Synthetic studies on the ambiguine family of alkaloids: Construction of the ABCD ring system

Article abstract of DOI:10.1016/j.tetlet.2010.09.086

A racemic synthesis of the ABCD ring core of the ambiguines that preserves the tertiary alcohol has been accomplished in a convergent synthesis in 10 synthetic steps, in an overall yield of 46% from commercially available 4-bromoindole and m-methylanisole

Full text of DOI:10.1016/j.tetlet.2010.09.086

Tetrahedron Letters 52 (2011) 2037–2040
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Tetrahedron Letters
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Synthetic studies on the ambiguine family of alkaloids: construction of the
ABCD ring system
Ryan J. Rafferty a, Robert M. Williams a,b,
⇑
a Department of Chemistry, Colorado State University, 1301 Center Avenue, Fort Collins, CO 80523, USA
b University of Colorado Cancer Center, Aurora, CO 80045, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A racemic synthesis of the ABCD ring core of the ambiguines that preserves the tertiary alcohol has been
accomplished in a convergent synthesis in 10 synthetic steps, in an overall yield of 46% from commer-
cially available 4-bromoindole and m-methylanisole.
Received 27 August 2010
Revised 14 September 2010
Accepted 15 September 2010
Available online 1 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Ambiguine
Hapalindole
Tin(IV) chloride
The ambiguines1–3 are a family of indole alkaloids that were
first isolated in 1991. They are structurally related to the hapalin-
doles4,5 family of alkaloids (Fig. 1). To date, the ambiguine family
has 15 members (Ambiguines A–O) that are broken down into
two subclasses; the tetracyclic and pentacyclic systems.
R1
R2
R1
R2
R1
R2
Me
NC
Me
Me
H
H
H
Me
Me
Me
Me
Me
Me
NC
NC
The tetracyclic ambiguines are structurally same as the hapalin-
doles with the exception of the presence of a reverse-prenyl group
on C2 of the indole ring. Pentacyclic ambuguines contain a seven-
membered ring, which contains either an epoxide, diol, vinyl cya-
Me
Me
Me
Me
N
H
N
H
N
H
Tetracyclic Ambiguine Core
Me
Hapalindole Core
Pentacyclic Ambiguine Core
Cl
Me
13
14
15
nide,
a-hydroxyl ketone or diene functionality. Carbon-13 of ring
D
NC
Me
Me
12
OH
D, in both families, can either have a methylene carbon (R1) or
chlorine-containing carbon. Likewise, both can either have a
hydrogen at the C10 position (R2) or possess an alcohol at said car-
bon. The common core for both the hapalindole and ambuguine
families for most of their members contains the C13 chlorine con-
taining stereocenter as well as the C10 tertiary alcohol.
The structural complexity and densely functionalized core have
attracted considerable synthetic attention and to date only ambi-
guine H has been conquered by total synthesis.6 We report herein,
our own preliminary efforts on the synthesis of these intriguing
substances.
H
Me
Me
5
NC
C
11
E
10
3
16
4
9
8
B
A
Me
Me
2
N
6
H
1
N
H
7
Ring System Notation
Common Core
Figure 1. Hapalindole, tetracyclic and pentacyclic ambiguine cores.
accessed from commercially available m-methylanisole and func-
tionalized indole 4 from 2-bromo-6-nitrotoluene.
Following the protocol of Rubottom and Gruber,7 commercially
available m-methylanisole was converted into 7 utilizing a Birch
reduction followed by hydrolysis (Scheme 2). Secondary alcohol
7 was protected with TBSCl and imidazole, followed by treatment
with vinylmagnesium bromide to afford the quaternary center
substrate as the corresponding TMS-enol ether. Cleavage of the
TMS-enol ether with an acetic acid/water/THF mixture afforded
racemic 5 in an overall 86% yield for the six steps.
We envisioned that the pentacyclic core 1 of the ambiguines
could arise from an intra-molecular RCM reaction of 2, which could
be assembled through a Mannich reaction with vinyl Grignard and
ammonium acetate followed by isonitrile formation from
3
(Scheme 1). Formation of the tetracyclic core 3 was anticipated
to arise from the manipulation of 4 and 5. The C12 quaternary
center was envisioned to arise from compound 5, which could be
Assembly of tetracycle 11 began with treating of racemic 5 with
LHMDS and Mander’s reagent to give the b-ketoester (Scheme 3).
⇑
Corresponding author. Tel.: +1 970 491 6747; fax: +1 970 491 1801.
E-mail address: rmw@lamar.colostate.edu (R.M. Williams).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.086

