An Enantioselective Approach to the Securinega Alkaloids: The Total Synthesis of (+)-Norsecurinine and (+)-Allonorsecurinine

1. Introduction

The Securinega alkaloids¹ are a small family of natural products isolated from the Euphorbiaceae family of plants (Figure 1). Structurally, they typically consist of either an indolizidine (securinine-type, 1) or pyrrolizidine (norsecurinine-type, 2) framework with an α, β, γ, δ-unsaturated bicyclic lactone moiety. Additionally, skeletally rearranged (i.e., secu’amamine, 5),² A-ring methoxylated (i.e., phyllanthine, 4)³, oxidized (i.e., phyllantidine, 6 and nirurine, 7),⁴ and dimeric (i.e., flueggenines, 8 and 9)⁵ congeners have been reported. The enantiomers of some Securinega alkaloids, virosecurinine (3),⁶ viroallosecurinine,⁷ and (−)-norsecurinine,⁸ have also been isolated from natural sources.

Figure 1.

Selected Securinega alkaloids

A broad spectrum of biological activities coupled with synthetically challenging morphologies has prompted many synthetic efforts towards this family of metabolites.^9-15 We became interested in this family of alkaloids upon recognizing the presence of a masked tertiary alcohol flanked by two carbonyls embedded in their structures (grayed bonds in 2). Conceivably, a flexible route to this functional group would provide a gateway to access any member of the Securinega alkaloids. Accordingly, we reckoned the enantioselective rhodium carbenoid-initiated O–H insertion/Claisen rearrangement/1,2-allyl migration domino process developed in our laboratory¹⁶ would provide an interesting stereo-controlled approach to the desired tertiary alcohol functionality. Herein, we report the application of this domino sequence to the synthesis of (+)-norsecurinine¹⁷ and (+)-allonorsecurinine.⁹

2. Results and Discussion

2.1 Retrosynthetic analysis for (+)-norsecurinine

Retrosynthetically, we envisioned completing the synthesis of (+)-norsecurinine with annulation of the butenolide from α-hydroxy enone 10 (Scheme 1).^14,18 Tricyclic enone 10 was imagined to arise from a halogenation-initiated cyclization of ketone 11 followed by β-elimination.¹⁵ Cyclohexene 11 would be prepared by ring-closing metathesis of allyl ketone 12, while the A-ring would be generated from 13 via a reductive amination. Tertiary alcohol 13 would result from the key domino process using (S)-(+)-3-buten-2-ol ((+)-14).¹⁹ Finally, α-diazo-β-ketoester 15 could easily be accessed from commercially available materials.

Scheme 1.

Retrosynthetic analysis of (+)-norsecurinine

2.2 Synthesis of (+)-norsecurinine

Our synthesis commenced with the opening of N-Boc-2-pyrrolidinone (16) with ethyl lithiodiazoacetate ²⁰ followed by Boc protection under standard conditions to yield diazoester 15 (Scheme 2). The optimal conditions determined in our original studies of the O–H insertion/Claisen rearrangement involved heating a solution of the diazoester, allylic alcohol and 0.1–1.0 mol% Rh₂(OAc)₄ in benzene at reflux.²¹ In our current preliminary studies, we found that heating the reaction to reflux in toluene provided more consistent results (data not shown). Conducting the O–H insertion/Claisen rearrangement using (±)-14 in the presence of 1 mol% Rh₂(OAc)₄in toluene at reflux resulted in 37% yield (unoptimized) of desired tertiary alcohol 19. Encouraged by this result we attempted to effect the 1,2-allyl migration by treatment of 19 with BF₃•Et₂O at room temperature. Unfortunately, these conditions yielded an intractable mixture of compounds. A screen of alternative Lewis and protic acids primarily resulted in recovered starting material or decomposition (see chart in Scheme 2). The problems encountered with our attempt to incorporate the requisite amine early in the synthesis prompted us to investigate an alternative route.

Scheme 2.

Initial investigation of the key domino process

Reviewing the retrosynthesis, it seemed feasible to begin the synthesis with a functional group that could be converted to an amine subsequent to the domino sequence. To this end, butyrolactone (20) was opened with ethyl lithiodiazoacetate and the resulting primary alcohol was tosylated to provide 21 in 62% yield over the two steps (Scheme 3). After some experimentation, we found that conducting the key domino process in one pot²² with (±)-14 in the presence of 0.1 mol% Rh₂(OAc)₄ in toluene at reflux followed by addition of BF₃•Et₂O at room temperature provided tertiary alcohol 22 in 69% yield. Treatment of 22 with NaN₃ in DMF cleanly provided azide 23, which was subjected to PPh₃ in wet THF to initiate a Staudinger reduction/aza-Wittig sequence²³ providing imine 24. A minor byproduct observed under these conditions was cyclopropane 25. Attempts to prevent the formation of 25 by changing temperature, equivalents of water or phosphine proved fruitless.

Scheme 3.

Butyrolactone-based strategy to imine 24

Although an effective route to imine 24 had been developed, some difficulties encountered with scale-up and variable yields for the opening of butyrolactone with ethyl lithiodiazoacetate led us to seek an alternative strategy. We found that adapting a procedure reported by Staudinger²⁴ and Bestmann²⁵ for the coupling of acid chlorides with diazoesters cleanly provided chloride 27 in high yield after removal of the byproduct (ethyl chloroacetate) by distillation at low pressure (Scheme 4). Chloride 27 was subjected to the optimized domino process conditions, 1.05 eq (+)-14 (98:2 er)²⁶ and 0.1 mol% Rh₂(OAc)₄, to give tertiary alcohol 28 in 63% yield and 95:5 er.²⁷ Substitution of the primary chloride with azide proceeded cleanly allowing the Staudinger reduction/aza-Wittig sequence to be carried out without purification of intermediate azide (+)-23, providing imine 24 in 76% yield over the two steps.

