Asymmetrie construction of rings A - D of Daphnicyclidin-type alkaloids

Article abstract of DOI:10.1021/ol902373m

[Chemical Equation Presented] The aza-Cope-Mannich reaction and ring-closing metathesis are key steps in the assembly of intermediates containing rings A - D of Daphniphyllum alkaloids of the daphnicyclidin type such as daphnipaxinin and oldhamine A.

Full text of DOI:10.1021/ol902373m

ORGANIC
LETTERS
2009
Vol. 11, No. 24
5658-5661
Asymmetric Construction of Rings A-D
of Daphnicyclidin-Type Alkaloids
Travis B. Dunn,† J. Michael Ellis,‡ Christiane C. Kofink,§ James R. Manning, and
Larry E. Overman*
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California,
IrVine, California 92697-2025
leoVerma@uci.edu
Received October 14, 2009
ABSTRACT
The aza-Cope-Mannich reaction and ring-closing metathesis are key steps in the assembly of intermediates containing rings A-D of
Daphniphyllum alkaloids of the daphnicyclidin type such as daphnipaxinin and oldhamine A.
Kobayashi reported in 2001 the first members of a structur-
ally unprecedented group of fused hexa- or pentacyclic
Daphniphyllum alkaloids, daphnicyclidins A (1)-H.1 Daph-
nicyclidin-type alkaloids, which now number more than 15,
have compact structures that are believed to derive via
extensive structural modification of Daphniphyllum alkaloids
generated from cyclization of squalene precursors.2 Four
representative examples are depicted in Figure 1. These
compounds illustrate several of the remarkable structural
features of these alkaloids, in particular ring E, which is
found in all but two members as either a fulvene or a
cyclopentadienyl anion unit. Structures for Daphniphyllum
alkaloids of the daphnicyclidin-type have been secured on
the basis of mass spectrometric, spectroscopic and X-ray
data,3 augmented by chemical correlations.2 Daphnipaxinin
(3) is notable as the first diamino Daphniphyllum alkaloid
† Current address: Abbott Laboratories, 1401 Sheridan Road, Dept R450/
NCR13-3, North Chicago, IL 60064.
Figure 1. Representative Daphniphyllum alkaloids of the daphni-
cyclidin type.
‡ Current address: Merck & Co., Inc., BMB-3, 33 Avenue Louis Pasteur,
Boston, MA 02115.
§ Current address: Boehringer Ingelheim RCV GmbH & Co KG,
Boehringer-Gasse 5-11, A-1121, Vienna, Austria.
(1) Kobayashi, J.; Inaba, Y.; Shiro, M.; Yoshida, N.; Morita, H. J. Am.
Chem. Soc. 2001, 123, 11402–11408.
isolated.4 Bioactivities of these alkaloids have been poorly
studied, although several display moderate cytotoxicity,1,2
and others were isolated from plants used in traditional
medicine; for example, daphnipaxinin (3) is found in D.
(2) Kobayashi, J.; Kubota, T. Nat. Prod. Rep. 2009, 26, 936–962, and
other reviews cited therein.
10.1021/ol902373m  2009 American Chemical Society
Published on Web 11/11/2009

paxianum, an herb used in Chinese folk medicine for the
treatment of inflammation.4
Scheme 2
Scheme 1
Stimulated by their unprecedented structures, their scarce
natural supply,5 and their largely unexplored pharmacological
profiles, we initiated chemical synthesis studies toward
Daphniphyllum alkaloids of the daphnicyclidin type. Ring
B is a piperidine in most members of this group, whereas it
is a pyrrolidine in daphnipaxinin (3) and oldhamine A (4).
We chose to pursue a potentially general strategy in which
ring B would be constructed at an advanced stage of the
synthesis by forming a bond to C18 from either N1 to form
a pyrrolidine ring (as suggested in Scheme 1) or the conjugate
base of a cyanomethyl derivative of this amine to construct
a piperidine ring. We planned to assemble rings A and C
and the five stereocenters of daphnicyclidin-type alkaloids
early in the synthesis by aza-Cope-Mannich rearrangement
(8 f 7) of a formaldiminium ion derived from an aminocy-
clohexanol precursor such as 8.6 We report herein enanti-
oselective construction of the tetracyclic A-D fragment of
daphnipaxinin (3) and oldhamine A (4) by this approach.7
The method we devised to access a 2-aminocyclohexanone
intermediate incorporating the C2, C4, and C18 stereocenters
of daphnicyclidin-type Daphniphyllum alkaloids is sum-
marized in Scheme 2. The synthesis began with (S)-
cyclohexenecarboxyaldehyde 11 (91% ee), which was pre-
pared by the organocatalytic Diels-Alder method of
MacMillan.8 To effectively carry out the cycloaddition of
2-acetoxy-1,3-butadiene and acrolein, it was important to use
the hydrotriflate salt of catalyst 10 (2.5 mol %) and water-
saturated nitromethane as the reaction solvent.9 The C18
(3) Alkaloids 1, 2 and 4 have been characterized by single crystal X-ray
analysis: (a) Reference 2. (b) Gan, X.; Bai, H.; Chen, Q.; Ma, L.; Hu, L.
Chem. BiodiVers. 2006, 3, 1255–1259. (c) Tan, C.; Di, Y.; Wang, Y.; Wang,
Y.; Mu, S.; Gao, S.; Zhang, Y.; Kong, N.; He, H.; Zhang, J.; Fang, X.; Li,
C.; Lu, Y.; Hao, X. Tetrahedron Lett. 2008, 49, 3376–3379.
(4) Yang, S. P.; Yue, J. M. Org. Lett. 2004, 6, 1401–1404.
(7) An enantiocontrolled route to a BCD ring fragment of daphnicyclidin
A was described recently, see: Ikeda, S.; Shibuya, M.; Kanoh, N.; Iwabuchi,
Y. Org. Lett. 2009, 11, 1833–1836.
(5) For example, daphnipaxinin (3) and oldhamine A (4) were isolated
in 0.00024 and 0.00007%, respectively, from their dried plant sources.
(6) For a recent brief review and leading references, see Overman, L. E.
Tetrahedron 2009, 65, 6432–6446.
(8) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243–4244.
Org. Lett., Vol. 11, No. 24, 2009
5659