2038
R. J. Rafferty, R. M. Williams / Tetrahedron Letters 52 (2011) 2037–2040
R
Me
OH
TBSO
TBSO
Me
Me
Br
Br
Me
Me
NC
NaH
MeI
t-BuLi
D
acetone
NC
Me
Me
Me
Me
Me
Me
THF
97%
O
Et2O
91%
C
1
N
N
H
E
N
Me
Me
17
16
18
B
A
Me
Me
N
Me
Me
Me
Me
N
H
N
H
H
Scheme 5. Synthesis of indole 18.
3
2
TBSO
Me
Br
enone that was subjected to methyl cuprate Michael conditions to
afford tricycle 10. Subjecting 10 to BF3-etherate afforded tetracycle
11 in an overall yield of 27% from 5 in 11 steps.
Me
Me
N
H
O
Muratake and Natsume8,9 in their total synthesis of hapalindole
U employed a dilute (1 M) tin(IV) chloride-mediated coupling to
form 14. Treating TMS-enol ether 12 with 4-(2-hydroxy-2-pro-
pyl)-N-tosyl-indole 13 with 1 M SnCl4 at À78 °C afforded tricyle
14 when quenched at À78 °C (Scheme 4).
4
5
Scheme 1. Retrosynthetic analysis.
OH
1. Liº, tBuOH
Et2O, NH3
OTBS
Me
1. TBSCl, Imid, DMF
2. VinylMgBr, CuBr,
TMEDA, TMSCl, THF
Murataka’s tricycle 14 and our tricyle 10 are similar in struc-
ture, with ours being more functionalized. Both routes close the
tricycle with BF3-etherate in THF to give rise to similar tetracycles.
Tetracycle 15 was formed in 58% over two steps, whereas tetracy-
cle 11 was formed in 27% over 11 steps clearly showing the advan-
tage of the tin-mediated chemistry. It was thought that utilizing
this methodology, which has been used in a variety of alkaloid syn-
theses,10–13 we could gain rapid access to the ABCD ring system of
the ambigiunes in a more efficient manner than that extant.
Accessing the required 4-(2-hydroxyl-2-propyl)-N-methyl-
indole for the tin-mediated coupling was accomplished from 2-
bromo-6-nitrotoluene under Leimgruber–Batcho14 conditions to
afford 16 in high yields (Scheme 5). N-Methylation of 16 was per-
formed with NaH and methyl iodide in THF to afford 17. Treatment
of 17 under lithium–halogen exchange conditions followed by
acetone addition furnished 18 in a 91% yield.
Me
Me
2. Oxalic acid
MeOH/H2O
3. AcOH/THF
(92% 3 steps)
OMe
3. mCPBA, NEt3
CH2Cl2
O
O
6
7
5
(93%, 3 steps)
Scheme 2. Synthesis of substrate 5.
Reduction of the ketone with NaBH4 followed by TMS protection of
the resulting alcohol gave 8 in good yields. Treatment of 8 with N-
methoxy-methylamine hydrochloride and Me3Al in THF afforded
the Weinreb amide. Subjecting 4-bromo-N-methylindole to lith-
ium–halogen exchange resulted in the corresponding 4-lithium
species that was added to the Weinreb amide and worked up un-
der acid conditions and carried on without further purification.
Methyl lithium was added to the crude material at À78 °C in
THF, warmed to room temperature, and worked up under acidic
conditions to afford a 2.5:1 mixture of the secondary alcohol and
its corresponding TMS ether. The crude mixture was treated with
acetic acid for 45 min, concentrated, and taken into THF and oxi-
dized with Dess–Martin Periodinane to afford 9 in good yields.
Dehydration of 9 with TsOH gave the b-methyl, b-indole-exocyclic
Treatment of 5 with LHMDS followed by TMSCl gave the re-
quired TMS-enol ether 19. A variety of conditions were probed to
optimize the coupling of 18 to 19 (Scheme 6 and Table 1). In the
event, it was observed that treating indole 18 and TMS-enol ether
19 with fuming tin(IV) chloride in DCM gave the tetracyclic species
20b in good yields. While we were anticipating the tricycle 20a,
Me
HN
HCl
OTBS
OTBS
1.
Me3Al, THF
OMe
1. LHMDS, MeO2CCN
Me
Me
THF
2. t-BuLi, THF
MeO
4-bromo-N-methyl-indole,
2. NaBH4, THF
3. NaH, TMSCl, THF
O
5
O
OTMS
8
3. MeLi, THF
4. AcOH;
73% (3 steps)
DMP, THF
59% (4 steps)
OTBS
O
OTBS
Me
OTBS
Me
Me
1. TsOH, THF, heat
2. MeMgBr, CuBr,
TMEDA, TMSCl
HO
Me
BF3•Et2O
Me
Me
Me
Me
3. AcOH:H2O:THF
(1:1:2)
THF
92%
O
67% (3 steps)
N
N
N
9
Me
Me
10
Me
11
Scheme 3. Weinreb amide route to tetracycle 11.
Me
Me
Me
Me
Me
OH
Me
Me
Me
Me
1M SnCl4
in CH2Cl2
BF3-etherate
80%
O
N
72%
OTMS
Ts
N
N
12
13
14
Ts
15
Ts
Scheme 4. Muratake and Natsume tricycle formation.