Scheme 4.

Improved route to imine 24

Proceeding forward, imine 24 was reduced with NaBH₄ in MeOH to yield an inseparable mixture of diastereomeric amino esters 29, which were directly converted to t-butyl carbamates 30 with Boc₂O and DMAP (Scheme 5). The derived carbamates proved separable by simple column chromatography and the major isomer (30a) was reduced to aldehyde 31a by treatment with DIBALH at low temperature, albeit in moderate yield. Warming the reaction above 0 °C resulted in a complex mixture of products.

Scheme 5.

Initial synthesis of aldehyde 31

To circumvent this problem we found that reduction of imine 24 with NaBH₄ in EtOH followed by oxidation of the inseparable mixture of diols 32 with IBX provided a separable mixture of aldehydes 31 in a more convenient manner (Scheme 6). ²⁸

Scheme 6.

Improved synthesis of aldehyde 31

Prior to continuing with the synthesis, the stereochemical outcome of the NaBH₄ reduction was delineated (Scheme 7). To this end, carbamate esters 30a and 30b were individually subjected to DIBALH at room temperature and the resulting crude diols were treated with NaH in THF. Nuclear Overhauser effect (nOe) analysis of cyclic carbamates 5S, 4S-33a and 5R-4S-33b revealed the illustrated stereochemical relationships (relevant nOes indicated with double headed arrows).

Scheme 7.

Synthesis of cyclic carbamates 33a and 33b, and relevant nOes

Having assigned the stereochemistry, the synthesis continued with alkylation of aldehyde 31a using allylmagnesium bromide to furnish 34 followed by ring-closing metathesis using Grubbs’s second generation catalyst to provide cyclohexene 35 as a mixture of diastereomers (Scheme 8). Given that the newly produced hydroxyl stereocenter would eventually undergo oxidation, the mixture of diastereomers was advanced without separation. Adopting a strategy used by Liras and coworkers for their synthesis of (±)-securinine,¹⁵ cyclohexene 35 was treated with Br₂ at 0 °C to yield dibromide 36 as a single diastereomer based on ¹H NMR analysis. We found that dropwise addition of Br₂ at 0 °C was essential to avoid the formation of 37 obtained from attack of the carbamate carbonyl on the secondary bromide.²⁹ After some experimentation, we found that Swern oxidation of alcohol 36 supplied enone 38 in good yield. During their syntheses of (−)-securinine, Honda¹³ and Figueredo¹¹ had demonstrated that the stereochemistry of the bromide was inconsequential for cyclization, and it was presumed that this would apply to norsecurinine as well.

Scheme 8.

Synthesis of penultimate intermediate enone 38

With enone 38 in hand, we were ready to construct the tricyclic core of norsecurinine (Scheme 9a). After some experimentation, we found that removal of the Boc group with excess TFA followed by addition of Et₃N furnished unstable tricycle 10. Some attempts were made to convert hydroxy enone 10 to norsecurinine directly using the Bestmann ketene ylide (39),³⁰ however, these attempts failed. Weinreb and coworkers also noted the recalcitrance of a similar substrate towards acylation with the Bestmann reagent.¹² Consequently, we turned to a two step procedure involving DCC mediated acylation of the tertiary alcohol with diethylphosphonoacetic acid followed by intramolecular Horner-Wadsworth-Emmons reaction to complete the synthesis of (+)-norsecurinine (2). Spectral data for (+)-2 were in accord with that reported in the literature. The synthesis of (+)-allonorsecurinine (40) was realized utilizing a similar route from aldehyde 31b (Scheme 9b).

Scheme 9.

Endgame strategy

3. Conclusion

We have presented the total synthesis of (+)-norsecurinine and (+)-allonorsecurinine highlighting an enantioselective rhodium carbenoid-initiated O–H insertion/Claisen rearrangement/1,2-allyl migration domino process. Targeting the tertiary alcohol moiety in these molecules provides a flexible strategy that will allow access to other members of the Securinega family of alkaloids. The synthesis of these compounds is underway.

4. Experimental

4.1 General Methods

Unless otherwise stated, reactions were stirred in flame-dried glassware under an atmosphere of nitrogen. Benzene, tetrahydrofuran, dichloromethane, toluene, and diethyl ether were dried using a solvent purification system manufactured by SG Water U.S.A., LLC. Anhydrous N, N-dimethylformamide was purchased from Sigma-Aldrich and stored under nitrogen atmosphere. Commercially available reagents were obtained from Sigma-Aldrich, Strem, or Alfa Aesar and were used as received. (S)-(+)-3-buten-2-ol ((+)-14) was synthesized according to a procedure by Klingler and Psiorz.¹⁹ (Triphenylphosporanylidene)-ketene (39) was synthesized according to the procedure described by Schobert.³¹ All known compounds were identified by comparison of NMR spectra to those reported in the literature.

