Studies toward gymnodimine: development of a single-pot Hua reaction for the synthesis of highly hindered cyclic imines.

Article abstract of DOI:10.1021/ol0155081

[structure: see text]. In studies directed toward gymnodimine and related marine toxins, a single-pot variation of the Hua cyclic imine synthesis has been developed. The reaction involves generation of N-trimethylsilyl lactams in situ followed by alkyllithium addition leading directly to cyclic imines. Importantly, this reaction proceeds efficiently with highly hindered alpha,alpha-dialkyl lactams, provided 1,2-dimethoxyethane (DME) is used as solvent, leading to stable cyclic imines. Overall, this transformation allows a one-pot coupling of an alkyliodide and a lactam to give a cyclic imine.

Full text of DOI:10.1021/ol0155081

ORGANIC
LETTERS
2
001
Vol. 3, No. 5
51-754
Studies toward Gymnodimine:
Development of a Single-Pot Hua
Reaction for the Synthesis of Highly
Hindered Cyclic Imines
7
Yong Ahn, Gabriela I. Cardenas, Ju Yang, and Daniel Romo*
Department of Chemistry, P.O. Box 30012, Texas A&M UniVersity,
College Station, Texas 77842-3012
romo@mail.chem.tamu.edu
Received January 2, 2001
ABSTRACT
In studies directed toward gymnodimine and related marine toxins, a single-pot variation of the Hua cyclic imine synthesis has been developed.
The reaction involves generation of N-trimethylsilyl lactams in situ followed by alkyllithium addition leading directly to cyclic imines. Importantly,
this reaction proceeds efficiently with highly hindered r,r-dialkyl lactams, provided 1,2-dimethoxyethane (DME) is used as solvent, leading
to stable cyclic imines. Overall, this transformation allows a one-pot coupling of an alkyliodide and a lactam to give a cyclic imine.
Gymnodimine is a potent marine toxin produced by the
dinoflagellate G. cf. mikimotoi that is responsible for a
neurotoxic shellfish poisoning incident that occurred on the
channels at 1.7 mM. However, this latter activity does not
appear to explain the highly potent effect of these toxins.
Wright postulated that the imine was the pharmacophore of
these toxins, as reduced (cyclic amine) or hydrolyzed (keto
amine) derivatives were no longer toxic and modeling studies
indicated that no significant conformational changes occurred
1
North Island of New Zealand in 1993. This toxin shares a
2
common imine-containing spirocycle with the pinnatoxins
3
and the spirolides. Interesingly, studies of the spirolides by
3
a
Wright and co-workers have shown that these compounds
do not inhibit N-methyl-D-aspartate (NMDA), R-amino-3-
hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), or
kainic acid (KA) receptors nor do they inhibit PP1 or PP2a
upon reduction or hydrolysis.
The unusual architecture of gymnodimine along with its
potential as a biochemical probe led us to pursue synthetic
4
studies toward gymnodimine and derivatives. Our previous
3
a
phosphatases, which are common targets of neurotoxins.
studies toward the synthesis of (-)-gymnodimine (1) resulted
in the synthesis of tetrahydrofuran 3a and spirocyclic lactam
Furthermore, the spirolides exhibited no effect on sodium
channels but only showed weak activation of type L calcium
5
4a. Our strategy toward the macrocycle of gymnodimine
6
(
1) involves a diastereoselective ring closure of 2 using an
(1) (a) Seki, T.; Satake, M.; Mackenzie, L.; Kaspar, H. F.; Yasumoto,
7
T. Tetrahedron Lett. 1995, 36, 7093-7096. (b) Stewart, M.; Blunt, J. W.;
Munro, M. H. G.; Robinson, W. T.; Hannah, D. J. Tetrahedron Lett. 1997,
intramolecular Nozaki-Hiayama-Kishi reaction and a
convergent coupling of fragments 3a and 4a to afford cyclic
3
8, 4889-4890.
2) (a) Pinnatoxin A: Chou, T.; Kamo, O.; Uemura, D. Tetrahedron
(
Lett. 1996, 37, 4023-4026. (b) Pinnatoxin D: Chou, T.; Haino, T.;
(4) For other synthetic studies toward gynmnoodimine, see: (a) Ishihara,
J.; Miyakawa, J.; Tsujimoto, T.; Murai, A. Synlett 1997, 1417-1419. (b)
Rainier, J. D.; Xu, Q. Org. Lett. 1999, 1, 27-29.
(5) Yang, J.; Cohn, S.; Romo, D. Org. Lett. 2000, 2, 763-767.
(6) (a) Pilli, R. A.; Victor, M. M. Tetrahedron Lett. 1998, 39, 4421-
4424. (b) MacMillan, D. W. C.; Overman, L. E. J. Am. Chem. Soc. 1995,
117, 10391-10392.
Kuramoto, M.; Uemura, D. Tetrahedron Lett. 1996, 37, 4027-4030.
(3) (a) Spirolides B and D: Hu, T.; Curtis, J. M.; Oshima, Y.; Quilliam,
M. A.; Walter, J. A.; Watson-Wright, W.; Wright, J. L. C. J. Chem. Soc.,
Chem. Commun. 1995, 2159-2161. (b) Spirolides E and F: Hu, T.; Curtis,
J. M.; Walter, J. A.; Wright, J. L. C. Tetrahedron Lett. 1996, 37, 7671-
7
674.
1
0.1021/ol0155081 CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/06/2001

