Total synthesis of haouamine A: the indeno-tetrahydropyridine core

Article abstract of DOI:10.1016/j.tet.2009.05.075

A full account of synthetic efforts toward the indeno-tetrahydropyridine core of haouamine A is presented. Initial failed strategies led to the unexpected discovery of a mild abnormal Chichibabin pyridine synthesis and provided knowledge and inspiration f

Full text of DOI:10.1016/j.tet.2009.05.075

Tetrahedron 65 (2009) 6600–6610
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of haouamine A: the indeno-tetrahydropyridine core
*
Noah Z. Burns, Mikkel Jessing, Phil S. Baran
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 April 2009
Received in revised form 24 May 2009
Accepted 26 May 2009
Available online 3 June 2009
A full account of synthetic efforts toward the indeno-tetrahydropyridine core of haouamine A is pre-
sented. Initial failed strategies led to the unexpected discovery of a mild abnormal Chichibabin pyridine
synthesis and provided knowledge and inspiration for the development of a cascade annulation that has
enabled rapid and scalable access to the core in either racemic or enantiopure form.
Ó 2009 Elsevier Ltd. All rights reserved.
Dedicated to Professor Larry Overman for
his pioneering work in organic chemistry
1. Introduction
interconverting isomers that is most likely due to slowed pyramidal
inversion at nitrogen coupled with conformational reorganization
The haouamines are a structurally unique and intriguing class of
of the tetrahydropyridine.2,32
natural products that originate from the ascidian Aplidium haouar-
These various features lay down a challenging synthetic
´
ianum collected off the coast of Tarifa in southern Spain. Zubıa and
gauntlet that was successfully navigated by our group in the case of
co-workers1 isolated haouamines A and B (1 and 2, Fig. 1) in 2003
and elucidated their structures using NMR and X-ray crystallo-
graphic analysis. In addition to displaying such an unprecedented
molecular architecture, the authors showed haouamine A to have
high and selective cytotoxic activity against HT-29 human colon
haouamine A, first with a racemic synthesis3 and later with an
carcinoma (IC50¼0.1
m
g/mL), while haouamine B exhibited milder
cytotoxicity against MS-1 mice endothelial cells (IC50¼5
mg/mL).
As seen in Figure 1, haouamine A (1) contains a total of seven
cycles with an atypical meta-hydroxylation pattern on its four
phenols. The core is an indeno-tetrahydropyridine, which has an
imbedded all-carbon quaternary center at C26. Fused onto this is
the hallmark structural feature of these natural products: a 3-aza-
[7]-paracyclophane macrocycle (containing a bridgehead olefin)
that is strained to such a point that one of its aromatic rings is bent
out of planarity into a boat-like conformation. As seen in Figure 1,
the two planes made from C9–C10–C14 and C11–C12–C13 are bent
out of the C10–C11–C13–C14 plane by 13.63ꢀ and 13.91ꢀ, re-
spectively. Haouamine B (2), isolated in a far smaller quantity than
1, (and characterized as the peracetyl derivative due to the in-
stability of the pentaphenol, possibly due to a greater propensity
for oxidation in 2 as compared to 1) differs in the presence of an
additional meta-hydroxyl group at C21 of its westernmost arene.
Both molecules exist in solution as an inseparable mixture of two
* Corresponding author. Tel.: þ1 858 784 7375; fax: þ1 858 784 7373.
E-mail address: pbaran@scripps.edu (P.S. Baran).
Figure 1. Haouamines A and B, their boat arene, and the indeno-tetrahydropyridine
core.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.075

N.Z. Burns et al. / Tetrahedron 65 (2009) 6600–6610
6601
enantioselective version.4 In addition to this work, the haouamine
alkaloids have been pursued by at least seven other research
groups: Rawal5 and Trauner6 have both reported routes to the core
indeno-tetrahydropyridine, Wipf7 has synthesized a model aza-
paracyclophane, and Weinreb,8 Fu¨rstner,9 and Ishibashi10 have all
completed a formal synthesis of haouamine A (1). Poupon11 had
reported initial progress toward a biomimetic synthesis of the
haouamines following a similar biosynthetic hypothesis to our
own. In this article, full details of efforts toward the indeno-tetra-
hydropyridine core of these molecules are reported, culminating in
a concise and scalable route.
2. Results and discussion
2.1. Retrosynthetic ruminations and initial strategies
From the outset of this project the question of the biological origin
of these fascinating molecules waspresent, particularly in the context
of trying to devise a feasible biomimetic synthesis. It is an intriguing
notion that the entire haouamine skeleton can be traced back to 4
equiv of meta-hydroxyphenylacetaldehyde 3 and 1 equiv of ammonia
through five condensations and two oxidative carbon–carbon bond
forming events (Scheme 1). Of particular note in this sequence is the
oxidative phenol coupling to close the paracyclophane between C8
and C9, for intermediates wherein one or both of these carbons is sp3-
hybridized appear to be considerably less strained than the bent
arene-containing macrocycle. It is possible that this stepwise ap-
proachfacilitates the bendingofanaromaticringduringbiosynthesis.
Scheme 2. Haouamine A retrosynthetic analysis.
Scheme 1. Original biosynthetic proposal.
Such a phenylacetaldehyde-based origin had been proposed and
studied by our group previously,4 and this guided some of the initial,
ultimately non-productive, strategies. A general retrosynthetic
blueprint is outlined in Scheme 2. Since the paracyclophane mac-
rocycle was anticipated to pose a significant challenge, its in-
stallation was deferred until the final steps. Thus, construction of an
indeno-tetrahydropyridine of generalized structure 4 was the first
goal. One strategy (pathway A) involved the tetrasubstituted pyri-
dine 5 of unspecified oxidation state as the precursor to 4. A pyr-
idinium such as 5 was identified as the product of a Chichibabin
pyridine synthesis12 of meta-methoxyphenylacetaldehyde 6 with
amino anisole 7. The prospect of employing such a Chichibabin
pyridine synthesis was additionally intriguing as it would allow in
a single step the introduction of all of the atoms present in 1. An al-
ternate strategy (pathway B) was envisioned wherein 4 would arise
fromindanone 8 via three independentevents: (1) installation of the
all-carbon quaternary center, (2) introduction of the nitrogen, and
(3) formation of the tetrahydropyridine ring.
Scheme 3. The abnormal Chichibabin pyridine synthesis of 9.
to react in the presence of ytterbium triflate the exclusive
product is pyridinium 9 as opposed to the previously reported11
erroneous structure 10. Confirmation of this assignment was
obtained from the crystal structure of 9 and its subsequent
transformation into 10.
This type of abnormal Chichibabin pyridine synthesis with
phenylacetaldehydes has been known in the literature since the
1950s, however the harsh conditions and low yields have ren-
dered it essentially useless. For example, Eliel13 reported that
As reported previously,4 Chichibabin pyridine syntheses of
arylacetaldehydes do not follow the expected pathway but rather
occur with the curious loss of an equivalent of benzaldehyde.
These substrates thus generate not the expected 2-benzyl-3,5-
diarylpyridiniums from such a reaction, but instead 3,5-diaryl-
pyridiniums. This transformation is shown for the system most
relevant to haouamine A in Scheme 3. When 6 and 7 are allowed

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N.Z. Burns et al. / Tetrahedron 65 (2009) 6600–6610
heating an ammonia-saturated solution of phenylacetaldehyde in
ethanol to 235 ꢀC at 1150 p.s.i. for 6 h yields 13.1% 3,5-diphe-
nylpyridine, and later Eckroth14 showed that the lithium alumi-
num hydride reduction of meta-methoxyphenylacetamide yields
17% 3,5-bis(meta-methoxyphenyl)pyridine. More recently, d’Ischia15
reported that phenylalanine and tyrosine derivatives could
be cyclotrimerized to 3,5-diarylpyridines in 3–15% isolated yield
upon exposure to excess hypochlorous acid. This version of the
reaction can be performed with mild reagents in either water or
a water–1,4-dioxane mixture (when the starting aldehyde is
a solid) at room temperature without an inert atmosphere and
generally takes 18–24 h for completion. The largest drawback of
this methodology is the typical instability of the phenyl-
acetaldehyde reactants. They are prone to polymerization and
should be made (usually by IBX or DMP oxidation of the alcohol)
and used without prolonged storage.
