Total syntheses of the dipyrrolobenzoquinone (+)-terreusinone enabled by an evaluation of 4-methylpent-1-yn-3-ols in the Larock indole synthesis

Article abstract of DOI:10.1016/j.tet.2013.04.025

The Larock indolization between 4-methylpent-1-yn-3-ols (alkynols) and ortho-bromo and ortho-iodoanilines has been studied. Although the unprotected alkynol was an unviable substrate for the annulation reaction, protected derivatives did proceed to the indole products. Interestingly, this reaction does not appear to occur by the widely accepted mechanism for the Larock indolization of internal alkynes, but by the initial formation of a cross-coupled arylalkyne followed by 5-endo-dig cyclization. Importantly, when a chiral alkynol is used, the stereochemical integrity is retained in the indole product. Although this methodology could not be successfully extended to a double Larock indolization approach to terreusinone, two separate total syntheses evolved from these studies: A bidirectional, double Sonogashira-hydroamination approach and a one-pot Larock indolization- Sonogashira coupling followed by hydroamination. This work has not only confirmed the gross structure and absolute configuration of the photoprotecting natural product terreusinone, but also uncovered several novel applications of known reaction conditions that should find broad applications in the field of heteroaromatic construction.

Full text of DOI:10.1016/j.tet.2013.04.025

Tetrahedron 69 (2013) 4563e4577
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Total syntheses of the dipyrrolobenzoquinone (þ)-terreusinone
enabled by an evaluation of 4-methylpent-1-yn-3-ols in the Larock
indole synthesis
*
Christy Wang, Jonathan Sperry
School of Chemical Sciences, University of Auckland, 23 Symonds St., Auckland, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
The Larock indolization between 4-methylpent-1-yn-3-ols (alkynols) and ortho-bromo and ortho-io-
doanilines has been studied. Although the unprotected alkynol was an unviable substrate for the an-
nulation reaction, protected derivatives did proceed to the indole products. Interestingly, this reaction
does not appear to occur by the widely accepted mechanism for the Larock indolization of internal al-
kynes, but by the initial formation of a cross-coupled arylalkyne followed by 5-endo-dig cyclization.
Importantly, when a chiral alkynol is used, the stereochemical integrity is retained in the indole product.
Although this methodology could not be successfully extended to a double Larock indolization approach
to terreusinone, two separate total syntheses evolved from these studies: A bidirectional, double
Sonogashira-hydroamination approach and a one-pot Larock indolizationeSonogashira coupling fol-
lowed by hydroamination. This work has not only confirmed the gross structure and absolute configu-
ration of the photoprotecting natural product terreusinone, but also uncovered several novel applications
of known reaction conditions that should find broad applications in the field of heteroaromatic
construction.
Received 25 January 2013
Received in revised form 21 March 2013
Accepted 4 April 2013
Available online 10 April 2013
Keywords:
Natural product
Palladium
Total synthesis
Alkaloid
Hydroamination
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
dipyrrolobenzoquinone 2 and its regioisomer 4 in poor yield.5 The
reaction of activated methylene derivatives with 3,6-diamino-2,5-
In 2003, Son and co-workers isolated the natural product ter-
reusinone (1) from the marine fungus Aspergillus terreus.1 Terreu-
sinone shows significant UV-A protecting properties, implying
a possible role in protecting the host organism from the harmful
effects of solar UV-irradiation. The UV-A protecting capability
dibromobenzoquinones 56 and ethyl 3-aminobut-2-enoate with
p-chloranil 67 furnishes the dipyrrolobenzoquinones 7 and 8, re-
spectively. Finally, the annulation of the 1,2-amino alcohol 9 with
indolequinone 10 provides 11 (along with its regioisomer), which
upon acid mediated cyclization and oxidation gives dipyrrolo-
benzoquinone 12.8
of 1 (ED50 w200
mm) is stronger than that of oxybenzone
(ED50¼350 m), a compound widely used in sunscreens, suggesting
m
The examples outlined in Scheme 1 are poor yielding,5 require
harsh conditions,5 afford heavily substituted products6,7 or proceed
in a non-regioselective manner.8 None of these methods can be
applied to the synthesis of dipyrrolobenzoquinones with chiral
substituents embedded on the heterocyclic ring(s), as observed in
1 (or analogues) have potential applications in sunscreen cos-
metics.2 Furthermore, the ongoing health concerns associated with
the use of sunscreens necessitates further research into viable al-
ternatives.3,4 The isolation of terreusinone (1) marked the first oc-
casion the pyrrolo[2,3-f]indole-4,8-dione ring system (2) had been
observed in a natural product (Fig. 1). The heterocyclic motif 2 shall
be termed ‘dipyrrolobenzoquinone’ throughout the remainder of
this manuscript.
The synthesis of compounds bearing the dipyrrolobenzoqui-
none 2 is an underexplored area with scope for development, with
an overview of existing synthetic methods shown in Scheme 1. The
flash vacuum pyrolysis of diketopiperazine 3 gives a mixture of the
* Corresponding author. E-mail address: j.sperry@auckland.ac.nz (J. Sperry).
Fig. 1. Terreusinone (1) and dipyrrolobenzoquinone (2).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.025

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C. Wang, J. Sperry / Tetrahedron 69 (2013) 4563e4577
Scheme 1. Existing methods for the synthesis of the dipyrrolobenzoquinones.
the natural product 1. When considering these existing methods, it
is immediately apparent that they all employ substrates at the
quinone oxidation state. We envisaged a novel approach to dipyr-
rolobenzoquinones of type 2 via the seemingly straightforward
oxidation of its benzenoid derivative, pyrrolo[2,3-f]indole 13
(Scheme 2). The literature syntheses of pyrroloindoles 13 are more
numerous than for 2, but they too possess narrow scope and none
have incorporated chiral substituents onto the heterocycle(s).9,10
a double Larock indolization of a suitable halogenated 1,4-dianiline
15 with the chiral alkynol (R)-4 (Scheme 3). Herein we report
a detailed study examining the use of 4-methylpent-1-yn-3-ols of
type 4 in the Larock indolization, the results of which served as the
support studies for our two separate total syntheses of the natural
product (þ)-terreusinone.12
The use of secondary alkynols in the Larock indolization is rel-
atively unexplored13 and the first task was to gauge the viability of
alkynols 4 as substrates in the proposal outlined in Scheme 3. Al-
though the alkynol (ꢀ)-4a is commercially available, it is rather
costly so we opted for its large-scale preparation by Grignard re-
action between ethynylmagnesium bromide and isobutyraldehyde.
Straightforward protection procedures were used to access pro-
tected alkynols (ꢀ)-4bed (Scheme 4).
With alkynols (ꢀ)-4aed and the commercially available ortho-
haloanilines 16a and 16b to hand, a model study examining the
feasibility of the proposal outlined in Scheme 3 was initiated
(Table 1). Subjecting ortho-iodoaniline 16a and alkynol (ꢀ)-4a to
the standard Larock conditions11 only delivered a poor yield of the
alkene 18 arising from successful indolization followed by elimi-
nation (entry 1). Conducting the reaction in a sealed tube did im-
prove the conversion rate of the reaction, although in this instance
the major product was the arylalkyne (ꢀ)-19a along with the allene
2014 (entry 2). Isolation of significant quantities of the arylalkyne
(ꢀ)-19a suggests that the Larock indolization of terminal alkynes
may proceed by initial Sonogashira coupling and 5-endo-dig cycli-
zation of the resulting arylalkyne, a complementary reaction
pathway to that of internal alkynes, which involves a migratory
Scheme 2. Proposed oxidation of pyrroloindole (13) to dipyrrolobenzoquinone (2).
2. Results and discussion
The initially proposed retrosynthesis of terreusinone is shown in
Scheme 3. As alluded to previously, the aim was to construct the
dipyrrolobenzoquinone by the late stage oxidation of the pyrro-
loindole 14. The palladium-catalyzed reaction between ortho-hal-
oanilines and alkynes (Larock indolization) is an extremely reliable
procedure for assembling indoles with excellent levels of regio-
control11 and as such, pyrroloindole 14 could be constructed using

C. Wang, J. Sperry / Tetrahedron 69 (2013) 4563e4577
4565
Scheme 3. Proposed double Larock indolization approach to (þ)-terreusinone.
discovered that the yield of (ꢀ)-17b could be increased further by
switching the reaction solvent from dimethylformamide to N-
methylpyrrolidone (entry 5). Next, we set out to see if altering the
protecting group on the alkynol has any effect on the indolization.
The triisopropyl (ꢀ)-4c (TIPS, entry 6) and ethoxymethyl (ꢀ)-4d
(EOM, entry 7) protected alkynols gave significantly poorer yields
of the desired indoles (ꢀ)-17c (23%) and (ꢀ)-17d (30%).
Considering the ortho-bromoanilines are generally more stable
and easy to access than their iodo counterparts, we next set out to
test ortho-bromoaniline 16b in the proposed approach. The use of
ortho-bromoanilines in the Larock indolization requires modified
catalytic systems17 and we chose to employ the conditions reported
by Senanayake.17a Thus, upon subjecting ortho-bromoaniline 16b
and alkynol (ꢀ)-4b to Senanayake’s modified Larock conditions
[Pd(OAc)2, 1,10-bis(di-tert-butylphosphino)ferrocene, K2CO3, NMP,
130 ꢁC] a poor yield of indole (ꢀ)-17b was obtained, along with
significant quantities of arylalkyne (ꢀ)-19b (entry 8). As our pre-
vious observations had demonstrated that the removal of bulky
triphenylphosphine ligand from the reaction increases the yield of
the desired indole (entries 3e5) it was postulated that the bulky
active catalytic species (Pd(OAc)2eDtBPF) was inhibiting azole ring
formation. As the electron-rich DtBPF ligand is vital for the reaction
to proceed, we sought to reduce the size of the protecting group on
the alkynol in order to promote azole formation. Indeed, it was
found that both the triisopropylsilyl (entry 9) and ethoxymethyl
ether (entry 10) protected alkynols (ꢀ)-4c and (ꢀ)-4d gave ac-
ceptable yields of the desired indoles (ꢀ)-17c (47%) and (ꢀ)-17d
(52%), with no trace of arylalkyne observed. These results led us to
draw several conclusions with relevance to the planned total syn-
thesis of terreusinone: whilst the alkynol (ꢀ)-4b should proceed
well in the Larock indolization with ortho-iodoanilines, it does not
appear to be a viable coupling partner with ortho-bromoanilines.
Alkynols (ꢀ)-4c and (ꢀ)-4d should be used with an ortho-bro-
moaniline in preference to an ortho-iodoaniline.
Scheme 4. Preparation of alkynol (ꢀ)-4a and protected derivatives (ꢀ)-4bed.
insertion of the intermediate aryl Pd(II) complex into the triple
bond followed by formation of a six-membered palladacycle and
reductive elimination.11,15,16 Considering the issues encountered
with elimination of the unprotected alkynol (ꢀ)-4a, employing
a protected derivative seemed inevitable. Gratifyingly, the annu-
lation between silylated alkynol (ꢀ)-4b and 16a gave the desired
indolization product (ꢀ)-17b, albeit in poor yield along with
a substantial quantity of arylalkyne (ꢀ)-19b (entry 3). However, by
removing the triphenylphosphine from the reaction,11 the yield of
the desired indole (ꢀ)-17b increased to a respectable 60% (entry 4).
TLC analysis of the reaction mixture clearly shows the indolization
reaction has two distinct stages: (i) conversion of (ꢀ)-4b and 16a to
arylalkyne (ꢀ)-19b: (ii) cyclization of arylalkyne (ꢀ)-19b to indole
(ꢀ)-17b, adding weight to our earlier postulate that terminal and
internal alkynes proceed through the annulation by different
mechanistic pathways. The large contrast in yield between entries 3
and 4 is striking and is presumably attributed to the bulky triphe-
nylphosphine ligands on the active catalyst hindering the 5-endo-
dig cyclization of (ꢀ)-19b to the desired indole (ꢀ)-17b. It was later
With a thorough optimization study conducted, the depro-
tection of indoles (ꢀ)-17bed was next considered (Scheme 5).
Subjecting the silylated indoles (ꢀ)-17b and (ꢀ)-17c to standard
TBAF-mediated cleavage gave good to excellent yields of the de-
sired indole (ꢀ)-17a, confirming the use of a silyl protecting group
is indeed a viable choice for the eventual total synthesis of ter-
reusinone. However, all attempts to deprotect the EOM-protected
indole (ꢀ)-17d led to very poor yields of (ꢀ)-17a. It was at this
stage EOM was ruled out as a possible protecting group for the total
synthesis, with attention focussing on silyl protecting groups.

