: copper · cyclization · re-
arrangement · sesquiterpenes · total
synthesis
Introduction
ment sequence.[7,8] By using one equivalent of copper(II)
complexes, we were able to exercise control over the fate of
the oxyallyl cation intermediate, allowing two sequential
[1,2]-shifts to occur. This strategy allowed us to access spiro-
cyclic compounds of type 3 from substrate 1 (see [Eq. (1)];
TMP=2,4,6-trimethoxyphenyl), and cyclopentenones with
vicinal quaternary centers (see 6, [Eq. (2)]). In particular,
we have learned that highly chemoselective Wagner–Meer-
wein shifts occur following the Nazarov cyclization of acyclic
substrates of type 4. The chemoselectivity was found to be
dependent upon two factors: the migratory aptitude and the
steric bulk of the competing migrating groups.[7]
Efficient and stereroselective carbon–carbon bond-forming
methods enable chemists to prepare biologically active mol-
ecules. Amongst them, the Nazarov reaction is a powerful
tool for the construction of functionalized cyclopente-
nones.[1,2] Over the past decade, many innovations have led
to the renaissance of this transformation. Several groups
have established the versatility of the interrupted Nazarov
cyclization, in which the oxyallyl cation intermediate is trap-
ped with nucleophiles to form a new stereocenter.[3] In addi-
tion, new alternative initiation protocols, including AuI- or
PtII-catalyzed [3,3]-rearrange-
ment/4p-electrocyclization,[4]
electrocyclic opening of dichlor-
ocyclopropanes,[5] or conjugate
addition[6] have been also re-
ported. These advances have
not only expanded the utility of
the Nazarov cyclization as a
preparative method for substi-
tuted
cyclopentenones, but have also
galvanized research activity in
4p-electrocyclization chemistry.
Over the past few years, we
have been engaged in the study
of
a
Nazarov cyclization/
Wagner–Meerwein rearrange-
Herein, we report the importance of a third factor: the
substitution pattern of the ligand on copper(II). This finding
allowed us to pursue a new strategic approach toward a
family of natural products, which is demonstrated in a total
synthesis of enokipodin B.
[a] Dr. D. Lebœuf, C. M. Wright, Prof. A. J. Frontier
Department of Chemistry, University of Rochester
Rochester, NY 14627 (USA)
E-mail: frontier@chem.rochester.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203395.
Chem. Eur. J. 2013, 19, 4835 – 4841
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4835

Results and Discussion
high yield of 92% (Table 1, entry 1). Fortunately, the elimi-
nation was completely suppressed when a bulkier copper(II)
bisoxazoline complex was used as promoter. In addition, we
were surprised to find that different copper(II) complexes
gave different ratios of rearrangement products 11a and
12a. Cyclization/rearrangements conducted with ligands L1
and L2 led to a mixture of 11a and 12a (Table 1, entries 2
and 3), whereas the L3 copper complex gave 11a selectively
in 83% yield and with an enantiomeric excess (ee) of 23%.
Although a chiral bisoxazoline ligand is expected to influ-
ence the sense of rotation in the Nazarov electrocyclization,
we and others have found that the impact on torquoselectiv-
ity is often modest.[7b,10,11] Thus, the poor enantioselectivity
observed here is not a surprise.
Controlling reaction pathways with copper(II) bisoxazoline
complexes: During our studies of acyclic substrates that ex-
hibit chemoselective [1,2]-rearrangement (see 4, [Eq. (2)],
we found that bisoxazoline ligands on the promoter have an
unexpectedly strong impact on selectivity in the cyclization/
rearrangements of type 9 substrates. These were prepared
through alkylation of the enone 7 with dimethylcarbonate to
give b-ketoester 8 in 88% yield (Scheme 1). Knoevenagel
In the next set of experiments, we examined the cycliza-
tion/rearrangement of a series of substrates 9. The sequence
afforded products of type 11 as major product, with alkyl
and alkoxy groups at the meta and para positions of the aro-
matic ring in good yields (up to 88%; Table 2, entries 1–5).
In some cases, two different ligands were tested, and ligand
L3 was found to be most selective for rearrangement prod-
ucts of type 11 (Table 2, entries 2–6). We observed also that
the steric hindrance had a strong impact on the migration.
For example, substrate 9h has electron-donating character
equivalent to that of para-methoxyphenyl 9 f, but in 9h the
methoxy group is expected to hinder aryl migration. Indeed,
a mixture of compounds 11h and 12h is obtained, in ratios
of 1:3 and 1:6 (Table 2, entry 7). On the other hand, sub-
strate 9i (bearing an ortho-dimethoxyphenyl group) furnish-
ed only the product 12i (Table 2, entry 8). The structure of
the ligand had an impact on chemoselectivity for substrates
containing both electron-donating and electron-deficient
aryl rings (Table 2, entry 5 (OMe) and entry 6 (Br)). Other
substituents at C5 (2-thienyl and cinammyl) were also tested
(Table 2, entries 9 and 10). In each case, compound 11 was
obtained as the major product in good yield. In most of
cases, the products of type 11 and 12 were separable by
flash chromatography.