As the production of 9 gave rise to none of the anticipated full
haouamine skeleton 10, other methods were sought to introduce
the requisite 2-benzyl moiety. After some difficulty with attempts
to add benzyl organometallic reagents into the N-alkyl pyridinium
substrate, it was discovered that the addition of 3,5-dimethoxy-
benzyllithium to 3,5-diarylpyridine-N-oxide 11 (synthesized from
the Chichibabin product 12 by removal of the N-benzyl by heating
in pyridine and N-oxide formation) produced the benzyl-contain-
ing pyridine-N-oxide 13 with unanticipated retention of the
N-oxide (Scheme 4). Unfortunately, however, attempts to either
directly or indirectly convert this compound into the haouamine B
indeno-tetrahydropyridine core 14 were unsuccessful. Also, re-
duction of the N-oxide to the free pyridine 15 resulted in a com-
pound that was extremely averse to alkylation (no reaction was
observed upon heating in neat iodomethane).
Scheme 5. Preparation of Stevens rearrangement substrates.
acetic acid in the presence of cerium trichloride gave tetrahy-
dropyridine 16. Nitrogen alkylation could then be performed
with a variety of benzyl electrophiles containing 2-bromo-3-
methoxy, 2-iodo-3-methoxy, and 3,5-dimethoxy substitution to
provide quaternary ammonium salts 17, 18, and 19, respectively,
as mixtures of diastereomers.
It was anticipated that a Stevens rearrangement would shift the
N-benzyl substituent to the 2-position of the tetrahydropyridine,
placing it proximal to the alkene for quaternary center formation.
An initial attempt at this reaction (Scheme 6) was performed with
haouamine B precursor 19. Exposure to potassium tert-butoxide at
80 ꢀC in toluene resulted in an instantaneous and quantitative
Hofmann elimination17 to diene 20 via deprotonation of the allylic–
benzylic position of 19. Altering these conditions to the rapid ad-
dition of 3 equiv of lithium hexamethyldisilazide to the substrate in
a 45 ꢀC solution of THF was found to produce the desired product
Scheme 4. Attempted use of a pyridine N-oxide.
A strategy to introduce the 2-benzyl group via a Stevens
rearrangement16 was next pursued in order to install it with the
pyridine at a lower oxidation state (Scheme 5). Reduction of
abnormal Chichibabin product 9 with sodium borohydride and
Scheme 6. Failure and success in the Stevens rearrangement.

N.Z. Burns et al. / Tetrahedron 65 (2009) 6600–6610
6603
Table 2
21 as well as the Hofmann product 20 in an approximate 1:1 ratio.
Optimization of cascade substrate 68
These conditions proved viable for the bromo- and iodo-substrates
17 and 18 as well, providing access to additional compounds 22 and
23 in which it was hoped the all-carbon quaternary center could be
formed. X-ray crystallographic analysis of 22 confirmed the
assigned structure of these products.
With compounds 21 to 23 in hand, attention was focused on
forming the quaternary center at C26. A number of conditions
were screened in order to effect this transformation, which ul-
timately proved unachievable (Table 1). Lewis and Brønsted acid-
mediated Friedel–Crafts chemistry as well as oxidative Heck
conditions were attempted on substrate 21 (Table 2, entries 1–7)
leading to either recovered starting material or intractable mix-
tures. Arylbromide substrate 22 was submitted to a variety of
Heck conditions (entries 8–19) including those of Fu18 and
Herrmann19 as well as highly active Ni(0). In no instance was
oxidative addition observed, with all conditions leading to re-
covered starting material. Radical conditions with tributyltin
hydride resulted in loss of the bromide (entry 20), but none of
the desired cyclization was observed. It was hoped that the
iodoaryl substrate 23 would lead to more facile insertion of
palladium(0), however standard conditions all led to recovered
starting material (entries 22–25).
Entry
Xþ source (equiv)
In0 (equiv)
% Yield
1
2
3
4
5
6
7
8
NIS
t-BuOCl
BDCP
NBA (1.1)
NBA (1.1)
NBS (1.1)
TBCHD (1.1)
TBCHD (2.2)
d
d
2.0
d
d
d
5.0
2.0
2.0
2.0
2.0
23%
33%
37%
43%
57%
Table 1
Conditions attempted to form the C26 quaternary center
Scheme 7. Preparation of starting ketone 8.
or readily synthesized on large scale from phenol by a tandem Fries/
Friedel–Crafts reactionwith 3-chloropropionoyl chloride followed by
methylation20) was treated with 3-methoxyphenylmagnesium bro-
mide 25 to give, following acid-mediated dehydration, aryl indene
26. Dihydroxylation and a second acid-mediated dehydration pro-
vided the key starting ketone 8 on 40 g-scale.
The next two approaches sought to utilize diazocarbonyl C–H
insertion methodology to install the all-carbon quaternary center.21
The first approach began with 8 (Scheme 8), which was reduced
with sodium borohydride to the syn aryl secondary alcohol and
activated as the tosylate 27 and displaced with sodium azide to
install the required nitrogen. Lithium aluminum hydride reduction
Entry
Substrate (Ar)
Conditions
Results
1
2
3
4
5
6
7
21
21
21
21
21
21
21
Pd(OAc)2, AcOH, O2
SM
decomp.
SM
SM
SM
Pd(OAc)2, AcOH,
Montmorillonite K10
p-TsOH,
D
D
2.5 N HCl/THF
H2SO4/THF
AuCl3/AgOTf
SM
SM
8
9
22
22
22
22
22
22
22
22
22
22
22
22
22
22
Pd(OAc)2, AcOH, Et3N
Pd(OAc)2, dppp, Et3N
Pd(OAc)2, dppp, Ag2CO3
Pd(OAc)2, dppp, Ag2CO3
Pd(OAc)2, K2CO3, TBABr
Pd(PPh3)4, Et3N
Pd(PPh3)4, DABCO
Pd2(dba)3, P(t-Bu)3, Cy2NMe
Ni(COD)2, NaI
Herrmann, NaOAc
Herrmann, Bu4NOAc
Pd2(dba)3, Ag3PO4
Bu3SnH, AIBN
SM
SM
SM
SM
SM
SM
SM
SM
SM
SM
SM
SM
[H]
SM
10
11
12
13
14
15
16
17
18
19
20
21
(TMS)3SiH, AIBN
22
23
24
25
23
23
23
23
Pd(OAc)2, PPh3, Et3N
Pd(OAc)2, K2CO3, TBACl
Herrmann, NaOAc
Pd(TFA)2, Et3N
SM
SM
SM
SM
2.2. Initial indanone-based strategies to the core
In order to investigate the alternative strategy shown in Scheme 2
(pathway B) wherein tetrahydropyridine construction is delayed
until after introduction of the quaternary center, 8 was prepared as
shown in Scheme 7. 7-Methoxyindanone 24 (commercially available
Scheme 8. Failed diazocarbonyl chemistry 1.

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N.Z. Burns et al. / Tetrahedron 65 (2009) 6600–6610
produced amine 28 that could be alkylated with 1-bromo-3-diazo-
acetone 29 to give diazoketone 30, an appropriate substrate for
a potential metal-mediated C–H insertion. Unfortunately, all at-
tempts to synthesize piperidinone 31 via reaction of 30 with vari-
ous rhodium or copper catalysts failed to produce detectable
amounts, possibly due to competitive insertion alpha to the het-
eroatom or into the benzylic methylene group. Protection of the
nitrogen as its N-Boc derivative 32 did not solve these problems (33
was not observed in the reaction mixture).
Attention then turned to utilization of a phenol-tethered diazo-
carbonyl (Scheme 9) beginning initially from free phenol contain-
ing aryl indene 34 (synthesized analogously to 26 via temporary
TBS protection of the phenol). Palladium on carbon hydrogenation
produced aryl indane 35. Heating these compounds (34 or 35) neat
with acetylketene precursor 36 followed by exposure to meth-
anesulfonyl azide led to diazoacetoacetates 37 and 38. It was hoped
that either indene 37 would undergo an initial intramolecular
cyclopropanation to produce 39 with sufficient strain so as to
fragment to quaternary center containing indene 40, or that indane
38 would be posed for insertion into the doubly benzylic C–H bond
to give 41. Unfortunately, exposure of either 37 or 38 to known C–H
insertion or cyclopropanation catalysts did not produce any 40 or
41 and only led to the observed compounds of type 42 wherein the
metal carbenoid had inserted into the ortho aryl hydrogen.