stereocenter was incorporated by nickel-catalyzed methyla-
tion of the aldehyde using 2 mol % of the (Rp,S,S)-
phosphoramidite catalyst 12, following the general prescrip-
tions of Woodward.10,11 In three conventional steps, product
13 was converted to siloxycyclohexadiene 14.12 The amino
substituent was then introduced by a two-step sequence that
began with hetero Diels-Alder reaction of diene 14 with
(nitrosocarbonyl)benzene to give a 6:1 mixture of major
adducts 15 and 16.13,14 Although these products could be
isolated in pure form and processed separately to intermediate
18, it was more convenient to directly reduce the mixture of
stereoisomeric cycloadducts with Mo(CO)6 to form cyclo-
hexenone 17 in good yield, as a ca. 5:1 mixture of
benzoylamino epimers.15 The silyl substituent, which we
envision as a precursor of a carbonyl group at C1, was
introduced at this point by conjugate addition of a zincate
reagent generated from phenyldimethylsilyllithium.16 Base-
catalyzed epimerization of this product then delivered
benzoylaminocyclohexanone 18 in 41% overall yield from
siloxycyclohexadiene 14. In three additional steps, this
intermediate was transformed to the N-benzyl,N-cyanomethyl
congener 19 in high overall yield.
the A and C rings and C5 and C6 stereocenters of the
daphnicyclidin-type alkaloids in high yield and with complete
stereocontrol.
Scheme 3
Aminoketone 19 can serve as a precursor for fashioning
various cycloheptapyrrolidine intermediates by the aza-Cope-
Mannich transformation. Considerable effort was invested
to find useful conditions for the addition of vinyl organo-
metallic nucleophiles to this hindered ketone. Premixing
ketone 19 with CeCl3·2LiCl17 at room temperature, addition
of vinyl iodide 20a, and subsequent dropwise addition of
t-BuLi at -78 °C provided tertiary alcohol 21a in 73% yield.
Exposing this product to 1.2 equiv of AgNO3 in ethanol at
room temperature delivered cycloheptapyrrolidine 22a18 as
a single stereoisomer in 89% yield. In related fashion, ketone
19 and vinyl iodide 20b were converted in two steps to
cycloheptapyrrolidine 22b (64% overall yield). The aza-
Cope-Mannich transformation to form 22a and 22b generated
Several approaches for forming the B and D rings were
investigated. In one approach, the B ring was formed first
by sequential treatment of cycloheptapyrrolidine 22b with
aqueous HF to cleave the TBDPS group, and methanesulfo-
nyl chloride to activate the alcohol for intramolecular
alkylation by the tertiary amine. Hydrogenolysis of the
resulting quaternary ammonium salt cleaved both benzyl
groups to deliver tricyclic aminoketone 23 in 70% overall
yield. Although this product could be elaborated to a
ꢀ-ketophosphonate derivative, all attempts to form the seven-
membered D ring by intramolecular Horner-Wadsworth-
Emmons reaction failed.19 Alternatively, 23 could be con-
verted to (Z)-vinyl iodide 24, but attempted ring closure by
lithium halogen exchange or under Nozaki-Hiyama-Kishi
conditions20 resulted in protodeiodination of the starting
material. Our first success in fashioning this ring was
achieved by first transforming amino ketone 23 to diene 25
by a sequence of three standard reactions. Ring-closing
metathesis of amino diene 25 proceeded in good yield using
the Grubbs second-generation catalyst 2621 to form tetracy-
clic amine 27 in 81% yield (Scheme 4).
(9) Kowalski, M. D. Ph.D. Dissertation, University of California, Irvine,
2008
.
(10) Biswas, K.; Prieto, O.; Goldsmith, P. J.; Woodward, S. Angew.
Chem., Int. Ed. 2005, 44, 2232–2234
.
(11) The expected10 configuration of the major alcohol epimer was
confirmed by X-ray analysis of a subsequent product.
(12) Minami, I.; Takahashi, K.; Shimizu, I.; Kimura, T.; Tsuji, J.
Tetrahedron 1986, 42, 2971–2977.
(13) (a) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology
in Organic Synthesis; Academic: San Diego, CA, 1987. (b) Streith, J.;
Defoin, A. Synthesis 1994, 1107–1117
.
(14) A minor amount of a third stereoisomeric adduct that derives
from the inseparable minor alcohol epimer of intermediate 13 was also
produced.
(15) Cabanal-Duvillard, I.; Berrien, J. F.; Ghosez, L.; Husson, H.-P.;
Royer, J. Tetrahedron 2000, 56, 3763–3769.
(16) Crump, R. A. N. C.; Fleming, I.; Urch, C. J. J. Chem. Soc., Perkin
Trans. 1 1994, 701–706.
(17) (a) Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem., Int. Ed.
2006, 45, 497–500. We employed a simpler procedure for preparing this
reagent (see Supporting Information); for a related procedure for preparing
a cerium acetylide, see: (b) Trost, B. M.; Waser, J.; Meyer, A. J. Am. Chem.
Soc. 2008, 130, 16424–16434.
Alternatively, the seven-membered D ring could be
fashioned prior to forming ring B (Scheme 5). Exposure of
cycloheptapyrrolidine 22a to an excess of vinylmagnesium
(18) Aza-Cope-Mannich product 22a was elaborated to a tricyclic
pyrrolidinium salt by cleavage of the TBDPS group and intramolecular
quaternization by the sequence illustrated in Schemes 4 and 5; see
Supporting Information for details. Single crystal X-ray analysis of this
derivative confirmed the relative and absolute configuration of 22a.
Crystallographic data for this compound were deposited with the Cambridge
Crystallographic Data Centre: CCDC 751136.
(19) For a pertinent example where this reaction also failed to form a
seven-membered ring, see: Dudley, G. B.; Danishefsky, S. J. Org. Lett.
2001, 3, 2399–2402.
(20) For a review, see: Fu¨rstner, A. Chem. ReV. 1999, 99, 991–1045.
(21) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953–956.
5660
Org. Lett., Vol. 11, No. 24, 2009

