Gold(I)-catalysed intramolecular hydroamination of α-quaternary alkynes: Synthetic studies towards spiroimine marine toxins

Article abstract of DOI:10.1016/j.tetlet.2011.07.048

Cyclic spiroimines form an essential component of the bioactive pharmacophore in a number of potent fast-acting marine biotoxins, including the pinnatoxins, gymnodimine and the spirolides. These present a significant challenge for the total synthesis of this class of natural products. A novel approach to these cyclic spiroimines based on metal-catalysed hydroamination of spiroaminoalkyne precursors is reported herein. Au(PPh₃)SbF ₆ was found to effect the formation of bench-stable 5,6- and 6,6-spiroimine systems in high yields, although the 7,6-analogue remained elusive. To the best of our knowledge these are the first reported examples of α-quaternary cyclic imines formed via alkyne hydroamination.

Full text of DOI:10.1016/j.tetlet.2011.07.048

Tetrahedron Letters 52 (2011) 4896–4898
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Gold(I)-catalysed intramolecular hydroamination of
synthetic studies towards spiroimine marine toxins
a-quaternary alkynes:
⇑
Yanchuan C. Zhang, Daniel P. Furkert, Stéphanie M. Guéret, Fanny Lombard, Margaret A. Brimble
Department of Chemistry, University of Auckland, Private Bag 92019, Auckland, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclic spiroimines form an essential component of the bioactive pharmacophore in a number of potent
fast-acting marine biotoxins, including the pinnatoxins, gymnodimine and the spirolides. These present
a significant challenge for the total synthesis of this class of natural products. A novel approach to these
cyclic spiroimines based on metal-catalysed hydroamination of spiroaminoalkyne precursors is reported
herein. Au(PPh3)SbF6 was found to effect the formation of bench-stable 5,6- and 6,6-spiroimine systems
in high yields, although the 7,6-analogue remained elusive. To the best of our knowledge these are the
Received 17 June 2011
Revised 30 June 2011
Accepted 11 July 2011
Available online 24 July 2011
Keywords:
first reported examples of
a
-quaternary cyclic imines formed via alkyne hydroamination.
Ó 2011 Elsevier Ltd. All rights reserved.
Hydroamination
Cyclic imine
Gymnodimine
Spirolide
Gold catalysis
Marine natural products containing a cyclic imine unit form an
important subclass of fast-acting toxins responsible for incidents of
shellfish toxicity.1 In addition to their potent biological activity, the
complex molecular architecture of compounds such as the pinna-
toxins (1a–d) (Fig. 1), gymnodimine (2) and the spirolides (3a–f)
has inspired synthetic endeavours in several laboratories.2 Inter-
estingly, the observed inactivity of spirolides E and F (3e,f) in
which the cyclic imine has been hydrolysed, highlights the impor-
tance of this motif in effective binding to its cellular target, the nic-
otinic acetylcholine receptor.3
HO
N
O
H
H
R
H
H
O
O O
O
O
OH
N
O
O
OH
H
1a
Pinnatoxin A ( ) R = CO2H
Gymnodimine (2)
Previous synthetic studies towards the pinnatoxins and gymn-
odimine report the necessity to use forcing conditions to form
the cyclic imine from azido-ketone or amino-ketone precursors
via an aza-Wittig or condensation reaction, respectively.4 These
cyclisations are typically performed at a late stage due to the sus-
ceptibility of imines to hydrolytic cleavage. The cyclic imines pres-
ent in natural products 1–3, however, are unusual in being highly
resistant to hydrolysis when incorporated into the complete mac-
rocycle and exist as protonated iminium salts in acidic aqueous
solution. The adjacent quaternary centre is proposed to impart ste-
ric protection from hydrolysis, along with the vicinal methyl
groups present in the pinnatoxins and spirolides. In support of this
hypothesis, a number of simple imine systems containing a quater-
nary centre prepared by the Romo group proved similarly resistant
to acidic and basic hydrolysis, although the methodology devel-
oped was not applicable to total synthesis.5
B (1b) R = CH(S-NH2)CO2H
C (1c) R = CH(R-NH2)CO2H
1d
D ( ) R = C(O)CH2CH2CO2H
R1
R
NH2
N
O
O
O
H
H
O
O
O
O
3
3
OH
O
OH
O
2
2
O
O
R3 OH
OH
R2
Spirolide A (3a) Δ2,3 ; R1 = H; R2 = Me; R3 = Me
Spirolide E (3e)
F (3f) R = H
Δ
2,3 ; R = H
B (3b) R1 = H; R2 = Me; R3 = Me
C (3c) Δ2,3 ; R1 = Me; R2 = Me; R3 = Me
D (3d) R1 = Me; R2 = Me; R3 = Me
⇑
Corresponding author.
