Stereoselective Synthesis of a Lactam Analogue of Brefeldin C

Abstract

A convergent, stereoselective synthesis of a brefeldin C lactam analogue is described. Novel features are application of the asymmetric iridium-catalyzed allylic substitution on a multigram scale for construction of the stereogenic centers C-9 as well as C-15 and an intermolecular Nozaki-Hiyama-Kishi reaction for introduction of the brefeldin enoate moiety.

Key words

brefeldin C - iridium-catalyzed allylic substitution - ring-closing metathesis - Nozaki-Hiyama-Kishi reaction - Julia-Kocieński olefination

References and Notes

• 1 Singleton VL. Bohonos N. Ullstrup AJ. Nature (London)  1958,  181:  1072 
• 2 Sciaky N. Presley J. Smith C. Zaal KJM. Cole N. Moreira JE. Terasaki M. Siggia E. Lippincott-Schwartz J. J. Cell Biol.  1997,  139:  1137 ; and literature cited therein
• 3a Betina V. Horakova K. Barath Z. Naturwissenschaften  1962,  51:  445 
• 3b Argade AB. Devraj R. Vroman JA. Haugwitz RD. Hollingshead M. Cushman M. J. Med. Chem.  1998,  41:  3337 
• 3c Fox BM. Vroman JA. Fanwick PE. Cushman M. J. Med. Chem.  2001,  44:  3915 
• 3d Anadu NO. Davisson VJ. Cushman M. J. Med. Chem.  2006,  49:  3897 
• 4 Phillips LR. Supko JG. Malspeis L. Anal. Biochem.  1993,  211:  16 
• 5 Zhu J.-W. Hori H. Nojiri H. Tsukuda T. Taira Z. Bioorg. Med. Chem. Lett.  1997,  139 
• 6 Zhu JW. Nagasawa H. Nagura F. Mohamad SB. Uto Y. Ohkura K. Hori H. Bioorg. Med. Chem.  2000,  8:  455 
• 7 Borzilleri RM. Zheng X. Schmidt RJ. Johnson JA. Kim S.-H. DiMarco JD. Fairchild CR. Gougoutas JZ. Lee FYF. Long BH. Vite GD. J. Am. Chem. Soc.  2000,  122:  8890 
• 8 Paek S.-MP. Seo S.-Y. Min K.-H. Shin DM. Chung YK. Suh Y.-G. Heterocycles  2007,  71:  1059 
• 9 Sunagawa M. Ohta T. Nozoe S. J. Antibiotics  1983,  25 
• 10 Zeeh J.-C. Zeghouf M. Grauffel C. Guibert B. Martin E. Dejaegere A. Cherfils J. J. Biol. Chem.  2006,  281:  11805 
• 11 Trost BM. Crawley ML. Chem. Eur. J.  2004,  10:  2237 ; this article contains an extensive bibliography of previous total syntheses of Brefeldin A
• 12a Latest total synthesis: Archambaud S. Aphecetche-Julienne K. Guingant A. Synlett  2005,  139 
• 12b First total synthesis: Schreiber SL. Meyers HV. J. Am. Chem. Soc.  1988,  110:  5198 
• 13 Hübscher T. Helmchen G. Synlett  2006,  1323 
• 14 Streiff S. Welter C. Schelwies M. Lipowsky G. Miller N. Helmchen G. Chem. Commun.  2005,  2957 
• General Procedure for the Preparation of the Iridium Catalyst: Under argon, a mixture of [Ir(cod)Cl]₂ (0.02 mmol), L* (0.04 mmol) and anhyd 1,5,7-triaza-bicyclo[4.4.0]dec-5-ene (TBD, 0.08 mmol) was dissolved in anhyd THF (1.0 mL, content of H₂O <30 mg/L, Karl Fischer titration) and the solution was stirred for 5 min (L2) or 1.5 h (L1). TBD is hygroscopic and was dried under vacuum in a Schlenk tube and stored under argon. For preparation of the ligands see:
• 15a L1: van Zijl AW. Arnold LA. Minnaard AJ. Feringa BL. Adv. Synth. Catal.  2004,  326:  413 ; supporting information
• 15b L2: Polet D. Alexakis A. Org. Lett.  2005,  7:  1621 ; supporting information
• 16 Gnamm C. Förster S. Miller N. Brödner K. Helmchen G. Synlett  2007,  790 
• 22 Weihofen R. Tverskoy O. Helmchen G. Angew. Chem. Int. Ed.  2006,  45:  5546 ; Angew. Chem. 2006, 118, 5673
• 23 We used a simplified version of a method described in: Ziegler FE. Klein SI. Pati UK. Wang TF. J. Am. Chem. Soc.  1985,  107:  2730 
• 24 Blakemore PR. Kocieński PJ. Marczak S. Wicha J. Synthesis  1999,  1209 
• 26 The ester 17 was prepared by cis-selective addition of HI to propargylic acid and esterification, cf.: Dixon JD. Ley SV. Longbottom AD. Org. Synth.  2003,  80:  129 
• 28 In principle, the side chains can be introduced in reversed order, because of a hidden symmetry of 6. However, the NHK reaction with aldehyde 6 proceeded with poor diastereoselectivity of 2:1. Various experiments to effect a reagent-controlled reaction using Kishi’s method failed: Namba K. Kishi Y. Org. Lett.  2004,  6:  5031 
• 29 Helmchen G. Tetrahedron Lett.  1974,  1527 
• 31a Corey EJ. Wollenberg RH. Tetrahedron Lett.  1976,  4705 
• 31b Bartlett PA. Green FR. J. Am. Chem. Soc.  1978,  100:  4858 