Scheme 1. Synthesis of substrates 9.
condensation with the appropriate aryl aldehyde provides
substrates of type 9. The Knoevenagel product is obtained
as an E/Z mixture, but E/Z isomerization is facile under the
reaction conditions, and only the Z isomer cyclizes.[9]
Our initial experiments focused on substrate 9a (Table 1).
The reaction was carried out under typical reaction condi-
tions: Dichloromethane under reflux in the presence of one
equivalent of [(MeCN)5CuACHTNUTRGNE[UNG SbF6]2]. However, the only prod-
uct obtained was the simple Nazarov cycloadduct 10a, in a
Table 1. Effect of the ligand on the rearrangement sequence.
Carrying out the cyclization of substrates 9d, 9e, 9h, and
9j with the acetonitrile copper(II) complex instead of the
bisACTHNUGRTENUNGoxazoline complexes afforded elimination products of
type 10 (see Table 1). Exceptions to this include 9 f, which
cyclized without incident to produce 11 f,[7d] and 9l, which
decomposed (Table 3, see below). On the whole, these find-
ings are consistent with earlier studies, in which we found
that the large bisoxazoline ligand can block elimination, al-
lowing rearrangement pathways to compete.[7b]
We continued our study of the impact of the ligand on the
migration pattern by preparing substrate 9l, which has an
ethyl group at C2. In this case, cyclization generates the oxy-
allyl cation 13, with two methyl groups in a position to mi-
grate from C2 to C1. The [1,2]-methyl shift was selective for
the methyl group opposite the bulky TMP, especially when
the complex employing ligand L3 (Table 3, 3:1 ratio of 12l
to 12’l by using either ligand L1 or L2 and 10:1 ratio using
ligand L3).
Entry
Ligand
(MeCN)5
L1
L2
L3
t
Product
ACHTUNGTRNE(NUNG ratio)
Yield
[%]
[h]
1
2
N
0.2
0.4
10a
11a/12a
AHCTUNGTRENNUNG
92
80
3
4
0.4
0.4
79
83
AHCTUNGTRENNUNG
U
ACHTUNGTRNE(NUNG ee 23%)
4836
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 4835 – 4841

Total Synthesis of Enokipodin B
FULL PAPER
Table 2. CuII-promoted Nazarov cyclization/Wagner–Meerwein re-
Table 3. Effect of the ligand on the rearrangement sequence.
ACHTUNGTRENNUNGarrangement.
Entry
1
Substrate
Ligand
Product
(ratio)
Yield
[%]
AHCTUNGTRENNUNG
11b/12b
L3
12:1
84
Entry
Ligand
(MeCN)5
L1
L2
L3
t
Product
ACHTUNGTRNE(NUNG ratio)
Yield
[%]
[h]
1
2
G
0.1
0.1
–
decomposition
87
12l/12’l
AHCTUNGTRENNUNG
2
11c/12c
1.5:1
>20:1
L1
L3
88
3
4
0.1
0.1
75
76
68[d]
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
3
4
11d/12d
2.2:1
4.3:1
L1
L3
85
76
Thus, although chiral bisoxazolines were not effective for
achieving asymmetric induction, our results suggest that
bisoxazoline ligands can affect selectivities in the rearrange-
ment sequence by virtue of their steric profile. Without the
bisoxazoline ligand, elimination of a proton was favored
over the first [1,2]-migration step (Table 1, entry 1;
Scheme 2, path A). The use of any bisoxazoline ligand (L1,
L2, or L3) led to suppression of this elimination. For the
competing [1,2]-methyl shifts in 9l (Table 3), the use of
ligand L3 led to high diastereoselectivity. The bisoxazoline
ligand architecture of L3 also had a strong impact on selec-
tivity in the second [1,2]-migration (Table 2, entries 2–6 and
Table 3, entries 2–4; Scheme 2, path C). A possible explana-
11e/12e
2:1
5:1
L1
L3
92
72[a],[12]
AHCTUNGTRENN(GUN ee=20%)
5
11 f/12 f
6:1
>20:1
L1
L3
90
88[d]
6
11g/12g
1:1.5
6:1
L1
L3
86
62[b,d]
7
11h/12h
1:3
1:6
L1
L3
63
67[c,d]
8
11i/12i
<1:20
L1
L1
L1
66[d]
9
11j/12j
10:1
85
10
11k/12k
10:1
76
[a] Yield of isolated 11e. [b] Yield of isolated 11g. [c] Yield of isolated
12h. [d] ee not determined.
Scheme 2. Cyclization/rearrangement pathways of substrates 9.
Chem. Eur. J. 2013, 19, 4835 – 4841
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4837

A. J. Frontier et al.
tion for the different selectivities may be that complexes
with ligands L1 and L2 disrupt overlap of the C5 aryl ring
with the C1 cation more effectively than the complex with
L3 does. This disruption would allow a hydride shift (path B,
Scheme 2) to compete with formation of the phenonium ion
intermediate and the subsequent aryl shift (path C,
Scheme 2), compromising the selectivity (i.e., the ratio of 11
to 12).
