Polysubstituted piperidines via iodolactonization: Application to the asymmetric synthesis of (+)-pseudodistomin D

Article abstract of DOI:10.1021/ol300209s

Conjugate addition of lithium (S)-N-allyl-N-(α-methyl-p- methoxybenzyl)amide to methyl (E,E)-hepta-2,5-dienoate furnished the corresponding β-amino ester. N-Protecting group manipulation, ring-closing metathesis, and ester hydrolysis gave enantiopure [N(1

Full text of DOI:10.1021/ol300209s

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1672–1675
Polysubstituted Piperidines via
Iodolactonization: Application to
the Asymmetric Synthesis of
(þ)-Pseudodistomin D
Stephen G. Davies,* Ai M. Fletcher, James A. Lee, Paul M. Roberts, Angela J. Russell,
Rachael J. Taylor, Anthony D. Thomson, and James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K.
steve.davies@chem.ox.ac.uk
Received January 26, 2012
ABSTRACT
Conjugate addition of lithium (S)-N-allyl-N-(R-methyl-p-methoxybenzyl)amide to methyl (E,E)-hepta-2,5-dienoate furnished the corresponding
β-amino ester. N-Protecting group manipulation, ring-closing metathesis, and ester hydrolysis gave enantiopure [N(10)-tert-butoxycarbonyl-
1,2,3,6-tetrahydropyridin-20-yl]ethanoic acid. Subsequent iodolactonization gave a bicyclic iodolactone scaffold. This key intermediate was
elaborated to (þ)-pseudodistomin D [in >99% ee and 7% yield over 16 steps from methyl (E,E)-hepta-2,5-dienoate].
The pseudodistomin alkaloids were the first piperidine
alkaloids to be isolated from a marine source, namely
the Okinawan tunicate Pseudodistoma kanoko1 and (later)
the ascidian Pseudodistoma megalarva.2 Six members of the
family (pseudodistomins AꢀF) have so far been isolated, the
structures of which differ in either the relative stereochemistry
of the C(2)-alkyl chain, C(4)-hydroxyl, and C(5)-amino
substituents of the piperidine ring, or in the structure of the
C(2)-alkyl chain (Figure 1).3 Pseudodistomin E is yet to
acquiesce to laboratory synthesis, while routes to pseudodis-
tomins A,3f,4 B,3b,4,5 C,6 D,7 and F5a have been reported.8,9
We have previously demonstrated that the ring-closing
metathesis of enantiopure, substituted N-allyl-N-but-3-
(4) Kiguchi, T.; Yuumoto, Y.; Ninomiya, I.; Naito, T. Chem. Pharm.
Bull. 1997, 45, 1212.
(5) (a) Ma, D.; Sun, H. J. Org. Chem. 2000, 65, 6009. (b) Davis, F. A.;
Zhang, J.; Li, Y.; Xu, H.; DeBrosse, C. J. Org. Chem. 2005, 70, 5413.
(6) Doi, Y.; Ishibashi, M.; Kobayashi, J. Tetrahedron 1996, 52,
4573. Langlois, N. Org. Lett. 2002, 4, 185. Tanaka, K.; Maesoba, T.;
Sawanishi, H. Heterocycles 2006, 68, 183.
(1) (a) Ishibashi, M.; Ohizumi, Y.; Sasaki, T.; Nakamura, H.; Hirata,
Y.; Kobayashi, J. J. Org. Chem. 1987, 52, 450. (b) Kobayashi, J.; Cheng,
J. F.; Ishibashi, M.; Nakamura, H.; Ohizumi, Y.; Hirata, Y.; Walchli,
M. R.; Sasaki, T. Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 1988,
30, 268. (c) Kobayashi, J.; Naitoh, K.; Doi, Y.; Deki, K.; Ishibashi, M.
J. Org. Chem. 1995, 60, 6941.
(2) 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.