17

Methyl (3 R )-2-Cyano-3-[(trityloxy)methyl]pent-4-enoate (3): A solution of the catalyst in anhyd THF (20 mL) was prepared according to the general procedure from
[Ir(cod)Cl]₂ (268 mg, 0.40 mmol), L1 (432 mg, 0.80 mmol) and TBD (222 mg, 1.60 mmol). Carbonate 2 (15.54 g, 40.0 mmol), the pronucleophile (5.11 g, 51.6 mmol) and anhyd THF (60 mL) were added, and the solution was stirred at 40 °C. Conversion as well as the ratio of branched and linear product were determined by GC. After 60 h the solvent was removed under reduced pressure, and the residue was subjected to flash column chromatography on silica gel (PE-EtOAc, 20:1) to yield 3 (70%) as a pale yellow oil which was an inseparable mixture of epimers. Their ratio was determined by ¹H NMR (64:36). ¹H NMR (300.13 MHz, CDCl₃, major epimer): δ = 2.90-3.09 (m, 1 H, CHCH₂), 3.17-3.40 (m, 2 H, CH₂O), 3.75 (s, 3 H, OMe), 4.14 (d, J = 4.3 Hz, 1 H, CHCN), 5.09-5.21 (m, 2 H, CH=CH₂), 5.63 (ddd, J = 8.8, 10.4, 17.0 Hz, 1 H, CH=CH₂), 7.20-7.35 (m, 9 H, ArH), 7.38-7.45 (m, 6 H, ArH). ¹³C NMR (75.48 MHz, CDCl₃): δ = 39.82 (d, CHCN), 44.98 (d, CHCH₂), 53.43 (q, CO₂CH₃), 63.72 (t, CH₂O), 87.42 (s, CPh₃), 114.76 (s, CN), 120.69 (t, CH=CH₂), 127.42, 128.12, 128.68 (3 × d, CAr), 132.27 (d, CH=CH₂), 143.67 (s, CAr), 166.32 (s, CO₂Me). MS (EI⁺): m/z (%) = 411 (3) [M⁺], 334 (4) [M - Ph⁺], 259 (9), 244 (37) [HCPh₃ ⁺], 243 (100) [CPh₃ ⁺], 165 (66), 152 (42)
[M - OCPh₃ ⁺], 105 (32) [PhCO⁺], 77 (16) [Ph⁺]. Anal. Calcd for C₂₇H₂₅NO₃: C, 78.81; H, 6.12; N, 3.40. Found: C, 78.83; H, 6.32; N, 3.28.

