reported the first synthesis of ent-(+)-nakadomarin A.4a
Shortly afterward, the Nishida group published the synthesis
of the naturally occurring enantiomer.4b However, these total
syntheses required 38 and 36 linear steps, respectively, from
commercially available materials. Thus, a concise, scaleable
synthesis of (-)-nakadomarin A remains a worthy objective
that would yield additional material for biological studies.
Furthermore, a synthesis amenable to the preparation of
analogues would allow structure-activity information to be
obtained.
2,5-cis-substituted pyrrolidines as a result of the syn-
orientation of substituents in the metallo-stabilized azome-
thine ylides (Figure 2, 13). However, azomethine ylides
Our retrosynthetic analysis of nakadomarin A is outlined
in Scheme 1. A late-stage construction of the macrocyclic
Figure 2. Syn-oriented metallo-stabilized azomethine ylide 13 and
anti-oriented azomethine ylide 14 (M ) transition metal).
Scheme 1. Retrosynthetic Analysis of Nakadomarin A
derived from the diphenyl morpholinone template 10 afford
2,5-trans-substituted pyrrolidines due to the preferential anti-
orientation of substituents with the use of bulky aldehydes
(Figure 2, 14).7
In this event, we observed the formation of the 2,5-trans-
cycloadduct 9 as a single diastereomer from the three-
component condensation reaction of 10-12 (35% yield based
on compound 10, Scheme 2). The intermediate E-azomethine
Scheme 2. Azomethine Ylide [1,3]-Dipolar Cycloaddition
F-ring was envisioned to occur through ring-closing metath-
esis of pentacyclic compound 4. Construction of the ABCDE
core was anticipated to be accessible through an intra-
molecular Heck reaction of the furylorganopalladium inter-
mediate 5. The key ADE precursor 6 was thus predicted from
ring-closing metathesis of spirocyclic diene 7. This species
was targeted via amino acid 8, which we envisioned would
be assembled by a stereoselective three-component [1,3]-
dipolar cycloaddition reaction of 10, 11, and 12 followed
by removal of the chiral template.
ylide 15 undergoes cycloaddition with enone 12 in an endo-
fashion from the stereoface opposite the phenyl moieties.
The stereochemistry of cycloadduct 9 was confirmed by
1
the H NMR NOE enhancements indicated in Figure 3.8
The cycloaddition precursors 10-12 are readily obtained
from commercially available materials. Morpholinone 109
and aldehyde 1110 were prepared in one step as described in
The [1,3]-dipolar cycloaddition of azomethine ylides is
one of the most powerful methods for the formation of
substituted pyrrolidine rings.5 While catalytic enantioselective
variants have recently been reported,6 these methods all yield
(5) For reviews of azomethine ylide [1,3]-dipolar cycloaddition reactions,
see: (a) Synthetic Applications of Dipolar Cycloaddition Chemistry towards
Heterocyclic and Natural Products; Padwa, A., Pearson, W., Ed.; Wiley-
VCH: Weinheim, 2002. (b) Gothelf, K. I. V.; Jørgensen, K. A. Chem. ReV.
1998, 98, 863. (c) Wade, P. A. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Semmelhack, M. F., Eds.; Pergamon Press: Oxford,
1991; Vol. 4, p 1111 and references therein.
(6) (a) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2002, 41, 4236. (b) Longmire, J. M.; Wang, B.;
Zhang, X. J. Am Chem. Soc. 2002, 124, 13400. (c) Chen, C.; Li, X.;
Schreiber, S. L. J. Am. Chem. Soc. 2002, 124, 10174.
(4) Nakadomarin: (a) Nagata, T.; Nakagawa, M.; Nishida, A. J. Am.
Chem. Soc. 2003, 125, 7484. (b) Ono, K.; Nakagawa, M.; Nishida, A.
Angew. Chem., Int. Ed. 2004, 42, 2020. (c) Fu¨rstner, A.; Guth, O.; Duffels,
A.; Seidel, G.; Liebl, M.; Gabor, B.; Mynott, R. Chem. Eur. J. 2001, 7,
4811. (d) Magnus, P.; Fielding, M. R.; Wells, C.; Lynch, V. Tetrahedron
Lett. 2002, 43, 947. (e) Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 1171.
Manzamine A: (f) Winkler, J. D.; Axten, J. M. J. Am. Chem. Soc. 1998,
120, 6425. (g) Martin, S. F.; Humphrey, J. M.; Hillier, M. C. J. Am. Chem.
Soc. 1999, 121, 866. (h) See ref 3a for a list of over 75 references on
synthetic efforts toward the manzamine alkaloids.
(7) (a) Williams, R. M.; Zhai, W.; Aldous, D.; Aldous, S. J. Org. Chem.
1992, 57, 6527. (b) Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc.
2000, 122, 5666. (c) Sebahar, P. R.; Williams, R. M. Heterocycles 2002,
58, 563.
(8) See the Supporting Information for spectral data.
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