First Total Synthesis of (+)-11-Hydroxyerythratidine

Abstract

The first total synthesis of (+)-11-hydroxyerythratidine is described. The strategy is featured by a highly stereoselective construction of the C(5) spiro center via the Lewis acid promoted cyclization of ortho-quinone acetal, derived from di-ortho-substituted biphenyl 9 with a chiral center at the side chain.

Key words

asymmetric synthesis - biphenyls - erythrinan alkaloids - natural product - spirocenter chirality

References and Notes

• 1a Dyke SF. Quessy SN. In The Alkaloids   Vol. 18:  Rodrigo RGA. Academic Press; New York: 1981.  p.1 
• 1b Tsuda Y. Sano T. In The Alkaloids   Vol 48:  Cordell GA. Academic Press; San Diego: 1996.  p.249 
• 1c Grove JF. Reimann E. Roy S. In Progress in the Chemistry of Organic Natural Products   Vol. 88:  Herz W. Falk H. Kirby GW. Springer; Wien / New York: 2007.  p.1 
• 2 Throughout this work, the commonly accepted erythrinan numbering is used. See: Boekelheide V. Prelog V. In Progress in Organic Chemistry   Vol. 3:  Cook JW. Butterworths Scientific; London: 1955. Chap. 5; see also ref. 1
• Recent examples of the total syntheses in racemic form:
• 3a Padwa A. Wang Q. J. Org. Chem.  2006,  71:  7391 
• 3b Gao S. Tu QY. Hu X. Wang S. Hua R. Jiang Y. Zhao Y. Fan X. Zhang S. Org. Lett.  2006,  8:  2373 
• 3c Wang Q. Padwa A. Org. Lett.  2006,  8:  601 
• 3d Shimizu K. Takimoto M. Mori M. Org. Lett.  2003,  5:  2323 
• 3e Fukumoto H. Esumi T. Ishihara J. Hatakeyama S. Tetrahedron Lett.  2003,  44:  8047 
• 3f Lee H. Cassidy MP. Rashatasakhon P. Padwa A. Org. Lett.  2003,  5:  5067 
• 3g Hosoi S. Nagao M. Tsuda Y. Isobe K. Sano T. Ohta T. J. Chem. Soc., Perkin Trans. 1  2000,  1505 
• The total syntheses in optically active form:
• 4a Blake AJ. Gill C. Greenhalgh DA. Simpkins NS. Zhang F. Synthesis  2005,  3287 
• 4b Allin SM. Streetley GB. Slater M. James SL. Martin WP. Tetrahedron Lett.  2004,  45:  5493 
• 4c Tsuda Y. Hosoi S. Katagiri N. Kaneko C. Sano T. Chem. Pharm. Bull.  1993,  41:  2087 
• 4d Tsuda Y. Hosoi S. Katagiri N. Kaneko C. Sano T. Heterocycles  1992,  33:  497 
• 5a Yasui Y. Koga K. Suzuki K. Matsumoto T. Synlett  2004,  615 
• 5b Yasui Y. Suzuki K. Matsumoto T. Synlett  2004,  619 
• 6 Isobe K. Mohri K. Takeda N. Hosoi S. Tsuda Y. J. Chem. Soc., Perkin Trans. 1  1989,  1357 
• The semisynthesis involving oxidation of the C(11) methylene of the natural substance:
• 7a Isobe K. Mohri K. Suzuki K. Haruna M. Ito K. Hosoi S. Tsuda Y. Heterocycles  1991,  32:  1195 
• Also see:
• 7b Isobe K. Mohri K. Takeda N. Suzuki K. Hosoi S. Tsuda Y. Chem. Pharm. Bull.  1994,  42:  197 
• 8a Chawla AS. Jackson AH. Nat. Prod. Rep.  1990,  565 
• 8b Soto-Hernandez M. Jackson AH. Planta Med.  1994,  60:  175 
• 8c Jackson AH. Chawla AS. Allertonia  1982,  3:  39 
• 12a Ishiyama T. Itoh Y. Kitano T. Miyaura N. Tetrahedron Lett.  1997,  38:  3447 
• 12b For a review, see: Miyaura N. Suzuki A. Chem. Rev.  1995,  95:  2457 
• 13 Yadav JS. Reddy BVS. Reddy KS. Synlett  2002,  468 
• Recent reviews of quinone acetals, see:
• 14a Magdziak D. Meek SJ. Pettus TRR. Chem. Rev.  2004,  104:  1383 
• 14b Quideau S. Pouysegu L. Deffieux D. Synlett  2008,  467 
• 15a Curtin DY. Rec. Chem. Prog.  1954,  15:  111 
• 15b Seeman JI. Chem. Rev.  1983,  83:  83 
• 18a Frigerio M. Santagostino M. Tetrahedron Lett.  1994,  35:  8019 
• 18b Frigerio M. Santagostino M. Sputore S. J. Org. Chem.  1999,  64:  4537 
• 20 Sakaitani M. Ohfune Y. J. Org. Chem.  1990,  55:  870 ; and references cited therein
• 23 Reimann E. Ettmayr C. Monatsh. Chem.  2004,  135:  959 

9

Iodide 5 (>99.5% ee) was prepared from varatraldehyde via the Sharpless asymmetric dihydroxylation (Scheme  [8] ). See Supporting Information.

