Iterative Assembly of Polycyclic Saturated Heterocycles from

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Iterative Assembly of Polycyclic Saturated Heterocycles from Monomeric Building Blocks Fumito Saito, Nils Trapp, and Jeffrey W. Bode J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b01537 • Publication Date (Web): 08 Mar 2019 Downloaded from http://pubs.acs.org on March 8, 2019

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Journal of the American Chemical Society

Iterative Assembly of Polycyclic Saturated Heterocycles from Monomeric Building Blocks

Fumito Saito, Nils Trapp and Jeffrey W. Bode*

Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH-Zürich, 8093 Zürich, Switzerland [email protected]

Abstract Polycyclic saturated heterocycles with predictable shapes and structures are assembled by iterative couplings of bifunctional stannyl amine protocol (SnAP) reagents and a single morpholine-forming assembly reaction. Combinations of just a few monomers enable the programmable construction of rotationally restricted, non-planar heterocyclic arrays with discrete sizes and molecular shapes. The three-dimensional structures of these constrained scaffolds can be quickly and reliably predicted by DFT calculations and the target structures immediately decompiled into the constituent building blocks and assembly sequences. As a demonstration, in silico combinations of the building blocks predict saturated heptacyclic structures with elementary shapes including helices, S-turns and Uturns, which are synthesized in 5-6 steps from the monomers using just three chemical reactions. Introduction Saturated polycyclic structures are among the most effective and sought-after classes of bioactive molecules, as exemplified by highly potent natural products including pinnatoxin A,

1

neothiobinupharidine, 2 azaspiracid-1, 3 ciguatoxin 3C, 4 norzoanthamine,5 and monensin 6 (Chart 1). In addition to their striking chemical structures, such molecules are notable for being water soluble and orally active despite their relatively large structures. These features have inspired heroic efforts towards their synthesis and impressive successes have been documented.7,8,9,10,11,12 The large number of chemical steps required to produce such molecules, however, has severely limited evaluation of Page 1 of 21

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non-natural polycyclic structures or attempts to use the unique features of polycyclic saturated heterocycles as a platform for drug discovery. O

H HN

N H

O

O

O

H

O O

HO

N S

CO2 OH

O

neothiobinupharidine

pinnatoxin A H

H O

OH OH O O H

O H

O O

H

O

O NH

azaspiracid-1

O HO

H HO

H

O

H

O

H

H

H OH

O

H HO

H O

H O

O

O H H

H

HO H

O H H

O H H

H

ciguatoxin 3C H

O

OH H O O

H

O H

O H

H

O

O H

H N

O

O

O

OH OH

O O

OH

H

O

OMe OH

norzoanthamine

monensin

Chart 1. Polycyclic natural products Inspired by the dedication of natural systems to prepare polycyclic, saturated structures as bioactive molecules, we sought to employ advances in C–C bond formation – using readily prepared reagents – to devise an iterative, programmable synthesis of oligocyclic structures featuring spirocyclic morpholines as the repeat units (Figure 1-II). This approach mimics the widely employed iterative amide-forming couplings of enantiomerically-pure building blocks used in peptide synthesis (Figure 1-I) – perhaps the most successful synthetic platform for preparing biologically active molecules.13 The need for just two key reactions – a coupling step and a deprotection – enables the rapid, predictable synthesis of a large number of molecules.

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I

resin

peptide

amino acid

HO

Fmoc

N H

OH O

II

OH

Fmoc

O

N H

O

O

Cbz

[Sn]

[Sn]

O

polycyclic saturated heterocycle O

[Sn]

NH

6 steps

O

O

H 2N

O

O H 2N

O O

iterative assembly

H 2N

O

O

O

N

O

O

O

O O

OH

N H OH

OH

iSnAP reagent

ketone

H N

N H

6 steps

OtBu N Boc

iterative assembly

N Me

O N Me N Cbz

Figure 1. Iterative synthesis of (I) peptides and (II) polycyclic saturated heterocycles In this manuscript, we document our first steps towards this goal by the synthesis and assembly of bifunctional, monomeric building blocks that can be iteratively coupled to give polycyclic structures in a predictable fashion. This chemistry relies on a single C–C bond-forming reaction using stannyl amine protocol (SnAP) chemistry to form spirocyclic morpholines from ketones.14 Using bifunctional iterative SnAP (iSnAP) reagents as monomers, a cycle of morpholine formation and ketone deprotection enables the rapid construction of polycyclic saturated heterocycles in just a few chemical steps. As a first application of this approach for accessing complex architectures, we prepare molecules exhibiting all elementary 3D shapes in a completely predictable manner and with near perfect correspondence to the a priori calculated structure. Results and Discussion Design of Bifunctional Building Blocks for Iterative Assembly. Iterative organic synthesis is a rapidly growing field that seeks to construct complex organic assemblies from small, preformed building blocks and a limited number of coupling reactions. Notable successes include Burke’s synthesis of polyenes with (MIDA)boronates

15

and Crudden’s preparation of polyarylated

structures 16 by iterative Suzuki-Miyaura cross-couplings, Aggarwal’s synthesis of stereodefined carbon chains by homologation of a boronic ester, 17 and Swager’s construction of iptycenes by iterative Diels-Alder reactions.18 As noted by Burke in a recent review, “the complex problem of molecular construction can be simplified into simply making and coupling building blocks. In theory, all the required functional groups, oxidation states and stereochemistry can be pre-installed into such Page 3 of 21



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building blocks and then faithfully translated into the growing target structure using only mild and stereospecific cross-coupling reactions.”19 Based on the outstanding scope of the SnAP reaction for N-heterocycle formation, along with the ability to form spirocyclic ring junctions from ketones, 20 we anticipated that an iterative SnAP protocol would allow for the sequence controlled assembly of oligocyclic saturated heterocycles from small, preformed SnAP reagents bearing a protected ketone. Given the high tolerance of SnAP conditions for most functional groups, we expected that both ketals – which would serve as the ketone protecting group – and the product amines would be compatible with the iterative synthesis. This consideration allowed the design and synthesis of relatively simple bifunctional building blocks such as A (Scheme 1). Scheme 1. Optimization of the SnAP cyclizationa O O

O

O

O

Bu3Sn

N Boc

N H Boc-azt-A(H)-ketal N

Boc H 2N

Boc-azt

A O

MS4A CH2Cl2 RT

Boc N

Cu(OTf)2 ligand

O

O

Bu3Sn

HFIP RT

N ligand

Me

N 1

N

MeO

Me

56%b

MeO

N

O

O

SnAP

OMe

N

OMe

OMe

2

3

46% 63%b

73% 63%b

N

N

OMe

5 57%

4 15% OMe

Me

N OMe 6 53%

N

N Cl

a

O

OMe

Me

7 33% O

Me

O

N 9 24%

8 39% Me

Me

O

Me

Cl

N

O

Me

10 56%

Yields determined based on 1H NMR. bNMR yield starting with the isolated ketimine.

