Total synthesis of sedum alkaloids via catalyst controlled aza-cope rearrangement and hydroformylation with formaldehyde

Article abstract of DOI:10.1021/ol302769r

The catalytic asymmetric aminoallylation of chiral aldehydes is developed as a new method for the catalyst controlled synthesis of syn-and anti-1,3-aminoalcohols. This methodology is highlighted in the synthesis of the sedum alkaloids (+)-sedridine and (+)-allosedridine both of which have their final carbon incorporated during closure of the piperidine ring via a hydroformylation with formaldehyde.

Full text of DOI:10.1021/ol302769r

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Total Synthesis of Sedum Alkaloids
via Catalyst Controlled aza-Cope
Rearrangement and Hydroformylation
with Formaldehyde
Hong Ren and William D. Wulff*
Department of Chemistry, Michigan State University, East Lansing, Michigan 48824,
United States
Wulff@chemistry.msu.edu
Received October 8, 2012
ABSTRACT
The catalytic asymmetric aminoallylation of chiral aldehydes is developed as a new method for the catalyst controlled synthesis of syn- and anti-
1,3-aminoalcohols. This methodology is highlighted in the synthesis of the sedum alkaloids (þ)-sedridine and (þ)-allosedridine both of which
have their final carbon incorporated during closure of the piperidine ring via a hydroformylation with formaldehyde.
The sedum alkaloids exist widely in nature, and these
types of alkaloids have memory-enhancing properties and
are effective in the treatment of cognitive disorders.1 The
most commonly occurring members of this alkaloid family
are 2-substituted piperidines with various combinations
of hydroxyl functionalities in the side chains, featuring the
(1) Meth-Cohn, O.; Yu, C. Y.; Lestage, P.; Lebrun, M. C.; Cagniard,
D. H.; Renard, P. Eur. Pat. 1050531, 2000.
(2) For a review, see: Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58,
5957–5978.
(3) For examples after 2008, see: (a) Chen, L.-J.; Hou, D.-R. Tetra-
hedron: Asymmetry 2008, 19, 715–720. (b) Chang, M. Y.; Lin, C. Y.; Wu,
T. C.; Sun, P. P. J. Chin. Chem. Soc. 2008, 55, 421–430. (c) Rice, G. T.;
White, M. C. J. Am. Chem. Soc. 2009, 131, 11707–11711. (d) Wang, G.;
Vedejs, E. Org. Lett. 2009, 11, 1059–1061. (e) Davies, S. G.; Fletcher,
A. M.; Roberts, P. M.; Smith, A. D. Tetrahedron 2009, 65, 10192–10213.
(f) Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P. Chirality 2010,
212–216. (g) Shaikh, T. M.; Sudalai, A. Eur. J. Org. Chem. 2010, 3437–
3444. (h) Coldham, I.; Leonori, D. J. Org. Chem. 2010, 75, 4069–4077.
(i)Bates, R. W.;Lu, Y.Org. Lett. 2010, 12, 3938–3941. (j) Boussonniere, A.;
Ranaivondrambola, T.; Lebreton, J.; Mathe-Allainmat, M. Synthesis
2010, 2456–2462. (k) Liu, J.-D.; Chen, Y.-C.; Zhang, G.-B.; Li, Z.-Q.;
Chem, P.; Du, J.-Y.; Tu, Y.-Q.; Fan, C.-A. Adv. Synth. Catal. 2011, 353,
2721–2730. (l) Riva, E.; Rencurosi, A.; Gagliardi, S.; Passarella, D.;
Martinelli Chem.;Eur. J. 2011, 17, 6221–6226. (m) Satyalakshmi, G.;
Suneel, K.; Shinde, D. B.; Das, B. Tetrahedron: Asymmetry 2011, 22,
1000–1005. (n) Bhat, C.; Tilve, S. Tetrahedron Lett. 2011, 52, 6566–
6568.
Figure 1. Sedum and related alkaloid natural products.
