Stereoselective synthesis of the eastern quinolizidine portion of himeradine A

Article abstract of DOI:10.1021/ol201704g

The synthesis of the C₁₅-C₁₇/N_1′- C_11′ quinolizidine portion of himeradine A is disclosed. An intramolecular, heteroatom Michael addition was employed to establish the C _6′ stereogenic center with high diastereoselectivity. The quinolizidine ring was constructed using microwave-induced cyclization at the N_1′-C_2′ position. The C₁₇ stereogenic center was introduced through a diastereoselective Overman rearrangement.

Full text of DOI:10.1021/ol201704g

ORGANIC
LETTERS
2011
Vol. 13, No. 15
4144–4147
Stereoselective Synthesis of the Eastern
Quinolizidine Portion of Himeradine A
Nathan D. Collett and Rich G. Carter*
Department of Chemistry, Oregon State University, Corvallis, Oregon 97331, United States
rich.carter@oregonstate.edu
Received June 24, 2011
ABSTRACT
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The synthesis of the C15ꢀC17/N1 ꢀC11 quinolizidine portion of himeradine A is disclosed. An intramolecular, heteroatom Michael addition was
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employed to establish the C6 stereogenic center with high diastereoselectivity. The quinolizidine ring was constructed using microwave-induced
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cyclization at the N1 ꢀC2 position. The C17 stereogenic center was introduced through a diastereoselective Overman rearrangement.
In 2003, Kobayashi and co-workers reported the isola-
tion and structural determination of the alkaloid himer-
adine A (1) from the club moss Lycopodium chinense in
small amounts (2 mg, 0.001%, Figure 1).1 Polycycle 1 was
assigned based on extensive 2D NMR techniques (COSY,
HOHAHA, HMQC, HMBC, and HMQC-HOHAHA);
however, they were unable to establish the correlation
between the eastern and western halves or the absolute
stereochemistry of the molecule. Alkaloid 1 showed mod-
est cytotoxicity against murine lymphoma L1210 cells
(IC50 10 μg/mL), but a thorough biological screening of
the compound has not been reported. Other members of
the Lycopodium family have shown intriguing biological
activity.2
(1) Morita, H.; Hirasawa, Y.; Kobayashi, J. J. Org. Chem. 2003, 68,
4563–4566.
(2) (a) Ma, X.; Gang, D. R. Nat. Prod. Rep. 2004, 21, 752–772. (b)
Kobayashi, J.; Morita, H. Alkaloids 2005, 61, 1–57. (c) Hirasawa, Y.;
Kobayashi, J.; Morita, H. Heterocycles 2009, 77, 679–729.
(3) Structure determination: (a) Ayer, W. A.; Iverach, G. G. Tetra-
hedron Lett. 1962, 3, 87–92. Enantioselective total syntheses: (b) Yang,
H.; Carter, R. G.; Zakharov, L. N. J. Am. Chem. Soc. 2008, 130, 9238–
9239. (c) Yang, H.; Carter, R. G. J. Org. Chem. 2010, 75, 4929–4938.
Racemic total syntheses: (d) Stork, G.; Kretchmer, R. A.; Schlessinger,
R. H. J. Am. Chem. Soc. 1968, 90, 1647–1648. (e) Ayer, W. A.; Bowman,
W. R.; Joseph, T. C.; Smith, P. J. Am. Chem. Soc. 1968, 90, 1648–1650.
(f) Kim, S.; Bando, Y.; Horii, Z. Tetrahedron Lett. 1978, 2293–2294. (g)
Heathcock, C. H.; Kleinman, E. F.; Binkley, E. S. J. Am. Chem. Soc.
1982, 104, 1054–1068. (h) Schumann, D.; Mueller, H. J.; Naumann, A.
Liebigs Ann. Chem. 1982, 1700–1705. (i) Kraus, G. A.; Hon, Y. S.
Heterocycles 1987, 25, 377–386. (j) Grieco, P. A.; Dai, Y. J. Am. Chem.