18

The isomers (cis-5/trans-5 = 59:41) could be separated by column chromatography on silica gel. Their relative configuration was determined by 1D NOE-¹H NMR spectroscopy. HPLC data for cis-5: Daicel Chiralcel AD-H (250 × 4.6 mm, 5 µm), with guard cartridge (10 × 4 mm, 5 µm), n-hexane-i-PrOH (99:1), flow rate = 0.5 mL min^-1, r.t., UV detection at λ = 210 nm, t _R[(+)-(1R,2S)-5] = 25 min, t _R[(-)-(1S, 2R)-5] = 32 min.

19

Analytical Data for (1 R ,2 R )-2-[(Trityloxy)methyl]cyclo-pentanecarbaldehyde (6): [α]_D ²⁰ -8.9 (c = 0.525, CHCl₃). ¹H NMR (300.13 MHz, CDCl₃): δ = 1.24-1.38 (m, 1 H, 3-H), 1.50-1.62 (m, 2 H, 4-H), 1.63-1.91 (m, 3 H, 3-H, 5-H), 2.39-2.58 (m, 2 H, 1-H, 2-H), 2.97 (dd, J = 8.2, 8.2 Hz, 1 H, CH₂O), 3.19 (dd, J = 5.5, 8.9 Hz, 1 H, CH₂O), 7.17-7.45 (m, 15 H, ArH), 9.70 (d, J = 2.3 Hz, 1 H, CHO). ¹³C NMR (75.48 MHz, CDCl₃): δ = 25.09 (t, C-4), 26.78 (t, C-5), 29.68 (t, C-3), 41.78 (d, C-2), 55.85 (d, C-1), 66.58 (t, CH₂OCPh₃), 86,81 (s, CPh₃), 127.07, 127.90, 128.81 (3 × d, CAr), 144.24 (s, CAr), 203.86 (s, CHO). HRMS (FAB⁺): m/z [M + Na⁺] calcd for C₂₆H₂₆O₂Na: 393.1831; found: 393.1839.

20

HPLC Data for (3 S ) - 3-[(Trityloxy)methyl]pent-4-enenitrile (3′) (Table 1): Daicel Chiralcel AD-H (250 × 4.6 mm, 5 µm) with guard cartridge (10 × 4 mm, 5 µm), n-hexane-i-PrOH (99:1), flow rate = 0.5 mL min^-1, r.t., λ = 210 nm, t _R[(-)-(R)-3′] = 18 min, t _R[(+)-(S)-3′] = 20 min.

21

tert -Butyl Formyl(1-methylprop-2-en-1-yl)carbamate
[(-)-(S)-9]: A solution of the catalyst in anhyd THF (1 mL) was prepared according to the general procedure from [Ir(cod)Cl]₂ (13.4 mg, 0.01 mmol), (R,R,R)-L2 (24.0 mg, 0.02 mmol) and TBD (11.1 mg, 0.40 mmol). Carbonate 7 (265 mg, 2.0 mmol) and Boc(CHO)NH (8; 477 mg, 2.2 mmol) were added, and the solution was stirred for 1.5 h at r.t. The solvent was removed under reduced pressure, and the ratio of branched and linear product was determined by ¹H NMR. Flash column chromatography on silica gel (PE-EtOAc, 20:1) afforded pure (-)-(S)-9 (85%) as a colorless oil; [α]_D ²⁰ -36.9 [c = 1.08, CHCl₃, 96% ee determined by chiral Chrompack permethyl-β-cyclodextrin (25 m × 0.25 mm), temperature program: gradient 4 °C/min: 50-90 °C, injector temperature 200 °C], t _R[(-)-(S)-9] = 37.8 min, t _R
[(+)-(R)-9] = 38.9 min. ¹H NMR (300.13 MHz, CDCl₃): δ = 1.41 (d, J = 6.9 Hz, 3 H, CHMe), 1.53 (s, 9 H, t-Bu), 5.01-5.19 (m, 3 H, CHN, CH=CH₂), 6.00 (ddd, J = 5.9, 10.3, 17.2 Hz, 1 H, CH=CH₂), 9.17 (s, 1 H, CHO). ¹³C NMR (75.48 MHz, CDCl₃): δ = 17.92 (q, CHMe), 28.21 (q, t-Bu), 49.40 (d, CHNH), 84.17 (s, t-Bu), 115.78 (t, CH=CH₂), 138.10 (d, CH=CH₂), 152.51 (s, CO₂ t-Bu), 163.25 (d, CHO). MS (EI⁺): m/z (%) = 143 (18) [M - C₄H₈ ⁺], 57 (100) [C₄H₇ ⁺]. Anal. Calcd for C₁₀H₁₇NO₃: C, 60.28; H, 8.60; N, 7.03. Found: C, 60.00; H, 8.54; N, 7.13.
This preparation was also carried out on a 77-mmol scale with 1 mol% of L1 as ligand to give 9 with 94% ee, branched/linear = 98:2. Amide 10 was obtained after saponification in 81% yield over two steps.