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C. Wang, J. Sperry / Tetrahedron 69 (2013) 4563e4577
Table 1
Feasibility studyaec
Entry
ortho-Halo aniline
Alkynol
Conditions
Time
Product distribution (% yield)
17
18
19
20
1
2
16a
16a
(ꢀ)-4a
(ꢀ)-4a
A
B
16 h
4 h
0
0
6
0
0
70
0
5
(ꢀ)-19a
R¼H
3
16a
16a
16a
16a
16a
16b
16b
16b
(ꢀ)-4b
(ꢀ)-4b
(ꢀ)-4b
(ꢀ)-4c
(ꢀ)-4d
(ꢀ)-4b
(ꢀ)-4c
(ꢀ)-4d
B
C
D
D
D
E
17 h
2 h
10
0
0
0
0
0
0
0
0
66
0
0
0
0
0
0
0
0
(ꢀ)-17b
R¼TBDPS
60
(ꢀ)-17b
R¼TBDPS
72
(ꢀ)-17b
R¼TBDPS
23
(ꢀ)-17c
R¼TIPS
30
(ꢀ)-17d
R¼EOM
15
(ꢀ)-17b
R¼TBDPS
47
(ꢀ)-17c
R¼TIPS
52
(ꢀ)-19b
R¼TBDPS
0
4
5
40 min
16 h
20 h
16 h
16 h
20 h
0
0
0
6
7
8
58
(ꢀ)-19b
R¼TBDPS
0
9
E
10
E
0
(ꢀ)-17d
R¼EOM
a
0.5 mmol of o-haloaniline and 1.5 mmol (3 equiv) alkynol were used in all entries.
b
c
In conditions AeD, the following ratios were used (based on o-haloaniline); 5 mol % catalyst, 5 mol % PPh3 (when added), 1 equiv LiCl, 5 equiv K2CO3, 7.5 mL solvent.
In conditions E, the following ratios were used (based on o-haloaniline); 5 mol % catalyst, 7.5 mol % DtBPF, 5 equiv K2CO3, 7.5 mL solvent.
Although it is well established that alkynes bearing a chiral
alkynol (ꢀ)-4a), as well as vast quantities of (R)-Alpine boraneÒ to
give moderate yields (47%) of (R)-4a (96% ee). Thus, a reported
biocatalytic approach20 was considered and the kinetic resolution
of (ꢀ)-4a with Novozyme 435Ò using vinyl acetate as acyl donor in
hexane at 32 ꢁC for 6 h gave the desired alkynol (R)-4a in excellent
yield and enantiomeric excess (Scheme 6). However, separating the
alkynol (R)-4a and the acetate (S)-21 by distillation proved trou-
blesome in our hands due to close proximity of the boiling points of
the two compounds. Furthermore, column chromatography was
not possible due to the instability of (R)-4a on silica gel. This issue
was eventually resolved by removing the enzyme from the reaction
upon completion of the kinetic resolution, followed by treating the
mixture of (R)-4a and (S)-21 with triisopropylsilyl triflate. The
centre adjacent to the triple bond proceed through the Larock
indolization with no stereochemical erosion,11c,18 this has never
been demonstrated with chiral alkynols.13 Having established that
the silylated alkynols (ꢀ)-4b and (ꢀ)-4c were the best candidates
for the Larock indole synthesis, we set out to investigate if the
enantioenriched (R)-4b and (R)-4c would proceed through the re-
action with no loss in stereochemical integrity. An efficient route to
alkynols (R)-4b and (R)-4c was sought and a review of the literature
revealed that alkynol (R)-4a is available in enantioenriched form by
Midland reduction of the corresponding alkynone.19 However, this
reported chiral reduction requires an alkynone that is not readily
available (obtained by the oxidation of the commercially available

C. Wang, J. Sperry / Tetrahedron 69 (2013) 4563e4577
4567
indole (R)-17c (Scheme 7). Chiral HPLC analysis21 of (R)-17c con-
firmed an enantiomeric excess of >95%, confirming that the an-
nulation reaction proceeded with no loss in stereochemical
integrity. However, upon TBAF mediated removal of the TIPS group
from (R)-17c, the enantiomeric excess of (R)-17a was determined as
73% by chiral HPLC and as such, a selection of deprotection condi-
tions were screened (Table 2). Although buffered TBAF (entry 2)
and triethylamine-hydrofluoride (entry 3) gave slightly improved
ee’s, the yields were dismal. Trifluoroacetic acid (entry 4) and acetic
acid (entry 5) failed to cleave the TIPS group and the trace amount
of product obtained from treatment of (R)-17c with hydrochloric
acid had fully racemized (entry 6).
Although the detailed model studies had only resulted in the
synthesis of indole (R)-17a with moderate levels of enantiopurity,
we pressed on regardless and looked to extend this methodology to
the synthesis of the natural product terreusinone. Accordingly,
a suitable halogenated 1,4-dianiline was sought to test the viability
of the double Larock indolization approach outlined in Scheme 1.
The known reduction22 of dinitro compound 22 to 1,4-dianiline 23
was optimized using a H-cubeÒ continuous-flow hydrogenation
reactor. However, despite subjecting 23 to a plethora of bromina-
tion and iodination conditions (including double ortho-metal-
ations), none of the desired dihalogenated products 15a or 15b
were ever isolated. The failure of this reaction was attributed to the
instability of the electron rich substrate 23, along with the sterically
congested nature of the desired products. We were also unable
to access the dihalogenated products 15c or 15d from the com-
mercially available dianiline 24, with complex mixtures obtained
Scheme 5. Deprotection of indoles (ꢀ)-17bed.
silylated alkynol (R)-4c could then be easily separated from the
acetate (S)-21 by flash chromatography. A small portion of the re-
action mixture was separately treated with (R)-Moshers acid,
confirming the kinetic resolution produced (R)-4a with an enan-
tiomeric excess of 96% (Scheme 6).
The model work in Table 1 inferred that (ꢀ)-4c fared best in
the annulation with ortho-bromoaniline (entry 6 vs 9) and as such,
(R)-4c was subjected to Larock indolization with 16b, affording
Scheme 6. Asymmetric synthesis of (R)-4c.
Scheme 7. Annulation with (R)-4c.

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C. Wang, J. Sperry / Tetrahedron 69 (2013) 4563e4577
Table 2
1,4-dibromide 28 in an acceptable 2:1 ratio with the 1,2-dibromide
Deprotection of indole (R)-17c
27. Nitro-group reduction then gave the desired double Larock
indolization precursor 15c, an unstable entity that had to be freshly
synthesized and used immediately in the next step. All attempts to
improve the stability of 15c by converting it to the diacetamide24
surprisingly failed, with degradation occurring before any trace of
30 was observed.
Entry
Conditions
Temp (ꢁC)
Time (h)
Yield
(R)-17a (%)
ee
(R)-17a (%)
1
2
3
4
5
6
TBAF
0
0.5
48
48
24
24
1
91
10
6
0
0
73
77
75
d
d
0
TBAFeAcOH
3HF$NEt3
TFA
AcOH
HCl
0/rt/60
0/rt/60
0/rt/60
rt
With 15c and (R)-4c to hand, the double Larock indolization
could be attempted (Scheme 10). Despite subjecting freshly syn-
thesized 15c and an excess of (R)-4c to the optimized Larock con-
ditions obtained from the model studies (and several others), none
of the desired pyrroloindole 31 was ever observed. Interestingly,
(albeit somewhat unexpectedly based on the earlier model work),
2,5-dialkynyl-1,4-dianiline 32 arising from double Sonogashira
cross-coupling was often observed in trace amounts, as a single
diastereomer. Upon careful optimization, the yield of 32 could be
increased to a synthetically useful 40%. It is important to note that
the exact conditions shown in Scheme 10 have to be employed to
obtain the 40% yield for the double Sonogashira reactiondeven
a slight deviation from the catalyst/ligand loadings, temperature or
scale causes the yield of 32 to plummet. Despite the initially pro-
posed double Larock indolization failing, some useful copper- and
amine-free conditions for the Sonogashira reaction of electron rich
arylbromides25,26 (i.e., 15c) had been serendipitously discovered.
Interestingly, subjecting 32 to several Larock conditions (including
those used for its formation), led to its degradation (ca. 12 h) and
ꢂ30/0
2
from several different bromination and iodination conditions
(Scheme 8).
Due to the poor outcome obtained from the attempted dihalo-
genation of dianilines 23 and 24, a stepwise route to precursor of
type 15 was considered (Scheme 9). Although commercially avail-
able 2-methoxy-4-nitroaniline 25 underwent successful dibromi-
nation with N-bromosuccinimide in sulfuric acid, the undesired
1,2-dibromide 27 was isolated as the sole product in poor yield, as
determined by NOE experiments. However, following the known23
monobromination of 2-methoxy-4-nitroaniline 25, bromide 26
underwent a second bromination with N-bromosuccinimide in
sulfuric acid, affording the 1,2-dibromide 27 and 1,4-dibromide 28
in a disappointing 97:3 ratio favouring the 1,2-regiosiomer. Despite
these undesirable regiochemical outcomes, upon acetylation of 26,
the resulting acetamide 29 underwent bromination to the desired
Scheme 8. Failed approaches to halogenated 1,4-dianilines 15aed.
Scheme 9. Synthesis of precursor 15c.

