Stereoselective Mn-mediated coupling of functionalized iodides and hydrazones: A synthetic entry to the tubulysin γ-amino acids

Article abstract of DOI:10.1021/ol048986v

(Chemical Equation Presented) Synthesis of γ-amino acids, important building blocks in bioorganic and natural product chemistry, is accomplished using a stereoselective carbon-carbon bond construction of the chiral amine. Alkyl iodides and chiral hydrazon

Full text of DOI:10.1021/ol048986v

ORGANIC
LETTERS
2004
Vol. 6, No. 19
3249-3252
Stereoselective Mn-Mediated Coupling of
Functionalized Iodides and Hydrazones:
A Synthetic Entry to the Tubulysin
γ-Amino Acids
Gregory K. Friestad,* Jean-Charles Marie´, and Amy M. Deveau
Department of Chemistry, UniVersity of Vermont, Burlington, Vermont 05405
gregory.friestad@uVm.edu
Received June 1, 2004
ABSTRACT
Synthesis of γ-amino acids, important building blocks in bioorganic and natural product chemistry, is accomplished using a stereoselective
carbon−carbon bond construction of the chiral amine. Alkyl iodides and chiral hydrazones with protected alcohol functionality are coupled
via highly diastereoselective photolytic Mn-mediated addition to the CdN bond, providing access to enantiomerically pure multifunctional
chiral r-branched amines. Reductive N−N bond cleavage and alcohol oxidation provides r-substituted γ-amino acid building blocks for
tubulysin D.
Tubulysins A-F1 were recently isolated in small quantities
(<4 mg/L) from myxobacterial culture broths of Archangium
gephyra and Angiococcus disciformis and were found to be
extraordinarily potent antimitotic agents. Cervical cancer cell
growth inhibition by tubulysin D (IC50 20 pg/mL2) exceeds
that of vinblastine and dolastatin-10. Incubation of mam-
malian cell lines with tubulysin led to disruption of micro-
tubuli, in contrast to the microtubule-stabilizing effects of
epothilone or taxol. The extraordinary potency of tubulysin
D and its interesting tubulin interactions offer an opportunity
to probe the chemical biology of tubulin.3 A total synthesis,
suitable for preparation of unnatural analogues of these
targets, is therefore an attractive goal.4
the carboxylate masked within a thiazole, while the C-ter-
minal residue tubuphenylalanine (B, P ) H) is an R-methyl-
γ-amino acid. These became the initial focus of our synthetic
planning.
Previous methods for syntheses of γ-substituted γ-amino
acids have exploited Wittig-type homologation of natural
R-amino acids,6a addition of enolates to nitroalkenes,6b C1-
(3) Hung, D. T.; Jamison, T. F.; Schreiber, S. L. Chem. Biol. 1996, 3,
623-639. Christian, M. C.; Pluda, J. M.; Ho, P. T. C.; Arbuck, S. G.; Murgo,
A. J.; Sausville, E. A. Semin. Oncol. 1997, 24, 219-240. Hamel, E.
Biopolymers 2002, 66, 142-160.
(4) Synthesis: Ho¨fle, G.; Leibold, T.; Steinmetz, H. German Patent DE
10008089, 2001. Also see: Henkel, B.; Beck, B.; Westner, B.; Mejat, B.;
Do¨mling, A. Tetrahedron Lett. 2003, 44, 8947-8950.
(5) γ-Substituted γ-amino acids have found use in designed mimics of
peptide secondary structures. See: Hanessian, S.; Luo, X.; Schaum, R.;
Michnick, S. J. Am. Chem. Soc. 1998, 120, 8569-8570. Seebach, D.;
Brenner, M.; Rueping, M.; Jaun, B. Chem. Eur. J. 2002, 8, 573-584.
Baldauf, C.; Gu¨nther, R.; Hofmann, H.-J. HelV. Chim. Acta 2003, 86, 2573-
2588. Seebach, D.; Schaeffer, L.; Brenner, M.; Hoyer, D. Angew. Chem.,
Int. Ed. 2003, 42, 776-778. Sanjayan, G. J.; Stewart, A.; Hachisu, S.;
Gonzalez, R.; Watterson, M. P.; Fleet, G. W. J. Tetrahedron Lett. 2003,
44, 5847-5851. Watterson, M. P.; Edwards, A. A.; Leach, J. A.; Smith,
M. D.; Ichihara, O.; Fleet, G. W. J. Tetrahedron Lett. 2003, 44, 5853-
5857.
