Tandem nucleophilic addition/oxy-2-azonia-cope rearrangement for the formation of homoallylic amides and lactams: Total synthesis and structural verification of motuporamine G

Article abstract of DOI:10.1021/ja310002m

In the presence of a Lewis acid, β,γ-unsaturated ketones and oximes or imines undergo nucleophilic addition to produce zwitterion intermediates, and subsequent oxy-2-azonia-Cope rearrangements give homoallylic amides. In the case of 2-vinylcycloalkanones, the process results in ring enlargement, providing a novel route to 9- to 16-membered lactams. The preparative significance of this protocol was evidenced by a short synthesis of macrocyclic alkaloid motuporamine G. The stereochemistry-defining step of this oxy-azonia-Cope rearrangement was further studied computationally. Despite a high-energy preequilibrium in the formation of zwitterionic intermediates, the [3,3]-sigmatropic step is the rate- and product-determining step. Chairlike transition states are generally preferred over boatlike ones.

Full text of DOI:10.1021/ja310002m

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Communication
Tandem Nucleophilic Addition / Oxy-2-azonia-Cope Rearrangement
for the Formation of Homoallylic Amides and Lactams: Total
Synthesis and Structural Verification of Motuporamine G
Lijun Zhou, Zhiming Li, Yue Zou, Quanrui Wang, Italo A
Sanhueza, Franziska Schoenebeck, and Andreas Goeke
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja310002m • Publication Date (Web): 27 Nov 2012
Downloaded from http://pubs.acs.org on November 30, 2012
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Tandem Nucleophilic Addition / Oxy-2-azonia-Cope Rear-
rangement for the Formation of Homoallylic Amides and Lac-
tams: Total Synthesis and Structural Verification of Mo-
tuporamine G
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Lijun Zhou,†,‡ Zhiming Li,† Yue Zou,‡ Quanrui Wang,*,† Italo A. Sanhueza,$ Franziska Schoenebeck*,$
and Andreas Goeke*,‡
†Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
$Laboratory for Organic Chemistry, ETH Zürich, WolfgangꢀPauliꢀStrasse 10, 8093 Zürich, Switzerland
‡Givaudan Fragrances (Shanghai) Ltd, 298 Li Shi Zhen Road, Shanghai 201203, China
Supporting Information Placeholder
the problem of reversibility: an oxyꢀ2ꢀazoniaꢀCope rearrangeꢀ
ment of crossꢀaddition product 4 into homoallylic amides 5
(Scheme 1, path B).
ABSTRACT: In the presence of a Lewis acid, β,γꢀunsaturated
ketones and oximes or imines undergo nucleophilic addition to
produce zwitterion intermediates, followed by oxyꢀ2ꢀazoniaꢀ
Scheme 1. The 2-azonia-Cope Rearrangement and its Novel
Extension to an Oxy-2-azonia Cope Rearrangement Reaction
Cope rearrangements to give homoallylic amides. In the case
of 2ꢀvinylcycloalkanones, the process results in ringꢀ
enlargement, providing a novel route to 9ꢀ to 16ꢀmembered
lactams. The preparative significance of this protocol was
evidenced by a short synthesis of macrocyclic alkaloid Moꢀ
tuporamine G. The stereochemistry defining step of this oxyꢀ
azoniaꢀCope rearrangement was further studied computationꢀ
ally. Despite a high energy preequilibrium in the formation of
zwitterionic intermediates, the [3,3]ꢀsigmatropic step is the
rate and product determining step. Chairꢀlike transition states
(TS) are generally preferred over boatꢀlike TS.
