Cycloaddition reactions of imines with 3-thiosuccinic anhydrides: Synthesis of the tricyclic core of martinellic acid

Article abstract of DOI:10.1021/ol061473z

Arylthio-substituted succinic anhydrides undergo cycloaddition reactions with imines to produce γ-lactams in high yield and with high diastereoselectivity. The origin of the selectivity is proposed to result from anion-π repulsion in the transition state. The utility of this technique is demonstrated in a synthesis of the carbon framework common to the alkaloids martinellic acid and martinelline in five steps.

Full text of DOI:10.1021/ol061473z

ORGANIC
LETTERS
2006
Vol. 8, No. 18
3999-4002
Cycloaddition Reactions of Imines with
3-Thiosuccinic Anhydrides: Synthesis
of the Tricyclic Core of Martinellic Acid
Pui Yee Ng, Craig E. Masse,† and Jared T. Shaw*
Broad Institute of HarVard and MIT, Chemical Biology Program, 7 Cambridge Center,
Cambridge Massachusetts 02142
shaw@broad.mit.edu
Received June 15, 2006
ABSTRACT
Arylthio-substituted succinic anhydrides undergo cycloaddition reactions with imines to produce
γ
-lactams in high yield and with high
diastereoselectivity. The origin of the selectivity is proposed to result from anion−π repulsion in the transition state. The utility of this technique
is demonstrated in a synthesis of the carbon framework common to the alkaloids martinellic acid and martinelline in five steps.
The diastereoselective synthesis of heterocyclic compounds
is important for the discovery of biologically relevant
compounds in drug discovery, chemical biology, and the
synthesis of natural products.1 γ-Lactams are an important
class of unsaturated heterocycles featured in natural products
and drug candidates.2 The reaction of imines with succinic
anhydrides represents an efficient, one-step synthesis of these
compounds. The isolated3 reports of lactam syntheses using
this reaction suggest that the substrate scope is quite narrow
(Figure 1, eqs 1 and 2). A recent report from our laboratory4
details the importance of electronic factors on the reactivity
of the anhydride component (Figure 1, eq 3). In this report,
we exploit this effect to establish the reaction of imines with
succinic anhydrides as a general method for γ-lactam
synthesis.
Our observations on how substituent effects influence the
rate of the reaction between aryl-substituted anhydrides and
imines prompted us to examine heteroatom-substituted
anhydrides. An inspection of substituted acetophenone acidity
data5 suggests that oxygen, nitrogen, and sulfur substituents
confer various levels of stabilization to the conjugate base
(Figure 2). On the basis of this trend, we hypothesized that
heteroatom-substituted anhydrides would facilitate the imine-
anhydride cycloaddition.
We tested this hypothesis by employing a series of
heteroatom-substituted anhydrides6 in addition reactions with
imine 15. Anhydrides 16-20 were allowed to react with the
N-benzyl imine of ortho-bromobenzaldehyde (15) using
conditions optimized for phenylsuccinic anhydride.4 The
reactions of nitrogen- and oxygen-substituted anhydrides
† Current address: Amgen, Inc., One Kendall Square, Bldg 1000,
Cambridge, MA 02139.
(1) Katritzky, A. R. Chem. ReV. 2004, 104, 2125-2126 and references
therein.
(2) (a) Najera, C.; Yus, M. Tetrahedron: Asymmetry 1999, 10, 2245-
2303. (b) Smith, M. B. Sci. Synth. 2005, 21, 647-711.
(3) (a) Castagnoli, N., Jr., J. Org. Chem. 1969, 34, 3187-3189. (b)
Castagnoli, N., Jr.; Cushman, M. J. Org. Chem. 1971, 36, 3404-3406. (c)
Cushman, M.; Castagnoli, N., Jr., J. Org. Chem. 1972, 37, 1268-1271. (d)
Dallacker, F.; Jouck, W. Chem.-Ztg. 1985, 109, 82-84. (e) Cushman, M.;
Madaj, E. J. J. Org. Chem. 1987, 52, 907-915.
(4) Masse, C. E.; Ng, P. Y.; Fukase, Y.; Sanchez-Rosello, M.; Shaw, J.
T. J. Comb. Chem. 2006, 8, 293-296.
(5) (a) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463. (b) Bordwell,
F. G.; Lynch, T. Y. J. Am. Chem. Soc. 1989, 111, 7558-7562.
10.1021/ol061473z CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/04/2006

