Spiroaminal model systems of the marineosins with final step pyrrole incorporation

Article abstract of DOI:10.1016/j.tetlet.2013.02.059

In this Letter, we describe a short, six step enantioselective route to spiroaminal lactam model systems reminiscent of marineosins A and B that has been developed starting from either (R)- or (S)-hydroxysuccinic acid, respectively, in ～9% overall yield. This route enables late stage incorporation of the pyrrole ring at C5 via nucleophilic displacement of an iminium triflate salt.

Full text of DOI:10.1016/j.tetlet.2013.02.059

Tetrahedron Letters 54 (2013) 2231–2234
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Spiroaminal model systems of the marineosins with final step
pyrrole incorporation
Joseph D. Panarese a,b, Leah C. Konkol a,b, Cynthia B. Berry a, Brittney S. Bates a, Leslie N. Aldrich a,
Craig W. Lindsley a,b,
⇑
a Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
b Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt Specialized Chemistry Center (MLPCN), Vanderbilt University Medical Center,
Nashville, TN 37232, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter, we describe a short, six step enantioselective route to spiroaminal lactam model systems
reminiscent of marineosins A and B that has been developed starting from either (R)- or (S)-hydrox-
ysuccinic acid, respectively, in ꢀ9% overall yield. This route enables late stage incorporation of the pyrrole
ring at C5 via nucleophilic displacement of an iminium triflate salt.
Received 1 February 2013
Revised 18 February 2013
Accepted 19 February 2013
Available online 27 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Marineosin
Iminium triflate
Enantioselective
Pyrrole
Alkaloid
In 2008, Fenical and co-workers reported the discovery of two
novel spiroaminals, marineosins A (1) and B (2), from a marine-
derived Streptomyces-related actinomycete (Fig. 1),1 and related
to the prodigiosin family.2 Both 1 and 2 displayed inhibition of
human colon carcinoma cell growth (HCT-116 IC50s of 0.5 and
After the unsuccessful biosynthetic approach,3 our lab has pur-
sued multiple synthetic strategies en route to a total synthesis of 1
and 2. Uniformly, routes with early incorporation of the C1–C4 pyr-
role moiety, led to reactivity/stability issues that forced abandon-
ment of advanced intermediates and strategies. Based on this
outcome, we decided to re-design our routes to install the pyrrole
moiety as the final step of the synthesis (Scheme 2). To determine
the viability of this new approach, we developed a short, enantio-
selective synthesis of two spiroiminal model systems of 1 and 2
(highlighted in red). This route enables late stage incorporation
of the pyrrole ring at C5 via a novel application of nucleophilic dis-
placement of an iminium triflate salt.
Our model system was inspired by the work of Huang for the
construction of aza-spiropyran derivatives by the addition of func-
tionalized Grignard reagents into maleimides.5 The synthesis of the
proposed model system began with the requisite THP-protected
bromobutanol 12 (Scheme 3) following a Grieco procedure.6 Here,
tetrahydrofuran is opened with HBr to afford 10 in 75% yield. Pro-
tection as the THP ether afforded 12 in 90% yield, which is then
converted into Grignard reagent 13.6
46 l
M, respectively).1 Fenical also proposed a biosynthesis of 1
and 2 that proceeded through an inverse-electron demand het-
ero Diels–Alder reaction with 3 to provide 4, which is then re-
duced to afford
1 and 2. We evaluated this biosynthetic
proposal, and while 3 was accessible in high yield, we were un-
able to affect the intramolecular inverse-electron demand hetero
Diels–Alder reaction under a variety of conditions. Attempts with
multiple substrates for intermolecular variants were equally
unsuccessful.3
In 2010, Snider and co-workers proposed an alternative biosyn-
thesis of 1 and 2 from undecylprodigiosin that only requires a sin-
gle two-electron oxidation.4 Based on this proposal, Snider
developed a seven step route to a model system 7 for the spiroimi-
nal moiety from methylvalerolactone 5 (Scheme 1). While an
important advance towards the synthesis of 1 and 2, we aimed
to avoid long equilibration times, inseparable equilibrium mix-
tures, and, importantly, early installation of the pyrrole.4
With 13 in hand, we prepared the maleimide fragment relevant
for a model system of 1.7,8 Starting from (R)-hydroxy succinic acid
14, refluxing in m-xylenes with p-methoxybenzyl amine 15 affords
the desired maleimide 16 in 78% yield (Scheme 4). Silver oxide
mediated alkylation with MeI in MeCN affords key coupling part-
⇑
Corresponding author. Tel.: +1 615 322 8700; fax: +1 615 345 6532.