Amides are ubiquitous motifs in natural products, pharmaceuꢀ
ticals and materials.1 The widespread occurrence of amides
often makes us overlook that amide formation under neutral
conditions and without generation of waste is a contemporary
challenge in organic synthesis. In 2005 the American Chemiꢀ
cal Society Green Chemistry Institute (comprising members
from leading global pharmaceutical corporations) voted ‘amꢀ
ides formation avoiding poor atom economy reagents’ is the
top priority research area in organic chemistry.2 Diversified or
improved methods for the synthesis of amide functionality are
in great demand.3
Recently, we discovered a novel crossꢀdimerization of a β,γꢀ
unsaturated carbonyl compound with another aldehyde to
produce homoallylic esters in an atomꢀeconomical way.11 The
proposed wellꢀorganized intermediates occurring in this oxyꢀ
oxoniaꢀCope rearrangement enable high degrees of diastereoꢀ
selectivities and transfer of chirality. It has been successfully
applied to a new synthesis of macrocyclic musks.11b In continꢀ
uation of our studies of atomꢀeconomical rearrangement
chemistry, we decided to examine the oxyꢀ2ꢀazoniaꢀCope
rearrangement in the context of the synthesis of odorants12 and
natural products. Macrolactams and related azacycles are
attractive targets which are often encountered in biologically
active natural products,13,14 and especially in drug candidates
such as bioisosteres of macrolides.15 However, direct cyclizaꢀ
tion approaches to the synthesis of macrolactams are often
limited by entropic reasons, applications wich require high
dilution techniques and the lack of functional diversity.16
2ꢀAzoniaꢀCope rearrangements constitute highly efficient
means to construct carbonꢀcarbon bonds under mild condiꢀ
tions.4 The inherent problem of the method is the reversibility
of the process. There have been four major approches to drive
2ꢀazoniaꢀCope rearrangements to completion: (1) by aryl
conjugation of the iminium ion;4,5 (2) by trapping the imminiꢀ
um ion in a subsequent nucleophile induced eneꢀiminium
cyclization;6 (3) by selectively cleaving the iminium ion of one
sigmatropic isomer7ꢀ9 (4) by a tandem Mannich cyclization
process. This fourth method is the particularly well established
2ꢀazoniaꢀCope/Mannich cyclization process which was first
introduced by Overman et al. (Scheme 1, path A). The reacꢀ
tion has been used as the key step in a number of alkaloid total
syntheses.10 Herein, we describe a new method to overcome
Our design of the oxyꢀ2ꢀazoniaꢀCope concept is based on the
assumption that intermediate 8 can be formed through a nuꢀ
cleophilic addition of an imine derivative to the carbonyl
group of 6, activated by a rather oxophilic Lewis acid (Table
1). Initial experiments revealed that oxyꢀazoniaꢀCope rearꢀ
rangements can indeed be performed by conversion of β,γꢀ
unsaturated ketone 6a with oxime ether 7a and a Lewis acid
such as SnCl4 (Table 1, entry 1). The expected homoallylic
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amide 9a was obtained in excellent yield in the presence of 1.0 nucleophilicity, such as those derived from α,βꢀunsaturated
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2
3
4
5
6
7
8
equivalent of SnCl4 at room temperature during 24h. The
reaction also works with catalytic amounts of Lewis acid (20%
eq. SnCl4), only a much longer reaction time, more than 6 days,
was required to reach quantitative conversion.17 We therefore
decided to use stoichometric amounts of Lewis acids in the
following investigations.
and aromatic aldehydes (entries 4,5). Comparatively electron
rich imines 7f-i were beneficially converted using 1.0 equivaꢀ
lent of more oxophilic EtAlCl2 (entries 6ꢀ9). Notably, precurꢀ
sor 7f, the trimeric form of Nꢀmethylenemethanamine, was
cleaved in situ to generate the desired rearrangement product
9f in excellent yield (entry 6). Reactions with cyclic imines
such as 7g and 7h resulted in acetyl protected piperidines 9g
and 9h (entry 7, 8). Interestingly, 1Hꢀindole reacted via its
tautomeric 3Hꢀindole18 with 6a to give indoline acetamide 9i
(entry 9). Rearrangement reactions of β,γꢀunsaturated ketones
carrying α protons such as 6b,c were also investigated. Both
substrates were converted into amides 9j and 9k in excellent
yields (entries 10, 11). Importantly, the double bond in product
9j is exclusively Eꢀconfigured (entry 10). Overꢀall, with regard
to substrate diversity, the scope of the oxyꢀazoniaꢀCope rearꢀ
rangement was found to be surprisingly broad.
Table 1. The Scope of 2-azonia-Cope Rearrangementsa
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entry
1
substrate 6
substrate 7
Lewis acid
(1.0 eq.)
SnCl4
Product 9
Yield
(%)b
97
In an attempt to design a new synthetic access to macrolacꢀ
tams, we now investigated the oxyꢀazoniaꢀCope reaction of 2ꢀ
vinylcycloalkanones 10: by simply linking R3 together with R5
(Scheme 1) in substrate 6 by a carbon chain of a given length.