(3) The initially proposed structures of pseudodistomins A and B (see
ref 1a and ref 1b) were subsequently revised (to those shown in Figure 1)
following synthetic studies and degradation experiments performed on
the natural products; see: (a) Naito, T.; Yuumoto, Y.; Ninomiya, I.;
Kiguchi, T. Tetrahedron Lett. 1992, 33, 4033. (b) Kiguchi, T.; Yuumoto,
Y.; Ninomiya, I.; Naito, T.; Deki, K.; Ishibashi, M.; Kobayashi, J.
Tetrahedron Lett. 1992, 33, 7389. (c) Kiguchi, T.; Yuumoto, Y.; Nino-
miya, I.; Naito, T. Tennen Yuki Kagobutsu Toronkai Koen Yoshishu
1992, 34, 392. (d) Ishibashi, M.; Deki, K.; Kobayashi, J. J. Nat. Prod.
1995, 58, 804. (e) Naito, T.; Yuumoto, Y.; Kiguchi, T.; Ninomiya, I.
J. Chem. Soc., Perkin Trans. 1 1996, 3, 281. (f) Kiguchi, T.; Yuumoto, Y.;
Ninomiya, I.; Naito, T. Heterocycles 1996, 42, 509.
(7) Trost, B. M.; Fandrick, D. R. Org. Lett. 2005, 7, 823.
(8) Several total syntheses (both racemic and asymmetric) of tetra-
hydropseudodistomin (the product resulting from hydrogenation of
either pseudodistomin A or pseudodistomin B) have also been reported;
see: ref 3a, ref3e and (a) Utsunomiya, I.; Ogawa, M.; Natsume, M.
Heterocycles 1992, 33, 349. (b) Knapp, S.; Hale, J. J. J. Org. Chem. 1993, 58,
2650. (c) Kiguchi, T.; Ikai, M.; Shirakawa, M.; Fujimoto, K.; Ninomiya, I.;
Naito, T. J. Chem. Soc., Perkin Trans. 1 1998, 893. For a synthesis of
octahydropseudodistomin F, see: (d) Ma, D.; Sun, H. Tetrahedron Lett.
1999, 40, 3609. For syntheses of the funcationalized piperidine core, see: (e)
Kiguchi, T.; Okazaki, M.; Naito, T. Heterocycles 1999, 51, 2711.
(f) Haddad, M.; Larcheveque, M.; Tong, H. M. Tetrahedron Lett. 2005,
46, 6015. (g) Leonard, N. M.; Woerpel, K. A. J. Org. Chem. 2009, 74, 6915.
(9) For reviews (including discussion of the structural revision of
pseudodistomins A and B), see: (a) Kobayashi, J.; Ishibashi, M.
Heterocycles 1996, 42, 943. (b) Ninomiya, I.; Kiguchi, T.; Naito, T.
The Alkaloids 1998, 50, 317. (c) Kobayashi, J.; Ishibashi, M. Stud. Nat.
Prod. Chem. 2000, 23, 185.
r
10.1021/ol300209s
Published on Web 03/14/2012
2012 American Chemical Society

enyl amines (prepared via our lithium amide conjugate
addition methodology)10 represents a rapid and efficient
entry to substituted tetrahydropyridine scaffolds, and have
demonstrated the elaboration of these useful templates to a
range of Sedum alkaloids,11 the Hemlock alkaloid
coniine,12 and homopipecolic acid 412 (Scheme 1). In order
to further extend this useful methodology, we envisaged
that iodolactonization of an enantiopure tetrahydropyr-
idine scaffold (such as the carboxylic acid resulting from
ester hydrolysis of 3) would generate the corresponding
iodolactone with high diastereoselectivity and that this
template would act as a key intermediate for the synthesis
of a range of alkaloid natural products, including the
pseudodistomin alkaloids and their analogues. We deline-
ate hereinour preliminaryinvestigations inthisarea, which
culminate in the synthesis of pseudodistomin D. To date,
only one other asymmetric synthesis of this natural pro-
duct has been reported by Trost and Fandrick.7 Their
approach employed dynamic kinetic resolution (DKR) of
a vinyl aziridine, epoxidation of an allylic carbamate with
m-CPBA, and a reductive alkyne hydroamination step
to set the stereochemistry within the piperidine core
of the final product, and delivered pseudodistomin D
in 12% yield and 94% ee over 12 steps from ethyl
2,4-dibromopropionate.
