Concise enantioselective construction of a bridged azatricyclic framework via domino semipinacol-Schmidt reaction

Article abstract of DOI:10.1039/c2cc31906c

A TiCl₄-promoted domino semipinacol-Schmidt reaction of oxaspiropentane-azide provides an easy access to bridged azatricyclic ring systems, which possess the azaquaternary center, present in the immunosupressant FR901483 and platelet aggregatio

Full text of DOI:10.1039/c2cc31906c

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COMMUNICATION
Concise enantioselective construction of a bridged azatricyclic framework
via domino semipinacol–Schmidt reactionw
Manohar Puppala, Annamalai Murali and Sundarababu Baskaran*
Received 15th March 2012, Accepted 17th April 2012
DOI: 10.1039/c2cc31906c
A TiCl4-promoted domino semipinacol–Schmidt reaction of
oxaspiropentane-azide provides an easy access to bridged azatri-
cyclic ring systems, which possess the azaquaternary center,
present in the immunosupressant FR901483 and platelet aggre-
gation inhibitor daphlongeranine B.
A number of alkaloids possessing linearly and angularly fused
as well as the bridged aza-polycyclic frameworks are widespread
in nature (Fig. 1).1–3 The stemoamide family of alkaloids possess a
linearly fused aza-polycyclic framework, whereas angularly fused
aza-polycyclic ring systems are widespread in the family of stenine
and stemonamine alkaloids.1 Likewise, structurally diverse bridged
aza-polycyclic ring systems are very common in Daphniphyllum2
and Lycopodium3 alkaloids. In recent years, biologically significant
alkaloids bearing an intriguing bridged azatricyclic core coupled
with the presence of an azaquaternary center have evoked
considerable interest among the synthetic chemists.4,5
Fig. 2 Biologically active alkaloids having a bridged azatricyclic core
coupled with an azaquaternary center.
Several synthetic approaches for the construction of linearly9
as well as angularly fused azatricyclic ring systems containing
an azaquaternary center have been reported, which include a
semipinacol–Schmidt based rearrangement,10a a tandem Prins–
Schmidt cyclization,10b and a nitrone based intramolecular
dipolar cycloaddition,10c however the stereoselective construc-
tion of a bridged azatricyclic system having an azaquaternary
center is synthetically quite demanding and only a few methods
have been devised to achieve this structural motif which includes
sequential formal [4+3] cycloaddition followed by stereocontrolled
enolate chemistry,5a an enoxysilane N-sulfonyliminium ion
cyclization,5b and highly diastereoselective formal [3+3] cyclo-
addition followed by transannular Mannich reaction.5c
The immunosuppressant FR901483 (1) possesses an unusually
novel bridged azatricyclic skeleton formed by the spiro fusion of
the morphan structural motif (2-azabicyclo[3.3.1]nonane) and
pyrrolidine ring (Fig. 2). As a consequence of its potent biological
activity and remarkable structural framework, a number of
approaches towards the synthesis of FR901483 (1) as well as
its bridged azatricyclic core, 5-azatricyclo[6.3.1.01,5]dodecane,
have been reported.6,7 Similarly, daphlongeranine B (2), a
member of the Daphniphyllum alkaloids, is a novel platelet
aggregation inhibitor having an unprecedented bridged hexa-
cyclic framework coupled with an azaquaternary center whose
synthesis has not been realized so far.8
Herein, we report an exceptionally simple and efficient
approach for the construction of a bridged azatricyclic ABC-
core of FR901483 (1) and daphlongeranine B (2) using domino
semipinacol–Schmidt cyclization as a key step.11–13 The retro-
synthetic analysis is shown in Scheme 1. Oxaspiropentane-azide
5, a key intermediate in the domino semipinacol–Schmidt
cyclization reaction, can be readily synthesized using the Trost
spiroannelation14 protocol from the corresponding azido-ketone 6,
Fig. 1 Prevalent aza-structural motifs present in natural products.
Department of Chemistry, Indian Institute of Technology Madras,
Chennai, 600036, India. E-mail: sbhaskar@iitm.ac.in;
Fax: +91-44-22570545; Tel: +91-44-22574218
w Electronic supplementary information (ESI) available: Representa-
tive experimental procedure and characterization of reaction products.