Scheme 8

10

The reaction with the corresponding mono-Boc derivative was not fruitful.

11

Boronic ester 6 was synthesized in three steps from isovanillin (Scheme 9). For the palladium-catalyzed boronic ester formation with bis(pinacolato)diboron, see:
(a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508. (b) Ishiyama, T.; Ishida, K.; Miyaura, N. Tetrahedron 2001, 57, 9813.

Scheme 9

16

Experimental Procedure
To a suspension of 4 Å MS (3.05 g) and Cu(OTf)₂ (1.06 g, 2.09 mmol) in toluene (13 mL) was added dropwise ortho-quinone acetal 10 (4.36 g, 5.78 mmol) in toluene (25 mL) at -20 ˚C, and the mixture was allowed to warm to 25 ˚C. After stirring for 13 h, the reaction was quenched by adding sat. aq NaHCO₃. The mixture was filtered through a Celite pad and the products were extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by flash column chromatography (hexane-EtOAc, 3:2) to afford spirocycle 13a (3.75 g, 90%) and 13b (261 mg, 6%).

17

Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 712628 (for compound 14) and 712629 (for compound 20). Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1 EZ, UK [fax:[phone] or e-mail: [e-mail]]; http://www.ccdc.cam.ac.uk/products/csd/deposit/.

19

Attempted cyclizations of the derivatives possessing hydroxy or protected hydroxy at C(11) resulted in affording tetracyle 21 (Figure  [³] ) with C(10)-C(11) double bond in various yields.

Figure 3

21

α-Orientation of the C(2)hydrogen in 16-18 was deduced as follows:(1) The assumed ketone intermediate, though not detected, was supposed to be prone to enolization at the C(2) carbonyl to be hydrogenated [cf. epimerization of ketone 19 at C(3)];(2) in compounds 16-18, the NOE was not observed between the hydrogens at C(2) and C(14) while observed in compound 3 with 2β-hydrogen (see ref. 26).

22

Acetylation of 20 [Ac₂O, DMAP, pyridine] gave the stereoisomer of ketone 19, which obviously shows that the conversion of 19 into 20 was the two-step process including the deacetylation and the epimerization at C(3). Because
α-orientation of the C(3) methoxy in 20 was confirmed by
X-ray crystal structure analysis, it leads to β-orientation of the C(3) methoxy in compound 19 as well as 16-18.

24

The 11β-configuration of 18 was confirmed by employing its C(11) epimer 22 (Scheme  [¹0] ), obtained as the minor isomer by the reduction with NaBH₄ (MeOH, r.t.), in which the NOE was observed between the hydrogens at C(8) and C(11).

Scheme 10

25

The preference of the hydride attack from the β-face could be ascribed to the steric hindrance to the α-attack by the axial hydrogen at C(4).

26

(+)-11-Hydroxyerythratidine (3)
Mp 188.5-190.3 ˚C (hexane-CHCl₃); [α]_D ^²4 +203 (c 1.1, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 1.82 (dd, 1 H, J ₁ = 12.5 Hz, J ₂ = 11.6 Hz), 1.93 (dd, 1 H, J ₁ = 11.6 Hz, J ₂ = 4.1 Hz), 2.00-2.25 (br, 2 H), 2.20-2.30 (m, 1 H), 2.40-2.60 (m, 1 H), 3.02 (ddd, 1 H, J ₁ = J ₂ = 9.3 Hz, J ₃ = 6.8 Hz), 3.14 (ddd, 1 H, J ₁ = J ₂ = 9.3 Hz, J ₃ = 3.0 Hz), 3.29 (dd, 1 H, J ₁ = 15.4 Hz, J ₂ = 1.2 Hz), 3.35 (s, 3 H), 3.62 (ddd, 1 H, J ₁ = 12.5 Hz, J ₂ = J ₃ = 4.1 Hz), 3.73 (dd, 1 H, J ₁ = 15.4 Hz, J ₂ = 5.7 Hz), 3.83 (s, 3 H), 3.91 (s, 3 H), 4.44-4.54 (br, 1 H), 4.56-4.66 (br, 1 H), 5.86-5.94 (br, 1 H), 6.50 (s, 1 H), 7.06 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 27.5, 35.5, 48.8, 50.5, 55.9, 56.1, 56.5, 62.9, 63.3, 64.7, 76.2, 109.8, 111.8, 120.8, 128.2, 128.3, 145.6, 148.0, 148.7. IR (ATR): 3393, 2926, 2866, 2852, 1509, 1462, 1255, 1101, 1057, 981, 873, 778, 750 cm^-¹. Anal. Calcd for C₁₉H₂₅NO₅: C, 65.69; H, 7.25; N, 4.03. Found: C, 65.48; H, 7.55; N, 3.83. HPLC [CHIRALCEL^® OD-H (Daicel), Ø 0.46 × 25 cm (2×), hexane-2-PrOH (4:1), 1.0 mL/min, 30 ˚C, 254 nm] t _R = 12.6 min for 3 (15.4 min for ent-3). NOE was observed between the hydrogens at C(2) and C(14) (Figure  [4] ).

Figure 4