Introduction

Results

References

Many natural products contain spiroacetals as characteristic structure elements. Synthesis methods for the most common [O,O]-spiroacetals are well known, e.g. under Lewis- or Brønsted-acid catalysis.[1,2] Other heterocyclic spiro compounds have been relegated to a niche existence. As a carbophilic Lewis-acid, gold has the ability to activate alkenes and alkynes for nucleophilic attack to form C-C-, C-O-, C-N- or C-S-bonds.[3] The obvious advantages of gold catalysis are mild reaction conditions at oftentimes room temperature, tolerance against different functional groups and its low toxicity, which is useful for the application in the synthesis of drugs.

A Gold-Catalyzed Entry to Heterocyclic Spiro Compounds

Bernd Wagner, Volker Belting and Norbert Krause*

Technische Universität Dortmund, Organic Chemistry, 44227 Dortmund, Germany

technische universität dortmund

Entry 1 R Catalyst Time Yield 2 dr

1 1a Ts Ph3PAuCl/AgOTf 40 min 74% 2a 88:12

2 1a Ts Au(IPr)Cl/AgOTf 3 h 82% 2a 91:9

4 1a Ts AgOTf 1 d[a] traces 2a 84:16

5 1b Ns Ph3PAuCl/AgOTf 1 d 74% 2b 90:10

6 1c Boc Ph3PAuCl/AgOTf 15 min 94% 2c 68:32

7 1c Boc Ph3PAuCl/AgBF4 10 h 65% 2c 67:33

8 1c Boc Au(IPr)Cl/AgOTf 15 min 57% 2c 63:37

10 1d H Ph3PAuCl/AgOTf[b] 2 d[a] --- 2d ---

[a] no conversion observed, reaction aborted. [b] 5 mol% of catalyst system

For the mechanism we propose the formation of a monocyclic intermediate. Via kinetic NMR-spectroscopy we were able to confirm this assumption by observing just one olefinic signal (Scheme 2).

[1] H. Stetter, M. M. Rauhut Chem. Ber. 1958, 91, 2543 – 2547. [2] B. Liu, J. K. De Brabander Org. Lett. 2006, 8, 4907 – 4910. [3] Review: A. S. K. Hashmi Chem. Rev. 2007, 107, 3180 – 3211; A. S. K. Hashmi, G. J. Hutchings

Angew. Chem. Int. Ed. 2006, 45, 7896 – 7936. [4] V. Belting, N. Krause Org. Lett. 2006, 8, 4489 – 4492.

[5] B. Wagner, V. Belting, N. Krause manuscript in preparation. [6] M.-E. Sinibaldi, I. Canet Eur. J. Org. Chem. 2008, 4391 – 4399. [7] L.-P. Liu, B. Xu, M. S. Mashuta, G. B. Hammond J. Am. Chem. Soc. 2008, 130, 17642 –

17643. [8] J. Piera, P. Krumlinde, D. Strübing, J.-E. Bäckvall Org. Lett. 2007, 9, 2235 – 2237.

2c (94 %, dr 68:32)

2a (74 %, dr 88:12)

2b (74 %, dr 90:10)

3 (45%, dr 90:10)

4 (60%, dr 61:39)

5 (60%, dr 63:37)

9 (82%, dr 86:14)

10 (75%, dr 82:18)

11 (72%, dr 86:14)

8 (94%, dr 88:12)

6 (33%, dr 92:8)

On closer inspection the appearance of a new amino signal could be observed during the reaction process. This fact can be an indication for a tetrahydrofuran derivative 13 as a possible intermediate. This observations leads to the proposed catalytic cycle shown in Scheme 3.

7 (32%, dr 71:29)

Mechanistic Investigations

olefinic proton

NHTs-group of compound 13

NHTs-group of compound 1a

Previously, we have shown that tetrahydrofuranyl ethers are accessible by gold-catalyzed tandem cycloisomerization-hydroalkoxylation of homopropargylic alcohols.[4]

We now disclose a new access to [N,O]-spiroacetals by cyclization of aminoalkynols in the presence of a gold catalyst.[5] This method tolerates various substituents and protecting groups and can be used to access spiroacetals with five- or six-membered rings. By changing the nucleophilic positions (eg. thiols or esters), this method provides a new access to a wide range of interesting heterocyclic spiro compounds.

Gold-Catalyzed Pathway to [N,O]-Spiroacetals

Gold-Catalyzed Synthesis of Heterocyclic Spirolactones

[N,O]-spiroacetals have received far less attention than their oxygenated analogues the spiroacetals, for which a plethora of synthetic strategies are available, in spite of their attractive skeletons, and fewer methods to elaborate these novel and attractive motifs have been reported to date.[6] With gold-catalysis we were able to synthesize various [N,O]-spiroacetals in good yields under mild conditions (Scheme 1).

The next challenge is the synthesis of other heterocyclic spiro compounds using starting materials bearing different possible nucleophiles. Therefore, we started to investigate a gold-catalyzed entry to heterocyclic spirolactones. First results show the potential of this method (Scheme 4). A possible catalytic cycle based on previous works by Hammond[7] and Bäckvall[8] is shown in Scheme 5.

Table 1: Gold-catalyzed cycloisomerization of 1 with selected catalysts and protection groups.

Scheme 1: Gold-catalyzed synthesis of [N,O]-Spiroacetals.

Scheme 2: Kinetic NMR-studies.

Scheme 3: Proposed mechanism of the gold-catalyzed cycloisomerization of aminoalkinols.

Scheme 4: Gold-catalyzed entry to heterocyclic spirolactones. Scheme 5: Proposed mechanism of the gold-catalyzed formation of heterocyclic spirolactones