The subsequent plan then became the use of more reliable enolate
alkylation chemistry in order to introduce the requisite all-carbon
quaternary center. To this end, allyl iodide electrophiles 43 and 44
(Scheme 10) were synthesized containing either anisole or bromo-
anisole as a functional handle for further elaboration of the macro-
cycle. Fischer esterification of 3-methoxyphenylacetic acid 45 and
methylenation with paraformaldehyde under phase-transfer condi-
tions provided aryl propenoate 46 that could be reduced to the allylic
alcohol with diisobutylaluminum hydride and further activated as
the allyl iodide 43 with triphenylphosphine and iodine. Bromoarene
allyl iodide 44 was synthesized identically via 47 starting from 6-
bromo-3-methoxyphenylacetic acid 48 (the product of treating 45
with bromine).
Scheme 10. Preparation of allyl iodide electrophiles.
The sodium enolate of aryl ketone 8 was reacted with allyl
iodide 43 to produce, gratifyingly, quaternary center containing
ketone 49 (Scheme 11). With the connectivity now established at
this center, the next task became introduction of the sole haou-
amine nitrogen atom. Indanone 49 could be reduced to an un-
determined single diastereomer with sodium borohydride and
activated with methanesulfonic anhydride to mesylate 50. How-
ever, attempts at displacing this neopentyl mesylate with azide to
51 resulted in either no reaction or elimination under forcing
conditions. Direct reductive amination also failed to install the
nitrogen as in 52. Whereas oxime 53 was formed by heating 49 in
Scheme 9. Failed diazocarbonyl chemistry 2.
Scheme 11. Success in installation of the all-carbon quaternary center.

N.Z. Burns et al. / Tetrahedron 65 (2009) 6600–6610
6605
2.3. Development of a cascade annulation to synthesize
the core
Inspection of three-dimensional models of oxime 53 (MM2
minimized structure, Scheme 13) provided evidence that alkene ac-
tivation could promote cyclization onto the oxime nitrogen due to
their spatial proximity. While a 6-endo-trig cyclization was desired
(Scheme 12) in order to directly access a structure such as 54, strong
precedent from Grigg22 suggested a probable 5-exo-trig pathway
leading to 55. Indeed, reaction of oxime 53 with tert-butyl hypo-
chlorite resulted in a facile 5-exo-trig cyclization to give two di-
astereomeric five-membered chloronitrones 56 and 57 (Scheme 13),
the structure of which was confirmed by X-ray crystallographic
analysis. As opposed to seeing this undesired cyclization as a dead-
end strategy en route to the indeno-tetrahydropyridine core, an idea
was formulated consisting of the following: reduction of the nitrone
functionality should occur stereospecifically to give a cis-fused N-
hydroxypyrroloindane that is poised to undergo an intramolecular
SN2 reaction to produce an N-hydroxypyrroloaziridinium species that
could fragment to N-hydroxytetrahydropyridine 58 with unsatura-
tion at either C1–C2 or the desired C2–C25 position (haouamine
numbering, Scheme 12).
Scheme 12. Possible modes of cyclization for 53 and a possible ring expansion to 58.
refluxing ethanol with a large excess of hydroxylamine hydro-
chloride and sodium acetate, it was also resistant to reduction (to
deliver 52). It thus became clear that initial annulation might be
a wiser approach.
Inpractice, thereactionof53with N-bromoacetamide(Scheme 13)
produced bromonitrones 59 and 60 that, upon in situ reaction with
Scheme 13. Development of a cascade annulation sequence.

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N.Z. Burns et al. / Tetrahedron 65 (2009) 6600–6610
sodium borohydride at 50 ꢀC underwent stereospecific reduction to
61 and 62, supposed 3-exo-tet displacement to fleeting N-hydroxy-
aziridiniums 63 and 64 (not observed spectroscopically), and the
desired regiospecific ring expansion to converge on N-hydroxyte-
trahydropyridine 58 (structure confirmed by X-ray). Exposure of this
crude material to indium powder23 chemoselectively reduced the
N-hydroxy functional group to secondary amine 65. Inspection of
model aziridines 66 and 67 provide a clear stereoelectronic rationale
for why none of the regioisomeric N-hydroxyenamine is produced in
this fragmentation step. The preferential hydrogen in both di-
astereomers to be involved in this eliminative fragmentation (pointed
out for clarity in 66 and 67) is well aligned for donation into the C–N
antibonding orbital that is breaking. Neither of the alternative
hydrogens on the aziridinium ring possesses such overlap so as to
preclude their involvement in this step.
This overall cascade sequence produces indeno-tetrahydropyr-
idine 65 in 51% overall yield (average 87% yield per transformation)
from oxime 53 in a single step as one diastereomer. A slight com-
plication arose when applying this sequence to bromooxime 68 as
the yield of the product bromoamine 69 fell to 33% utilizing the same
conditions. Optimization of these conditions is shown in Table 2.
Some halogen sources such as N-iodosuccinimide and bromonium
dicollidine perchlorate failed to elicit initial nitrone formation (en-
tries 1 and 3) and tert-butyl hypochlorite (entry 2) did not produce
any product due to the lower nucleofugality of chlorine with respect
to bromine in the hydroxyaziridinium-forming step. As mentioned
earlier, the use of N-bromoacetamide with 2 equiv of indium resulted
in a 33% yield (entry 5) while increasing the indium only lowered the
yield to 23% (entry 4) due to competitive arylbromide reduction. N-
Bromosuccinimide led to comparable yields (entry 6). Final success
was achieved with the use of tetrabromocyclohexadienone as the
bromonium source with 1.1 equiv resulting in a 43% yield (entry 7)
and 2.2 equiv raising this to a satisfactory 57% (entry 8).
stereoselectivity resulting from addition to an already chiral sub-
strate. A model study was thus performed starting from racemic
diol 72 (Scheme 15). TEMPO/NaOCl oxidation27 proved to be the
only viable method of oxidation (this diol is particularly susceptible
to oxidative glycol cleavage) providing alpha-hydroxy ketone 73,
which was treated with allyl magnesium bromide to give the
homoallylic diol 74 with high diastereoselectivity as a likely result
of direction by the neighboring alcohol. Exposure of this compound
to stoichiometric boron trifluoride diethyl etherate at 0 ꢀC then
elicited a pinacol rearrangement28 to produce the model quater-
nary ketone 75 in high yield. Even with these results, three further
issues arose before a workable asymmetric route to the indeno-
tetrahydropyridine core could be developed: access to enantiopure
diol 72, diastereoselective addition of a fully elaborated allyl sub-
stituent to the enantiopure alpha-hydroxy ketone, and a successful
pinacol rearrangement occurring on this substrate without loss of
stereochemical information.
2.4. Enantioselective synthesis of the core
Scheme 15. Pinacol rearrangement model study.
Whereas a route to the core of haouamine A (as well as a sub-
sequent conversion of this into the natural product) that addressed
the issues of chemo- and diastereoselectivity had now been de-
veloped,3 it fell short of achieving absolute stereocontrol; as the ab-
solute configuration of the haouamines was not known, the
development of an asymmetric route was required. As all of the ste-
reochemicalinformationwithinourracemicsynthesisisderivedfrom
the all-carbon quaternary center, it initially seemed that an asym-
metric route to these molecules would be trivial since all that would
be required is an enantioselective alkylation. However, attempts to
achieve such a reaction from aryl ketone 8 (Scheme 14) with an
electrophile 70 (R¼halogen, OAc) using conditions such as Trost’s
palladium-catalyzed asymmetric allylic alkylation,24 Enders’ SAMP/
RAMP hydrazone alkylation,25 or asymmetric phase-transfer-cataly-
sis26 did not provide 71 with levels of enantiomeric excess above 30%.
