A concise stereoselective synthesis of Preussin, 3-epi-Preussin, and analogues

Article abstract of DOI:10.1021/ol0606435

A new stereoselective synthesis of the antifungal and antitumor agents Preussin and 3-epi-Preussin via a Pd-catalyzed carboamination of a protected amino alcohol is described. The key transformation leads to simultaneous formation of the N-C2 bond and the C1′-aryl bond, and allows installation of the aryl group one step from the end of the sequence. This strategy permits the facile construction of a variety of preussin analogues bearing different aromatic groups.

Full text of DOI:10.1021/ol0606435

ORGANIC
LETTERS
2006
Vol. 8, No. 11
2353-2356
A Concise Stereoselective Synthesis of
Preussin, 3-epi-Preussin, and Analogues
Myra Beaudoin Bertrand and John P. Wolfe*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue,
Ann Arbor, Michigan, 48109-1055
jpwolfe@umich.edu
Received March 15, 2006
ABSTRACT
A new stereoselective synthesis of the antifungal and antitumor agents Preussin and 3-epi-Preussin via a Pd-catalyzed carboamination of a
protected amino alcohol is described. The key transformation leads to simultaneous formation of the N C2 bond and the C1′−aryl bond, and
−
allows installation of the aryl group one step from the end of the sequence. This strategy permits the facile construction of a variety of
preussin analogues bearing different aromatic groups.
The natural product preussin (1) was first isolated in 1988
by Schwartz and co-workers from the fermentation extracts
of Preussia sp. and Aspergillus ochraceus.1 Initial screens
revealed that this compound had significant antifungal
activity,1,2 and more recent work has demonstrated that
preussin induces apoptosis in a number of human cancer cell
lines and is a potent (IC50 ) 500 nm) inhibitor of cyclin-E
kinase.3 Preussin has also shown antiviral activity, and is
believed to inhibit -1 ribosomal frameshifting of RNA-based
viruses.4 Interestingly, all eight stereoisomers of preussin
exhibit biological activity.5
employ phenylalanine as the source of the C1′-phenyl group,
and most other routes also install this group early in the
synthetic sequence.7,10 Thus, the previously described syn-
theses of preussin are generally not well suited to the rapid
generation of preussin analogues that differ in the nature of
the aryl substituent. A concise approach to this molecule that
involves the installation of the aryl group near the end of
(6) Kitahara has described a nonstereoselective route that affords all eight
stereoisomers of preussin in a two-step sequence. The isomers were
separated by preparative chiral HPLC. See ref 5.
(7) For a recent review, see: Basler, B.; Brandes, S.; Spiegel, A.; Bach,
T. Top. Curr. Chem. 2005, 243, 1.
Owing to its interesting biological properties, preussin has
been a popular target for total synthesis, and has been
prepared via 22 different routes ranging from 5 steps to over
23 steps.6-9 However, the large majority of these syntheses
(8) For early synthetic studies see: (a) Shimazaki, M.; Okazaki, F.;
Nakajima, F.; Ishikawa, T.; Ohta, A. Heterocycles 1993, 36, 1823. (b)
McGrane, P. L.; Livinghouse, T. J. Am. Chem. Soc. 1993, 115, 11485. (c)
Overhand, M.; Hecht, S. M. J. Org. Chem. 1994, 59, 4721. (d) Deng, W.;
Overman, L. E. J. Am. Chem. Soc. 1994, 116, 11241.
(9) For recent syntheses, see: (a) Canova, S.; Bellosta, V.; Cossy, J.
Synlett 2004, 1811. (b) Davis, F. A.; Deng, J. Tetrahedron 2004, 60, 5111.
(c) Raghavan, S.; Rasheed, M. A. Tetrahedron 2003, 59, 10307. (d) Huang,
P.-Q.; Wu, T.-J.; Ruan, Y.-P. Org. Lett. 2003, 5, 4341. (e) Dikshit, D. K.;
Goswami, L. N.; Singh, V. S. Synlett 2003, 1737.
(1) Schwartz, R. E.; Liesch, J.; Hensens, O.; Zitano, L.; Honeycutt, S.;
Garrity, G.; Fromtling, R. A.; Onishi, J.; Monaghan, R. J. Antibiot. 1988,
41, 1774.
(2) (a) Johnson, J. H.; Phillipson, D. W.; Kahle, A. D. J. Antibiot. 1989,
42, 1184. (b) Kasahara, K.; Yoshida, M.; Eishima, J.; Takesako, K.; Beppu,
T.; Horinouchi, S. J. Antibiot. 1997, 50, 267.
(3) Achenbach, T. V.; Slater, P. E.; Brummerhop, H.; Bach, T.; Mu¨ller,
R. Antimicrob. Agents Chemother. 2000, 44, 2794.
(4) Kinzy, T. G.; Harger, J. W.; Carr-Schmid, A.; Kwon, J.; Shastry,
M.; Justice, M.; Dinman, J. D. Virology 2002, 300, 60.
(5) Okue, M.; Watanabe, H.; Kasahara, K.; Yoshida, M.; Horinouchi,
S.; Kitahara, T. Biosci. Biotechnol. Biochem. 2002, 66, 1093.
(10) Two strategies allow installation of the aryl moiety within 1-3 steps
of the final target. Davis generated the C-2 benzyl group as the final step
via reaction of lithium diphenyl cuprate with a pyrrolidinylmethyl iodide
(40% yield, single diastereomer; 10 steps total, 9% overall yield). Bach
employed a Paterno`-Bu¨chi reaction of benzaldehyde with a dihydropyrrole
(4:1 dr, 53% yield after separation of diastereomers) followed by a two-
step deprotection sequence to generate the benzyl substituent (39% over 3
steps; 9 steps total, 11% overall yield). See: (a) Reference 9b. (b) Bach,
T.; Brummerhop, H. Angew. Chem., Int. Ed. 1998, 37, 3400.
10.1021/ol0606435 CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/27/2006