Thin layer chromatography was performed using Silicycle glass-backed extra hard layer, 60 Å plates (indicator F-254, 250 μm). Developed plates were visualized using a 254 nm UV lamp and/or with the appropriate dip solution (ethanolic anisaldehyde or potassium permanganate) followed by heating. Flash chromatography was generally performed according to the protocol described by Still et al.,³² with Silicycle SiliaFlash® P60 (230-400 mesh) silica gel as the stationary phase. Melting points were obtained using a Gallenkamp melting point apparatus and are uncorrected.

Chiral high performance liquid chromatography (HPLC) was performed on an Agilent 1100 series HPLC. Infrared spectra were recorded on a Nicolet Avatar 320 FT-IR and samples were analyzed as thin films on NaCl plates (sample dissolved in CH₂Cl₂) and are reported as wavenumber (cm⁻¹). High-resolution mass spectrometry was conducted on an Agilent 6210 TOF LCMS. Proton (¹H) and carbon (¹³C) NMR spectra were recorded on a Varian Inova 400 or 300 spectrometer. Spectra were obtained at 22 °C in CDCl₃ unless otherwise noted. Chemical shifts (δ) are reported in parts per million (ppm) and are referenced to the residual solvent peak. Coupling constants (J) are reported in Hertz (Hz) and are rounded to the nearest 0.1 Hz. Multiplicities are defined as: s = singlet, d = doublet, t = triplet, q = quartet, quint. = quintuplet, m = multiplet, dd = doublet of doublets, ddd = doublet of doublet of doublets, dddd = doublet of doublet of doublet of doublets, br = broad, app = apparent, par = partial.

4.2 Experimental Procedures

4.2.1 Mono-t-butylcarbamate 18

Freshly prepared LDA (7.0 mL, 3.6 mmol) was added dropwise to a solution of ethyl diazoacetate (373 uL, 3.6 mmol) and Boc-2-pyrrolidinone (16) (517 mg, 2.8 mmol) in dry THF (19 mL) at −78 °C. After 1.5 hours the reaction was quenched at −78 °C by the dropwise addition of acetic acid (5 mL). The mixture was concentrated to about 10% of its original volume in vacuo and diluted with EtOAc (10 mL). The organic layer was washed with NaHCO₃ (sat. 2 × 5 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (1 × 10 mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified by flash chromatography (gradient elution, 90:10 to 70:30 hexanes/EtOAc) then recrystallized from hot hexanes to yield 18 (649 mg, 77% yield) as yellow needles. R_f = 0.34, 70:30 hexanes:EtOAc; mp 61–62 °C; ¹H NMR (CDCl₃, 400 MHz) δ 4.66 (brs, 1H), 4.29 (q, J=7.1 Hz, 2H), 3.18–3.14 (m, 2H), 2.88 (t, J=7.2 Hz, 2H), 1.83 (quint, J=7.0 Hz, 2H), 1.43 (s, 9H), 1.32 (t, J=7.1 Hz, 3H) 192.5, 161.5, 156.1, 79.3, 61.6, 40.1, 37.5, 28.5, 24.7, 14.5; ¹³C NMR (CDCl₃, 100 MHz) δ; IR (thin film, NaCl) 3382(w), 2135(m), 1717(s), 1654(m), 1522(m), 1368(m), 1304(m), 1250(m), 1172(m), 1135(w), 1089(w), 1022(w); HRMS (ESI-APCI) m/z calcd. for C₁₃H₂₂N₃NaO₅ [M+Na]⁺: 322.1373, found: 322.1375.

4.2.2 Bis-t-butylcarbamate 15

To a solution of 18 (300 mg, 1.00 mmol) and DMAP (12 mg, 0.010 mmol) in CH₃CN (1 mL) was added Boc₂O (240 mg, 1.10 mmol) as a solution in CH₃CN (1 mL). The reaction was refluxed for 10 hours. Upon completion the mixture was diluted with EtOAc (5 mL) and H₂O (3 mL). The aqueous layer was extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine (1 × 3 mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified by flash chromatography (gradient elution, 90:10 to 85:15 hexanes/EtOAc) to yield 15 (265 mg, 66% yield) as a yellow oil. R_f = 0.43, 70:30 hexanes:EtOAc; ¹H NMR (CDCl₃, 400 MHz) δ 4.27 (q, J=7.1 Hz, 2H), 3.62 (t, J=7.1 Hz, 2H), 2.85 (t, J=7.3 Hz, 2H), 1.90 (quint, J=7.2 Hz, 2H), 1.49 (s, 18H), 1.31 (t, J=7.1Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 192.1, 161.4, 152.7, 82.4, 61.5, 45.8, 37.5, 28.2, 23.6, 14.5; IR (thin film, NaCl) 2980(m), 2935(m), 2134(s), 1789(w), 1719(s), 1659(m), 1456(w), 1368(s), 1303(s), 1174(m), 1136(s), 1109(m), 1020(w), 854(w), 746(w); HRMS (ESI-APCI) m/z calcd. for C₁₈H₂₉N₃NaO₇ [M+Na]⁺: 422.1914, found:422.1896.

