Intramolecular hydroamination of dithioketene acetals: An easy route to cyclic amino acid derivatives

Article abstract of DOI:10.1021/ol102193x

Catalytic intramolecular hydroamination of dithioketene acetals was developed for the synthesis of cyclic amino acid derivatives. Triggered by the addition of a catalytical amount of n-BuLi, the reaction proceeds to give proline and pipecolic acid derivat

Full text of DOI:10.1021/ol102193x

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5174-5177
Intramolecular Hydroamination of
Dithioketene Acetals: An Easy Route To
Cyclic Amino Acid Derivatives
Hai-Chao Xu and Kevin D. Moeller*
Department of Chemistry, Washington UniVersity, St. Louis,
Missouri 63130, United States
moeller@wustl.edu
Received September 13, 2010
ABSTRACT
Catalytic intramolecular hydroamination of dithioketene acetals was developed for the synthesis of cyclic amino acid derivatives. Triggered
by the addition of a catalytical amount of n-BuLi, the reaction proceeds to give proline and pipecolic acid derivatives in excellent yields and
diastereoselectivity.
Recently, we reported that the anodic coupling1 of a
dithioketene acetal and an amine provided an efficient route
to cyclic amino acid derivatives2-6 containing a tetrasub-
Scheme 1
.
Anodic Cyclizations to Form Cyclic Amino Acid
Derivatives
(1) For a recent account of anodic olefin coupling reactions, see: Moeller,
K. D. Synlett 2009, 1208. For a more general review of anodic electro-
chemistry, see: Yoshida, J.; Kataoka, K.; Horcajada, R.; Nagaki, A. Chem.
ReV. 2009, 108, 2265.
(2) For reviews of cyclic amino acid derivatives, see: (a) Park, K. -H.;
Kurth, M. J. Tetrahedron 2002, 58, 8629. (b) Cativiela, C.; Diaz-de-Villegas,
M. D. Tetrahedron: Asymmetry 2000, 11, 645
.
(3) For recent references, see: (a) Mitsunaga, S.; Ohbayashi, T.;
Sugiyama, S.; Saitou, T.; Tadokoro, M.; Satoh, T. Tetrahedron: Asymmetry
2009, 20, 1697. (b) Wang, Y.-G.; Mi, H.; Kano, T.; Maruoka, K. Bioorg.
Med. Chem. Lett. 2009, 19, 3795. (c) Kaname, M.; Yamada, M.; Yoshifuji,
S.; Sashida, H. Chem. Pharm. Bull. 2009, 57, 49. (d) Dickstein, J. S.; Fennie,
M. W.; Norman, A. L.; Paulose, B. J.; Kozlowski, M. C. J. Am. Chem.
Soc. 2008, 130, 15794. (e) Prazeres, V. F. V.; Castedo, L.; Gonzalez-Bello,
C. Eur. J. Org. Chem. 2008, 23, 3991. (f) Simila, S. T. M.; Martin, S. F.
Tetrahedron Lett. 2008, 49, 4501. (g) Undheim, K. Amino Acids 2008, 34,
stituted R carbon atom (Scheme 1).7,8 The reactions are
intriguing because they utilize the cyclization to lower the
(5) For synthetic routes to peptidomimetics containing cyclic amino acid
derivatives: (a) Scott, W. L.; Alsina, J.; Kennedy, J. H.; O’Donnell, M. J.
Org. Lett. 2004, 6, 1629. (b) Palomo, C.; Aizpurua, J. M.; Benito, A.;
Miranda, J. I.; Fratila, R. M.; Matute, C.; Domercq, M.; Gago, F.; Martin-
Santamaria, S.; Linden, A. J. Am. Chem. Soc. 2003, 125, 16243. (c)
Colombo, L.; Di Giacomo, M.; Vinci, V.; Colombo, M.; Manzoni, L.;