E-mail address: craig.lindsley@vanderbilt.edu (C.W. Lindsley).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.059

2232
J. D. Panarese et al. / Tetrahedron Letters 54 (2013) 2231–2234
19
HO
20
MeO
O
p-OMeBnNH2
23
OMe
24
OH
O
O
22
H
N
18
17
Ag2O, MeI
15
21
N
CO2H
7
O
O
9
O
8
m-xylene
6
N
PMB
10
HO2C
MeCN
78%
N
HN
N
HN
16
15
78%
5
PMB
17
11
13
4
3
OMe
14
16
12
14
HN
2
1
Scheme 4. Synthesis of the key maleimide 17.
1
2
, marineosin B
, marineosin A
MgBr
23
24
H
O
OMe
O
MeO
O
OMe
H
13
OTHP
H
H
N
O
H
p-TsOH
H
THPO HO
PMB
9
O
N
N
O
N
N
N
N
8
N
PMB
PMB
THF
80%
-
O
80%
OTs
19
O
MeO
17
18
NH
3
4
MeO
O
OMe
O
MeO
N
H
Figure 1. Structures and proposed biosynthesis of marineosins A (1) and B (2).
7
O
CAN
2
O
O
N
H
MeCN:H2O
67%
N
PMB
PMB
O
O
OTES
O
OMe
20
21
O
O
3 steps
59%
4 steps
N
Scheme 5. Synthesis of the spiroaminal moiety of 1.
4.4-7.7%
HN
O
N
N
SEM
5
6
7
H
H
Scheme 1. Snider’s spiroiminal model system.
MeO
H
7
H
O
H
H
2
N
OMe
O
OMe
O
PMB
O
O
conditions
HN
HN
20
N
HN
Figure 2. Diagnostic NOE correlations in the (6S,7R)-spiroaminal 20 model system
reminiscent of 1.
HN
, marineosin A
1
8
Scheme 2. Envisioned disconnection for the synthesis of 1.
With 21 in hand, we were poised to evaluate conditions to in-
stall the pyrrole moiety at C5 to validate our retrosynthetic ap-
proach aimed at accessing 8. Our initial thought was to install
the pyrrole through classical Vilsmeier-type chemistry (POCl3/pyr-
role);9 however, this failed to provide the desired 22. We surveyed
a number of known strategies to convert the lactam carbonyl into a
suitable electrophile, followed by treatment with pyrrole under a
variety of reaction conditions, but none proved successful. The lac-
tam was converted into the corresponding triflate 23 through
treatment with Tf2O or PhNTf2, followed by a Suzuki coupling with
various forms of N-protected, 2-pyrrole boronic acid. Unfortu-
nately, all attempts with multiple Pd(0) and Ni(0) sources, bases
and solvents afforded either no product or only trace amounts of
22 (Scheme 6).
A deeper perusal of the literature led us to consider the chem-
istry of triflic anhydride/amide adducts, and the opportunity to
potentially intercept the in situ generated triflate with the pyrrole
nucleophile in a single pot reaction.10–12 It has been demonstrated
that treatment of an indolin-2-one with Tf2O, to generate the imin-
ium triflate salt, followed immediately by the addition of a func-
tionalized indole affords the bis-indole product.11 With this lone
precedent, we treated 21 with 2.0 equiv of Tf2O, to generate the
iminium triflate salt, followed by the addition of 5.0 equiv of pyr-
role in CH2Cl2 at 0 °C. Unfortunately, these conditions afforded only
a trace (<5%) of the desired 22. Evaluation and refinement of the
reaction conditions identified that employing 1.0 equiv of Tf2O, to
generate the iminium triflate salt, followed by the addition of
O
O
Br
MgBr
Br
Mg
aq. HBr
75%
11
cat. p-TsOH
THF
Et2O, 90%
OTHP
OTHP
13
OH
9
10
12
Scheme 3. Synthesis of the key Grignard reagent 13.
ner 17 in 78% yield. Addition of 13 into 17 provided hydroxy ami-
nal 18 in 80% yield (Scheme 5).15
Treatment with p-TsOH cleaves the THP ether and generates
iminium salt 19 which is attacked by the free hydroxyl leading
to formation of the spiroaminal 20 in 80% yield.16 Finally, ceric
ammonium nitrate (CAN)-mediated removal of the p-methoxyben-
zyl (PMB) group provides lactam 21 in 67% yield.17 Model system
21 possessed the correct stereochemistry at C7 for 1, but the oppo-
site absolute stereochemistry at C8. However, 21 is a valuable
model from which to develop chemistry for the late stage installa-
tion of the pyrrole at C5, and not consume valuable late stage 8.