Application to the synthesis of enokipodins: The ability to
install adjacent quaternary centers in cyclopentenones of
type 11 encouraged us to employ this sequence toward the
total synthesis of enokipodins A–D (Figure 1). They are nat-
Scheme 3. Attempt towards a synthesis of the core of enokipodins.
Since the cyclization and rearrangement of compound 9e
had proceeded with good selectivity (Table 2, entry 4), we
chose to examine 11e as the pivotal intermediate in the syn-
thesis.[20] By using the general approach in which the b-keto-
AHCTUNGTREGeNNUN ster 8 serves as the starting point for assembly of the skele-
ton, compound 11e was obtained after two synthetic opera-
tions (Scheme 4). Then, in an attempt to remove the carbo-
methoxy group with retention of the enone functionality, we
applied the conditions developed by Agosta (NaI/AcOH in
diglyme under reflux conditions).[21] We were surprised to
Figure 1. Enokipodins A—D.
ural products isolated by Ishikawa et al. from the edible
mushroom Flammulina vellutepes (Enokitake).[13] They pos-
sess antifungal activity against Cladosporium herbarum and
antibiotic activity against the Gram-positive bacteria Bacil-
lus subtilis and Staphylococcus aureus.[13] The enokipodins
are highly oxidized members of a large family of sesquiter-
pene natural products that includes cuparene,[14] d-cupar
enol,[14a,15] herbertene,[14e,16] b-herbertenol,[16b–d,17] and g-her-
bertenol (Figure 1).[18] The syntheses of many herbertane
and cuparane family members, including the enokipodins,[19]
have been disclosed over the years, with different strategies
for the introduction of the adjacent quaternary centers of
the cyclopentane ring.
Application of the cyclization/rearrangement sequence to
the synthesis of the cuparane and herbertane natural prod-
ucts requires reactions that are highly selective for products
of type 11, favoring the [1,2]-aryl migration pathway
(Scheme 2). First, we carried out cyclization of substrate 9m
by using the reaction conditions shown in Table 2, hoping to
directly access the ring system corresponding to the enoki-
podins. Poor selectivity was observed in this reaction: both
the elimination product 10m and the hydride-shift product
12m were obtained along with desired compound 11m,
even with ligand L3 (Scheme 3). The steric bulk of the
ortho-methoxy group is probably responsible for the poor
efficiency of the [1,2]-aryl shift.
Scheme 4. Synthesis of enokipodin B from b-ketoester 8.
4838
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 4835 – 4841

Total Synthesis of Enokipodin B
FULL PAPER
(neat): n˜ =2974, 1755, 1724, 1612, 1508, 1458, 1435, 1338, 1250,
1134 cmÀ1; HRMS (EI+): m/z calcd for C18H22O4: 302.1518 [M+H+];
found: 302.1511.
observe that ketone 18 was the only product isolated from
this reaction, a product that represents the unexpected net
reduction of precursor 11e. Demethylation with boron tri-
bromide provides intermediate 19 (64% over two steps),
which was easily converted to enokipodin B through oxida-
tion with Fremyꢁs salt.[22] By using this strategy, the total syn-
thesis of enokipodin B was achieved in only six steps and in
33.9% overall yield from enone 7. Furthermore, Kuwahara
has shown that it was possible to obtain enokipodin A from
reduction of the benzoquinone moiety of enokipodin B.[19b]
This strategy is both concise and general, enabling the
synthesis of enokipodin B and the carbon skeleton of sever-
al other family members from a common precursor (b-keto-
1
Compound 11c: Pale yellow oil. H NMR (400 MHz, CDCl3): d=8.51 (s,
1H), 7.26–7.22 (m, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.98–6.94 (m, 2H), 3.89
(s, 3H), 2.36 (s, 3H), 1.49 (s, 3H), 1.24 (s, 3H), 0.58 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=207.4, 175.7, 162.8, 141.8, 138.2, 132.1,
128.4, 127.9, 127.5, 123.9, 53.8, 52.9, 52.1, 26.2, 25.3, 21.6, 19.8 ppm; IR
(neat): n˜ =2978, 2940, 1732, 1462, 1331, 1254, 1161, 1022, 964 cmÀ1
;
HRMS (EI+): m/z calcd for C17H20O3: 272.1413 [M+H+]; found:
272.1415.
1
Compound 11e: Pale yellow oil. H NMR (400 MHz, CDCl3): d=8.49 (s,
1H), 7.09 (d, J=7.7 Hz, 1H), 6.64 (dd, J=7.7 Hz, 1H), 6.58 (s, 1H), 3.89
(s, 3H), 3.82 (s, 3H), 2.20 (s, 3H), 1.49 (s, 3H), 1.24 (s, 3H), 0.61 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=207.4, 175.5, 162.9, 157.8, 140.6,
132.2, 130.6, 125.8, 118.9, 108.6, 55.4, 53.9, 53.1, 52.2, 26.1, 25.4, 19.9,
15.8 ppm; IR (neat): n˜ =2924, 2855, 1755, 1724, 1612, 1582, 1508, 1250,
1203, 1134, 991 cmÀ1; HRMS (EI+): m/z calcd for C18H22O4: 302.1518
[M+H+]; found: 302.1515.