Establishment of conditions for iterative SnAP Chemistry. Initial efforts to apply our previously reported conditions for spirocyclic ring formation with iSnAP monomers identified two key problems: 1) poor conversion to the ketimine and 2) the formation of an oxidized side product in the SnAP cyclization. In seeking to improve the cyclization reaction, we reasoned that variation of the ligand on copper could modulate the reactivity and favor the desired morpholine product. Using the Page 4 of 21


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cyclization of the ketimine derived from ketone Boc-azt and iSnAP reagent A to form Boc-azt-A(H)ketal as a model, 21 a screen of alternative ligands 2–10 identified more electron rich pyridine derivatives as superior and we selected 2,6-dimethoxypyridine (2) as the ligand of choice (Scheme 1). Although other ligands such as 2,4-dimethoxyquinoline (3) gave slightly better results in the screen, we favored 2 due to its broad applicability – particularly with more challenging ketone substrates – and its commercial availability. Next, we sought to improve conditions for ketimine formation using ketone Cbz-pip and iSnAP reagent A as model substrates (Scheme 2). Inspired by Ellman’s work on the ketimine formation with tert-butanesulfinamide,22 a protocol employing Ti(OiPr)4 at room temperature proved best suited to this challenging task, giving the desired product in full conversion. We found that the reaction mixture could be used directly in the SnAP cyclization without the need to remove the titanium reagent or byproducts prior to the copper-promoted cyclization. These revised conditions were applied to the coupling of Cbz-pip with A to give Cbz-pip-A(H)-ketal in 60% yield while reducing the formation of the oxidized side product 11. Scheme 2. Synthesis of Cbz-pip-A(H)-ketal employing (I) optimized and (II) previous conditions.a Cu(OTf)2 2,6-dimethoxypyridine

Ti(OiPr)4

HFIP RT

CH2Cl2 RT

cond I : optimized O

O

Cbz

N

Cbz-pip

O

O

O

Bu3Sn

Cbz

A

H 2N

cond II : previously reported MS4A benzene reflux

aCbz-pip-A(H)-ketal

based on 1H NMR.

O

O

O

O

O

N

N H Cbz

Cbz-pip-A(H)-ketal cond I : 60% cond II : 19%

N H

N 11 7% 16%

Cu(OTf)2 2,6-lutidine CH2Cl2/HFIP RT

and 11 were obtained as a mixture after column chromatography. Their yields were determined

With the first cyclization complete, we established conditions for ketal deprotection using Cbz-pipA(H)-ketal as a model compound. Although it is not strictly necessary, we elected to N-methylate the newly formed morpholine ring (Scheme 3). Alkylation – as opposed to acylation or protection – was chosen to avoid the formation of rotamers that could complicate structure determination but has the potential disadvantage of retaining the basic amine. After careful purification of Cbz-pip-A(H)ketal, the N-methylation was most effectively accomplished with aqueous formaldehyde and NaBH(OAc)3. 23 The high tolerance of SnAP chemistry to functional groups, including tertiary amines, gave us confidence that this choice would not interfere with the subsequent steps, although

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preserving the basic amine could hamper ketal deprotection. Fortunately, we found that aqueous HCl in THF worked well for deprotection to give the ketone in 94% yield after purification.

Scheme 3. Iteration of SnAP chemistry for the synthesis of oligocyclic heterocyclesa O O

O

Cbz

N

N H

O

aq formaldehyde NaBH(OAc)3 CH2Cl2, RT Nm Cbz

Cbz-pip-A(H)-ketal

O

O

82%

N Me

N

O

aq HCl THF, RT

O

Dp

N Me

Cbz 94%

Cbz-pip-A(Me)-ketal

N

Ti(OiPr)4 vacuum RT

Cbz-pip-A(Me)-ketone

O H 2N

SnAP O O

Cbz [X-ray]

aSnAP:

N

N Me

O

N H

O

O O Cbz

Cbz-pip-A(Me)-β-B(H)-ketal 17%

N

N Me

Bu3Sn

N H

O O

O

O

B

Cu(OTf)2 2,6-dimethoxypyridine HFIP RT

Cbz-pip-A(Me)-α-B(H)-ketal 33%

SnAP reaction (imine formation followed by cyclization); Nm: N-methylation; Dp: deprotection.

The key experiment was to establish whether or not ketone Cbz-pip-A(Me)-ketone would be a suitable substrate for a second SnAP reaction. For this, we chose iSnAP reagent B, prepared via a straightforward route, to test the second SnAP reaction. Despite the presence of the tertiary amine, ketimine formation assisted by Ti(OiPr)4 proceeded smoothly under vacuum,24 as did the cyclization with Cu(OTf)2 to give two separable diastereomers in approximately 2:1 ratio, in 50% isolated yield. The structure of one of the diastereomers, Cbz-pip-A(Me)-b-B(H)-ketal, was confirmed by x-ray diffraction of a single crystal. Preparation of iSnAP reagents. With this encouraging result in hand, we designed and synthesized several iSnAP monomers based on well-known routes or chiral pool starting materials. Chiral reagent C was prepared in two steps from amino ester 12, whose synthesis in an enantiopure form has been reported by Tanaka et al. (Scheme 4-I).25 Reduction of the ester and subsequent alcohol alkylation was performed, without protecting the free amine, to provide iSnAP reagent C. Starting with D-malic acid, we synthesized iSnAP reagent c, the enantiomer of C. Next, iSnAP reagent D, poised for the formation of [6,6]-fused ring system, was prepared via resolution of chiral azido alcohol 14 (Scheme 4-II). Our attempts to resolve 14 with lipases were unsuccessful.26,27 Fortunately, diastereomers 15a and 15b, which were synthesized by an ester formation with Boc-L-alanine, were separable by column chromatography, and a single crystal of 15b was analyzed by x-ray diffraction to determine the absolute configuration. The ester bond of 15a was cleaved by NaOMe/MeOH, and alkylation of the hydroxyl group followed by azide reduction furnished iSnAP reagent D. We prepared iSnAP reagent E via enantiopure amino alcohol (S,S)-17 (Scheme 4-III).28 Protecting group manipulations of the Page 6 of 21