Stereochemical assignments of 20, with anti O-1, O-7 geometry,
were made based on literature precedent and from extensive NOE
studies (Fig. 2).9

J. D. Panarese et al. / Tetrahedron Letters 54 (2013) 2231–2234
2233
5.0 equiv of pyrrole in CH2Cl2 at 0 °C did provide the desired model
system 22 of marineosin A, 1, in 36% yield (Scheme 7).18 The ste-
reochemistry was further confirmed at this stage by NOE studies
on 22. Irradiation of H-7 supported the 6R,7S stereochemical
assignment of 22; no equilibration to the syn O-1, O-7 isomer
had occurred after installation of the pyrrole, even after a period
of 2 weeks in CDCl3.4,9 Identical NOE data were seen in model sys-
tem 22. Although the configuration of the spirocenter in model 22
is opposite to marineosins A, we envision that a syn O-1, O-7 iso-
mer can be obtained by increasing the steric demands of the pyran
ring through stereoselective functionalization of a carbon fragment
similar to Grignard 13. Repetition of this sequence, starting from
the (S)-hydroxy succinic acid, afforded the model system 24 remi-
niscent of marineosin B in ꢀ9% overall yield. Once again, literature
precedent and extensive NOE data confirmed the stereochemical
assignment.
In summary, we have developed chemistry to enable late stage
introduction of the pyrrole moiety at C5 in marineosin A (1) and B
(2) via a novel application of the nucleophilic displacement of an
iminium triflate salt by pyrrole. Moreover, we have performed an
enantioselective synthesis of two spiroaminal model systems rem-
iniscent of 1 and 2 starting from chiral pool molecules. Overall
yields for both 22 and 24 averaged ꢀ9% from commercial tetrahy-
drofuran. This synthetic approach is currently being applied to the
total synthesis of 1, and results will be presented in due course.
Acknowledgments
This work was supported, in part, by the Department of Phar-
macology (Vanderbilt University) and William K. Warren, Jr. Fund-
ing for the NMR instrumentation was provided in part by a Grant
from NIH (S10 RR019022). The authors thank Brenda Crews (Mar-
nett lab) for performing the HCT-116 viability/toxicity assays.
As both 1 and 2 displayed inhibition of human colon carcinoma
(HCT-116 IC50s of 0.5 and 46 lM, respectively), and due to the fact
that many related, bi- and tricyclic prodigiosin natural products
have potent cytotoxicity,13,14 we evaluated 22 and 24 in our
HCT-116 cytotoxicity assay in order to ascertain if the model sys-
tems represented a minimum pharmacophore for 1 and 2, respec-
tively. Interestingly, both model systems were inactive in this
assay, suggesting the larger construct, and/or stereochemical con-
formation, of 1 and 2 are important for the observed biological
activity, thus warranting completion of the total synthesis of 1
and 2.
References and notes
1. Boonlarppradab, C.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. Org. Lett. 2008, 10,
5505–5508.
2. Fuerstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582–3603.
3. Aldrich, L. N.; Dawson, E. W.; Lindsley, C. W. Org. Lett. 2010, 12, 1048–1051.
4. Cai, X.-C.; Wu, X.; Snider, B. B. Org. Lett. 2010, 12, 1600–1603.
5. Zheng, J.-F.; Chen, W.; Huang, S.-Y.; Ye, J.-L.; Huang, P-Q. Beilstein J. Org. Chem.
2007, 3, 1–6.
6. Grieco, P. A.; Larsen, S. D. J. Org. Chem. 1986, 51, 3553–3555.
7. Naylor, A.; Judd, D. B.; Scopes, D. I. C.; Hayes, A. G.; Birch, P. J. J. Med. Chem.
1994, 37, 2138–2144.
8. Zheng, J.-L.; Liu, H.; Zhang, Y.-F.; Zhao, W.; Tong, J.-S.; Ruan, Y.-P.; Huang, P-Q.
Tetrahedron: Asymmetry 2011, 22, 257–263.
9. Rapoport, H.; Castagnoli, N., Jr. J. Am. Chem. Soc. 1962, 84, 2178–2181.
10. Sforza, S.; Dossena, A.; Corradini, R.; Virgili, E.; Marchelli, R. Tetrahedron Lett.
1998, 39, 711–714.
