Download PDF
Synlett 2010(15): 2283-2284  
DOI: 10.1055/s-0030-1258016
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Protecting-Group-Free Total Synthesis of Goniothalesdiol A

Junpeng Lia, Huaiji Zhenga, Yingpeng Sua, Xingang Xie*a, Xuegong She*a,b
a State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
b State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, P. R. of China
Fax: +86(931)8912582; e-Mail: shexg@lzu.edu.cn;

Further Information

Publication History

Received 7 May 2010
Publication Date:
06 August 2010 (online)

 PDF Download Permissions and Reprints All articles of this category

Abstract

A concise asymmetric total synthesis of goniothalesdiol A was accomplished using protecting-group-free strategy, in which silyl-Prins cyclization was used as the key step.

Key words

goniothalesdiol A - protecting-group-free - silyl-Prins cyclization - dihydroxylation

The concept of protecting-group-free (PGF) synthesis was not extensively explored until the twenty-first century, although a number of protecting-group-free total syntheses were reported. [¹] [²] Today, organic chemists invest great enthusiasm to pursue the ‘ideal syntheses’; [³] one area that offers this prospect is to minimize the use of protecting groups in synthesis. A protection-deprotection event introduces at least two steps into a sequence, increasing costs from additional reagents and waste disposal, and generally leads to a reduced overall yield. This made the development of PGF synthesis very attractive and urgent in laboratory and industry. [4] [5]

Pyrans are widely found in both natural products and pharmaceutically active compounds, and may contribute to a wide range of biological activities. In 2006, goniothalesdiol A (Scheme  [¹] , compound 1), a cis-2,6-disubstituted 3,4-dihydroxy pyran, was isolated from the stem of a southern Taiwan tree Goniothalamus amuyon by Wu and co-workers. [6] There were two independent synthetic efforts toward goniothalesdiol A reported by Yadav and Fadnavis. [7] [8] In the Yadav’s synthesis, goniothalesdiol A was achieved in 11 steps and 35.1% overall yield by using Chan alkyne reduction, Sharpless kinetic resolution and intramolecular oxy-Michael addition as key steps. [7] Fadnavis synthesized goniothalesdiol A in 22% overall yield and ten steps via stereoselective allylation, Grignard reaction, cross-metathesis and intramolecular oxy-Michael addition as key steps. [8] As part of our ongoing program towards the syntheses of bioactive pyran- and pyranone-type natural products, [9] [¹0] herein we report a concise and protecting-group-free asymmetric total synthesis of goniothalesdiol A 1, in which silyl-Prins cyclization [¹¹] was used as the key step.

Retrosynthetic analysis of 1 is briefly outlined in Scheme  [¹] , which suggests that it could be obtained from 3,6-dihydro-2H-pyran ester 2 via stereoselective dihydroxylation. As for the key intermediate 2, we envisioned that it could be constructed by an intramolecular silyl-Prins reaction of (Z)-silyl-β-hydroxyenoate 3 which could be prepared from (R)-2-(chloromethyl)oxirane 4 and tri­­methylsilylacetylene 5.

Scheme 1 Retrosynthetic analysis for goniothalesdiol A

Synthesis of (Z)-silyl-β-hydroxyenoate 3 was initiated with commercially available (R)-2-(chloromethyl)oxirane 4. After a regioselective ring opening of epoxide 4 with trimethylsilylalkynyllithium, [¹²] homopropargyl alcohol 6 was obtained. DIBAL-H reduction [¹³] of 6 gave (Z)-homo­allyl alcohol 7 which was transformed to (Z)-silyl-β-­hydroxyenoate 3 by lithio orthothioformate alkylation and hydrolysis. [¹4] [¹5]

Scheme 2 Protecting-group-free total synthesis of goniothalesdiol A

With 3 in hand, the silyl-Prins reaction with benzaldehyde was employed to afford 3,6-dihydro-2H-pyran ester 2 in the presence of InBr3. [¹³] It is noteworthy that aromatic aldehydes were commonly recognized as less successful substrates in the Prins reaction as they gave a mixture of cis and trans adducts in low yields in most cases. [¹6] To our delight, utility of InBr3 as the Lewis acid led to cis/trans >9:1 DHP products in a comparable yield. After a highly stereoselective dihydroxylation reaction, [¹6b] [c] goniothalesdiol A 1 was obtained in 92% yield (Scheme  [²] ), whose spectral data were in good agreement with those reported in the literature. [7] [8] [¹7]

In summary, a concise asymmetric total synthesis of ­goniothalesdiol A 1 was achieved in six steps and 30% overall yield. The cis-2,6-disubstituted pyran moiety was effectively constructed via silyl-Prins reaction, while C-3 and C-4 vicinal dihydroxy groups were secured by stereo­selective dihydroxylation. There was no protecting group utilized in this route.

Acknowledgment

We are grateful for the generous financial support by the MOST (2010CB833200) and the NSFC (20872054, 20732002).

17

Goniothalesdiol A (1): powder; [α]D ²5 -21.0 (c = 0.2, CHCl3). IR (KBr): 700, 758, 1047, 1078, 1170, 1203, 1438, 1735, 2920, 2952, 3425 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.77 (td, J = 2.4, 14.0 Hz, 1 H), 1.94 (br s, 1 H), 2.08 (ddd, J = 2.0, 3.0, 14.0 Hz, 1 H), 2.47 (dd, J = 6.0, 15.2 Hz, 1 H), 2.59 (br s, 1 H), 2.63 (dd, J = 7.2, 15.2 Hz, 1 H), 3.53 (d, J = 9.6 Hz, 1 H), 3.66 (s, 3 H), 4.22 (d, J = 3.0 Hz, 1 H), 4.41 (m, 1 H), 4.55 (d, J = 9.6 Hz, 1 H), 7.31-7.41 (m, 5 H). ¹³C NMR (100 MHz, CDCl3): δ = 37.1, 40.5, 51.7, 67.1, 68.5, 72.7, 77.8, 127.4, 128.3, 128.6, 139.2, 171.3. HRMS (ESI): m/z [M + NH4]+ calcd for C14H22NO5: 284.1492; found: 284.1488.

17

Goniothalesdiol A (1): powder; [α]D ²5 -21.0 (c = 0.2, CHCl3). IR (KBr): 700, 758, 1047, 1078, 1170, 1203, 1438, 1735, 2920, 2952, 3425 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.77 (td, J = 2.4, 14.0 Hz, 1 H), 1.94 (br s, 1 H), 2.08 (ddd, J = 2.0, 3.0, 14.0 Hz, 1 H), 2.47 (dd, J = 6.0, 15.2 Hz, 1 H), 2.59 (br s, 1 H), 2.63 (dd, J = 7.2, 15.2 Hz, 1 H), 3.53 (d, J = 9.6 Hz, 1 H), 3.66 (s, 3 H), 4.22 (d, J = 3.0 Hz, 1 H), 4.41 (m, 1 H), 4.55 (d, J = 9.6 Hz, 1 H), 7.31-7.41 (m, 5 H). ¹³C NMR (100 MHz, CDCl3): δ = 37.1, 40.5, 51.7, 67.1, 68.5, 72.7, 77.8, 127.4, 128.3, 128.6, 139.2, 171.3. HRMS (ESI): m/z [M + NH4]+ calcd for C14H22NO5: 284.1492; found: 284.1488.

   Permissions and Reprints All articles of this category

Scheme 1 Retrosynthetic analysis for goniothalesdiol A

Scheme 2 Protecting-group-free total synthesis of goniothalesdiol A