Soc. 1998, 120, 5128–5129. Formal syntheses: (k) Padwa, A.; Brodney,
M. A.; Marino, J. P., Jr.; Sheehan, S. M. J. Org. Chem. 1997, 62, 78–87.
(l) Mori, M.; Hori, K.; Akashi, M.; Hori, M.; Sato, Y.; Nishida, M.
Angew. Chem., Int. Ed. 1998, 37, 637–638.
Figure 1. Himeradine A and related Lycopodium alkaloids.
The heptacyclichimeradineA (1) possessesachallenging
array of structural features: ten stereogenic centers includ-
ing one all-carbon quaternary center, a densely packed
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pentacyclic western half, the C8 ꢀC10 -trans-disubstituted
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quinolizidine, and the challenging sigma linkage at C11
(Figure 1). The carbon framework of the western portion is
similar to that found in lycopodine (2);3 however, the
r
10.1021/ol201704g
Published on Web 07/12/2011
2011 American Chemical Society

additional challenge of the C3ꢀC14 linkage increases the
complexity of any synthetic endeavor. A related structural
scaffold can be found in fastigiatine (3).4 The relative
stereochemistries of the eastern quinolizidine ring systems
are distinct from typical stereochemical combinations
found in related natural products such as cermizine D
Synthesis of cyclization precursor 11 isshowninScheme2.
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The key C10 stereocenter was constructed from a Grignard
addition of organomagnesium species 1210 with the known
Ellman imine 1311 in good levels of diastereoselectivity and
chemical yield. Removal of the sulfoxamine under acid-
catalyzed conditions followed by Cbz protection revealed
the carbamate 15. Cross metathesis of alkene 15 with
crotonaldehyde (16) cleanly provided the enal 11. We have
previously shown that cross metathesis of monosubsti-
tuted alkenes with R,β-unsaturated carbonyl compounds
proceeds in higher chemical yield when the unsaturated
carbonyl compound contains a β-methyl substitution
(e.g., 16).3b,c,12
(4).5 In particular, the axially disposed C10 moiety creates
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added synthetic challenges. To date, no synthetic endeav-
ors have been published toward himeradine A.6 Herein, we
disclose the synthesis of the eastern portion of himeradine
A and the development of a viable model coupling strategy
for incorporation of the C15ꢀC17 carbons including the
C17 stereogenic center.
Scheme 1. Retrosynthesis
Scheme 2. Synthesis of Cyclization Precursor
The key Lewis acid catalyzed intramolecular, hetero-
atomMichael additionisshowninScheme3.Wehadhypo-
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thesized that the C8 and C10 stereogenic centers would
work in concert to direct facial attack on an R,β-unsatu-
rated oxonium ion, as shown in possible transition state
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model 17. The planar carbamate at C10 should force the
Our retrosynthetic strategy is shown in Scheme 1. For the
polycyclic western portion of himeradine, we intend to
adapt our previously developed route to lycopodine for
the construction of the carbon framework.3b,c Compound 5
will be formed via a diastereoselective Overman rearrange-
ment7 of the trichloroimidate derived from alcohol 6. The
required C15 stereogenic center will be introduced through
an organozinc addition to an R,β-unsaturated aldehyde.
This aldehyde will be accessible in turn from a Juliaꢀ
KocienskiꢀBlakemore olefination8 with the known 1-phe-
nyl-1H-tetrazol-5-yl (PT) sulfone 89 and aldehyde 9 fol-
lowed by acid-catalyzed deacetalization with in situ alkene
migration. The quinolizidine ring system 9 will be formed
(5) Structure determination: (a) Morita, H.; Hiraswa, Y.; Shinzato,
T.; Kobayashi, J. Tetrahedron 2004, 60, 7015–7023. Total synthesis: (b)
Nishikawa, Y.; Kitajima, M.; Takayama, H. Org. Lett. 2008, 10, 1987–
1990. (c) Nishikawa, Y.; Kitajima, M.; Kogure, N.; Takayama, H.
Tetrahedron 2009, 65, 1608–1617.