C. Wang, J. Sperry / Tetrahedron 69 (2013) 4563e4577
4569
Scheme 10. Failed double Larock and successful double Sonogashira approaches.
not the formation of pyrroloindole 31. A separate set of reaction
conditions were clearly required in order to affect the desired
double hydroamination.
from 32 (three steps, Path A) was a little low and in an attempt to
improve this, the order of synthetic steps (from 32/35, Path B)
was inverted. Although deprotection of 32 gave 34 in excellent
yield and as a single diastereomer, the double hydroamination
only gave poor yields of 35, meaning this alternative route de-
livered the natural product in 13% yield from 32 (three steps, Path B,
Scheme 11).12b Synthetic (þ)-terreusinone obtained from paths A
and B possessed identical optical rotations and melting points.
Considering the effort that had been dedicated to uncovering
suitable reagents and conditions for the Larock indolization de-
scribed in Table 1, it seemed a shame not to at least pursue a total
synthesis of (þ)-terreusinone that incorporated this methodology.
Although the initially proposed double Larock indolization failed,
ready access to nitroaniline 28 (Scheme 9) and the knowledge
that Senanayake’s modified Larock conditions promote Sonoga-
shira coupling (Scheme 10) led us to envisage a one-pot Lar-
ockeSonogashira coupling between 28 and (R)-4c to give indole
36 (Scheme 12).12a Nitro group reduction, followed by the
deprotection/hydroamination/oxidation sequence described in
Various acid27 and base28 conditions, along with various metal
based catalytic systems including Pd(II),29 Cu(I),30 Cu(II),31 Zn(II),32
Pt(II),33 Ir(III),34 Rh(I)35 and In(III)36 are known to catalyze the
hydroamination of unsubstituted ortho-alkynylanilines to indoles.
However, the field of gold-catalysis has increased exponentially
over the past few years37 and the catalysts involved are typically
air- and water-stable and reactions can be performed in an open
flask under mild conditions. All of the gold(III)38 and gold(I)39
-
catalysts reported to facilitate the synthesis of indoles from ortho-
alkynylanilines failed to affect our desired double hydroamination
of 32 to 31. In a final attempt, we turned to Echavarren’s cationic
gold(I) complex40 (acetonitrile)[(2-biphenyl)di-tert-butylphos-
phine]gold(I) hexafluoroantimonate 33 (Fig. 2), a particularly useful
gold(I)-catalyst as the weakly coordinating acetonitrile ligand ne-
gates the need for the addition of a silver co-catalyst. To our delight,
upon exposing 32 to 15 mol % of complex 33 in toluene at 60 ꢁC,
pyrroloindole 31 was isolated in excellent yield after 4 h.9m,41 The
cationic gold(I)-complex 33 has been reported to facilitate a num-
ber of transformations,40 but to the best of our knowledge this is
the first example of 33 being used in a hydroamination to form
a five-membered azole. In contrast to the model studies (Table 2),
no racemization was evident after the TBAF-mediated silyl ether
Scheme 11 would then provide
a complementary route to
(þ)-terreusinone.
Upon subjecting 28 and an excess of (R)-4c to the modified
Larock conditions,17a both the Larock indolization and Sonogashira
coupling successfully occurred, furnishing indole 36 in 26% yield
(Scheme 13). 1H and 13C NMR spectroscopy showed only one di-
astereomer of 12 was present, inferring that as the model studies
indicated, the stereochemical integrity in (R)-4c had been retained
in the product. The desired regiochemical outcome of the Larock
indolization was confirmed by NOE studies. Despite the poor yield
of this step, we were content with the formation of three key bonds
(2ꢄ CeC, 1ꢄ CeN) in a single operation and the discovery of a one-
pot reaction that may find broad use as an efficient synthesis of
alkynylindoles. Nitro group reduction in 36 gave the indole 37 in
good yield. As observed during the bidirectional synthesis, no ra-
cemization was evident after the TBAF-mediated silyl ether cleav-
cleavage of 31, delivering pyrroloindole 35 as
a single di-
astereomer.42 Finally, oxidation with Fremy’s salt gave (þ)-terreu-
sinone 1, which was spectroscopically identical to the reported
data1 and thus confirming the gross structure of the natural
product. The optical rotation of (þ)-1 {½a D21
þ49.6 (c 0.19, MeOH)}
ꢃ
was in excellent agreement with the isolation report {[
a
]
þ47
D
(c 0.3, MeOH)}1 affirming that stereocentres present in the natural
product (þ)-terreusinone possess (R)-configuration. Despite
achieving a total synthesis of the natural product, the yield of 25%
age of 37, delivering ortho-alkynylaniline 38 as
a single
diastereomer in good yield,42 setting the scene for the key hydro-
amination. Upon exposing 38 to 12 mol % of complex 33 in toluene
at 60 ꢁC, pyrroloindole 35 was isolated in excellent yield after
30 min (Scheme 13). Oxidation of 35 as described previously gave
terreusinone (þ)-1, which was spectroscopically identical to the
reported data.1 The optical rotation of (þ)-1 {½a 2D1
ꢃ
þ43.7 (c 0.16,
D þ47 (c 0.3,
MeOH)} was in agreement with the isolation report {[a]
Fig. 2. Echavarren’s complex.
MeOH)}1 and that of the natural product obtained from the

4570
C. Wang, J. Sperry / Tetrahedron 69 (2013) 4563e4577
Scheme 11. Bidirectional total synthesis of (þ)-1.12b
bidirectional synthesis outlined in Scheme 10 {½a D21
ꢃ
þ49.6 (c 0.19,
sample of natural (þ)-terreusinone is available for comparison to
MeOH)}. Unfortunately, we have never been able to establish
contact with the authors of the isolation report1 and as such, no
our synthetic material.43
3. Conclusions
The Larock indolization of 4-methylpent-1-yn-3-ols (alkynols)
with ortho-bromo and ortho-iodoanilines has been studied. Al-
though the unprotected 4-methylpent-1-yn-3-ol was not a viable
substrate, protected derivatives did proceed to the indole prod-
ucts. When a chiral alkynol is used, the stereochemical integrity is
retained in the product. Although these indolizations could not be
conducted simultaneously as planned in the initially proposed
double Larock approach, two separate total syntheses evolved
from this initial idea:
hydroamination approach and
A
bidirectional, double Sonogashira-
one-pot Larock indoliza-
a
tioneSonogashira coupling followed by hydroamination. Along
with confirming the gross structure and absolute stereochemistry
of the natural product, these synthetic studies uncovered some
interesting results: (1) in a mechanism that is contrary to the
Larock indolization of internal alkynes, protected 4-methylpent-1-
yn-3-ols appear to undergo an initial Sonogashira cross-coupling
followed by 5-endo-dig cyclization; (2) the hydroamination of or-
tho-alkynylanilines to indoles can be catalyzed by Echavarren’s
cationic complex 33; (3) Pd(OAc)2eDtBPF appears to be an excel-
lent catalytic system for the Sonogashira coupling with electron
rich aryl bromides; (4) a one-pot Larock indolizationeSonogashira
coupling has been used to access an alkynylindole.
Scheme 12. Proposed one-pot LarockeSonogashira reaction.12a