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amine and alkylation of the alcohol transformed (S,S)-17 into iSnAP reagent E. Finally, enantiopure reagent F was prepared from achiral epoxide 2129 by Cr(III)-catalyzed desymmetrization30 to give ring-opened product 22 in 93% ee (Scheme 4-IV). Desilylation, alcohol alkylation and azide reduction provided iSnAP reagent F. Scheme 4. Preparation of iSnAP reagents C, D, E, and Fa I

Me

II MeO OH HO2C L-malic

Bu3Sn

O O

ref 25 H 2N

CO2H

O

O

LiAlH4 THF 90%

Bu3Sn NaH

O

THF/DMF 53%

C

NaOMe, MeOH

H 2N

O

Bu3Sn

O

HO

13

I Bu3Sn

NaH O

Bn

N H

MeOH 97%

O

O H 2N

(S,S)-17

O

Trt-Cl, NEt3 CH2Cl2 89%

N3

N tBu

O N H

O

18

19

O

O O H 2N

O

E

TFE AcOH CH2Cl2 38%

Bu3Sn Trt

O O N H

O 20

KH Bu3Sn

O O

MeOH/THF 99%

H 2N

D

Cl

N O

tBu

O

TMSN3 40% 93% ee

O

tBu

tBu TMSO

O

K2CO3

N3

O

MeOH 91%

22

I

THF/DMF 97%

Bu3Sn

e (ent-E) was prepared from (R,R)-17

aAll

Cr

O

21

Bu3Sn

O

cat.

HO Trt

Bu3Sn

Pd/C, H2

16

IV HO

O

O

O

THF/DMF 79%

N3

III Pd(OH)2/C, H2

15b [X-ray]

15a 14%

(R,R)-14 63%, 94% ee

O

O

O N3

rac-14

c (ent-C) was prepared from D-malic acid

HO

O

O

N H

O

O H 2N

Me Boc

CH2Cl2/DMF

N3

HO

I

OH

N H

O DIC cat. DMAP

O

HO

12

acid

O

Boc

O

O

Pd/C, H2

H 2N

O

MeOH 98%

F

Bu3Sn

O

O

N3

O 23

NaH Bu3Sn

I

DMF 74%

iSnAP reagents were prepared on a gram scale. See the Supporting Information for full experimental details and

characterization data.

With these iSnAP reagents in hand, we explored their iterative assembly into a variety of dimeric and trimeric structures by sequential SnAP reactions and ketone deprotections. Importantly, although occasional fine-tuning of reaction conditions was advantageous, in most cases the SnAP reactions, N-methylation (if applicable), and ketone deprotection were achieved using a standard set of conditions. This allows a substantial number of structurally unique pentacyclic saturated heterocycles to be rapidly assembled (Table 1 and Figure 2). It is worth noting that except for the reaction of A with Cbz-pip, we did not observe the formation of oxidized side products. The complex molecules prepared required the establishment of a nomenclature based on the constituent building blocks, the initiating ketone, the substituents on the morpholine nitrogen atoms, and the stereochemistry of the ring junctions. Please see the Supporting Information for the nomenclature system.

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Table 1. Iterative assembly of dimeric structures with various iSnAP reagents entry

starting ketone

[Sn]

N

[Sn]

O

O

Cbz H 2N

Cbz-azt

O

H 2N

O

[Sn]

O

O

N H

[Sn]

O

SnAP

O

O

88% quant α: 16% β: 25%

O

O

B

SnAP

c

Dp

SnAP

Me (+)-Cbz-azt-A(Me)-β-F(H)-ketal

O

O

32% quant α: 6% β: 6%

Cbz

3

[Sn]

O

[Sn] O

N

H 2N

Cbz Cbz-azt

O H 2N

O

e

O

Nm

SnAP

e

71%

Dp

SnAP

82% 94% α: 12% β: 14%

Cbz

H N

O

O

HN O

N Me

N

(–)-Cbz-azt-B(H)-β-c(H)-ketal

O

N

O

4 Cbz

[Sn]

N

H 2N

Cbz-pip

[Sn]

O

O

O

O

H 2N

O

A

Nm

SnAP

F

56%

Dp

O

SnAP

82% 94% α: 17% β: 22%

Cbz

O

O

N H

O

O O

5

Cbz

Me

O H 2N

[Sn]

Cbz-pip

O

O

B

SnAP

C

58%

Dp

SnAP

Cbz

85% α: 16% β: 10%

O

H N

N H

N

(+)-Cbz-pip-A(Me)-β-F(H)-ketal

O

O

O

O

H 2N

N

[Sn]

Cbz

N

N H

O

O O

(+)-Cbz-pip-B(H)-α-C(H)-ketal

O 6

Cbz

N Cbz-pip

[Sn]

O H 2N

O

O O

[Sn]

A

O H 2N

O

SnAP

A

56%

Nm

Dp

SnAP

O

82% 94% α: 23% β: 21% Cbz

(+)-Cbz-pip-B(H)-β-C(H)-ketal O

O

O

N H

N Me

N

O

H N

O O

O O

N

N Me

N

HN

Cbz N

O

O

O O

(–)-Cbz-azt-e(Me)-β-e(H)-ketal

(+)-Cbz-pip-A(Me)-α-F(H)-ketal

O

N Me

Cbz (+)-Cbz-azt-e(Me)-α-e(H)-ketal

O

O O

O

O

O

O

H N

N H

N

O (–)-Cbz-azt-B(H)-α-c(H)-ketal

O

O O

N

O

H N

N H

N

Cbz

HN

Cbz N

N Cbz Me (+)-Cbz-azt-A(Me)-α-F(H)-ketal N

O

H 2N

Cbz-azt

O

O O

Cbz

75%

Dp

Nm

SnAP

F

O

H 2N

N

O

A

O

O 2

products

O

O 1

reaction sequence

building blocks

Cbz-pip-A(Me)-α-A(H)-ketal

O

Cbz

N

O

N H

N Me

Cbz-pip-A(Me)-β-A(H)-ketal

Reagents and reaction conditions: imine formation followed by cyclization (SnAP): a) MS4A, CH2Cl2, RT or b) Ti(OiPr)4, CH2Cl2, RT or c) Ti(OiPr)4, neat, RT, vacuum; Cu(OTf)2, 2,6-dimethoxypyridine, HFIP, RT; N-methylation (Nm): aqueous formaldehyde, NaBH(OAc)3, CH2Cl2, RT; deprotection (Dp): aq. HCl, THF, RT. See the Supporting Information for experimental details. a