anhydride. Iodo-substituted acid 23 was prepared in analogy
to 21 and converted to amide 24, which yielded a crystalline
sample that was analyzed using X-ray crystallography
(Scheme 1). The observed stereochemical outcome is con-
Scheme 1. Synthesis of 24 and Establishment of the Relative
Stereochemistry by X-ray Crystallography
Figure 1. Reactions of imines with succinic anhydrides: increasing
the enolate stabilization facilitates the reaction.
Figure 2. Effect of heteroatom substitution on enolate stability.
sistent with a favorable π-stacking interaction in the transition
state 25 between the two aromatic rings (eq 6).
showed either no conversion or the formation of unidentified
byproducts (eq 4). In contrast, sulfur-substituted anhydride
20 afforded the desired lactam product 21 in high yields and
with the highest diastereoselectivity yet observed in this
reaction (eq 5).
The importance of π-stacking was evaluated by testing
the reactivity of a thioalkyl-substituted succinic anhydride.
N-Butylthio-substituted anhydride 26 was allowed to react
with imine 15 under the standard conditions, and a nearly
identical selectivity was observed for the anti diastereomer.7
This result demonstrates that steric and/or electrostatic
factors, rather than a π-stacking interaction, are mainly
responsible for the selectivity observed in this reaction.
The observed selectivity in the reactions of thio-substituted
anhydrides with imines can be rationalized by invoking a
repulsive interaction between the negative charge of the
The reaction of imines with anhydride 20 preferentially
leads to the anti diastereomer, as found with phenylsuccinic
(6) Anhydride 18 was purchased from Sigma-Aldrich. Anhydrides 16,
17, 19, and 20 were synthesized by reported methods, with minor
modifications (see Supporting Information). 16: (a) Barton, D. H. R.;
Benechie, M.; Khuong-Huu, F., Potier, P.; Reyna-Pinedo, V. Tetrahedron
Lett. 1982, 23, 651-654. 17: (b) Sheppard, G. S. Synlett 1999, 1207-
1210. 19: (c) Box, S. J.; Corbett, D. F. Tetrahedron Lett. 1981, 22, 3293-
3296. (d) D’Silva, C.; Walker, D. A. J. Org. Chem. 1998, 63, 6715-6718.
20: (e) Zienty, F. B.; Vineyard, B. D.; Schleppnik, A. A. J. Org. Chem.
1962, 27, 3140-3146.
(7) The relative configuration of this compound was proven by conversion
to the p-methoxyphenethyl amide and NOE spectroscopy. See Supporting
Information.
4000
Org. Lett., Vol. 8, No. 18, 2006