Attention then turned to a less direct chirality transfer strategy
in order to introduce the requisite asymmetry via a non-alkylative
method. Specifically, installation of the allyl group nucleophilically
(as opposed to electrophilically) was envisaged with the
Achievement of these goals is shown in Scheme 16. Sharpless
asymmetric dihydroxylation29 on aryl indene 26 achieved moderate
levels of enantioselectivity yielding optically active diol (þ)-72 in
70% ee (ee determined by 1H NMR analysis of the monoester derived
from the R-Mosher acid). The racemic diol within this mixture (30%
by weight) could then be selectively crystallized as the centro-
symmetric racemate leaving the enantiopure diol in solution (iso-
lated in 60% overall yield from 26). According to the Sharpless
mnemonic the diol produced in this reaction should have the 1S,2R
absolute configuration as shown in Scheme 16. This compound was
then oxidized as before to alpha-hydroxy ketone (þ)-73, the sub-
strate for incorporation of an appropriate allyl nucleophile. At-
tempts to synthesize an allyl Grignard reagent 70 (R¼MgX) were
complicated by the presence of an arylbromide in the substrate, and
the appropriate allylsilane or allylboronate did not have sufficient
reactivity for addition. Attention then turned to an allylindium
species, in particular that formed via transmetalation from an
organotin with indium(III).30 Exposure of tributylallyltin 76 to
(þ)-73 in the presence of indium(III) triflate gave the desired
product 77 in 86% yield.
Furthermore, the pinacol rearrangement occurred smoothly on
this fully functionalized diol to intercept the previous ketone
(þ)-71.
Additionally pleasing was the fact that there was no loss in ste-
reochemical information throughout this sequence as deduced by
reduction of (þ)-71 to a single alcohol diastereomer and 1H NMR
analysis of the ester derived from the (R)-Mosher acid and compar-
ison to that with the racemic 71. The absolute stereochemistry of
(þ)-71 was established by X-ray crystallographic analysis and found
Scheme 14. Failed asymmetric alkylation.

N.Z. Burns et al. / Tetrahedron 65 (2009) 6600–6610
6607
Scheme 16. A successful enantioselective route to ketone (þ)-71.
to have the R configuration as shown in Scheme 16. This sequence
thus renders the previously developed route enantioselective.
A question regarding the mechanism of the pinacol rearrange-
ment still lingered and prompted an investigation. Assuming that
the transition state of addition resembles 78 to give anti 1,2-diol in
77, the shift of the allyl group must occur with facial retention
across the cyclopentane of the indane. There was lack of clarity as to
whether such a shift was occurring in a [1,2]-sense with or without
allylic rearrangement. In order to differentiate between these two
mechanisms, the model homoallylic diol 74 was ozonolyzed to the
aldehyde (Scheme 17) and treated with a methylene-d2 Wittig re-
agent to give 79 with 80% deuterium incorporation. When sub-
mitted to the pinacol rearrangement conditions the product 80 was
found to still contain deuterium incorporation solely at the vinylic
terminus. This evidence strongly suggests that a [1,2]-shift is
transpiring without allylic rearrangement within this reaction as
shown in 81 (Scheme 16).
Scheme 18. Summary of synthetic efforts.
while the dihydroxylation step is rendered enantioselective using
Sharpless chemistry. This synthesis is short, scalable, high yielding,
and compares favorably with other reported approaches.5–10
However, one could imagine further improvements to the current
approach if certain redox fluctuations could be avoideddparticu-
larly with regard to the oxidation state of the oxime in 68 (both the
C]N and N–O bond are reduced).31 Nevertheless, access to deca-
gram quantities of 69 enabled both an initial3,4 as well as a pre-
parative-scale total synthesis of 1.32
4. Experimental section
4.1. General
All reactions were carried out under a nitrogen atmosphere with
dry solvents using anhydrous conditions unless otherwise stated. Dry
tetrahydrofuran (THF), diethyl ether, dichloromethane (DCM), ben-
zene, toluene, methanol (MeOH), acetonitrile, 1,2-dimethoxyethane
(DME), N,N-dimethylformamide (DMF), and triethylamine (Et3N)
were obtained by passing these previously degassed solvents
through activated alumina columns. Reagents were purchased at the
highest commercial quality and used without further purification,
unless otherwise stated. Yields refer to chromatographically and
spectroscopically (1H NMR) homogeneous materials, unless other-
wise stated. Reactions were monitored by thin layer chromatography
(TLC) carried out on 0.25 mm E. Merck silica gel plates (60F254) using
UV light as the visualizing agent and an acidic mixture of anisalde-
hyde, phosphomolybdic acid, orceric ammonium molybdate, or basic
aqueous potassium permanganate (KMnO4), and heat as developing
agents. E. Merck silica gel (60, particle size 0.043–0.063 mm) was
used for flash column chromatography. Preparative thin layer chro-
matography (PTLC) separations were carried out on 0.25 or 0.5 mm E.
Merck silica gel plates (60F254). NMR spectra were recorded on
Bruker DRX-600, DRX-500, and AMX-400 or Varian Inova-400
Scheme 17. Mechanistic study of the pinacol rearrangement.
3. Conclusions
In summary, a full account of efforts toward the indeno-tetra-
hydropyridine of haouamine A (1) has been presented. Biosynthetic
questions, failed routes, and necessity-driven invention have led to
efficient routes that access the core of this natural product in either
racemic or enantiopure fashion. The developed cascade annulation
sequence is particularly enabling as it allows for the rapid con-
struction of the heterocycle portion in a chemo- and stereoselective
fashion in a single step from a readily available oxime intermediate.
This chemistry has enabled the production of large quantities of the
indeno-tetrahydropyridine core (>15 g to date) that is available
from commercial material racemically in five steps (15% overall) or
enantioselectively in seven steps (13% overall) (Scheme 18). In the
former case, four steps form key skeletal bonds; two extra steps are
required in the latter case (TEMPO oxidation and pinacol shift)

6608
N.Z. Burns et al. / Tetrahedron 65 (2009) 6600–6610
instruments and calibrated using residual undeuterated solvent as an
internal reference (CHCl3 at 7.26 ppm 1H NMR, 77.0 ppm 13C NMR).
The following abbreviations (or combinations thereof) were used to
explain the multiplicities: s¼singlet, d¼doublet, t¼triplet, q¼quartet,
m¼multiplet, br¼broad. High-resolution mass spectra (HRMS) were
recorded on Agilent LC/MSD TOF time-of-flight mass spectrometer by
electrospray ionization time-of-flight reflectron experiments. IR
spectra were recorded on a Perkin Elmer Spectrum BX FTIR spec-
trometer. Melting points were recorded on a Fisher-Johns 12–144
melting point apparatus. Optical rotations were obtained on a Pekin–
Elmer 431 Polarimeter.
