A two-step mimic for direct, asymmetric bromonium- and chloronium-induced polyene cyclizations

Article abstract of DOI:10.1016/j.tet.2010.03.037

Although direct, asymmetric, halonium-induced cyclizations have proven difficult to achieve in the absence of enzymes, this report provides a two-step alternative based on reacting polyenes with chiral mercury(II) complexes to afford a number of polycyclic organomercurials that can be subsequently converted, with retention, into their corresponding chlorine, bromine, and iodine derivatives in good yield and enantioselectivity. A five-step asymmetric total synthesis of the natural product 4-isocymobarbatol is also described.

Full text of DOI:10.1016/j.tet.2010.03.037

Tetrahedron 66 (2010) 4796–4804
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A two-step mimic for direct, asymmetric bromonium- and chloronium-induced
polyene cyclizations
*
Scott A. Snyder , Daniel S. Treitler, Andreas Schall
Department of Chemistry, Columbia University, 3000 Broadway, New York, NY 10027, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Although direct, asymmetric, halonium-induced cyclizations have proven difficult to achieve in the
absence of enzymes, this report provides a two-step alternative based on reacting polyenes with chiral
mercury(II) complexes to afford a number of polycyclic organomercurials that can be subsequently
converted, with retention, into their corresponding chlorine, bromine, and iodine derivatives in good
yield and enantioselectivity. A five-step asymmetric total synthesis of the natural product 4-iso-
cymobarbatol is also described.
Received 28 January 2010
Received in revised form 8 March 2010
Accepted 9 March 2010
Available online 15 March 2010
Dedicated to Professor Brian M. Stoltz on the
occasion of his receipt of the Tetrahedron
Young Investigator Award
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Halogenation
Polyene Cyclization
1. Introduction
from geraniol, farnesol, and nerol, leading to the ability to fashion
ring systems pertinent to several hundred natural products, poten-
In the fifty years since Stork and Eschenmoser first delineated the
cation- cyclization hypothesis to account for the formation of
tially including 3–5.9,10 This manuscript details some of our recent
p
studies to synthesize such products enantioselectively.
various polycyclic scaffolds in Nature,1 many investigators have
developed useful laboratory protocols to effect such reactions in
laboratory flasks, several of which are enantioselective.2 One major
area of synthetic deficiency, however, is the field of bromonium- and
chloronium-inducedpolyene cyclizations, examplesof whichwould
include the conversion of napyradiomycin A1 (1, Scheme 1) into
either napyradiomycin B4 (2) or B3 (3).3,4 In Nature, these reactions
are known to be accomplished enantiospecifically through the use of
vanadium-based haloperoxidases;5,6 in the laboratory, however,
these transformations have proven difficult to achieve racemically,
let alone enantioselectively. For example, most simple chemical
initiators like Br2, Cl2, N-bromosuccinimide (NBS), or N-chloro-
succinimide (NCS) convert polyene starting materials into com-
pounds such as 8 and 9 via the intermolecular attack of an external
nucleophile or proton elimination in advance of intramolecular
cyclization to 10, especially if the proximal olefin is electron
deficient.7 As partof a researchprogram seeking totackle this overall
challenge, we recently described the development of a reagent
(Et2SBr$SbBrCl5, BDSB)8 that can smoothly effect direct, racemic,
bromonium-induced cyclizations for a variety of substrates derived
2. Results and discussion
2.1. Logic of approach pursued
To date, only asymmetric iodonium-based polyene cyclizations
have been achieved successfully as described by Ishihara and
co-workers11 through complexation of N-iodosuccinimide (NIS) by
a stoichiometric amount of a phosphorous-based chiral ligand.
This approach has enabled access to 3 aryl-containing products,
including 12 (Scheme 2), in high enantioselectivity and reasonable
yield following 24 h of controlled reaction at ꢀ40 ꢁC. As of yet,
however, application of the same strategy to bromonium- and
chloronium-based cyclizations has not met with success in terms
of asymmetry. This result likely reflects the profound differences
in reactivity between iodine and its halogen cousins,12 where the
rapid transfer of bromonium to unreacted alkenes in solution prior
to intramolecular cyclization provides a pathway to degrade any
enantioselectivity initially imparted by
a chiral electrophilic
halogen reagent, and chloronium species behave more like car-
bocations prone to eliminations and rearrangements.13 Given this
knowledge, we felt that an indirect (i.e., two-step) solution might
be an effective way to solve this longstanding problem. Indeed,
* Corresponding author. Tel.: þ1 212 854 3817; fax: þ1 212 932 1289; e-mail
address: sas2197@columbia.edu (S.A. Snyder).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.037

S.A. Snyder et al. / Tetrahedron 66 (2010) 4796–4804
4797
HO
O
HO
O
O
Scheme 2 provides three possible alternatives. Two of these, the
use of a chiral epoxide (#2)14 or a halohydrin (#3)15 starting
material followed by a Lewis-acid mediated cyclization (15/16
and 17/18), were both anticipated to be difficult to reduce to
practice. For instance, the chiral epoxide case requires two likely
low-yielding inversion reactions following cyclization, while the
other approach requires methodology to access halohydrins
Cl
Cl
Asymmetric
chloronium-
induced
Cl
Cl
Me
Me
Me
Me
HO
Cl
O
HO
O
Me
O
Me
cyclization
Me
OH
Me
Me
Me
1: napyradiomycin A1
Asymmetric
2: napyradiomycin B4
bromonium-
HO
enantioselectively. The final alternative, one inspired by recent
16
cyclization
´
work from the Gagne group to form alkene products, would be
Br
HO
O
O
the use of a chiral metal-based complex to effect asymmetric
cyclization (19/20), followed by a second step to replace that
metal within 20 with retention to afford all halogen derivatives
with high enantiocontrol. This option appeared the most attractive.
Cognizant of the unique power of Hg(II) salts to initiate a number
Cl
Me Me
4: ma'ilione
Me
O
Cl
Me
Me
HO
Br
O
Me
Br
H
Me Me Me OH
Me
of racemic cation-p
cyclizations17 and the capability to convert the
3: napyradiomycin B3
5:
resultant organomercurials into the corresponding iodides18 and
bromides19 with the potential for retention,20 we wondered if the
cyclization step could be rendered asymmetric and thus provide
a realization of this indirect alternative. However, while simply
stated, precedent in support of such a notion was not encouraging.
Indeed, even though many chiral forms of Hg(II) are known, such
reagents have enabled only one reaction, an intramolecular
mercurioetherification, to proceed with high levels of enantiocon-
trol;21 most other attempts, including efforts to accomplish asym-
metric oxymercuration with isoprenes,22 have afforded little
selectivity thus far.23 Moreover, our desired application, a carbo-
cyclization reaction, could not benefit from the ability of reactive
groups to directly bind to the metal center prior to reaction, thereby
rendering the reaction process arguably more difficult than those
reported to date. Nevertheless, we hoped that with the right chiral
ligand complex and an appropriately activated Hg(II) center, an
asymmetric version of this reaction could be developed.
R =
Me
Me
Me
Me
Me
aryl,
Me
X
"
"
alkyl
X
X
R
R
R
R
Me
6
Me
7
Me
10
R = CN, OAc, CO2Y
Me
Me
Me
Me
cation-
and/or
cyclization
products
X
X
R
Nu Me
9: Nu = Halogen or OH
8
Scheme 1. Selected natural products, which likely result from asymmetric halonium-
induced cation-
racemic format.
p cyclizations and challenges in achieving these reactions, even in
Ishihara and co-workers were able to develop one such approach
by converting their chiral iodides (such as 12) into the corres-
ponding bromides and chlorides through lithiation and stereo-
retentive halide capture (to give 13 and 14).11 Other solutions for
this problem, however, should exist, particularly ones with greater
substrate generality.
2.2. Chiral ligand selection and optimization
Based on several studies by Nishizawa, which revealed that
simple amine complexes of Hg(OTf)2 possess good solubility and
electrophilic reactivity profiles,24 we decided to begin our studies
by screening a variety of chiral heteroatom-based ligands to
determine if they could enable an asymmetric, Hg(II)-induced
1. Asymmetric iodocyclization and replacement
Me
1. L3P-I
,
Me
Me
toluene,
Me
Me
-40 °C, 24 h;
Me
I
2. ClSO3H,
-78 °C, 4 h
Me
Me
cation-p cyclization to be achieved. As shown in Scheme 3, our
(57%, 95% e.e.)
12
11
initial model substrate was the geraniol-derived polyene 21,
a molecule which we expected to cyclize to organomercurial 22
following its exposure to a complex formed by admixing 1.1 equiv
of Hg(OTf)2 with 1.2 equiv of a chiral ligand. Subsequent treatment
with Br2 (3.0 equiv) in oxygenated pyridine, according to the pro-
cedure of Hoye and Kurth,19c was anticipated to then complete the
synthesis of 23 as a single diastereomer (with aryl bromination).
In the absence of any chiral ligand, these operations proceeded
smoothly in 83% yield. However, once the Hg(OTf)2 was complexed,
only a few of the added ligands out of over 30 screened (including
24–32)25 led to any enantioselectivity (ee) in the opening step, with
bis-oxazolines linked by a single carbon bridge being the only class
that gave more than 25% ee with any of the commercially available
structural variants screened (entries 1–4, Table 1) at ꢀ78 ꢁC in a 1:1
mixture of CH2Cl2 and acetonitrile (MeCN) followed by warming.
Though a modest start, the general ease of synthesis for members of
this ligand class26 led us to attempt optimization of this result.