11. Baraznenok, I. L.; Nenajdenko, V. G.; Balenkova, E. S. Tetrahedron 2000, 56,
3077–3119.
12. Black, D. StC; Ivory, A. J.; Kumar, N. Tetrahedron 1996, 52, 4697–4705.
13. Aldrich, L. N.; Stoops, S. L.; Crews, B. C.; Marnett, L. J.; Lindsley, C. W. Bioorg.
Med. Chem. Lett. 2010, 20, 5207–5211.
14. Melvin, M. S.; Calcutt, M. W.; Noftle, R. E.; Manderville, R. A. Chem. Res. Toxicol.
2002, 15, 742–748.
POCl3, pyrrole
or
MeO
O
MeO
O
HCl, pyrrole
O
or
N
H
21
N
PhNTf2, pyrrole
HN
22
15. A flame-dried flask was charged with magnesium powder (447 mg, 18.4 mmol)
and placed under an inert argon atmosphere. The magnesium was suspended
in anhydrous THF (21 mL). To this mixture was added pyran 12 (1.4 mL,
7.5 mmol). After warming to 50 °C, pyran 12 (2.0 mL, 10.7 mmol) was added
dropwise. The reaction mixture was heated periodically until it sustained
B(OH)2
MeO
Pd(0),
Ni(0)
NGP
Tf2O
CH2Cl2
base,
OTf
solvent
temp
N
O
reflux.
A separate flame-dried flask was charged with ether 17 (1.5 g,
6.0 mmol) and THF (30 mL). After cooling to ꢁ20 °C, the solution of Grignard
13 was added dropwise via syringe. The reaction mixture was kept between
ꢁ10 and ꢁ15 °C. After 2.5 h, water (5 mL) was added and the reaction was
allowed to reach rt. The product was extracted with diethyl ether (3 ꢂ 20 mL).
The combined organics were washed with brine, dried over Na2SO4 and
concentrated. The residue was purified on silica gel (30:70 EtOAc/hexanes) to
provide 6.61 g (80%) of tertiary alcohol 18. 1H NMR (CDCl3, 400 MHz) d 1.48–
1.59 (m, 5H), 1.61–1.75 (m, 2H), 1.77–1.90 (m, 1H), 2.12–2.24 (m, 2H), 2.57 (d,
J = 17.9 Hz, 1H), 2.71 (dddd, J = 1.9, 7.2, 17.8 Hz, 1H), 3.27 (s, 3H), 3.29–3.34 (m,
1H), 3.45–3.50 (m, 1H), 3.63–3.71 (m, 1H), 3.77 (s, 3H), 3.80–3.85 (m, 1H),
4.49–4.52 (m, 1H), 4.55–4.66 (m, 3H), 4.85 (q, J = 6.8 Hz, 1H), 6.81 (d, J = 8.6 Hz,
2H), 7.13 (d, J = 8.6 Hz, 2H). 13C NMR (CDCl3, 100 MHz) d 19.6, 19.8, 23.4, 23.5,
25.4 (2C), 30.1, 30.2, 30.7, 30.8, 36.0 (2C), 42.9 (2C), 55.1, 55.2, 62.3, 62.6, 66.5,
66.7, 72.0 (2C), 98.9, 99.0, 107.0, 107.1, 113.9 (2C), 127.9, 128.3, 128.4, 139.2,
139.3, 158.8 (2C), 173.0, 173.1. HRMS (TOF, ES+): C22H33NO6Na [M+Na]+ calcd
23
Scheme 6. Attempts to install the pyrrole moiety at C5.
MeO
O
MeO
O
Tf2O (1.0 equiv.)
CH2Cl2, 0 oC
O
N
H
N
pyrrole
HN
(5.0 equivalents)
21
22
36%
430.2206, found 430.2210. ½a D22
¼ ꢁ15:0 (c 0.6, CHCl3).
ꢃ
16. To a stirred solution of tertiary alcohol 18 (390 mg, 1.0 mmol) in CH2Cl2 (6 mL)
at 0 °C was added p-toluenesulfonic acid monohydrate (41 mg, 0.2 mmol).