(6) (a) Collett, N. D.; Carter, R. G. 241st NationalAmerican Chemical
Society Meeting, Anaheim, CA, March27ꢀ31, 2011, ORGN-400. (b)Saha,
M.; Carter, R. G. 241st National American Chemical Society Meeting,
Anaheim, CA, March 27ꢀ31, 2011, ORGN-263.
(7) (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597–599.
(b) Overman, L. E.; Carpenter, N. E. Org. React. 2005, 66, 1–107.
(c) Kitamoto, K.; Sampei, M.; Nakayama, Y.; Sato, T.; Chida, N. Org.
Lett. 2010, 12, 5756–5759.
(8) (a) Kocienski, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000, 365–
366. (b) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563–
2585.
(9) Lear, M. J.; Hirama, M. Tetrahedron Lett. 1999, 40, 4897–900.
(10) Comins, D. L.; Libby, A. H.; Al-awar, R. S.; Foti, C. J. J. Org.
Chem. 1999, 64, 2184–2185.
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via a N1 ꢀC2 lactamization strategy. The piperidine ring
system 10 will be constructed from a substrate-controlled,
intramolecular heteroatom Michael addition of enal 11.
(11) Tang, T. P.; Volkman, S. K.; Ellman, J. A. J. Org. Chem. 2001,
66, 8772–8778.
(12) Carlson, E. K.; Rathbone, L. K.; Yang, H.; Collett, N. D.;
Carter, R. G. J. Org. Chem. 2008, 73, 5155–5158.
(4) Structure determination: (a) Gerard, R. V.; MacLean, D. B.;
Fagianni, R.; Lock, C. J. Can. J. Chem. 1986, 64, 943–949. (b) Gerard,
R. V.; MacLean, D. B. Phytochemistry 1986, 25, 1143–1150. Total
synthesis: (c) Liau, B. B; Shair, M. D. J. Am. Chem. Soc. 2010, 132,
9594–9595.
(13) (a) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679–
3681. (b) Martin, R.; Murruzzu, C.; Pericas, M. A.; Riera, A. J. Org.
Chem. 2005, 70, 2325–2328. (c) Coombs, T. C.; Lushington, G. H.;
ꢀ
Douglas, J.; Aube, J. Angew. Chem., Int. Ed. 2011, 50, 2734–3737.
Org. Lett., Vol. 13, No. 15, 2011
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CH2OBn moiety into a pseudoaxial position in the transi-
tion state in order to minimize steric repulsions with the Cbz
moiety.13 We were pleased to see that our hypothesis
proved accurate as aldehyde 10 was isolated as the sole
diastereomer (>20:1 dr) in excellent chemical yield (98%).
revealed the aldehyde 9. We had feared 9 might be prone to
epimerization; however, 9 appeared to be configurationally
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stable at C10 , likely due to the presence of the lactam
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carbonyl again disfavoring placement of the C10 substituent
in an equatorial position due to A1,3 strain.13
Scheme 3. Intramolecular Heteroatom Michael Addition
Scheme 4. Synthesis of the Quinolizidine Core
The next hurdle was the construction of the quinolizodine
ring system (Scheme 4). Wittig olefination of aldehyde 10
provided the R,β-unsaturated ester 21 in excellent yield. We
had anticipated that hydrogenation of 21 would not only
reduce the alkene but also induce Cbz deprotection and
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debenzylation at C11 . To our surprise, only two of the three
predicted events occurred, delivering the benzyl ether 22 as
the sole product in high yield. Lactam formation of 22 (or its
corresponding carboxylic acid) under a variety of conditions
proved unusually challenging. Fortunately, we ultimately
identified that thermolysis under microwave irradiation
cleanly induced lactam formation in high yield. The syn-
thetic challenge with this bond formation may be due to the
With the aldehyde 9 in hand, we shifted our attention to
the incorporation of the C15ꢀC17 carbon atoms and the
C
17 stereogenic center (Scheme 5). Olefination of 9 with the
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required placement of the C10 substituent in the axial
known PT sulfone 89 gave the desired β,γ-unsaturated
acetal in good yield with an inconsequential 14:1 E/Z
selectivity. Treatment of acetal 7 under aqueous acidic
conditions induced both acetal deprotection and alkene
isomerization to cleanly provide the desired R,β-unsatu-
rated aldehyde 26 with excellent E/Z selectivity (>20:1).