4.2.3 α-Keto-ester (±)-19

To a solution of 15 (55.6 mg, 0.140 mmol) in toluene (700 μL) was added (±)-3-buten-2-ol (12.0 μL, 0.140 mmol) and Rh₂(OAc)₄ (0.6 mg, 0.0014 mmol). The mixture was immediately placed in an oil bath preheated to 120 °C. After 15 minutes the reaction was cooled to room temperature, concentrated and purified by flash chromatography (gradient elution, 90:10 to 85:15 hexanes/EtOAc) to give (±)-19 (23.2 mg, 37% yield) as a clear, pale yellow oil. R_f = 0.54, 70:30 hexanes:EtOAc; ¹H NMR (CDCl₃, 400 MHz) δ 5.54 (dddd, J=12.9, 6.4, 6.4, 6.4 Hz, 1H), 5.35–5.27 (m, 1H), 4.32 (q, J=7.1 Hz, 2H), 3.55 (t, J=7.1 Hz, 2H), 3.28 (s, 1H), 2.65 (dd, J=14.0, 7.3 Hz, 1H), 2.41 (dd, J=14.0, 7.3, Hz, 1H), 1.94 (ddd, J=13.6, 11.1, 4.9 hz, 1H), 1.79–1.61 (m, 2H), 1.64 (dd, J=6.3, 1.1 Hz, 3H), 1.48 (s, 18H), 1.48–1.44 (m, 1H), 1.35 (t, J=7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 199.5, 162.4, 152.7, 131.2, 123.8, 82.4, 81.4, 62.5, 46.3, 41.9, 35.0, 28.2, 23.3, 18.2, 14.1; IR (thin film, NaCl) 3486(m), 2980(m), 2936(m), 1733(s), 1698(s), 1456(m), 1368(s), 1300(m), 1131(s), 1045(m), 969(m), 856(w), 782(w), 667(w); HRMS (ESI-APCI) m/z calcd. for C₂₂H₃₇NNaO₈ [M+Na]⁺: 466.2411, found:466.241.

4.2.4 Diazo tosylate 21

p-Toluenesulfonic acid (4.70 g, 24.8 mmol) was added to a solution of ethyl 2-diazo-6-hydroxy-3-oxohexanoate³³ (3.30 g, 16.5 mmol) and Et₃N (4.00 mL, 28.9 mmol) in CH₂Cl₂ (37 mL). The reaction was stirred at room temperature for 9 hours before adding NaHCO₃ (sat. 20 mL) and extracting the aqueous layer with CH₂Cl₂ (3 × 20 mL). The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo. The resulting orange oil was purified by flash chromatography (gradient elution, 90:10 to 80:20 hexanes/EtOAc) to yield 21 (4.35 g, 75% yield) as a yellow oil. R_f = 0.59, 50:50 hexanes:EtOAc; ¹H NMR (CDCl₃, 400 MHz) δ 7.76 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 4.28 (q, J=7.1 Hz, 2H), 4.07 (t, J=6.2 Hz, 2H), 2.88 (t, J=7.0 Hz, 2H), 2.43 (s, 3H), 1.97 (quint, J=6.5 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 191.4, 161.3, 144.9, 133.1, 130.0, 128.1, 69.7, 61.7, 35.9, 23.4, 21.8, 14.5; IR (thin film, NaCl) 2137(s), 1715(s), 1652(s), 1362(s), 1303(s), 1213(m), 1176(s), 1096(m), 927(m), 554(m); HRMS (APCI) m/z calcd. for C₁₅H₁₉N₂O₆S [M+H]⁺:355.0956, found: 355.0955.

4.2.5 Tosylate (±)-22

To a solution of 21 (994 mg, 2.80 mmol) in toluene (14 mL) was added (±)-3-buten-2-ol (242 μL, 2.80 mmol) and Rh₂(OAc)₄ (12.4 mg, 0.028 mmol). The mixture was immediately placed in an oil bath preheated to 120 °C. After 15 minutes the reaction was cooled to room temperature before adding BF₃•Et₂O (443 μL, 3.50 mmol). After two hours, the reaction was concentrated and purified by flash chromatography (gradient elution 98:2 to 90:10 benzene/EtOAc) to give (±)-22 (772 mg, 69% yield) as a clear, pale yellow oil. R_f = 0.52, 90:10 benzene:EtOAc (2x); ¹H NMR (CDCl₃, 400 MHz) δ 7.75 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 5.55 (dddd, J=15.1, 6.5, 6.5, 6.5 Hz, 1H), 5.31–5.23 (m, 1H), 4.22 (dddd, J=17.9, 10.8, 7.1, 3.6 Hz, 2H), 4.01 (ddd, J=6.4, 5.9, 1.3 Hz, 2H), 3.91 (s, 1H), 2.79 (ddd, J= 18.8, 7.0, 7.0 Hz, 1H), 2.71 (dddd, J=14.3, 7.0, 1.2, 1.2 Hz, 1H), 2.59–2.49 (m, 2H), 2.43 (s, 3H), 1.90 (app quint, J=6.5 Hz, 2H), 1.62 (dd, J=6.5, 1.5 Hz, 3H), 1.26 (t, J=7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 205.7, 170.7, 145.0, 133.0, 131.0, 130.0, 128.0, 123.1, 83.7, 69.4, 63.0, 38.8, 33.2, 23.0, 21.8, 18.2, 14.2; IR (thin film, NaCl) 3483(m), 2981(m), 1721(s), 1598(m), 1447(m), 1361(s), 1189(m), 1177(s), 1098(m), 971(m), 925(m), 816(m), 664(m), 555(m); HRMS (ESI-APCI) m/z calcd. for C₁₉H₂₆NaO₇S [M+Na]⁺:421.1308, found: 421.1294.