25

Preparation of 14: A solution of KHMDS in toluene (0.5 M, 5.6 mL) was added dropwise to a cooled solution (-78 °C) of 12 (1.188 g, 2.907 mmol) in DME (11 mL, freshly dried over sodium, containing 70 µg H₂O/mL DME, Karl Fischer titration). After 35 min a solution of 6 (821 mg, 2.216 mmol) in DME (11 mL) was added dropwise. After 3 h at -78 °C the solution was allowed to warm to r.t. and was stirred for 60 min. Then H₂O (10 mL) and brine (10 mL) were added and the mixture was extracted with Et₂O (3 × 20 mL). The combined organic layers were dried over Na₂SO₄, filtered, and the solvent was evaporated in vacuo. The residue was subjected to flash column chromatography on silica gel (PE-EtOAc, 10:1) to give 14 (1.030 g, 83%) as a colorless oil; [α]_D ²⁰ -19.5 (c = 1.33, CHCl₃). ¹H NMR (500.13 MHz, CDCl₃): δ = 1.06 (d, J = 6.6 Hz, 3 H, CHMe), 1.20-1.40 (m, 5 H, 3-H₂, 2-H₂, 5′-H), 1.40-1.68 (m, 3 H, 3′-H, 4′-H₂), 1.44 (s, 9 H, t-Bu), 1.71-1.83 (m, 2 H, 2′-H, 5′-H), 1.83-1.95 (m, 3 H, 4-H₂, 3′-H), 2.14 (m_c, 1 H, 1′-H), 2.92 (dd, J = 6.5, 8.8 Hz, 1 H, CH₂O), 3.10 (dd, J = 4.9, 8.8 Hz, 1 H, CH₂O), 3.59 (br s, 1 H, 1-H), 4.26 (br s, 1 H, NH), 5.21 (ddd, J = 6.3, 6.3, 15.3 Hz, 1 H, 5-H), 5.28 (dd, J = 7.6, 15.3 Hz, 1 H, 6-H), 7.19-7.47 (m, 15 H, H-Ar). ¹³C NMR (125.76 MHz, CDCl₃): δ = 21.42 (q, CHMe), 24.26 (t, C-4′), 26.12 (t, C-3), 28.61 (q, t-Bu), 29.82 (t, C-3′), 32.55 (t, C-4), 33.63 (t, C-5′), 36.92 (t, C-2), 46.25 (d, C-1′), 46.58 (d, C-1), 46.58 (d, C-2′), 65.79 (t, CH₂O), 79.06 (s, t-Bu), 86.27 (s, CPh₃), 126.89, 127.75, (2 × d, C-Ar), 128.96 (d, C-Ar), 129.10 (d, C-5), 134.80 (d, C-6), 144.69 (s, CAr), 155.51 (s, CO₂ t-Bu). Anal. Calcd for C₃₇H₄₇NO₃: C, 80.25; H, 8.55; N, 2.53. Found: C, 80.00; H, 8.46; N, 2.57. MS (FAB⁺): m/z = 576.3 [M + Na⁺].

