Synthesis of All diastereomers of the piperidine - alkaloid substructure of cyclopamine

Article abstract of DOI:10.1021/ol902270f

"Chemical Equation Presented" All four diastereomers of the trisubstituted piperidine-alkaloids of the veratramine and jervine type were synthesized with complete stereocontrol starting from enantiopure citronellic acids. The flexible, high-yielding, and scalable route described here will facilitate convergent syntheses and give access to analogues of cyclopamine and other biologically active and diverse steroid alkaloids.

Full text of DOI:10.1021/ol902270f

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5410-5412
Synthesis of All Diastereomers of the
Piperidine-Alkaloid Substructure of
Cyclopamine
Philipp Heretsch, Sebastian Rabe, and Athanassios Giannis*
Institut fu¨r Organische Chemie, UniVersita¨t Leipzig, 04103 Leipzig, Germany
giannis@uni-leipzig.de
Received September 30, 2009
ABSTRACT
All four diastereomers of the trisubstituted piperidine-alkaloids of the veratramine and jervine type were synthesized with complete stereocontrol
starting from enantiopure citronellic acids. The flexible, high-yielding, and scalable route described here will facilitate convergent syntheses
and give access to analogues of cyclopamine and other biologically active and diverse steroid alkaloids.
Cyclopamine (1) is the most prominent member of the
biologically and structurally highly diverse family of Ve-
ratrum steroid alkaloids (Figure 1). Despite their C-nor-D-
homo-[14(13f12)-abeo] carbon ring system, these natural
products further possess characteristic trisubstituted piperi-
dine substructures that are linked by a furan (jervine-type)
or a carbon atom (veratramine-type) to the steroid skeleton.1
Especially cyclopamine as the first inhibitor of the Hedgehog-
signaling pathway (Hh), which is of vital importance for both
correct embryonic development and adult tissue homeostasis,
has drawn a lot of attention in this decade.2 Its first synthesis
was recently accomplished by our group and proceeds in 20
Figure 1. Structure of cyclopamine and carbon numbering.
linear steps and 1% total yield from commercially available
dehydroepiandrosterone (DHEA).3 Since great demand exists
for metabolically more stable and biologically more active
analogues of cyclopamine, a convergent route to these com-
pounds could be of high value.
(1) Li, H.-J.; Jiang, Y.; Li, P. Nat. Prod. Rep. 2006, 23, 735–752.
(2) (a) Lum, L.; Beachy, P. A. Science 2004, 304, 1755–1759. (b)
Taipale, J.; Beachy, P. A. Nature 2001, 411, 349–354. (c) Taipale, J.; Chen,
K. C.; Cooper, M. K.; Wang, B.; Mann, R. K.; Milenkovic, L.; Scott, M. P.;
Beachy, P. A. Nature 2000, 406, 1005–1009.
10.1021/ol902270f CCC: $40.75
Published on Web 11/02/2009
 2009 American Chemical Society