C. Wang, J. Sperry / Tetrahedron 69 (2013) 4563e4577
4571
Scheme 13. Total synthesis of (þ)-1 using a one-pot LarockeSonogashira reaction.
4. Experimental
4.1. General
0 ꢁC over 30 min. Then the reaction mixture was warmed to room
temperature and stirred for an additional 5 h. The reaction was
quenched with ammonium chloride solution (150 mL) and the
aqueous layer was extracted with dichloromethane (2ꢄ150 mL).
The combined organic layers were washed with water (200 mL)
and brine (200 mL), dried (MgSO4), filtered and concentrated in
vacuo to give an orange-brown residue. The crude material was
purified by distillation to yield the title compound as a colourless oil
(2.1 g, 20.9 mmol, 48%); bp 130e131 ꢁC (760 mmHg); dH (400 MHz,
CDCl3) 4.17 (1H, d, J 4.0, H-3), 2.45 (1H, s, H-1), 1.92 (1H, m, H-4),
1.03 (6H, t, J 8.0, 2ꢄ Me), OH not observed; The spectroscopic data
was in agreement with that reported in the literature.44
All reactions were carried out in oven-dried or flame-dried
glassware under a nitrogen atmosphere unless otherwise stated.
Analytical thin layer chromatography was performed using 0.2 mm
Kieselgel F254 (Merck) silica plates and compounds were visualized
under 365 nm ultraviolet irradiation followed by staining with ei-
ther alkaline permanganate or ethanolic vanillin solution. Infrared
spectra were obtained using a Perkin Elmer spectrum One Fourier
Transform Infrared spectrometer as thin films between sodium
chloride plates. Absorption maxima are expressed in wavenumbers
(cmꢂ1). Optical rotations were measured using a PerkineElmer 341
4.1.2. tert-Butyl[(4-methylpent-1-yn-3-yl)oxy]diphenylsilane
(ꢀ)-4b. To a solution of alkynol (ꢀ)-4a (1.0 g, 10 mmol) in DMF
(10 mL) at 0 ꢁC was added imidazole (1.7 g, 25 mmol) in one portion
followed by tert-butyl(chloro)diphenylsilane (3.1 mL, 12 mmol)
dropwise. The reaction mixture was warmed to room temperature
and stirred for 12 h. Cold water (50 mL) was added and the aqueous
layer was extracted with ether (3ꢄ50 mL). The combined organic
extracts were dried over MgSO4, filtered and concentrated in vacuo
to give crude material that was purified by flash chromatography
on silica gel using hexaneseethyl acetate (9:1) as eluent to yield the
title compound as a colourless oil (3.0 g, 8.9 mmol, 89%); nmax (neat)/
cmꢂ1 3605, 3072, 2959, 2858, 1471, 1428, 1388, 1362, 1185, 1110,
1072, 998; dH (400 MHz, CDCl3) 7.74e7.68 (4H, m, ArH), 7.45e7.35
(6H, m, ArH), 4.19 (1H, d, J 4.4, H-3), 2.25 (1H, s, H-1), 1.87e1.84 (1H,
m, H-4), 1.09 (9H, s, 3ꢄ Me), 1.04 (3H, d, J 6.4, Me), 0.90 (3H, d, J 6.8,
Me); dC (100 MHz, CDCl3) 136.3 (2ꢄ CH), 136.0 (2ꢄ CH), 133.84 (C),
133.82 (C), 129.8 (CH), 129.7 (CH), 127.7 (2ꢄ CH),127.5 (2ꢄ CH), 83.6
(C), 73.5 (CH), 69.0 (CH), 35.0 (CH), 27.1 (3ꢄ Me), 19.6 (C), 18.2 (Me),
17.1 (Me); m/z (ESI) 359 (100%, [MNa]þ), 301 (30), 257 (5), 179 (5),
149 (15); HRMS (ESI, [MNa]þ) found 359.1795. [C22H28OSiþNa]þ
requires 359.1802.
polarimeter at
l
¼598 nm and are given in 10ꢂ1 deg cm2 gꢂ1
.
Melting points were recorded on an Electrothermal melting point
apparatus and are uncorrected. NMR spectra were recorded as in-
dicated on either a Bruker DRX-400 spectrometer operating at
400 MHz for 1H nuclei and 100 MHz for 13C nuclei or on a Bruker
Avance 300 spectrometer operating at 300 MHz and 75 MHz for 1H
and 13C nuclei, respectively. Chemical shifts are reported in parts
per million (ppm) relative to the tetramethylsilane peak recorded
as
7.26 ppm), DMSO (
13C NMR values were referenced to CDCl3, DMSO-d6 or methanol-d4
peaks. 13C NMR values are reported as chemical shift
, multiplicity
and assignment. 1H NMR shift values are reported as chemical shift
, relative integral, multiplicity (s, singlet; d, doublet; t, triplet; q,
d
0.00 ppm in CDCl3/TMS solvent, or the residual chloroform (
d
d
2.50 ppm) or methanol ( 3.31 ppm) peaks. The
d
d
d
quartet; m, multiplet), coupling constant (J in Hertz) and assign-
ment. Assignments are made with the aid of DEPT 135, COSY,
NOESY and HSQC experiments. High resolution mass spectra were
recorded on a VG-70SE mass spectrometer at a nominal acceler-
ating voltage of 70 eV. Chiral HPLC analysis was performed using an
UltiMate 3000 series system (Dionex, California, United States)
with an AD-H column (250 mmꢄ4.6 mm, 5
mm; Daicel Group).
4.1.3. Triisopropyl[(4-methylpent-1-yn-3-yl)oxy]silane
a solution of alkynol (ꢀ)-4a (0.4 g, 4.1 mmol) in dichloromethane
(10 mL) at 0 ꢁC was added 2,6-lutidine (857 mg, 930
L, 8 mmol)
and triisopropylsilyl triflate (1.1 g, 0.9 mL, 4.8 mmol). The reaction
(ꢀ)-4c. To
4.1.1. 4-Methylpent-1-yn-3-ol (ꢀ)-4a. A solution of ethynylmagne-
sium bromide (150 mL, 75 mmol, 0.5 M in THF) was added slowly to
a solution of isobutyraldehyde (3.6 g, 50 mmol) in THF (20 mL) at
m

4572
C. Wang, J. Sperry / Tetrahedron 69 (2013) 4563e4577
mixture was allowed to warm to room temperature over 3 h. The
reaction was quenched with saturated sodium bicarbonate solution
(10 mL) and the whole extracted with dichloromethane (3ꢄ10 mL).
The combined organic extracts were washed with brine (20 mL),
dried (Na2SO4), filtered and concentrated in vacuo. The crude res-
idue was purified by flash chromatography on silica gel using
hexaneseethyl acetate (4:1) as eluent to yield the title compound as
a colourless oil (846 mg, 3.3 mmol, 83%); nmax (neat)/cmꢂ1 3311,
2943, 2867, 1463, 1385, 1367, 1247, 1099, 1067, 997, 883, 883, 825,
800, 681, 654; dH (400 MHz, CDCl3) 4.32 (1H, d, J 4.8, CHOSi), 2.34
(1H, s, alkyneeH), 1.90e1.85 (1H, m, CH(Me)2), 1.12 (3H, m, 3ꢄ CH),
1.11e1.07 (18H, m, 6ꢄ Me), 1.01 (3H, d, J 6.8, 0.8, Me), 0.96 (3H, dd, J
6.4, 0.8, Me); dC (100 MHz, CDCl3) 84.2 (C), 72.7 (CH), 68.2 (CH), 35.3
(CH), 18.1 (6ꢄ Me), 17.0 (2ꢄ Me), 12.3 (3ꢄ CH); m/z (ESI) 277 [62%,
(MþNa)þ], 253 (4), 235 (100), 207 (5), 149 (12); HRMS [ESI,
(MþNa)þ] found 277.1964. [C15H30OSiþNa]þ requires 277.1958.
dichloromethane at ambient temperature for 16 h. A short filtration
through silica and analysis by 19F NMR showed an enantiomeric
excess of 96.1%.
4.2. Model Larock indolizations
4.2.1. 1-(2-Aminophenyl)-4-methylpent-1-yn-3-ol (ꢀ)-19a. Yellow
oil (5.7 mg, 30 m
mol, 6%); nmax (neat)/cmꢂ1 3354, 2960, 2871, 2213,
1723, 1614, 1574, 1492, 1383, 1314, 1260, 1158, 1024, 748; dH
(400 MHz, CDCl3) 7.27 (1H, d, J 1.2, ArH); 7.12 (1H, dd, J 7.6, 0.8, ArH),
6.70e6.65 (2H, m, 2ꢄ ArH), 4.45 (1H, d, J 5.6, H-3), 4.19 (2H, br s,
NH2), 2.03e1.97 (1H, m, H-4), 1.64 (1H, br s, OH), 1.10e1.05 (6H, m,