E-mail address: m.brimble@auckland.ac.nz (M.A. Brimble).
Figure 1. Spiroimine-containing marine natural products.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.048

Y. C. Zhang et al. / Tetrahedron Letters 52 (2011) 4896–4898
4897
R1
Table 1
Hydroamination of amino alkynes 6a–c
N
H2
N
n
hydro-
N
N
NH2
amination
n
n
PGO
Table 1
n
PGO
O
5
6a-c
4
6a-c
5a-c
Figure 2. Putative advanced spirolide AE ring intermediate 4 and model system 5
selected for this study.
Substrate
Cat.a
Conditions
Result (%)
6b
6c
6c
6c
6c
6a
6b
6c
6c
6c
6b
6c
6a
6b
6c
13
13
14
15
14
16
16
16
16
17
17
17
17
17
17
NH4PF6,a 100 °C, PhMe, 4 h
NH4PF6, 100 °C, PhMe, 4 h
rt, CH2Cl2, 3 d
rt, CH2Cl2, 3 d
80 °C, PhMe, 1 d
95 °C, MeCN, 1 h
95 °C, MeCN, 1 h
95 °C, MeCN, 1 h
95 °C, MeCN, 1 d
c.m.b
c.m.
c
—
We were interested to investigate alternative synthetic meth-
ods for preparation of these key spiroimines that either (a) were
suitable for mild late-stage cyclic imine formation involving ad-
vanced intermediates, or (b) enabled access to highly functional-
ised imines that might be stable enough to be viable synthetic
intermediates themselves. In addition, any spiroimines prepared
would be novel entities and potentially interesting subjects for bio-
logical activity investigations.
In recent years hydroamination has received an increasing
amount of attention as a direct and atom-efficient method to ac-
cess nitrogen-containing compounds.6 Catalysts based on a variety
of metals including titanium,7 zirconium, yttrium, lanthanides and
most notably, gold,8 have been found to promote intramolecular
hydroamination affording cyclic imines from amino-alkynes,
including two seven-membered examples.9 It seemed reasonable
that similar cyclisation of a suitable amino-alkyne precursor might
afford the bicyclic spiroimine ring systems of possible imine-con-
taining intermediates (e.g., 4, Fig. 2) required for synthesis of the
complex marine natural products 1-3. To this end, we designed a
simplified model system 5 that would allow us to investigate the
feasibility of this approach, starting from amino-alkynes 6a-c.
In parallel sequences, readily available diols 7a–c (Scheme 1)
were monoprotected as PMB ethers and converted into the iodides
8a–c. Formation of lithium enolate of commercially available
methyl cyclohexane carboxylate (9) at ꢀ78 °C using LDA, followed
by addition of 8a–c and slow warming to room temperature
—
—
c.m.d
c.m.d
—
c.m.