Given the ease of altering aromatic rings versus aliphatic
systems like tert-butyl or adamantyl, and considering the
2-naphthyl case within Table 1 (entry 6) as a potentially improved
derivative of the phenyl reagent in entry 3, we began our initial
screening by keeping phenyl constant and altering the bis-
oxazoline structure in other locations. As indicated in Table 2,
any additional substituent at R2 afforded no improvement in
enantioselection, while a modest increase (to 40% ee) was
Me
Me
t-BuLi,
BrCF2CF2Br or
ClCF2CF2Cl
Me
H
Me
H
(85% for 13)
(70% for 14)
I
X
Me Me
Me Me
12
13: X = Br
14: X = Cl
2. Chiral epoxides
1. Lewis-acid
mediated
Me
Me
Me
O
cyclization
2. OH inversion
X
X
H
Me
3. OH to halogen
Me Me
15
16
3. Chiral halohydrins
Lewis-acid
mediated
cyclization
Me
Me
Me
X
H
HO Me
Me Me
17
18
4. Metal-mediated cyclizations
Me
Me
Me
chiral metal
complex
[M]
H
Me
Me Me
19
20
Scheme 2. Possible multi-step alternatives for forming the effective products of direct,
asymmetric halonium-induced cation- cyclization.
p

4798
S.A. Snyder et al. / Tetrahedron 66 (2010) 4796–4804
OMe
Hg(OTf)2,
chiral ligand,
solvent;
and linker structure (not shown) led either to no improvement or,
MeO
Me
OMe
more commonly, inferior enantioselection.27,28 The same absence
of improvement was observed when the reaction solvent was
Me
Me
Me
BrHg
aq. NaBr
quench
OMe
Me
22
Me
switched to one typically employed for Hg(II)-based cation-
cyclizations, such as pure MeCN or nitromethane.
p
21
Br2, LiBr,
O2, pyridine
However, when the reaction was performed in pure CH2Cl2,
a solvent that is not typically associated with cation- cyclizations,
MeO
Me
OMe
Br
MeO
Me
p
OMe
Me
substantial improvements in ee for compound 23 were obtained for
several bis-oxazoline ligands, particularly those possessing longer
backbone substituents (entries 3 and 6) than that of the original
lead structure (entry 2). By exploring this lead further as shown in
Table 3, enantioselection was maximized to 72% ee when pentyl
chains were attached to the ligand backbone (entry 3), with de-
creasing control observed upon the addition of extra carbon atoms
(entries 4–6) or additional branching (entry 7). With an optimized
backbone in hand, exploration of a number of additional versions of
the original C2-symmetric aromatic rings revealed that adding
electron donating groups (Table 4, entry 3) or bulk (entry 5)
afforded no improvement in enantiocontrol, while strongly
electron-withdrawing substitutents were deleterious; as an in-
ternal check that extra substitution at R2 was not tolerated, we
prepared the ligand in entry 2 and obtained the expected decrease
in enantiocontrol. Thus, the optimized ligand (that of entry 1 in
Table 4, named hereafter as 32a) allowed for the synthesis of 23 in
a total of 79% yield and an enantiomeric ratio of 6.4:1 (72% ee).
Pleasingly, if the intermediate organomercurial (22) so produced
was recrystallized prior to its conversion into 23, the resultant solid
was nearly racemic, providing a means to remove the minor en-
antiomer through filtration. Concentration of the mother liquor,
followed by conversion of the resultant material into its bromide
counterpart, accomplished a synthesis of 23 from 21 in 53% overall
yield and 99% ee, a result commensurate to the Ishihara precedent.11
We note that the absolute configuration of 22 was confirmed via
X-ray crystallographic analysis to be that as drawn within Scheme 3.
Br
Br
Br
H
Me
23
Me Me
23
Selected examples of ligand classes screened:
N
N
O
O
PPh2
PPh2
Me
Me
PPh2
PPh2
R
OH HO
R
R
R
24
Ph Ph
25
26: R = t-Bu
CN
O
O
Me
Me
OH
OH
O
O
R
O
O
N
N
N
NH
N
Ph Ph
27
R
R
R
28
29
Me Et
O
O
Me
N
O
R
O
O
O
O
O
N
N
N
N
N
N
R
Ph
R
R
Ph
30
31
32
Scheme 3. Preliminary studies to effect a mercury(II)-induced asymmetric carbocyc-
lization reaction.
Table 1
Preliminary studies with bis-oxazoline ligands
Me Me
O
O
N
N
Table 3
R
R
Further optimization efforts with bis-oxazoline ligands
R
R
Entry
R
% ee 23 in 1:1 CH2Cl2/MeCN
O
O
1
2
3
4
5
6
Benzyl
CH(CH3)2
Ph
C(CH3)3
Adamantyl
2-Naphthyl
0
4
28
30
33
35
N
N
Entry
R
% ee 23 in CH2Cl2
1
2
3
4
5
6
7
CH2CH3
59
70
72
70
64
64
69
observed by altering the alkyl backbone substituents from the
original methyl-based lead (entry 2) to ethyl groups (entry 3).
Unfortunately, intensive efforts to improve upon this result
through a number of other substantive changes to both backbone
(CH2)3CH3
(CH2)4CH3
(CH2)5CH3
(CH2)7CH3
(CH2)9CH3
(CH2)2CH(CH3)2
Table 2
Initial optimization efforts with bis-oxazoline ligands
R1 R1
O
O
Table 4
R2
R2
N
N
Final optimization efforts with bis-oxazoline ligands
O
O
R2
R2
Entry
R1
R2
% ee 23 in 1:1 CH2Cl2/MeCN
% ee 23 in CH2Cl2
N
N
1
2
3
4
5
6
7
8
9
H
CH3
H
H
H
H
H
H
Ph
Ph
Ph
0
28
40
18
20
25
8
9
30
59
d
d
52
d
d
d
R1
R1
CH2CH3
–(CH2)3–
–(CH2)4–
Benzyl
H
Entry
R1
R2
% ee 23 in CH2Cl2
1
2
3
4
5
Ph
Ph
p-OMePh
p-CF3Ph
H
Ph
H
H
H
72
52
72
41
68
CH3
CH2CH3
29
33
2-Naphthyl

S.A. Snyder et al. / Tetrahedron 66 (2010) 4796–4804
4799
2.3. Exploration of substrate scope
diastereoselectivity was observed for the iodine exchange in line
with literature precedent18 for this particular halogen. In addition, it
is worth noting that every intermediate organomercurial we have
produced thus far is crystalline; thus, enhancements in optical ac-
tivity by recrystallization should be facile whenever needed.
With this promising result in hand, we next tested the ability of
the same optimized ligand (32a) to effect asymmetric cation-p cy-
clizations with a variety of other substrates as shown in Table 5,
including those possessing smaller (entries 2–4) and larger aromatic
systems (entry 5), as well as a series of non-aromatic terminating
groups (entries 6–8) with differing degrees of electron-deficiency in
the intervening chain. In all cases but one, cyclization yields and
enantioselectivities were good. The one poor substrate (41, entry 7),
at least in terms of enantioselection, was a model compound for
a napyradiomycin B3 or B4 (2 and 3, cf. Scheme 1) total synthesis,
likely failing due to the steric bulk imparted by the two methyl
groups adjacent to the ketone, especially in light of the good enan-
tioselectivity observed in the cyclization of compound 43 (entry
8).29 Nevertheless, in all other cases, the reaction worked well in
terms of chiral selection, and the optimized chiral ligand (32a) could
be recovered at the end of each transformation and reused with no
subsequent loss in enantiocontrol. We have also exchanged the in-
termediate organomercurial produced from the cyclization of 33 for
chlorine, bromine, and iodine with equal efficiency to serve as proof-
of-principle for broad halide generation, though some erosion in
2.4. Total synthesis of 4-isocymobarbatol
In a final exploration of the power of the developed chemistry,
we decided to test a slightly more complex intermediate, namely
polyene 47 (Scheme 4), in hopes of accomplishing an asymmetric
total synthesis of the natural product 4-isocymobarbatol (49).30,31
Pleasingly, this material, prepared readily via addition of lithium
species 46 (derived from protection and lithiation of commercially
available 2,5-dibromohydroquinone) to commercially available
geranyl bromide (45), smoothly underwent cyclization (with con-
comitant cleavage of one of the methoxymethyl ethers) and bro-
mination to afford 48 in 81% yield and 51% ee using optimized
ligand 32a; recrystallization of the bromide product afforded access
to 48 in 48% yield and 90% ee (19:1 er). As a point of comparison for
this key step, direct bromonium-induced cyclization of 47 with
2,4,4,6-tetrabromocyclohexa-2,5-dienone (TBCO) provided racemic
48 in only 35% yield.31 A final, acid-induced deprotection of the
remaining methoxymethyl ether then completed the synthesis of
the target molecule (49).
Table 5
Exploration of the generality of mercury-induced cation-
mized chiral ligand 32a
p
cyclization with opti-
1. Hg(OTf)2 (1.1 equiv),
OMOM
Me
Me
Me
32a (1.2 equiv),
Me
CH2Cl2; aq. NaX
X
Br
2. X2, LiX, O2, pyridine
46
Me
Me
Me
Me
Br
OMOM
(75%)
Me
Me
Me
Me
Entry
1
Starting material
Product
MeO
Yield (%) ee (%)
45
47
1. Hg(OTf)2, 32a,
CH2Cl2; NaBr
2. Br2, LiBr,
(81%, 51% e.e.)
(48%, 90% e.e.
after
MOMO
Br
46
OMe
Br
OMe
Me
Me
Me
Li
OMOM
Br
recrystallization)
O2, pyridine
79
72
53a
99a
OMe
Me
O
Me
O
Br
H
Me
Br
HCl,
THF
Me Me
23
21
(97%)
Br
OH
Br
H
OMOM
H
Me Me
Me Me
Me
H
49: 4-isocymobarbatol
48
Me
Me
2
3
4
67
66
72
81b
81b
Scheme 4. Enantioselective total synthesis of 4-isocymobarbatol (49) via an asym-
metric cation- cyclization.