the synthetic route would be of value for the straightforward
construction of preussin derivatives, particularly if the arene
could be incorporated in a manner that would permit
synthesis of functionalized and/or heteroaryl analogues from
readily available precursors.
alized arenes one step from the end of the sequence, which
permits the facile construction of a number of preussin
analogues. It also allows control of the relative stereochem-
istry at C2 through use of A(1,3)-strain15 in conjunction with
a favorable eclipsed orientation of the Pd-N and alkene
C-C bonds during the stereochemistry determining step of
the carboamination,14 which promotes cyclization through
transition state 3 in which the C-3 oxygen substituent is
oriented in a pseudoaxial position.
To probe the feasibility of the key Pd-catalyzed carboami-
nation reaction, our initial studies focused on the develop-
ment of a synthesis of (()-preussin. As outlined in Scheme
2, aldol reaction between commercially available 2-unde-
Due to the limitations of existing synthetic routes, very
little work has been conducted on the synthesis and study
of preussin analogues.11 However, limited studies on the
effect of arene substitution on the activity of the related
alkaloid anisomycin (2) have been performed that demon-
strate the nature of the C1′-aryl group has a profound effect
on biological activity.12,13 For example, an anisomycin
analogue bearing a phenyl group in place of the p-
methoxyphenyl moiety showed 40-fold less cytotoxic po-
tency than 2 against a human KB cell line.13 Thus, a synthetic
route to preussin that allows facile modification of the arene
moiety may be of significant biological interest.
Scheme 2. Synthesis of (()-Preussin
In this Letter we describe a new strategy for the stereo-
selective synthesis of preussin via the Pd-catalyzed car-
boamination14 of a protected amino alcohol. The key
disconnection is a retrosynthetic cleavage of both the N-C2
bond and C1′-aryl bond to yield starting amino alcohol 5
and aryl bromide 6 (Scheme 1). This strategy has two
Scheme 1. Key Disconnection and Stereocontrol
canone and acrolein provided keto-alcohol 7 in 76% yield.
Conversion of 7 to the O-benzyl oxime 8 proceeded
smoothly, and was followed by a one-pot sequence of LiAlH4
reduction and Boc-protection to provide an 86% yield of a
1:1.2 mixture of readily separable amino alcohol diastereo-
mers 9 and 10. Although stereoselective reductions of
â-hydroxy oxime ethers have been previously described,16
we elected to employ nonselective conditions to allow access
to both syn- and anti-amino alcohol substrates for the Pd-
catalyzed cyclization reactions, which ultimately provide two
different biologically active pyrrolidine derivatives (1 and
14).
TBS protection of anti-amino alcohol 9 provided 5, the
substrate for the key Pd-catalyzed carboamination reaction.
In the event, treatment of 5 with bromobenzene and NaOtBu
in the presence of catalytic Pd(OAc)2/dpe-phos17 provided
pyrrolidine 11 in 62% isolated yield with >20:1 diastereo-
significant implications for the construction of the molecule.
It allows the installation of a variety of different function-
(11) To date, no analogues of preussin have been prepared that are
modified on the aromatic ring. Bach has reported the synthesis of two
analogues that differ in the nature of the C5 alkyl chain, and four analogues
that differ in the nature of the C-3 substituent have been described in the
patent literature. See: (a) Bach, T.; Brummerhop, H.; Harms, K. Chem.
Eur. J. 2000, 6, 3838. (b) Suzuki, K.; Miike, N.; Kawamoto, E. Jpn. Kokai.
Tokkyo Koho 2003277357, 2003.
(12) Hall, S. S.; Loebenberg, D.; Schumacher, D. P. J. Med. Chem. 1983,
26, 469.
(13) Schwardt, O.; Veith, U.; Gaspard, C.; Ja¨ger, V. Synthesis 1999, 1473.
(14) (a) Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43, 3605.
(b) Ney, J. E.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 8644. (c) Bertrand,
M. B.; Wolfe, J. P. Tetrahedron 2005, 61, 6447. (d) Yang, Q.; Ney, J. E.;
Wolfe, J. P. Org. Lett. 2005, 7, 2575.
(15) For a discussion of allylic strain related to the partial double bond
character between the nitrogen atom and the carbonyl carbon in R-substituted
amides and carbamates see: (a) Hoffmann, R. W. Chem. ReV. 1989, 89,
1841. (b) Hart, D. J. J. Am. Chem. Soc. 1980, 102, 397. (c) Williams, R.
M.; Sinclair, P. J.; Zhai, D.; Chen, D. J. Am. Chem. Soc. 1988, 110, 1547.
(d) Kano, S.; Yokomatsu, T.; Iwasawa, H.; Shibuya, S. Heterocycles 1987,
26, 2805.
(16) Narasaka, K.; Ukaji, Y.; Yamazaki, S. Bull. Chem. Soc. Jpn. 1986,
59, 525.
2354
Org. Lett., Vol. 8, No. 11, 2006