dropwise. A disappearance in color signified the completion of the
reaction (more sodium borohydride was added if complete decolo-
ration did not occur within 30 min). The reaction mixture was then
diluted with 1.0 M NaOH (40 mL), and the aqueous layer was
extracted with EtOAc (2ꢁ50 mL). The combined organics were
dried over MgSO4, filtered, and concentrated. Flash column chro-
matography (silica gel, 5:1 hexanes/EtOAc) afforded 16 as a clear oil
(229 mg, 72%). Rf¼0.29 (silica gel, 3:1 hexanes/EtOAc); IR (film) nmax
2930, 2827, 1598, 1580, 1484, 1462, 1451, 1429, 1285, 1259, 1148,
1045, 780, 691 cmꢂ1; 1H NMR (600 MHz, CDCl3)
d
7.28 (d, J¼7.9 Hz,
1H), 7.25 (d, J¼8.0 Hz, 1H), 7.21 (t, J¼7.8 Hz, 1H), 7.02 (d, J¼7.7 Hz,
1H), 6.96 (s, 1H), 6.90 (d, J¼7.5 Hz, 1H), 6.86–6.75 (m, 6H), 6.19 (s,
1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H), 3.79 (m, 1H), 3.68 (d,
J¼15.8 Hz, 1H), 3.37 (dt, J¼2.5, 15.6 Hz, 1H), 3.16 (dd, J¼5.5, 11.2 Hz,
1H), 2.88 (dd, J¼11.3, 9.4 Hz, 2H), 2.81 (dd, J¼9.7, 10.9 Hz, 2H), 2.43
4.2. 1-(3-Methoxyphenethyl)-3,5-bis(3-methoxyphenyl)-
pyridinium triflate (9)
A
solution of m-methoxyphenylacetaldehyde (324 mg,
(dd, J¼9.0, 11.1 Hz, 1H); 13C-APT NMR (150 MHz, CDCl3)
d 159.7,
2.16 mmol, 4.0 equiv) and 2-(meta-methoxyphenyl)-ethylamine
hydrochloride (101 mg, 0.54 mmol) in water (1.1 mL, 0.5 M) was
treated with ytterbium triflate (167 mg, 0.27 mmol, 0.5 equiv), and
the reaction mixture was stirred vigorously for 24 h. The reaction
mixture was diluted with water (20 mL), extracted with EtOAc
(2ꢁ20 mL), dried over MgSO4, filtered, and concentrated. Purifica-
tion by flash column chromatography (silica gel, 99:1/95:5 DCM/
MeOH) afforded 9 as a white solid (131 mg, 57%). Mp¼158–160 ꢀC;
Rf¼0.22 (silica gel, 9:1 DCM/MeOH); IR (film) nmax 2937, 1735, 1594,
1583, 1488, 1454, 1255 (s), 1152, 1027, 783, 691, 636 cmꢂ1; 1H NMR
159.6 (2C), 145.2, 141.9, 141.3, 136.1, 129.42, 129.35, 129.34, 126.2,
121.1, 120.5, 117.7, 114.5, 114.0, 112.5, 111.8, 111.3, 111.2, 59.8, 58.3,
55.23, 55.19, 55.1, 54.6, 43.2, 33.9; HRMS (ESI) calcd for C28H31NO3
[MþHþ] 430.2377, found 430.2370.
4.5. 7-Methoxy-1-(3-methoxyphenyl)-1H-inden-2(3H)-one (8)
To 7-methoxyindanone 24 (37 g, 228 mmol) in THF (500 mL) at
0 ꢀC was added a solution of 3-(methoxyphenyl)magnesium bro-
mide 25 (500 mL, 319 mmol, 1.4 equiv) [prepared by adding 3-
bromoanisole (40.4 mL, 319 mmol, 1.4 equiv) dropwise over the
course of 1.5 h to a solution of magnesium turnings (38.9 g, 1.6 mol,
7 equiv) and 1,2-dibromoethane (0.1 mL) in THF (500 mL)]. The re-
action mixture was allowed to warm to room temperature and
stirred for 1 h. Saturated aqueous NH4Cl (200 mL) was added and
the mixture was extracted with Et2O (3ꢁ250 mL), dried over MgSO4,
filtered, and concentrated. The resultant oil was dissolved in CH3CN
(500 mL), treated with H2SO4 (10%, 50 mL), and heated to 60ꢀ for
1 h. The reaction mixture was cooled to room temperature and
stirred overnight. The mixture was then diluted with brine (200 mL)
and extracted with DCM (3ꢁ250 mL); the combined extracts were
dried over MgSO4, filtered, and concentrated. Flash column chro-
matography (silica gel, 2:1 to 1:1 hexanes/DCM) afforded indene 26
(43 g, 170 mmol) as an unstable oil that was immediately dissolved
in 9:1 acetone/H2O (550 mL) and cooled to 0ꢀ. 4-Methylmorpho-
line-N-oxide (34.5 g, 255 mmol, 1.5 equiv) was added followed by
osmium tetroxide (2.5% in t-BuOH; 21 mL,1.7 mmol, 0.01 equiv) and
the solution was warmed to room temperature and stirred for 7.5 h.
Saturated aqueous Na2S2O3 (100 mL) was added and the mixture
was stirred for 1 h. Saturated aqueous NaHCO3 (500 mL) was added
and the aqueous mixture extracted with EtOAc (3ꢁ500 mL); the
extracts were dried over MgSO4, filtered, and concentrated. The
dark oil was dissolved in benzene (500 mL) and treated with
p-toluenesulfonic acid (3.2 g, 17.0 mmol, 0.1 equiv). The flask was
equipped with a Dean–Stark trap and refluxed for 6 h. The reaction
was cooled, diluted with EtOAc (500 mL), and washed subsequently
with saturated aqueous NaHCO3 (100 mL) and brine (100 mL). The
combined aqueous washings were back extracted with EtOAc
(500 mL), and the combined organic extracts were dried over
MgSO4, filtered, and concentrated. Flash column chromatography
(9:1 hexanes/EtOAc) afforded 8 as an off-white solid (40.4 g, 66%
overall); mp 104–105 ꢀC; Rf¼0.35 (silica gel, 4:1 hexanes/EtOAc); IR
(film) nmax 2939, 2359, 1749 (s), 1598 (s), 1484 (s), 1290, 1265, 1135,
(500 MHz, CDCl3)
d
8.76 (d, J¼1.6 Hz, 2H), 8.50 (t, J¼1.6 Hz, 1H), 7.41
(t, J¼8.0 Hz, 2H), 7.17–7.14 (m, 3H), 7.10 (t, J¼2.0 Hz, 2H), 7.03 (dd,
J¼2.4, 8.3 Hz, 2H), 6.74 (dd, J¼2.4, 8.2 Hz, 1H), 6.68 (t, J¼2.1 Hz, 1H),
6.63 (d, J¼7.7 Hz,1H), 5.15 (t, J¼6.5 Hz, 2H), 3.89 (s, 6H), 3.72 (s, 3H),
3.30 (t, J¼6.5 Hz, 2H); 13C-APT NMR (150 MHz, CDCl3)
d 160.7, 141.4,
140.5, 139.9, 136.9, 134.0, 130.8, 130.2, 121.1, 119.6, 116.7, 114.2, 113.5,
112.4, 63.6, 55.7, 55.3, 37.9; HRMS (ESI) calcd for C28H28NO3 [Mþ]
426.2069, found 426.2062.
4.3. 2-(3-Methoxybenzyl)-1-(3-methoxyphenethyl)-3,5-
bis(3-methoxyphenyl)pyridinium triflate (10)
The title compound was prepared from 9 in four steps4 as a yel-
low solid. Rf¼0.32 (silica gel, 9:1 DCM/MeOH); IR (film) nmax 2926,
1600,1584,1490,1468,1258 (s),1224,1153, 1030, 787, 698 cmꢂ1; 1H
NMR (600 MHz, CDCl3)
d
8.96 (d, J¼2.0 Hz, 1H), 8.36 (d, J¼2.0 Hz,
1H), 7.41 (t, J¼8.0 Hz,1H), 7.37 (t, J¼7.9 Hz,1H), 7.26 (t, J¼7.9 Hz,1H),
7.20 (t, J¼7.9 Hz, 1H), 7.16–7.14 (m, 2H), 7.04 (ddd, J¼8.3, 2.4, 0.7 Hz,
1H), 7.01 (ddd, J¼8.4, 2.5, 0.7 Hz, 1H), 6.93 (ddd, J¼7.5, 1.4, 0.8 Hz,
1H), 6.89 (m, 1H), 6.83–6.79 (m, 2H), 5.00 (t, J¼7.0 Hz, 2H), 4.29 (s,
2H), 3.91 (s, 3H), 3.761 (s, 3H), 3.760 (s, 3H), 3.75 (s, 3H), 3.02 (t,
J¼7.0, 2 Hz); 13C-APT NMR (150 MHz, CDCl3):
d 160.7, 160.5, 160.2,
159.9,152.1,144.0,143.2,139.0,136.8,136.7,136.4,133.5,130.8,130.7,
130.4, 130.3, 121.1, 120.7, 119.8, 119.6, 116.9, 115.7, 114.6, 114.1, 114.0,
113.4, 112.9, 112.3, 60.1, 55.8, 55.4, 55.33, 55.32, 37.1, 35.6; 13C-APT
NMR (150 MHz, CD2Cl2):
d 161.3, 161.1, 160.9, 160.6, 152.6, 144.8,
144.4, 144.3, 139.6, 137.4, 137.1, 136.8, 134.2, 131.4, 131.3, 131.0, 130.9,
121.7, 121.3, 120.3, 120.1, 117.0, 116.0, 115.2, 114.8, 114.6, 113.8, 113.5,
113.1, 60.8, 56.3, 55.95, 55.88, 55.8, 37.7, 36.1; HRMS (ESI) calcd for
C36H36NO4 [Mþ] 546.2644, found 546.2635.