Figure 2. X-ray crystal structure of (+)-Cbz-pip-B(H)-a-C(H)-ketal In all cases, the two diastereomers formed during the second cyclization could be separated by column chromatography. In terms of yield and the need for separation, the formation of diastereomers is obviously a disadvantage. Efforts to employ chiral ligands to control the diastereoselectivity are ongoing, inspired by preliminary results on ligand controlled, enantioselective cyclizations.31 In the Page 8 of 21


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meantime, the formation of both diastereomers can be seen as advantageous, as it allows us to target defined molecular shapes with confidence that all structures can be prepared. The stereodefined, dimeric products served as starting materials for the coupling of a third iSnAP reagent to form trimeric compounds, which are saturated heptacyclic structures assembled in just a few operations from the constituent building blocks. Four examples of these remarkable structures are shown in Scheme 5. Scheme 5. Iterative synthesis of trimeric structuresa O

O

Cbz

O O

O N H

73%

Cbz-pip-A(Me)-β-A(H)-ketal

Cbz

O

N Me

O Nm

N Me

N

O O

O

N Me

N

N Me

O Dp 98%

Cbz-pip-A(Me)-β-A(Me)-ketal

Cbz

[X-ray]

N Me

N

Cbz-pip-A(Me)-β-A(Me)-ketone O

O

[Sn]

O O

O O O

[X-ray]

N Me

N

20%

Cbz

N Me

N

E SnAP

N Me

O

O

O

O

O

N Me

O

Cbz

N H

H 2N

HN

24%

(+)-Cbz-pip-A(Me)-β-A(Me)-β-E(H)-ketal

(+)-Cbz-pip-A(Me)-β-A(Me)-α-E(H)-ketal

O O O

Cbz

N

N Me

[Sn]

O

N H

O

O O

Cbz-pip-A(Me)-α-B(H)-ketal

Dp 87%

Cbz

N

O

O

H 2N

N H

A

O

N Me

SnAP

Cbz-pip-A(Me)-α-B(H)-ketone O

O O

Cbz

[X-ray] aSnAP:

N

N H

N Me

H N

O

O

21% Cbz-pip-A(Me)-α-B(H)-α-A(H)-ketal

O O

Cbz

N

N H

N Me

H N O

17% Cbz-pip-A(Me)-α-B(H)-β-A(H)-ketal

O O


The three-dimensional structure of (+)-Cbz-pip-A(Me)-b-A(Me)-a-E(H)-ketal was determined by x-ray diffraction, revealing a well-defined polycyclic scaffold with discretely positioned functional groups. Although the saturated rings – particularly the morpholine repeat units – can adopt multiple ring conformations, the lack of rotatable bonds suggested that a few major molecular conformations should dominate. This encouraged us to perform DFT calculations to predict the major conformations, with the aim of being able to design – a priori – easily assembled polycyclic saturated ring structures with predictable three-dimensional shapes and vectors.

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DFT Calculation of Molecular Structures We performed conformational analysis of H-pip-A(Me)-b-A(Me)-a-E(H)-ketal using molecular mechanics (Merck Molecular Force Field, MMFF). All conformers within 5.02 kcal mol–1 of the global minimum were subjected to DFT geometry optimizations and frequency calculations at B3LYP/6-31G(d). In this manner, we identified the major conformers – i.e. the three-dimensional molecular shape – of H-pip-A(Me)-b-A(Me)-a-E(H)-ketal. As shown in Figure 3, the x-ray crystal and calculated structures are in good agreement with root-mean square deviation (RMSD) 0.85 Å. The match between the two structures indicated the three-dimensional shape of oligocyclic assemblies could be accurately predicted by computational methods. O O O

N

O

N Me

O

Cbz

N H

N Me

[X-ray] (+)-Cbz-pip-A(Me)-β-A(Me)-α-E(H)-ketal

RMSD = 0.85 Å

[calculated] H-pip-A(Me)-β-A(Me)-α-E(H)-ketal

Figure 3. Comparison between the crystal and calculated structures of (+)-Cbz-pip-A(Me)-bA(Me)-a-E(H)-ketal Computational Prediction and Programmed Synthesis of Elementary Shapes As each new morpholine ring junction can form a new stereocenter, the 10 iSnAP reagents (including enantiomers) employed in this study can be combined to form about 200 dimers and 4000 trimers. Using the computational approach developed for H-pip-A(Me)-b-A(Me)-a-E(H)-ketal, we calculated the structures of dozens of dimeric and trimeric assemblies. These computational efforts revealed that the stereochemistry of the spirocyclic ring junctions strongly influenced the predicted shapes and for each combination we examined both stereochemical possibilities. In all cases, the calculations predicted topologically defined structures composed of either a single, dominant conformer or a mixture of a few closely related conformers of almost identical shape. Pleasingly, the Page 10 of 21


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elementary structures – rods, U-turns, S-turns, and helices – are accessible by combinations of just three monomers, A, B, and D (Figure 4); further fine tuning of the shapes and positioning of functional groups arises from the inclusion of other building blocks.