Identifiable within tubulysin D are two unusual amino acid
subunits unique to the tubulysin family, both of which are
R,γ-disubstituted γ-amino acids.5 Tubuvaline (Figure 1) is
comprised of an R-hydroxy-γ-amino acid (A, P ) H) with
(1) Sasse, F.; Steinmetz, H.; Heil, J.; Ho¨fle, G.; Reichenbach, H. J.
Antibiot. 2000, 53, 879-885. Ho¨fle, G.; Glaser, N.; Leibold, T.; Karama,
U.; Sasse, F.; Steinmetz, H. Pure Appl. Chem. 2003, 75, 167-178.
(2) Data for human cervical carcinoma DSM ACC 158 (ref 1).
10.1021/ol048986v CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/18/2004

Figure 2. (a) Asymmetric radical addition approach to chiral
amines using chiral N-acylhydrazones. (b) Photolysis of Mn2(CO)10
producing alkyl radicals from iodides. (c) Mn-mediated coupling
of a difunctional iodide and hydrazone.9
Figure 1. Retrosynthetic analysis of tubulysins A-F, antimitotic
agents with picomolar potency, revealing R,γ-disubstituted γ-amino
acids as key subgoals.
known to generate alkyl radicals from alkyl halides (Figure
2b),11 and permits coupling of N-acylhydrazones and primary
iodides bearing additional halide functionality (e.g., Figure
2c).9a The functional group tolerance and nonbasic conditions
of this coupling method suggested its potential utility in
synthesis of multifunctional amines such as the tubulysin
γ-amino acids. Our previous studies had not exploited
oxygen-containing iodides or hydrazones, so preparation of
A and B would constitute an important test of the synthetic
versatility of the Mn-mediated coupling reactions.
carboxylate modification of glutamic acid,6c allyl addition
to sulfinimines,6d reaction of enolates with aziridines,6e and
reductive coupling of nitrones with R,â-unsaturated carbonyl
compounds.6f
We envisioned a new, general, and versatile synthesis of
γ-amino acids involving a C-C bond construction approach
to installation of the chiral amine moiety. This plan would
obviate the limitations of naturally occurring R-amino acid
precursors, facilitating preparation of γ-amino acids bearing
unusual functionality or substitution patterns. For versatility,
the ideal method would be applicable to strategic construction
of either the Câ-Cγ or Cγ-Cδ bonds (Figure 1) as desired,
depending on circumstances such as the availability or
reactivity of the proposed precursors, and would be inde-
pendent of the function or configuration of substituents at
the R-position. Here we report application of such strategic
bond constructions for preparation of the γ-amino acid
subunits of tubulysins.
Application of the Mn-mediated coupling to the γ-amino
acid progenitor of tubuvaline required enantiocontrolled
preparation of chiral â-alkoxyhydrazone 4 (Scheme 1).
(7) Reviews of radical additions to imines and related acceptors: (a)
Friestad, G. K. Tetrahedron 2001, 57, 5461-5496. (b) Fallis, A. G.; Brinza,
I. M. Tetrahedron 1997, 53, 17543-17594.
(8) (a) Ueda, M.; Miyabe, H.; Nishimura, A.; Sugino, H.; Naito, T.
Tetrahedron: Asymmetry 2003, 14, 2857-2859. Ueda, M.; Miyabe, H.;
Teramachi, M.; Miyata, O.; Naito, T. J. Chem. Soc., Chem. Commun. 2003,
426-427. Miyabe, H.; Fujii, K.; Naito, T. Org. Biomol. Chem. 2003, 1,
381-390. (b) Bertrand, M.; Feray, L.; Gastaldi, S. Comptes Rend. Acad.
Sci. Paris, Chim. 2002, 5, 623-638. Bertrand, M. P.; Coantic, S.; Feray,
L.; Nouguier, R.; Perfetti, P. Tetrahedron 2000, 56, 3951-3961. (c)
Yamada, K.; Yamamoto, Y.; Maekawa, M.; Tomioka, K. J. Org. Chem.
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2003, 5, 1797-1799. Yamada, K.; Fujihara, H.; Yamamoto, Y.; Miwa, Y.;
Taga, T.; Tomioka, K. Org. Lett. 2002, 4, 3509-3511. (d) Ferna´ndez, M.;
Alonso, R. Org. Lett. 2003, 5, 2461-2464. Torrente, S.; Alonso, R. Org.
