Total synthesis of dehaloperophoramidine using a highly diastereoselective Hosomi-Sakurai reaction

Article abstract of DOI:10.1039/c6cc05747k

The synthesis of dehaloperophoramidine, a non-halogenated derivative of the marine natural product perophoramidine, and its biological activity towards HCT116, HT29 and LoVo colorectal carcinoma cells is reported. A [3,3]-Claisen rearrangement and an epoxide opening/allylsilylation reaction installed the contiguous all-carbon quaternary stereocentres with the required relative stereochemistry.

Full text of DOI:10.1039/c6cc05747k

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A. Slawin, T. Lebl, P. Mullen, D. J. Harrison, C. M. Ireland and N. J. Westwood, Chem. Commun., 2016,
DOI: 10.1039/C6CC05747K.
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Total Synthesis of Dehaloperophoramidine using a highly
diastereoselective Hosomi-Sakurai reaction
Received 00th January 20xx,
Accepted 00th January 20xx
[
a]
[a]
[a]
[a]
Ross. P. Wilkie†, Andrew R. Neal†, Craig A. Johnston, Nicholas Voute, Christopher S.
[
a]
[a]
[a]
[a]
[a]
Lancefield, [Ma] atthew D. Stell, Federico Medda, Edward F. Makiyi, Emma M. Turne[br] , O.
Stephen Ojo, Alexandra M.Z. Slawin, [a]Tomas Lebl, Peter Mullen, David J. Harrison, Chris
DOI: 10.1039/x0xx00000x
[a]
[a]
[b]
[
c]
www.rsc.org/
M. Ireland and Nicholas J. Westwood*
O
The synthesis of dehaloperophoramidine, a non-halogenated
derivative of the marine natural product perophoramidine, and its
biological activity towards HCT116, HT29 and LoVo colorectal
carcinoma cells is reported. A [3,3]-Claisen rearrangement and an
epoxide opening/allylsilylation reaction installed the contiguous
all-carbon quaternary stereocentres with the required relative
stereochemistry.
H
Me
N
Me
N
H
N
N
Cl
N
N
1
1
11
N
7
1
0b
10b
N
Cl
N
H
N
H
N
H
N
Br
H
(
+)-Perophoramidine (1)
Dehaloperophoramidine(2)
Communesin F (3)
Fig. 1 The structures of (+)-perophoramidine (1), (+)-dehaloperophoramidine (2) and
communesin F (3).
The natural product (+)-perophoramidine (1) was isolated by
1
Ireland from the marine ascidian Perophora namei. The authors
also reported the structure of dehaloperophoramidine (2), which
they obtained via transfer hydrogenation of (+)-1. These interesting
alkaloids are structurally related to a more complex family of
purification in any of the first five steps, enables access to enantio-
enriched ketones. Whilst we view these ketones as flexible starting
points for the synthesis of a number of optically pure complex ring
systems, here we report conversion of racemic material to 2.
Our retrosynthetic analysis of 2 (Scheme 1) identified lactam 4
as the cornerstone of the approach. Lactam 4 was viewed as
2
natural products that includes Communesin F (3). Targets,
including 1, 2 and 3, that possess contiguous all-carbon quaternary
3
stereocentres present a significant synthetic challenge. The
presence of this structural unit and the anticancer activity reported
4
for 1 has led to several total and formal syntheses. Previous accessible from diallyl-substituted alcohol 5, which contains both
approaches to
2
have involved
a
spirocyclisation of
a
2- the required C-10b and C-11 stereocentres. A key challenge in this
5
6
thiotryptamine analogue , a dearomatising arylation of a quinoline
part of the synthesis was the need to differentiate between the two
and an efficient synthesis from a commercially available indigo allyl groups in 5. This was achieved using two different selective
7
dye.
In work aimed at the synthesis of the communesins, we have
iodocyclisation protocols. Whilst this transformation is precedented
9
in simpler systems, it has been used sparingly in the synthesis of
1
0
explored a [3,3]-Claisen approach to establish the required C7
more complex alkaloid-based structures. Alcohol 5 could be
prepared from allyl-ketone 6, which itself could be constructed
from commercially available 7 and 8.