Scolastico, C. Tetrahedron 2003, 59, 4501. (d) Dolbeare, K.; Pontoriero,
G. F.; Gupta, S. K.; Mishra, R. K.; Johnson, R. L. J. Med. Chem. 2003, 46,
727. (e) Khalil, E. M.; Pradhan, A.; Ojala, W. H.; Gleason, W. B.; Mishra,
R. K.; Johnson, R. L. J. Med. Chem. 1999, 42, 2977. (f) Aube, J. AdV.
Amino Acid Mimetics and Peptidomimetics 1997, 1, 193. (g) Tong, Y.;
Olczak, J.; Zabrocki, J.; Gershengorn, M. C.; Marshall, G. R.; Moeller,
K. D. Tetrahedron 2000, 56, 9791. (h) Duan, S.; Moeller, K. D. Tetrahedron
2001, 57, 6407. (i) Liu, B.; Brandt, J. D.; Moeller, K. D. Tetrahedron 2003,
357, and references therein
.
(4) For leading references concerning the use of lactam-based peptido-
mimetics containing cyclic amino acid derivatives, see: (a) Cluzeau, J.;
Lubell, W. D. Biopolymers 2005, 80, 98. (b) I-lalab, L.; Gosselin, F.; Lubell,
W. D. Biopolymers 2000, 55, 101. (c) Hanessian, S.; McNaughton-Smith,
G.; Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789. For
additional lead references, see: (d) Polyak, F.; Lubell, W. D. J. Org. Chem.
1998, 63, 5937. (e) Curran, T. P.; Marcaurell, L. A.; O’Sullivan, K. M.
Org. Lett. 1999, 1, 1225. (f) Gosselin, F.; Lubell, W. D. J. Org. Chem.
2000, 65, 2163. (g) Polyak, F.; Lubell, W. D. J. Org. Chem. 2001, 66,
1171. (h) Feng, Z.; Lubell, W. D. J. Org. Chem. 2001, 66, 1181
.
59, 8515.
10.1021/ol102193x  2010 American Chemical Society
Published on Web 10/14/2010

oxidation potential of the substrate to a point lower than that
of the product.9 This avoids overoxidation of the product
and allows for the use of the unprotected amine nucleophile.
The reactions are compatible with the synthesis of both
proline and pipecolic acid derivatives.
Scheme 3. Mechanism for Elimination
While these reactions are excellent for building amino acid
derivatives with tetrasubstituted R carbon atoms, they fail
when the tetrasubstituted R carbon is not required. For
example, while the oxidation of substrate 1a led to an 84%
isolated yield of the corresponding proline derivative, oxida-
tion of substrate 1b led to none of the cyclized product
(Scheme 2).7
Scheme 2.
Limitations to the Anodic Cyclizationsa
derivatives that did not contain tetrasubstituted R carbons.
To this end, an anionic hydroamination looked very attractive
(Scheme 4).11
a RVC ) Reticulated vitreous carbon.
Scheme 4. Proposed Hydroamination
Cyclic voltammetry data suggest both that cyclizations are
very fast and that the difference between these two reactions
does not result from the cyclization step.7 The oxidation
potential for the dithioketene acetal in 1a is Ep/2 ) +1.06 V
vs Ag/AgCl.10 Substrate 1a has a potential of Ep/2 ) +0.60
V vs Ag/AgCl, a 460 mV drop in potential from the isolated
dithioketene acetal indicating a rapid cyclization. For com-
parison, the potential for substrate 1b was measured to be
Ep/2 ) +0.54 V vs Ag/AgCl, again a large drop in potential
that is indicative of a fast cyclization (the dithioketene acetal
in 1b has an Ep/2 ) +1.10 V vs Ag/AgCl).
A possible explanation for the failure of the reaction
originating from 1b is that it leads to an intermediate like 4
(Scheme 3) that suffers from the elimination of a proton to
give a very electron-rich N-substituted dithioketene acetal
(5). Once formed, 5 would undergo immediate oxidation
leading to undesired products. Efforts to avoid this elimina-
tion during the electrolysis met with failure.
Deprotonation of the amine would lead to an anion (6)
that can add across the double bond to lead to a dithiane-
stabilized intermediate (7). In this case, the cyclized inter-
mediate has the opposite polarity relative to intermediate 4
in the oxidative pathway. No elimination to reform a
dithioketene acetal is possible. Reprotonation would then lead
to the product. While the reaction leads to an aldehyde
equivalent at the C-terminus of the amino acid derivative
and would therefore require a subsequent oxidation reaction,
it would allow for utilization of the same substrates used in
the electrolysis reaction thereby taking advantage of the
synthetic strategies already developed for their preparation.
The initial substrates (1a-1h) used in this study were
either the same as the ones reported earlier7 or synthesized
from previously utilized alcohols (Scheme 5).12
With this in mind, we looked for an alternative strategy
for cyclizing substrates like 1b and making amino acid
(6) For examples using electrochemistry to functionalize cyclic amino
acids, see: (a) Beal, L. M.; Liu, B.; Chu, W.; Moeller, K. D. Tetrahedron
2000, 56, 10113. (b) Simpson, J. C.; Ho, C.; Shands, E. F. B.; Gershengorn,
M. C.; Marshall, G. R.; Moeller, K. D. Bioorg. Med. Chem. 2002, 10, 291.
and citations therein.
(7) Xu, H.-C.; Moeller, K. D. Angew. Chem. Intl. Ed. 2010, ASAP.
(8) For related reactions using toluene sulfonamide nucleophiles, see:
(a) Xu, H.-C.; Moeller, K. D. J. Am. Chem. Soc. 2008, 130, 13542. (b) Xu,
H.-C.; Moeller, K. D. J. Am. Chem. Soc. 2010, 132, 2839.
(9) For previous examples, see: (a) Moeller, K. D.; Tinao, L. V. J. Am.
Chem. Soc. 1992, 114, 1033. (b) Reddy, S. H. K.; Chiba, K.; Sun, Y.;
Moeller, K. D. Tetrahedron 2001, 57, 5183. (c) Huang, Y.; Moeller, K. D.
Tetrahedron 2006, 62, 6536.
The first substrates studied were 1a and 1b. The results
were exactly opposite to those obtained with the oxidative
(10) All potentials were measured by cyclic voltammetry using a BAS
100B Electrochemical Analyzer, a carbon working electrode and a Pt wire
auxiliary electrode, a Ag/AgCl reference electrode, a 0.1 M Et4NOTs in
acetonitrile electrolyte solution, a substrate concentration of 0.025 M, and
a sweep rate of 25 mV/s.
(11) (a) Quinet, C.; Sampoux, L.; Marko, I. E. Eur. J. Org. Chem. 2009,
1806. (b) Aggarval, V. K.; Thomas, A.; Schade, S. Tetrahedron 1997, 53,
16213.
(12) For details please see the Supporting Information.
Org. Lett., Vol. 12, No. 22, 2010
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The presence of the benzyl protecting group also improved
the hydroamination originating from 1b. As shown in entry
4, hydroamination of 1d led to a 97% isolated yield of the
product 2d. The cyclization originating from 1d was faster
than the one originating from 1b, proceeding in 10 min
relative to the 30 min required for the cyclization of 1b.
When a methyl group was placed on the allylic carbon of
the dithioketene acetal (entry 5), the hydroamination led to
a 98% yield of cyclic product 2e as a single diastereomer.
The stereochemistry of the product was assigned using a
NOESY experiment as having the dithioacetal trans to the
methyl group in position R2 (Figure 1). When the methyl
Scheme 5. Synthesis of Substrates 1c-h and 1k
cyclizations (Table 1, entries 1 and 2). The cyclization
challenged with the formation of a tetrasubstituted carbon
failed to afford any cyclic product, while the cyclization not
challenged in this manner led to a 92% isolated yield of the
desired product. In this way, the hydroamination reaction
strategy is complementary to the earlier oxidative approach.
A hint as to why the hydroamination reaction originating
from 1a failed was obtained when 1,3-dithiane was isolated
from the reaction. A likely source of the 1,3-dithiane is
deprotonation of the secondary amine in the product 2a
followed by an elimination of the 1,3-dithiane group. The
elimination reaction would relieve the congestion surrounding
the tetrasubstituted carbon and generate a more stable
dithiane anion. If this was the case, then protecting the amine
and removing the NH proton in the cyclized product would
stop this side reaction. For this reason, 1c was synthesized
and exposed to the hydroamination conditions (Table 1, entry
3). The reaction led to a 98% yield of the cyclic product.