CCDC 840274. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2cc31906c
Scheme 1 Retrosynthetic analysis of a bridged azatricyclic ABC-core
of alkaloids 1 and 2.
c
5778 Chem. Commun., 2012, 48, 5778–5780
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Table 2 TiCl4-promoted domino semipinacol–Schmidt reaction of
oxaspiropentane-azide 5a
Oxaspiro
pentane-azide
5
Azatricyclic
lactam 4c
(% yield)
Azatricyclic
amine 3c
(% yield)
Ratio of 5b
(syn/anti)
Entry
Scheme 2 Synthesis of oxaspiropentane-azide 5. Reagents: (a)
CH2(CO2Me)2, K-OtBu, THF, RT, 92–95%; (b) (CH2OH)2, PTSA,
toluene, reflux; (c) NaCl–DMSO, 145 1C, 62–65% over two steps;
(d) LiAlH4, THF, RT; (e) MsCl, Et3N, CH2Cl2, 0 1C; (f) NaN3, DMF,
65 1C; (g) PPTS, acetone–H2O reflux, 48–50% over four steps;
(h) ylide, KOH, DMSO, 25 1C, 90–94%.
1
1 : 0
which in turn can be prepared in a few steps starting from
cycloalkenone 8 (Scheme 2).
2
1 : 1
Azido-ketone 6a was stereoselectively converted to the
corresponding syn-oxaspiropentane-azide 5a in excellent yield as
a single diastereomer using the Trost spiroannelation reaction.
Under similar reaction conditions, azido-ketone 6b gave a 1 : 1
inseparable mixture of syn- and anti-oxaspiropentane-azide 5b in
90% yield, whereas azido-ketone 6c furnished a 5 : 1 mixture of
syn- and anti-oxaspiropentane-azide 5c, respectively, in 92% yield
(Scheme 2).
3
5 : 1
a
b
Reactions were performed using 2.5 equiv. of TiCl4. Syn- and anti-
When exposed to BF3ÁOEt2, the syn-oxaspiropentane-azide
5a in DCM at À78 1C underwent domino semipinacol–Schmidt
rearrangement to give the corresponding bridged azatricyclic
lactam 4a in 25% yield (Scheme 3).
c
mixture was used in the reaction. Yield is shown in parentheses.
d
Isolated yield based on the syn-isomer.
Scheme 3 Domino semipinacol–Schmidt reaction of syn-oxaspiro-
pentane-azide 5a.
Encouraged by this preliminary observation, this novel
cyclization was carried out with different Lewis acids and
the results obtained are summarized in Table 1.
Fig. 3 ORTEP-diagram of thiolactam derivative (Æ)-10b of the ABC
ring system of daphlongeranine B.
Among the Lewis acids screened, TiCl4 was found to be the
most efficient catalyst to bring about this domino transforma-
tion and furnished the corresponding bridged azatricyclic
ABC-core 4a of immunosuppressant FR901483 (1) in a
stereoselective manner, which on subsequent reduction with
LiAlH4 furnished the known bridged azatricyclic system 3a,
whose mass and NMR spectral data are found to be in
complete agreement with the literature values.7a Similarly,
the mixture of syn- and anti-oxaspiropentane-azide 5b on
exposure to TiCl4 resulted in the corresponding bridged
azatricyclic ABC-core 4b of daphlongeranine B (2) in 80%
yield, based on the syn-isomer (Table 2).15 The structure and
the relative stereochemistry of the cyclized product 4b was
unambiguously confirmed by single crystal X-ray analysis
of the corresponding thiolactam derivative (Æ)-10b (Fig. 3).
Interestingly, this is the first stereoselective approach for
the construction of the bridged azatricyclic ABC-core of
daphlongeranine B (2). Under similar cyclization conditions,
the syn- and anti-mixture of oxaspiropentane-azide 5c afforded
the corresponding bridged azatricyclic lactam 4c in 80% yield
based on the syn-isomer. Reduction of cyclized azatricyclic
lactams 4b and 4c afforded the corresponding bridged azatricyclic
amines 3b and 3c, respectively, in excellent yields (Table 2).