After 30 min the solvent was removed. The residue was purified on silica gel
(30:70 EtOAc/hexanes) to provide 244 mg (80%) of spiroaminal 20. 1H NMR
(CDCl3, 400 MHz) d 1.39–1.51 (m, 4H), 1.63–1.70 (m, 1H), 1.85–1.92 (m, 1H),
2.47 (d, J = 17.4 Hz, 1H), 2.65 (dd, J = 5.5, 17.4 Hz, 1H), 3.32 (s, 3H), 3.61 (m, 1H),
3.73 (s, 3H), 3.84 (dd, J = 2.4, 11.2 Hz, 1H), 3.95 (d, J = 5.5 Hz, 1H), 4.11 (d,
J = 16.0 Hz, 1H), 4.70 (d, J = 16.0 Hz, 1H), 6.78 (d, J = 8.7 Hz, 2H), 7.14 (d,
J = 8.7 Hz, 2H). 13C NMR (CDCl3, 100 MHz) d 20.0, 24.6, 27.9, 34.3, 41.8, 55.0,
56.6, 64.7, 74.9, 94.9, 113.5, 127.9, 130.5, 158.2, 174.5. HRMS (TOF, ES+):
Key nOes observed
H
MeOH
7
H
O
H
H
2
N
HN
22
C
17H24NO4 [M+H]+ calcd 306.1705, found 306.1702. ½a 2D2
¼ ꢁ50:6 (c 1, CHCl3).
ꢃ
17. To a stirred solution of spiroaminal 20 (258 mg, 0.85 mmol) in acetonitrile
(27 mL) and water (3.5 mL) was added ceric ammonium nitrate (1.4 g,
2.5 mmol). After 1.5 h,
a second portion of ceric ammonium nitrate
(467 mg, 0.8 mmol) was added. After 1 h, the acetonitrile was removed
under reduced pressure. The product was extracted with CH2Cl2
Scheme 7. Late stage installation of the pyrrole and completion of the model
systems of 1.

2234
J. D. Panarese et al. / Tetrahedron Letters 54 (2013) 2231–2234
(4 ꢂ 15 mL). The combined organic layers were washed with brine, dried
over Na2SO4 and concentrated. The residue was purified on silica gel
(30:70 EtOAc/hexanes) to provide 105 mg (67%) of amide 21. 1H NMR
(CDCl3, 400 MHz) 1.54–1.63 (m, 2H), 1.63–1.73 (m, 1H), 1.73–1.83 (m,
2 min, pyrrole (119.8 lL, 1.7 mmol) was added. After 10 min, the reaction was
quenched with saturated NaHCO3 and allowed to reach rt. The product was
extracted with CH2Cl2 (3 ꢂ 5 mL). The combined organics were dried over
Na2SO4 and concentrated. The residue was purified on silica gel (30:70 EtOAc/
hexanes) to provide 29 mg (36%) of pyrrole 22. 1H NMR (CDCl3, 400 MHz) d
1.54–1.78 (m, 5H), 1.86–1.99 (m, 2H), 2.78 (dd, J = 5.3, 16.5 Hz, 1H), 3.21 (dd,
J = 6.8, 16.5 Hz, 1H), 3.44 (s, 3H), 3.72 (d, J = 10.8 Hz, 1H), 3.84 (t, J = 6.2 Hz, 1H),
4.15 (dt, J = 2.8, 11.1 Hz, 1H), 6.21 (t, J = 3.2 Hz, 1H), 6.57 (d, J = 3.5 Hz, 1H), 6.90
(s, 1H). 13C NMR (CDCl3, 100 MHz) d 19.6, 25.8, 29.2, 38.7, 58.2, 64.2, 85.3,
102.8, 110.7, 112.8, 121.1, 126.3, 164.6. HRMS (TOF, ES+): C13H19N2O2 [M+H]+
d
3H), 2.29 (dd, J = 1.7, 17.2 Hz, 1H), 2.70 (dd, J = 5.6, 17.2 Hz, 1H), 3.34 (s,
3H), 3.66–3.72 (m, 3H), 8.64 (br s, 1H). 13C NMR (CDCl3, 100 MHz) d 19.4,
25.2, 29.3, 35.7, 57.3, 62.7, 82.4, 91.8, 177.3. HRMS (TOF, ES+): C9H16NO3
[M+H]+ calcd 186.1130, found 186.1131. ½a 2D2
¼ ꢁ97:1 (c 1.1, CHCl3).
ꢃ
18. A flame-dried flask was charged with amide 21 (64 mg, 0.3 mmol) and placed
under an inert argon atmosphere. After cooling to 0 °C, CH2Cl2 (4 mL) and
trifluoromethanesulfonic anhydride (58.2
l
L, 0.3 mmol) were added. After
calcd 235.1447, found 235.1447. ½a D22
= ꢁ65.2 (c 1.6, CHCl3).
ꢃ