2ꢄ Me); dC (100 MHz, CDCl3) 148.0 (C), 132.5 (CH), 129.9 (CH),
118.0 (CH), 114.5 (CH), 107.6 (C), 94.5 (C), 82.4 (C), 68.7 (CH), 34.8
(CH), 18.4 (Me), 17.8 (Me); m/z (ESI) 190 (4%, [MH]þ), 172 (100), 157
(38), 143 (19), 130 (21); HRMS (ESI, [MH]þ) found 190.1221.
[C12H15NOþH]þ requires 190.1226.
4.1.4. 3-(Ethoxymethoxy)-4-methylpent-1-yne (ꢀ)-4d. To a solution
of alkynol (ꢀ)-4a (393 mg, 4 mmol) in dichloromethane (15 mL) was
4.2.2. 2-(4-Methylpenta-1,2-dien-1-yl)aniline 20. Yellow oil (4.3 mg,
added tetrabutylammonium iodide (15 mg, 40
mmol), diisopropy-
30 m
mol, 5%); nmax (neat)/cmꢂ1 3340, 2956, 2878, 1743, 1620, 1578,
lethylamine (1.5 g, 2 mL, 11.5 mmol) and chloromethyl ethyl ether
(1.1 g, 1.1 mL, 12 mmol). The reaction mixture was stirred at room
temperature for 2 h and diluted with dichloromethane (30 mL). The
resulting organic solution was washed with water (30 mL) and brine
(30 mL), dried (Na2SO4), filtered and concentrated in vacuo. The
crude material was purified by Hickman distillation to give the title
compound (612 mg, 3.9 mmol, 98%) as a pale yellow oil; nmax (neat)/
cmꢂ1 3308, 2964, 2877, 1678, 1572, 1524, 1470, 1386, 1368, 1353,
1269, 1179, 1155, 1095, 946; dH (400 MHz, CDCl3) 4.93 (1H, d, J 6.8,
CH2), 4.66 (1H, d, J 6.8, CH2), 4.10 (1H, dd, J 5.6, 2, H-3), 3.68e3.62
(1H, m, CH2), 3.59e3.49 (1H, m, CH2), 2.36 (1H, s, H-1), 1.93e1.88
(1H, m, H-4),1.20e1.16 (3H, m, OCH2Me),1.00e0.97 (6H, m, 6ꢄ Me);
dC (100 MHz, CDCl3) 92.8 (CH2), 81.5 (C), 74.0 (CH), 70.9 (CH), 63.7
(CH2), 32.9 (CH),18.4 (Me),17.8 (Me),15.1 (Me); m/z (ESI) 179 (100%,
[MNa]þ), 166 (30), 152 (15), 144 (9); HRMS (ESI, [MNa]þ) found
179.1045. [C9H16O2þNa]þ requires 179.1043.
1492, 1250, 1151, 1022, 801; dH (400 MHz, CDCl3) 7.77 (1H, d, J 15.6,
ArH), 7.42 (1H, dd, J 7.9, 1.2, ArH), 7.18 (1H, t, J 7.4, ArH), 6.69e6.78
(3H, m, ArH, H-1, H-3), 3.99 (2H, br s, NH2), 2.88e2.86 (1H, m, H-4),
1.18 (6H, d, J 6.8, 2ꢄ Me); dC (100 MHz, CDCl3) 203.8 (C), 146.1 (C),
137.9 (CH), 131.5 (CH), 128.2 (CH), 124.3 (C), 120.3 (C), 119.1 (CH),
116.9 (CH), 40.0 (CH),18.6 (2ꢄ Me); m/z (ESI) 172 (46%, [MꢂH]þ),156
(100), 143 (20), 130 (35), 117 (13); HRMS (ESI, [MꢂH]þ) found
172.1122. [C12H15NꢂH]þ requires 172.1121.
4.2.3. 2-{3-[(tert-Butyldiphenylsilyl)oxy]-4-methylpent-1-yn-1-yl}
aniline (ꢀ)-19b. Brown oil (70 mg, 160
mmol, 66%); nmax (neat)/
cmꢂ1 2959, 2930, 2857, 1613, 1492, 1470, 1456, 1352, 1261, 1110,
1061, 998; dH (400 MHz, CDCl3) 7.79e7.73 (4H, m, ArH), 7.40e7.32
(6H, m, ArH), 7.07e7.00 (2H, m, ArH), 6.61e6.58 (2H, m, ArH), 4.48
(1H, d, J 4.8, H-3), 3.82 (2H, br, NH2), 1.98 (1H, m, H-4), 1.11 (3H, d, J
8.0, Me), 1.09 (9H, s, 3ꢄ Me), 0.99 (3H, d, J 6.8, Me); dC (100 MHz,
CDCl3) 147.9 (C), 136.2 (2ꢄ CH), 136.1 (2ꢄ CH), 134.3 (C), 133.8 (C),
132.4 (CH), 129.8 (CH), 129.6 (CH), 129.4 (CH), 127.8 (2ꢄ CH), 127.5
(2ꢄ CH), 117.7 (CH), 114.2 (CH), 108.0 (C), 94.7 (C), 82.4 (C), 69.9
(CH), 35.5 (CH), 27.1 (3ꢄ Me),19.6 (C), 18.5 (Me),17.6 (Me); m/z (ESI)
428 (30%, [MH]þ), 172 (100); HRMS (ESI, [MH]þ) found 428.2392.
[C28H33NOSiþH]þ requires 428.2404.
4.1.5. (R)-Triisopropyl[(4-methylpent-1-yn-3-yl)oxy]silane (R)-4c.
To a 50 mL Erlenmeyer flask containing n-hexane (HPLC grade,
10 mL), vinyl acetate (0.9 g, 1 mL, 10.8 mmol) and Novozyme 435Ò
(300 mg) was added alkynol (ꢀ)-4a (465 mg, 500
mL, 4.7 mmol).
The reaction mixture was shaken (32 ꢁC, 700 rpm) for 6 h. The
reaction mixture was filtered, concentrated in vacuo to give a crude
mixture of (R)-4a and (S)-10 that was taken up in dichloromethane
(8 mL) and cooled to ꢂ78 ꢁC. 2,6-Lutidine (643 mg, 0.7 mL,
For indoles (ꢀ)-17b, (ꢀ)-17c, (ꢀ)-17d and (R)-17c the pro-
cedures that resulted in the best yields are provided:
6.0 mmol) and triisopropylsilyl triflate (670 mg, 540
mL, 3 mmol)
4.2.4. Synthesis of 2-{1-[(tert-butyldiphenylsilyl)oxy]-2-methyl-
propyl}2-indole (ꢀ)-17b using conditions D. In a 4-dram vial
equipped with a stirring bar and Teflon-lined screw cap, a solution
were added sequentially and the reaction mixture allowed to warm
to room temperature over 3 h. The reaction was quenched with
saturated sodium bicarbonate solution (10 mL) and the whole
extracted with dichloromethane (3ꢄ10 mL). The combined organic
extracts were washed with brine (20 mL), dried (Na2SO4), filtered
and concentrated in vacuo. The crude residue was purified by flash
chromatography on silica gel using hexaneseethyl acetate (4:1) as
eluent to yield the title compound as a colourless oil (512 mg,
of palladium diacetate (5.6 mg, 30 mmol), lithium chloride (21.2 mg,
0.5 mmol), potassium carbonate (345 mg, 2.5 mmol), 2-iodoaniline
(109.5 mg, 0.5 mmol), alkynol (ꢀ)-4b (540 mg, 1.5 mmol) and
N-methyl-2-pyrrolidone (7.5 mL) was degassed by bubbling argon
through the solution for 15 min. After heating at 120 ꢁC for 40 min,
the reaction mixture was diluted with diethyl ether and washed
with aqueous ammonium chloride followed by water. The organic
layer was dried (MgSO4), filtered, concentrated in vacuo and the
crude residue purified by flash chromatography on silica gel eluting
with hexaneseethyl acetate (19:1) to give the title compound
(153 mg, 0.4 mmol, 72%) as a brown oil; nmax (neat)/cmꢂ1 2959,
2931, 2857, 1727, 1470, 1384, 1287, 1110, 1048, 937; dH (400 MHz,
CDCl3) 8.14 (1H, br s, NH), 7.65 (2H, m, ArH), 7.41e7.29 (8H, m, ArH),
7.21e7.03 (4H, m, ArH), 6.07 (1H, d, J 1.6, H-2), 4.71 (1H, d, J 5.2,
H-3), 1.96e1.94 (1H, m, H-4), 1.06 (9H, s, 3ꢄ Me), 0.82 (6H, dd, J
7.6, 6.8, 2ꢄ Me); dC (100 MHz, CDCl3) 139.1 (C), 136.0 (2ꢄ CH), 135.9
(2ꢄ CH), 135.5 (C), 134.0 (C), 133.5 (C), 129.9 (CH), 129.7 (CH), 128.4
(C), 127.7 (2ꢄ CH), 127.6 (2ꢄ CH), 121.3 (CH), 120.4 (CH), 119.6 (CH),
2.0 mmol, 42%); ½a D20
ꢃ
þ27.1 (c 2.0, CH2Cl2); nmax (neat)/cmꢂ1 3311,
2943, 2867, 1463, 1385, 1367, 1247, 1099, 1067, 997, 883, 883, 825,
800, 681, 654; dH (400 MHz, CDCl3) 4.32 (1H, d, J 4.8, CHOSi), 2.34
(1H, s, alkyneeH), 1.90e1.85 (1H, m, CH(Me)2), 1.12 (3H, m, 3ꢄ CH),
1.11e1.07 (18H, m, 6ꢄ Me), 1.01 (3H, d, J 6.8, 0.8, Me), 0.96 (3H, dd, J
6.4, 0.8, Me); dC (100 MHz, CDCl3) 84.2 (C), 72.7 (CH), 68.2 (CH), 35.3
(CH), 18.1 (6ꢄ Me), 17.0 (2ꢄ Me), 12.3 (3ꢄ CH); m/z (ESI) 277 [62%,
(MþNa)þ], 253 (4), 235 (100), 207 (5), 149 (12); HRMS [ESI,
(MþNa)þ] found 277.1964. [C15H30OSiþNa]þ requires 277.1958.
After filtration of the enzyme, a small portion of the reaction
mixture was subjected to Mosher’s ester analysis by treatment with
(R)-(þ)-a-methoxytrifluorophenylacetic acid, DCC and DMAP in