selectivity. As noted above, the desired stereoisomer most
likely arises from transition state 3 (Scheme 1) in which the
C9 chain is oriented in a pseudoaxial position to minimize
A(1,3)-strain between this substituent and the N-Boc group.15
Although the C3-OTBS group is also pseudoaxial, the
energetic cost of this conformation is lower than that of the
A(1,3)-strain in transition state 4 in which both the C9 chain
and the OTBS group are equatorial. One-pot reduction and
deprotection of 11 afforded (()-preussin (1) in 90% yield
as a single diastereomer. This six-step sequence proceeded
with an overall yield of 15% from 2-undecanone.
Scheme 4. Synthesis of (+)-Preussin
The syn-amino alcohol 10 was converted to (()-3-epi-
preussin (14)8a,d by using a sequence of reactions analogous
to that described above (Scheme 3). The stereoselectivity of
Scheme 3. Synthesis of (()-3-epi-Preussin
racemic route, and provided (+)-preussin {[R]23 +21.2 (c
D
1.0, CHCl3) [lit.2 [R]25 +22.0 (c 1.0, CHCl3)]} with an
D
overall yield of 12% in nine steps from commercially
available decanal.
To demonstrate the amenability of this strategy toward
the synthesis of differentially arylated preussin analogues,
Pd-catalyzed reactions of 5 and 12 were conducted with a
variety of different aryl bromide coupling partners. To
illustrate the utility of this method for the rapid generation
of useful quantities of analogues the Pd/dpe-phos catalyst
was employed for all substrate combinations. However,
previous studies indicate that other ligands may provide
superior results for certain aryl bromide coupling partners.14c
Thus, the yields obtained in these transformations are not
optimized on a case-by-case basis. As shown in Table 1,
the cyclization reactions proceed in moderate to good yields
for a variety of different aryl bromides including substrates
that are electron-rich (entries 3 and 4),22 electron poor (entries
1-2, 5-6, 9, and 12), or sterically hindered (entry 8). Several
functional groups are tolerated, and heterocyclic aryl bro-
mides can also be employed (entries 10 and 11). In most
cases examined, the cyclizations of anti-amino alcohol
derivative 5 proceeded in higher yield than the analogous
reactions of syn-amino alcohol derivative 12. In all cases
the reactions proceeded with >20:1 diastereoselectivity as
the Pd-catalyzed cyclization of 12 was high, although the
chemical yield obtained in the reaction of the syn-diastere-
omer 12 (54%) was slightly lower than that achieved for
the reaction of the anti-isomer 5 (62%). This route provided
the desired pyrrolidine 14 as a single isomer in an overall
yield of 15%. Thus, the strategy described herein provides
straightforward access to both racemic preussin diastereomers
in comparable yields and stereoselectivities.18
Having demonstrated the feasibility of Pd-catalyzed car-
boamination for the construction of preussin, we turned our
attention toward the development of an asymmetric synthesis
of the naturally occurring (+)-enantiomer. As shown in
Scheme 4, addition of allylmagnesium bromide to enan-
tiopure sulfinylimine 15 under Ellman’s conditions19 afforded
16, which was isolated in 77% yield as a single diastereomer
upon purification.20 Cleavage of the chiral auxiliary and
protection of the resulting primary amine afforded 17 in 85%
yield. Ozonolysis of 17 (67%) followed by vinylcuprate
addition21 to the resulting â-amino aldehyde 18 generated
(+)-9 with 3:1 diastereoselectivity; the desired pure anti-
diastereomer was obtained in 54% yield after chromato-
graphic separation. The remaining three steps proceeded with
similar yields and selectivities to those obtained from the
1
judged by H and 13C NMR analysis.
To illustrate that the N-Boc-O-TBS-preussin analogues
could be converted to N-methyl-3-hydroxy-2-(arylmethyl)-
pyrrolidines that are closely related to the natural product, a
subset of the products shown in Table 1 were deprotected
in a 1-2 step sequence. As shown in Table 2, deprotection
was effected by using LiAlH4 followed by treatment with
aqueous base or TBAF for products bearing unreactive
aromatic functionality. Alternatively, deprotection was also
achieved through one-pot Boc cleavage and reductive ami-
(17) Dpe-phos ) bis(2-diphenylphosphinophenyl) ether.
(18) The (-)-B-chlorodiisopinocampheylborane-mediated asymmetric
aldol reaction between 2-undecanone and acrolein provided 7 in 78% yield
and 48% ee, using Paterson’s conditions. See: Paterson, I.; Goodman, J.
M.; Lister, M. A.; Schumann, R. C.; McClure, C. K.; Norcross, R. D.
Tetrahedron 1990, 46, 4663.
(22) Use of high-purity starting material (>97% by NMR and GC) was
essential to obtain high yields in reactions of electron-rich aryl bromides.
Use of starting material with trace (ca 5%) impurities led to catalyst
deactivation and formation of complex mixtures of products with these
substrate combinations.
(19) Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55, 8883.
(20) The crude reaction mixture was judged to contain a 10:1 mixture
1
of diastereomers by H NMR analysis.
(21) Toujas, J.-L.; Toupet, L.; Vaultier, M. Tetrahedron 2000, 56, 2665.
Org. Lett., Vol. 8, No. 11, 2006
2355