After nucleophilic addition of imine 7, the resulting zwitteriꢀ
onic intermediates of type 8 were expected to undergo spontaꢀ
neous rearrangements to afford the corresponding ringꢀ
expanded lactams 11 (Table 2).17,19 Depending on the ringꢀsize
of 2ꢀvinylcycloalkanones 10, the products are mediumꢀring or
macrocyclic homoallylic lactams. In comparison to classical
macrocyclic lactam formations, which require activated carꢀ
boxylic acid derivatives in high dilution,20 the described lacꢀ
tam formation is rather a [n+4] ring enlargement and offers a
new opportunity for the rapid assembly of complex macrolacꢀ
tams. As illustrated in Table 2, cyclic 5ꢀ8 and 12ꢀmembered
substrates 10a-e and various oxime ethers and imines 7a-j
were smoothly converted to the desired homoallylic macrolacꢀ
tams. 9ꢀMembered lactam 11a was exclusively obtained with
Zꢀconfiguration (entry 1). The 10ꢀ, 11ꢀ, and 12ꢀmembered
lactam products were formed with prevailing Eꢀconfiguration
(entries 2ꢀ13), while the double bond in the 16ꢀmembered
rings (entry 14) was constructed less stereoselectively. Notaꢀ
bly, cyclic imines such as 7g, 7h and indole 7i were also apꢀ
plicable and resulted in bicyclic and tricyclic lactam products
of higher structural complexity (entries 7ꢀ9). The structures
and double bond configurations of these lactams were uneꢀ
quivocally determined by NMR analysis and confirmed in
several cases by Xꢀray analysis.17
2
3
6a
6a
SnCl4
SnCl4
89
94
4
5
6a
6a
SnCl4
SnCl4
67
39
6
6a
EtAlCl2
92c
7
8
6a
6a
EtAlCl2
EtAlCl2
29 c
83 c
9
6a
EtAlCl2
58 c
10
11
7a
7a
SnCl4
SnCl4
84
93
To demonstrate the preparative benfit, the new protocol was
further utilized to synthesize motuporamine G (Scheme 2), a
natural alkaloid isolated from the marine sponge Xestospongia
exigua by Andersen et al.21 The reaction of compound 12 and
imine 13 with EtAlCl2 gave 13ꢀmembered lactam 14 in excelꢀ
lent yield.22 Three additional simple standard transformations,
i.e. hydrogenation of 14, conversion to 15 followed by reducꢀ
tion of both amide groups, completed this short total synthesis
of rac-16. In the crude extract of the sponge, Motuporamines
A, B, and C and the mixture of motuporamine G, H, and I
were found to be primarily responsible for antiꢀinvasion activiꢀ
ty against cancer cells.21b However, as motuporamines G, H,
and I were all obtained in very small quantities, the exact
location of the methyl branch within the macrocyclic ring of
Motuporamine G, I and H had only been tentatively assigned.
By means of comparison of the NMR data of compound 16
with the corresponding data reported for authentic samples
aExperimental conditions: 1,2ꢀdichloroethane solution (50ml) of 6 (10 mmol), imine 7
(12mmol) and Lewis acid (10 mmol) were stirred under argon atmosphere for 24 hours at
room temperature. bIsolated yield after chromatography or Kugelrohr distillation. cWhen
1.0eq of SnCl4 was used, the conversion is less than 20% detected by GC analysis.
Encouraged by the efficiency of this concept, we employed
β,γꢀunsaturated ketones 6a-c to define the scope of this novel
rearrangement with regard to the tolerated diversity of imine
substrates (Table 1). Oxime ethers and imine derivatives 7
smoothly underwent the desired transformation to give
homoallylic amides 9b-k in moderate to excellent yields. The
reactions with oxime ethers were run in the presence of 1.0
equivalent of SnCl4 at room temperature (entries 1ꢀ5, 10, 11).
Lower yields were obtained with oxime ethers of decreased
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carene 17 with oxime ether 2 in the presence of the Lewis acid
of motuporamines G, H and I,21b we can confirm that the
constitution of 16 is identical with that of motuporamine G.
1
2
3
4
5
6
7
(LA) AlEtCl2 (Scheme 3) was investigated experimentally as
well as computationally, using Density Functional Theory.23,24
Table 2. Oxy-2-azonia-Cope [n+4] Ring Enlargement to Mac-
ro Lactamsa
entry
1
substrate 10
substrate
7
Lewis
acid
(1.0
Product 11
Yield
(%)b
[E/Z]
Scheme 3. Chirality Transfer Study of Oxy-2-azonia-Cope
Rearrangement of Acetyl Carene 17 and Oxime 7a
eq.)
7a
7a
SnCl4
35
[<1:99]
8
9
10
11
12
13
14
15
16
17
18
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2
SnCl4
84
[>99:1]
11b: R1 = MeOꢀ,R2
Me
=
=
=
=
The transformation of 17 to 18 was calculated to proceed via
the mechanism illustrated in Figure 1. After initial addition of
the oxime ether to Lewis acid activated 17, the zwitterionic
intermediate Int-17 is formed. A concerted, asynchronous
Cope rearrangement subsequently takes place as the rateꢀ
determining step to give 18. The reaction was calculated to be
relatively facile and exergonic (ꢁꢁG‡ = 16.6 kcal/mol and
ꢁGrxn= –11.5 kcal/mol at M06ꢀ2X level of theory, see Figure
1). As such, the reaction mirrors the reactivity of our recently
investigated oxoniaꢀCope transformation,11a,25 and the the
Cope rearrangement constitutes the selectivity determining
step.