—
—
100 °C, PhMe, 2 d
Et3N,a 100 °C, PhMe, 2 d
Et3N, 100 °C, PhMe, 2 d
Et3N, 95 °C, MeCN, 0.5 h
Et3N, 95 °C, MeCN, 0.5 h
Et3N, 95 °C, MeCN, 2 d
—
5a (91)
5b (80)
—
a
b
c
5 mol %.
Complex mixture.
No reaction, starting material recovered.
Contained trace spiroimine by 1H NMR spectroscopy.
d
Ru3(CO)12
13
iPr
iPr
MeCN
Au SbF6
NaAuCl4
tBu
N
N
P
tBu
16
iPr
iPr
Au
Cl
Ph
Au(PPh3)SbF6
14
15
17
Figure 3. Hydroamination catalysts examined in this study.
O
OMe
afforded methyl esters 10a–c containing a quaternary centre, in
excellent yields.
OH
I
a,b
c
OPMB
n
OH
The resulting methyl esters were then transformed into the cor-
responding alkynes 11a-c by a standard three-step sequence
involving reduction to the alcohol with lithium aluminium hy-
dride, Swern oxidation and alkyne formation from the aldehyde
with freshly-prepared Ohira-Bestmann reagent. It is worth noting
that the Corey–Fuchs protocol failed to yield any of the desired al-
kyne in the last step of this sequence. Installation of the primary
amine was achieved by oxidative PMB deprotection and subse-
quent tosylation to give 12a–c, followed by nucleophilic displace-
ment with sodium azide in DMF at 50 °C and Staudinger reduction
using triphenylphosphine, to give the desired amino-alkynes 6a-c.
With required precursors 6a–c in hand, the hydroamination
reaction was investigated (Table 1) using readily available cata-
lysts, stable under standard laboratory conditions, that would be
applicable to a robust and scalable synthetic program (Fig. 3).
Ru3(CO)12 (13) has been reported to be effective for the formation
of imines, including a cyclic seven-membered example, albeit in
low yield under forcing conditions.10 Unfortunately, no cyclisation
products were obtained under these conditions, even with the
additive NH4PF6.11 Among a number of gold catalysts recently
developed for alkyne hydroamination, both phosphine 1412 and
N-heterocyclic carbene 1513 have been applied successfully in a
range of systems. Disappointingly, however, neither catalyst was
effective in cyclisation of any of the amino-alkyne precursors
OPMB
n
n
8a-c
7a n = 0
10a-c
b
c
n = 1
n = 2
OPMB
OTs
d,e,f
g,h
n
n
11a-c
12a-c
NH2
O
OMe
i,j
9
n
6a-c
Scheme 1. Preparation of hydroamination precursors 6a–c. Reagents and condi-
tions: (a) NaH, PMBCl, DMF, 0 °C to rt, 18 h; (b) PPh3, I2, imidazole, CH2Cl2, 0 °C to rt,
2 h, 8a (70%), 8b (65%), 8c (83%) over 2 steps; (c) LiHMDS, 9, THF, ꢀ78 °C then 8a–c,
ꢀ78 °C to rt, 18 h, 10a (81%), 10b (83%), 10c (89%); (d) LiAlH4, THF, rt, 3 h; (e)
(COCl)2, DMSO, Et3N, ꢀ78 °C; (f) diethyl 1-diazo-2-oxopropylphosphonate, K2CO3,
MeOH, 0 °C to rt, 18 h, 11a (43%), 11b (59%), 11c (78%) over 3 steps; (g) DDQ,
CH2Cl2-H2O (10:1), rt, 2 h; (h) TsCl, Et3N, DMAP, CH2Cl2, rt, 18 h, 12a (70%), 12b
(62%), 12c (85%) over 2 steps; (i) NaN3, DMF, 50 °C, 3 h; (j) PPh3, THF-H2O (40:1),
50 °C, 4 h, 6a (73%), 6b (74%), 6c (74%) over 2 steps.

4898
Y. C. Zhang et al. / Tetrahedron Letters 52 (2011) 4896–4898
2011, 9, 3726; (c) Kong, K.; Romo, D.; Lee, C. Angew. Chem., Int. Ed. 2009, 48,
7402; (d) White, J. D.; Quaranta, L.; Wang, G. J. Org. Chem. 2007, 72, 1717; (e)
Johannes, J. W.; Wenglowsky, S.; Kishi, Y. Org. Lett. 2005, 7, 3997; (f) Tsujimoto,
T.; Ishihara, J.; Horie, M.; Murai, A. Synlett 2002, 399. Spirolides: see reference 1,
Part 5.
6a-c. Reasoning that the reaction might be hindered by the bulky
ligands of catalysts 14 and 15, especially given the presence of
the quaternary spirocentre
a to the acetylene, it was decided to
investigate simple gold salts 16 and 17. Elevated temperatures ini-
tially failed to provide any cyclised product 5c in either acetonitrile
or toluene.
3. (a) Bourne, Y.; Radi, Z.; Aráoz, R.; Talley, T.; Benoit, E.; Servent, D.; Taylor, P.;
Molgo, J.; Marchot, P. Proc. Nat. Acad. Sci. 2010, 107, 6076; (b) Aráoz, R.; Servent,
D.; Molgo, J.; Iorga, B. I.; Fruchart-Gaillard, C.; Benoit, E.; Gu, Z.; Stivala, C.;
Zakarian, A. J. Am. Chem. Soc. 2011. doi: 10.1021/ja201254c.
Finally, we were pleased to discover that heating 6a or 6b in
acetonitrile under sealed-tube conditions, in the presence of gold
phosphine catalyst 17 and triethylamine,14 afforded the respective
five- and six-membered cyclic imines 5a and 5b in 91% and 80%
yields. Based on these results, use of the non-coordinating anti-
mony hexafluoride counterion appears important for any reaction
to occur. The reactions were notably rapid, affording a single prod-
uct cleanly according to TLC in less than 30 min and requiring only
simple filtration to provide nearly pure products.15,16 Contrary to
our initial concerns, the imines 5a and 5b appeared relatively resis-
tant to hydrolysis, proving stable to benchtop storage open to air
for prolonged periods. However, despite all efforts, it remained
impossible to isolate any of the corresponding seven-membered
cyclic imine 5c upon subjecting amino-alkyne 6c to the same con-
ditions used successfully for 6a and 6b. Further studies will be re-
quired to determine whether this is due to a prohibitive energy
barrier or the instability of the product.
4. During preparation of this manuscript
a related cyclic imine study was
published by the Evans group: Marcoux, D.; Bindschädler, P.; Speed, A. W. H.;
Chiu, A.; Pero, J. E.; Borg, G. A.; Evans, D. A. Org. Lett. 2011. doi: 10.1021/
ol201448h.
5. Ahn, Y.; Cardenas, G.; Yang, J.; Romo, D. Org. Lett. 2001, 3, 751.
6. (a) Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008,
108, 3795; (b) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079.
7. Doye, S. Synlett 2004, 1653.
8. Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180.
9. (a) Kim, H.; Livinghouse, T.; Lee, P. H. Tetrahedron 2008, 64, 2525; (b) Kim, H.;
Livinghouse, T.; Shim, J. H.; Lee, S. G.; Lee, P. H. Adv. Synth. Catal. 2006, 348, 701;
(c) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1996, 118, 9295.
10. Kondo, T.; Okada, T.; Suzuki, T.; Mitsudo, T. J. Organomet. Chem. 2001, 622,
149.
11. Tokunaga, M.; Eckert, M.; Wakatsuki, Y. Angew. Chem., Int. Ed. 1999, 38, 3222.
12. Nieto-Oberhuber, C.; Lopez, S.; Munoz, M.; Cardenas, D.; Bunuel, C.;
Echavarren, A. Angew. Chem., Int. Ed. 2005, 44, 6146.