4.4. 1-(3-Methoxyphenethyl)-3,5-bis(3-methoxyphenyl)-
1,2,3,6-tetrahydropyridine (16)
1047 cmꢂ1; 1H NMR (600 MHz, CDCl3)
d
7.35 (t, J¼7.9 Hz,1H), 7.20 (t,
To a solution of pyridinium 9 (426 mg, 0.74 mmol) in methanol
(3.7 mL) and DCM (3.7 mL) at 0 ꢀC was added cerium trichloride
(276 mg, 0.74 mmol, 1.0 equiv). Sodium borohydride was added
CAUTIOUSLY (560 mg, 14.8 mmol, 20.0 equiv). A distinct bright
color is observed upon addition. The reaction mixture was stirred
for 20 min, and acetic acid (3.7 mL) was then added CAUTIOUSLY
J¼7.9 Hz, 1H), 7.00 (d, J¼7.5 Hz, 1H), 6.83 (d, J¼8.3 Hz, 1H), 6.78 (dd,
J¼8.3, 2.2 Hz, 1H), 6.70–6.67 (m, 2H), 4.64 (s, 1H), 3.77 (s, 3H), 3.73–
3.67 (m, 1H), 3.66 (s, 3H); 13C-APT NMR (150 MHz, CDCl3)
d 213.2,
159.6, 156.6,138.9,138.8,129.4,129.3,128.4,119.7,116.9,113.4,112.1,
109.4, 57.3, 55.3, 55.1, 42.8; HRMS (ESI) calcd for C17H17O3 [MþHþ]
269.1172, found 269.1171.

N.Z. Burns et al. / Tetrahedron 65 (2009) 6600–6610
6609
4.6. 2-(2-Bromo-5-methoxyphenyl)prop-2-en-1-ol (44a)
added followed by sodium borohydride (399 mg, 10.5 mmol,
5.0 equiv). The reaction mixture was heated to 50 ꢀC for 1 h and
then poured into 1:1 5% aqueous NaHCO3/brine (100 mL) and
extracted with DCM (3ꢁ100 mL). The combined organics were
dried over MgSO4, filtered, concentrated, and diluted with EtOH
(14.0 mL). The solution was heated to reflux and indium powder
(484 mg, 4.22 mmol, 2.0 equiv) was added followed by saturated
aqueous NH4Cl (7.0 mL). The reaction was heated to reflux for 3.5 h
then cooled and diluted with EtOAc (100 mL) and 5% aqueous
NaHCO3 (100 mL). The aqueous layer was further extracted with
EtOAc (3ꢁ100 mL) and the combined organics were dried over
MgSO4, filtered, and concentrated. Flash column chromatography
(silica gel, 4:1/2:1 hexanes/EtOAc) afforded 69 as a white foam
(592 mg, 57%). Mp 57–61 ꢀC; Rf¼0.25 (silica gel, 1:1 hexanes/
EtOAc); IR (film) nmax 2935, 1587 (s), 1478 (s), 1463 (s), 1288, 1263
To a solution of 3-methoxyphenylacetic acid (30.2 g, 182 mmol)
in DCM (250 mL) at 0 ꢀC was added bromine (10.3 mL, 200 mmol,
1.1 equiv) dropwise. The solution was allowed to warm to room
temperature and stirred for 2 h. Saturated aqueous Na2S2O3
(200 mL) was added and the aqueous layer further extracted with
DCM (2ꢁ200 mL). The combined organics were dried over MgSO4,
filtered, and concentrated. The crude mixture was dissolved in
methanol (200 mL) and treated dropwise with thionyl chloride
(39.8 mL, 546 mmol, 3.0 equiv). The solution was heated to reflux
for 4 h and then cooled and concentrated. This material was dis-
solved in toluene (500 mL) and treated with tetrabutylammonium
iodide (66.5 g, 180 mmol, 1.0 equiv), potassium carbonate (49.8 g,
360 mmol, 2.0 equiv), and paraformaldehyde (27.3 g, 900 mmol,
5.0 equiv). The resulting mixture was heated to reflux for 8 h and
then cooled and diluted with EtOAc (500 mL) and washed with
water (500 mL) and brine (500 mL). The organic was dried over
MgSO4, filtered, and concentrated. This crude mixture was dis-
solved in toluene (700 mL) and cooled to ꢂ78 ꢀC. A toluene solution
of diisobutylaluminum hydride (345 mL, 1.5 M, 517 mmol,
3.0 equiv) was added and the solution stirred at ꢂ78 ꢀC for 1 h. The
reaction was quenched with EtOAc (200 mL) and allowed to warm
to room temperature. Saturated aqueous potassium sodium tar-
trate (1.0 L) and Et2O (1.0 L) were added and the solution stirred for
1 h. The layers were separated and the aqueous was further
extracted with Et2O (2ꢁ500 mL). The combined organics were
dried over MgSO4, filtered, and concentrated. Flash column chro-
matography (silica gel, 9:1 hexanes/EtOAc) afforded 44a as a clear
oil (23.4 g, 56% overall). Rf¼0.19 (silica gel, 4:1 hexanes/EtOAc); IR
(film) nmax 3341 (br), 2360, 2341, 1590, 1567, 1464 (s), 1290, 1224 (s),
(s), 1080, 1051, 1028 cmꢂ1 1H NMR (600 MHz, CDCl3)
; d 7.43 (d,
J¼8.7 Hz, 1H), 7.26 (t, J¼8.7 Hz, 1H), 7.18 (t, J¼7.9 Hz, 1H), 6.94 (d,
J¼7.4 Hz, 1H), 6.83 (s, 1H), 6.79–6.67 (m, 5H), 6.36 (s, 1H), 3.82 (d,
J¼17.0 Hz, 1H), 3.77 (s, 3H), 3.76 (s, 3H), 3.68 (dd, J¼6.8, 4.6 Hz, 1H),
3.60 (s, 3H), 3.53 (d, 17.0 Hz, 1H), 3.17 (dd, J¼16.0, 6.9 Hz, 1H), 2.95
(dd, J¼16.0, 4.3 Hz, 1H), 2.31 (br s, 1H); 13C-APT NMR (150 MHz,
CDCl3)
d 159.5, 158.8, 157.4, 147.2, 143.6, 143.5, 139.0, 133.2, 132.3,
130.0, 129.1, 129.0, 119.4, 117.8, 116.0, 114.2, 113.1, 112.8, 111.3, 109.6,
66.4, 55.6, 55.5, 55.2, 55.1, 45.1, 36.0; HRMS (ESI) calcd for
C27H27BrNO3 [MþHþ] 491.1169, found 492.1163.