Table 1. Synthesis of N-Boc-O-TBS-Preussin Analoguesa
Table 2. Deprotection of N-Boc-O-TBS-Preussin Analoguesa
a Reagents and conditions: Method A: (i) LiAlH4, THF, 60 °C; (ii) H2O
or TBAF. Method B: (i) HCO2H, HCHO; (ii) TBAF, THF.
These routes feature a new strategy for the synthesis of
2-benzylpyrrolidine alkaloids that allows the construction of
both the C2-N and the C1′-Ar bonds in a single step near
the end of the synthetic sequence. This strategy allows the
facile synthesis of differentially arylated preussin analogues,
and provides straightforward access to derivatives that could
not be easily and rapidly prepared with previously developed
routes. This strategy is potentially applicable to other
members of this class of natural products; further studies in
this area are currently underway.
Acknowledgment. This research was supported by the
NIH-NIGMS (GM 071650) and the University of Michigan.
J.P.W. thanks the Camille and Henry Dreyfus Foundation
for a New Faculty Award, Research Corporation for an
Innovation Award, and Eli Lilly for a Grantee Award.
Additional unrestricted support was provided by Amgen, Eli
Lilly, and 3M.
a Reagents and conditions: 1.0 equiv ofsubstrate, 1.2 equiv of ArBr,
2.3 equiv of NaOtBu, 2 mol % of Pd(OAc)2, 4 mol % of dpe-phos, toluene,
90 °C.
nation with formic acid/formaldehyde followed by treatment
with TBAF. The latter conditions tolerate functional groups
(e.g., ketones, trifluoromethyl substituents) that would be
reduced by LiAlH4. Both deprotection protocols provided
the desired products in excellent yields.
In conclusion, we have developed concise, stereoselective
routes to (+)-preussin, (()-preussin, and (()-3-epi-preussin.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and copies of 1H and 13C spectra
for all compounds reported in the text. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0606435
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Org. Lett., Vol. 8, No. 11, 2006