Scheme 4
Scheme 5
bromide and CeCl3·2LiCl in THF at -78 °C provided a
single allylic alcohol product 28 in 72% yield. Cyclization
of this diene in refluxing CH2Cl2 in the presence of catalyst
26 provided tricyclic amine 29 in nearly quantitative yield.
Although one-step procedures for converting tertiary allylic
alcohol 29 to enone 30 failed, this transformation could be
realized in a stepwise fashion. Thus, exposing allylic alcohol
29 to thionyl chloride and pyridine, followed by hydrolysis
of the resulting transposed allylic chloride upon adding
alumina and water and subsequent Dess-Martin oxidation22
provided enone 30 in 45% yield. The B ring could then be
constructed in good yield by the previously described two-
step sequence.
In summary, an enantioselective synthesis of an advanced
tetracyclic intermediate containing all of the stereocenters
found in daphnipaxinin and oldhamine A has been developed.
A high-yielding aza-Cope-Mannich reaction was utilized to
generate the A and C ring cycloheptapyrrolidine core and
install both the C5 quaternary carbon stereocenter as well
as the adjacent C6 stereocenter. An intramolecular amino
alkylation/RCM sequence was then used to form the B and
D rings, respectively. Efforts toward construction of the
remaining E and F rings to complete an enantioselective
synthesis of daphnipaxinin are currently underway.
Acknowledgment. This research was supported by the
NIH Neurological Disorders & Stroke Institute (NS-12389),
and by postdoctoral fellowship support for T.B.D. (HL-
078104), J.M.E. (GM-082113), C.C.K. (Alexander von
Humboldt Foundation), and J.R.M. (CA-139868). NMR,
mass spectra, and the X-ray analyses were obtained at UC
Irvine using instrumentation acquired with the assistance of
NSF and NIH Shared Instrumentation grants. We thank Dr.
Joe Ziller, University of California, Irvine, for the single-
crystal X-ray analyses and Dr. John Greaves, University of
California, Irvine, for mass spectrometric analyses.
Supporting Information Available: Experimental details
and procedures, tabulated NMR data for compounds 27 and
1
31, copies of H and 13C NMR spectra of new compounds,
and an X-ray crystallographic file. This material is available
free of charge via the Internet at http://pubs.acs.org.
(22) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
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