Lett. 2001, 3, 1985-1987. (e) Masson, G.; Py, S.; Valle´e, Y. Angew. Chem.,
Int. Ed. 2002, 41, 1772-1775. (f) Alves, M. J.; Fortes, G.; Guimara˜es, E.;
Lemos, A. Synlett 2003, 1403-1406. (g) Liu, X.; Zhu, S.; Wang, S.
Synthesis 2004, 683-691. (h) Singh, N.; Anand, R. D.; Trehan, S.
Tetrahedron Lett. 2004, 45, 2911-2913.
As part of a program to develop asymmetric C-C bond
construction approaches to chiral amines, we have developed
stereoselective intermolecular additions of alkyl radicals to
CdN bonds7,8 using chiral N-acylhydrazones9,10 (Figure 2a).
One approach exploits photolysis of the Mn-Mn bond,
(6) (a) Reetz, M. T.; Griebenow, N.; Goddard, R. J. Chem. Soc., Chem.
Commun. 1995, 1605-1606. Hanessian, S.; Schaum, R. Tetrahedron Lett.
1997, 38, 163-167. Smrcina, M.; Majer, P.; Majerova, E.; Guerassina, T.
A.; Eisenstat, M. A. Tetrahedron 1997, 53, 12867-12874. Loukas, V.;
Noula, C.; Kokotos, G. J. Peptide Sci. 2003, 9, 312-319. (b) Brenner, M.;
Seebach, D. HelV. Chim. Acta 1999, 82, 2365-2379. Enders, D.; Teschner,
P.; Raabe, G.; Runsink, J. Eur. J. Org. Chem. 2001, 4463-4477. (c) El
Marini, A.; Roumestant, M. L.; Viallefont, P.; Razafindramboa, D.; Bonato,
M.; Follett, M. Synthesis 1992, 11, 1104-1108. Dexter, C. S.; Jackson, R.
F. W.; Elliott, J. J. Org. Chem. 1999, 64, 7579-7585. (d) Hua, D. H.;
Miao, S. W.; Chen, J. S.; Iguchi, S. J. Org. Chem. 1991, 56, 4-6. (e)
Vicario, J. L.; Bad´ıa, D.; Carrillo, L. J. Org. Chem. 2001, 66, 5801-5807.
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150-154. Riber, D.; Skrydstrup, T. Org. Lett. 2003, 5, 229-231. Masson,
G.; Zeghida, W.; Cividino, P.; Py, S.; Vallee, Y. Synlett 2003, 1527-1529.
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9923. (b) Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2000, 123, 8329-
8330.
(10) For chiral Lewis acid control in radical addition to CdN bonds,
see: (a) Friestad, G. K.; Shen, Y.; Ruggles, E. L. Angew. Chem., Int. Ed.
2003, 42, 5061-5063. (b) Halland, N.; Jørgensen, K. A. J. Chem. Soc.,
Perkin Trans. 1 2001, 1290-1295. (c) Miyabe, H.; Ushiro, C.; Ueda, M.;
Yamakawa, K.; Naito, T. J. Org. Chem. 2000, 65, 176-185.
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Scheme 1
Scheme 2
Known alcohol 1, produced by asymmetric glycolate ally-
Our attention turned to the functional group manipulations
required to access the tubulysin building blocks (Scheme 3).
lation according to the procedure of Crimmins,12 was con-
verted to the corresponding TBS ether. The terminal alkene
was then oxidized in two steps to afford the corresponding
aldehyde 2.13 Condensation with N-amino oxazolidinone
(S)-314 provided hydrazone 4.
Scheme 3
With the required â-alkoxyhydrazone in hand, we pro-
ceeded to the key Mn-mediated addition reaction (Scheme
1). Upon photolysis (300 nm, Rayonet) in the presence of
InCl3 (2.2 equiv) and Mn2(CO)10 (1 equiv) in CH2Cl2,
hydrazone 4 underwent addition of isopropyl iodide (5 equiv)
providing adduct 5 in 77% isolated yield as a single
diastereomer (1H NMR).15 The configuration was determined
after a subsequent step (vide infra). No byproduct from elimi-
nation of the â-benzyloxy substituent was detected, a fact
that underscores the nonbasic character of these reactions.
Preparation of the iodide and hydrazone components for
tubuphenylalanine began with commercial (R)-(-)-3-bromo-
2-methyl-1-propanol (6, Scheme 2) and phenylacetaldehyde.
Silylation of the primary alcohol and Finkelstein reaction
afforded known iodide 716 in 91% yield after distillation.
Phenylacetaldehyde was condensed with N-aminooxazoli-
dinone (R)-314 to give N-acylhydrazone 8. Merging the
components in the key coupling reaction, Mn-mediated
addition of iodide 7 (5 equiv) to hydrazone 8 provided 917
in 56% yield.
We recently disclosed a method for facile trifluoroacetyl-
activated reductive N-N bond cleavage of hydrazines by
SmI2.18 This method results in an amine bearing a protecting
group suitable for further synthetic manipulations. Treating
5 with TFAA and DMAP in pyridine gave the corresponding
trifluoroacetyl derivative,19 upon which the N-N bond
cleavage with SmI2 proceeded smoothly to provide differ-
entially protected amino diol 10. By the same transforma-
tions, adduct 9 was converted to TFA-protected tubuphenyl-
alanine amino alcohol 11 in good overall yield.20
Reinforcing the substantial precedent on the mode of
stereocontrol by chiral N-acylhydrazones,9 the configuration
(17) Configuration of 9 was assigned by analogy with precedents resting
on crystallography and chemical correlation. See ref 9.
(12) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett. 2000, 2,
2165-2167.
(18) Ding, H.; Friestad, G. K. Org. Lett. 2004, 6, 637-640.
(13) Ozonolysis was also effective, but the two-step dihydroxylation and
periodate cleavage gave cleaner and more practical conversion to 2.
(14) Shen, Y.; Friestad, G. K. J. Org. Chem. 2002, 67, 6236-6239.
(15) Small amount (7%) of unreacted hydrazone was recovered in this
experiment. Aged samples of Mn2(CO)10 gave lower yields (ca. 50-60%)
due to incomplete conversion in these reactions, but the mass balance was
still >80%.
(19) Acylation of tubuphenylalanine precursor 9 as described previously
(n-BuLi, TFAA) resulted in 69% yield. Similar results were found with
tubuvaline precursor 5 (77% yield).
(20) (a) Alternatively, sequential treatment with BH3‚THF and Boc2O
converted 9 to the corresponding Boc-amino alcohol in 74% yield. (b) For
examples of N-N cleavage with borane, see refs 9a and 10a. See also:
Feuer, H.; Brown, F., Jr. J. Org. Chem. 1970, 35, 1468. Enders, D.;
Lochtman, R.; Meiers, M.; Muller, S.; Lazny, R. Synlett 1998, 1182.
(16) Nakamura, Y.; Mori, K. Eur. J. Org. Chem. 2000, 2745-2753.
Org. Lett., Vol. 6, No. 19, 2004
3251

and enantiomeric purity (>96% ee) of 10 were established
by 1H NMR analysis using Boc-phenylglycine amide deriva-
tives according to the method of Riguera.21
the scope of our previous Mn-mediated coupling studies,9a
this work suggests potential access to a broad range of
γ-substituted γ-amino acids.
Finally, 10 and 11 were oxidized to γ-amino acids A and
B (Figure 1, P ) TFA), respectively, in a two-step process
with excellent overall yield. Removal of the TBS protection
(TBAF, THF) and oxidation of the resulting primary alcohols
with PhI(OAc)2 in the presence of catalytic TEMPO22
(2,2,6,6-tetramethyl-1-piperidinyloxy) afforded γ-amino acids
A (96%, two steps) and B (81%, two steps).
Acknowledgment. We thank NIH (NIGMS, GM-67187-
01) for generous support of this work.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 1, 2, 4, 5,
8-11, A, and B. This material is available free of charge
via the Internet at http://pubs.acs.org.
In conclusion, a new C-C bond construction approach to
synthesis of R,γ-disubstituted γ-amino acids has been
developed, providing access to enantiomerically pure build-
ing blocks for total synthesis of tubulysins. The key step for
each is a highly stereoselective Mn-mediated coupling of
an alkyl iodide and a hydrazone, methodology extended by
this study to incorporate oxygen-containing functionality in
either the iodide or hydrazone precursor. Taken together with
OL048986V
(21) (a) Seco, J. M.; Quin˜oa´, E.; Riguera, R. J. Org. Chem. 1999, 64,
4669-4675. (b) The amides were prepared via DCC-mediated coupling of
the free amines. For spectra used in configuration analysis, see Supporting
Information.
(22) For previous applications of TEMPO-catalyzed oxidation to R-alkoxy-
acids with remote secondary amide functionality, see: Vescovi, A.; Knoll,
A.; Koert, U. Org. Biomol. Chem. 2003, 2983-2997. Yeung, B. K. S.;
Hill, D. C.; Janicka, M.; Petillo, P. A. Org. Lett. 2000, 2, 1279-1282.
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