27

Preparation of 16: Under an atmosphere of argon, CrCl₂ (573 mg, 4.68 mmol) was added to a mixture of 15 (362 mg, 1.17 mmol), methyl (2E)-3-iodoacrylate (17; 495 mg, 2.34 mmol) and NiCl₂ (2.6 mg, 0.012 mmol) in anhyd THF (5 mL) at r.t. After stirring the brownish suspension for 1 h TLC monitoring showed complete conversion. The mixture was treated with H₂O and filtered through a pad of silica gel, which was washed with Et₂O. The solvent was evaporated in vacuo and the residue was subjected to flash chromatography on silica gel (PE-EtOAc, 9:1) to yield 16 (338 mg, 72%) as a colorless oil.
NMR data of the major diastereoisomer 16b: ¹H NMR (500.13 MHz, CDCl₃): δ = 1.10 (d, J = 6.6 Hz, 3 H, CHMe), 1.30-1.48 (m, 6 H, 5′′-H₂, 4′′-H₂, 5′-H, 3′-H), 1.43 (s, 9 H, t-Bu), 1.48-1.70 (m, 2 H, 4′-H), 1.71-1.86 (m, 3 H, 1′-H, 5′-H, 3′-H), 1.94-2.06 (m, 2 H, 3′′-H), 2.25-2.35 (m, 1 H, 2′-H), 2.40 (br s, 1 H, OH), 3.56-3.67 (m, 1 H, CHNH), 3.74 (s, 3 H, OMe), 4.24 (m_c, 1 H, CHOH), 4.34 (br s, 1 H, NH), 5.42 (dd, J = 8.5, 15.3 Hz, 1 H, CH=CHCH₂), 5.50 (ddd, J = 6.4, 6.4, 15.2 Hz, 1 H, CH=CHCH₂), 6.06 (dd, J = 1.7, 15.6 Hz, 1 H, CH=CHCO₂Me), 6.94 (dd, J = 4.0, 15.6 Hz, 1 H, CH=CHCO₂Me). ¹³C NMR (125.76 MHz, CDCl₃): δ = 21.31 (q, CHMe), 24.15 (t, C-4′), 25.84 (t, C-4′′), 28.37 (t, C-5′), 28.59 (q, t-Bu), 32.25 (t, C-3′′), 34.15 (t, C-3′), 36.72 (t, C-5′′), 46.43 (d, CHNH), 48.04 (d, C-2′), 51.69 (q, OMe), 51.74 (d, C-1′), 75.42 (d, C-4), 79.16 (s, t-Bu), 120.42 (d, CH=CHCO₂Me), 130.72 (d, CH=CHCH₂), 135.50 (d, CH=CHCH₂), 148.95 (d, CH=CHCO₂Me), 155.54 (s, CO₂ t-Bu), 167.19 (s, CO₂Me). MS (HR-EI⁺): m/z [M⁺] calcd for C₂₂H₃₇O₅N: 395.2689; found: 395.2672. MS: m/z [M - CO₂ - C₄H₈ ⁺] calcd for C₁₇H₂₉O₃N: 295.2147; found: 295.2106.