1,3-amino alcohol moiety, and a select set are shown in
Figure 1.2 A review of the syntheses of sedium alkaloids
has appeared,2 and the field has remained very active.3
Our efforts in this field began with an interest in devel-
oping an approach to the sedum alkaloids that has a
r
10.1021/ol302769r
XXXX American Chemical Society

Scheme 1. Retrosynthesis of (þ)-Sedridine and (þ)-Allosedridine
Scheme 2. Hydroformylation with Formaldehyde
from the incorporation of a molecule of benzoic acid into
the VANOL boroxinate catalyst 6.7,8
The pertinent issue to address here is whether the pre-
sence of a chiral center in the aldehyde 1 (Scheme 3) will
interfere with the normal operations of the boroxinate/
benzoate catalyst in the aza-Cope rearrangement? If the
answer is no then this reaction would represent a new
method for the controlled synthesis of syn- and anti-1,3-
aminoalcohols. The controlled synthesis of both syn- and
anti-1,3-aminoalcohols from a single substrate have been
hydroformylation with formaldehyde and a catalyst con-
trolled asymmetric aza-Cope rearrangement (or amino-
allylation) as the key steps (Scheme 1). The catalyst
controlled aza-Cope rearrangement was envisioned to
be featured in ordered stereoselective syntheses of
(þ)-sedridine and (þ)-allosedridine which constitute one
of the diastereomeric pairs of natural products in the
sedum alkaloid family.4
Scheme 3. Direct Aminoallylation of Nonchiral Aldehydes
Conventionally, hydroformylation utilizes syngas
(CO/H2) in the presence of a transition metal catalyst
to give homologous linear and/or branched aldehydes. A
recent innovation in hydroformylation chemistry features
an experimentally convenient alternative using formalde-
hyde as a syngas substitute. This synthetically attractive
method was recently described by Morimoto and co-work-
ers when they smartly applied two types of in situ generated
catalysts to separately direct the two cooperative catalytic
processes involved: (1) decarbonylation of an aldehyde and
(2) hydroformylation of an olefin (Scheme 2).5 This dual
catalyst system provides homologated aldehydes in excel-
lent yields and with very high linear to branched ratios. The
intention for the application of thishydroformylation in the
synthesis of sedum alkaloids will be to incorporate it into an
intramolecular amidocarbonylation6 that takes the alkenyl
amino alcohol directly to a piperidine ring.
The key transformation in the synthesis of sedridine and
allosedridine involves an aza-Cope rearrangement of an in
situ generated imine 3 to give imine 4 which upon hydro-
lysis provides the homoallyic amine 5 in high asymmetric
inductions over a broad range of aromatic, alkenyl, and
aliphatic substrates.7 The successful catalyst system results
(8) (a) Hu, G.; Gupta, A. K.; Huang, R. H.; Mukherjee, M.; Wulff,
W. D. J. Am. Chem. Soc. 2010, 132, 14669–14675. (b) Vetticatt, M. J.;
Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13104–13107.
(9) (a) Pillim, R. A.; Russowsky, D.; Dias, L. C. J. Chem. Soc., Perkin
Trans. 1 1990, 1213–1214. (b) Keck, G. E.; Truong, A. P. Org. Lett. 2002,
4, 3131–3134. (c) Davis, F. A.; Gaspari, P. M.; Nolt, B. M.; Xu, P. J. Org.
Chem. 2008, 73, 9619–9626. (d) Gonzalez-Gomez, J. C.; Foubelo, F.;
Yus, M. Synthesis 2009, 2083–2088. (e) De Lamo Marin, S.; Catala, C.;
Kumar, S. R.; Valleix, A.; Wagner, A.; Mioskowski, C. Eur. J. Org.
Chem. 2010, 3985–3989.
(4) For leading references, see ref 3s and: (a) Butruille, D.; Fodor, G.;
Huber, C. S.; Letourneau, F. Tetrahedron 1971, 27, 2055–2067.
(5) Makado, G.;Morimoto, T.;Sugimoto, Y.; Tsutsumi, K.;Kagawa,
N.; Kiuchi, K. Adv. Synth. Catal. 2010, 352, 299–304.
(6) For a review on intramolecular amidocarbonylation, see: Chiou,
W.; Lee, S.; Ojima, I. Can. J. Chem. 2005, 83, 681–692.
(7) Ren, H.; Wulff, W. D. J. Am. Chem. Soc. 2011, 133, 5656–5659.