carboxylate and the aromatic ring of the imine in the
transition state (Figure 3). Although the attractive interactions
Figure 4. Interaction between a Lewis base (ammonia) which has
been calculated to be attractive (A) when the arene is electron
deficient and to be repulsive (B) when the arene is electron rich.
Interaction energy calculated at the MP2/aug-ccpVDZ//B3LYP/6-
311G(d) level.11
To demonstrate the utility of this technique, a cycloaddi-
tion/reduction sequence was used to prepare the tricyclic core
shared by martinellic acid and martinelline in a short
synthetic sequence. These two natural products were isolated
Figure 3. Reaction of 15 with thiobutyl succinic anhydride 26
(eq 7). The stereoselectivity is explained by anion-π repulsion in
transition state 28b.
of cations with π-systems have been extensively studied,8
analogous studies of anion-π interactions are less common.
Deya has described the attraction of anions to electron-
deficient arenes in detail.9 This interaction has also been used
to explain the bonding of aromatic heterocycles in macro-
molecular structures.10 Although one would assume that the
interaction of an anion with an electron-rich arene would
be repulsive, this phenomenon has not been well-docu-
mented. One study of Lewis acids and bases interacting with
arenes concludes that ammonia experiences an attractive
interaction with hexafluoro-benzene and a repulsive interac-
tion with the π-face of benzene (Figure 4).11 Although the
repulsion of the carboxylate and the aryl ring in the transition
state of the imine-anhydride reaction (Figure 3) is consistent
with the observed stereochemistry, further experimentation
will bolster this argument.12 To our knowledge, this is the
first instance in which anion-π repulsion has been invoked
in a transition state to explain the stereochemical outcome
of a reaction.
Table 1. Reaction of Anhydride 20 with Various Imines
entry
R1
R2
yielda
diastereoselectivityb
1
2
3
4
5
NO2
N3
H
H
H
Bn
Bn
80%
85%
62%
58%
76%
>95:5
>95:5
>95:5
>95:5
>95:5
CH2(iPr)
iPr
PMBc
a Yield over two steps from aldehyde starting material. b Determined by
1H NMR spectroscopy. c PMB ) p-methoxybenzyl.
from the tropical plant Martinella iquitosensis.13 These two
compounds share a common tricyclic core and their “de-
ceptively simple”14d structures have attracted much synthetic
effort.14 Commercially available aldehyde 31 was treated with
benzylamine, followed by anhydride 20, to produce lactam
We explored the scope of this reaction with a variety of
substituted imines (Table 1). Regardless of the N-substitution
or the presence or absence of ortho substituents on the
aromatic ring, good yields and excellent diastereoselectivities
were observed for the reactions of imines with anhydride
20.
(13) Witherup, K. M.; Ransom, R. W.; Graham, A. C.; Bernard, A. M.;
Salvatore, M. J.; Lumma, W. C.; Anderson, P. S.; Pitzenberger, S. M.;
Varga, S. L. J. Am. Chem. Soc. 1995, 117, 6682-6685.
(8) Dougherty, D. A. Science 1996, 271, 163-168.
(14) Enantioselective synthesis of martinellic acid: (a) Ma, D.; Xia, C.;
Jiang, J.; Zhang, J. Org. Lett. 2001, 3, 2189-2191. Syntheses of racemic
martinellic acid and martinelline: (b) Snider, B. B.; Ahn, Y.; O’Hare, S.
M. Org. Lett. 2001, 3, 4217-4220. (c) Xia, C.; Heng, L.; Ma, D.
Tetrahedron Lett. 2002, 43, 9405-9409. (d) Powell, D. A.; Batey, R. A.
Org. Lett. 2002, 4, 2913-2916. Syntheses of the tricyclic core: (e) He,
Y.; Moningka, R.; Lovely, C. J. Tetrahedron Lett. 2005, 46, 1251-1254.
(f) Takeda, Y.; Nakabayashi, T.; Shirai, A.; Fukumoto, D.; Kiguchi, T.;
Naito, T. Tetrahedron Lett. 2004, 45, 3481-3484. (g) Hadden, M.;
Nieuwenhuyzen, M.; Osborne, D.; Stevenson, P. J.; Thompson, N.
Tetrahedron Lett. 2001, 42, 6417-6419. (h) Hara, O.; Sugimoto, K.;
Makino, K.; Hamada, Y. Synlett 2004, 1625-1627. (i) Hara, O.; Sugimoto,
K.; Hamada, Y. Tetrahedron 2004, 60, 9381-9390. (j) Hadden, M.;
Nieuwenhuyzen, M.; Osborne, D.; Stevenson, P. J.; Thompson, N.; Walker,
A. D. Tetrahedron 2006, 62, 3977-3984.
(9) (a) Quinonero, D.; Garau, C.; Rotger, C.; Frontera, A.; Ballester, P.;
Costa, A.; Deya, P. M. Angew. Chem., Int. Ed. 2002, 41, 3389-3392. (b)
Garau, C.; Quinonero, D.; Frontera, A.; Ballester, P.; Costa, A.; Deya, P.
M. New J. Chem. 2003, 27, 211-214. (c) Garau, C.; Frontera, A.;
Quinonero, D.; Ballester, P.; Costa, A.; Deya, P. M. Chem. Phys. Lett. 2004,
399, 220-225.
(10) (a) Schottel, B. L.; Chifotides, H. T.; Shatruk, M.; Chouai, A.; Perez,
L. M.; Bacsa, J.; Dunbar, K. R. J. Am. Chem. Soc. 2006, 128, 5895-5912.
(11) Kawahara, S.-i.; Tsuzuki, S.; Uchimaru, T. Chem.-Eur. J. 2005,
11, 4458-4464.
(12) We have attempted a reaction between the benzylimine of pen-
tafluorobenzaldehyde and anhydride 20, which was expected to give the
lactam product with reduced diastereoselectivity. No conversion was
observed, possibly due to reduced basicity of the imine nitrogen.
Org. Lett., Vol. 8, No. 18, 2006
4001