30

Preparation of (-)-1b: A solution of 16 (338 mg, 0.86 mmol) in THF (7 mL) was treated with an aqueous solution of LiOH (1 M, 7 mL). After stirring for 24 h at r.t. HCl (1 M, 10 mL) and EtOAc (10 mL) were added. The aqueous layer was separated and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over NaSO₄, filtered and the solvent was removed in vacuo. The residue was dissolved in CH₂Cl₂ (9 mL) and TFA (2 mL) was added. After stirring for 1 h at r.t. the volatile components were removed in vacuo. A solution of the residue in MeOH-H₂O (10:1) was filtered through a column of the strongly acidic ion-exchange resin Dowex 50 W X 8 (10 g). The column was eluted with a solution of NH₃ (0.2-2 M) in MeOH-H₂O (10:1) to yield 18 as a white microcrystalline powder (194 mg, 80%).
Under argon EDCI (310 mg, 1.62 mmol) and HOBt (122 mg, 0.91 mmol) were added to a cooled (0 °C) suspension of 18 (182 mg, 0.65 mmol) in DMF (26 mL). After 20 min the mixture was allowed to warm to r.t. The mixture became a clear solution after 10 min that was stirred for further 24 h. Then brine (20 mL) and EtOAc (20 mL) were added. The aqueous layer was separated and extracted with EtOAc (4 × 20 mL). The combined organic layers were washed with an aqueous solution of NaOH (1 M, 10 mL), dried over Na₂SO₄, filtered, and the solvent was evaporated in vacuo. The residue was subjected to flash chromatography on silica gel (EtOAc) to yield a mixture of 1a and 1b (143 mg, 84%) as small needles. The components were separated by flash chromatography using PE-EtOAc (1:5) as eluent.
Analytical data of the major epimer 1b: [α]_D ²⁰ -18.5 (c = 0.40, MeOH). ¹H NMR (300.13 MHz, CD₃OD): δ = 1.00-1.40 (m, 3 H, 7-H or 13-H, 14-H₂), 1.14 (d, J = 6.8 Hz, 3 H, Me), 1.40-1.68 (m, 2 H, 7-H or 13-H), 1.68-2.10 (m, 9 H, 5-H, 6-H₂, 12-H₂, 8-H₂, 7-H or 13-H, OH), 2.57 (m_c, 1 H, 9-H), 3.85-4.03 (m, 1 H, 15-H), 4.45 (br s, 1 H, 4-H), 5.14 (dd,
J = 3.7, 14.9 Hz, 1 H, 10-H), 5.52 (ddd, J = 3.9, 10.7, 14.7 Hz, 1 H, 11-H), 6.08 (dd, J = 1.3, 15.8 Hz, 1 H, 2-H), 6.48 (dd, J = 4.1, 15.8 Hz, 1 H, 3-H). ¹³C NMR (75.48 MHz, CD₃OD): δ = 21.16 (q, Me), 27.16 (t, C-7 or C-13), 27.21 (t, C-7 or C-13), 31.43 (t, C-6), 34.41 (t, C-12), 37.34 (t, C-8), 38.01 (t, C-14), 43.39 (d, C-9), 47.64 (d, C-15), 50.67 (d, C-5), 72.61 (d, C-4), 123.53 (d, C-2), 130.96 (d, C-11), 138.46 (d, C-10), 147.59 (d, C-3), 170.85 (s, CONH). MS (HR-EI⁺): m/z [M⁺] calcd for C₁₆H₂₅O₂N: 263.1886; found: 263.1868. MS: m/z [M - H₂O⁺] calcd for C₁₆H₂₃ON: 245.1780; found: 245.1788.