B
Org. Lett., Vol. XX, No. XX, XXXX

reported from β-aminoketones9 and β-borylamines.10 We
only know of a single example where a catalyst controlled
processcanbeusedtoaccesssyn-oranti-1,3-aminoalcohols
from a single substrate.11,12
The initial screen of chiral aldehydes was carried out
with the TBS protected aldehyde (R)-8a derived from the
commercially available methyl (R)-3-hydroxybutyrate
(Table 1). The diastereoselectivity is nearly equal and
down (Table 1, entry 5) giving an 87% yield and a 20:1
diastereoselectivity in favor of 11 with (R)-VANOL and a
74% yield and a 26:1 diastereoselectivity infavor of10with
(S)-VANOL (these two reactions were with (S)-8).
The interplay of the catalyst with a pre-existing R-chiral
center was also investigated. As shown in Scheme 4, the
reaction of the chiral aldehyde (S)-13 is not under catalyst
control but rather displays a matched and mismatched
relationship. A 12:1 selectivity was observed for the
matched case with the (S)-VANOL catalyst resulting in a
71% isolated yield. The same diastereomer predominated
in the mismatched case with the (R)-VANOL catalyst, but
the selectivity dropped to 2.5:1. The stereochemistry of 14
was assigned as anti since the matched case would be
expected to be with the Re-face addition to the imine with
the (S)-VANOL catalyst since this is the preference with
nonchiral aldehydes.7
Table 1. Direct Aminoallylation of Chiral β-Alkoxy Aldehydes
Scheme 4. Direct Aminoallylation of a Chiral R-Alkoxy Aldehyde
conv (10 þ 11):
% yield
10:11d (10 þ 11)e
entrya series
ligand
PG
(%)b
12c
1
2
a
a
b
c
(R)-VANOL TBS
(S)-VANOL TBS
(R)-VANOL Bn
73 (70)
72 (67)
(80)
3:1
33:1
1:23
nd
48
44
nd
nd
87
74
4:1
3
4:1
4
(R)-VANOL TBDPS (52)
1:10
100:0
100:0
nd
5f
6f
d
d
(R)-VANOL TES
(S)-VANOL TES
100
100
1:20
26:1
a Unless otherwise specified all reactions were run at 0.2 M in amine 2
with 1.1 equiv of 8. The catalyst was prepared from 1 equiv of the
ligand, 2 equiv of 2,4,6-trimethylphenol, 3 equiv of H2O, and 3 equiv
BH3•SMe2. nd = not determined. b Calculated from the 1H NMR
spectrum of the crude reaction mixture from the ratio (10 þ 11):2 (or
2 þ imine 9) and the isolated yield of 10 þ 11. The value in parentheses
based on the ratios of 2 (or 2 þ imine 9), 10, 11, and 12 and assuming no
other products are formed. In most cases, the unreacted material is in the
form of amine 2, but in some cases a small amount of imine 9 formed
from 8 and 2 is present. c Determined from the 1H NMR spectrum of the
crude reaction mixture. d Isolated ratio. e Isolated yield of a mixture of
10 þ 11 after chromatography on silica gel. f Reaction performed on
(S)-8 also of 98% ee. This reaction gives the enantiomer of 10 and 11.
When Morimoto’s protocol was applied to an intra-
molecular amidocarbonylation with a homoallylic amine,
some branched hydroformylation and other side products
were obtained. When formalin, which contains methanol
as a stabilizer, was utilized as the formaldehyde source, a
significant amount of the 2-alkoxypiperidine 18 was ob-
1
served in the H NMR spectrum of the crude reaction
opposite with the (R)- and (S)-ligands of VANOL (33:1
vs 1:23), and thus this is a case of catalyst control (entries 1
and 2). The total yield of 10a and 11a was low, and the
elimination product 12 was observed as a byproduct. The
reaction of the benzyl protected aldehyde 8b with amine 2
gave a 4:1 mixture of aza-Cope product (10b þ 11b) and
byproduct 12 (entry 3). Incorporation of a larger protect-
ing group (TBDPS) lead to a mixture largely consisting
of the eliminated imine 12 (entry 4). However, when the
sterically less hindered triethylsilyl protecting group (TES)
was installed, the formation of 12 was completely shut
mixture (Table 2, entry 1). para-Formaldehyde gave dide-
hydropiperidine 17 and its five-membered analog 19 along
with some of the olefin isomerization product 20. Even
with less than complete regio- and chemoselection, the
didehydropiperidine 17 could be obtained in 73% isolated
yield (Table 2, entry 3).13
The intramolecular amidocarbonylation was then ap-
plied to the synthesis of (ꢀ)-coniine 22. The chiral center is
installed in acyclic amine 21 in 83% yield and 95% ee with
catalytic asymmetricdirectaminoallylation ofn-butanalas
shown in Scheme 5.7 The piperidine ring is closed using the
intramolecular amidocarbonylation in 71% yield. Subse-
quent reduction of the double bond and cleavage of Boc
(10) Sole, C.; Whiting, A.; Gulyas, H.; Fernandez, E. Adv. Synth.