8
stereocentre in 3 (Figure 1). In the first part of this new report we
describe a significant extension of this work resulting in the large
scale synthesis (62 grams) and resolution of a novel ketone using
our [3,3]-Claisen rearrangement method (Scheme 1). This highly
efficient sequence, that does not require chromatographic
H
N
OH
O
2
N
N
+
N
N
Bn
Bn
4
5
CO2Me
O
HN
Bn
N
N
H
8
N
7
6
Bn
Scheme 1 Retrosynthetic analysis of 2 starting from commercially available 7 and 8.
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Journal Name
O
OMe
Ph
Cl
a
N
b, c
7
+
8
N
H
Bn
N
N
9
10 Bn
O
e
d
6
N
N
~62 g scale
1
1
Bn
Scheme 2 Construction of key intermediate 6: a) NCS, DMP, DCM, 0 °C, 2 hrs; then TCA,
°C – rt, 2 hrs, 93%; b) Ph O, reflux, 2.5 hrs, 79%; c) POCl , reflux, 95%; d) Na (3 eq.),
0
2
3
allyl alcohol (5.7 eq.), rt, 18 hrs, 92%; e) PhMe, reflux, 1.5 hrs, 88%.
The key challenge in the conversion of 6 to 5 is the incorporation of
the second contiguous all carbon stereogenic centre with the
required relative stereochemistry. Conversion of the ketone in 6 to
the corresponding epoxide was planned. Subsequent Lewis acid
catalysed epoxide opening followed by trapping with allylsilane was
predicted to lead to 5 with the approach of the allyl nucleophile
Scheme 3 Obtaining the (R) and (S) enantiomers of ketone 6 from their respective
imines 13 and 14. The ORTEP representation of 15 is also shown and was used to infer
occurring from the opposite face to the allyl group that is already the absolute configuration of 14 and (S)-6 (and hence 13 and (R)-6). Reagents and
o
present. This reaction, which we refer to as a modified Hosomi- conditions: a) R-(12) (10 eq.), Ti(OEt)
4
(15 eq.), toluene, 85 C, 9 hrs b) 12M HCl, MeOH,
1
1
12
rt, 0.5 hr; c) NaBH (2.5 eq), MeOH, rt, 0.5 hr, 92%.
4
Sakurai reaction , has been used in natural product synthesis, but
to the best of our knowledge has not been used in the construction
of contiguous all-carbon quaternary centres. Alternative
approaches to lactam 4 involving the early development of the allyl
group in 6 or alkylation of a C11-based ester were explored but
were either ultimately unsuccessful or led to significantly longer
reaction sequences (data not shown).
(
R)-6). Whilst (R)-6 and (S)-6 have been prepared, their conversion
to enantio-enriched alternative complex ring systems will be
reported in the future. Here we decided to continue the
development of a route to 2 using the much larger quantities of (±)-
6
available to us.
With the novel ketone 6 in hand, the ketone functionality was
The C10b stereocentre in 6 was installed in 5 steps from 7 and 8
as described in Scheme 2. After coupling of 7 and 8 to give 9, the
1
6
2
converted to the corresponding epoxide using ClCH I (see Scheme
13
S2 for the stereochemical assignment of 16). Allylsilylation of 16
tetracyclic system was formed using
a high temperature
1
3
under Lewis acidic conditions with allylTMS (17) in a modified
electrophilic aromatic substitution reaction (see Scheme S1 for
additional studies). The cyclisation was scalable up to 100 g with no
detrimental effect on the yield. Functional group manipulations
then enabled the preparation, via 10, of the [3,3]-Claisen
rearrangement substrate 11. Highly efficient conversion of 11 to the
required novel ketone 6 occurred on heating in toluene for 1.5
hours in 88% yield. This reaction was robust and scalable with 62 g
of 6 being prepared in a single batch and without the need for
purification by column chromatography at any stage. Ketone 6
could be resolved by treatment with (R)-tertbutanesulfinamide (12)
to generate the readily separable diastereomeric imines 13 and 14
1
1
Hosomi-Sakurai reaction gave the desired alcohol 5 as a single
1
diastereoisomer (as judged by H NMR analysis of the crude
reaction mixture). This reaction proved highly robust and scalable
with ca. 42 g of 16 being reproducibly converted to 38 g of 5. X-ray
crystallographic analysis of
5 confirmed the required anti-
relationship of the two allyl substituents at C-10b and C-11
1
3
(
Schemes 4 and S3).
(
Scheme 3). This approach was inspired by the reported resolution
14
of a ketone-containing intermediate en route to epiboxidine.
Hydrolysis of imines 13 and 14 with 12M HCl in MeOH gave (R)-6
and (S)-6 respectively in > 99% ee after recrystallisation (confirmed
13
by chiral HPLC analysis ). The absolute configuration of the
intermediate imines 13 and 14 were assigned following X-ray
1
5
crystallographic analysis of 15 which was obtained following
diastereoselective reduction of 14 with NaBH (Scheme 3). The X-
ray analysis indicated that the absolute configuration of the C10b
stereogenic centre in 15 (and hence in 14) was (R). Hydrolysis of Scheme 4 Construction of all-carbon quaternary stereocentres. The ORTEP
4
1
5
representation of
MeLiBr (2.2 M solution in Et
eq.), TiCl (4 eq.), DCM, -78 °C, 78% (2 steps).
5
is also shown. Reagents and conditions: a) ClCH
2
I (1.1 eq.),
imine 14 therefore provided the (S)-enantiomer of 6 (and 13 gave
2
O, 1.5 eq.), THF, -78 °C, 2 hrs; b) AllylTMS (17) (2.5
4
2
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H
R
H
to generate the diastereomeric mixture 24. Oxidation of 24 with the
R
O
O
O
*
I
*
I
1
8
Dess-Martin periodinane gave 25 in a reasonable yield (52%) for
this relatively complex process which also involves acid-mediated
deprotection of the sulfinamide. Interestingly, 25 underwent
oxidation with NaClO2 to give the required lactam 4. This
transformation was inspired by a report by Tomioka et al. on an
a, b, c
h
5
N
N
N
N
Bn
Bn
1
1
8 R = CH2 and its C* epimer
9 R = O and its C* epimer
22 R = CH2 and its C* epimer
23 R = O and its C* epimer
i
d
1
9
unrelated system. The new approach was robust and overall
reduced the length of the reaction sequence to 4.
e, f
j, k
O
O
S
S
NH
NH
Having successfully synthesised the desired lactam 4, its
conversion to 2 was completed (Scheme 6) The remaining alkene in
lactam 4 was oxidatively cleaved and the resulting aldehyde
tBu
O
OH
tBu
OH
2
reductively aminated using MeNH .HCl under basic conditions to
N
N
N
N
give 26 (Scheme 6). Boc protection of 26 gave 27 which underwent
Bn
Bn
20
24
20
13
alkylation with Meerwein’s reagent to give 28. Deprotection of
28 with trifluoroacetic acid gave 29 which cyclised on refluxing in
toluene to give N-benzyl-dehaloperophoramidine (30) in excellent
yield. X-ray crystallographic analysis of 30 confirmed the successful
g
l
H3N
O
O
N
1
5
formation of the C-4’ amidine motif. The synthesis of 2 was
completed by N-benzyl deprotection of 30 via a single electron
transfer process with a freshly prepared solution of sodium
m
4
N
N
N
N
Bn
Bn
21
25
naphthalenide.
21
13
Synthetic 2 was converted to the corresponding TFA salt and
1
3
Scheme 5 Two alternative approaches to lactam 4. Reagents and conditions: a) PCC compared to an authentic sample of 2.TFA (Figures S7 - S9).
A
(
1.1 eq.) DCM, rt, 16 hrs; b) Jones reagent (1.5 eq.), acetone, rt, 16 hrs; c) NIS (1.1 eq.),
NaHCO (1.1.eq.), DCM, rt, 16 hrs, d.r. 3:1, 47%, (over 5 steps from 7); d) OsO (0.13
mol%), NMO (1.5 eq.), acetone/H
hrs, 86%; e) (±)-12 (1.1 eq.), TiOEt
doping experiment with authentic 2.TFA and synthetic 2.TFA
3
4
confirmed that the desired compound had been successfully
2
O (10:1), rt, 18 hrs, then PhI(OAc) (1.5 eq.), rt, 1.5
2
prepared (see Figures S8A and S8B for a comparison of a selected
4
(3 eq.) CHCl , rt, 16 hrs, then NaBH (4 eq. in MeOH),
3
4
1
0
1
.5 hrs, rt, 75%; f) Zn, EtOH, reflux, 16 hrs, 89%; g) 4M HCl in dioxane/MeOH (10:1), rt, region of the
3
H NMR analysis carried out in CD OD).
hr, then HBTU (1.5 eq.) and DIPEA (5 eq.), 16 hrs, 71%; h) I
(0.19 mol%), NMO (1.5 eq.), THF: H
3
(1.5 eq.), rt, 2 hrs, 66%; j) (R)-16 (1.1 eq.), Ti(OEt) (2 eq.), CHCl ,
2
(2.5 eq.), K
2 3
CO
(2.5 eq.),
1
1
Superimposition of the H NMR of the doped sample with the H
rt, MeCN, 16 hrs, d.r. 11:1, 96%; i) OsO
6 hrs, then PhI(OAc)
rt, 16 hrs, then NaBH
0%; l) Dess-Martin periodinane (1.5 eq.), DCM, rt, 0.5 hrs, 52%, m) NaClO
NaH PO (5 eq.), 2-methylbuten-2-ene (10 eq.), THF/H O (1.5:1), rt, 2 hrs, 58%.
4
2
O (9:1), rt,
NMR of authentic 2.TFA alone displayed enhancement of the
1
2
4
4
(5 eq.) in MeOH, rt, 1 hr, 68%; k) Zn (31 eq.), EtOH, reflux, 16 hrs, signals corresponding to the product whilst an impurity from
8
2
(2.5 eq.),
authentic 2.TFA remained unchanged (Figure S8C for selected aryl
2
4
2
13
and Figure S8D for alkyl signals)
The challenge of selectively functionalising the two allyl groups in 5
now had to be overcome. A two-step oxidation of 5, followed by
regioselective iodolactonisation gave 18 and its epimer at the
indicated carbon as an inconsequential mixture of diastereoisomers
(Scheme 5, d.r. 3:1). The relative configuration of the newly formed
stereocentre in the major isomer 18 was determined by nOe
13
analysis (Scheme S4 and Figures S2-S4). Oxidative cleavage on
treatment with catalytic OsO and NMO followed by in situ reaction
4
1
3
with PhI(OAc) gave 19 and its epimer (Schemes 5 and S5). After
2
incorporation of the required nitrogen by reductive amination using
1
7
(±)-12
(Scheme 3), retro-iodolactonisation to give the
diastereomeric mixture 20, acid-mediated deprotection and
subsequent treatment of 21 with HBTU and DIPEA, lactam 4 was
obtained. However, cyclisation of 20 to 4 proved irreproducible (for
13
further discussion see Schemes S6-S8 and Figure S5). An
alternative route to 4 was investigated in an attempt to circumvent
the reproducibility issue. Di-allyl alcohol 5 underwent a regio- and
Scheme 6 Completion of the synthesis of (±)-2. Reagents and conditions: a) OsO
mol%), NMO (1.5 eq.), THF/H O, rt, 16 hrs, then PhI(OAc) 1.5 hrs, 62% (over 2 steps
.HCl (2.5 eq.), NaOAc (2.5 eq.), MeOH, rt, 16 hrs, then NaBH (3
eq.), rt, 0.5 hrs c) (Boc) O (1.5 eq.), TEA (1.5 eq.), rt, 1 hr, 44% (2 steps); d) Meerwein’s
4
(3.2
2
2
highly diastereo-selective iodoetherification to give 22 (and its from 25); b) MeNH
2
4
1
3
epimer, d.r. 11:1, Figure S6) in the presence of iodine under basic
conditions. A one-pot oxidative cleavage of the alkene gave 23 (and
its epimer) which underwent successful reductive amination with
2
o
reagent (1 M solution in DCM, 8 eq.), DIPEA (8 eq.), DCM, 0 C – rt, 2 hrs, 72%; e) 5%
°
TFA, DCM, 0 C, 0.5 hrs; f) DIPEA (2 eq.), toluene, reflux, 16 hrs, 83% (over 2 steps); g)
°
Na/naphthalene (1 M solution), THF, 0 C – rt, 2 hrs, 50%.
(R)-12 followed by a retro-iodoetherification in the presence of Zn
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When reanalysed in CDCl , our sample of 2.TFA gave chemical shifts
Journal Name
3
Notes and references
13
analogous to those previously reported (Table S2). Comparison of
1
S. M. Verbitski, C. L. Mayne, R. A. Davis, G. P. Concepcion, C.
M. Ireland, J. Org. Chem., 2002, 67, 7124.
1
3
the H NMR analysis of our synthetic free base 2 in CDCl was also
13
2
For selected reviews, see a) B. M. Trost, M. Osipov,
Chemistry, 2015, 21, 16318; b) P. Siengalewicz, T. Gaich, J.
Mulzer, Angew. Chem. Int. Ed., 2008, 47, 8170. For total
syntheses of Communesins A, B and F see c) J. Yang, H. Wu,
L. Shen, Y. Qin, J. Am. Chem. Soc., 2007, 129, 13794; d) J.
Yang, H. Wu, L. Shen, Y. Qin, Synfacts, 2008, 226; e) P. Liu, J.
consistent with the previous literature (Tables S3).
Preliminary biological activity associated with 1 has been
1
reported by Ireland et al., however, no information on the activity
of 2 is available. Therefore our sample of 2 was tested against the
same cancer cell line (HCT116) used to assess the activity of 1
H. Seo, S. M. Weinreb, Angew. Chem. Int. Ed., 2010, 49
000; f) Z. Zuo, W. Xie, D. Ma, J. Am. Chem. Soc., 2010, 132
13226; g) Z. Zuo, D. Ma, Angew. Chem. Int. Ed., 2011, 50
2008; h) J. Belmar, R. L. Funk, J. Am. Chem. Soc., 2012, 134
6941.
,
,
,
,
(Figure 2). Estimation of an IC50 inhibitory concentration showed
2
that 2 killed HCT116 cells with similar potency to 1, suggesting that
the halogens present in 1 are not essential for biological activity.
Analogous studies using the colorectal cancer lines HT29 and LoVo
showed that both were more sensitive to 2 than the HCT116 cells.
Attempts to test the synthetic precursor N-benzyl-
dehaloperophoramidine (30) proved difficult due to its insolubility
at the concentrations used in these assays.
1
1
3
4
E. Peterson, L. E. Overman, Proc. Natl. Acad. Sci. USA, 2004,
01, 11943.
For total and formal syntheses of perophoramidine see a) J.
R. Fuchs, R. L. Funk, J. Am. Chem. Soc., 2004, 126, 5068; b) H.
Wu, F. Xue, X. Xiao, Y. Qin, J. Am. Chem. Soc., 2010, 132,
4052; c) H. Zhang, L. Hong, H. Kang, R. Wang, J. Am. Chem.
1
1
In conclusion, a synthesis of dehaloperophoramidine (2) from
commercially available starting materials has been achieved. A
highly efficient [3,3]-Claisen rearrangement to give novel ketone 6
was followed by a diastereoselective epoxide opening/allylsilylation
Soc., 2013, 135, 14098; d) S.-J. Han, F. Vogt, J. A. May, S.