Compound 11 f: Pale yellow oil. 1H NMR (400 MHz, CDCl3): d=8.46 (s,
1H), 7.07 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 3.89 (s, 3H), 3.81
(s, 3H), 1.48 (s, 3H), 1.22 (s, 3H), 0.57 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=207.5, 175.7, 162.9, 158.6, 133.9, 132.1, 127.9, 113.9, 55.3, 54.0,
52.5, 52.2, 26.1, 25.3, 19.9; IR (neat): n˜ =2970, 2932, 1755, 1721, 1612,
1512, 1439, 1296, 1250, 1184, 1030 cmÀ1; HRMS (EI+): m/z calcd for
C17H20O4: 288.1361 [M+H+]; found: 288.1353.
ACHTUNGTRENNUNGester 8). The condensation of 8 with appropriate aldehydes,
and subsequent cyclization/rearrangement allowed the prep-
aration of cyclopentenones bearing the substitution patterns
of b-herbertenol (11b), cuparene (11c), herbertene (11d),
d-cuparenol (11e), and infuscol A (11 f)[23] (Table 2, en-
tries 1–5).
Conclusion
1
Compound 11g: Pale yellow oil. H NMR (400 MHz, CDCl3): d=8.43 (s,
1H), 7.48 (d, J=8.7 Hz, 2H), 7.04 (d, J=8.5 Hz, 2H), 3.89 (s, 3H), 1.48
(s, 3H), 1.23 (s, 3H), 0.58 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
205.7, 174.4, 162.6, 141.0, 132.6, 131.7, 128.5, 121.3, 53.7, 52.7, 52.2, 26.2,
25.3, 19.8 ppm; IR (neat) n˜ =2974, 2928, 1756, 1720, 1624, 1435, 1389,
1338, 1250, 1076, 1007 cmÀ1; HRMS (EI+): m/z calcd for C16H17O3Br:
336.0361 [M+H+]; found: 336.0365.
Compound 12h: Yellow oil. 1H NMR (400 MHz, CDCl3): d=7.39 (ddd,
J=8.4, 7.5, 1.7 Hz, 1H), 7.19 (dd, J=7.6, 1.7 Hz, 1H), 7.01 (dt, J=7.5,
1.0 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 3.79 (s, 3H), 3.68 (s, 3H), 3.19 (q,
J=7.4 Hz, 1H), 1.24 (s, 3H), 1.10 (s, 3H), 0.96 ppm (d, J=7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=208.0, 177.4, 164.4, 156.3, 131.2, 131.0,
128.4, 123.4, 120.5, 111.0, 55.3, 51.7, 48.8, 47.7, 25.9, 20.6, 14.1 ppm; IR
(neat): n˜ =2947, 2924, 1740, 1697, 1612, 1510, 1462, 1346, 1288, 1258,
1230, 1203, 1126, 1022, 995 cmÀ1; HRMS (EI+): m/z, calcd for C17H20O4:
288.1368 [M+H+]; found: 288.1361.
We have developed an efficient and convergent strategy to
access the carbon framework of several natural products
based on a Nazarov cyclization/rearrangement sequence
mediated by the copper complex [tBuBox-CuACHTNUTRGNE[UNG SbF6]2]. By
using this strategy, the total synthesis of enokipodin B was
achieved in only six steps from enone 7. Chemoselectivity of
the sequence can be favored or disfavored by both substitu-
ents on the substrate and bisoxazoline ligands on the pro-
moter. Ongoing work in our laboratory is focused on im-
proving the enantioselective version of this reaction se-
quence.
Compound 12i: Yellow oil. 1H NMR (400 MHz, CDCl3): d=7.30 (t, J=
8.3 Hz, 1H), 6.58 (d, J=8.4 Hz, 2H), 3.76 (s, 6H), 3.64 (s, 3H), 3.25 (q,
J=7.4 Hz, 1H), 1.23 (s, 3H), 1.09 (s, 3H), 0.91 (d, J=7.4 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3): d=208.4, 178.5, 163.8, 156.7, 131.4, 130.7,
112.7, 103.8, 55.7, 51.5, 48.7, 48.2, 25.4, 20.8, 13.5 ppm; IR (neat): n˜ =
2947, 2928, 1732, 1601, 1574, 1454, 1331, 1234, 1207, 1150, 1122,
1034 cmÀ1; HRMS (EI+): m/z calcd for C18H22O5: 318.1467 [M+H+];
found: 318.1462.
Compound 11j: Pale yellow oil. 1H NMR (400 MHz, CDCl3): d=8.22 (s,
1H), 7.34–7.26 (m, 5H), 6.30 (d, J=16.4 Hz, 1H), 6.06 (d, J=16.3 Hz,
1H), 3.87 (s, 3H), 1.33 (s, 3H), 1.14 (s, 3H), 1.04 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=207.0, 174.4, 162.8, 140.8, 136.5, 132.4, 132.1,
128.7, 127.9, 126.3, 53.8, 52.1, 50.9, 23.5, 22.1, 21.7 ppm; IR (neat): n˜ =
2918, 1755, 1724, 1620, 1455, 1435, 1338, 1260, 1207, 991 cmÀ1; HRMS
(EI+): m/z calcd for C18H20O3: 284.1413 [M+H+]; found: 284.1419.