Catal. 2011, 353, 376–384.
(11) Jha, V.; Kondekar, N. B.; Kumar, P. Org. Lett. 2010, 12, 2762–
2765.
(12) Another example would presumably be a catalyst controlled
process if the enantiomer of the enzyme was available: Millet, R.; Traff,
(13) 2-Alkoxypiperidines and didehydropiperidines are both useful
intermediates for the synthesis of piperidine compounds,6 and in the
present case both could be reduced to provide access to the target
alkaloids. This possibility was not pursued in the present work.
€
A. M.; Petrus, M. L.; Backvall, J.-E. J. Am. Chem. Soc. 2010, 132,
15182–15184.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2. Optimization of the Intramolecular Amidocarbonylation
with Formaldehyde
Scheme 6. Synthesis of (þ)-Sedridine and (þ)-Allosedridine
formaldehyde
source
temp yield 17
entrya PG
(°C)
(%)b
17:19:20c
d
1
Cbz formalin
90
90
90
90
46
69
73
nd
ꢀ
2
Cbz paraformaldehyde
Boc paraformaldehyde
Boc paraformaldehyde
6:1:1
6:1:1
2:3:0
3
4e
a Unless otherwise specified all reactions were run at 0.15 M in 16
with 5.0 equiv of formaldehyde. nd = not determined. b Isolated yield
after chromatography on silica gel. c Calculated from the 1H NMR
spectrum of the crude reaction mixture. d A 38% yield of 18 also formed
in this reaction. e PPTS (5 mol %) was added to this reaction.
gave (þ)-sedridine in 83% yield. (þ)-Allosedridine was
obtained in a similar manner utilizing the boroxinate
catalyst 6 derived from (S)-VANOL which allowed for
the isolation of 23 in 61% yield as a single diastereomer.
Protection with TBS and hydroformylation with formal-
dehyde gave 25 in 72% yield and subsequently a final
conversion to (þ)-allosedridine in 74% yield in two steps.
This work has demonstrated that chiral aldehydes bear-
ing a β-alkoxy group will undergo a chiral Brønsted acid
catalyzed 2-aza-Cope rearrangement with an in situ gen-
erated imine to give either syn- or anti-1,3-homoallylic
amino alcohols depending on the absolute configuration
of the catalyst. This catalyst controlled 2-aza-Cope rear-
rangement is coupled with a syngas-free hydroformylation
in a highly stereoselective synthesis of (þ)-sedridine and
(þ)-allosedridine from the same β-alkoxy aldehyde.
Scheme 5. Synthesis of (ꢀ)-Coniine
give the target compound (ꢀ)-coniine 22 in 91% yield over
two steps.
Finally, we coupled the catalyst controlled aza-Cope
rearrangement and intramolecular amidocarbonylation in
the total synthesis of (þ)-sedridine and (þ)-allosedridine
(Scheme 6). Chiral aldehyde (S)-8d was subjected to a
diastereoselective aza-Cope rearrangement catalyzed by
the boroxinate catalyst 6 derived from (R)-VANOL
(Scheme 6). Following hydrolysis and protection with a
Boc group, purification gave 26 as a single diastereomer
in 72% yield over three steps in a one-pot fashion. After
protection an intramolecular amidocarbonylation reac-
tion afforded 28 in 78% yield. Reduction and deprotection
Acknowledgment. Support provided by the National
Institute of General Medical Sciences (GM094478).
Supporting Information Available. Procedures and
spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX