Total Synthesis of Gabosine H

Abstract

Stereoselective total synthesis and assignment of the absolute configuration of the keto carba sugar gabosine H is presented. Pivotal reactions in the sequence include desymmetrization of the dimethylamide of tartaric acid and ring-closing metathesis.

gabosine H - natural products - stereoselective synthesis - ring-closing metathesis

References and Notes

<A NAME="RD04511ST-1A">1a</A> Bach G. Breiding-Mack S. Grabley S. Hammann P. Hütter K. Thiericke R. Uhr H. Wink J. Zeeck A. Ann. Chem.  1993,  241 

<A NAME="RD04511ST-1B">1b</A> Tang YQ. Maul C. Hofs R. Sattler I. Grabley S. Feng XZ. Zeeck A. Thiericke R. Eur. J. Org. Chem.  2000,  149 

For a review on carba sugars, see:

<A NAME="RD04511ST-1C">1c</A> Arjona O. Gómez AM. Lóopez JC. Plumet J. Chem. Rev.  2007,  107:  1919 

For recent asymmetric syntheses of gabosines, see: Gabosine F and gabosine O:

<A NAME="RD04511ST-2A">2a</A> Shing TKM. So KH. Kwok WS. Org. Lett.  2009,  11:  5070 

Gabosine I and gabosine G:

<A NAME="RD04511ST-2B">2b</A> Shing TKM. Cheng HM. J. Org. Chem.  2007,  72:  6610 

Gabosine O:

<A NAME="RD04511ST-2C">2c</A> Carreňo MC. Merino E. Ribagorda M. Somoza Ã. Urbano A. Chem. Eur. J.  2007,  13:  1064 

Gabosine N and gabosine O:

<A NAME="RD04511ST-2D">2d</A> Alibés R. Bayón P. de March P. Figueredo M. Font J. Marjanet G. Org. Lett.  2006,  8:  1617 

Gabosine C, COTC gabosine C, and COTC:

<A NAME="RD04511ST-2E">2e</A> Ramana GV. Rao BV. Tetrahedron Lett.  2005,  46:  3049 

<A NAME="RD04511ST-2F">2f</A> Shinada T. Fuji T. Ohtani Y. Yoshida Y. Ohfune Y. Synlett  2002,  1341 

Gabosine A:

<A NAME="RD04511ST-2G">2g</A> Banwell MG. Bray AM. Wong DJ. New J. Chem.  2001,  25:  1351 

Racemic synthesis of gabosine B and the putative structure of gabosine K:

<A NAME="RD04511ST-2H">2h</A> Mehta G. Lakshminath S. Tetrahedron Lett.  2000,  41:  3509 

Gabosine C and COTC:

<A NAME="RD04511ST-2I">2i</A> Lubineau A. Billault I. J. Org. Chem.  1998,  63:  5668 

For a general approach to the synthesis of γ-ketoamides by addition of alkyl or aryl Grignard reagents to tartaric acid derived amides, see:

<A NAME="RD04511ST-3A">3a</A> Prasad KR. Chandrakumar A. Tetrahedron  2007,  63:  1798 

For recent application of γ-keto amides derived from tartaric acid in natural product synthesis, see:

<A NAME="RD04511ST-3B">3b</A> Prasad KR. Pawar AB. Synlett  2010,  1093 

<A NAME="RD04511ST-3C">3c</A> Prasad KR. Pawar AB. ARKIVOC  2010,  (vi):  39 

<A NAME="RD04511ST-3D">3d</A> Prasad KR. Gandi VR. Nidhiry JE. Bhat KS. Synthesis  2010,  2521 

<A NAME="RD04511ST-3E">3e</A> Prasad KR. Gandi VR. Synlett  2009,  2593 

<A NAME="RD04511ST-3F">3f</A> Prasad KR. Gholap SL. J. Org. Chem.  2008,  73:  2 

<A NAME="RD04511ST-3G">3g</A> Prasad KR. Gholap SL. J. Org. Chem.  2008,  73:  2916 

<A NAME="RD04511ST-3H">3h</A> Prasad KR. Swain B. Tetrahedron: Asymmetry  2008,  19:  1134 

<A NAME="RD04511ST-3I">3i</A> Prasad KR. Chandrakumar A. J. Org. Chem.  2007,  72:  6312 

<A NAME="RD04511ST-3J">3j</A> Prasad KR. Gholap SL. J. Org. Chem.  2006,  71:  3643 

<A NAME="RD04511ST-4">4</A> For the synthesis of symmetric 1,4-diketones by addition of vinylmagnesium bromide to tartaric acid Weinreb amide, see: Conrad RM. Grogan MJ. Bertozzi CR. Org. Lett.  2002,  4:  1359 

<A NAME="RD04511ST-5">5</A>

Formation of minor amounts of 1,4-diketone resulting from the addition of Grignard reagent to both amides is observed.

<A NAME="RD04511ST-6">6</A>

The dr of the product alcohol was estimated to be 9:1 by ^¹H NMR.

<A NAME="RD04511ST-7">7</A>

All compounds exhibited satisfactory analytical data.
Compound 5: [α]_D -25.5 (c 2.6, CHCl₃). IR (neat): 2989, 2938, 1654, 1374, 1157, 1054 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 6.29 (s, 1 H), 6.00 (d, J = 1.0 Hz, 1 H), 5.68 (d, J = 5.8 Hz, 1 H), 4.99 (d, J = 5.8 Hz, 1 H), 3.16 (s, 3 H), 2.98 (s, 3 H), 1.90 (s, 3 H), 1.44 (s, 3 H), 1.43 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 197.4, 168.0, 142.3, 128.8, 112.2, 78.1, 75.1, 37.0, 35.8, 26.3, 26.2, 17.5. HRMS: m/z calcd for C₁₂H₁₉NO₄ + Na: 264.1212; found: 264.1205.
Compound 3: mp 74-75 ˚C; [α]_D -26.5 (c 1.8, CHCl₃). IR (KBr): 3386, 2970, 2984, 2948, 1641, 1057, 1040, 890 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 5.06 (s, 1 H), 4.95 (s, 1 H), 4.82-4.79 (m, 1 H), 4.52 (d, J = 7.0 Hz, 1 H), 4.08 (dd, J = 7.9, 3.0 Hz, 1 H), 3.13 (s, 3 H), 2.96 (s, 3 H), 2.59 (d, J = 8.2 Hz, 1 H), 1.82 (s, 3 H), 1.46 (s, 3 H), 1.38 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 168.7, 144.7, 112.1, 110.6, 78.6, 74.6, 73.7, 37.0, 35.7, 26.8, 26.1, 18.8. HRMS: m/z calcd for C₁₂H₂₁NO₄ + Na: 266.1368; found: 266.1357.
Compound 2: [α]_D +23.3 (c 1.8, CHCl₃). IR (neat): 3459, 2989, 2924, 1699, 1609, 1403, 1374, 1213, 1088, 1061 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 6.82 (ddd, J = 17.4, 10.6, 2.4 Hz, 1 H), 6.45 (ddd, J = 17.4, 2.4, 1.5 Hz, 1 H), 5.86 (ddd, J = 17.4, 2.4, 1.5 Hz, 1 H), 5.04-4.96 (m, 2 H), 4.51-4.49 (m, 1 H), 4.38-4.34 (m, 1 H), 4.13-4.12 (m, 1 H), 2.50-2.48 (br s, 1 H), 1.79 (s, 3 H) 1.49 (s, 3 H) 1.34 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 198.7, 144.1, 131.5, 130.8, 113.0, 111.3, 80.8, 78.7, 74.7, 26.8, 26.0, 18.6. HRMS: m/z calcd for C₁₂H₁₈O₄ + Na: 249.1103; found: 249.1101.
Compound 6: mp 122-126 ˚C; [α]_D +88.2 (c 1.0, CHCl₃). IR (KBr): 3453, 2989, 2929, 2873, 1708, 1378, 1232, 1072, 1059 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 5.86 (s, 1 H), 4.55 (br d, J = 7.4 Hz, 1 H), 4.09 (d, J = 10.7 Hz, 1 H), 3.85 (dd, J = 10.4, 8.4 Hz, 1 H), 3.45-3.25 (br s, 1 H), 2.07 (s, 3 H), 1.46 (s, 6 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 192.4, 161.3, 125.8, 113.0, 81.4, 79.7, 73.5, 26.8, 26.5, 19.5. HRMS: m/z calcd for C₁₀H₁₄O₄ + Na: 221.0790; found: 221.0802.
Gabosine H: mp 118-119 ˚C; [α]_D -74.0 (c 0.6, MeOH).
IR (KBr): 3431, 2894, 2876, 1657, 1625 cm^-¹. ^¹H NMR (400 MHz, CD₃OD): δ = 5.92 (s, 1 H), 4.23 (d, J = 8.4 Hz, 1 H), 4.01 (d, J = 10.8 Hz, 1 H), 3.56 (dd, J = 10.8, 2.4 Hz, 1 H), 2.07 (s, 3 H). ^¹³C NMR (100 MHz, CD₃OD): δ = 199.4, 165.7, 125.0, 79.1, 78.0, 75.1, 20.0. HRMS: m/z calcd for C₇H₁₀O₄ + Na: 181.0477; found: 181.0477.