procedure involves the preparation of N-silyl lactams fol-
lowed by a Peterson-like reaction involving addition of
organolithium reagents to the silylated lactams, directly
generating imines by presumed elimination of silanoxides.
We wished to apply Hua’s reaction in the complex setting
of a gymnodimine synthesis involving coupling of iodide
3
b and lactam 4a. However, one of the key questions to be
addressed was whether addition would occur to sterically
hindered lactams (e.g., 4a) possessing an adjacent quaternary
center. Furthermore, we felt it would be convenient to
develop a one-pot procedure that would avoid the need to
isolate the labile silyl lactam 4b.
R,R-Dimethylated lactams 7 and 8 with adjacent quater-
nary centers were chosen as model substrates. These
substrates, which are effectively more hindered than the
projected spirofused lactams (i.e., 4a), should represent some
of the most difficult cases for additions of nucleophiles to
lactam carbonyls. Silylation of lactams 5 and 6 followed by
a one-pot, double enolization/alkylation sequence gave
10
dimethylated lactams 7 and 8. With these model substrates
in hand, we then studied the single-pot Hua reaction. We
determined that the lactams could be silylated in situ by
treatment of a solution of the lactams 5 or 6 in ethereal
solvents at -78 °C with n-BuLi followed by addition of
trimethylsilyltriflate (TMSOTf). Concentration of the crude
1
reaction mixture and H NMR analysis indicated that
silylation was ∼95% complete under these conditions. The
product of silylation of the valerolactam 8 under these
conditions was determined to be the N-silyllactam 11 and
not the O-silyllactim ether 12 on the basis of GOESY
experiments. Enhancement of the C-6 proton signals was
observed upon irradiation of the trimethylsilyl protons (Figure
2). This enhancement would not be expected for the
Figure 1. Fragment assembly strategy toward gymnodimine (1).
imine 2. Herein, we report a single-pot method for the
conversion of lactams to cyclic imines that is applicable to
the synthesis of the proposed imine pharmacophore of
gymnodimine and related toxins. The method builds on the
work of Hua, who developed a method for the conversion
of silyl lactams to cyclic imines.8
1
1
Scheme 1
Figure 2. The two possible products from in situ silylation of
lactams (observed NOE is indicated by the double-headed arrow).
O-silyllactim ether 12. Furthermore, irradiation of the gem-
dimethyl did not show enhancement of the trimethylsilyl
protons. The generation of an N-silyllactam supports a
(9) (a) Zezza, C. A.; Smith, M. B.; Ross, B. A.; Arhin, A.; Cronin P. L.
E. J. Org. Chem. 1984, 49, 4397-4399. (b) Larcheveque, M.; Debal, A.;
Cuvigny, T. Bull. Soc. Chim. Fr. 1974, 1710-1714. (c) Pearson, W. H.;
Stevens, E. P. J. Org. Chem. 1998, 63, 9812-9827. (d) Tsuge, O.;
Kanemasa, S.; Yamada, T.; Matsuda, K. J. Org. Chem. 1987, 52, 2523-
Several procedures have been developed for the formation
9
of cyclic imines. Hua disclosed a concise, two-step proce-
8
dure for the conversion of lactams to cyclic imines. The
2530. (e) Padwa, A.; Gasdaska, J. R.; Haffmanns, G.; Rebello, H. J. Org.
Chem. 1987, 52, 1027-1035. (f) Hoffman, R. V.; Buntain, G. A. J. Org.
(
7) (a) Jin, H.; Uenishi, J.-I.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc.
986, 108, 5644-5646. (b) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama,
T.; Nozaki, H. Tetrahedron Lett. 1983, 24, 5281-5284
8) Hua, D. H.; Miao, S. W.; Bharathi, S. N.; Katsuhira, T.; Bravo, A.
A. J. Org. Chem. 1990, 55, 3682-3684.
Chem. 1988, 53, 3316-3321.
1
(10) (a) Fisher, M. J.; Overman, L. E. J. Org. Chem. 1990, 55, 1447-
1459. (b) Grieco, P. A.; Kaufman, M. D. J. Org. Chem. 1999, 64, 6041-
6048. (c) Padwa, A.; Coats, S. J.; Semones, M. A. Tetrahedron 1995, 51,
6651-6668.
(
752
Org. Lett., Vol. 3, No. 5, 2001

mechanism involving Peterson-like reaction rather than an
addition-elimination sequence to the O-silyllactim ether 12.
The identical N-silyllactam 11 is also prepared when using
nucleophile increased (i.e., addition of s-BuLi), a significant
decrease in conversion of lactam to imine was observed
(Table 1, entry 3). Attempted addition of t-BuLi gave no
imine formation despite prolonged reaction times (entry 4).
The corresponding butyrolactam derived imines could also
be prepared in similar yields as judged by crude H NMR;
however, the volatility of these products lowered the yields
dramatically.
3
Hua’s method (TMSCl, Et N, reflux).
Having established that the silylation proceeds efficiently,
addition of alkyllithiums to the in situ generated N-silyl-
lactams was investigated. Generation of the N-silyllactam
1
2
11 in Et O, as described above, followed by addition of
n-BuLi at -20 °C gave only recovered starting material even
after warming to 25 °C. Presumably the reactivity of the
alkyllithium is not sufficient to overcome the energy barrier
for addition to a highly hindered lactam carbonyl. It is well
documented that addition of certain additives to organo-
lithium solutions can result in more reactive nucleophiles
by deaggregation of the reagent. After some experimenta-
tion, we found that use of DME as solvent promoted
nucleophilic addition of alkyllithium reagents to the silylated
lactams. Thus, in situ silylation of lactam 8 followed by
addition of MeLi or n-BuLi gave imines 10a and 10b,
respectively, in good crude yields (entries 1 and 2, Table
Direct generation of alkyllithiums from alkyl iodides is
critical for our projected total synthesis of gymnodimine (1)
involving coupling of iodide 3b and lactam 4a. Bailey and
co-workers reported that use of Et O as solvent for halogen-
2
metal exchange affords good yields of alkyllithiums from
alkyl iodides with minimal competing elimination reactions.13
Treatment of the model alkyl iodide 13 with 2.1 equiv of
12
t-BuLi in Et O at -78 °C, followed by addition of the
2
silyllactam 16 generated in situ in DME, gave imine 9a in
good yield (Scheme 2). In a similar manner, treatment of
the lactam 8 under similar conditions gave a 63% yield of
imine 10e.
1
). However, purification by chromatography or distillation
To apply this process to more complex substrates such as
lactam 4b projected for our gymnodimine synthesis, lower
reaction temperatures are preferable to avoid any side
reactions due to the organolithium reagents. Thus, a tem-
perature study of the alkyllithium addition was performed
to determine the lowest reaction temperature that could be
employed without compromising conversion. As shown in
Table 2, a reaction temperature of 0 °C seems optimal for
Table 1. Cyclic Imines Synthesized Using the Single-Pot
Variant of the Hua Synthesis (Scheme 1)
Table 2. Effect of Temperature on Yield of Imine 10b Derived
from n-BuLi Addition to Silyl Lactam 16a
temp (°C)
time (h)
% conversionb
-
20
0
0
5
8
4
8
2
NR
50
90
2
70
a
A solution of 8 was treated with n-BuLi and TMSOTf at -78 °C, and
then n-BuLi was added after the mixture warmed to -20 °C. The solution
was then stirred for the times and at the temperatures indicated. The percent
conversions are estimated on the basis of H NMR (300 MHz) analysis of
b
1
the crude reaction mixtures.
a
Isolated yield obtained after Kugelrohr distillation or flash column
1
chromatography. Crude yields, which were >90% pure ( H NMR), are given
in parantheses. This imine was not isolated. Yield is based on crude H
NMR (300 MHz).
this transformation. Addition of an alkyllithium to the N-silyl
lactam 16 occurs readily at 25 °C (Table 2). At 0 °C, the
reaction was 50% complete after 4 h and 90% complete after
b
1
8
h. However, no reaction occurred at -20 °C even after 8
h.
led to loss of material apparently as a result of the polar
nature of these products and also their volatility. Alkyl-
amines, derived from double addition and previously ob-
tained in related reactions,9 were not observed.
We noted that the R,R-dimethyl cyclic imines synthesized
in this study were remarkably stable, even though imines in
a
14
general are known to undergo hydrolysis quite readily. We
found that imine 10e does not hydrolyze to the ketoamine
Although use of DME as solvent led to addition of primary
alkyllithiums, not surprisingly, as the steric bulk of the
(
13) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404-
5
406.
(
11) Stonehouse, J.; Adell, P.; Keeler, J.; Shaka, A. J. J. Am. Chem.
Soc. 1994, 116, 6037-6038
12) (a) Smith, M. B. Organic Synthesis; McGraw-Hill: New York,
994. (b) Schlosser, M. J. Organomet. Chem. 1967, 8, 9-16.
(14) (a) March, J. AdVanced Organic Chemistry, 4th ed.; Wiley-
Interscience: New York, 1992. (b) For kinetic and mechanistic studies on
Schiff base hydrolysis, see: Cordes, E. H.; Jencks, W. P. J. Am. Chem.
Soc. 1962, 84, 832-837.
(
1
Org. Lett., Vol. 3, No. 5, 2001
753

Scheme 2
Scheme 3
as a result of their masked enamine character. Thus, Nature
may have devised a way to protect an otherwise readily
hydrolyzed functionality that has latent nucleophilic char-
acter.
In summary, we have developed a convenient one-pot
procedure for preparation of cyclic imines from sterically
hindered lactams building on the work of Hua. Use of DME
as solvent was crucial to promote alkyllithium addition to
R,R-dimethylated lactams. Overall, the procedure described
herein allows a direct coupling of alkyliodides and lactams
and is thus applicable to our projected fragment coupling
toward gymnodimine. Currently, we are applying this
procedure to the coupling of tetrahydrofuran 3b and lactam
4a en route to gymnodimine.
after stirring in 1 N HCl/THF (1:1) or 1 N NaOH/ THF (1:
1) solution for 12 h at 25 °C. Likewise, stirring imine 10e
in 6 N HCl/THF (1:1) or 3 N NaOH/EtOH for 6 h at 25 °C
led to no apparent hydrolysis. This is consistent with our
finding that even highly reactive organolithiums must be
deaggregated with DME to promote nucleophilic addition
to N-silyl R,R-dimethyllactams.
The stability of these imines raises questions regarding
their exact role in gymnodimine and related toxins. The
results presented herein and the stability of these imine-
containing toxins suggests that the mechanism of action does
not involve formation of a covalent bond via nucleophilic
addition to the imine. However, as previously observed by
Yasumoto during isolation of gymnodimine, not unexpect-
edly, these imines are in equilibrium with their enamine
tautomers as evidenced by complete incorporation of deu-
terium at the exocyclic methylene carbon after prolonged
Acknowledgment. We thank the NIH (GM 52964-06)
and Zeneca Pharmaceuticals for support of these investiga-
tions. D.R. is an Alfred P. Sloan Fellow and a Camille-Henry
Dreyfus Teacher-Scholar. Mass spectral analyses were
performed at the Texas A&M Center for Characterization
using instruments acquired by generous funding from the
NSF (CHE-8705697) and the TAMU Board of Regents
Research Program.
1a
Supporting Information Available: General experimen-
tal procedures for R-dialkylation and imine synthesis;
exposure to CD
incorporation at the exocyclic methylene carbon of imine
0e after ∼6 h in CD OD at 25 °C to afford 19 presumably
via enamine 18 (Scheme 3). Considering the requirement of
3
OD. We also found complete deuterium
1
13
complete characterization data including H and C NMR
spectra for compounds 7-9, 10b, 10e, and 19. This material
is available free of charge via the Internet at http://pubs.acs.org
1
3
3b
the imine for toxicity, it is tempting to speculate that these
R-quaternary substituted imines serve as latent nucleophiles
OL0155081
754
Org. Lett., Vol. 3, No. 5, 2001