C. Wang, J. Sperry / Tetrahedron 69 (2013) 4563e4577
4573
110.9 (CH), 100.3 (CH), 75.7 (CH), 35.6 (CH), 27.3 (3ꢄ Me), 19.7 (C),
18.9 (Me),17.5 (Me); m/z (ESI) 428 (100%, [MH]þ), 350 (80), 311 (38),
172 (25); HRMS (ESI, [MH]þ) found 428.2404. [C28H33NOSiþH]þ
requires 428.2404.
THF). The reaction mixture was stirred at 0 ꢁC for 30 min. The
solvent was removed under reduced pressure and the crude resi-
due was purified with flash chromatography on silica gel using
ethyl acetate as eluent to give the title compound as an orange solid
(15 mg, 80 mmol, 91%); The ee was determined to be 73% by HPLC
4.2.5. Synthesis of 2-{2-methyl-1-[(triisopropylsilyl)oxy]propyl}-in-
dole (ꢀ)-17c using conditions E. In a 4-dram vial equipped with
a stirring bar and Teflon-lined screw cap, a solution of palladium
diacetate (5.6 mg, 0.025 mmol), 1,10-bis(di-tert-butylphosphino)
analysis; ½a 2D0
ꢃ
þ10.0 (c 1.0, CH2Cl2); mp 76e80 ꢁC; nmax (neat)/cmꢂ1
3538, 3499, 3272, 3052, 2951, 2868, 1722, 1615, 1492, 1457, 1386,
1288, 1204, 1152, 990, 960; dH (400 MHz, CDCl3) 8.36 (1H, br s, NH),
7.57 (1H, d, J 7.8, ArH), 7.34 (1H, d, J 7.8, ArH), 7.15 (1H, dt, J 6.8, 1.0,
ArH), 7.08 (1H, dt, J 6.8, 1.0, ArH), 6.35 (1H, s, H-2), 4.64 (1H, d, J 6.0,
ferrocene (14.2 mg, 30
mmol), potassium carbonate (345 mg,
2.5 mmol), 2-bromoaniline (86 mg, 0.5 mmol), alkynol (ꢀ)-4c
(416 mg, 1.5 mmol) in N-methyl-2-pyrrolidone (7.5 mL) was
degassed by bubbling argon through the solution for 15 min. After
being heated for 16 h at 130 ꢁC, the reaction mixture was diluted
with diethyl ether and washed with aqueous ammonium chloride
followed by water. The organic layer was dried (MgSO4), filtered,
concentrated in vacuo and the crude residue purified by flash
chromatography on silica gel using hexaneseethyl acetate (19:1) to
give the title compound (80 mg, 0.2 mmol, 47%) as a brown oil; nmax
(neat)/cmꢂ1 3480, 2942, 2866, 1457, 1418, 1383, 1365, 1350, 1287,
1256, 1153, 1080, 1059, 1013, 997, 882; dH (400 MHz, CDCl3) 8.25
(1H, br s, NH), 7.58 (1H, d, J 8.0, ArH), 7.38 (1H, d, J 8.0, ArH), 7.16
(1H, dt, J 9.6, 1.2, ArH), 7.10 (1H, dt, J 9.6, 1.2, ArH), 6.25 (1H, d, J
Ha), 2.12e2.05 (1H, m, CH), 2.04 (1H, br s, OH), 1.04 (3H, d, J 6.8,
Me), 0.92 (3H, d, J 6.8, Me); dC (100 MHz, CDCl3) 140.2 (C), 135.7 (C),
128.4 (C), 121.8 (CH), 120.5 (CH), 119.9 (CH), 111.0 (CH), 99.8
(CH), 74.2 (CH), 34.5 (CH), 18.9 (Me), 18.1 (Me); m/z (ESI) 212
(100%, [MNa]þ), 172 (23); HRMS (ESI, [MNa]þ) found 212.1045.
[C12H15NOþNa]þ requires 212.1046.
4.2.9. N-(2-Bromo-6-methoxy-4-nitrophenyl)acetamide 29. To a so-
lution of 2-bromo-6-methoxy-4-nitroaniline23 26 (2.0 g, 8 mmol)
in dichloromethane (40 mL) at 0 ꢁC was added trifluoroacetic acid
(149
mg, 0.1 mL, 1.3 mmol) followed by acetic anhydride (2.8 g,
2.6 mL, 27.6 mmol). The reaction mixture was warmed to room
temperature over 3 h then diluted with dichloromethane (100 mL).
The whole was washed with water (100 mL), brine (100 mL),
dried (MgSO4), filtered and concentrated in vacuo. The crude ma-
terial was recrystallized from boiling ethanol (w30 mL) to yield
the title compound (2.2 g, 7.6 mmol, 95%) as a white solid; mp
232.5e235.8 ꢁC; nmax (neat)/cmꢂ1 3205, 3184, 3095, 1674, 1509,
1400, 1370, 1343, 1310, 1283, 1252, 1098, 1036, 879, 834, 749; dH
(400 MHz, DMSO-d6) 9.73 (1H, br s, NH), 8.08 (1H, d, J 2.4, ArH), 7.85
(1H, d, J 2.4, ArH), 3.93 (3H, s, OMe), 2.04 (3H, s, Me); dC (100 MHz,
DMSO-d6) 167.9 (C]O), 156.1 (C), 146.6 (C), 132.6 (C), 123.2 (C),
119.0 (CH), 106.2 (CH), 56.8 (Me), 22.6 (Me); m/z (ESI) 311 [40%,
(MþNa)þ], 251 (48), 237 (100), 195 (45), 181 (51), 137 (48), 123 (82);
HRMS [ESI, (MþNa)þ] found 310.9647. [C9H979BrN2O4þNa]þ re-
quires 310.9638.
1.6, H-3), 4.85 (1H, d, J 5.2, Ha), 2.07 (1H, m, CH), 1.13e1.06 (3H, m,
3ꢄ CH), 1.06e1.02 (21H, m, 7ꢄ Me), 0.86 (3H, d, J 6.8, Me); dC
(100 MHz, CDCl3) 139.7 (C), 135.4 (C), 128.5 (C), 121.2 (CH), 120.3
(CH), 119.6 (CH), 110.8 (CH), 99.7 (CH), 74.9 (CH), 36.1 (CH), 19.0
(Me), 18.2 (3ꢄ Me), 17.1 (Me), 12.5 (3ꢄ Me); m/z (ESI) 346 (48%,
[MH]þ), 229 (100), 187 (8), 172 (28), 149 (28); HRMS (ESI, [MH]þ)
found 346.2548. [C21H35NOSiþH]þ requires 346.2561.
4.2.6. 2-{2-Methyl-1-[(triisopropylsilyl)oxy]propyl}-indole (R)-17c
was prepared as described for (ꢀ)-17c but using the alkynol
(R)-4c. The ee was determined to be >95% by HPLC analysis;
½
a 2D0
(ꢀ)-17c.
ꢃ
þ43.7 (c 3.1, CH2Cl2); spectroscopic data as described for
4.2.7. Synthesis of 2-[1-(ethoxymethoxy)-2-methylpropyl]-indole
(ꢀ)-17d using conditions E. In a 4-dram vial equipped with a stir-
ring bar and Teflon-lined screw cap, a solution of palladium diac-
4.2.10. 2,3-Dibromo-6-methoxy-4-nitroaniline 27 and 3,6-dibromo-
2-methoxy-4-nitroaniline 28. Freshly recrystallized bromide 29
(1.0 g, 3.5 mmol) was added slowly to concentrated sulfuric acid
(10 mL) over 20 min at 0 ꢁC. N-Bromosuccinimide (677 mg,
3.8 mmol) was added portionwise to the resulting solution over
30 min and the reaction mixture was warmed to room temperature
over 15 h. Ice (w100 mL) was added and the resulting suspension
extracted with ethyl acetate (150 mL). The organic phase was
separated and washed repeatedly with water (100 mL) until the
aqueous layer was neutral, dried (Na2SO4), filtered and concen-
trated in vacuo. The residue was purified by flash chromatography
on silica gel using toluene (100%) as eluent affording the title
compound 27 (less polar) and 28.
Compound 27: (230 mg, 0.7 mmol, 21%) yellow solid; mp
134e136 ꢁC; nmax (neat)/cmꢂ1 3496, 3389, 3104, 1602, 1553, 1480,
1298, 1234, 1036, 744; dH (400 MHz, CDCl3) 7.48 (1H, s, ArH), 5.04
(2H, br s, NH2), 3.94 (3H, s, OMe); dC (100 MHz, CDCl3) 144.3 (C),
140.8 (C), 139.9 (C), 111.9 (C), 111.3 (C), 107.1 (CH), 56.4 (Me); m/z
(ESI) 346 [0.2%, (MþNa)þ], 329 (70), 312 (100), 282 (1); HRMS
[ESI, (MþNa)þ] found 346.8636. [C7H679Br2N2O3þNa]þ requires
346.8637.
etate (5.6 mg, 30
(14.2 mg, 30 mol), potassium carbonate (345 mg, 2.5 mmol),
m
mol), 1,10-bis(di-tert-butylphosphino)ferrocene
m
2-bromoaniline (86 mg, 0.5 mmol), alkynol (ꢀ)-4d (270 mg,
1.5 mmol) in N-methyl-2-pyrrolidone (7.5 mL) was degassed by
bubbling argon through the solution for 15 min. After being heated
for 20 h at 130 ꢁC, the reaction mixture was diluted with diethyl
ether and washed with aqueous ammonium chloride and water.
The organic layer was dried (MgSO4), filtered, concentrated in
vacuo and the crude residue purified by flash chromatography on
silica gel using hexaneseethyl acetate (7:3) to give the title com-
pound (64.3 mg, 0.3 mmol, 52%) as a yellow solid; mp 81e84 ꢁC;
nmax (neat)/cmꢂ1 2966, 2954, 2889, 1460, 1422, 1267, 1223, 1164,
1903, 972; dH (400 MHz, CDCl3) 8.24 (1H, br, NH), 7.56 (1H, d, J 8.0,
ArH), 7.35 (1H, d, J 8.0, ArH), 7.18e7.06 (2H, m, ArH), 6.40 (1H, s, CH),
4.61 (2H, s, CH2), 4.47 (1H, d, J 7.2, H-3), 3.80e3.72 (1H, m, CH2),
3.54e3.46 (1H, m, CH2), 2.10e2.04 (1H, m, H-4), 1.20 (3H, t, J 6.8,
Me), 1.08 (3H, d, J 6.4, Me), 0.84 (3H, d, J 6.8, Me); dC (100 MHz,
CDCl3) 137.5 (C), 135.9 (C), 128.2 (C), 121.7 (CH), 120.4 (CH), 119.7
(CH), 110.8 (CH), 102.3 (CH), 93.1 (CH2), 78.0 (CH), 63.7 (CH2), 33.7
(CH), 19.2 (Me), 18.9 (Me), 15.1 (Me); m/z (ESI) 270 (21%, [MNa]þ),
172 (100); HRMS (ESI, [MNa]þ) found 270.1448. [C15H21NO2þNa]þ
requires 270.1465.
Compound 28: (470 mg, 1.4 mmol, 41%) yellow solid; mp
142e145 ꢁC; nmax (neat)/cmꢂ1 3483, 3364, 1608, 1554, 1505, 1472,
1445, 1403, 1292, 1228, 1159, 1007, 938, 880; dH (400 MHz, CDCl3)
8.05 (1H, s, ArH), 3.89 (3H, s, OMe), 4.92 (2H, br s, NH2); dC
(100 MHz, CDCl3) 144.2 (C), 144.0 (C), 139.5 (C), 126.8 (CH), 111.4 (C),
105.5 (C), 59.9 (Me); m/z (ESI) 346 [0.5%, (MþNa)þ], 329 (70), 312
(100), 301 (27); HRMS [ESI, (MþNa)þ] found 346.8638.
[C7H679Br2N2O3þNa]þ requires 346.8637.
4.2.8. (R)-1-(Indol-2-yl)-2-methylpropan-1-ol (R)-17a. To a solu-
tion of (R)-17c (30 mg, 87
tetra-n-butylammonium fluoride (87
m
mol) in THF (5 mL) at 0 ꢁC was added
mL, 87 mmol, 1 M solution in