32

Preparation of (-)-19: Mesyl chloride (142 µL, 1.82 mmol) was added dropwise to a solution of 1b (80 mg, 0.30 mmol), Et₃N (253 µL, 1.82 mmol) and DMAP (37 mg, 0.30 mmol) in pyridine (10 mL) at 0 °C. The bright orange solution was stirred for 0.5 h at this temperature. Then H₂O (10 µL) was added, and the mixture was allowed to warm to r.t. After stirring for 10 min the solution was diluted with EtOAc (10 mL) and a sat. aq solution of CuSO₄ (10 mL) was added. The aqueous layer was separated and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with a sat. aq solution of NaHCO₃ (20 mL), dried over Na₂SO₄, filtered, and the solvent was removed under reduced pressure. A mixture of the residue with DMF (10 mL) and CsOAc (350 mg, 1.82 mmol) was heated at 80 °C. After 19 h, brine and EtOAc were added. The aqueous layer was separated and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na₂SO₄ and filtered. The solvents were removed under reduced pressure and the residue was subjected to flash chromatography on silica gel (PE-EtOAc, 1:5) to yield 19 (29.8 mg, 32%) as colorless needles and 1a (14.3 mg, 18%): [α]_D ²⁰ -64.9 (c = 0.32, MeOH). ¹H NMR (300.13 MHz, CD₃OD): δ = 1.15 (d, J = 6.8 Hz, 3 H, 16-H), 1.00-1.20 (m, 1 H, 13-H or 7-H), 1.20-1.50 (m, 3 H, 14-H, 8-H, 6-H), 1.50-1.70 (m, 2 H, 13-H₂ or 7-H₂), 1.70-1.90 (m, 5 H, 8-H or 14-H, 12-H, 7-H or 13-H, 5-H), 1.90-2.10 (m, 2 H, 6-H, 12-H), 2.07 (s, 3 H, MeCO), 2.19-2.32 (m, 1 H, 9-H), 3.85-4.00 (m, 1 H, 15-H), 5.05-5.23 (m, 2 H, 4-H, 10-H), 5.55-5.71 (m, 1 H, 11-H), 5.91 (d, J = 16.1 Hz, 1 H, 2-H), 6.43 (dd, J = 6.7, 16.1 Hz, 1 H, 3-H). ¹³C NMR (75.48 MHz, CD₃OD): δ = 20.88 (q, CHMe or CO₂Me), 21.15 (q, CHMe or CO₂Me), 25.79 (t, C-7 or C-13), 27.45 (t, C-7 or C-13), 32.12 (C-6), 33.97 (t, C-12), 36.75 (t, C-14 or C-8), 37.72 (t, C-14 or C-8), 47.62 (d, C-15), 48.62, (d, C-9), 50.80 (d, C-5), 79.81 (d, C-4), 125.93 (d, C-2), 131.75 (d, C-11), 137.16 (d, C-10), 142.00 (d, C-1), 169.71 (s, C-1), 172.04 (s, CO₂Me). MS (HR-EI⁺): m/z [M⁺] calcd for C₁₈H₂₇O₃N: 305.1991; found: 305.1969. MS: m/z [M - C₂H₃O₂ ⁺] calcd for C₁₆H₂₄ON: 246.1858; found: 246.1867.

33

A Mitsunobu reaction with 1b failed to give a useful result.

34

Analytical Data for (-)-1a: [α]_D ²⁰ -20.1 (c = 0.165, MeOH). ¹H NMR (500.13 MHz, CD₃OD): δ = 0.97-1.08 (m, 1 H, 13-H or 7-H), 1.15 (d, J = 6.8 Hz, 3 H, Me), 1.21-1.45 (m, 2 H, 8-H, 14-H), 1.45-1.71 (m, 4 H, 6-H, 13-H₂ or 7-H₂, 5-H), 1.71-1.86 (m, 5 H, 8-H, 12-H, 14-H, 13-H or 7-H, OH), 1.92-2.05 (m, 2 H, 6-H, 12-H), 2.20 (m_c, 1 H, 9-H), 3.87-3.96 (m, 2 H, 4-H, 15-H), 5.16 (dd, J = 9.6, 15.2 Hz, 1 H, 10-H), 5.64 (ddd, J = 4.2, 10.7, 15.0 Hz, 1 H, 11-H), 5.91 (dd, J = 1.1, 16.1 Hz, 1 H, 2-H), 6.63 (dd, J = 5.9, 16.1 Hz, 1 H, 3-H). ¹³C NMR (125.75 MHz, CD₃OD): δ = 21.26 (q, Me), 25.95 (t, C-7 or C-13), 27.70 (t, C-7 or C-13), 32.49 (t, C-6), 33.79 (t, C-12), 36.78 (t, C-8), 37.55 (t, C-14), 47.55 (d, C-15), 48.69 (d, C-9), 53.76 (d, C-5), 77.80 (d, C-4), 123.58 (d, C-1), 131.33 (d, C-11), 137.88 (d, C-10), 147.44 (d, C-3), 170.56 (s, C-1). MS (HR-EI⁺): m/z [M⁺] calcd for C₁₆H₂₅O₂N: 263.1886; found: 263.1904. MS: m/z [M - H₂O⁺] calcd for C₁₆H₂₃ON: 245.1780; found: 245.1785.