Scheme 1
Saponification of 312 gave the corresponding carboxylic
acid, but attempts at effecting iodolactonization of this
substrate returned only complex mixtures of products, pos-
sibly due to competing oxidative processes at the nitrogen
atom. In order to suppress any such unwanted side reactions,
an alternative strategy was devised. Conjugate addition
of lithium (S)-N-allyl-N-(R-methyl-p-methoxybenzyl)amide
(>99% ee)13 to methyl (E,E)-hepta-2,5-dienoate 114 gave
β-amino ester (S,S)-5in >95:5 dr, which was isolated in 59%
yield (∼90% purity). The absolute (S,S)-configuration with-
in 5 was assigned by reference to the transition state mne-
monic developed by us to rationalize the very high facial
selectivity observed upon conjugate addition of this class of
lithium amides to R,β-unsaturated esters and amides.15
Chemoselective removal of the N-R-methyl-p-methoxyben-
zyl group within 5 was achieved upon treatment with formic
acid in the presence of triethylsilane,16 with subsequent
N-Boc protection of the resultant secondary amine 6 giving
tert-butyl carbamate 717 in 80% yield over the 2 steps.
Treatment of 7 with Grubbs I gave tetrahydropyridine 8 in
97% isolated yield, with saponification of 8 giving carboxylic
acid 9 quantitatively (Scheme 2).
Iodolactonization of 9 upon treatment with I2 and
NaHCO3 in MeCN proceeded to give the bicyclic iodo-
lactone 10 in 87% isolated yield as a single diastereoisomer
(Scheme 3). The relative configuration within 10 was
(11) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Smith, A. D.
Tetrahedron 2009, 65, 10192.
(12) (a) Davies, S. G.; Iwamoto, K.; Smethurst, C. A. P.; Smith,
A. D.; Rodriguez-Solla, H. Synlett 2002, 1146. (b) Chippindale, A. M.;
Davies, S. G.; Iwamoto, K.; Parkin, R. M.; Smethurst, C. A. P.; Smith,
A. D.; Rodriguez-Solla, H. Tetrahedron 2003, 59, 3253.
(13) Enantiopure (S)-R-methyl-p-methoxybenzylamine (>99% ee)
is commercially available. Alkylation of (S)-R-methyl-p-methoxybenzy-
lamine upon treatment with BuLi followed by allyl bromide gave (S)-N-
allyl-N-(R-methyl-p-methoxybenzyl)amine; subsequent deprotonation
with BuLi in THF generated a yellow solution of lithium (S)-N-allyl-
N-(R-methyl-p-methoxybenzyl)amide.
(14) Methyl (E,E)-hepta-2,5-dienoate 5 was prepared via palladium-
catalyzed coupling of methyl acrylate with 1,3-butadiene according to
our previously reported procedure; see: Davies, S. G.; Haggitt, J. R.;
Ichihara, O.; Kelly, R. J.; Leech, M. A.; Price Mortimer, A. J.; Roberts,
P. M.; Smith, A. D. Org. Biomol. Chem. 2004, 2, 2630.
Figure 1. Structures of the pseudodistomin alkaloids.
(10) (a) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2,
183. (b) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asym-
metry 2005, 16, 2833. (c) Davies, S. G.; Garrido, N. M.; Kruchinin, D.;
Ichihara, O.; Kotchie, L. J.; Price, P. D.; Price Mortimer, A. J.; Russell,
A. J.; Smith, A. D. Tetrahedron: Asymmetry 2006, 17, 1793. (d) Davies,
S. G.; Mulvaney, A. W.; Russell, A. J.; Smith, A. D. Tetrahedron:
Asymmetry 2007, 18, 1554. (e) Davies, S. G.; Fletcher, A. M.; Roberts,
P. M. Org. Synth. 2010, 87, 143.
(15) Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron: Asym-
metry 1994, 5, 1999.