4574
C. Wang, J. Sperry / Tetrahedron 69 (2013) 4563e4577
4.2.11. 2,5-Dibromo-3-methoxy-1,4-dianiline 15c. To a solution of
nitroaniline 28 (85 mg, 0.3 mmol) and ammonium chloride
(139 mg, 2.6 mmol) in methanolewater (22 mL, 10:1) was added
zinc powder (170 mg, 2.6 mmol) and the reaction mixture heated
under reflux for 30 min. The solvents were removed under reduced
pressure and the residue was taken up in diethyl ether (60 mL). The
organic solution was washed with water (50 mL), dried (Na2SO4),
filtered and concentrated in vacuo to give the title compound as
a purple oil; nmax (neat)/cmꢂ1 3341, 2924, 2852, 1708, 1592, 1463,
1258, 1173, 1075, 961; dH (300 MHz, DMSO-d6) 6.75 (1H, s, AreH),
4.73 (2H, br s, NH2), 4.35 (2H, br s, NH2), 3.65 (3H, s, OMe); dC
(75 MHz, DMSO-d6) 144.9 (C), 138.5 (C), 131.0 (C), 114.1 (CH), 109.1
(C), 104.5 (C), 59.4 (Me); m/z (ESI) 316 [14%, (MþNa)þ], 281 (100);
HRMS [ESI, (MþNa)þ] found 316.8911. [C7H879Br2N2OþNa]þ re-
quires 316.8896. This compound was used immediately in the
subsequent step due to its instability.
18.3 (Me), 18.2 (Me), 13.3 (6ꢄ CH); m/z (ESI) 665 [34%, (MþNa)þ],
491 (100), 469 (42); HRMS [ESI, (MþNa)þ] found 665.4499.
[C37H66N2O3Si2þNa]þ requires 665.4504.
4.3.3. (3R,30R)-1,10-(2,5-Diamino-3-methoxy-1,4-phenylene)bis(4-
methylpent-1-yn-3-ol) 34. To a solution of 32 (25 mg, 38
THF (7 mL) at 0 ꢁC was added tetra-n-butylammonium fluoride
(60 L, 60 mol, 1 M solution in THF) and the reaction mixture was
mmol) in
m
m
stirred at 0 ꢁC for 20 min. The solvent was removed under reduced
pressure and the crude residue was purified with flash chroma-
tography on silica gel using hexaneseethyl acetate (1:1, 0.5% Et3N)
as eluent to give the title compound as a yellow oil (11.7 mg,
35.3
m
mol, 92%); ½a 2D0
ꢃ
þ28.1 (c 0.30, EtOAc); nmax (neat)/cmꢂ1 3334,
2960, 2927, 1603, 1554, 1459, 1430, 1289, 1194, 1153, 1027, 864; dH
(400 MHz, acetone-d6) 6.47 (1H, s, AreH), 4.44e4.36 (6H, br m, 2ꢄ
CH, 2ꢄ OH, NH2), 4.16 (2H, br s, NH2), 3.82 (3H, s, OMe), 1.97e1.88
(2H, m, 2ꢄ (CH3)2CH), 1.10e1.06 (6H, m, 2ꢄ Me), 1.05e1.02 (6H, m,
2ꢄ Me); dC (100 MHz, acetone-d6) 148.6 (CeO), 141.9 (C), 134.2 (C),
112.6 (CH), 110.5 (C), 104.8 (C), 101.2 (C), 97.0 (C), 82.1 (C), 78.7 (C),
68.5 (CH), 68.3 (CH), 60.0 (Me), 35.64 (CH), 35.60 (CH), 18.72 (Me),
18.69 (Me), 18.2 (Me), 18.1 (Me); m/z (ESI) 331 [10%, (MþH)þ], 313
(18), 295 (26), 280 (100), 264 (23), 241 (12), 226 (11); HRMS [ESI,
(MþH)þ] found 331.2022. [C19H26N2O3þH]þ requires 331.2016.
4.3. Bidirectional total synthesis of (D)-terreusinone
4.3.1. 3-Methoxy-2,5-bis{(R)-4-methyl-3-[(triisopropylsilyl)oxy]
pent-1-yn-1-yl}benzene-1,4-diamine 32. In a 4-dram vial equipped
with a stirring bar and Teflon-lined screw cap, N-methyl-2-
pyrrolidone (15 mL) was purged with nitrogen for 1 h. Palladium
diacetate (5.8 mg, 26
cene (14.8 mg, 31 mol), potassium carbonate (180 mg, 1.3 mmol),
m
mol), 1,10-bis(di-tert-butylphosphino)ferro-
m
4.3.4. (1R,10R)-1,10-(4-Methoxy-1,5-dihydropyrrolo[2,3-f]indole-2,6-
dianiline 15c (76 mg, 0.3 mmol) and alkynol (R)-4c (330 mg,
1.3 mmol) were added and the reaction mixture was heated at
138 ꢁC for 2 h. After cooling to room temperature, the reaction
mixture was filtered through a pad of CeliteÒ and the cake washed
with ethyl acetate (100 mL). The filtrate was washed with water
(80 mL), brine (80 mL), dried (Na2SO4), filtered and concentrated in
vacuo. The residue was purified with flash chromatography on
silica gel using hexaneseethyl acetate (19:1) as eluent to yield the
diyl)bis(2-methylpropan-1-ol) 35. Path A: To a solution of pyrro-
loindole 31 (15 mg, 23
n-butylammonium fluoride (47
m
mol) in THF (7 mL) at 0 ꢁC was added tetra-
m
L, 47 mmol, 1 M solution in THF)
and the reaction mixture was stirred at 0 ꢁC for 20 min. The solvent
was removed under reduced pressure and the crude residue was
purified with flash chromatography on silica gel using hex-
aneseethyl acetate (1:1, 0.5% Et3N) as eluent to give the title com-
pound as a crimson oil (4.3 mg, 13
Path B: To a solution of dianiline 34 (3.0 mg, 9.1
(6 mL) was added (acetonitrile)[(2-biphenyl)di-tert-butylphos-
mmol, 56%).
title compound (67.6 mg, 0.11 mmol, 40%) as an orange oil; ½a D20
ꢃ
mmol) in toluene
þ54.4 (c 1.0, EtOAc); nmax (neat)/cmꢂ1 2943, 2866, 1598, 1459, 1431,
1384, 1366, 1304, 1239, 1156, 1088, 1055, 996; dH (400 MHz, ace-
tone-d6) 6.51 (1H, s, AreH), 4.77 (1H, d, J 4.8, CH), 4.69 (1H, d, J 5.2,
CH), 4.40 (2H, br s, NH2), 4.13 (2H, br s, NH2), 3.82 (3H, s, OMe),
2.03e1.96 (2H, m, 2ꢄ (CH3)2CH), 1.24e1.19 (6H, m, 6ꢄ TIPSCH),
1.15e1.12 (36H, m, 12ꢄ TIPSMe), 1.08 (6H, t, J 6.4, 2ꢄ Me), 1.05 (6H,
d, J 6.4, 2ꢄ Me); dC (100 MHz, acetone-d6) 148.9 (C), 142.1 (C), 134.3
(C), 112.8 (CH), 110.6 (C), 104.9 (C), 100.3 (C), 96.3 (C), 82.7 (C), 79.2
(C), 69.9 (CH), 69.7 (CH), 60.0 (OMe), 36.6 (CH), 36.5 (CH), 18.6 (6ꢄ
TIPSMe),18.5 (6ꢄ TIPSMe),17.7 (2ꢄ Me),17.5 (2ꢄ Me),13.1 (6ꢄ CH);
m/z (ESI) 665 [90%, (MþNa)þ], 650 (100); HRMS [ESI, (MþNa)þ]
found 665.4482. [C37H66N2O3Si2þNa]þ requires 665.4504.
phine]gold(I) hexafluoroantimonate 33 (1.1 mg, 1.4 mmol, 15 mol %)
and the reaction mixture heated to 60 ꢁC for 1 h. The reaction
mixture was concentrated in vacuo and the crude residue purified
by flash chromatography on silica gel using hexaneseethyl acetate
(1:1, 0.5% Et3N) as eluent to yield the title compound as a yellow oil
(0.7 mg, 2.2
mmol, 24%).
½
a 2D0
ꢃ
þ63.0 (c 0.18, EtOAc); nmax (neat)/cmꢂ1 3302, 2960, 2930,
2877, 1727, 1524, 1462, 1388, 1357, 1324, 1264, 1210, 1197, 1160, 1113,
1093, 1001, 964, 932, 903, 830, 771, 750, 702, 630; dH (400 MHz,
DMSO-d6) 10.32 (1H, br s, NH), 10.04 (1H, br s, NH), 7.02 (1H, s,
ArH), 6.27 (1H, d, J 1.2, H-3), 6.15 (1H, d, J 2.0, H-7), 5.17 (1H, d, J 4.4,
H-10), 4.97 (1H, d, J 5.6, H-100), 4.36 (2H, t, J 4.8, 10-OH, 100-OH), 4.03
(3H, s, OMe), 2.05e1.99 (2H, m, H-20, H-200), 0.93 (6H, t, J 6.8, 2ꢄ
Me), 0.81 (6H, d, J 6.8, 2ꢄ Me); dC (100 MHz, DMSO-d6) 143.0 (C),
141.5 (C), 135.2 (C), 134.8 (C), 127.0 (C), 123.4 (C), 116.0 (C), 97.4 (CH),
94.0 (CH), 93.9 (CH), 72.72 (CH), 72.68 (CH), 59.6 (Me), 33.8 (CH),
33.7 (CH), 19.3 (Me), 19.1 (Me), 18.4 (Me), 18.2 (Me); m/z (ESI) 330
[90%, (Mþ)], 313 (100); HRMS (ESI, Mþ) found 330.1933.
[C19H26N2O3]þ requires 330.1938.
4.3.2. 4-Methoxy-2,6-bis{(R)-2-methyl-1-[(triisopropylsilyl)oxy]pro-
pyl}-1,5-dihydropyrrolo[2,3-f]indole 31. To a solution of 32 (26.0 mg,
40.5
di-tert-butylphosphine]gold(I) hexafluoroantimonate 33 (4.7 mg,
6.1
mol,15 mol %) and the reaction mixture was heated to 60 ꢁC for
mmol) in toluene (5 mL) was added (acetonitrile)[(2-biphenyl)
m
4 h. The reaction mixture was concentrated in vacuo and the crude
residue purified by flash chromatography on silica gel using hex-
aneseethyl acetate (9:1) as eluent to give the title compound
mol, 76%) as a yellow oil; ½a D20
ꢃ
þ73.5 (c 0.65, EtOAc);
4.3.5. Terreusinone (þ)-1. A solution of Fremy’s salt (4.1 mg,
ꢀ
(19.6 mg, 31.1
m
nmax (neat)/cmꢂ1 3484, 2942, 2866, 1462, 1383, 1342, 1297, 1223,
1080, 1057, 1013, 919; dH (400 MHz, acetone-d6) 9.59 (1H, br s, NH),
9.21 (1H, br s, NH), 7.17 (1H, s, AreH), 6.45 (1H, d, J 1.6, H-20), 6.27
(1H, d, J 2.4, H-2), 4.86 (1H, d, J 6.0, CH), 4.80 (1H, J 6.4, CH), 4.08
(3H, s, OMe), 2.80e2.12 (2H, m, 2ꢄ (CH3)2CH), 1.12e1.09 (6H, m, 6ꢄ
TIPSCH), 1.08e1.01 (36H, m, 12ꢄ TIPSMe), 1.00 (6H, d, J 2.0, 2ꢄ Me),
0.88 (6H, d, J 2.0, 2ꢄ Me); dC (100 MHz, acetone-d6) 141.7 (C), 140.4
(C), 136.8 (C), 136.3 (CH), 128.6 (C), 124.9 (C), 117.4 (C), 100.0
(CH), 96.8 (CH), 95.4 (CH), 76.3 (CH), 76.2 (CH), 60.3 (OMe), 36.7
(2ꢄ CH), 19.6 (Me), 19.4 (Me), 18.5 (6ꢄ TIPSMe), 18.4 (6ꢄ TIPSMe),
15 mmol) in dihydrogen phosphate buffer (pH 6, 0.3 M; 1 mL) was
added dropwise to a solution of pyrroloindole 35 (3.5 mg, 11 mmol)
in acetone (2 mL) and the reaction mixture was stirred at room
temperature for 20 min. The solvents were concentrated in vacuo
and the resulting residue was taken up in ethyl acetate (15 mL) and
washed with water (10 mL). The organic solution was dried
(Na2SO4), filtered and concentrated in vacuo and the crude material
purified by preparative thin layer chromatography on silica gel
using hexaneseethyl acetate (1:3) as eluent to give the title com-
pound (2.0 mg, 6.2
m
mol, 59%) as an orange solid; mp 223 ꢁC