Experimental Section
General procedure for the cyclization: The copper complex [L-CuACTHUNRTGNEUNG[SbF6]2]
(1 equiv) was added to a stirred solution of a-alkylidene b-keto esters in
CH2Cl2 (0.03m) under argon. The reaction mixture was stirred at room
temperature or heated at reflux until completion of the reaction and then
quenched with aqueous NH4OH and extracted with diethyl ether. The
combined organic layers were washed with brine, dried over magnesium
sulfate, and filtered. After removal of the solvents under reduced pres-
sure, the crude product was purified by flash column chromatography by
using different gradients of pentane and ethyl acetate to obtain the pure
desired products.
1
Compound 11a: Pale yellow oil. H NMR (400 MHz, CDCl3): d=8.51 (s,
1H), 7.37–7.34 (m, 2H), 7.30–7.26 (m, 1H), 7.18–7.16 (m, 2H), 3.89 (s,
3H), 1.50 (s, 3H), 1.24 (s, 3H), 0.57 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=207.3, 175.4, 162.8, 141.9, 132.2, 128.6, 127.3, 126.9, 53.8, 53.1,
52.2, 26.2, 25.3, 19.8; IR (neat): n˜ =2970, 1755, 1720, 1624, 1435, 1339,
1319, 1284, 1250, 995 cmÀ1; HRMS (EI+): m/z calcd for C16H18O3:
258.1254 [M+H+]; found: 258.1251.
Compound 11k: Orange oil. 1H NMR (400 MHz, CDCl3): d=8.33 (s,
1H), 7.24 (d, J=5.2 Hz, 1H), 6.99 (dd, J=5.1, 3.6 Hz, 1H), 6.74 (d, J=
3.5 Hz, 1H), 3.88 (s, 3H), 1.56 (s, 3H), 1.21 (s, 3H), 0.72 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=206.4, 173.2, 162.7, 146.2, 132.4, 126.9,
124.7, 124.4, 54.6, 52.2, 51.4, 26.1, 24.9, 20.2 ppm; IR (neat): n˜ =2970,
2928, 1755, 1720, 1620, 1435, 1335, 1315, 1281, 1254, 1207, 991 cmÀ1
;
1
Compound 11b: Pale yellow oil. H NMR (400 MHz, CDCl3): d=8.47 (s,
HRMS (EI+): m/z calcd for C14H16O3S: 264.0820 [M+H+]; found:
1H), 6.93–6.90 (m, 2H), 6.78 (d, J=8.4 Hz, 1H), 3.89 (s, 3H), 3.82 (s,
3H), 2.22 (s, 3H), 1.46 (s, 3H), 1.22 (s, 3H), 0.58 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3): d=207.6, 176.0, 162.9, 156.8, 133.4, 132.0, 129.1,
126.7, 125.2, 109.7, 55.3, 54.0, 52.5, 52.1, 26.2, 25.4, 19.9, 16.4 ppm; IR
264.0826.
Synthesis of enokipodin B: Potassium nitrosodisulfonate (21.5 mg,
0.08 mmol) and disodium hydrogen phosphate buffer pH 7 (0.1 mL) were
Chem. Eur. J. 2013, 19, 4835 – 4841
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4839

A. J. Frontier et al.
added to a solution of 19 (7.5 mg, 0.032 mmol) in acetone (0.75 mL) and
water (0.15 mL). The reaction mixture was stirred at room temperature
overnight. Then, the solvent was evaporated and the mixture was extract-
ed with ethyl acetate. The combined organic layers were washed with
brine, dried over magnesium sulfate, and filtered. The solvent was re-
moved by rotary evaporation. The crude product was purified by flash
column chromatography (eluent pentane/ethyl acetate 8:2) to give enoki-
podin B (7 mg, 91%) as an orange solid.
Enokipodin B: Orange solid. M.p. 138–1428C; 1H NMR (400 MHz,
CDCl3): d=6.69 (s, 1H), 6.56 (d, J=1.6 Hz, 1H), 2.50–2.42 (m, 2H), 2.27
(ddd, J=12.8, 10.1, 9.8 Hz, 1H), 2.04 (d, J=1.6 Hz, 3H), 1.88 (ddd, J=
12.8, 8.6, 2.4 Hz, 1H), 1.32 (s, 3H), 1.22 (s, 3H), 0.76 ppm (s, 3H).
13C NMR (100 MHz, CDCl3): d=220.9, 188.2, 187.8, 153.5, 144.5, 135.3,
134.1, 52.4, 49.0, 33.8, 31.1, 23.1, 22.1, 20.6, 14.9 ppm; IR (neat): n˜ =2966,
2924, 1740, 1655, 1597, 1462, 1381, 1246, 1095, 1063, 935 cmÀ1; HRMS
(EI+): m/z calcd for C15H18O3: 246.1256 [M+H+]; found: 246.1257.