4.2.6 Diazo chloride 27

A 3-necked 100 mL flask charged with 4-chlorobutyryl chloride (26) was fitted with a glass stopper, a cold water condenser topped with a drying tube containing solid KOH open to the atmosphere, and an addition funnel charged with ethyl diazoacetate (18.0 mL, 174 mmol). The flask was placed in a room temperature water bath before dropwise addition of ethyl diazoacetate. Once addition was complete, the reaction was heated to 60 °C for six hours. Removal of byproducts by distillation (1.5 torr, 50 °C bath temperature) provided pure 27 (17.2 g, 91% yield) as a clear, yellow oil. R_f = 0.5, 85:15 hexanes:EtOAc; ¹H NMR (CDCl₃, 400 MHz) δ 4.30 (q, J=7.1 Hz, 2H), 3.61 (t, J=6.4 Hz, 2H), 3.03 (t, J=7.1 Hz, 2H), 2.12 (quint., J=6.8 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) 191.7, 161.4, 61.7, 44.4, 37.4, 27.0, 14.5; IR (thin film, NaCl) 2983(m), 2137(s), 1716(s), 1657(s), 1445(w), 1373(s), 1305(s), 1223(s), 1174(w), 1126(m), 1020(m), 745(w); HRMS (APCI) m/z calcd. for C₈H₁₂ClN₂O₃ [M+H]⁺: 219.0531, found: 219.0531.

4.2.7 Chloride (−)-28

To a solution of 27 (5.00 g, 22.8 mmol) in toluene (114 mL) was added (S)-(+)-3-buten-2-ol (2.07 mL, 23.9 mmol) and Rh₂(OAc)₄ (10.2 mg, 0.023 mmol). The mixture was immediately placed in an oil bath preheated to 120 °C. After 15 minutes the reaction was cooled to room temperature before adding BF₃•Et₂O. After two hours, the reaction was concentrated and purified by flash chromatography (90:10 hexanes:EtOAc) to give (−)-28 (5.90 g, 63% yield) as a clear, colorless oil. R_f = 0.43 85:15 hexanes:EtOAc; ¹H NMR (CDCl₃, 400 MHz) δ 5.63–5.45 (m, 1H), 5.34–5.26 (m 1H), 4.29–4.19 (m, 1H), 4.05 (s, 1H), 3.53 (t, J=6.22 Hz, 2H), 2.86 (dt, J=18.7, 6.8 Hz, 1H), 2.75–2.58 (m, 3H), 2.07–2.01 (m, 2H), 1.63 (d, J=6.43 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 205.8, 170.7, 130.9, 123.1, 83.7, 62.9, 44.1, 38.6, 34.2, 26.2, 18.2, 14.2; IR (thin film, NaCl) 3482(m), 2975(m), 2934(m), 1721(s), 1449(m), 1367(m), 1260(s), 1214(s), 1142(m), 1096(m); HRMS (ESI-APCI) m/z calcd. for C₁₂H₁₉ClO₄Na [M+Na]⁺: 285.0864, found 285.0864. [α]²²_D = +3.96 (c = 2.20, CHCl₃)

4.2.8 Imine (−)-24

To a solution of (−)-28 (5.70 g, 21.7 mmol) in anhydrous N,N-dimethylformamide (50.0 mL) was added sodium azide (7.1 g, 108 mmol). The mixture was heated to 80 °C for three hours. Upon completion, the reaction was passed through filter paper and the filtrate diluted with diethyl ether (50 mL) and water (100 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (4 × 50 mL). The organic layers were then washed with water (5 × 50 mL), and brine (1 × 50 mL). The combined organic layers were dried over MgSO₄. Concentration in vacuo yielded a crude orange oil, which was dissolved in wet THF (80 mL). To this solution was added PPh₃ and the mixture was heated to 50 °C for 1.5 hours. Upon completion, the reaction was concentrated to about 20% of the initial volume. The resulting viscous oil was triturated with hexanes:EtOAc (90:10, 30 mL) and purified by flash chromatography (90:10 to 70:30 hexanes:EtOAc). The first fraction, eluting at 90:10 hexanes:EtOAc, consisted of cyclopropyl ketone (−)-25 (393 mg, 8% yield) as a clear, pale yellow oil. The second fraction, eluting at 70:30 hexanes:EtOAc, consisted of desired imine (−)-24 (3.71 g, 76% yield, 2 steps) as a clear, pale yellow oil. R_f = 0.24 70:30 hexanes:EtOAc; ¹H NMR (CDCl₃, 300 MHz) δ 5.62–5.50 (m, 1H), 5.48–5.33 (m, 1H), 4.42 (br s, 1H), 4.27–4.18 (m, 2H), 3.87–3.82 (m, 2H), 2.75–2.52 (m, 4H), 2.00–1.90 (m, 2H), 1.63 (d, J=6.28 Hz, 3H), 1.26 (t, J=7.1 Hz, 3H); ¹³C NMR (CDCl3, 75 MHz) δ 177.4, 172.3, 130.1, 124.1, 78.5, 62.2, 60.3, 40.1, 34.0, 23.6, 18.3, 14.4; IR (thin film, NaCl) 3422(w), 2976(m), 2938(m), 2870(w), 1731(s), 1448(w), 1431(w), 1367(w), 1258(m), 1212(s), 1135(m), 1096(m), 1057(w), 1029(w), 972(m), 861(w); HRMS (ESI-APCI) m/z calcd. for C₁₂H₂₀NO₃ [M+H]⁺: 226.1437, found: 226.1441. [α]²²_D = −25.9 (c = 1.48, CHCl₃)