C. Wang, J. Sperry / Tetrahedron 69 (2013) 4563e4577
4575
(decomp.). [lit.1, 230 ꢁC (decomp.)]; ½a 2D1
ꢃ
þ49.6 (c 0.19, MeOH). {lit.1
(Me), 18.4 (Me), 18.2, 18.03, 17.95 (12ꢄ TIPSMe), 17.2 (Me), 17.1 (Me),
12.43 (3ꢄ CH), 12.36 (3ꢄ CH); m/z (ESI) 643 [25%, (MþH)þ], 599
(10), 469 (100), 425 (8), 338 (5), 295 (40), 240 (26), 149 (5); HRMS
[ESI, (MþH)þ] found 643.4657. [C37H66N2O3Si2þH]þ requires
643.4685.
½
a 2D0
ꢃ
þ47 (c 0.3, MeOH)}; dH (400 MHz, DMSO-d6) 12.18 (2H, br s,
2ꢄ NH), 6.28 (2H, s, H-3, H-7), 5.15 (2H, d, J 4.8, 2ꢄ OH), 4.24 (2H,
dd, J 6.4, 5.6, H-1ʹ, H-1ʹʹ), 1.91 (2H, sext, J 6.8, H-2ʹ, H-2ʹʹ), 0.87 (2H, d,
J 6.4, H-3ʹ, H-3ʹʹ), 0.76 (2H, d, J 6.4, H-4ʹ, H-4ʹʹ); dC (100 MHz, DMSO-
d6) 174.0 (2ꢄ C]O), 143.4 (2ꢄ C), 131.3 (2ꢄ C), 126.0 (2ꢄ C), 104.1
(2ꢄ CH), 71.5 (2ꢄ CH), 33.8 (2ꢄ CH),18.7 (2ꢄ Me),18.1 (2ꢄ Me); m/z
(ESI) 353 [40%, (MþNa)þ], 338 (100), 321 (40), 311 (4), 303 (32), 297
(5), 282 (3), 269 (8); HRMS [ESI, (MþNa)þ] found 353.1476.
[C18H22N2O4þNa]þ requires 353.1472.
4.4.3. (R)-1-{5-Amino-2-[(R)-1-hydroxy-2-methylpropyl]-7-
methoxyindol-6-yl}-4-methylpent-1-yn-3-ol 38. To a solution of
indole 37 (12 mg, 18.7
n-butylammonium fluoride (40
m
mol) in THF (5 mL) at 0 ꢁC was added tetra-
mL, 40 mmol, 1 M solution in THF)
and the reaction mixture was warmed to room temperature over
1 h. The solvent was removed under reduced pressure and the
crude residue immediately purified with flash chromatography on
silica gel using hexaneseethyl acetate (1:3, 0.5% Et3N) as eluent to
4.4. Total synthesis of (D)-terreusinone by one-pot Lar-
ockeSonogashira coupling
4.4.1. 7-Methoxy-2-{(R)-2-methyl-1-[(triisopropylsilyl)oxy]propyl}-
6-{(R)-4-methyl-3-[(triisopropylsilyl)oxy]pent-1-yn-1-yl}-5-
nitroindole 36. In a 4-dram vial equipped with a stirring bar and
Teflon-lined screw cap, N-methyl-2-pyrrolidone (7.5 mL) was
give the title compound as a crimson oil (5.3 mg, 15.9 mmol, 85%);
½
a 2D0
ꢃ
þ25.3 (c 0.35, EtOAc); nmax (neat)/cmꢂ1 3370, 2962, 2929,
2871, 1632, 1571, 1455, 1319, 1176, 1030, 957; dH (400 MHz, DMSO-
d6) 10.48 (1H, br s, NH), 6.47 (1H, s, ArH), 6.01 (1H, d, J 2.0, H-3), 5.35
(1H, d, J 5.6, H-1), 5.07 (1H, d, J 4.8, H-30), 4.64 (2H, br s, NH2), 4.34
(1H, d, J 1.6, OH), 4.33 (1H, d, J 1.6, OH), 3.92 (3H, s, OMe), 2.03e1.98
(1H, m, H-2), 1.93e1.85 (1H, m, H-4), 1.03 (6H, dd, J 11.6, 6.8, 2ꢄ
Me),0.91 (3H, d, J 6.8, Me), 0.81 (3H, d, J 6.4, Me); dC (100 MHz,
DMSO-d6) 146.6 (C), 145.2 (C), 142.6 (C), 131.1 (C), 121.8 (C), 98.3 (C)
97.8 (CH), 97.6 (CH), 95.8 (C), 78.9 (C), 72.3 (CH), 66.8 (CH), 60.5
(Me), 34.4 (CH), 33.8 (CH), 19.1 (Me), 18.4 (Me), 18.1 (Me), 17.7 (Me);
m/z (ESI) 331 [43%, (MþH)þ], 313 (58), 295 (20), 280 (50), 259 (82),
241 (94), 226 (88), 210 (100), 186 (42), 162 (30); HRMS [ESI,
(MþH)þ] found 331.2010. [C19H26N2O3þH]þ requires 331.2016.
purged with argon for 3 h. Palladium diacetate (5.6 mg, 25
1,10-bis(di-tert-butylphosphino)ferrocene (14.2 mg, 30
mol), po-
tassium carbonate (86.5 mg, 625 mol), nitroaniline 28 (40.8 mg,
125 mol) and alkynol (R)-4c (190.5 mg, 0.8 mmol) were added.
mmol),
m
m
m
The reaction mixture was heated at 130 ꢁC for 30 min, then 158 ꢁC
for 15 h. After cooling to room temperature, the reaction mixture
was filtered through a pad of CeliteÒ and the cake washed with
ethyl acetate (50 mL). The filtrate was the washed with water
(40 mL), brine (40 mL), dried (Na2SO4), filtered and concentrated in
vacuo. The residue was purified with flash chromatography on
silica gel using hexaneseethyl acetate (19:1) as eluent to yield the
title compound as a yellow oil (21.5 mg, 31.9
m
mol, 26%); ½a 2D0
ꢃ
þ65.4
4.4.4. (1R,10R)-1,10-(4-Methoxy-1,5-dihydropyrrolo[2,3-f]indole-2,6-
diyl)bis(2-methylpropan-1-ol) 35. To a solution of indole 38 (5.3 mg,
(c 1.27, CH2Cl2); nmax (neat)/cmꢂ1 3486, 3290, 2943, 2867, 1528,
1463, 1330, 1094, 1064, 883, 826, 682, 604; dH (400 MHz, CDCl3)
8.69 (1H, br s, NH), 8.04 (1H, s, ArH), 6.37 (1H, d, J 2.0, H-3), 4.84
(1H, d, J 5.2, H-1), 4.69 (1H, d, J 4.4, H-30), 4.11 (3H, s, OMe),
2.10e2.00 (2H, m, H-2, H-4), 1.19e1.16 (6H, m, 6ꢄ CH), 1.12e1.09
(24H, m, 8ꢄ Me), 1.05e1.00 (9H, m, 3ꢄ Me), 0.98e0.96 (12H, m, 4ꢄ
Me), 0.82 (3H, d, J 6.8, Me); dC (100 MHz, CDCl3) 147.9 (C), 145.0
(C), 143.9 (C), 130.5 (C), 127.5 (C),113.9 (CH), 103.4 (C), 102.0 (CH),
100.0 (C), 76.4 (C), 74.4 (CH), 69.3 (CH), 61.5 (Me), 35.88 (CH), 35.85
(CH), 18.7 (Me), 18.2 (Me), 17.9, 18.0, 18.1 (12ꢄ TIPSMe), 17.1
(Me), 16.9 (Me), 12.4 (3ꢄ CH), 12.3 (3ꢄ CH); m/z (ESI) 695 [100%,
(MþNa)þ], 521 (99); HRMS [ESI, (MþNa)þ] found 695.4221.
[C37H64N2O5Si2þNa]þ requires 695.4246.
15.9
di-tert-butylphosphine]gold(I) hexafluoroantimonate 33 (1.5 mg,
1.9
mol, 12 mol %) and the reaction mixture heated to 60 ꢁC for
mmol) in toluene (6 mL) was added (acetonitrile)[(2-biphenyl)
m
30 min. The reaction mixture was concentrated in vacuo and the
crude residue purified by flash chromatography on silica gel using
hexaneseethyl acetate (1:3, 0.5% Et3N) as eluent to yield the title
compound as a yellow oil (4.5 mg, 13.5
mmol, 85%), spectroscopic
data identical to that described previously.
The pyrroloindole 35 prepared by this route was oxidized to
terreusinone (þ)-(1) as described previously (4.3.5), providing
material was spectroscopically identical to that obtained from the
bidirectional synthesis, albeit with a slightly lower melting point
[216 ꢁC (decomp.)] and optical rotation; ½a 2D1
þ43.7 (c 0.19, MeOH).
ꢃ
4.4.2. 7-Methoxy-2-{(R)-2-methyl-1-[(triisopropylsilyl)oxy]propyl}-
6-{(R)-4-methyl-3-[(triisopropylsilyl)oxy]pent-1-yn-1-yl}-indol-5-
Acknowledgements
amine 37. To a solution of nitroindole 36 (20 mg, 29.7
ammonium chloride (15.9 mg, 29.7 mol) in methanolewater
(11 mL, 10:1) was added zinc powder (19.4 mg, 29.7 mol) and the
mmol) and
m
We thank to the Royal Society of New Zealand Marsden Fund for
supporting this work.
m
reaction mixture heated under reflux for 30 min. The solvents were
removed under reduced pressure and the residue was taken up in
diethyl ether (20 mL). The organic solution was washed with water
(15 mL), dried (Na2SO4), filtered and concentrated in vacuo. The
residue was purified with flash chromatography on silica gel using
hexaneseethyl acetate (19:1, 5% Et3N) as eluent to yield the title
Supplementary data
Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2013.04.025.
compound as a crimson oil (17.5 mg, 27.2
m
mol, 92%); ½a 2D0
þ66.8
ꢃ
(c 0.95, CH2Cl2); nmax (neat)/cmꢂ1 3485, 2942, 2866, 2207, 1635,
1571, 1496, 1462, 1334, 1307, 1226, 1164, 1081, 1059, 1013, 996, 957,
919, 882, 825, 679; dH (400 MHz, CDCl3) 8.14 (1H, br s, NH), 6.59
(1H, s, ArH), 6.01 (1H, d, J 2, H-3), 4.74 (1H, d, J 5.2, H-1), 4.69 (1H, d,
J 4.4, H-30), 4.04 (3H, s, OMe), 4.04 (2H, br s, NH2), 2.04e2.00 (2H, m,
H-2, H-4), 1.19e1.16 (6H, m, 6ꢄ CH), 1.13e1.07 (18H, m, 6ꢄ Me),
1.05e1.02 (18H, m, 6ꢄ Me), 0.98 (6H, m, 2ꢄ Me), 0.94 (3H, d, J 6.8,
Me), 0.81 (3H, d, J 6.8, Me); dC (100 MHz, CDCl3) 147.2 (C), 142.1 (C),
141.8 (C), 131.0 (C), 122.5 (C), 99.3 (CH), 99.0 (CH), 98.6 (C), 97.4 (C),
78.8 (C), 74.7 (CH), 69.3 (CH), 61.0 (Me), 36.0 (CH), 35.9 (CH), 18.8
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despite attempting several chiral HPLC conditions.
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