O

Cbz

N

N H

Me Me N

O

O H N

O

O

N

O NH

O

N

Cbz-pip-B(H)-α-A(Me)-α-B(H)-ketal

O

S-turn

Cbz-azt-D(Me)-β-D(Me)-β-D(H)-ketal

U-turn

O

[Sn]

O

[Sn]

O

B

B

H 2N

O

A

O O

H 2N

Cbz-azt

O O

O

N Cbz

[Sn] O

[Sn]

O O

H 2N

Cbz-pip

H 2N

helix

O

O Cbz

O

O Cbz-pip-B(H)-α-A(Me)-β-B(H)-ketal

N

O HN

Me

O

Cbz

O N

N

O

O

Me

Cbz N

HN

[Sn]

O

O

[Sn]

O

O H 2N

D

D O O

H 2N

D

Figure 4. Computational prediction of the molecular shapes and corresponding monomers. The ability to predict and reliably synthesize molecules with a predetermined molecular shape is a long-standing goal of synthetic chemistry. Tremendous efforts have been made in the field of foldamer chemistry to mimic biomolecules, in particular proteins, that rely on folding to form their unique three-dimensional structures. 32 In foldamers, non-covalent interactions such as hydrogen bonding,33 p-p stacking,34 and dipole repulsion35 have been employed to dictate their conformation. Despite the power to form biologically relevant structures (especially helices), reliance on folding often limits shape predictability and accessible three-dimensional structures. In the 1980s, Stoddart introduced a “Molecular LEGO” concept where repetitive Diels-Alder reactions provide the rigid, fused polycyclic systems including molecular belts, cages and waves.36 In the decades of 2000s and 2010s, Schafmeister developed the elegant concept of “shapeprogrammable synthesis” using rigid, peptidomimetic structures prepared by rigidification of linear precursors. 37 The rigid structure based on spiro/fused bicyclic backbones with diketopiperazine repeat units enables computational prediction of the three-dimensional shape of polycyclic assemblies. Furthermore, this approach enables a considerable number of iterations to assemble large peptidomimetic scaffolds in enantio- and diastereopure form that can display a variety of shapes

Page 11 of 21



Page 12 of 21

including helices and U-turns. Recently, Inokuma reported an elegant approach to inducing specific molecular shapes into linear, oligomeric ketones by post-assembly functionalization.38 Scheme 6. Iterative synthesis of S-turn Cbz-pip-B(H)-a-A(Me)-a-B(H)-ketal and U-turn Cbz-pipB(H)-a-A(Me)-b-B(H)-ketala O

O

O Cbz

[Sn]

O

[X-ray] Cbz-pip-B(H)-β-A(H)-ketal 23%

[X-ray]

O

H 2N

B

N

Dp

SnAP 58%

Cbz

N H

N

A

O

O

Cbz-pip

O

[Sn]

O

H 2N

SnAP

85%

O

Cbz

O

N H

N

O HN

O

Cbz-pip-B(H)-ketal Cbz-pip-B(H)-α-A(H)-ketal 26% O

Me O

N NH

O O

Cbz

HN

N

N H

N

H 2N

O H N

O

[Sn]

O

O U-turn

O

Cbz-pip-B(H)-α-A(Me)-β-B(H)-ketal 38%

aSnAP:

O

Me N O

Cbz

O

S-turn

O

B

Nm Dp 69%, quant

O SnAP

Cbz-pip-B(H)-α-A(Me)-α-B(H)-ketal 22%


For sequences leading to S-turn and U-turn structures, we targeted S-turn Cbz-pip-B(H)-a-A(Me)a-B(H)-ketal and its stereoisomer, U-turn Cbz-pip-B(H)-a-A(Me)-b-B(H)-ketal (Scheme 6).

These molecules were assembled from ketone Cbz-pip and iSnAP reagents A and B (Figure 4). The first morpholine formation proceeded in 58% yield, followed by ketal deprotection and formation of the second morpholine ring junction with iSnAP reagent A. After column chromatography, we obtained two diastereomers Cbz-pip-B(H)-a-A(H)-ketal and Cbz-pip-B(H)-b-A(H)-ketal in pure form. The latter isomer was crystallized, and its solid-state structure was resolved. Using Cbz-pipB(H)-a-A(H)-ketal, methylation of the less hindered amine and ketal deprotection proceeded smoothly; a third SnAP reaction with reagent B led to the formation of trimeric S-turn structure Cbzpip-B(H)-a-A(Me)-a-B(H)-ketal in 22% yield and U-turn structure Cbz-pip-B(H)-a-A(Me)-bB(H)-ketal in 38% yield. Our computational efforts predicted that several different helical structures would be formed by homotrimerization of various iSnAP monomers. For example, a trimer of e gives a helical structure with a complete turn after three repeat units where the pitch is 13 Å (Figure 5). A helix with a longer pitch (19 Å) can be formed from oligomerization of D, in which an assembly of four monomers constitutes a complete turn. Page 12 of 21


Page 13 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


N Me

HN

O

Me N

O

O

O N H

O

Me

HN

O N

O

N

O

HN

Me

H-azt-e(Me)-β-e(Me)-α-e(H)-ketal

O

O

H-azt-D(Me)-β-D(Me)-β-D(H)-ketal

Figure 5. Two examples of helices formed by homotrimeric assemblies of iSnAP reagents We prepared helix (–)-Cbz-azt-D(Me)-b-D(Me)-b-D(H)-ketal starting from iSnAP reagent D and ketone Cbz-azt (Scheme 7). The first SnAP reaction proceeded in 75% yield, followed by amine methylation and ketal deprotection to reveal ketone (–)-Cbz-azt-D(Me)-ketone. Formation of the second morpholine ring junction with D provided two diastereomers, (+)-Cbz-azt-D(Me)-a-D(H)ketal and (–)-Cbz-azt-D(Me)-b-D(H)-ketal, in roughly equal amounts. The exceptionally rigid structure of these diastereomers enabled the assignment of their relative stereochemistry based on the 13

C NMR spectra. The third cyclization was performed with (–)-Cbz-azt-D(Me)-b-D(Me)-ketone,

which was prepared from (–)-Cbz-azt-D(Me)-b-D(H)-ketal by a reaction sequence of N-methylation and ketal deprotection. In this cyclization reaction, we obtained only a single diastereomer in 18% yield. 39 The isolated stereoisomer was our target, (–)-Cbz-azt-D(Me)-b-D(Me)-b-D(H)-ketal, as confirmed by the x-ray crystallographic analysis. The crystal structure also revealed that the heptacyclic assembly is a helical shape with the properties and pitch almost identical to that predicted by the calculated structure (RMSD 0.23 Å). Scheme 7. Iterative synthesis of helical structure (–)-Cbz-azt-D(Me)-b-D(Me)-b-D(H)-ketala O