Figure 1. Key NOE interactions in compounds 2e and 2f.
group was placed on the carbon bearing the amine (entry
6), a 95% yield of 2f was obtained as a 10:1 ratio of
diastereomers. Since the methyl group in this case is remote
from the forming tetrasubstituted carbon, the stereoselectivity
observed in this reaction must result from the conformation
of the coiling chain. The major product was assigned as
having the two methyl groups trans to each other using a
NOESY experiment (Figure 1). A related cyclization using
a PMB protecting group proceeded in a nearly identical
fashion leading to the product in a high yield with excellent
diastereoselectivity (entry 7).
The first attempt to synthesize pipecolic acid derivatives
using the hydroamination reaction met with failure (Table
1, entry 8). Treatment of substrate 1h with n-BuLi led to
none of the desired product. The reaction led to recovery of
the starting material suggesting that the twin challenges of
six-membered ring and tetrasubstituted carbon formation
stopped the cyclization. Evidence for this suggestion was
gathered using substrates 1i and 1j (Table 1, enties 9 and
10). Substrates 1i and 1j were synthesized as outlined in
Scheme 6.12
Table 1. Hydroamination Reactionsa
Hydroamination of 1i led to a 95% yield of product
indicating that six-membered ring formation proceeded nicely
when not challenged with the formation of a tetrasubstituted
carbon (Table 1, entry 9). The product was formed as a single
diastereomer, and the trans stereochemistry was assigned in
analogy to the five-membered ring cyclization (entry 5) and
early observations.7,8 The cyclization was also compatible
with the use of a benzyl-protected amine (Table 1, entry 10).
Further evidence that steric interactions can interfere with
the hydroamination reaction was obtained when a chiral
auxiliary was used as the amine protecting group (Scheme
7). With the more bulky group on the nitrogen, the reaction
led to none of the desired cyclic product, even though the
reaction would have led to the formation of a five-membered
ring.
a Results listed as isolated yield and diastereomeric ratio (dr) if appliable.
b PMB ) p-methoxybenzyl. c 30% n-BuLi was used.
5176
Org. Lett., Vol. 12, No. 22, 2010

of cyclic proline and pipecolic acid derivatives. The reactions
complement earlier oxidative cyclizations that require the
formation of cyclic amino acids having tetrasubstituted R
carbon atoms. The hydroamination reactions do not have this
restriction. They can also be used to synthesize proline
derivatives with tetrasubstituted R carbon atoms but in these
cases require protection of the amine. The nature of a desired
amino acid derivative will dictate whether the hydroamina-
tion or oxidative cyclization method is most useful. For
amino acid derivatives having a tetrasubstituted R carbon,
the anodic cyclizations are preferred because they do not
require protection of the amine and directly afford a product
having the correct oxidation state for the amino acid. For
amino acid derivatives either not having a substituted R
carbon or requiring an aldehyde at the C-terminus, use of
the hydroamination reaction is preferred.
Scheme 6.
Synthesis of Substrates 1i and 1ja
a DEAD ) diethyl azodicarboxylate; DPPA ) diphenylphosphoryl azide.
Acknowledgment. We thank the National Science Foun-
dation (CHE-0809142) for their generous support of our
work. We also gratefully acknowledge the Washington
University High Resolution NMR facility, partially supported
by NIH grants RR02004, RR05018, and RR07155, and the
Washington University Mass Spectrometry Resource Center,
partially supported by NIHRR00954, for their assistance.
Scheme 7. Evidence of Steric Hindrance
Supporting Information Available: Full experimental
and characterization data, copies of proton and carbon NMR.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, base-catalyzed intramolecular hydroamination
of dithioketene acetals has been developed for the synthesis
OL102193X
Org. Lett., Vol. 12, No. 22, 2010
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