We therefore developed an efficient and scalable route to
all four diastereomers of the piperidine substructure of the
Veratrum steroid alkaloids that can be used not only to access
cyclopamine and analogues but also for the total synthesis
of other members of this family.
The piperidine substructures of the Veratrum steroid
alkaloids are substituted in position 2 with a two-carbon chain
that will form C-20 and C-21 in the steroid alkaloid, a
hydroxy group in position 3, that may be part of the furan
(jervine-alkaloids) or be a free hydroxy group (veratramine-
type) and a methyl group in position 5.
these compounds from cheaper materials. While (-)-(S)-
citronellic acid (-)-6 was accessible by oxidation of (-)-
(S)-citronellal using silveroxide, (+)-(R)-citronellic acid was
synthesized from (+)-(R)-pulegone by known procedures.9,10
The chiral valerolactames could then be accessed in three
steps and 75% total yield.11 Starting with a Curtius rear-
rangement of the carboxylic acid (-)-6 or (+)-6 to the
corresponding benzyl-carbamate (-)-7 or (+)-7, and then
an osmium(VIII)-catalyzed oxidative cleavage of the double
bond,12 these reactions already afforded the cyclic lactamoles,
which in turn were oxidized to the lactames (-)-8 and (+)-
8, respectively, using Ley’s TPAP/NMO (tetrapropylammo-
nium perrhutenate/4-methyl-morpholine-4-oxide) system.
With both enantiopure protected lactames in hand, we
searched for a way to introduce the hydroxy group diaste-
reoselectively. Finally, the treatment of the lithium enolates
with 8,8-dichlorocamphoryl-sulfonyl oxaziridine (DCCSO,
commercially available in both enantiomeric forms or easily
prepared from the camphorsulfonic acids13) proved to be
ideal. Under optimized conditions, these reactions proceeded
with complete diastereocontrol and a yield of 83-89% that
already includes the subsequent protection as a pivaloate.
These reactions were routinely conducted on the 10 g scale.
The use of (+)-DCCSO gave rise to the 23-(S)-stereochem-
istry (as in (-)-10), and (-)-DCCSO yielded the 23-(R)-
diastereomer, e.g. (+)-9 (Scheme 1). The orientation of the
Three of the four possible diastereomers occur in natural
products (see Figure 2). For the two most common diaste-
Scheme 1. Synthesis of the Hydroxylated Lactames 9 and 10
Figure 2. Structures, stereochemistry (steroid numbering), and
occurrence in natural products of synthetic alkaloid precursors 2,
3, 4, and 5.4-8
reomers (stereochemistry as in 2 and 4), the corresponding
enantiomers can also be found. Only the all-cis diastereomer
(stereochemistry as in 5) does not occur in nature. Since in
compound 2 all substituents are placed equatorially, it is of
no surprise that this stereochemistry is the most common
and that the well-known natural products cyclopamine,
veratramine, and jervine bear this structure.
A retrosynthetic analysis led us to define the order in which
the three substituents should be introduced to the piperidine
nucleus. Since the methyl group in position 5 was thought
to be of no influence to the generation of the remaining
stereocenters in 2- and 3-position, it could be placed in the
beginning. The hydroxy group in the 3-position could (after
its diastereoselective introduction) be utilized as an element
of control for the attachment of the carbon substituent in
the 2-position. As starting material, a carbon building block
with a chiral methyl substituent was needed that, in addition,
should be available in both enantiomeric forms. This task
was fulfilled by the enantiopure citronellic acids.
methyl group had no influence on the stereochemical
outcome.14
Although both enantiomers of citronellic acid are com-
mercially available, it was found more suitable to synthesize
To introduce the remaining stereocenter for once in a trans-
fashion with regard to the adjacent hydroxy group, the
addition of a carbon nucleophile was envisioned. A quantita-
tive yield with complete stereocontrol could be gained by
the reaction of the corresponding acetate and a stabilized
(3) Giannis, A.; Heretsch, P.; Sarli, V.; Sto¨ꢀel, A. Angew. Chem. 2009,
121, 8052-8055; Angew. Chem., Int. Ed. 2009, 48, 7911-7914.
(4) Mimaki, Y.; Sashida, Y. Chem. Pharm. Bull. 1990, 38, 1090–1092.
(5) Usubillaga, A. Phytochemistry 1988, 27, 3031–3032.
Org. Lett., Vol. 11, No. 23, 2009
5411