O

O

O [Sn]

O

O

[Sn] O

O

H 2N

O

D

Cbz-azt

SnAP

Cbz

N

O

N H

(+)-Cbz-azt-D(H)-ketal 75%

Cbz

O

O

O

H 2N

O

N Cbz

O

O

Cbz

Nm Dp

N

N Me

N

N H

N Me

(+)-Cbz-azt-D(Me)-α-D(H)-ketal 18%

D

O

SnAP

O HN

Cbz N

(–)-Cbz-azt-D(Me)-ketone

O

N

91%, 92%

O

Me

(–)-Cbz-azt-D(Me)-β-D(H)-ketal 21%

O Cbz N

Me N

O

N

HN

Me

[calculated]

RMSD = 0.23 Å

[X-ray]

[Sn]

O

O

(–)-Cbz-azt-D(Me)-β-D(Me)-β-D(H)-ketal

O

O O

H 2N

O SnAP

18%

aSnAP:


Page 13 of 21


D

Nm Dp 72%, 90%


Page 14 of 21

Elaboration of Oligocyclic Heterocycles The saturated heterocycles prepared by this chemistry are stable, soluble compounds that are easily handled and further transformed. For example, following ketal deprotection, Cbz-pip-B(H)-bA(Me)-ketone can be converted into an extended amino acid by a two-step protocol involving Horner-Wadsworth-Emmons olefination with reagent 24 followed by decarboxylative hydrolysis with aqueous hydrogen peroxide (Scheme 8-I). The amino acid was isolated as a 3:1 mixture of diastereomers under the present conditions; further optimization and stereoselective protocols are in development. Scheme 8. Functionalization of the terminal ketones O EtO P EtO

Ia O

O

O

O NH

O

OH

O

N Me

aq NaOH, MeOH; aq H2O2

24 TMG, LiCl THF, RT 58%

N Cbz

NH

71% (dr 3:1)

N Cbz

O

H 2N

O

H N

H N O OMe

HCl 25

N Me

Cbz

Cbz-pip-A(Me)-β-A(Me)-indole

O Me O

Cbz

N

N Me

N

N H

O

aProduct

N N

N

N Me

CO2Me 26

MS4A MS4A CHCl3, 40 ℃ CHCl3, 40 ℃ 42% (2 steps)

(+)-Cbz-azt-A(Me)-β-F(Me)-ketone

OMe

N Me

N

Cbz-pip-A(Me)-β-A(Me)-ketone

III

N Me

O

AcOH, 90 ℃ 82%

N Me

N

2 TFA

Cbz-pip-B(H)-β-A(Me)-acid

II

O

N Me

O

Cbz-pip-B(H)-β-A(Me)-ketone

Cbz

O

O

O

Cbz

N

CO2Me N O

N Me

(–)-Cbz-azt-A(Me)-β-F(Me)-pyridine

was obtained as TFA salts after reverse-phase HPLC purification. TMG: 1,1,3,3-tetramethylguanidine.

The ketone also serves as a convenient handle for numerous annulation chemistries leading to fused heteroaromatic systems. For example, Cbz-pip-A(Me)-b-A(Me)-ketone underwent Fischer indole synthesis with hydrazine 25 to give Cbz-pip-A(Me)-b-A(Me)-indole in 82% yield (Scheme 8-II). Likewise, (+)-Cbz-azt-A(Me)-b-F(Me)-ketone was regioselectively transformed to (–)-Cbz-aztA(Me)-b-F(Me)-pyridine with Boger’s pyridine-forming reaction (Scheme 8-III).40 We anticipate that these polycyclic structures will be suitable substrates for other transformations of ketones,

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thereby allowing the facile elaboration of the heterocyclic sequences to molecules bearing precisely placed substituents and binding elements. Conclusion We have realized the iterative synthesis of oligocyclic saturated heterocycles using iSnAP reagents as monomeric building blocks. In analogy to peptide synthesis, this work provides a one-to-one correspondence between a targeted molecular shape and the building blocks and assembly sequence needed to prepare it. In doing so, this integrated approach offers a rare platform where strikingly complex molecules can be prepared in a predictable manner by the immediate decompilation of the target into the constituent building blocks and necessary reactions. Ongoing efforts from our group on automating SnAP reactions will allow machine-assisted synthesis of oligocyclic heterocycles. Already at the current stage of development, a range of discrete molecular shapes including helices, S-turns, and U-turns are accessible in just a few operations from stable, preformed building blocks. The inclusion of new iSnAP monomers that form different ring junctions – including piperazines, oxazepanes, and pyrrolidines – will expand the shapes and structures accessible in a predictable fashion. With further improvements to the chemistry – including stereoselective ring formation – one could easily imagine the iterative construction of longer sequences and compound topologies incorporating multiple turn or helix elements.41 Associated Content Supporting Information. The Supporting Information is available free of charge on the ACS Publications website. Synthetic procedures, characterization data, and NMR spectra for all new compounds, computational procedures, calculated structures, and X-ray crystallographic data (PDF). X-ray crystallographic data for 10 compounds including 4 dimers and 3 trimers (CIF). Calculated structures of dimers and trimers, the target molecular shapes (helix, S-turn, and U-turn), and the calculated structures used for comparison with X-ray structures (PSE). Author Information Corresponding Author

[email protected]

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Page 16 of 21

Funding Sources

Financial support was provided by the European Research Council (ERC Starting Grant 306793 – CASAA) and ETH Zürich. Notes The authors declare no competing interests. Acknowledgement We thank the LOC MS Service for analysis. X-ray services were provided by SMoCC – The Small Molecule Crystallography Center of ETH Zurich (www.smocc.ethz.ch). We are grateful to Tony Georgiev for the scale-up preparation of iSnAP reagent F, Dr. Sizhou M. Liu and Yi-Chung Dzeng for introduction to the Euler cluster at ETH Zurich, and Dr. Yusuke Ota for helpful discussions. References

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2

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3

Satake, M.; Ofuji, K.; Naoki, H.; James, K. J.; Furey, A.; McMahon, T.; Silke, J.; Yasumoto, T. Azaspiracid, a new marine toxin having unique spiro ring assemblies, isolated from Irish mussels, Mytilus edulis. J. Am. Chem. Soc. 1998, 120, 9967–9968.

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5

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7

Pinnatoxin A: (a) McCauley, J. A.; Nagasawa, K.; Lander, P. A.; Mischke, S. G.; Semones, M. A.; Kishi, Y. Total synthesis of pinnatoxin A. J. Am. Chem. Soc. 1998, 120, 7647–7648. (b) Sakamoto, S.; Sakazaki, H.; Hagiwara, K.; Kamada, K.; Ishii, K.; Noda, T.; Inoue, M.; Hirama,

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9

Azaspiracid-1: Nicolaou group: (a) Nicolaou, K. C.; Vyskocil, S.; Koftis, T. V.; Yamada, M. A. Y.; Ling, T.; Chen, D. Y.-K.; Tang, W.; Petrovic, G.; Frederick, M. O.; Li, Y.; Satake, M. Structural revision and total synthesis of azaspiracid-1, Part 1: Intelligence gathering and tentative proposal. Angew. Chem., Int. Ed. 2004, 43, 4312–4318. (b) Nicolaou, K. C.; Koftis, T. V.; Vyskocil, S.; Petrovic, G.; Ling, T.; Yamada, M. A. Y.; Tang, W.; Frederick, M. O. Structural revision and total synthesis of azaspiracid-1, Part 2: Definition of the ABCD domain and total synthesis. Angew. Chem., Int. Ed. 2004, 43, 4318–4324. (c) Nicolaou, K. C.; Koftis, T. V.; Vyskocil, S.; Petrovic, G.; Tang, W.; Frederick, M. O.; Chen, D. Y.-K.; Li, Y.; Ling, T.; Yamada, M. A. Y. Total synthesis and structural elucidation of azaspiracid-1. Final assignment and total synthesis of the correct structure of azaspiracid-1. J. Am. Chem. Soc. 2006, 128, 2859–2872. Evans group: (d) Evans, D. A.; Kværnø, L.; Mulder, J. A.; Raymer, B.; Dunn, T. B.; Beauchemin, A.; Olhava, E. J.; Juhl, M.; Kagechika, K. Total synthesis of (+)-azaspiracid1. Part I: Synthesis of the fully elaborated ABCD aldehyde. Angew. Chem., Int. Ed. 2007, 46, 4693–4697. (e) Evans, D. A.; Dunn, T. B.; Kværnø, L.; Beauchemin, A.; Raymer, B.; Olhava, E. J.; Mulder, J. A.; Juhl, M.; Kagechika, K.; Favor, D. A. Total synthesis of (+)-azaspiracid-1. Part II: Synthesis of the EFGHI sulfone and completion of the synthesis. Angew. Chem., Int. Ed. 2007, 46, 4698–4703. (f) Evans, D. A.; Kværnø, L.; Dunn, T. B.; Beauchemin, A.; Raymer, B.; Mulder, J. A.; Olhava, E. J.; Juhl, M.; Kagechika, K.; Favor, D. A. Total synthesis of (+)azaspiracid-1. An exhibition of the intricacies of complex molecule synthesis. J. Am. Chem. Soc. 2008, 130, 16295–16309.

10 Ciguatoxin 3C: (a) Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.; Maruyama, M.; Oguri, H.; Satake, M. Total synthesis of ciguatoxin CTX3C. Science 2001, 294, 1904–1907. (b) Inoue, M.; Miyazaki, K.; Uehara, H.; Maruyama, M.; Hirama, M. First- and second-generation total synthesis of ciguatoxin CTX3C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12013–12018. 11 Norzoanthamine: (a) Miyashita, M.; Sasaki, M.; Hattori, I.; Sakai, M.; Tanino, K. Total synthesis of norzoanthamine. Science 2004, 305, 495–499. (b) Yamashita, D.; Murata, Y.; Hikage, N.; Takao, K.; Nakazaki, A.; Kobayashi, S. Total synthesis of (–)-norzoanthamine. Angew. Chem., Int. Ed. 2009, 48, 1404–1406.

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12 Monensin: Kishi group: (a) Schmid, G.; Fukuyama, T.; Akasaka, K.; Kishi, Y. Total synthesis of monensin. 1. Stereocontrolled synthesis of the left half of monensin. J. Am. Chem. Soc. 1979, 101, 259–260. (b) Fukuyama, T.; Wang, C.-L. J.; Kishi, Y. Total synthesis of monensin. 2. Stereocontrolled synthesis of the right half of monensin. J. Am. Chem. Soc. 1979, 101, 260– 262. (c) Karanewsky, D. S.; Wang, C.-L. J.; Schmid, G.; Kishi, Y. Total synthesis of monensin. 3. Stereocontrolled total synthesis of monensin. J. Am. Chem. Soc. 1979, 101, 262–263. Still group: (d) Collum, D. B.; McDonald, J. H., III; Still, W. C. Synthesis of the polyether antibiotic monensin. 1. Strategy and degradations. J. Am. Chem. Soc. 1980, 102, 2117–2118. (e) Collum, D. B.; McDonald, J. H., III; Still, W. C. Synthesis of the polyether antibiotic monensin. 2. Preparation of intermediates. J. Am. Chem. Soc. 1980, 102, 2118–2120. (f) Collum, D. B.; McDonald, J. H., III; Still, W. C. Synthesis of the polyether antibiotic monensin. 3. Coupling of precursors and transformation to monensin. J. Am. Chem. Soc. 1980, 102, 2120–2121. 13 Merrifield, R. B. Solid phase peptide synthesis. I. The synthesis of a tetrapeptide. J. Am. Chem. Soc. 1963, 85, 2149–2154. 14 Luescher, M. U.; Geoghegan, K.; Nichols, P. L.; Bode, J. W. SnAP reagents for a crosscoupling approach to the one-step synthesis of saturated N-heterocycles. Aldrichimica Acta 2015, 48, 43–48. 15 Woerly, E. M.; Roy, J.; Burke, M. D. Synthesis of most polyene natural product motifs using just 12 building blocks and one coupling reaction. Nat. Chem. 2014, 6, 484–491. 16 Crudden, C. M.; Ziebenhaus, C.; Rygus, J. P. G.; Ghozati, K.; Unsworth, P. J.; Nambo, M.; Voth, S.; Hutchinson, M.; Laberge, V. S.; Maekawa, Y.; Imao, D. Iterative protecting groupfree cross-coupling leading to chiral multiply arylated structures. Nat. Commun. 2016, 7, 11065. 17 Burns, M.; Essafi, S.; Bame, J. R.; Bull, S. P.; Webster, M. P.; Balieu, S.; Dale, J. W.; Butts, C. P.; Harvey, J. N.; Aggarwal, V. K. Assembly-line synthesis of organic molecules with tailored shapes. Nature 2014, 513, 183–188. 18 Zhao, Y.; Rocha, S. V.; Swager, T. M. Mechanochemical synthesis of extended iptycenes. J. Am. Chem. Soc. 2016, 138, 13834–12837. 19 Lehmann, J. W.; Blair, D. J.; Burke, M. D. Towards the generalized iterative synthesis of small molecules. Nat. Rev. Chem. 2018, 2, 0115. 20 Siau, W.-Y.; Bode, J. W. One-step synthesis of saturated spirocyclic N-heterocycles with stannyl amine protocol (SnAP) reagents and ketones. J. Am. Chem. Soc. 2014, 136, 17726– 17729. 21 For the nomenclature of the polycyclic compounds, see the Supporting Information.

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Therapeutic potential of foldamers: from chemical biology tools to drug candidates? J. Med. Chem. 2016, 59, 9599–9621. 33 For seminal work, see: (a) Appella, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D. R.; Gellman, S. H. b-Peptide foldamers: robust helix formation in a new family of b-amino acid oligomers. J. Am. Chem. Soc. 1996, 118, 13071–13072. (b) Seebach, D.; Overhand, M.; Kühnle, F. N. M.; Martinoni, B.; Oberer, L.; Hommel, U.; Widmer, H. b-Peptides: synthesis by Arndt-Eistert homologation with concomitant peptide coupling. Structure determination by NMR and CD spectroscopy and by X-ray crystallography. Helical secondary structure of a bhexapeptide in solution and its stability towards pepsin. Helv. Chim. Acta 1996, 79, 913–941. (c) Hamuro, Y.; Geib, S. J.; Hamilton, A. D. Novel molecular scaffolds: formation of helical secondary structure in a family of oligoanthranilamides. Angew. Chem., Int. Ed. 1994, 33, 446– 448. (d) Berl, V.; Huc, I.; Khoury, R. G.; Krische, M. J.; Lehn, J.-M. Interconversion of single and double helices formed from synthetic molecular strands. Nature 2000, 407, 720–723. (e) Zhu, J.; Parra, R. D.; Zeng, H.; Skrzypczak-Jankun, E.; Zeng, X. C.; Gong, B. A new class of folding oligomers: crescent oligoamides. J. Am. Chem. Soc. 2000, 122, 4219–4220. For a review, see: (f) Goodman, C. M.; Choi, S.; Shandler, S.; DeGrado, W. F. Foldamers as versatile frameworks for the design and evolution of function. Nat. Chem. Biol. 2007, 3, 252–262. 34 Lokey, R. S.; Iverson, B. L. Synthetic molecules that fold into a pleated secondary structure in solution. Nature 1995, 375, 303–305. 35 (a) Ohkita, M.; Lehn, J.-M.; Baum, G.; Fenske, D. Helicity coding: programmed molecular self-organization of achiral nonbiological strands into multiturn helical superstructures: synthesis and characterization of alternating pyridine-pyrimidine oligomers. Chem. Eur. J. 1999, 5, 3471–3481. (b) Clayden, J.; Lund, A.; Vallverdu, L.; Helliwell, M. Ultra-remote stereocontrol by conformational communication of information along a carbon chain. Nature 2004, 431, 966–971. (c) German, E. A.; Ross, J. E.; Knipe, P. C.; Don, M. F.; Thompson, S.; Hamilton, A. D. b-Strand mimetic foldamers rigidified through dipolar repulsion. Angew. Chem., Int. Ed. 2015, 54, 2649–2652. 36 Mathias, J. P.; Stoddart, J. F. Constructing a molecular LEGO set. Chem. Soc. Rev. 1992, 21, 215–225. 37 (a) Schafmeister, C. E. Molecular legos. Scientific American 2007, 17, 22–29. (b) Schafmeister, C. E.; Brown, Z. Z.; Gupta, S. Shape-programmable macromolecules. Acc. Chem. Res. 2008, 41, 1387–1398. 38 Uesaka, M.; Saito, Y.; Yoshioka, S.; Domoto, Y.; Fujia, M.; Inokuma, Y. Oligoacetylacetones as shapable carbon chains and their transformation to oligoimines for construction of metalorganic architectures. Commun. Chem. 2018, 1, 23. Page 20 of 21


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39 Considering that we always obtained two diastereomers in dimer- and trimer-forming reactions, we believe that this cyclization step also formed two diastereomers, but we failed to isolate one of them. 40 Anderson, E. D.; Boger, D. L. Inverse electron demand Diels-Alder reactions of 1,2,3-triazines: pronounced substituent effects on reactivity and cycloaddition scope. J. Am. Chem. Soc. 2011, 133, 12285–12292. 41 a) Delsuc, N.; Léger, J.-M.; Massip, S.; Huc, I. Proteomorphous objects from abiotic backbones. Angew. Chem., Int. Ed. 2007, 46, 214–217. (b) Lamouroux, A.; Sebaoun, L.; Wicher, B.; Kauffmann, B.; Ferrand, Y.; Maurizot, V.; Huc, I. Controlling dipole orientation through curvature: aromatic foldamer bent b-sheets and helix-sheet-helix architectures. J. Am. Chem. Soc. 2017, 139, 14668–14675.

ketone

polycyclic saturated heterocycles

iSnAP reagents O O

Cbz

O O

H 2N

N [Sn]

O

iterative assembly

Me

N H

N O

O O

O O H 2N [Sn]

O

O O

[Sn]

O H 2N

3 cycles O

1) coupling 2) deprotection

NH

N Cbz

TOC graphic (height: 3.6 cm, width: 8.5 cm)

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Iterative Assembly of Polycyclic Saturated Heterocycles from

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