The scope of this novel stereoselective transformation was
further explored in the enantioselective construction of the
bridged azatricyclic ABC-core of FR901483. The asymmetric
Table 1 Domino semipinacol–Schmidt reaction of syn-oxaspiropentane-
azide 5a with different Lewis acidsa
Entry
Lewis acid
Time/h
Yield of 4ab (%)
1
2
3
TMSOTf
EtAlCl2
TiCl4
4
6
4
59
62
78
a
b
Reactions were performed using 2.5 equiv. of Lewis acid. Isolated yield.
c
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Table 3 Enantioselective synthesis of the bridged azatricyclic system
S. no. Michael adduct 9 eea (%) Azatricyclic lactam 4b eea (%)
Notes and references
1 For reviews on aza-polycyclic systems, see: (a) R. A. Pilli,
G. B. Rosso and M. C. F. de Oliveira, Nat. Prod. Rep., 2010,
27, 1908; (b) J. Bonjoch, F. Diaba and B. Bradshaw, Synthesis,
2011, 993.
2 For a recent review on the Daphniphyllum alkaloids: J. Kobayashi
and T. Kubota, Nat. Prod. Rep., 2009, 26, 936.
3 For recent reviews on the Lycopodium alkaloids, see:
(a) Y. Hirasawa, J. Kobayashi and H. Morita, Heterocycles,
2009, 77, 679; (b) M. Kitajima and H. Takayama, Lycopodium
Alkaloids: Isolation and Asymmetric Synthesis, in Topics in Current
1
99
99
99
99
Chemistry, ed. H.-J. Knolker, Springer, Berlin, 2011.
¨
4 (a) H. Li, X. Wang and X. Lei, Angew. Chem., Int. Ed., 2012,
51, 491; (b) X. M. Zhang, Y. Q. Tu, F. M. Zhang, H. Shao and
X. Meng, Angew. Chem., Int. Ed., 2011, 50, 3916.
2
5 (a) A. S. Kende, T. L. Smalley, Jr. and H. Huang, J. Am. Chem.
Soc., 1999, 121, 7431; (b) M. H. Becker, P. Chua, R. Downham,
C. J. Douglas, N. K. Garg, S. Hiebert, S. Jaroch, R. T. Matsuoka,
J. A. Middleton, F. W. Ng and L. E. Overman, J. Am. Chem. Soc.,
2007, 129, 11987; (c) B. B. Liau and M. D. Shair, J. Am. Chem.
Soc., 2010, 132, 9594.
a
b
% ee calculated using chiral HPLC. HPLC analysis was done on
the corresponding thiolactam derivative.
6 For the total synthesis of FR901483, see: (a) B. B. Snider and
H. Lin, J. Am. Chem. Soc., 1999, 121, 7778; (b) G. Scheffler,
H. Seike and E. J. Sorensen, Angew. Chem., Int. Ed., 2000,
39, 4593; (c) M. Ousmer, N. A. Braun and M. A. Ciufolini, Org.
Lett., 2001, 3, 765; (d) J. H. Maeng and R. L. Funk, Org. Lett.,
2001, 3, 1125; (e) C. A. Carson and M. A. Kerr, Org. Lett., 2009,
11, 777.
7 Approaches to the core structure of FR901483, see:
(a) N. Yamazaki, H. Suzuki and C. Kibayashi, J. Org.
Chem., 1997, 62, 8280; (b) D. J. Wardrop and W. Zhang, Org.
Lett., 2001, 3, 2353; (c) J. E. Kropf, I. C. Meigh, M. W. P.
Bebbington and S. M. Weinreb, J. Org. Chem., 2006, 71, 2046;
(d) S. Kaden and H. U. Reissig, Org. Lett., 2006, 8, 4763;
(e) D. B. Gotchev and D. L. Comins, J. Org. Chem., 2006,
71, 9393; (f) S. T. M. Simila and S. F. Martin, J. Org. Chem.,
2007, 72, 5342.
8 For recent reports on the construction of the core structure of
Daphniphyllum alkaloids see: F. Sladojevich, I. N. Michaelides,
B. Darses, J. W. Ward and D. J. Dixon, Org. Lett., 2011, 13, 5132
and references cited therein.
Scheme 4 Plausible mechanism for the domino semipinacol–Schmidt
reaction of syn-oxaspiropentane-azide.
