Stereoselective Formal Total Synthesis of (-)-Didemniserinolipid B

Abstract

A formal total synthesis of (-)-didemniserinolipid B from l-(+)-tartaric acid is presented. Key features of the synthesis include construction of the bicyclic acetal core from bisdimethyl amide of tartaric acid and further elaboration by cross metathesis.

Key words

didemniserinolipid B - marine natural product - stereoselective synthesis - tartaric acid

References and Notes

• 1 Kiyota H. Top. Heterocycl. Chem.  2006,  5:  65 
• 2 Gonzalez N. Rodriguez J. Jimenez C. J. Org. Chem.  1999,  64:  5705 
• 3 Mitchell SS. Rhodes D. Bushman FD. Faulkner DJ. Org. Lett.  2000,  2:  1605 
• 4a Kiyota H. Dixon DJ. Luscombe CK. Hettstedt S. Ley SV. Org. Lett.  2002,  4:  3223 
• 4b Marvin CC. Voight EA. Burke SD. Org. Lett.  2007,  9:  5357 
• 4c Marvin CC. Voight EA. Suh JM. Paradise CL. Burke SD. J. Org. Chem.  2008,  73:  8452 
• 4d Ramana CV. Induvadana B. Tetrahedron Lett.  2009,  50:  271 
• 5a Prasad KR. Anbarasan P. Tetrahedron Lett.  2006,  47:  1433 
• 5b Prasad KR. Anbarasan P. Tetrahedron: Asymmetry  2006,  17:  850 
• 5c Prasad KR. Anbarasan P. Tetrahedron  2006,  62:  8303 
• 5d Prasad KR. Anbarasan P. Synlett  2006,  2087 
• 6a For a general approach to the synthesis of γ-keto amides from tartaric acid, see: Prasad KR. Chandrakumar A. Tetrahedron  2007,  63:  1798 
• 6b Prasad KR. Gholap SL. J. Org. Chem.  2008,  73:  1 
• 6c Prasad KR. Gholap SL. J. Org. Chem.  2008,  73:  2916 
• 6d Prasad KR. Swain B. Tetrahedron: Asymmetry  2008,  19:  1134 
• 6e Prasad KR. Gandi V. Tetrahedron: Asymmetry  2008,  19:  2616 
• 6f Prasad KR. Chandrakumar A. J. Org. Chem.  2007,  72:  6312 
• 6g Prasad KR. Dhaware M. Synthesis  2007,  3697 
• 6h Prasad KR. Gholap SL. J. Org. Chem.  2006,  71:  3643 
• 9 Barton DHR. McCombie SW. J. Chem. Soc., Perkin Trans. 1  1975,  1574 
• For FeCl₃-mediated deprotection of acetals, see:
• 10a Sen SE. Roach SL. Boggs JK. Ewing GJ. Magrath J.
  J. Org. Chem.  1997,  62:  6684 
• 10b Prasad KR. Chandrakumar A. Tetrahedron: Asymmetry  2005,  16:  1897 
• 10c

  Ref. 5 and 6

7

Formation of minor amount (8%) of diketone resulting from the addition of Grignard reagent to both amide groups is observed.

8

Diastereomeric ratio of the product alcohol was estimated to be >95:5 within detectable limits by ^¹H NMR. Alcohols were inseparable at this stage. However, stereochemistry of the alcohol is of no consequence because it is deoxygenated in the next step.

11

It was cumbersome to purify the cross-metathesis product 12 by column chromatography from traces of an unidentified impurity. However, this was of no consequence in the next reaction sequence, and pure 13 was isolated after the reduction of the olefin and the ester.