N-Methyl diphenylprolinol catalyzed addition of Et2Zn to
the aldehyde 26 revealed the allylic alcohol 27 in 10:1
dr.16,17 Formation of the trichloroacetimidate was accom-
plished using DBU as the base followed by thermolysis at
90 °C in the presence of K2CO3 to cleanly generate the
rearranged amide 5. The presence of the carbonate base
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orientation to facilitate C2 ꢀN1 bond formation. Interest-
ingly, heating of amine 22 in refluxing xylenes (approx-
imately 140 °C) using an oil bath provided the product 23 in
significantly lower yield (40% conversion after 48 h). Mi-
crowave irradiation’s ability to provide purely rotational
energy transfer14 may facilitate this transformation more
efficiently than standard thermal conditions, thereby indu-
cing rotation of the side arm into close proximity for the 2°
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amine to attack the C2 ester. Next, hydrogenation of the
benzyl ether 23 under essentially the same conditions as
employed previously with compound 21 provided the free
alcohol 24. One possible explanation for the divergent
reactivity (compounds 21 vs 23) may be the presence of
the free amine in compound 22, which may poison the
catalyst. The stereochemistry of the newly formed quinoli-
zidine ring system was conclusively established by X-ray
crystallographic analysis on the thiolactam 25.15 Oxidation
of 1° alcohol 24 under buffered DessꢀMartin conditions
(16) (a) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem.
Soc. 1987, 109, 7111–7115. (b) Shibata, T.; Tabira, H.; Soai, K. J. Chem.
Soc., Perkin Trans. 2 1998, 177–178. (c) Nishiyama, T.; Kusumoto, Y.;
Okumura, K.; Hara, K.; Kusaba, S.; Hirata, K.; Kamiya, Y.; Isobe, M.;
Nakano, K.; Kotsuki, H.; Ichikawa, Y. Chem.;Eur. J. 2010, 16, 600–
610.
(17) Stereochemical assignment at C15 was established via advanced
Mosher ester analysis as detailed in the Supporting Information. Ohtani,
I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991,
113, 4092–4096.
(14) Loupy, A., Ed. In Microwaves in Organic Synthesis; Wiley-VCH
Verlag GmbH & Co: Weinheim, 2002; pp 1ꢀ73.
(18) Nishikawa, T.; Asai, M.; Ohyabu, N.; Isobe, M. J. Org. Chem.
1998, 63, 188–192.
(15) See Supporting Information of crystallographic information.
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Org. Lett., Vol. 13, No. 15, 2011

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In summary, the synthesis of the C15ꢀC17/N1 ꢀC11
quinolizidine core of himeradine A has been accom-
plished. Key steps in the synthetic sequence include
a diastereoselective Overman rearrangement, a sub-
strate-controlled, intramolecular heteroatom Michael
addition, and a microwave-induced lactam formation.
Further studies toward the total synthesis of himeradine
A and other related Lycopodium alkaloids will be re-
ported in due course.
Scheme 5. Incorporation of the C15ꢀC17 Portion
Acknowledgment. Financial support was provided by
the National Institutes of Health (NIH) (GM63723).
The National Science Foundation (CHE-0722319) and
the Murdock Charitable Trust (2005265) are acknowl-
edged for their support of the NMR facility. We thank
Dr. Lev N. Zakharov (OSU and University of Oregon)
for X-ray crystallographic analysis of compound 25 as
ꢀ
well as Professor Max Deinzer and Dr. Jeff Morre
(OSU) for mass spectra data. Finally, the authors are
grateful to Professor James D. White (OSU) and Dr.
Roger Hanselmann (Rib-X Pharmaceuticals) for their
helpful discussions.
Supporting Information Available. Complete experi-
1
mental procedures are provided, including H and 13C
spectra, of all new compounds. X-ray crystallographic
data (CIF) for compound 25 is also provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
appeared to prevent decomposition under the reaction
conditions.18
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