Krishnan, M. Gatti, S. C. Virgil, B. M. Stoltz, J. Org. Chem.,
2014, 80, 528; e) S.-J. Han, F. Vogt, S. Krishnan, J. A. May, M.
Gatti, S. C. Virgil, B. M. Stoltz, Org. Lett., 2014, 16, 3316; f) B.
M. Trost, M. Osipov, S. Krüger, Y. Zhang, Chem. Sci., 2015,
349.
J. D. Ranier, Angew. Chem. Int. Ed., 2006, 45, 4317.
6,
(modified Hosomi-Sakurai) reaction. In combination these reaction
enabled construction of the required contiguous all carbon
quaternary stereocentres. Detailed spectroscopic comparison with
an authentic sample of 2 confirmed that it was identical to our
synthetic TFA salt of 2. Preliminary biological activity associated
with 2 has also been reported for the first time.
5
6
T. Ishida, H. Ikota, K. Kurahashi, C. Tsukano, Y. Takemoto,
Angew. Chem. Int. Ed., 2013, 52, 10204.
K. Popov, A. Hoang, P. Somfai, Angew. Chemie. Int. Ed.,
2016, 55, 1801.
N. Voûte, D. Philp, A. M. Z. Slawin, N. J. Westwood, Org.
7
8
9
Biomol. Chem., 2010,
C. V. Ramana, R. Murali, K. Ravikumar, M. Nagarajan, J.
Chem. Res (S), 1996, , 226
8, 442
We would like to acknowledge EPSRC for PhD funding through
the Doctoral Training Schemes, the EPSRC National Mass
5
Spectrometry Service Centre, Swansea and Professor Andrew Smith 10 For a recent example of a regioselective iodoetherification in
a total synthesis, see Y. Li, S. Zhu, J. Li, A. Li, J. Am. Chem.
for support with chiral HPLC analysis.
Soc., 2016, 138, 3982.
1 A. Hosomi, H. Sakurai, Tetrahedron Lett. 1976, 17, 1295.
2 S. V. Pansare, K. G. Kulkarni, RSC Adv., 2013, 3, 19127.
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4 C. Dallanoce, L. Rizzi, L. Pucci, C. Gotti, F. Clementi and C. De
Micheli, Chirality, 2012, 24, 543.
1
1
1
1
Effect of 2 on the growth of HCT116, HT29 and
LoVo colorectal cancer cells (day 4).
HCT116 (500)
HT29 (500)
LoVo (1000)
1
5 CCDC 1486344 (15), CCDC 1478153 (S16), CCDC 1478152 (
(
5)
and CCDC 1478154 30 contain the supplementary
1
.5
0
)
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif
1
1
6 K. M. Sadhu, D. S. Matteson, Tetrahedron Lett., 1986, 27
95.
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7
2
Chem. Rev., 2010, 3600.
1
1
8 D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155.
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Lett., 2009, 50, 3436; b) K. Yamada, Y. Mogi, M. A.
Mohamed, K. Takasu, K. Tomioka, Org. Lett., 2012, 14, 5868.
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Prakt. Chemie, 1937, 147, 257.
control 10µM 20µM 40µM 50µM 60µM 70µM 80µM 90µM 100µM
Concentration (μM)
Fig. 2 Dose-response curves for the effect of our synthetic sample of 2 on the growth of
three colorectal cancer cell lines. Growth data (relative to untreated controls but
containing equimolar concentrations of DMSO carrier) are shown for HCT116 (solid
line), HT29 (dashed line) and LoVo cells (dotted line), assessed by SRB assay four days
after treatment. The number of cells plated per well at the beginning of the
experiment is shown in parentheses. IC50 values of 60-70 µM (HCT116), 60 µM (HT29)
and 50 µM (LoVo) were calculated using Graphpad Prism software and are equivalent
2
2
1 S. C. Bergmeier, P. P. Seth, Tetrahedron Lett., 1999, 40, 6181.
1
to the IC50 of 60 µM reported for compound 1 by Ireland et al.
4
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