13. Marion, N.; Nolan, S. P. Chem. Soc. Rev. 2008, 37, 1776.
14. Ritter, S.; Horino, Y.; Lex, J.; Schmalz, H. G. Synlett 2006, 3309.
15. Cyclic imines 5a and 5b were stable to TLC and flash chromatography using
10% EtMA (ethyl acetate containing 10% 9:1 MeOH-aq.NH3).
16. General hydroamination procedure: To a stirred solution of amino-alkyne 6a
(20.0 mg, 0.13 mmol) in MeCN (0.5 ml) in a sealed tube were added Au(PPh3)Cl
In summary, we have described the successful synthesis of spi-
rocyclic imines 5a and 5b in high yield via intramolecular alkyne
hydroamination, using the convenient gold phosphine catalyst
Au(PPh3)SbF6. All efforts to obtain the analogous seven-membered
imine 5c have proved fruitless to date. These results demonstrate
(3.30 mg, 6.60 mmol), AgSbF6 (2.30 mg, 6.60 mmol) and Et3N (0.9 ll,
6.60 mmol). The mixture was heated at 95 °C for 0.5 h then filtered and
concentrated in vacuo to afford cyclic imine 5a (18.2 mg, 91%) as a yellow oil:
Rf 0.85 (10% EtMA); IR vmax(film) 2926, 2855, 1641, 1437, 750, 694, 623 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 1.11–1.50 (6H, m, 6-H0, 7-H, 9-H, 10-H0), 1.68–1.73
(4H, m, 6-H00, 8-H, 10-H00), 1.82 (2H, t, J = 7.2 Hz, 4-H), 1.96 (3H, t, J = 1.6 Hz, 10-
H), 3.68–3.72 (2H, m, 3-H); 13C NMR (100 MHz, CDCl3) d 15.9 (CH3, C-10), 23.1
(CH2, C-6, C-10), 25.7 (CH2, C-8), 32.8 (CH2, C-7, C-9), 33.3 (CH2, C-4), 54.7 (C, C-
5), 56.9 (CH2, C-3), 182.5 (C@N, C-1); m/z (ESI+, %) 152 (M+H+, 100); HRMS M+
found 152.1432, C10H18N+ requires 152.1434.
the feasibility of hydroamination of
a-quaternary alkyne sub-
strates and also suggest that the five- and six-membered cyclic
imine products may be stable enough to be utilised as viable inter-
mediates in synthesis.
Data for 5b: Rf 0.85 (10% EtMA); IR vmax(film) 2927, 2855, 1644, 1449, 695, 657,
623 cmꢀ1 1H NMR (400 MHz, CDCl3) d 1.44–1.72 (14H, m, 4-H, 5-H, 7-H, 8-H,
.
References and notes
9-H, 10-H, 11-H), 2.02 (3H, s, 10-H), 3.51–3.54 (2H, m, 3-H); 13C NMR
(100 MHz, CDCl3) d 18.7 (CH2, C-9), 20.6 (CH2, C-7, C-11), 22.7 (CH3, C-10), 25.7
(CH2, C-5), 27.6 (CH2, C-4), 33.1 (CH2, C-8, C-10), 39.6 (C, C-6), 49.6 (CH2, C-3),
177.0 (C@N, C-1); m/z (ESI+, %) 166 (M+H+, 100); HRMS M+ found 166.1594,
1. Gueret, S. M.; Brimble, M. A. Nat. Prod. Rep. 2010, 27, 1350.
2. Pinnatoxin: (a) Beaumont, S.; Ilardi, E.; Tappin, N. D. C.; Zakarian, A. Eur. J. Org.
Chem. 2010, 5743. and references therein; Gymnodimine: (b) Toumieux, S.;
Beniazza, R.; Desvergnes, V.; Araoz, R.; Molgo, J.; Landais, Y. Org. Biomol. Chem.
C
11H20N+ requires 166.1590.