X
81b,c
Me
p
Me Me
34: X = Cl
35: X = Br
36: X = I
33
Finally, we note that while all the above studies were conducted
with stoichiometric amounts of chiral ligand, the reaction can also
be performed with sub-stoichiometric quantities as well, since
Hg(OTf)2 itself is only barely soluble in CH2Cl2 while its ligand-
complexed form is completely soluble. As indicated in Table 6, li-
gand loadings as low as 0.33 equiv still allowed for a productive
Me
Me
Me
5
77
64
Br
H
Me
Me Me
38
37
Me
OH
Me
Me
6
7
OAc
65
80
62
28
OAc
Br
Table 6
Me
Me Me
40
Explorations into the ability to use sub-stoichiometric amounts of 32a in the
asymmetric mercury(II)-induced cation-p cyclization of 21
39
Me
Me OH
O
O
1. Hg(OTf)2, chiral
ligand 32a, CH2Cl2,
-78 to 0 °C;
Me
Me
MeO
Me
OMe
Br
OMe
Me
Me
Me
Me
Br
Me Me
41
aq. NaBr
H
Me
Me Me
42
2. Br2, LiBr,
OMe
O2, pyridine Br
Me
H
21
23
Me Me
Me
Me
O
O
8
74
69d
Entry
Ligand 32a (equiv)
Yield (%)
ee (%)
Me
H
1
2
3
4
5
6
1.20
1.00
79
78
80
70
65
47
72
68
59
56
31
13
43
Me Me
44
a
0.50a
0.33a
0.20a
0.10a
After recrystallization.
b
c
TfOH added at end of first step to promote final closure.
Generated as a 3.4:1 mixture of diastereomers in final conversion to alkyl iodide,
with the ee the same for both diastereomers.
d
The intermediate organomercurial was reduced upon reaction with NaBH4.
a
K2CO3 (5 equiv) added.
OTf¼trifluoromethanesulfonate.

4800
S.A. Snyder et al. / Tetrahedron 66 (2010) 4796–4804
cyclization of 21 without significant erosion in either the yield or
enantioselectivity of 23, with the addition of 5.0 equiv of K2CO3
performed to ensure that the ligand was not protonated (and thus
turnover was possible).
4.2. Synthesis of optimized ligand 32a
Diethyl malonate (3.00 mL, 19.8 mmol, 1.0 equiv) was added
dropwise under a constant flow of argon to a suspension of NaH
(1.03 g, 60% in mineral oil, 25.7 mmol, 1.3 equiv) in THF (20 mL) at
0 ꢁC. 1-Iodopentane (3.88 mL, 29.7 mmol, 1.5 equiv) was then
added and the solution was refluxed at 75 ꢁC for 12 h. Upon
completion, the reaction mixture was cooled to 0 ꢁC and quenched
slowly with 1 M HCl (40 mL) and brine (20 mL). The crude product
was extracted into EtOAc (3ꢂ20 mL) and the combined organic
layers were washed with saturated aqueous NaHCO3 (20 mL) and
brine (20 mL), dried (MgSO4), and concentrated. This crude mixture
of mono- (w80%) and bis-alkylated (w19%) material was resub-
jected to the identical alkylation procedure outlined above. The
resultant crude product was purified by flash column chromato-
graphy (silica gel, hexanes/EtOAc, 19:1) to afford diethyl dipentyl-
malonate (4.78 g, 80% yield) as a light yellow oil.
3. Conclusions
We have developed a procedure capable of mimicking the di-
rect, asymmetric, halonium-induced cation-
p cyclizations com-
monly used in Nature to fashion complex architectures. Although it
requires two steps and a stoichiometric amount of an activated
metal, the process proceeds in good yield and enantioselectivity
with a range of aryl- and non-aryl-containing geraniol derivatives
with an easily prepared, and recoverable, chiral ligand. And, while it
must be conceded that other, less potentially toxic, initiators would
ultimately be more advantageous for this overall process,32
mercury does provide some advantages that would be difficult to
otherwise replicate, including: (1) the intermediate organomercu-
rials are not only air stable but also readily recrystallized to provide
near optically-pure products, and (2) the incorporated mercury can
be replaced with many atoms other than halides (C, H, and OH, for
example)33 to afford a multiplicity of additional enantioenriched
compounds. For now, however, this work provides a foundation for
future studies, which hopefully will enable the enantioselective
synthesis of materials as complex as the napyradiomycins to be
achieved in a reaction flask without enzymatic intervention.
A solution of NaOH (9.50 g, 239 mmol, 15 equiv) in deionized
water (40 mL) was added to diethyl dipentylmalonate (4.78 g,
15.9 mmol, 1.0 equiv) in 1-propanol (20 mL). The resultant mixture
was refluxed with vigorous stirring at 110 ꢁC for 14 h, during which
time it became homogeneous. Upon completion, the reaction con-
tents were cooled to 0 ꢁC and the resultant upper layer was isolated,
concentrated, and then returned to the reaction mixture, which was
subsequently acidified by the slow addition of concentrated HCl.
The crude product was then extracted into Et2O (5ꢂ100 mL) and the
combined organic layers were concentrated to give dipentylmalonic
acid (3.90 g, quantitative) as a light yellow solid. Although ap-
proximately 98% pure based on 1H NMR analysis, the crude diacid
could be purified further by recrystallization from boiling hexanes
(w0.2 g/mL; first crop¼3.45 g of large white needles, 89% yield;
second crop¼0.355 g of off-white needles, 98% combined yield).
Dipentylmalonic acid (1.00 g, 4.09 mmol, 1.0 equiv) and N,N-
dimethylformamide (0.064 mL, 0.82 mmol, 0.2 equiv) were dis-
solved in dry CH2Cl2 (25 mL). Oxalyl chloride (1.73 mL, 20.5 mmol,
5.0 equiv) was added dropwise at 25 ꢁC under a constant flow of
argon. The reaction mixture was heated to 40 ꢁC for 1 h, then cooled
and concentrated by rotary evaporation in a fume hood to remove
excess oxalyl chloride. The crude diacid chloride was redissolved in
CH2Cl2 (20 mL) and added via addition funnel (over approximately
30 min) to a suspension of (R)-phenylglycinol (1.23 g, 9.00 mmol,
2.2 equiv) in CH2Cl2 (75 mL) containing Et3N (2.84 mL, 20.5 mmol,
5.0 equiv) at ꢀ78 ꢁC. Once the addition was complete, the reaction
mixture was allowed to warm slowly to 0 ꢁC over the course of 2 h,
then quenched by the addition of 1 M HCl (50 mL) and extracted
into CH2Cl2 (3ꢂ150 mL). The combined organic layers were washed
with a mixture of saturated aqueous NaHCO3/brine (1:1, 100 mL),
which was back-extracted with CH2Cl2 (100 mL). The combined
organic layers were then dried (MgSO4), concentrated, and
recrystallized from boiling EtOAc (w40 mL, then 10 mL) to yield the
desired diamide product (first crop¼1.54 g, 78% yield; second
crop¼0.250 g, 91% combined yield) as a white crystalline solid.
Methanesulfonyl chloride (1.24 mL, 16.0 mmol, 5.0 equiv) was
added dropwise to a solution of the diamide obtained above (1.54 g,
3.19 mmol, 1.0 equiv) in Et3N (4.4 mL, 31.9 mmol, 10 equiv) and
CH2Cl2 (60 mL) at ꢀ78 ꢁC. After 10 min of stirring at ꢀ78 ꢁC, the
reaction contents were allowed to warm to 25 ꢁC, and 4 M KOH
(20 mL) and (n-Bu)4NCl (0.20 g, 0.80 mmol, 0.25 equiv) were added
sequentially. After 3 h of vigorous stirring, the organic layer was
separated and the aqueous layer was washed with CH2Cl2
(2ꢂ15 mL). The combined organic layers were dried (MgSO4) and
concentrated to yield a dark yellow amorphous solid, which was
purified by flash column chromatography (silica gel, hexanes/EtOAc,
4:1) to afford ligand 32a (1.36 g, 95% yield) as a colorless amorphous
solid. The total yield for 32a over four steps was 68%. Compound 32a:
Rf¼0.55 (silica gel, hexanes/EtOAc, 3:2); IR (film) nmax 2952, 2922,
4. Experimental section
4.1. General
All reactions were carried out under an argon atmosphere with
dry solvents under anhydrous conditions, unless otherwise noted.
Dry methylene chloride (CH2Cl2) and tetrahydrofuran (THF) were
obtained by passing commercially available pre-dried, oxygen-free
formulations through activated alumina columns; acetonitrile
(MeCN) was dried over 3 Å molecular sieves, distilled, and stored
over 3 Å molecular sieves; pyridine was distilled from CaH2 and
stored over 3 Å molecular sieves; triethylamine (Et3N) was distilled
from KOH and stored over 3 Å molecular sieves. Yields refer to
chromatographically and spectroscopically (1H and 13C NMR) ho-
mogeneous materials, unless otherwise stated. Reagents were
purchased at the highest commercial quality and used without
further purification, unless otherwise stated. Reactions were mag-
netically stirred and monitored by thin-layer chromatography (TLC)
carried out on 0.25 mm E. Merck silica gel plates (60F-254) using
UV light as visualizing agent and an aqueous solution of phos-
phomolybdic acid and cerium sulfate, and heat as developing
agents. Preparative thin-layer chromatography was carried out on
0.50 mm E. Merck silica gel plates (60F-254). SiliCycle silica gel (60,
academic grade, particle size 0.040–0.063 mm) was used for flash
column chromatography. NMR spectra were recorded on Bruker
DRX-300 and DRX-400 instruments and calibrated using residual
undeuterated solvent as an internal reference. The following
abbreviations were used to explain the multiplicities: s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet, br¼broad,
app¼apparent. IR spectra were recorded on a Nicolet Avatar 370
DTGS series FT-IR spectrometer. Melting points were taken on an
Electrothermal MEL-TEMPÒ Model 1201D instrument, and are un-
corrected. High-resolution mass spectra (HRMS) were recorded in
the Columbia University Mass Spectral Core facility on a JOEL HX110
mass spectrometer using FAB (Fast Atom Bombardment) and EI
(Electron Ionization) techniques. All enantiomeric excess (ee)
values were obtained by HPLC using a Daicel CHIRALCEL OD
column. Compounds 39, 45, 46, and 47 were prepared according to
the procedures defined in Ref. 8.