These data matched with the data reported previously.[14a]
Flynn, Org. Lett. 2012, 14, 1740; y) N. Shimada, C. Stewart, W. F.
Bow, A. Jolit, K. Wong, Z. Zhou, M. A. Tius, Angew. Chem. 2012,
124, 5825; Angew. Chem. Int. Ed. 2012, 51, 5727; z) Y.-K. Wu, T.
Niu, F. G. West, Chem. Commun. 2012, 48, 9186.
[3] For review, see a) T. N. Grant, C. J. Rieder, F. G. West, Chem.
Commun. 2009, 5676 and references cited therein. For other rele-
vant examples, see: b) M. Janka, W. He, I. E. Haedicke, F. R. Fronc-
zek, A. J. Frontier, R. Eisenberg, J. Am. Chem. Soc. 2006, 128, 5312;
c) F. Dhoro, T. E. Kristensen, V. Stockmann, G. P. A. Yap, M. A.
Tius, J. Am. Chem. Soc. 2007, 129, 7256; d) J. Nie, H. W. Zhu, H. F.
Cui, M. Q. Hua, J. A. Ma, Org. Lett. 2007, 9, 3053; e) V. M. Marx,
D. J. Burnell, Org. Lett. 2009, 11, 1229; f) M. Fujiwara, M. Kawat-
sura, S. Hayase, M. Nanjo, T. Itoh, Adv. Synth. Catal. 2009, 351, 123;
g) V. M. Marx, T. S. Cameron, D. J. Burnell, Tetrahedron Lett. 2009,
50, 7213; h) V. M. Marx, D. J. Burnell, J. Am. Chem. Soc. 2010, 132,
1685; i) C. J. Rieder, R. J. Fradette, F. G. West, Heterocycles 2010,
80, 1413; j) O. Scadeng, F. G. West, Org. Lett. 2011, 13, 114; k) V. M.
Marx, F. M. LeFort, D. J. Burnell, Adv. Synth. Catal. 2011, 353, 64;
l) Y.-K. Wu, R. McDonald, F. G. West, Org. Lett. 2011, 13, 3584;
m) V. M. Marx, R. L. Stoddard, G. S. Heverly-Coulson, D. J. Burnell,
Chem. Eur. J. 2011, 17, 8098; n) M. Rueping, W. Ieawsuwan, Chem.
Commun. 2011, 47, 11450.
Acknowledgements
[4] a) L. Zhang, S. Wang, J. Am. Chem. Soc. 2006, 128, 1442; b) G. Le-
miꢃre, V. Gandon, K. Cariou, A. Hours, T. Fukuyama, A.-L. Dhi-
mane, L. Fensterbank, M. Malacria, J. Am. Chem. Soc. 2009, 131,
2993; c) H. Zheng, X. Xie, J. Yang, C. Zhao, P. Jing, B. Fang, X. She,
Org. Biomol. Chem. 2011, 9, 7555.
We thank the National Science Foundation (Grant CHE-0847851, sup-
porting D. L.) for funding this work. We also thank Prof. R. Eisenberg
(University of Rochester) for helpful discussions.
[5] T. N. Grant, F. G. West, Org. Lett. 2007, 9, 3789.
[1] For reviews, see: a) C. Santelli-Rouvier, M. Santelli, Synthesis 1983,
429; b) K. L. Habermas, S. E. Denmark, T. K. Jones in Organic Re-
actions, Vol. 45, (Ed.: L. A. Paquette, L. A.), John Wiley & Sons,
New York, 1994, pp. 1–158; c) M. Harmata, Chemtracts 2004, 17,
416; d) H. Pellissier, Tetrahedron 2005, 61, 6479; e) A. J. Frontier, C.
Collison, Tetrahedron 2005, 61, 7577; f) M. A. Tius, Eur. J. Org.
Chem. 2005, 2193; g) W. Nakanishi, F. G. West, Curr. Opin. Drug
Discov. Devel. 2009, 12, 732; h) N. Shimada, C. Stewart, M. A. Tius,
Tetrahedron 2011, 67, 5851; i) T. Vaidya, R. Eisenberg, A. J. Frontier,
ChemCatChem 2011, 3, 1531.
[6] J. L. Brooks, P. Caruana, A. J. Frontier, J. Am. Chem. Soc. 2011, 133,
12454.
[7] a) J. Huang, A. J. Frontier, J. Am. Chem. Soc. 2007, 129, 8060; b) J.
Huang, D. Lebœuf, A. J. Frontier, J. Am. Chem. Soc. 2011, 133,
6307; c) D. Lebœuf, J. Huang, V. Gandon, A. J. Frontier, Angew.
Chem. 2011, 123, 11173; Angew. Chem. Int. Ed. 2011, 50, 10981;
d) D. Lebœuf, V. Gandon, J. Ciesielski, A. J. Frontier, J. Am. Chem.
Soc. 2012, 134, 6296.
[8] For other examples, see: a) G. Ohloff, K. H. Schulte-Elte, E.
Demole, Helv. Chim. Acta 1971, 54, 2913; b) L. A. Paquette, W. E.
Fristad, D. S. Dime, T. R. Bailey, J. Org. Chem. 1980, 45, 3017;
c) S. E. Denmark, G. A. G. Hite, Helv. Chim. Acta 1988, 71, 195;
d) J. Motoyoshiya, T. Yazaki, S. Hayashi, J. Org. Chem. 1991, 56,
735; e) A. G. Gruhn, W. Reusch, Tetrahedron 1993, 49, 8159; f) C.
Kuroda, H. Koshio, A. Koito, H. Sumiya, A. Murase, Y. Hirono, Tet-
rahedron 2000, 56, 6441; g) P. Chiu, S. L. Li, Org. Lett. 2004, 6, 613.
[9] W. He, I. R. Herrick, T. A. Atesin, P. A. Caruana, C. A. Kellenberg-
er, A. J. Frontier, J. Am. Chem. Soc. 2008, 130, 1003.
[2] For recent examples of Nazarov cyclizations, see: a) D. R. Williams,
L. A. Robinson, C. R. Nevill, J. P. Reddy, Angew. Chem. 2007, 119,
933; Angew. Chem. Int. Ed. 2007, 46, 915; b) W. He, J. Huang, X.
Sun, A. J. Frontier, J. Am. Chem. Soc. 2008, 130, 300; c) A. P.
Marcus, A. S. Lee, R. L. Davis, D. J. Tantillo, R. Sarpong, Angew.
Chem. 2008, 120, 6479; Angew. Chem. Int. Ed. 2008, 47, 6379;
d) A. Y. Bitar, A. J. Frontier, Org. Lett. 2009, 11, 49; e) C. J. Rieder,
K. J. Winberg, F. G. West, J. Am. Chem. Soc. 2009, 131, 7504; f) J. A.
Malona, K. Cariou, A. J. Frontier, J. Am. Chem. Soc. 2009, 131,
7560; g) R. Singh, M. K. Parai, G. Panda, Org. Biomol. Chem. 2009,
7, 1858; h) P. Cordier, C. Aubert, M. Malacria, E. Lacꢂte, V.
Gandon, Angew. Chem. 2009, 121, 8913; Angew. Chem. Int. Ed.
2009, 48, 8757; i) M. Wang, F. Han, H. Yuan, Q. Liu, Chem.
Commun. 2010, 46, 2247; j) P. A. Wender, R. T. Stemmler, L. E.
Sirois, J. Am. Chem. Soc. 2010, 132, 2532; k) K. Murugan, S. Srimur-
ugan, C. Chen, Chem. Commun. 2010, 46, 1127; l) T. Vaidya, A. C.
Atesin, I. R. Herrick, A. J. Frontier, R. Eisenberg, Angew. Chem.
2010, 122, 3435; Angew. Chem. Int. Ed. 2010, 49, 3363; m) D. J.
Kerr, J. M. White, B. L. Flynn, J. Org. Chem. 2010, 75, 7073; n) A. P.
Marcus, R. Sarpong, Org. Lett. 2010, 12, 4560; o) Z. Cai, M. Harma-
ta, Org. Lett. 2010, 12, 5668; p) C. J. Hastings, M. D. Pluth, R. G.
Bergman, K. N. Raymond, J. Am. Chem. Soc. 2010, 132, 6938;
q) C. J. Rieder, K. J. Winberg, F. G. West, J. Org. Chem. 2011, 76,
50; r) W. T. Spencer, III, M. D. Levin, A. J. Frontier, Org. Lett.
2011, 13, 414; s) W.-D. Z. Li, W. G. Duo, C. H. Zhang, Org. Lett.
2011, 13, 3538; t) M. E. Krafft, D. V. Vidhani, J. W. Cran, M. Mano-
haran, Chem. Commun. 2011, 47, 6707; u) J. A. Malona, K. Cariou,
W. T. Spencer, III, A. J. Frontier, J. Org. Chem. 2012, 77, 1891; v) P.
Magnus, W. A. Freund, E. J. Moorhead, T. Rainey, J. Am. Chem.
Soc. 2012, 134, 6140; w) D. J. Kerr, M. Miletic, J. H. Chaplin, J. M.
White, B. L. Flynn, Org. Lett. 2012, 14, 1732; x) D. J. Kerr, B. L.
[10] a) G. Liang, S. N. Gradl, D. Trauner, Org. Lett. 2003, 5, 4931;
b) V. K. Aggarwal, A. J. Belfield, Org. Lett. 2003, 5, 5075.
[11] For other examples of asymmetric Nazarov cyclizations, see: a) G.
Liang, D. Trauner, J. Am. Chem. Soc. 2004, 126, 9544; b) M. Ruep-
ing, W. Ieawsuwan, A. P. Antonchick, B. J. Nachtsheim, Angew.
Chem. 2007, 119, 2143; Angew. Chem. Int. Ed. 2007, 46, 2097;
c) A. R. Banaag, M. A. Tius, J. Org. Chem. 2008, 73, 8133; d) I.
Walz, A. Togni, Chem. Commun. 2008, 4315; e) M. Rueping, W.
Ieawsuwan, Adv. Synth. Catal. 2009, 351, 78; f) K. Yaji, M. Shindo,
Synlett 2009, 2524; g) P. Cao, C. Deng, Y.-Y. Zhou, X.-L. Sun, J.-C.
Zheng, W. Xie, Y. Tang, Angew. Chem. 2010, 122, 4565; Angew.
Chem. Int. Ed. 2010, 49, 4463; h) W. F. Bow, A. K. Basak, A. Jolit,
D. A. Vicic, M. A. Tius, Org. Lett. 2010, 12, 440; i) A. K. Basak, N.
Shimada, W. F. Bow, D. A. Vicic, M. A. Tius, J. Am. Chem. Soc.
2010, 132, 8266; j) S. Raja, W. Ieawsuwan, V. Korotkov, M. Rueping,
Chem. Asian J. 2012, 7, 2361.
[12] The enantiomeric excess was determined by the formation of the de-
rivative with (À)-menthol. The analysis of the 1H NMR spectra of
this product indicated a diastereomeric ratio (d.r.) of 1.4:1.
[13] a) N. K. Ishikawa, K. Yamaji, S. Tahara, Y. Fukushi, K. Takahashi,
Phytochemistry 2000, 54, 777; b) N. K. Ishikawa, Y. Fukushi, K.
Yamaji, S. Tahara, K. Takahashi, J. Nat. Prod. 2001, 64, 932.
4840
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 4835 – 4841

Total Synthesis of Enokipodin B
FULL PAPER
[14] For recent syntheses, see: a) A. Abad, C. Agullꢄ, M. Arnꢄ, A. C.
CuÇat, M. T. Garcꢅa, R. J. Zaragozꢆ, J. Org. Chem. 1996, 61, 5916;
b) C. Fuganti, S. Serra, J. Org. Chem. 1999, 64, 8728; c) T. Cohen, T.
Kreethadumrongdat, X. Liu, V. Kulkarni, J. Am. Chem. Soc. 2001,
123, 3478; d) R. S. Grainger, A. Patel, Chem. Commun. 2003, 1072;
<lit e>A. Nayek, M. G. B. Drew, S. Ghosh, Tetrahedron 2003, 59,
5175.
[18] A. Srikrishna, P. C. Ravikumar, Synthesis 2007, 65.
[19] a) A. Srikrishna, M. S. Rao, Synlett 2004, 0374; b) S. Kuwahara, M.
Saito, Tetrahedron Lett. 2004, 45, 5047; c) M. Saito, S. Kuwahara,
Biosci. Biotechnol. Biochem. 2005, 69, 374; d) F. Secci, A. Frongia, J.
Ollivier, P. P. Piras, Synthesis 2007, 999; e) M. Yoshida, Y. Shoji, K.
Shishido, Org. Lett. 2009, 11, 1441; f) J. A. Lujꢆn-Montelongo, J. G.
Avila-Zꢆrraga, Tetrahedron Lett. 2010, 51, 2232.
[15] J. Gagnepain, F. Castet, S. Quideau, Angew. Chem. 2007, 119, 1555;
Angew. Chem. Int. Ed. 2007, 46, 1533.
[20] This reaction was also carried out in the presence of [tBuBox-Cu-
AHCTUNGTREN[GNUN SbF6]2] (10 mol%) and NaBAr4F (90 mol%; see references [7c]
[16] For recent syntheses, see: a) A. Abad, C. Agullꢄ, A. C. CuÇat, R. H.
Perni, J. Org. Chem. 1999, 64, 1741; b) P. D. Gupta, A. Pal, A. Roy,
D. Mukherjee, Tetrahedron Lett. 2000, 41, 7563; c) A. Srikrishna,
M. S. Rao, Synlett 2002, 0340; d) A. Srikrishna, G. Satyanarayana,
Tetrahedron Lett. 2003, 44, 1027; e) A. M. Bernard, A. Frongia, F.
Secci, P. P. Piras, Chem. Commun. 2005, 3853.
and [7d]), but this combination led to the formation of 20e in a
poor yield (28%).
[21] V. B. Rao, S. Wolff, W. C. Agosta, Tetrahedron 1986, 42, 1549.
[22] E. Alvarez-Manzaneda, R. Chahboun, E. Cabrera, E. Alvarez, A.
Haidour, J. M. Ramos, R. Alvarez-Manzaneda, M. Hmamouchi, H.
Es-Samti, Chem. Commun. 2009, 592.
[17] a) T. Paul, A. Pal, P. D. Gupta, D. Mukherjee, Tetrahedron Lett.
2003, 44, 737; b) S. P. Chavan, R. K. Kharul, R. R. Kale, D. A. Kho-
bragade, Tetrahedron 2003, 59, 2737; c) S. P. Chavan, M. Thakkar,
R. K. Kharul, A. B. Pathak, G. V. Bhosekar, M. M. Bhadbhade, Tet-
rahedron 2005, 61, 3873.
[23] A. Srikrishna, G. Satyanarayana, Synth. Commun. 2004, 34, 3847.
Received: September 21, 2012
Revised: November 26, 2012
Published online: February 21, 2013
Chem. Eur. J. 2013, 19, 4835 – 4841
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4841