Scheme 2. Imine-Anhydride Cycloaddition and Reductive
Scheme 3. Completion of the Tricyclic Core of Martinellic
Desulfurization/Cyclization
Acid and Martinelline
32 in 61% yield and >95:5 diastereoselectivity (Scheme 2).
Treatment of this compound with Raney nickel effected
reductive cleavage of the arylthio group as well as reduction
of the nitro group to the corresponding aniline, which
underwent partial cyclization with the ester to form tricyclic
lactam 33b. The resultant mixture of cyclized and uncyclized
material was treated with DBU to complete cyclization in
41% yield. In a model study, a similar sequence was used
to convert 30a into 33a, for which we obtained crystals
suitable for X-ray crystallography, confirming the expected
cis ring fusion. Thus, the complete core connectivity of
martinellic acid is produced in two linear steps, the shortest
preparation of this intermediate to date.
Tricyclic core 33b was converted to the complete carbon
framework of martinellic acid and martinelline in three steps
(Scheme 3). Attachment of a Boc group to the amine
produced imide 34. This compound was chemoselectively
reduced to the N,O-acetal using LIHBEt3 and acetic anhy-
dride.15 Formation of an N-acyliminium ion using Sc(OTf)3
and trapping with allyltrimethylsilane were accompanied by
simultaneous loss of the N-Boc group in 73% overall yield.
A single diastereomer of tricyclic lactam 35 was observed,
and the relative configuration was assigned with NOE
spectroscopy.16 Although a related approach using an imi-
nium ion precursor was attempted by Lovely, it was
unsuccessful.14e We attribute the higher conversion and lack
of byproduct formation in our case to the increased reactivity
of the N-acyl iminium ion intermediate.17
In summary, we report a diastereoselective cycloaddition
reaction that is used to produce 1,4,5-trisubstituted γ-lactams.
The two-step sequence is synthetically equivalent to the direct
reaction of succinic anhydride with imines but more efficient
and with higher diastereoselectivity. We have used this
process to synthesize the tricyclic core of martinellic acid
and martinelline, and we are currently executing a short,
enantioselective synthesis of these natural products.
Acknowledgment. This research was supported by the
NIGMS under the aegis of the Center for Methodology and
Library Development (CMLD). J.T.S. thanks Amgen Phar-
maceuticals for financial support. The authors thank Prof.
Stuart Schreiber (Broad Institute, Harvard University, and
the Howard Hughes Medical Institute) for enlightening
discussions and Richard Staples for X-ray crystallographic
analyses.
Supporting Information Available: Experimental pro-
cedures and NMR spectra for all new compounds, as well
as X-ray crystallographic data for 24 and 33a. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL061473Z
(15) (a) Huang, P.-Q.; Wei, B.-G.; Ruan, Y.-P. Synlett 2003, 1663-
1667. (b) Pilli, R. A.; Robello, L. G. Synlett 2005, 2297-2300.
(16) See Supporting Information.
(17) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817-
3856.
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Org. Lett., Vol. 8, No. 18, 2006