Org. Lett., Vol. 14, No. 7, 2012
1673

Scheme 2a
Scheme 3
a PMP = p-methoxyphenyl.
unambiguously established by single-crystal X-ray diffrac-
tion analysis (Figure 2),18 with the absolute (S,S,S)-
configuration being assigned by inference from the con-
figuration of the C(5)-stereocenter, originally formed upon
conjugate addition of lithium (S)-N-allyl-N-(R-methyl-
p-methoxybenzyl)amide to R,β-unsaturated ester 1.15
Reduction of lactone 10 with DIBAL-H followed by
treatment of the resultant iodohydrin 11 with aq. NaOH
gave aldehyde 12 in 85% yield over the 2 steps. Wittig
olefination of 12 with the ylide derived from
[Ph3P(CH2)4OBn]þBrꢀ19 gave alkene 13 in 95% yield.
Due to overlapping resonances in the 1H NMR spectrum
of both the crude and purified product, the diastereoselec-
tivity of this olefination reaction was tentatively assessed as
>95:5. The (Z)-configuration was assigned to the major
diastereoisomer. Mitsunobu reaction21 of 14 with N(1)-phe-
nyl-1H-tetrazole-5-thiol (PTSH) gave sulfide 15 in 83% yield,
and subsequent oxidation upon treatment of 15 with m-
CPBA gave sulfone 16 in 78% isolated yield (Scheme 3).
1
3
diastereoisomeric product 13 on the basis of H NMR J
0
0
coupling constant analysis (J2 ,3 < 11 Hz), and by analogy
to the well-established stereochemical outcome of this type
of Wittig olefination reaction.20 In any case, subsequent
treatment of 13 with H2 in the presence of Pd(OH2)/C
gave alcohol 14 in 95% isolated yield as a single
(16) Zhong, M. H.; Cohen, J. H.; Abdel-Magid, A. F.; Kenney, B. D.;
Maryanoff, C. A.; Shah, R. D.; Villani, F. J., Jr.; Zhang, F.; Zhang, X.
Tetrahedron Lett. 1999, 40, 7721.
(17) tert-Butyl carbamate 7 and all subsequent carbamate-containing
compounds in this synthesis were rotameric in CDCl3 (and PhMe-d8 or
DMSO-d6) at rt. However, coalescence occurred when the spectrum was
recorded at 90 °C (in PhMe-d8 or DMSO-d6).
(18) Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as supple-
mentary publication number CCDC 858971.
(19) [Ph3P(CH2)4OBn]þBrꢀ was prepared from butane-1,4-diol
(92% yield over 3 steps).
(20) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
(21) (a) Mitsunobu, O.; Yamada, M.; Mukaiyama, T. Bull. Chem.
Soc. Jpn. 1967, 40, 935. (b) Mitsunobu, O.; Yamada, Y. Bull. Chem. Soc.
Jpn. 1967, 40, 2380. (c) Kumara Swamy, K. C.; Bhuvan Kumar, N. N.;
Balaraman, E.; Pavan Kumar, K. V. P. Chem. Rev. 2009, 109, 2551.
Figure 2. Chem 3D representation of the single crystal X-ray
diffraction structure of 10 (selected H-atoms are omitted for clarity).