R. J. Rafferty, R. M. Williams / Tetrahedron Letters 52 (2011) 2037–2040
2039
TBSO
TBSO
Me
TBSO
Me
OH
TBSO
Me
Me
LHMDS
H
H
Me
Me
Me
Me
THF, -78 ºC
quant.
O
O
5
OTMS
19
Lewis
Acid
N
N
Me
Me
TBSO
20b
20a
Me
OH
Me
Me
Me
Me
N
Me
18
N
Me
20c
Scheme 6. Lewis acid-mediated coupling of 18 + 19.
synthesis of 20b gives the carbon core along with the desired ter-
tiary alcohol at the C10, which is present in several ambiguines.
Further studies into the coupling of 18 and 19 with fuming ti-
n(IV) chloride revealed that the reaction afforded diastereomeric
tetracycles 21a and 21b (4:1 ratio) (Scheme 7), but not the dehy-
drated tetracycle as seen in Scheme 4. Quenching the fuming ti-
n(IV) chloride reaction at À78 °C proved to be essential in
forming the tertiary alcohol. When quenching the reaction at any
temperate above À50 °C formation of the dehydrated tetracycle
20c was observed. When 18 and 19 were treated with the 1 M ti-
n(IV) chloride solution a similar tricyle as seen in Scheme 4 was
formed. Subjecting this tricycle to BF3-etherate afforded the dehy-
drated tetracycle 20c. When performing the same procedure with
either the corresponding N-Boc or N-silyl (TMS, TBS, or TIPS) pro-
tecting groups only dehydrated tetracycles were observed. Inter-
estingly, when attempting the reaction on a substrate bearing the
N-tosyl group under the same conditions, only the tricycle was ob-
tained. Other alkyl protecting groups such as PMB or benzyl groups
can be used with the current methodology, however the yields
from the coupling reactions are significantly lower, 7% and 11%,
respectively.
Having accessed the ABCD ring system of the ambiguines, along
with the tertiary alcohol at C10, efforts were directed toward gain-
ing access to the same ABCD system with the reverse-prenyl group
on C-2 of the indole. Chlorination of the previously described 4-
bromoindole with NCS in DMF afforded 22 in excellent yields
(Scheme 8). Installation of the reverse-prenyl group was accom-
plished using Danishefsky chemistry15 followed by N-methylation
of the indole nitrogen to afford 22. Subjecting 22 to lithium–halo-
gen exchange conditions followed by acetone gave access to 24 in
98% yield.
Table 1
Lewis-acid and conditions screened for Scheme 6
Lewis acid
Conditions
Product
20a
20b
20c
TiCl4 (fuming)
TiCl4 (fuming)
Toluene, À78 °C
Toluene, À44 °C
Toluene, À78 °C
Toluene, À44 °C
DCM, À78 °C
7%
X
X
X
13%
X
X
X
X
X
X
X
X
X
24%