12

All new compounds exhibited satisfactory spectral data. In the NMR data that follow, * indicates rotamer peaks.
Compound 3: [α]_D +8.7 (c 1.3, CHCl₃). IR (neat): 2940, 2863, 1716, 1652, 1506, 1374 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.40-7.24 (m, 5 H), 5.13 (d, J = 6.0 Hz, 1 H), 4.78 (d, J = 5.7 Hz, 1 H), 4.90 (s, 2 H), 3.47 (t, J = 6.0 Hz, 2 H), 3.13 (s, 3 H), 2.98 (s, 3 H), 2.83-2.56 (m, 2 H), 1.79-1.55 (m, 4 H), 1.42 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 209.2, 168.1, 138.5, 128.3, 128.3, 127.6, 127.5, 112.1, 82.1, 74.9, 72.9, 69.9, 39.2, 37.0, 36.0, 29.1, 26.4, 26.0, 19.8. HRMS: m/z calcd for C₁₈H₂₅NO₅ + Na: 386.1943; found: 386.1925
Compound 13: [α]_D -21.2 (c 3, CHCl₃). IR (neat): 3448, 2926, 1455, 1097, 734 cm^-¹. ^¹H NMR (300 MHz, CDCl₃):
δ = 7.50-7.10 (m, 10 H), 4.62 (s, 2 H), 4.5 (s, 2 H), 4.17 (br s, 1 H), 3.90-3.73 (m, 1 H), 3.63 (t, J = 6.6 Hz, 2 H), 3.46 (t, J = 6.6 Hz, 2 H), 3.29 (br s, 1 H), 2.30 (t, J = 7.5 Hz, 2 H), 2.00-1.15 (m, 40 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 138.7, 138.5, 128.37, 128.32, 127.63, 127.58, 127.47, 109.3, 80.0, 77.8, 72.8, 72.3, 70.3 (2 C), 63.1, 37.4, 35.3, 32.8, 30.7, 29.8, 29.62, 29.58, 29.41, 26.1, 25.7, 25.4, 22.8, 22.0. HRMS:
m/z calcd for C₄₀H₆₂O₅ + Na: 645.4495; found: 645.4484.
Compound 15: [α]_D -18.3 (c 0.3, CHCl₃). IR (neat): 3069, 2927, 1700, 1454, 1388, 734 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.50-7.20 (m, 10 H), 4.61 (s, 2 H), 4.49 (s, 2 H), 4.17 (br s, 1 H), 4.10-3.85 (m, 3 H), 3.85-3.70 (m, 1 H), 3.70-3.30 (m, 6 H), 3.29 (br s, 1 H), 2.00-1.15 (m, 55 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 152.2/151.7*, 138.7/138.5*, 128.4, 128.35, 127.66, 127.60, 127.5, 109.3, 93.7/93.3*, 80.1/79.7*, 80.0, 77.8, 72.9, 72.3, 71.4, 70.3 (2 C), 70.1/69.3*, 65.7/65.4*, 56.5/56.4*, 37.43, 35.3, 30.8, 29.8, 29.7, 29.64, 29.60, 29.5, 28.48, 28.43, 27.5/26.8*, 26.11, 26.06, 25.43, 24.4/23.1*, 22.8, 21.96. HRMS: m/z calcd for C₅₁H₈₁NO₈ + Na: 858.5860; found: 858.5861.
Compound 16: [α]_D -41.4 (c 1.2, CHCl₃) [Lit.^4d [α]_D +36.3 (c 0.2, CHCl₃ for the enantiomer)]. IR (CHCl₃): 3463, 2928, 1700, 1389, 1366, 1088, 770 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 4.07 (br s, 1 H), 4.05-3.96 (m, 1 H), 3.95-3.86 (m, 3 H), 3.65 (t, J = 6.5 Hz, 2 H), 3.62-3.55 (m, 1 H), 3.54-3.37 (m, 2 H), 3.36-3.14 (m, 2 H), 2.52-2.30 (m, 1 H), 2.10-1.81 (m, 1 H), 1.79-1.41 (m, 30 H), 1.38-1.22 (m, 25 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 152.2/151.7*, 109.6, 93.7/93.3*, 82.4, 80.3/79.7*, 77.8, 71.4, 70.0/69.3*, 66.3, 65.7/65.4*, 56.5/56.3*, 37.5, 35.2, 32.7, 30.2, 29.8, 29.7 (2 C), 29.6 (2 C), 29.5, 28.48/28.43*, 27.5/26.8*, 26.1, 25.6, 25.3, 25.1, 24.4/23.1*, 23.0. HRMS: m/z calcd for C₃₇H₆₉NO₈ + Na: 678.4921; found: 678.4935.
Compound 18: [α]_D -29.3 (c 0.3, CHCl₃) [Lit.^4b [α]_D +37.6 (c 0.98, CHCl₃)]. ^¹H NMR (400 MHz, CDCl₃): δ = 6.95 (dt, J = 15.5, 7.0 Hz, 1 H), 5.80 (d, J = 15.6 Hz, 1 H), 4.17 (q, J = 7.2 Hz, 2 H), 4.06 (br s, 1 H), 4.02-3.96 (m, 1 H), 3.95-3.81 (m, 3 H), 3.61 (br s, 1 H), 3.59-3.24 (m, 4 H), 2.50-2.26 (m, 1 H), 2.19 (q, J = 7.0 Hz, 2 H), 2.16-1.36 (m, 25 H), 1.35-1.21 (m, 33 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 166.7, 152.5/151.7*, 148.8, 121.4, 109.6, 93.7/93.2*, 82.3, 80.3/79.7*, 77.6, 71.3, 69.97/69.19*, 66.2, 65.6/65.3*, 60.1, 56.4/56.3*, 37.4, 35.0, 32.0, 30.0, 29.7, 29.4, 28.7/28.4*, 27.8, 27.4/26.7*, 26.0, 25.0, 24.3/23.0*, 22.9, 14.2. HRMS: m/z calcd for C₄₁H₇₃NO₉ + Na: 746.5183; found: 746.5188.