4.9. (1S,2R)-7-Methoxy-1-(3-methoxyphenyl)-2,3-dihydro-
1H-indene-1,2-diol ([D]-72)
To a solution of indene 26 (2.78 g, 11.0 mmol, synthesized as
previously described) in t-BuOH (55 mL) was added sequentially
methanesulfonamide (5.2 g, 55.0 mmol, 5.0 equiv), (DHQD)2PHAL
(428.0 mg, 0.55 mmol, 0.05 equiv), K2CO3 (4.56 g, 33.0 mmol,
3.0 equiv), and H2O (55.0 mL). This solution was cooled to 0 ꢀC and
treated with potassium ferricyanide (10.9 g, 33.0 mmol, 3.0 equiv)
followed by osmium tetroxide (2.5% in t-BuOH; 1.38 mL, 0.11 mmol,
0.01 equiv). The reaction flask was placed in a 5 ꢀC cold room and
stirred for 44 h. The reaction was quenched with saturated aqueous
Na2S2O3 (100 mL) and allowed to warm to room temperature and
stir for 1 h. The aqueous layer was then extracted with EtOAc
(3ꢁ150 mL), dried over MgSO4, filtered, and concentrated. Flash
column chromatography (silica gel, 4:1/3:1 hexanes/EtOAc)
afforded the diol (3.10 g, 98%). To the solid was added hexanes
(40 mL) and EtOAc (10 mL), and the solution heated to a brief reflux
with a heat gun in order to assure complete dissolution. The hot
solution was then seeded with a sample of racemic diol and
allowed to cool to room temperature. Clear needles of racemic diol
crystallized out of the mixture, and the supernatant was then re-
moved from the resulting crystals and concentrated to afford
enantiomerically pure (þ)-72 as a thick oil (1.89 g, 60%). Rf¼0.24
1039 (s), 1012 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
7.42 (d, J¼8.8 Hz,
1H), 6.75 (d, J¼3.1 Hz, 1H), 6.71 (dd, J¼8.7, 3.1 Hz, 1H), 5.51 (d,
J¼1.5 Hz, 1H), 5.13 (d, J¼1.3 Hz, 1H), 3.77 (s, 3H); 13C-APT NMR
(125 MHz, CDCl3)
112.6, 65.3, 55.4.
d 158.7, 149.1, 141.8, 133.3, 116.3, 115.0, 114.8,
4.7. 1-Bromo-2-(3-iodoprop-1-en-2-yl)-4-
methoxybenzene (44)
Allylic alcohol 44a (13.9 g, 57.1 mmol) was dissolved in DCM
(286 mL) and sequentially treated at 0ꢀ with triphenylphosphine
(19.5 g, 74.2 mmol, 1.30 equiv), imidazole (5.44 g, 79.9 mmol,
1.4 equiv), and iodine (19.6 g, 77.1 mmol, 1.35 equiv). The solution
was stirred at 0 ꢀC for 30 min and quenched with saturated aque-
ous Na2S2O3 (250 mL). Et2O (500 mL) was added and the organic
layer washed with water (200 mL) and brine (200 mL). The organic
layer was dried over MgSO4, filtered, concentrated, and passed
through a plug of silica gel eluting with 9:1 hexanes/Et2O (1 L) to
give allyl iodide 44 (19.5 g, 97%) as an unstable oil, which was used
immediately or stored at ꢂ78 ꢀC. Rf¼0.44 (silica gel, 9:1 hexanes/
Et2O); IR (film) nmax 1590, 1565, 1463, 1404, 1303, 1226, 1155, 1117,
(silica gel, 2:1 hexanes/EtOAc); [
nmax 3447 (br), 2937, 2835, 1589, 1480 (s), 1262 (s), 1078 (s), 1044
(s) cmꢂ1; 1H NMR (500 MHz, CDCl3)
a]
D þ43.4 (c 0.53, CHCl3); IR (film)
1045, 1015, 916, 804 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d
7.43 (d,
d
7.32 (t, J¼8.1 Hz, 1H), 7.19 (t,
J¼8.8 Hz, 1H), 6.84 (d, J¼3.1 Hz, 1H), 6.76 (dd, J¼8.8, 3.1 Hz, 1H),
J¼8.0 Hz, 1H), 6.95 (d, J¼7.5 Hz, 1H), 6.83–6.78 (m, 3H), 6.70–6.68
(m, 1H), 4.29 (d, J¼4.6 Hz, 1H), 4.15 (s, 1H, D2O exchangeable), 3.77
(s, 3H), 3.75 (s, 3H), 3.48 (s, 1H, D2O exchangeable), 3.02 (dd, J¼16.5,
4.5 Hz, 1H), 2.90 (d, J¼16.4 Hz, 1H); 13C-APT NMR (150 MHz, CDCl3)
5.65 (d, J¼0.8 Hz, 1H), 5.15 (d, J¼0.9 Hz, 1H), 4.31 (d, J¼0.7 Hz, 2H),
3.82 (s, 3H); 13C NMR (100 MHz, CDCl3)
119.6, 117.2, 115.1, 112.1, 55.5, 9.1.
d 158.6, 146.7, 141.4, 133.3,
d
159.6, 156.7, 145.8, 143.6, 130.5, 130.0, 129.1, 118.3, 118.2, 112.5,
4.8. 3-(2-Bromo-5-methoxyphenyl)-5-methoxy-4a-
(3-methoxyphenyl)-2,4a,9,9a-tetrahydro-1H-
indeno[2,1-b]pyridine (69)
111.8, 109.1, 85.8, 80.5, 55.3, 55.1, 38.1; HRMS (ESI) calcd for
C17H18O4 [MþNaþ] 309.1097, found 309.1092.
4.10. (S)-1-Hydroxy-7-methoxy-1-(3-methoxyphenyl)-
1H-inden-2(3H)-one ([D]-73)
To a solution of oxime 68 (1.07 g, 2.11 mmol) in 1,2-di-
chloroethane (21.1 mL) at 0 ꢀC was added 2,4,4,6-tetrabromo-2,5-
cyclohexadienone (1.73 g, 4.22 mmol, 2.2 equiv) at once. Stirring
was continued for 30 min at 0 ꢀC and EtOH (21.1 mL) was then
To a solution of (þ)-72 (599 mg, 2.09 mmol) in DCM (10.5 mL)
at 0 ꢀC was added sequentially: saturated aqueous NaHCO3

6610
N.Z. Burns et al. / Tetrahedron 65 (2009) 6600–6610
(4.2 mL), potassium bromide (12.0 mg, 0.10 mmol, 0.05 equiv),
TEMPO (16.0 mg, 0.10 mmol, 0.05 equiv), and aqueous sodium
hypochlorite (6.2 mL, 4.18 mmol, 2.0 equiv). The reaction mixture
was stirred at 0 ꢀC for 30 min and quenched with saturated
aqueous NaHSO4 (10 mL) and allowed to warm to room tem-
perature. The aqueous layer was extracted with EtOAc (3ꢁ30 mL),
and the combined organics were washed once with brine
(20 mL). The organic layer was dried over MgSO4, filtered, and
concentrated. Flash column chromatography (silica gel, 3:1 hex-
anes/EtOAc) afforded (þ)-72 as an off-white solid. Mp 117–
55.2, 54.6, 42.9, 41.3; HRMS (ESI) calcd for C27H25BrO4 [MþHþ]
493.1014, found 493.0988.
Acknowledgements
We thank Dr. D.-H. Huang and Dr. L. Pasternack for NMR spec-
troscopic assistance, Dr. G. Siuzdak for mass spectrometric and both
Dr. Raj Chadha (TSRI) and Dr. Arnold Rheingold (UCSD) for X-ray
crystallographic assistance. Financial support for this work was
provided by The Scripps Research Institute, Bristol-Myers Squibb,
the Searle Scholarship Fund, The Technical University of Denmark
(predoctoral fellowship to M.J.) and the ARCS Foundation (pre-
doctoral fellowship to N.Z.B.).
119 ꢀC; Rf¼0.24 (silica gel, 2:1 hexanes/EtOAc); [
D þ37.9 (c 0.43,
a
]
DCM); IR (film) nmax 3467 (br), 3011, 1744 (s), 1587 (s), 1484 (s),
1291 (s), 1053 (s) cmꢂ1 1H NMR (600 MHz, CDCl3)
; d 7.39 (t,
J¼8.0 Hz, 1H), 7.19 (t, J¼8.0 Hz, 1H), 7.01 (d, J¼7.6 Hz, 1H), 6.97 (m,
1H), 6.89 (d, J¼8.3 Hz, 1H), 6.82 (m, 1H), 6.77 (dd, J¼7.7, 0.8 Hz,
1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.67 (d, J¼21.5 Hz, 1H), 3.58 (d,
J¼1.2 Hz, 1H), 3.49 (d, J¼21.5 Hz, 1H); 13C NMR (151 MHz, CDCl3)
References and notes
1. Garrido, L.; Zubı´a, E.; Ortega, M. J.; Salva´, J. J. Org. Chem. 2003, 68, 293–299.
2. For a theoretical investigation of this dynamic equilibrium, see: Belostotskii, A. M.
J. Org. Chem. 2008, 73, 5723–5731.
3. Baran, P. S.; Burns, N. Z. J. Am. Chem. Soc. 2006, 128, 3908–3909.
4. Burns, N. Z.; Baran, P. S. Angew. Chem., Int. Ed. 2008, 47, 205–208.
5. Smith, N. D.; Hayashida, J.; Rawal, V. H. Org. Lett. 2005, 7, 4309–4312.
6. Grundl, M. A.; Trauner, D. Org. Lett. 2006, 8, 23–25.
d
210.5, 160.0, 157.0, 141.7, 137.7, 130.9, 129.8, 129.6, 118.1, 117.5,
113.9, 111.5, 110.2, 82.4, 55.6, 55.4, 40.3; HRMS (ESI) calcd for
C17H16O4 [MþNaþ] 307.0941, found 307.0929.