9 For the construction of linearly fused azatricyclic ring systems, see:
(a) R. A. Pilli and M. C. F. de Oliveira, Nat. Prod. Rep., 2000,
17, 117; (b) R. Alibes and M. Figueredo, Eur. J. Org. Chem., 2009,
´
2421; (c) Y. Wang, L. Zhu, Y. Zhang and R. Hong, Angew. Chem.,
Int. Ed., 2011, 50, 2787.
10 For the construction of angularly fused azatricyclic ring
Michael addition of dimethyl malonate with cyclohexenone
and cycloheptenone in the presence of Shibasaki (S)-ALB
catalyst16 furnished the corresponding adducts (À)-9a and
(À)-9c, respectively, in 99% ee. Following a similar sequence
of reactions as shown in Scheme 2, the Michael adducts were
further converted to the azatricyclic lactam (À)-4a and (À)-4c,
respectively, in good yields (Table 3). The azatricyclic lactam
(À)-4a is the enantiomer of the ABC core of FR901483.17
A plausible mechanism for the formation of a bridged
azatricyclic framework from syn-oxaspiropentane-azide 5
via domino semipinacol–Schmidt cyclization is depicted in
Scheme 4.
systems, see: (a) J. Aube and G. L. Milligan, J. Am. Chem.
´
Soc., 1991, 113, 8965; Y. M. Zhao, P. Gu, Y. Q. Tu, C. A.
Fan and Q. Zhang, Org. Lett., 2008, 10, 1763; (b) A. M.
Meyer, C. E. Katz, S. W. Li, D. V. Velde and J. Aube, Org. Lett.,
´
2010, 12, 1244; Z. H. Chen, Y. Q. Tu, S. Y. Zhang and
F. M. Zhang, Org. Lett., 2011, 13, 724; (c) A. C. Flick, M. J. A.
Cabellero, H. I. Lee and A. Padwa, J. Org. Chem., 2010, 75,
1992.
11 For intramolecular Schmidt reaction of azido-epoxides, see:
(a) P. G. Reddy, B. Varghese and S. Baskaran, Org. Lett., 2003,
5, 583; (b) P. G. Reddy and S. Baskaran, J. Org. Chem., 2004,
69, 3093; (c) P. G. Reddy, M. G. Sankar and S. Baskaran,
Tetrahedron Lett., 2005, 46, 4559.
12 S. Lang, A. R. Kennedy, J. A. Murphy and A. H. Payne, Org.
Lett., 2003, 5, 3655.
13 For domino reactions in organic synthesis, see: L. F. Tietze,
G. Brasche and K. Gericke, Domino Reactions in Organic Synthesis,
Wiley-VCH, Weinheim, 2006.
In summary, a novel and general approach for the stereo-
and enantioselective construction of bridged azatricyclic ring
systems having an azaquaternary center has been developed
based on a domino semipinacol–Schmidt reaction. This new
method has provided an elegant entry for the compact synthesis
of the ABC-core of the biologically significant alkaloids such as
FR901483 and daphlongeranine B. Since our approach is
simple and effective, it can be readily implemented in the stereo-
and enantioselective synthesis of natural products possessing
bridged aza-polycyclic frameworks.
14 B. M. Trost and M. J. Bogdanowicz, J. Am. Chem. Soc., 1973,
95, 5321.
15 Due to geometrical constraints, only the syn-isomer is anticipated
to undergo intramolecular Schmidt cyclization.
16 S. Shimizu, K. Ohori, T. Arai, H. Sasai and M. Shibasaki, J. Org.
Chem., 1998, 63, 7547.
17 In the asymmetric Michael addition step, use of Shibasaki (R)-ALB
catalyst,16 in place of (S)-ALB catalyst, would lead to the natural
enantiomer of the ABC core of FR901483.
We thank DST (New Delhi) for financial support and
DST-FIST (New Delhi) for the infrastructure facilities. M. P.
(SRF) thanks CSIR (New Delhi) for research fellowship. Authors
thank Mr V. Ramkumar for single crystal X-ray analysis.
c
5780 Chem. Commun., 2012, 48, 5778–5780
This journal is The Royal Society of Chemistry 2012