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

1a Bach G. Breiding-Mack S. Grabley S. Hammann P. Hütter K. Thiericke R. Uhr H. Wink J. Zeeck A. Ann. Chem.  1993,  241 

1b 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:

1c 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:

2a Shing TKM. So KH. Kwok WS. Org. Lett.  2009,  11:  5070 

Gabosine I and gabosine G:

2b Shing TKM. Cheng HM. J. Org. Chem.  2007,  72:  6610 

Gabosine O:

2c Carreňo MC. Merino E. Ribagorda M. Somoza Ã. Urbano A. Chem. Eur. J.  2007,  13:  1064 

Gabosine N and gabosine O:

2d 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:

2e Ramana GV. Rao BV. Tetrahedron Lett.  2005,  46:  3049 

2f Shinada T. Fuji T. Ohtani Y. Yoshida Y. Ohfune Y. Synlett  2002,  1341 

Gabosine A:

2g Banwell MG. Bray AM. Wong DJ. New J. Chem.  2001,  25:  1351 

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

2h Mehta G. Lakshminath S. Tetrahedron Lett.  2000,  41:  3509 

Gabosine C and COTC:

2i 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:

3a Prasad KR. Chandrakumar A. Tetrahedron  2007,  63:  1798 

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

3b Prasad KR. Pawar AB. Synlett  2010,  1093 

3c Prasad KR. Pawar AB. ARKIVOC  2010,  (vi):  39 

3d Prasad KR. Gandi VR. Nidhiry JE. Bhat KS. Synthesis  2010,  2521 

3e Prasad KR. Gandi VR. Synlett  2009,  2593 

3f Prasad KR. Gholap SL. J. Org. Chem.  2008,  73:  2 

3g Prasad KR. Gholap SL. J. Org. Chem.  2008,  73:  2916 

3h Prasad KR. Swain B. Tetrahedron: Asymmetry  2008,  19:  1134 

3i Prasad KR. Chandrakumar A. J. Org. Chem.  2007,  72:  6312 

3j Prasad KR. Gholap SL. J. Org. Chem.  2006,  71:  3643 

4 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 

5

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

6

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

7

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.