(−)-25: R_f = 0.43 85:15 hexanes:EtOAc; ¹H NMR (CDCl₃, 400 MHz) δ 5.77–5.72 (m, 1H), 5.52–5.44 (m, 1H), 4.44–4.37 (m, 3H), 2.98 (dd, J=14.2, 6.90 Hz, 1H), 2.88 (dd, J=14.3, 7.38 Hz, 1H), 2.51–2.47 (m, 1H), 1.79 (d, J=6.24 Hz, 3H), 1.43 (t, J=7.1 Hz, 3H), 1.29–1.14 (m, 4H); ¹³C NMR (CDCl₃, 100 MHz) δ 206.3, 170.4, 130.3, 123.2, 83.8, 62.1, 38.5, 17.9, 16.1, 14.0, 12.8, 12.2; IR (thin film, NaCl) 3465(s), 2983(m), 2919(w), 1738(s), 1705(s), 1447(m), 1379(m), 1262(s), 1221(s), 1156(w), 1070(m), 1032(m), 971(m), 860(w), 668(w); HRMS (ESI-APCI) m/z calcd. for C₁₂H₁₉O₄ [M+H]⁺: 227.1278, found 227.1274. [α]²²_D = −30.0 (c = 1.80, CHCl₃)

4.2.9 Diol 32

To a solution of (−)-24 (3.35 g, 14.8 mmol) in absolute EtOH (50 mL) was added NaBH₄ (1.6 g, 44.4 mmol). After stirring the reaction at room temperature for 4 hours, DMAP (170 mg, 1.39 mmol) was added and the reaction was cooled to 0 °C before adding Boc₂O (3.5 g, 16.3 mmol) portionwise. After addition, the ice bath was removed and the reaction stirred for one hour at room temperature. Upon completion, the EtOH was removed in vacuo and the residue diluted with water (50 mL) and CH₂Cl₂ (50 mL). The layers were separated and the aqueous was extracted with CH₂Cl₂ (4 × 25 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO₄ and concentrated. The residue was purified by flash chromatography (90:10 to 80:20 hexanes:EtOAc). The first fraction, eluting at 90:10 hexanes:EtOAc, consisted of a separable diasteromeric mixture of the N-Boc amino esters (−)-30a and (+)-30b (756 mg, 16% yield, dr 1.4:1). The second fraction, eluting at 80:20 hexanes:EtOAc, consisted of an inseparable diastereomeric mixture of N-Boc amino diols 32 (2.31 g, 55% yield, 2 steps) as a clear, colorless oil. R_f = 0.31 70:30 hexanes:EtOAc; (partially characterized) ¹³C NMR (CDCl₃, 100 MHz) δ 157.8, 128.7, 128.1, 126.0, 125.8, 80.8, 80.7, 66.0, 65.5, 62.4, 62.0, 61.9, 48.2, 48.2, 37.2, 36.8, 28.5, 27.1, 26.6, 24.6, 24.3, 18.2; HRMS (ESI-APCI) m/z calcd for C₁₅H₂₈NO₄ [M+H]⁺: 286.2013, found 286.2016.

(−)-30a: clear, colorless oil; R_f = 0.52 70:30 hexanes:EtOAc; ¹H NMR (CDCl₃, 400 MHz) δ 5.54–5.42 (m, 2H), 5.24 (br s, 1H), 4.22–4.16 (m, 3H), 3.57 (br s, 1H), 3.16 (br s, 1H), 2.55 (br s, 1H), 2.38 (br s, 1H), 1.93 (br s, 1H), 1.62 (br s, 4H), 1.46 (br s, 9H), 1.26 (br s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 174.6, 156.9, 129.0, 124.9, 81.5, 80.1, 63.8, 61.3, 47.9, 39.9, 28.3, 27.4, 24.2, 18.0, 14.2; IR (thin film, NaCl) 3511(m), 3320(m), 2977(s), 2934(s), 1724(s), 1696(s), 1394(s), 1367(s), 1168(s), 1109(s), 1055(m), 972(m), 772(m); HRMS (ESI-APCI) m/z calcd for C₁₇H₃₀NO₅ [M+H]⁺: 328.2118, found 328.2122. [α]²²_D = −43.0 (c = 0.82, CHCl₃)

(+)-30b: white solid; R_f = 0.61 70:30 hexanes:EtOAc; ¹H NMR (CDCl₃, 400 MHz) δ 5.57–5.48 (m, 1H), 5.40–5.33 (m, 1H), 4.29 (dq, J=10.7, 7.1 Hz), 4.18–4.15 (m, 1H), 4.11 (par dq, J=10.6, 7.1 Hz, 1H), 3.71 (br s, 1H), 3.53 (br s, 1H), 3.26–3.19 (m 1H), 2.48 (app dd, J=8.0, 6.9, 5.7 Hz, 1H), 2.31 (app dd, J=8.02, 5.9, 5.8 Hz, 1H), 2.05–1.83 (m, 3H), 1.74–1.67 (m, 1H), 1.63 (d, J=6.3 Hz, 3H), 1.42 (s, 9H), 1.30 (t, J=7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 175.1, 155.7, 129.4, 124.9, 79.9, 79.8, 63.0, 62.1, 48.1, 38.4, 26.6, 24.6, 18.2, 14.2; IR (thin film, NaCl) 3434(s), 2978(w), 1725(m), 1698(s), 1654(m), 1390(s), 1258(w), 1213(w), 1171(m), 1096(w), 969(w); HRMS (ESI-APCI) m/z calcd. for C₁₇H₃₀NO₅ [M+H]⁺: 328.2118, found 328.2108. [α]²²_D = +55.4 (c = 2.42, CHCl₃)

4.2.10 Cyclic carbamates (±)-33a and (±)-38b

DIBALH (619 uL, 0.619mmol) was added to a solution of (±)-30a (169 mg, 0.516 mmol) in dry CH₂Cl₂ (2.6 mL) at 0 °C. The solution was then warmed to room temperature and stirred for two hours. Upon completion, the reaction was quenched with MeOH/H₂O (1:1, 5 mL) at 0 °C. The mixture was filtered through Celite with CH₂Cl₂ to yield crude (±)-32a. (±)-30b (138 mg, 0.422 mmol) was subjected to similar conditions to yield crude (±)-32b. (±)-32a (82.4 mg, 0.290 mmol) and (±)-32b (51.9 mg, 0.180 mmol) were independently treated with excess NaH in dry THF (1.5 mL) at room temperature to provide (±)-33a (34.8 mg, 32% yield, two steps) and (±)-33b (14.8 mg, 17% yield, 2 steps) respectively after purification by flash chromatography (gradient elution, 90:10 to 70:30 hexanes/EtOAc).

(±)-33a: ¹H NMR (C₆D₆, 400 MHz) δ 5.45–5.37 (m, 1H), 5.28–5.19 (m, 1H), 5.13 (s, 1H), 4.10 (d, J=11.2 Hz, 1H), 3.65 (d, J=11.1 Hz, 1H), 3.61 (par dd, J=7.5, 3.0 Hz, 1H), 3.34–3.29 (m, 1H), 2.77 (dd, J=10.5, 5.7 Hz, 1H), 2.14 (app dd, J=14.1, 6.6 Hz, 1H), 2.02–1.92 (m, 1H), 1.87 (dd, J=14.2, 7.9 Hz, 1H), 1.58–1.49 (m, 1H), 1.50 (d, J=6.3 Hz, 1H), 1.43–1.37 (m, 1H), 1.25–1.12 (m, 1H); ¹³C NMR (C₆D₆, 100 MHz) δ 152.9, 128.6, 125.2, 74.5, 66.1, 63.0, 47.3, 39.4, 25.8, 22.6, 17.8; HRMS (ESI-APCI) calcd. for C₁₁H₁₈NO₃ [M+H]⁺: 212.1281, found: 212.1284.

(±)-33b: ¹H NMR (CDCl₃, 400 MHz) δ 5.66 (dddd, J=15.2, 6.4, 6.4, 6.3 Hz, 1H), 5.53–5.45 (m, 1H), 4.02 (d, J=10.7 Hz, 1H), 3.84 (d, J=10.6 Hz, 1H), 3.61 (dd, J=10.5, 5.5 Hz, 1H), 3.49–3.44 (m, 2H), 2.77 (d, J=4.1 Hz, 1H), 2.19 (d, J=7.4 Hz, 2H), 2.07–1.93 (m, 2H), 1.85–1.74 (m, 1H), 1.74 (d, J=6.4 Hz, 3H), 1.69-1.61 (m, 1H); ¹³C NMR (CDCl₃, 100 MHz) δ 152.4, 132.5, 123.3, 71.5, 66.9, 65.1, 47.2, 33.7, 26.8, 22.9, 18.3; HRMS (ESI-APCI) calcd. for C₁₁H₁₈NO₃ [M+H]⁺: 212.1281, found: 212.1284.

4.2.11 Aldehydes (+)-31a and (−)-31b

To a solution of 32 (2.10 g, 7.40 mmol) in wet EtOAc (50 mL) was added IBX²⁸ (6.20 g, 22.2 mmol). The mixture was refluxed open to the atmosphere for 6 hours. The reaction was filtered through a pad of Celite, concentrated and directly purified by flash chromatography (90:10 hexanes:EtOAc) to provide the desired N-Boc amino aldehyde (1.85 g, 89% yield) as a mixture of diastereomers. The diastereomers were separated by flash chromatography (98:2 to 95:5 EtOAc:CH₂Cl₂) to provide (+)-31a as a clear, colorless oil and (−)-31b as a clear, colorless oil.

(+)-31a: R_f = 0.35 95:5 CH₂Cl₂:EtOAc; ¹H NMR (CDCl₃, 400 MHz) δ 9.62 (s, 1H), 5.55–5.47 (m, 1H), 5.30–5.22 (m, 1H), 4.12 (br s, 1H), 3.71 (s, 1H), 3.40 (br s, 1H), 3.21–3.17 (m, 1H), 2.42 (dd, J=14.3, 7.8 Hz, 1H), 2.34–2.29 (m, 1H), 2.09–1.89 (m, 3H), 1.73–1.68 (m, 1H) 1.59 (d, J=6.2 Hz, 3H), 1.38 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz) δ 201.8, 155.4, 129.9, 123.4, 82.8, 79.9, 60.6, 47.4, 37.3, 28.2, 25.7, 24.7, 17.9; IR (thin film, NaCl) 3479(m), 2976(s), 1723(s), 1682(s), 1479(m), 1393(s), 1255(m), 1169(s), 1118(m), 971(m), 915(m), 856(w), 817(w), 772(w); HRMS (ESI-APCI) m/z calcd. for C₁₅H₁₅NO₄Na [M+Na]⁺: 306.1676, found 306.1672. [α]²²_D = +39.3 (c = 2.68, CHCl₃)