X
X
X
61%
8%
X
5%
X
X
X
TiCl4 (1 M PhCH3)
TiCl4 (1 M PhCH3)
TiCl4 (1 M DCM)
TiCl4 (1 M DCM)
TiCl4 (fuming)
DCM, À44 °C
X
DCM, À78 °C
X
X
36%
13%
X
X
X
X
X
42%
TiCl4 (fuming)
DCM, À44 °C
SnCl4 (1 M PhCH3)
SnCl4 (1 M PhCH3)
SnCl4 (1 M DCM)
SnCl4 (1 M DCM)
SnCl4 (fuming)
SnCl4 (fuming)
Toluene, À78 °C
Toluene, À44 °C
DCM, À78 °C
15%
X
83%
54%
5%
13%
DCM, À44 °C
DCM, À78 °C
DCM, À44 °C
TBSO
TBSO
Me
Me
OH
Me
Me
OH
TBSO
SnCl4
Me
H
H
FUMING
Me
Me
Me
Me
OH
CH2Cl2
-78 ºC
61%
N
Me
OTMS
19
N
N
18
Me
Me
(4:1)
21b
21a
Scheme 7. Fuming SnCl4-mediated tetracycle formation.
1. Et3N, THF
Me
OH
Me
9-BBN
Me
Br
Cl
Br
t-BuLi
The coupling of 24 and 19 with fuming tin(IV) chloride was at-
tempted as described previously in Table 1. Unfortunately, no tet-
racyclic product was observed when subjecting 24 and 19 to any of
the previous coupling conditions. Furthermore, only fuming tin(IV)
chloride allowed access to the tricycle 25 in 36% yield (Scheme 9).
Treating tricycle 25 with BF3-etherate at room temperature for
acetone
Me
THF
98%
2. NaH, MeI
THF
Me
Me
N
H
Me
Me
N
N
Me
Me
78% (2 steps)
22
23
24
Scheme 8. Synthesis of indole 24.
TBSO
H
Me
O
TBSO
Me
OH
Me
TBSO
SnCl4
Me
OH
Me
H
(fuming)
Me
Me
Me
Me
CH2Cl2
-78 ºC
Me
Me
N
OTMS
Me
Me
Me
Me
Me
N
N
Me
25, 36%
Me
26 (not observed)
24
19
Scheme 9. Attempted tetracycle formation.

2040
R. J. Rafferty, R. M. Williams / Tetrahedron Letters 52 (2011) 2037–2040
24 h failed to give the desired tetracycle, but rather the dehydrated
tetracyclic system. Similar results were obtained when attempting
the same methodology on methyl, ethyl, vinyl, and propyl C2
substituted indoles.
References and notes
1. Smitka, T. A.; Bonjouklian, R.; Doolin, L.; Jones, N. D.; Deeter, J. B.;
Yoshida, W. Y.; Prinsep, M. R.; Moore, R. E.; Patterson, G. M. J. Org. Chem.
1992, 57, 857.
In summary, we have shown two methods of accessing the
ABCD cores of both the hapalindoles and ambiguines. Utilizing
fuming tin(IV) chloride-mediated coupling of tertiary benzylic
alcohols of indoles and TMS-enol ethers we have also gained access
to more functionalized tetracyclic cores. Current efforts to deploy
this methodology for the concise total synthesis of several mem-
bers of this family of alkaloids are under investigation.
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Acknowledgments
This Letter is warmly dedicated to Professor Harry H. Wasser-
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.09.086.