silylenol ether.15 Therefore the protected hydroxylactames
were reduced with superhydride and directly converted to
the acetates (mixture of epimers) with Ac2O. Treatment of
the latter with ethyl-3-phenyl-3-trimethylsiloxy-acrylate (21,
see Supporting Information) under Sc(OTf)3 catalysis pro-
ceeded smoothly and afforded 11 (Scheme 2). Cleavage of
Scheme 3. Synthesis of the Methylketones 4 and 5
Scheme 2. Synthesis of the Lactones 2 and 3
In conclusion, any enantiomer of any diastereomer of the
trisubstituted piperidine-alkaloid substructures of cyclop-
amine and all other jervine- and veratramine-steroid alka-
loids can be obtained from readily available enantiopure
citronellic acids by the two general routes described above,
choosing either (+)-DCCSO or (-)-DCCSO in the hydroxy-
lation step. Hence complete control of stereochemistry of
the three substituents was demonstrated. Furthermore, all
transformations proceeded in high yield and were shown to
be scalable up to multigram quantities. We are therefore
confident that implementation of this route will open access
to new analogues and total syntheses of this interesting class
of natural products.
the benzoyl moiety was affected by a retro-Claisen reaction
using LiOH, and deprotection of the hydroxy group and the
carboxylic acid gave the seco-acid which was immediately
cyclized with EDC (1-(3-dimethylaminopropyl)-3-ethylcar-
bodiimide) to give the five-membered lactones 2 and 3,
respectively (63-59% yield over five steps). From both 2
and 3, several grams were prepared using this sequence.
A syn-addition to C-2 was achieved by the following
sequence: Methylenation using the Petasis conditions16 and
subsequent hydroboration/oxidation gave the regioisomeric
alcohols 13 and 14 with complete stereocontrol. The occur-
rence of 14 in this reaction must be attributed to a pivaloyl
shift. Both compounds 13 and 14 were converted to the
benzyl-protected diol 15 using standard protecting group
manipulations.
Acknowledgment. We thank Dr. Lothar Hennig (Univer-
sita¨t Leipzig) for recording NMR spectra and for his help in
interpreting the 2D-NMR spectra. The Deutsche Forschungs-
gemeinschaft (DFG) is acknowledged for partial financial
support. Dr. Philipp Heretsch is a fellow of Fonds der
Chemischen Industrie.
Further elaboration into 4 was carried out by oxidation
using the Dess-Martin-periodinane (DMP), Grignard reac-
tion with methylmagnesium bromide, and again oxidation
of the epimeric alcohols with DMP to yield the methylketone
4 as the only product. These transformations proceeded in a
total yield of 15% over seven or nine steps, respectively.
Starting from (-)-9 the all-cis substituted methylketone 5
could be accessed in the same way but with only minute
amounts of pivaloyl-shifted material to be produced during
the hydroboration/oxidation reaction, in a total yield of 23%
over nine steps (Scheme 3).
Supporting Information Available: Experimental pro-
1
cedures, compound characterization, and H NMR and 13C
NMR data for all compounds. 2D-NMR spectral data for
selected compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL902270F
(11) This access is both shorter and more efficient than a seminal work
by Woodward et al. dealing with the assignment of the absolute stereo-
chemistry of the Veratrum alkaloids: Jeger, O.; Prelog, V.; Sundt, E.;
Woodward, R. B. HelV. Chim. Acta 1954, 37, 2302–2306.
(12) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6,
3217–3219.
(6) (a) Jiang, Y.; Li, H.; Li, P.; Cai, Z.; Ye, W. J. Nat. Prod. 2005, 68,
264–267. (b) Jiang, Y.; Li, P.; Li, H.-J.; Yu, H. Steroids 2006, 71, 843–
848. (c) Li, H.-J.; Jiang, Y.; Li, P.; Ye, W.-C. Chem. Pharm. Bull. 2006,
54, 722–724.
(13) Chen, B.-C.; Murphy, C. K.; Kumar, A.; Thimma Reddy, R.; Clark,
C.; Zhou, P.; Lewis, B. M.; Gala, D.; Mergelsberg, I.; Scherer, D.; Buckley,
J.; DiBenedetto, D.; Davis, F. A. Org. Synth. 1996, 73, 159–167.
(14) A chemoenzymatic approach described by Willis et al. is both more
tedious and of lower total yield and gives in addition only access to products
with stereochemistry resembling that of (-)-9 and (-)-10: Crosby, S.;
Hateley, M. J.; Willis, C. L. Tetrahedron Lett. 2000, 41, 397–401.
(15) Okitsu, O.; Suzuki, R.; Kobayashi, S. J. Org. Chem. 2001, 66, 809–
823.
(7) Qian, Z.-Z.; Nohara, T. Phytochemistry 1995, 40, 979–981.
(8) Zhang, J. X.; Lao, A. N.; Xu, R. S. Chin. J. Org. Chem. 1994, 14,
289–292.
(9) Hashimoto, S.-I.; Yamada, S.-I.; Koga, K. Chem. Pharm. Bull. 1979,
27, 771–782.
(10) Overberger, C. G.; Weise, J. K. J. Am. Chem. Soc. 1968, 90, 3525–
3532.
(16) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392–
6394.
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