7. Wipf, P.; Furegati, M. Org. Lett. 2006, 8, 1901–1904.
8. Jeong, J. H.; Weinreb, S. M. Org. Lett. 2006, 8, 2309–2312.
9. Fu¨rstner, A.; Ackerstaff, J. Chem. Commun. 2008, 2870–2872.
10. Taniguchi, T.; Zaimoku, H.; Ishibashi, H. J. Org. Chem. 2009, 74, 2624–2626.
11. Retracted article: Gravel, E.; Poupon, E.; Hocquemiller, R. Chem. Commun. 2007,
719–721.
12. (a) Chichibabin, A. E. J. Russ. Phys. Chem. Soc. 1906, 37, 1229; (b) Chichibabin, A. E.
J. Prakt. Chem. 1924, 107, 122–128.
13. (a) Eliel, E. L.; McBride, R. T.; Kaufmann, S. J. Am. Chem. Soc. 1953, 75, 4291–
4296; (b) Farley, C. P.; Eliel, E. L. J. Am. Chem. Soc. 1956, 78, 3477–3484.
14. Eckroth, D. R. Chem. Ind. (London) 1967, 920–921.
4.11. (R)-1-(2-(2-Bromo-5-methoxyphenyl)allyl)-7-methoxy-
1-(3-methoxyphenyl)-1H-inden-2(3H)-one ([D]-71)
To a solution of
a
-hydroxy ketone (þ)-73 (490 mg, 1.72 mmol)
and allyl stannane 76 (1.78 g, 3.45 mmol, 2.0 equiv) in THF (11.5 mL)
at 0 ꢀC was added indium(III) trifluoromethanesulfonate (1.16 g,
2.06 mmol, 1.2 equiv). After complete dissolution, the reaction
mixture was allowed to warm to room temperature and stirred for
1.5 h. Saturated aqueous sodium potassium tartrate (20 mL) and
EtOAc (50 mL) were added, and the organic layer was washed with
brine (20 mL). The combined aqueous layers were back extracted
with EtOAc (50 mL), and the combined organics were dried over
MgSO4, filtered, and concentrated. Flash column chromatography
(silica gel, 6:1/4:1 hexanes/EtOAc) afforded the homoallylic diol
77 as a clear oil (755 mg, 86%). To a solution of this diol (755 mg,
1.48 mmol) in DCM (14.8 mL) at 0 ꢀC was added boron triflouride
15. Panzella, L.; Di Donato, P.; Comes, S.; Napolitano, A.; Palumbo, A.; d’Ischia, M.
Tetrahedron Lett. 2005, 46, 6457–6460.
´
16. For a review, see: Marko, I. E. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 913–974.
17. Hofmann, A. W. Ann. 1851, 78, 253–281.
18. Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989–7000.
¨
19. Herrmann, W. A.; Brossmer, C.; Ofele, K.; Reisinger, C.-P.; Priermeier, T.; Beller,
M.; Fischer, H. Angew. Chem., Int. Ed. Engl. 1995, 34, 1844–1848.
20. Minuti, L.; Taticchi, A.; Marrocchi, A.; Lanari, D.; Broggi, A.; Gacs-Baitz, E. Tet-
rahedron: Asymmetry 2003, 14, 481–487.
21. Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417–424.
22. Dondas, H. A.; Grigg, R.; Hadjisoteriou, M.; Markandu, J.; Kennewell, P.;
Thornton-Pett, M. Tetrahedron 2001, 57, 1119–1128.
diethyl etherate (204 mL, 1.62 mmol, 1.1 equiv) dropwise. After
stirring for 10 min at 0 ꢀC, satd aq NaHCO3 (20 mL) and EtOAc
(20 mL) were added. The organic layer was washed with brine
(20 mL), and the combined aqueous layers were back extracted
with EtOAc (20 mL). The organic layers were dried over MgSO4,
filtered, and concentrated. Flash column chromatography (silica
gel, 9:1/6:1 hexanes/EtOAc) afforded (þ)-71 as a white solid
(603 mg, 83%). Mp¼88–90 ꢀC; Rf¼0.39 (silica gel, 1:1 hexanes/
23. Cicchi, S.; Bonanni, M.; Cardona, F.; Revuelta, J.; Goti, A. Org. Lett. 2003, 5, 1773–
1776.
24. (a) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759–6760; (b)
Trost, B. M.; Schroeder, G. M.; Kristensen, J. Angew. Chem., Int. Ed. 2002, 41,
3492–3495; (c) Trost, B. M.; Schroeder, G. M. Chem.dEur. J. 2005, 11, 174–184.
25. For a review, see: Enders, D.; Klatt, M. Synthesis 1996, 1403–1418.
26. (a) Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106, 446–
447; (b) Bhattacharya, A.; Dolling, U.-H.; Grabowski, E. J. J.; Karady, S.; Ryan, K. M.;
Weinstock, W. M. Angew. Chem., Int. Ed. Engl. 1986, 25, 476–477; (c) Conn, R. S. E.;
Lovell, A. V.; Karady, S.; Weinstock, L. M. J. Org. Chem. 1986, 51, 4710–4711; (d)
Hughes, D. L.; Dolling, U.-H.; Ryan, K. M.; Schoenewaldt, E. F.; Grabowski, E. J. J.
J. Org. Chem. 1987, 52, 4745–4752.
27. Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem. 1987, 52, 2559–2562.
28. For a review, see: Rickborn, B. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 721–732.
29. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–
2547.
Et2O); [
(s), 1463 (s), 1289 (s), 1264 (s), 1050 (s), 1016 cmꢂ1
(600 MHz, CDCl3)
a
]
D þ6.8 (c 0.5, DCM); IR (film) nmax 1749 (s), 1586 (s), 1482
1H NMR
7.27 (d, J¼6.0 Hz, 1H), 7.23 (t, J¼7.9 Hz, 1H), 7.16
;
d
(t, J¼8.0 Hz, 1H), 6.91 (d, J¼7.2 Hz, 1H), 6.79 (d, J¼7.9 Hz, 1H), 6.76
(dd, J¼8.4, 6.3 Hz, 1H), 6.74 (dd, J¼8.1, 1.9 Hz, 1H), 6.53 (dd, J¼8.8,
3.1 Hz, 1H), 6.51 (d, J¼10.0 Hz, 1H), 5.63 (d, J¼3.1 Hz, 1H), 5.24 (s,
1H), 4.88 (d, J¼1.4 Hz, 1H), 3.91 (d, J¼13.2 Hz, 1H), 3.74 (s, 3H), 3.72
(d, J¼13.1 Hz, 1H), 3.57 (s, 3H), 3.48 (d, J¼22.5 Hz, 1H), 3.42 (m, 3H),
30. (a) Marshall, J. A.; Hinkle, K. W. J. Org. Chem. 1995, 60, 1920–1921; (b) Miyai, T.;
Inoue, K.; Yasuda, M.; Baba, A. Synlett 1997, 699–700.
31. Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem., Int. Ed. 2009, 48, 2854–
2867.
32. Burns, N. Z.; Krylova, I. N.; Hannoush, R. N.; Baran, P. S. J. Am. Chem. Soc.,
in press. doi:10.1021/ja903745s.
3.11 (d, J¼22.5 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d 215.2, 159.6,
158.0, 157.3, 147.5, 143.7, 142.4, 138.5, 132.7, 130.3, 129.6, 129.3,
120.4, 119.2, 116.8, 115.6, 114.6, 113.2, 112.7, 111.8, 109.2, 63.4, 55.3,