DYKAT of vinyl aziridines: Total synthesis of (+)-pseudodistomin D

Article abstract of DOI:10.1021/ol047513l

(Chemical Equation Presented) A concise total synthesis of (+)-pseudodistomin D was developed. The absolute stereochemistry was established through a dynamic kinetic asymmetric cycloaddition of an isocyanate to a vinyl aziridine. The piperidine core was c

Full text of DOI:10.1021/ol047513l

ORGANIC
LETTERS
2005
Vol. 7, No. 5
823-826
DYKAT of Vinyl Aziridines: Total
Synthesis of ( )-Pseudodistomin D
+
Barry M. Trost* and Daniel R. Fandrick
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@stanford.edu
Received December 3, 2004
ABSTRACT
A concise total synthesis of (+)-pseudodistomin D was developed. The absolute stereochemistry was established through a dynamic kinetic
asymmetric cycloaddition of an isocyanate to a vinyl aziridine. The piperidine core was constructed through a silver(I)-catalyzed hydroamination
of an alkyne and subsequent diastereo- and regioselective reduction.
The synthesis of natural products constitutes an important
arena in organic chemistry by not only providing sufficient
quantities of biologically active materials but also by
developing useful methodologies. Such efforts have focused
on the pseudodistomin alkaloids (Scheme 1). Pseudo-
antagonistic activity and potent cytotoxicity against both
murine leukemia and human epidermoid carcinoma KB
cells.1
Progress toward the synthesis of the pseudodistomins has
been limited. Only pseudodistomins A-C and F have been
synthesized,2,4,5 although several racemic and asymmetric
syntheses of the substituted piperidine core have been
Scheme 1. Pseudodistomins
(1) (a) Ishibashi, M.; Ohizumi, Y.; Sasaki, T.; Nakamura, H.; Hirata,
Y.; Kodayashi, J. J. Org. Chem. 1987, 52, 450-453. (b) Kobayashi, J.;
Naitoh, K.; Doi, Y.; Deki, K.; Ishibashi, M. J. Org. Chem. 1995, 60, 6941-
6945.
(2) (a) Kiguchi, T.; Yuumoto, Y.; Ninomiya, I.; Naito, T.; Deki, K.;
Ishibashi, M.; Kobayashi, J. Tetrahedron Lett. 1992, 33, 7389-7390. (b)
Ishibashi, M.; Deki, K.; Kobayashi, J. J. Nat. Prod. 1995, 58, 804-806.
(c) Kiguchi, T.; Yuumoto, Y.; Ninomiya, I.; Naito, T. Heterocycles 1996,
42, 509-512.
(3) Freyer, A. J.; Patil, A. D.; Killmer, L.; Troupe, N.; Mentzer, M.;
Carte, B.; Faucette, L.; Johnson, R. K. J. Nat. Prod. 1997, 60, 986-990.
(4) (a) Glanzer, B. I.; Gyorgydeak, Z.; Bernet, B.; Vasella, A. HelV. Chim.
Acta 1991, 74, 343-369. (b) Naito, T.; Yuumoto, Y.; Ninomiya, I.; Kiguchi,
T. Tetrahedron Lett. 1992, 33, 4033-4036. (c) Utsunomiya, I.; Ogawa,
M.; Natsume, M. Heterocycles 1992, 33, 349-356. (d) Knapp, S.; Hale, J.
J. J. Org. Chem. 1993, 58, 2650-2651. (e) Naito, T.; Yuumoto, Y.; Kiguchi,
T.; Ninomiya, I. J. Chem. Soc., Perkin Trans. 1 1996, 3, 281-288. (f)
Kiguchi, T.; Ikai, M.; Shirakawa, M.; Fujimoto, K.; Ninomiya, I.; Naito,
T. J. Chem. Soc., Perkin Trans. 1 1998, 893-899. (g) Kiguchi, T.; Okazaki,
M.; Naito, T. Heterocycles 1999, 51, 2711-2722. (h) Ma, D.; Sun, H.
Tetrahedron Lett. 1999, 40, 3609-3612. (i) Langlois, N. Org. Lett. 2002,
4, 185-187.
distomins A-C were isolated from the Okinawan tunicate
Pseudodistomina kanoko by Kobayashi et al.1 The structure
of pseudodistomins A and B were subsequently revised by
degradation and synthetic studies.2 Later, the extract of the
ascidian Pseudodistomina megalarVa provided pseudo-
distomins B-F.3 These alkaloids exhibit calmodulin-
(5) (a) Doi, Y.; Ishibashi, M.; Kobayashi, J. Tetrahedron 1996, 52, 4573-
4580. (b) Kiguchi, T.; Yuumoto, Y.; Ninomiya, I.; Naito, T. Chem. Pharm.
Bull. 1997, 45, 1212-1215. (c) Ma, D.; Sun, H. J. Org. Chem. 2000, 65,
6009-6016.
10.1021/ol047513l CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/01/2005

reported.4 Pseudodistomin D, which contains a unique
piperidine core from the synthesized pseudodistomins, has
not been synthesized, although its piperidine core has been
constructed in several nonselective approaches4f,g and one
route from D-glucosamine.4a Herein we report the first total
synthesis of (+)-pseudodistomin D 1.
Scheme 3. Synthesis of the Head Portion 7a
Recently, we reported the dynamic kinetic asymmetric
cycloaddition of isocyanates to vinyl aziridines as an efficient
process for the construction of chiral diamines.6 We therefore
began our studies toward the synthesis of pseudodistomin
D where all other stereocenters would be directed by the
stereocenter created through our DYKAT methodology
(Scheme 2). We envisioned the piperidine core to be
Scheme 2. Retrosynthesis
a DMB ) 2,4-dimethoxybenzyl.
(2,4-dimethoxybenzylamino)-3-butene in 92% yield for two
steps. Initial efforts to synthesize the BOC-protected diamines
6 from the bis-DMB-protected amines focused on first
installing the BOC group prior to DMB deprotection.
Unfortunately, standard conditions for DMB deprotection
with DDQ afforded irreproducible results with only moderate
yields. Removal of the DMB groups under acidic conditions
using TsOH8 and subsequent BOC protection of the primary
amines in situ with excess Et3N9 afforded the requisite BOC-
protected amines 6 in a reasonable 56% yield after recrys-
tallization. Directed epoxidation with buffered mCPBA of
olefin 6 afforded the desired diamino epoxide 7 in 84% yield
and 4:1 dr.10 The diastereomers can be tentatively assigned
by correlation of the proton chemical shifts of the threo and
erythro products to analogous BOC-protected amino
epoxides10a and confirmed by the completion of the total
synthesis.
constructed through a novel catalytic diastereo- and regio-
selective reductive intramolecular hydroamination of diamino
alkyne 2. The requisite diamine 2 could be furnished through
an aluminum-mediated acetylene addition to a terminal
epoxide, which in turn could be constructed through a
directed expoxidation. Finally, the absolute stereochemistry
could be established through a dynamic kinetic asymmetric
transformation (DYKAT) of vinyl aziridine 4.
The synthesis of the head portion 7 was performed as
illustrated in Scheme 3. Standard bis-substitution of com-
mercially available ethyl 2,3-dibromopropionate 5 with 2,4-
dimethoxybenzylamine followed by DIBAL-H reduction to
the corresponding aldehyde and Wittig olefination furnished
the protected vinyl aziridine 4 in high yield. The subsequent
dynamic kinetic asymmetric cycloaddition of 2,4-dimethoxy-
benzyl isocyanate to the vinyl aziridine 4 provided DMB-
protected vinyl imidazolidinone 3 in 94% ee and 88% yield.
Following our previously reported procedure for the synthesis
of diamines from imidazolidinones,6 LAH reduction of the
imidazolidinone 3 provided the sensitive imidazolidine in
nearly quantative yield. Subsequent hydrolysis with hydroxyl-
amine under weakly acidic conditions furnished (R)-1,2-bis-
The synthesis of the tail portion 11 commences with the
coupling of alkyne 8, readily prepared in two operations from
3-heptyn-1-ol according to published procedures11 and known
vinyl iodide 9 (Scheme 4).12 The hydro-zirconated adduct
of alkyne 8 was directly cross-coupled with vinyl iodide 9
under a modified Negishi protocol13 to furnish the THP-
Scheme 4. Synthesis of the Tail Portion 11
(6) Trost, B. M.; Fandrick, D. R. J. Am. Chem. Soc. 2003, 125, 11836-
11837.
(7) (a) Funaki, I.; Bell, R. P. L.; Thijs, L.; Zwanenburg, B. Tetrahedron
1996, 52, 12253-12274. (b) Alezra, V.; Bonin, M.; Micouin, L.; Policar,
C.; Husson, H.-P. Eur. J. Org. Chem. 2001, 2589-2594.
824
Org. Lett., Vol. 7, No. 5, 2005

protected adduct of diene 10. Standard THP deprotection of
the cross-coupling product afford dienyl alcohol 10 in 82%
yield for both steps. Moffatt-Swern oxidation of alcohol
10 and subsequent Ohira-Bestmann modification of the
Seyferth-Gilbert reaction14,15 furnished alkyne 11 in excel-
lent yield.
The addition of the dimethylaluminum alkyne adduct of
alkyne 11 to epoxide 7 efficiently furnished the complete
carbon skeleton of pseudodistomin D (Scheme 5). Treatment
AuCl3-HCl catalyst resulted in complete decomposition
within 10 min at 60 °C.19 To minimize the competing
decomposition, optimization studies were focused on utilizing
less reactive hydroamination conditions. Hydroamination
with 10% silver tosylate in acetonitrile at 40 °C for 2 h
proved to be optimal. The hydroamination reaction was
immediately quenched, by reduction of the Ag(I) catalyst,
and the intermediate imine reduced in situ by sodium cyano-
borohydride to provide piperidine 13 in a reasonable 52%
yield for the overall two-step BOC deprotection and reductive
hydroamination sequence. The reductive hydroamination
proceeded with no detectable diastereomer or pyrrolidine
byproducts.20 Standard and quantitative silyl deprotection
Scheme 5. Synthesis of Pseudodistomin D
provided pseudodistomin D [R]25 ) +6° (c 0.2, MeOH)
D
(lit.3 [R]25D ) +5° (c 0.26, MeOH)). The 1H and 13C NMR
spectra correlate with the listed chemical shifts and coupling
constants reported for the isolated material.3
The piperidine core of pseudodistomin D, where all of
the substituents can occupy equatorial positions in a chair
conformation, presented a unique opportunity to exploit a
reductive hydroamination strategy. By utilizing the free
diamines in compound 2, the hydroamination proceeded in
a significantly increased rate over related 6-exo-dig cycliza-
tions18,19 and circumvented the need for another protecting
group. There are several explanations that can be put forward
to rationalize the selective formation of the piperidine
product. One rationalization is that the hydroamination of
alkyne 2 proceeds through a kinetic 5-exo-dig cyclization
to furnish imine 14, which is in a rapid equilibrium with
imine 16 (Scheme 6). Due to the significant difference in
of compound 12 with TBSOTf and 2,6-lutidine16 and
subsequent hydrolysis of the resulting TBS carbamates in
one pot cleanly deprotected the BOC groups while simul-
taneously protecting the alcohol in near quantitative yield
to provide silyl ether 2. Of the plethora of transition metal
catalysts for hydroamination of alkynes,17 we focused on
silver and gold catalysis due to their increased tolerance of
Lewis basic functionalities over other systems.18 Initial
hydroamination experiments with 10% AgOTs at 60 °C in
acetonitrile for 1 h proved to be problematic due to
competitive decomposition of the imine intermediate by the
catalyst. Furthermore, hydroamination with the more reactive
Scheme 6. Reductive Hydroamination of Alkyne 2
(8) Chern, C.-Y.; Huang, Y.-P.; Kan, W. M. Tetrahedron Lett. 2003,
44, 1039-1041.
(9) Kabalka, G. W.; Li, N.-S.; Pace, R. D. Synth. Commun. 1995, 25,
2135-2143.
(10) (a) Luly, J. R.; Dellaria, J. F.; Plattner, J. J.; Soderquist, J. L.; Yi,
N. J. Org. Chem. 1987, 52, 1487-1492. (b) Romeo, S.; Rich, D. H.
Tetrahedron Lett. 1993, 34, 7187-7190. (c) Romeo, S.; Rich, D. H.
Tetrahedron Lett. 1994, 35, 4939-4942.
(11) (a) Ma, D.; Lu, X. Tetrahedron 1990, 46, 6319-6330. (b) Huang,
H.; Forsyth, C. J. J. Org. Chem. 1997, 62, 8595-8599.
(12) Chen, M.-J.; Narkunan, K.; Liu, R.-S. J. Org. Chem. 1999, 64,
8311-8318.
(13) Negishi, E.; Takahashi, T.; Baba, S.; Van Horn, D. E.; Okukado,
N. J. Am. Chem. Soc. 1987, 109, 2393-2401.
reduction rates of an sp2 to a sp3 carbon between a 5 and
six-membered rings,21 the reduction of imine 16 is favored.22
Therefore, a Curtin-Hammett situation is created wherein
the reduction specifically yields the desired piperidine 13.
(19) 1H NMR experiment with 10% AuCl3-HCl and 2 in CD3CN
afforded complete decomposition in 10 min at 60 °C. No competitive
decomposition was observed under analogous hydroamination conditions
with undec-5-ynylamine.
(14) (a) Ohiro, S. Synth. Commun. 1989, 19, 561-564. (b) Muller, S.;
Liepold, B.; Roth, B.; Bestmann, H. J. Synlett 1996, 521-522.
(15) Ohira-Bestmann reagent ) dimethyl(acetyldiazomethyl)phos-
phonate.
(20) Using a more standard strategy in which the appropriate keto-
diamine undergoes an intramolecular reductive amination, the pyrrolidine
and/or piperidine products were obtained in modest yields. Given the
additional steps necessary to furnish the keto-diamine and the modest yield
of the subsequent reductive amination, this strategy was disfavored over
the reductive hydroamination reported herein. By both chromatographic and
spectroscopic methods, the pyrrolidine and piperidine are easily distinguish-
able.
(21) Brown, H. C.; Ichikawa, K. Tetrahedron 1957, 1, 221-230.
(22) Examples of six-membered imine reduction occurring selectively
over five-membered imine reduction in an approach toward thiostrepton
are: (a) Higashibayashi, S.; Hashimoto, K.; Nakata, M. Tetrahedron Lett.
2002, 43, 105-110. (b) Nicolaou, K. C.; Nevalainen, M.; Safina, B. S.;
Zak, M.; Bulat, S. Angew. Chem., Int. Ed. 2002, 41, 1941-1945.
(16) Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870-876.
(17) (a) Muller, T. E.; Beller, M. Chem. ReV. 1998, 98, 675-703. (b)
Muller, T. E.; Pleier, A.-K. J. Chem. Soc., Dalton Trans. 1999, 583-587.
(c) Su, R. Q.; Muller, T. E. Tetrahedron 2001, 57, 6027-6033. (d) Beller,
M.; Breindl, C.; Eichberger, M.; Hartung, C. G.; Seayad, J.; Thiel, O. R.;
Tillack, A.; Trauthwein, H. Synlett 2002, 10, 1579-1594. (e) Pohlki, F.;
Doye, S. Chem. Soc. ReV. 2003, 32, 104-114.
(18) (a) Fukuda, Y.; Utimoto, K. Synthesis 1991, 975-978. (b) Muller,
T. E.; Grosche, M.; Herdtweck, E.; Pleier, A.-K.; Walter, E.; Yan, Y.-K.
Organometallics 2000, 19, 170-183.
Org. Lett., Vol. 7, No. 5, 2005
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An alternate rationalization relates to the equilibrium strongly
favoring imine 16,23 and the observed selectivity is simply
the result of the reduction of the dominant species.
Acknowledgment. We thank the National Science Foun-
dation and the National Institutes of Health, General Medical
Sciences Institute (GM-13598), for their generous support
of our programs. Mass spectra were provided by the Mass
Spectrometry Facility of the University of California-San
Francisco, supported by NIH Division of Research Re-
sources. D.R.F. thanks Eli Lilly and Company for the Eli
Lilly Graduate Fellowship.
In conclusion, we have completed the first total synthesis
of pseudodistomin D in a concise fashion. In addition to
establishing the absolute stereochemistry of pseudodistomin
D, we utilized the DYKAT technology to establish the
absolute stereochemistry and developed a unique hydro-
amination approach to efficiently synthesize diamino hetero-
cycles.
Supporting Information Available: Complete experi-
mental procedures, characterization data, and copies of NMR
spectra and HPLC traces. This material is available free of
charge via the Internet at http://pubs.acs.org.
(23) Semiempirical PM3 calculations indicate that the equilibrium favors
imine 16 over imine 14 by 3-7 kcal/mol. Spartan ’02; Wave Function,
Inc.: Irivine, CA, 2002.
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