1674
Org. Lett., Vol. 14, No. 7, 2012

Staudinger conditions24 gave aminopiperidine 19, which
was isolated in 87% yield, 90:10 dr [(E,E)/(60Z,80E)], and
>99% ee.25 Finally, treatment of 19 with HCl in MeOH gave
Scheme 4
pseudodistomin
D
as its hydrochloride salt, with
subsequent sequential recrystallization and basification giv-
ing pseudodistomin D 20 in 80% yield and >95:5 dr
[(E,E)/(60Z,80E)]. The spectroscopic properties of our syn-
thetic sample of pseudodistomin D 20 were in excellent
agreement with those originally reported for the nat-
ural product {[R]D þ5.6 (c 0.3 in MeOH); lit.2 for
25
25
sample isolated from natural source [R]D þ5 (c 0.26 in
MeOH)} and with the synthetic sample reported by
25
Trost and Fandrick {lit.7 [R]D þ6 (c 0.2 in MeOH) for
94% ee}. Given the known enantiomeric purity of the
lithium (S)-N-allyl-N-(R-methyl-p-methoxybenzyl)amide
12 (i.e., >99% ee) employed for the conjugate addition to
R,β-unsaturated ester 1, and the enantiomeric purity of
aminopiperidine 19 (i.e., >99% ee), the enantiomeric purity
of pseudodistomin D 20 and intermediates 5ꢀ18 (and 180)
can be confidently inferred as >99% ee (Scheme 4).
In conclusion, conjugate addition of lithium (S)-N-allyl-
N-(R-methyl-p-methoxybenzyl)amide to methyl (E,E)-
hepta-2,5-dienoate furnished the corresponding β-amino
ester. N-Protecting group manipulation, ring-closing
metathesis, and ester hydrolysis gave enantiopure [N(10)-tert-
butoxycarbonyl-1,2,3,6-tetrahydropyridin-20-yl]ethanoic
acid. Subsequent iodolactonization gave a bicyclic iodo-
lactone scaffold. This key intermediate was elaborated to
(þ)-pseudodistomin D [in >99% ee and 7% yield over 16
steps from methyl (E,E)-hepta-2,5-dienoate]. The key
bicyclic iodolactone intermediate of this synthesis should
prove readily applicable to diversification to facilitate the
synthesis of the other members of the pseudodistomin
family, and further investigations toward this aim are
currently underway within our laboratory.
22
ꢀ
JuliaꢀKocienski olefination of sulfone 16 with (E)-
hept-2-enal (commercially available, 97% purity) furn-
ished (E,E)-17 in 90:10 dr, which was isolated in 82% yield
(and 90:10 dr) after chromatography [the minor product
was assigned as the (60Z,80E)-isomer].23 Ring opening of
the epoxide functionality within 17 upon treatment with
NaN3 in the presence of NH4Cl in DMSO gave an ∼75:25
mixture of regioisomeric azides 18 and 180, from which the
major product 18 was isolated in 58% yield and 90:10 dr
[(E,E)/(60Z,80E)] and the minor product 180 in 20% yield
and 90:10 dr [(E,E)/(60Z,80E)]. Reduction of 18 under
Supporting Information Available. Experimental pro-
cedures, characterization data, copies of 1H and 13C
NMR spectra, and crystallographic information file (for
structure CCDC 858971). This material is available free
of charge via the Internet at http://pubs.acs.org.
ꢀ
(22) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Synlett 1998, 26.
(25) The enantiomeric purity of 20 was confirmed as >99% ee by 500
MHz 1H NMR spectroscopic analyses in the presence of (S)-O-acet-
ylmandelic acid and (R,S)-O-acetylmandelic acid; see: Parker, D. Chem.
Rev. 1991, 91, 1441. This value is consistent with the enantiomeric purity
of the lithium (S)-N-allyl-N-(R-methyl-p-methoxybenzyl)amide 12 (i.e.,
>99% ee) employed for the conjugate addition to R,β-unsaturated ester 1.
(23) This assignment was made from the known purity of the (E)-
hept-2-enal used in the olefination reaction, and from comparison of the
13C NMR chemical shift values associated with the diene moiety in the
alkyl side chain of the minor diastereoisomeric product with those
previously reported for pseudodistomin A triacetate [i.e., (60E,80Z)]
and its (60Z,80E)-geometric isomer; see: ref 3f.
(24) (a) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635.
(b) Gololobov, Y. G. Tetrahedron 1981, 37, 437.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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