3
4
5
6
7
10b
10b
10b
10b
7b
7c
7e
7f
SnCl4
SnCl4
11c: R1 = EtOꢀ, R2
Me
80
[>99:1]
59
[98:2]
70
11d: R1 = MeOꢀ, R2
nꢀpentyl
SnCl4
11e: R1 = MeOꢀ, R2
Ph
[>99:1]
EtAlCl2
11f: R1 = Me, R2 = H
96 c
[>99:1]
10b
10b
7g
7h
EtAlCl2
EtAlCl2
69 c
[>99:1]
8
92 c
[>99:1]
9
10b
7i
EtAlCl2
SnCl4
77 c
[>99:1]
10
7a
90
[>99:1]
11j: R1 = MeOꢀ, R2
Me
=
=
11
12
13
10c
10c
7b
7f
SnCl4
SnCl4
11k: R1 = EtOꢀ, R2
Me
73
[>99:1]
59
11l: R1 = Me, R2 = H
[>99:1]
7a
SnCl4
89
[95:5]
14
EtAlCl2
35c
[25:75]
aExperimental conditions: 1,2ꢀdichloroethane solution (50ml) of 10 (10 mmol), imine 7
(12mmol) and Lewis acid (10 mmol) were stirred under argon atmosphere for 24 hours at
room temperature. bIsolated yield after chromatography or Kugelrohr distillation. cWhen
1.0eq of SnCl4 was used, the conversion is less than 20% detected by GC analysis.
Scheme 2. Application of an Oxy-azonia-Cope Rearrangem-
ment to the Total Synthesis of Motuporamine G
Figure 1. Selectivity (ꢁꢁG‡) in favor of 18 (top) and free energy
reaction profile leading to product 18 with AlEtCl2 as Lewis acid
(bottom); calculated at CPCM(DCE) M062X/6ꢀ
31+G(d,p)//B3LYP/6ꢀ31G(d) with SDD (for Al). Standard state
was converted to 1M.21
The chairꢀlike transition state (TS(S)-17) is calculated to be
significantly favored in the oxyꢀ2ꢀazonia Cope rearrangement,
consistent with the experimental finding of Sꢀstereochemistry
in the product.17 The next higherꢀenergy TS (ꢁꢁG‡ = 2.5
kcal/mol), i.e. TS(R)-17, would lead to 18b - the product of
opposite stereochemistry with respect to the forming CꢀN
bond (Figure 2). This selectivity trend is found to be largely
To gain deeper insight into the stereochemistryꢀdefining step
of the oxyꢀ2ꢀazonia Cope rearrangement, the reaction of acetyl
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M. A.; Martin, V. S.; Padron, J. I. Org. Lett. 2010, 12, 5334–
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3905–3908.
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(17) For the screening of Lewis acids, characterization of compounds,
Xꢀray crystal structure analysis, additional experimental details
as well as compilation of all possible TS conformers and their
relative energies for the computation part, see the supporting inꢀ
formation (SI).
(18) (a) Gut, I. G.; Wirz, J. Angew. Chem. Int. Ed. 1994, 33, 1153–
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methodꢀ and also Lewisꢀacidꢀindependent (see SI for further
information).24, 25
1
2
3
4
5
6
7
8
In summary, we have found a novel, atom economical way for
the preparation of homoallylic tertiary amides and macrolacꢀ
tams via a tandem nucleophilic addition / oxyꢀ2ꢀazoniaꢀCope
rearrangement mediated by a Lewis acid. The transformation
proceeds at room temperature. Most of the transformations
proceed with high E/Z selectivity. The synthetic potential of
the present protocol was illustrated by total synthesis and
structure verification of the motuporamine G. In addition, a
chirality transfer study and computational analysis disclosed a
highlyꢀordered transition state of this transformation.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures, compound characterization, compilaꢀ
tion of computational and crystallographic data (CIF). This mateꢀ
rial is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
qrwang@fudan.edu.cn; schoenebeck@org.chem.ethz.ch; andreꢀ
as.goeke@givaudan.com
ACKNOWLEDGMENT
We thank Dr. G. Brunner for NMR experiments, Dr. Z. Chen at
Fudan University for Xꢀray measurements, and G. Tang at Fudan
University for the highꢀresolution MS data and the National Natuꢀ
ral Science Foundation of China (No. 21102019). Calculations
were performed on the ETH HighꢀPerformance Cluster Brutus.
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(20) Selected examples: (a) Nicolaou, K. C.; Ramanjulu, J. M.;
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(23) Calculations were performed with Gaussian09 (see supporting
information for full reference and computational details).
(24) Calculations have also been performed with the Lewis acids BF3
and SnCl4. See supporting information for further details.
(25) Calculations on the 2ꢀoxonia Cope rearrangement also suggest a
chairꢀlike TS to be favored. The predicted selectivity in the 2ꢀ
oxonia Cope reaction was ꢁꢁG‡ = 3.5ꢀ4.8 kcal/mol (depending
of level of theory), see ref. 11a.
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