S.A. Snyder et al. / Tetrahedron 66 (2010) 4796–4804
4801
2865, 1652, 1491, 1448, 698 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.37–
(dt, J¼3.6, 14.0 Hz, 1H), 2.96 (dd, J¼17.6, 3.6 Hz, 1H), 2.67 (ddd,
J¼19.2, 12.4, 6.8 Hz, 1H), 2.30 (dq, J¼3.6, 13.2 Hz, 1H), 2.13 (dq,
J¼13.6, 4.0 Hz, 1H), 1.96 (dd, J¼13.2, 6.8 Hz, 1H), 1.62 (dq, J¼5.6,
12.4 Hz, 1H), 1.32 (s, 3H), 1.28 (m, 2H), 1.16 (s, 3H), 1.05 (s, 3H); 13C
7.24 (m, 10H), 5.24 (dd, J¼10.0, 8.0 Hz, 2H), 4.65 (dd, J¼10.0, 8.4 Hz,
2H), 4.12 (t, J¼8.0 Hz, 2H), 2.11 (m, 4H), 1.33 (br s, 12H), 0.88 (t,
J¼6.4 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 169.3 (2C), 142.6 (2C),
128.8 (4C), 127.6 (2C), 126.9 (4C), 75.1 (2C), 69.7 (2C), 46.4, 32.7 (2C),
32.1 (2C), 27.8 (2C), 22.6 (2C), 14.1 (2C); HRMS (FAB) calcd for
C29H39N2Oþ2 [MþH]þ 447.3012, found 447.2991.
NMR (75 MHz, CDCl3) d 158.3, 154.4, 138.0, 131.0, 106.1, 95.6, 69.4,
56.4, 55.5, 53.8, 40.4, 39.6, 38.4, 35.2, 32.0, 31.0, 20.6, 19.6, 19.0;
HRMS (FAB) calcd for C19H26Br2Oþ2 [M]þ 444.0300, found
444.0304; HPLC (OD column, 1.5% 2-propanol in hexanes, 1.0 mL/
min, 30 ꢁC, 288 nm) tR (major)¼6.21 min, tR (minor)¼6.94 min.
4.3. Typical procedure for enantioselective mercury-induced
cation-p cyclization
4.4.1. Tricyclic bromide 35. White solid; Rf¼0.45 (silica gel, hex-
anes/EtOAc, 19:1); IR (film) nmax 3058, 2968, 2947, 1488, 1476, 1448,
Hg(OTf)2 (0.055 g, 0.110 mmol, 1.1 equiv) and 32a (0.054 g,
0.120 mmol, 1.2 equiv) were suspended in dry CH2Cl2 (9 mL) under
an argon atmosphere and stirred vigorously at 25 ꢁC for 10 min, at
which time no precipitate remained; the resultant solutionwas then
cooled to ꢀ78 ꢁC. A solution of substrate 21 (0.029 g, 0.100 mmol,
1.0 equiv) in CH2Cl2 (1 mL) was added dropwise and the reaction
mixture was stirred at ꢀ78 ꢁC for 1 h. The reaction contents were
then allowed to warm slowly to 0 ꢁC over the course of 2 h. Upon
completion, a mixture of saturated aqueous NaBr (1 mL), saturated
NaHCO3 (2 mL), and water (2 mL) was added to the reaction, and the
resultant slurry was stirred vigorously at 25 ꢁC for 15 min. The re-
action contents were then extracted with CH2Cl2 (3ꢂ10 mL), and the
combined organic layers were then dried (MgSO4) and concen-
trated. Purification of the resultant crude amorphous solid by flash
column chromatography (silica gel, hexanes/EtOAc, 1:0/1:1)
afforded organomercurial 22 (0.052 g, 92% yield) as a white crys-
talline solid along with recovered ligand 32a (0.052 g, 97% recovery).
Enhancement of ee by recrystallization was achieved by dissolving
the solid organomercury bromide 22 in warm EtOAc (5 mL), diluting
with warm hexanes (50 mL), and storing at ꢀ20 ꢁC for 24 h. Sub-
sequently, the small white crystals (0.017 g, 30% yield) of nearly ra-
cemic 22 were isolated by filtration; concentration of the mother
liquor afforded enantiopure 22 (0.035 g, 62% yield) as a white solid.
Note: following bromination, ee values were determined to be 12%
for the crystals and 99% for the filtrate. Compound 22: mp¼200 ꢁC
(with decomposition); Rf¼0.40 (silica gel, hexanes:EtOAc, 4:1); IR
(film) nmax 2979, 2924, 2848, 2831, 1607, 1577, 1460, 1292, 1157,
1377, 764, 724 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 7.21 (m, 1H), 7.16–
7.02 (m, 3H), 4.05 (dd, J¼12.8, 4.4 Hz, 1H), 3.00–2.83 (m, 2H), 2.42–
2.22 (m, 3H), 1.98 (m, 1H), 1.81 (m, 1H), 1.60 (dt, J¼3.2, 13.2 Hz, 1H),
1.48 (dd, J¼12.0, 2.0 Hz, 1H), 1.25 (s, 3H), 1.16 (s, 3H), 1.07 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 148.8, 134.9, 129.2, 126.0, 125.7, 124.6, 69.0,
51.4, 40.2, 40.0, 38.0, 31.7, 30.9, 30.7, 25.0, 20.7, 18.4; HRMS (EI)
calcd for C17H23Brþ [M]þ 306.0983, found 306.0981; HPLC (OD
column, 2.0% 2-propanol in hexanes, 1.0 mL/min, 30 ꢁC, 265 nm) tR
(minor)¼6.92 min, tR (major)¼9.43 min.
4.4.2. Tetracyclic bromide 38. White solid; Rf¼0.80 (silica gel, hex-
anes/EtOAc, 9:1); IR (film) nmax 3058, 2969, 2949, 1509, 1453, 1376,
1038, 976, 811, 744 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 7.97 (d,
J¼8.0 Hz, 1H), 7.78 (d, J¼8.0 Hz, 1H), 7.68 (d, J¼8.2 Hz, 1H), 7.54–7.37
(m, 3H), 4.07 (dd, J¼12.4, 4.0 Hz, 1H), 3.38 (dd, J¼17.6, 6.0 Hz, 1H),
3.21–3.09 (m, 1H), 2.46–2.37 (m, 2H), 2.30 (m, 1H), 2.19 (m, 1H), 1.92
(m, 1H), 1.65–1.52 (m, 2H), 1.35 (s, 3H), 1.22 (s, 3H), 1.12 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 145.5, 132.3, 131.7, 129.5, 128.3, 126.7, 126.2,
125.3,123.3 (2C), 68.9, 51.5, 40.4, 40.0, 38.4, 31.7, 30.7, 28.2, 24.4, 20.6,
18.4; HRMS (EI) calcd for C21H25Brþ [M]þ 356.1140, found 356.1146;
HPLC (OD column, 1.0% 2-propanol in hexanes, 1.0 mL/min, 30 ꢁC,
233 nm) tR (minor)¼7.53 min, tR (major)¼9.83 min.
4.4.3. Cyclic acetate 40. Colorless amorphous solid; Rf¼0.28 (silica
gel, hexanes/EtOAc, 1:1); IR (film) nmax 3456 (br), 2973, 2948, 2875,
1736, 1367, 1243, 1155, 1030 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 4.43
1087 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
6.27 (d, J¼2.4 Hz, 1H), 6.18
(dd, J¼12.0, 5.2 Hz, 1H), 4.33 (dd, J¼12.0, 5.2 Hz, 1H), 3.98 (dd,
J¼12.4, 4.0 Hz, 1H), 2.50 (s, 1H), 2.19 (dq, J¼14.0, 4.0 Hz, 1H), 2.07 (s,
3H), 2.02 (dq, J¼3.6,13.6 Hz,1H),1.81 (dt, J¼13.6, 3.6 Hz, 1H),1.72 (t,
J¼5.2 Hz, 1H), 1.59 (dt, J¼4.0, 14.0 Hz, 1H), 1.24 (s, 3H), 1.18 (s, 3H),
(d, J¼2.4 Hz, 1H), 3.75 (s, 6H), 3.18 (dt, J¼3.6, 13.6 Hz, 1H), 2.92–2.81
(m, 3H), 2.27 (dq, J¼3.6, 13.6 Hz, 1H), 1.97 (dq, J¼14.0, 3.6 Hz, 1H),
1.81 (m,1H),1.62 (m,1H),1.38 (d, J¼11.2 Hz,1H),1.31 (s, 3H),1.21 (dt,
J¼3.6,13.6 Hz,1H),1.15 (s, 3H),1.13 (s, 3H); 13C NMR (75 MHz, CDCl3)
1.00 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 171.2, 71.9, 66.0, 63.6, 55.7,
d
159.6, 158.2, 138.7, 129.3, 104.9, 97.8, 77.4, 56.6, 55.3, 55.2, 40.3,
43.1, 39.9, 32.2, 30.4, 24.0, 21.3, 17.8; HRMS (FAB) calcd for
C12H22BrOþ3 [MþH]þ 293.0752, found 293.0742; HPLC (OD column,
8.0% 2-propanol in hexanes, 1.0 mL/min, 30 ꢁC, 209 nm) tR
(minor)¼7.84 min, tR (major)¼8.55 min.
39.9, 38.9, 37.2, 33.6, 27.7, 26.5, 20.9, 19.9; HRMS (FAB) calcd for
C19H2881Br198HgOþ2 [MþH]þ 567.0881, found 567.0903.
4.4. Procedure for the replacement of mercury by bromine
4.4.4. Cyclic hemiketal 42. White solid; Rf¼0.71 (silica gel, hex-
anes/EtOAc, 8:2); IR (film) nmax 3522 (br), 2968, 2948, 2870, 1478,
Pure organomercurial 22 (0.035 g, 0.062 mmol, 1.0 equiv) and
anhydrous LiBr (0.027 g, 0.308 mmol, 5.0 equiv) were sealed under
an O2 atmosphere. Anhydrous pyridine (0.6 mL) was then added
and the resultant mixture was stirred for 10 min at 25 ꢁC. The re-
action flask was then covered with aluminum foil, and a solution of
Br2 in pyridine (0.284 mL,104 mg of Br2/mL, 0.185 mmol, 3.0 equiv)
was added dropwise via syringe. The resultant mixture was stirred
at 25 ꢁC for 2 h in the dark. Upon completion, the reaction contents
were quenched with freshly prepared 0.5 M aqueous Na2SO3
(5 mL) and extracted with CH2Cl2 (3ꢂ5 mL). The combined organic
layers were then dried (MgSO4) and concentrated. Purification of
the resultant crude solid by flash column chromatography (silica
gel, hexanes/EtOAc, 9:1) afforded pure 23 (0.024 g, 86% yield) as
a white solid. Compound 23: Rf¼0.40 (silica gel, hexanes/EtOAc,
7:3); IR (film) nmax 2943, 2871, 2838, 1589, 1456, 1434, 1344, 1312,
1447, 1379, 1149, 1043, 1020, 994, 708 cmꢀ1 1H NMR (400 MHz,
;
CDCl3)
d
7.51 (dd, J¼8.4, 1.6 Hz, 2H), 7.34–7.24 (m, 3H), 4.05 (dd,
J¼12.4, 4.8 Hz, 1H), 2.30–2.10 (m, 3H), 2.06 (t, J¼12.8 Hz, 1H),
1.82–1.68 (m, 3H), 1.51 (s, 3H), 1.32 (dd, J¼12.8, 1.6 Hz, 1H), 1.08 (s,
3H), 1.05 (s, 3H), 0.96 (s, 3H), 0.65 (s, 3H); 13C NMR (75 MHz,
CDCl3)
d 144.1, 127.8, 127.4 (4C), 101.9, 75.8, 67.2, 48.8, 42.1, 39.2,
38.7, 32.8, 32.1, 29.7, 26.2, 26.1, 24.3, 17.9; HRMS (FAB) calcd for
C20H28BrOþ2 [MꢀH]þ 379.1273, found 379.1272; HPLC (OD
column, 2.0% 2-propanol in hexanes, 1.0 mL/min, 30 ꢁC, 257 nm)
tR (major)¼4.60 min, tR (minor)¼5.74 min.
4.5. Procedure for the replacement of mercury by chlorine
Cl2 gas (7.4 mg, 0.104 mmol, 2.0 equiv) was syringed in-
crementally into a solution of anhydrous LiCl (6.6 mg, 0.155 mmol,
3.0 equiv) and the tricyclic organomercury chloride obtained from
1201, 1179, 1073, 1022, 696 cmꢀ1; 1H NMR (400 MHz, CDCl3)
(s, 1H), 4.04 (dd, J¼12.8, 4.4 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.09
d 6.38

4802
S.A. Snyder et al. / Tetrahedron 66 (2010) 4796–4804
starting material 33 (0.024 g, 0.052 mmol, 1.0 equiv) in anhydrous
pyridine (1 mL) at ꢀ40 ꢁC. After 20 min of stirring at ꢀ40 ꢁC, the
reaction contents were quenched with freshly prepared 0.5 M
aqueous Na2SO3 (5 mL) and extracted with CH2Cl2 (3ꢂ5 mL). The
combined organic layers were then dried (MgSO4) and concentrated.
Purification of the resultant crude solid by preparative TLC (silica gel,
hexanes) afforded 34 (0.012 g, 87% yield) as a white solid. Compound
34: Rf¼0.48 (silica gel, hexanes/EtOAc,19:1); IR (film) nmax 3059, 2969,
2947, 1489, 1448, 1378, 878, 770, 758, 722 cmꢀ1; 1H NMR (400 MHz,
(0.019 g, 96% yield) as a colorless amorphous solid. Compound 44:
Rf¼0.49 (silica gel, hexanes/CH2Cl2, 2:1); IR (film) nmax 2926, 2865,
1651, 1447, 1376, 1326, 1098, 1061, 1051, 753 cmꢀ1
;
1H NMR
(400 MHz, CDCl3)
d
7.55 (app d, J¼8.0 Hz, 2H), 7.32–7.21 (m, 3H),
5.30 (dd, J¼5.6, 2.4 Hz, 1H), 2.17 (dt, J¼17.6, 5.2 Hz, 1H), 2.06–1.93
(m, 2H), 1.69–1.51 (m, 4H), 1.47 (app d, J¼11.6 Hz, 1H), 1.32 (app t,
J¼12.0 Hz, 1H), 1.27 (s, 3H), 0.97 (s, 3H), 0.88 (s, 3H); 13C NMR
(75 MHz, CDCl3)
d 149.2, 137.0, 128.2 (2C), 127.7, 124.8 (2C), 97.0,
77.0, 48.6, 41.8, 40.1, 33.5, 32.4, 20.9, 20.0 (2C), 19.2; HRMS (FAB)
calcd for C18H24Oþ [Mþ] 256.1827, found 256.1812; HPLC (OD col-
umn, 0.2% 2-propanol in hexanes, 1.0 mL/min, 30 ꢁC, 261 nm) tR
(minor)¼5.81 min, tR (major)¼6.88 min.
CDCl3)
d
7.23–7.02 (m, 4H), 3.81 (dd, J¼12.0, 4.8 Hz,1H), 3.01–2.82 (m,
2H), 2.36(m,1H), 2.25–2.05 (m, 2H),1.94 (m,1H),1.80 (m,1H),1.58(dt,
J¼12.8, 4.4 Hz, 1H), 1.42 (dd, J¼12.0, 2.4 Hz, 1H), 1.23 (s, 3H), 1.15 (s,
3H),1.02 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 148.9,134.9,129.2,126.0,
125.7,124.6, 72.8, 51.4, 40.1, 38.9, 37.9, 30.8, 30.4, 29.4, 25.0, 20.1,16.9;
HRMS (EI) calcd for C17H23Clþ [M]þ 262.1488, found 262.1493; HPLC
(OD column, 2.0% 2-propanol in hexanes,1.0 mL/min, 30 ꢁC, 265 nm)
tR (minor)¼6.83 min, tR (major)¼9.33 min.
4.8. Acid-catalyzed Friedel–Crafts step in the synthesis
of 34, 35, and 36
TfOH (0.026 mL, 0.298 mmol, 3.0 equiv) was syringed dropwise
into a solution of the mixture of chromatographically purified
monocyclic and tricyclic organomercury chloride products (0.046 g,
0.099 mmol, 1.0 equiv) derived from the cyclization of 33 in dry
CH2Cl2 (10 mL) at ꢀ78 ꢁC. After stirring for 2 h at ꢀ78 ꢁC, the re-
action contents were quenched with saturated aqueous NaHCO3
and extracted with CH2Cl2 (3ꢂ10 mL). The combined organic layers
were then dried (MgSO4), concentrated, and purified by flash col-
umn chromatography (silica gel, hexanes/EtOAC, 19:1) to afford the
fully cyclized organomercurials as single diastereomers (0.042 g,
91% yield).
4.6. Procedure for the replacement of mercury by iodine
A solution of the organomercurial iodide obtained from starting
material 33 (0.032 g, 0.058 mmol, 1.0 equiv) in pyridine (3 mL) at
25 ꢁC was stirred for 1 h under an oxygen atmosphere in a reaction
flask covered in aluminum foil. Next, a solution of I2 (0.073 g,
0.288 mmol, 5.0 equiv) in pyridine (1 mL), also covered in foil, was
added very slowly by syringe pump over the course of 5 h. Once the
addition was complete, the reaction contents were stirred for an
additional 24 h at 25 ꢁC in the dark and then quenched with freshly
prepared 0.5 M aqueous Na2SO3 (10 mL) and extracted with CH2Cl2
(3ꢂ10 mL). The combined organic layers were then dried (MgSO4)
and concentrated. Purification of the resultant crude solid by flash
column chromatography (silica gel, hexanes/CH2Cl2, 4:1) afforded
36 (3.4:1 dr favoring the equatorial iodide, 0.019 g, 93% yield) as
a colorless amorphous solid. Compound 36: Rf¼0.43 (silica gel,
hexanes/EtOAc, 19:1); IR (film) nmax 3058, 2963, 2943, 2853, 1488,
4.9. Synthesis of cyclization precursors
4.9.1. Homogeranyl-3,5-dimethoxybenzene
(21). Approximately
0.5 mL of a solution of 3,5-dimethoxybenzyl chloride (0.373 g,
2.00 mmol, 2.0 equiv) in THF (5 mL) was added to magnesium
turnings (activated with an acidic rinse and thoroughly flame dried;
0.097 g, 4.0 mmol, 4.0 equiv) under argon at 25 ꢁC. Following initi-
ation (w2 min), the reaction mixture was cooled to 0 ꢁC and the
remainder of the 3,5-dimethoxybenzyl chloride solution was added
dropwise. After stirring for 1 h at 0 ꢁC, the resultant Grignard solu-
tion was cooled to ꢀ40 ꢁC and syringed quickly into a solution of
geranyl diethyl phosphate (0.290 g, 1.00 mmol, 1.0 equiv) in THF
(1 mL) at ꢀ40 ꢁC. The reaction mixture was then warmed slowly to
25 ꢁC over the course of 4 h and stirred for an additional 12 h at
25 ꢁC. Upon completion, the reaction contents were quenched with
saturated aqueous NH4Cl (10 mL) and water (10 mL) and extracted
with hexanes/EtOAc (2:1, 3ꢂ20 mL). The combined organic layers
were then washed with saturated aqueous NaHCO3 (20 mL) and
brine (20 mL), dried (MgSO4), and concentrated. The resultant crude
yellow oil was purified by removal of 3,5-dimethoxytoluene via
distillation (100 ꢁC at 2 mmHg) followed by flash column chroma-
tography (silica gel, hexanes/CH2Cl2, 1:1) to afford 21 (0.274 g, 95%
yield) as a light yellow oil. Compound 21: Rf¼0.41 (silica gel, hex-
anes/EtOAc, 9:1); IR (film) nmax 2928, 2855, 2837, 1596, 1462, 1428,
1448, 1376, 1191, 737, 722 cmꢀ1
torial isomer)
2.95–2.87 (m, 2H), 2.54 (dq, J¼3.6, 13.6 Hz, 1H), 2.45 (dq, J¼14.0,
4.0 Hz, 1H), 2.18 (m, 1H), 2.00 (m, 1H), 1.81 (m, 1H), 1.63–1.54 (m,
2H), 1.25 (s, 3H), 1.14 (s, 3H), 1.09 (s, 3H); 1H NMR (400 MHz, CDCl3,
;
1H NMR (400 MHz, CDCl3, equa-
7.20–7.02 (m, 4H), 4.28 (dd, J¼12.8, 4.0 Hz, 1H),
d
axial isomer) d 7.27 (m, 1H), 7.18–7.01 (m, 3H), 4.69 (br s, 1H), 2.97–
2.89 (m, 2H), 2.25–2.10 (m, 4H), 1.86–1.70 (m, 3H), 1.23 (s, 3H), 1.18
(s, 3H), 1.14 (s, 3H); 13C NMR (75 MHz, CDCl3, equatorial isomer)
d
148.9, 134.8, 129.2, 126.0, 125.7, 124.6, 53.6, 50.0, 42.0, 39.7, 38.3,
34.5, 33.2, 31.0, 25.0, 21.8, 21.3; 13C NMR (75 MHz, CDCl3, axial
isomer) 149.3, 135.0, 129.2, 126.0, 125.5, 124.4, 55.4, 44.8, 38.1,
d
38.0, 37.9, 35.2, 31.0, 30.0, 26.4, 20.1, 18.6; HRMS (EI) calcd for
C17H23Iþ [M]þ 354.0845, found 354.0855; HPLC (OD column,1.0% 2-
propanol in hexanes, 1.0 mL/min, 30 ꢁC, 265 nm) axial iodine: tR
(minor)¼4.39 min, tR (major)¼4.71 min; equatorial iodine: tR
(minor)¼7.54 min, tR (major)¼10.99 min.
4.7. Procedure for the replacement of mercury by hydrogen
1205, 1155, 1068, 829 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 6.37 (d,
J¼2.0 Hz, 2H), 6.30 (t, J¼2.0 Hz, 1H), 5.19 (dt, J¼1.2, 7.2 Hz, 1H), 5.10
(tt, J¼6.8, 1.2 Hz, 1H), 3.78 (s, 6H), 2.59 (app t, J¼8.0 Hz, 2H), 2.30 (q,
J¼7.6 Hz, 2H), 2.12–1.96 (m, 4H),1.69 (s, 3H),1.61 (s, 3H),1.59 (s, 3H);
A solution of the cyclic organomercury bromide obtained from
starting material 43 (0.042 g, 0.078 mmol, 1.0 equiv) in a mixture of
CH2Cl2/EtOH (1:1, 4 mL) was sparged with argon and then covered
with aluminum foil. A solution of NaBH4 (7.4 mg, 0.196 mmol,
2.5 equiv) in 4 M aqueous NaOH (0.1 mL) was then added dropwise
and the resultant reaction contents were stirred at 25 ꢁC for 15 min.
Upon completion, solid MgSO4 (w0.5 g) was added to the reaction
mixture, and the resultant contents were filtered. The filtrate was
concentrated, added to saturated aqueous NH4Cl (10 mL), and
extracted into hexanes (3ꢂ10 mL). The combined organic layers
were then dried (MgSO4), concentrated, and purified by flash col-
umn chromatography (silica gel, hexanes/CH2Cl2, 4:1) to afford 44
13C NMR (75 MHz, CDCl3)
d 160.8 (2C), 145.0, 135.9, 131.5, 124.5,
123.7,106.7 (2C), 97.8, 55.4 (2C), 39.9, 36.6, 29.9, 26.9, 25.8,17.8,16.2;
HRMS (FAB) calcd for C19H28Oþ2 [M]þ 288.2089, found 288.2086.
4.9.2. Homogeranylbenzene (33). Prepared as in Section 4.9.1 in 92%
yield, substitutingbenzylchloridefor 3,5-dimethoxybenzyl chloride
and omitting the distillation portion of the purification. Compound
33: colorless oil; Rf¼0.58 (silica gel, hexanes/CH2Cl2, 4:1); IR (film)
nmax 3027, 2966, 2922, 2855, 1496, 1453, 1376, 746, 698 cmꢀ1 1H
;
NMR (400 MHz, CDCl3)
d
7.29 (m, 2H), 7.20 (m, 3H), 5.21 (dt, J¼1.2,

S.A. Snyder et al. / Tetrahedron 66 (2010) 4796–4804
4803
7.2 Hz,1H), 5.11 (tt, J¼6.8,1.2 Hz,1H), 2.66 (app t, J¼8.0 Hz, 2H), 2.32
(q, J¼7.6 Hz, 2H), 2.12–1.97 (m, 4H), 1.71 (s, 3H), 1.62 (s, 3H), 1.57 (s,
an argon atmosphere and stirred vigorously at 25 ꢁC for 10 min, at
which time no precipitate remained; the resultant solution was
then cooled to ꢀ78 ꢁC. A solution of substrate 47 (0.033 g,
0.080 mmol, 1.0 equiv) in CH2Cl2 (1 mL) was then added dropwise
at ꢀ78 ꢁC. The reaction contents were allowed to warm slowly to
ꢀ40 ꢁC and stirred at that temperature for an additional 6 h. Upon
completion, a mixture of saturated aqueous NaBr (1 mL), saturated
NaHCO3 (4 mL), and water (4 mL) was added to the reaction, and
the resultant slurry was stirred vigorously at 25 ꢁC for 15 min. The
reaction contents were then extracted with CH2Cl2 (3ꢂ10 mL), and
the combined organic layers were dried (MgSO4) and concentrated.
Purification of the resultant crude solid by flash column chroma-
tography (silica gel, hexanes/EtOAc, 9:1) gave the desired organo-
mercury bromide intermediate (0.043 g, 83% yield) as a white
crystalline solid. Next, this newly prepared organomercurial
(0.043 g, 0.066 mmol, 1.0 equiv) and anhydrous LiBr (0.029 g,
0.332 mmol, 5.0 equiv) were sealed under an O2 atmosphere. An-
hydrous pyridine (0.7 mL) was then added and the resultant mix-
ture was stirred for 10 min at 25 ꢁC. The reaction flask was then
covered with aluminum foil, and a solution of Br2 in pyridine
(0.267 mL, 119 mg of Br2/mL, 0.199 mmol, 3.0 equiv) was added
dropwise via syringe. The resultant mixture was stirred at 25 ꢁC for
6 h in the dark. Upon completion, the reaction contents were
quenched with freshly prepared 0.5 M aqueous Na2SO3 (5 mL) and
extracted with CH2Cl2 (3ꢂ5 mL). The combined organic layers were
then dried (MgSO4) and concentrated. Purification of the resultant
crude solid by flash column chromatography (silica gel, hexanes/
EtOAc, 1:0/4:1) afforded pure 48 (0.029 g, 97% yield, 51% ee) as
a white solid. Two consecutive recrystallizations from 2 mL boiling
hexanes afforded enantioenriched 48 (0.017 g, 58% yield, 90% ee).
HPLC conditions for 48: (OD column, 2.0% 2-propanol in
hexanes, 1.0 mL/min, 30 ꢁC, 295 nm) tR (minor)¼5.97 min, tR
(major)¼6.90 min. Finally, 12 M HCl (0.21 mL, 2.57 mmol, 40 equiv)
was added dropwise to a solution of 48 (0.029 g, 0.064 mmol,
1 equiv) in THF (2 mL) at 25 ꢁC. After stirring for 6 h at 25 ꢁC, the
reaction contents were diluted with water (5 mL) and extracted
with EtOAc (3ꢂ10 mL). The combined organic layers were then
dried (MgSO4), concentrated, and purified by flash column chro-
matography (silica gel, hexanes/EtOAc, 9:1) to afford 4-iso-
cymobarbatol (49, 0.025 g, 97% yield) as a light yellow solid.
3H); 13C NMR (75 MHz, CDCl3)
d 142.6, 135.9, 131.5, 128.6 (2C),128.3
(2C), 125.8, 124.5, 123.8, 39.9, 36.3, 30.1, 26.9, 25.8, 17.8, 16.1; HRMS
(EI) calcd for C17Hþ24 [M]þ 228.1878, found 228.1891.
4.9.3. 1-(Homogeranyl)naphthalene (37). Prepared as in Section
4.9.1 in 71% yield, substituting 1-(chloromethyl)-naphthalene for
3,5-dimethoxybenzyl chloride and omitting the distillation
portion of the purification. Compound 37: colorless oil; Rf¼0.8
(silica gel, hexanes/EtOAc, 1:9); IR (film) nmax 3047, 2965, 2924,
2855, 1597, 1510, 1445, 1377, 777; 1H NMR (400 MHz, CDCl3)
d 8.08
(d, J¼8.0 Hz, 1H), 7.86 (d, J¼8.0 Hz, 1H), 7.72 (d, J¼8.0 Hz, 1H),
7.55–7.31 (m, 4H), 5.30 (t, J¼7.2 Hz, 1H), 5.12 (t, J¼6.8 Hz, 1H), 3.11
(app t, J¼7.6 Hz, 2H), 2.46 (q, J¼7.6 Hz, 2H), 2.12–1.96 (m, 4H), 1.71
(s, 3H), 1.62 (s, 3H), 1.55 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 138.6,
136.0, 134.0, 132.1, 131.5, 128.9, 126.6, 126.1 125.8, 125.7, 125.5,
124.5, 124.0 (2C), 39.9, 33.3, 29.4, 26.9, 25.9, 17.8, 16.2; HRMS (EI)
calcd for C21Hþ26 [M]þ 278.2035, found 278.2025.
4.9.4. Geranylisobutyrophenone (41). A solution of lithium diiso-
propyl amide was prepared by the slow addition of an n-BuLi so-
lution (1.41 mL,1.42 M in hexanes, 2.00 mmol, 2.0 equiv) to i-Pr2NH
(0.42 mL, 3.00 mmol, 3.0 equiv) in THF (5 mL) at ꢀ78 ꢁC. After
stirring for 10 min at ꢀ78 ꢁC, the solution was stirred at 25 ꢁC for
15 min, and then re-cooled to ꢀ78 ꢁC. Isobutyrophenone (0.301 mL,
2.00 mmol, 2.0 equiv) was then added dropwise, and the solution
was stirred for 30 min at ꢀ78 ꢁC and then warmed to ꢀ40 ꢁC. The
resulting enolate solution was added via cannula into a solution of
geranyl bromide (0.217 g, 1.00 mmol, 1.0 equiv) in THF (1 mL) at
ꢀ40 ꢁC. The reaction contents were then warmed slowly to 25 ꢁC
over the course of 4 h and stirred an additional 12 h at 25 ꢁC. Upon
completion, the reaction contents were quenched with saturated
aqueous NH4Cl (10 mL) and water (10 mL), and extracted with
hexanes/EtOAc (2:1, 3ꢂ20 mL). The combined organic layers were
then washed with saturated aqueous NaHCO3 (20 mL) and brine
(20 mL), dried (MgSO4), and concentrated. The resultant crude
yellow oil was purified by flash column chromatography (silica gel,
hexanes/CH2Cl2, 1:0/2:1) and the remaining isobutyrophenone
was distilled off (100 ꢁC at 2 mmHg) to afford pure 41 (0.203 g, 71%
yield) as a colorless oil. Compound 41: Rf¼0.30 (silica gel, hex-
anes:CH2Cl2, 1:1); IR (film) nmax 2966, 2915, 2855, 1687, 1448,
Compound 49: mp¼140.0–144.0 ꢁC; Rf¼0.51 (silica gel, hexanes/
23
EtOAc, 7:3); [
a
]
ꢀ44.8 ((c 0.61, CHCl3) 90% ee; lit. ꢀ51.4ꢁ for
D
690 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.63 (m, 2H), 7.47–7.35 (m,
enantiopure natural material30); IR (film) nmax 3518 (br), 2999,
3H), 5.11–5.01 (m, 2H), 2.43 (d, J¼7.2 Hz, 2H), 2.08–1.94 (m, 4H),
2975, 2868, 1487, 1476, 1219, 1148, 913, 868, 783 cmꢀ1
;
1H NMR
1.66 (s, 3H), 1.58 (s, 3H), 1.54 (s, 3H), 1.30 (s, 6H); 13C NMR (75 MHz,
(400 MHz, CDCl3) 6.88 (s, 1H), 6.74 (s, 1H), 5.03 (s, 1H), 4.03 (dd,
d
CDCl3)
d
209.6, 139.6, 138.0, 131.5, 130.7, 128.1 (2C), 127.6 (2C), 124.3,
J¼12.8, 4.0 Hz, 1H), 2.77–2.60 (m, 2H), 2.27 (dq, J¼14.0, 4.0 Hz, 1H),
2.11 (dq, J¼3.6, 14.0 Hz, 1H), 1.96 (dt, J¼13.2, 3.6 Hz, 1H), 1.81–1.69
(m, 2H), 1.20 (s, 3H), 1.16 (s, 3H), 1.02 (s, 3H); 13C NMR (75 MHz,
119.9, 48.5, 40.1, 38.9, 26.7, 25.8 (3C), 17.8, 16.3; HRMS (FAB) calcd
for C20H28Oþ [M]þ 284.2140, found 284.2142.
CDCl3)
d 147.1, 145.8, 123.1, 119.8, 115.8, 108.1, 76.0, 65.8, 48.1, 40.7,
4.9.5. Geranylacetophenone (43). Prepared as in Section 4.9.4 in
41% yield, substituting acetophenone for isobutyrophenone and
omitting the distillation step of the purification. Compound 43:
light yellow oil; Rf¼0.25 (silica gel, hexanes/CH2Cl2, 1:1); IR (film)
39.3, 31.6, 29.7, 24.7, 19.8, 17.0; HRMS (FAB) calcd for C16H20Br2O2þ
[M]þ 401.9830, found 401.9840. All spectral data for this natural
product matched those originally reported by Wall and co-workers
as reported in Ref. 30.
nmax 2968, 2926, 1675, 1468, 1445, 1386, 1178, 961, 716, 699 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d 7.96 (app d, 2H), 7.55 (app t, 1H), 7.46
(app t, 2H), 5.19 (dt, J¼1.2, 7.2 Hz, 1H), 5.08 (tt, J¼6.8, 1.2 Hz, 1H),
3.00 (app t, J¼7.6 Hz, 2H), 2.43 (q, J¼7.2 Hz, 2H), 2.11–1.96 (m, 4H),
1.67 (s, 3H), 1.63 (s, 3H), 1.59 (s, 3H); 13C NMR (75 MHz, CDCl3)
Acknowledgements
We thank the NSF (CHE-0619638) for an X-ray diffractometer
and Prof. Gerard Parkin and Mr. Aaron Sattler for analyzing 22. We
also acknowledge the generous gift of several aza-BOX ligands from
Prof. Oliver Reiser at Regensburg University. Financial support was
provided by Columbia University, an NSF CAREER Award (CHE-
0844593), the ACS Petroleum Research Fund (47481-G), an Eli Lilly
Grantee Award, the National Science Foundation (Predoctoral Fel-
lowship to D.S.T.), the Deutscher Akademischer Austausch Dienst
(Postdoctoral Fellowship to A.S.), New Faculty Awards from the
d
200.2, 137.2, 136.6, 133.0, 131.5, 128.7 (2C), 128.2 (2C), 124.4, 122.9,
39.8, 38.9, 26.8, 25.8, 23.0,17.8,16.2; HRMS (FAB) calcd for C18H25Oþ
[MþH]þ 257.1905, found 257.1918.
4.10. Asymmetric total synthesis of 4-isocymobarbatol
Hg(OTf)2 (0.044 g, 0.088 mmol, 1.1 equiv) and 32a (0.043 g,
0.096 mmol, 1.2 equiv) were suspended in dry CH2Cl2 (4 mL) under

4804
S.A. Snyder et al. / Tetrahedron 66 (2010) 4796–4804
Takahashi, K.; Imagawa, H.; Sugihara, T.; Nishizawa, M. Tetrahedron Lett. 2004,
45, 1079–1082; (f) Nishizawa, M.; Morikuni, E.; Asoh, K.; Kan, Y.; Uenoyama, K.;
Imagawa, H. Synlett 1995, 169–170.
Camille and Henry Dreyfus Foundation, Amgen, and Eli Lilly, and
a Sloan Research Fellowship (all to S.A.S.).
18. Stevens, R. V.; Albizati, K. F. J. Org. Chem. 1985, 50, 632–640.
19. (a) Jensen, F. R.; Gale, L. H. J. Am. Chem. Soc. 1959, 81, 1261–1262; (b) Jensen, F. R.;
Gale, L. H. J. Am. Chem. Soc. 1960, 82, 148–151; (c) Hoye, T. R.; Kurth, M. J. J. Org.
Chem. 1979, 44, 3461–3467.
20. Direct chlorine replacement with retention is, to the best of our knowledge,
unknown in the primary literature. However, a few isolated examples, some
with high control and others with little selectivity, are mentioned as
unpublished results in the following monograph: Jensen, F. R.; Rickborn, B.
Electrophilic Substitution of Organomercurials; McGraw Hill: New York, NY,
1968; pp 75–100.
21. (a) Kang, S. H.; Kim, M. J. Am. Chem. Soc. 2003, 125, 4684–4685; (b) Kang, S. H.;
Kim, M.; Kang, S.-Y. Angew. Chem., Int. Ed. 2004, 43, 6177–6180; (c) Kang, S. H.;
Kang, S. Y.; Park, C. M.; Kwon, H. Y.; Kim, M. Pure Appl. Chem. 2005, 77,
1269–1276.
22. (a) Carlson, R. M.; Funk, A. H. Tetrahedron Lett. 1971, 12, 3661–3664; (b) Sugita,
T.; Yamasaki, Y.; Itoh, O.; Ichikawa, K. Bull. Chem. Soc. Jpn. 1974, 47, 1945–1947
Enantioselectivities in these cases were, at best, between 25 and 35%, though
5–15% was common for many substrates.
23. Some of these negative results may stem the modest solubility profiles that
many Hg(II) reagents possess. For instance, Hg(OTf)2 is soluble in MeCN, ace-
tone, MeOH and H2O, but only slightly soluble in nitromethane and EtOAc. It is
essentially insoluble in CH2Cl2, CHCl3, benzene, Et2O, and hexanes. In addition,
the use of chiral ligands that decreased the electrophilicity of the metal center
and thus led to the need for elevated reaction temperatures might also have
been deleterious to enantiocontrol.
24. (a) Nishizawa, M.; Takenaka, H.; Nishide, H.; Hayashi, Y. Tetrahedron Lett. 1983,
24, 2581–2584; (b) Nishizawa, M.; Takenaka, H.; Hayashi, Y. J. Org. Chem. 1986,
51, 806–813.
25. These ligands were prepared primarily following the procedures of: (a) Evans,
D. A.; Peterson, G. S.; Johnson, J. S.; Barnes, D. M.; Campos, K. R.; Woerpel, K. A.
J. Org. Chem. 1998, 63, 4541–4544; (b) Bandini, M.; Cozzi, P. G.; Gazzano, M.;
Umani-Ronchi, A. Eur. J. Org. Chem. 2001, 1937–1942; (c) Glos, M.; Reiser, O. Org.
Lett. 2000, 2, 2045–2048; (d) Werner, H.; Vicha, R.; Gissibl, A.; Reiser, O. J. Org.
Chem. 2003, 68, 10166–10168.
References and notes
1. (a) Stork, G.; Burgstahler, A. W. J. Am. Chem. Soc. 1955, 77, 5068–5077; (b)
Eschenmoser, A.; Ruzicka, L.; Jeger, O.; Arigoni, D. Helv. Chim. Acta 1955, 38,
1890–1904; For a recent perspective on this work fifty years after its original
publication, see: (c) Eschenmoser, A.; Arigoni, D. Helv. Chim. Acta 2005, 88,
3011–3050.
2. For reviews, see: (a) Sutherland, J. K. In Comprehensive Organic Synthesis; Trost,
B. M., Ed.; Pergamon: Oxford, 1991; Vol. 5, pp 341–377; (b) Yoder, R. A.;
Johnston, J. N. Chem. Rev. 2005, 105, 4730–4756; For a recent paper, including
excellent references to the primary literature, see: (c) Zhao, Y.-J.; Loh, T.-P. J. Am.
Chem. Soc. 2008, 130, 10024–10029.
3. For the isolation of the napyradiomycins, see: (a) Shiomi, K.; Nakamura, H.;
Iinuma, H.; Naganawa, H.; Takeuchi, T.; Umezawa, H.; Iitaka, Y. J. Antibiot. 1987,
40, 1213–1219; (b) Shiomi, K.; Iinuma, H.; Hamada, M.; Naganawa, H.; Manabe,
M.; Matsuki, C.; Takeuchi, T.; Umezawa, H. J. Antibiot. 1986, 39, 487–493; (c)
Shiomi, K.; Nakamura, H.; Iinuma, H.; Naganawa, H.; Isshiki, K.; Takeuchi, T.;
Umezawa, H.; Iitaka, Y. J. Antibiot. 1986, 39, 494–501.
4. For a recent asymmetric total synthesis of napyradiomycin A1 (1), see: (a)
Snyder, S. A.; Tang, Z.-Y.; Gupta, R. J. Am. Chem. Soc. 2009, 131, 5744–5745; For an
earlier, racemic total synthesis, see: (b) Tatsuta, K.; Tanaka, Y.; Kojima, M.;
Ikegami, H. Chem. Lett. 2002, 14–15.
5. For work illustrating that both the snyderols and the napyradiomycins are
prepared via vanadium-based haloperoxidases, see: (a) Carter-Franklin, J. N.;
Butler, A. J. Am. Chem. Soc. 2004, 126, 15060–15066; (b) Winter, J. M.;
Moffitt, M. C.; Zazopoulos, E.; McAlpine, J. B.; Dorrestein, P. C.; Moore, B. S.
J. Biol. Chem. 2007, 282, 16362–16368; For more recent references, see: (c)
Butler, A.; Moriah, S. Nature 2009, 460, 848–854; (d) Winter, J. M.; Moore, B. S.
J. Biol. Chem. 2009, 284,18577–18581; (e) Wagner, C.; Omari, M. E.; Koenig, G. J. Nat.
Prod. 2009, 72, 540–553.
6. For reviews, see: (a) Vaillancourt, F. A.; Yeh, E.; Vosburg, D. A.; Garneau-Tso-
dikova, S.; Walsh, C. T. Chem. Rev. 2006, 106, 3364–3378; (b) Butler, A.; Walker,
J. V. Chem. Rev. 1993, 93, 1937–1944.
26. For reviews on this ligand class, see: (a) McManus, H. A.; Guiry, P. J. Chem. Rev.
2004,104, 4151–4202; (b) Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006,
106, 3561–3651; (c) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325–335.
27. Interestingly, if the mono-oxazoline version of the same ligand class was
used, we achieved the opposite stereoselection with substrate 21 as in-
dicated in the table below. Mono-oxazoline ligands have been used
effectively in asymmetric reactions only on a few occasions: Yamauchi, M.;
Aoki, T.; Li, M.-Z.; Honda, Y. Tetrahedron: Asymmetry 2001, 12, 3133–3138.
7. For selected examples, see: (a) van Tamelen, E. E.; Hessler, E. J. J. Chem. Soc.,
Chem. Commun. 1966, 411–413; (b) Wolinsky, L. E.; Faulkner, D. J. J. Org. Chem.
1976, 41, 597–600; (c) Kato, T.; Ichinose, I.; Kamoshida, A.; Kitahara, Y. J. Chem.
´
´
´
Soc., Chem. Commun. 1976, 518–519; (d) Gonzalez, A. G.; Martın, J. D.; Perez, C.;
Ramı´rez, M. A. Tetrahedron Lett. 1976, 17, 137–138; (e) Hoye, T. R.; Kurth, M. J.
J. Org. Chem. 1978, 43, 3693–3697; (f) Kato, T.; Ichinose, I. J. Chem. Soc., Perkin
Trans. 1 1980, 1051–1056; (g) Shieh, H.-M.; Prestwich, G. D. Tetrahedron Lett.
1982, 23, 4643–4646; (h) Kato, T.; Mochizuki, M.; Hirano, T.; Fujiwara, S.;
Uyehara, T. J. Chem. Soc., Chem. Commun. 1984, 1077–1078; (i) Yamaguchi, Y.;
Uyehara, T.; Kato, T. Tetrahedron Lett.1985, 26, 343–346; (j) Fujiwara, S.; Takeda, K.;
Uyehara, T.;Kato, T. Chem. Lett.1986,1763–1766;(k)Tanaka, A.;Sato, M.;Yamashita,
K. Agric. Biol. Chem. 1990, 54, 121–123.
% e.e. ent-22
R
Entry
Me
Me
O
in CH2Cl2
H
Ph
R
N
1
2
3
OH
Cl
13
28
46
O
N
8. Snyder, S. A.; Treitler, D. S. Angew. Chem., Int. Ed. 2009, 48, 7899–7903.
9. For the isolation of 4, see: (a) Juagdan, E. G.; Kalidindi, R.; Scheuer, P. Tetrahe-
dron 1997, 53, 521–528; (b) Davyt, D.; Fernandez, R.; Suescun, L.; Mombru´ , A. W.;
Ph
Br
´
Saldan˜a, J.; Domınguez, L.; Coll, J.; Fujii, M. T.; Manta, E. J. Nat. Prod. 2001, 64,1552–
1555; For the isolation of 5, see: (c) Young, D. N.; Howard, B. M.; Fenical, W. Tet-
rahedron Lett. 1976, 17, 41–44.
10. For an excellent review on halogenated natural products, see: Gribble, G. W.
Acc. Chem. Res. 1998, 31, 141–152.
28. In all these studies, a reaction temperature of ꢀ78 ꢁC was utilized; lower
temperatures did not lead to improved enantioselectivity, though erosion was
observed above ꢀ50 ꢁC.
29. At present, we do not have an appropriately refined model to account for the
observed stereoselection. We have attempted to secure a crystal structure of an
Hg(OTf)2/bis-oxazoline complex to assist in our transition state model, but
have been unsuccessful thus far in our efforts. For two simpler Hg(II)-based
crystal structures, see: (a) Halfpenny, J.; Small, R. W. H. Acta Crystallogr. 1997,
C53, 438–443; (b) Grdenic, D.; Popvic, Z.; Bruvo, M.; Korpar-Colig, B. Inorg.
Chim. Acta 1991, 190, 169–172.
11. Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445, 900–903.
12. White, E. P.; Robertson, P. W. J. Chem. Soc. 1939, 1509–1515.
13. (a) Brown, R. S. Acc. Chem. Res. 1997, 30, 131–137; (b) Denmark, S. E.; Burk, M. T.;
Hoover, A. J. J. Am. Chem. Soc. 2010, 132, 1232–1233; For similar challenges in
achieving the enantioselective addition of chalcogens such as sulfur onto
alkenes, see: (c) Denmark, S. E.; Collins, W. R.; Cullin, M. D. J. Am. Chem. Soc.
2009, 131, 3490–3492.
14. For some recent examples of the initial step, see: (a) Surendra, K.; Corey, E. J. J.
Am. Chem. Soc. 2009, 131, 13928–13929; (b) Surendra, K.; Corey, E. J. J. Am. Chem.
Soc. 2008, 130, 8865–8869; For a classic example, see: (c) Fish, P. V.; Sudhakar,
A. R.; Johnson, W. S. Tetrahedron Lett. 1993, 34, 7849–7852.
30. For the isolation of this natural product, see: (a) Wall, M. E.; Wani, M. C.;
Manikumar, G.; Taylor, H.; Hughes, T. J.; Gaetano, K.; Gerwick, W. H.; McPhail,
A. T.; McPhail, D. R. J. Nat. Prod. 1989, 52, 1092–1099; (b) Wall, M. E. J. Nat. Prod.
1992, 55, 1561–1568.
31. For a previous total synthesis of this compound, see: Tanaka, A.; Oritani, T. Biosci.
Biotechnol. Biochem. 1995, 59, 516–517. Ref. 8 provides an improved synthesis.
32. Although certain compounds like MeHgCl and Me2Hg are quite dangerous,
higher molecular weight organomercurials are not anywhere near as toxic, and
in fact are used in agrochemicals and medicine: Imagawa, H.; Iyenaga, T.;
Nishizawa, M. Org. Lett. 2005, 7, 451–453 See also Ref. 20.
15. For an example of such a cyclization of a bromohydrin precursor, see: Coula-
douros, E. A.; Vidali, V. P. Chem.dEur. J. 2004, 10, 3822–3835.
16. (a) Mullen, C. A.; Campbell, A. N.; Gagne´, M. R. Angew. Chem., Int. Ed. 2008, 47,
´
6011–6014; (b) Koh, J. H.; Gagne, M. R. Angew. Chem., Int. Ed. 2004, 43, 3459–3461.
17. For selected examples, see: (a) Corey, E. J.; Tius, M. A.; Das, J. J. Am. Chem. Soc.
1980, 102, 1742–1744; (b) Corey, E. J.; Reid, J. G.; Myers, A. G.; Hahl, R. W. J. Am.
Chem. Soc. 1987, 109, 918–919; (c) Hoye, T. R.; Caruso, A. J.; Kurth, M. J. J. Org.
Chem. 1981, 46, 3550–3552; (d) Gopalan, A. S.; Prieto, R.; Mueller, B.; Peters, D.
Tetrahedron Lett. 1992, 33, 1679–1682; (e) Takao, H.; Wakabayashi, A.;
33. For selected examples of carbon replacement, see: (a) Kocovsky, P. J. Organomet.
Chem. 2003, 687, 256–268; (b) To¨ke´s, A. L.; Litkei, G.; Gula´csi, K.; Antus, S.;
´
´
´
Baits-Gacs, E.; Szantay, C.; Darko, L. L. Tetrahedron 1999, 55, 9283–9296.