(−)-31b: R_f = 0.48 95:5 CH₂Cl₂:EtOAc; ¹H NMR (CDCl₃, 400 MHz) δ 9.64 (s, 1H), 6.39 (br s, 1H), 5.57–5.48 (m, 2H), 3.98 (t, J=7.1 Hz, 1H), 3.57 (br s, 1H), 3.09 (br s, 1H), 2.4–2.26 (m, 2H), 2.05–1.91 (m, 2H), 1.80 (br s, 1H), 1.63 (d, J=5.2, 3H), 1.45 (s, 9H) ; ¹³C NMR (CDCl₃, 100 MHz) δ 206.7, 157.8, 129.5, 124.5, 82.1, 81.3, 64.0, 48.2, 37.3, 27.4, 24.3, 18.2; IR (thin film, NaCl) 3297(s), 2977(s), 2888(m), 1730(s), 1693(s), 1658(s), 1402(s), 1250(m), 1166(s), 1112(m), 974(m), 855(m), 776(m); HRMS (ESI-APCI) m/z calcd. for C₁₅H₂₅NO₄Na [M+Na]⁺: 306.1676, found 306.1673. [α]²²_D = −40.3 (c = 2.63, CHCl₃)

4.2.12 Allyl alcohol 34

To a solution of (+)-31a (1.00 g, 3.55 mmol) in THF (18 mL) was added freshly prepared allylmagnesium bromide (1.0 M in Et₂O, 10.6 mL, 10.6 mmol) at 0 °C. The reaction was stirred at 0 °C for 30 mins before warming to room temperature and stirring for 1 hour more. The reaction was quenched with sat. NH₄Cl (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO₄, and concentrated. The residue was purified by flash chromatography (gradient elution, 90:10 to 85:15 hexanes:EtOAc) to yield (−)-34a and (−)-34b (824 mg, 72% yield, combined) as pale yellow oils. The diastereomers were characterized separately.

(−)-34a (β-OH): R_f = 0.44 70:30 hexanes:EtOAc; ¹H NMR (CDCl₃, 400 MHz) δ 5.98–5.88 (m, 1H), 5.50–5.47 (m, 2H), 5.10–5.03 (m, 2H), 4.65 (br s, 1H), 4.10–4.07 (m, 1H), 3.57–3.49 (m, 3H), 3.24–3.17 (m, 1H), 2.36–2.22 (m, 3H), 2.08–1.85 (m, 4H), 1.78–1.71 (m, 1H), 1.66 (d, J=3.3 Hz, 3H), 1.44 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz) δ 157.8, 136.8, 128.3, 126.0, 116.4, 80.8, 78.0, 72.7, 62.8, 48.2, 37.6, 35.7, 28.5, 27.15, 24.3, 18.3; IR (thin film, NaCl) 3416(s), 3074(w), 2977(m), 2933(m), 1662(s), 1395(m), 1255(w), 1168(m), 976(w), 907(w), 774(w); HRMS (ESI-APCI) m/z calcd. for C₁₈H₃₂NO₄ [M+H]⁺: 326.2326, found: 326.2327. [α]²²_D = − 48.9 (c = 2.02, CHCl₃)

(−)-34b (α-OH): R_f = 0.53 70:30 hexanes:EtOAc; ¹H NMR (CDCl₃, 400 MHz) δ 5.87–5.78 (m, 1H), 5.69 (br s, 1H), 5.55–5.48 (m, 1H), 5.13–5.09 (m, 2H), 4.02 (dd, J=8.5, 6.7 Hz), 3.68–3.63 (m, 1H), 3.55–3.53 (m, 1H), 3.26–3.20 (m, 1H), 2.66–2.62 (m, 1H), 2.27–2.18 (m, 3H), 2.07–1.98 (m, 3H), 1.88–1.83 (m, 1H), 1.68–1.59 (m, 4H), 1.46 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz) δ 158.2, 136.8, 127.9, 126.9, 118.1, 80.8, 77.5, 74.1, 65.2, 48.6, 36.9, 36.2, 28.5, 27.8, 24.3, 18.4; IR (thin film, NaCl) 3420(s), 2977(w), 2932(w), 1650(s), 1408(m), 1367(m), 1251(w), 1167(m), 977(w), 907(w); HRMS (ESI-APCI) m/z calcd. for C₁₈H₃₂NO₄ [M+H]⁺: 326.2326, found: 326.2327. [α]²²_D = −51.9 (c = 1.73, CHCl₃)

4.2.13 Cyclohexene 35

To a solution of (−)-34a and (−)-34b (794 mg, 2.44 mmol) in CH₂Cl₂ (24 mL) was added Grubbs’s 2^nd generation catalyst, and the reaction was refluxed for 1.5 hours. The mixture was concentrated and purified by flash chromatography (gradient elution, 85:15 to 75:25 hexanes:EtOAc) to yield (−)-35a and (+)-35b (598 mg, 87% yield, combined) as beige foams. The diastereomers were characterized separately.

(−)-35a (β-OH): R_f = 0.11 70:30 hexanes:EtOAc; ¹H NMR (CDCl₃, 400 MHz) δ 5.67–5.60 (m, 1H), 4.11 (br s, 1H), 3.82 (br s, 1H), 3.66 (br s, 1H), 3.20 (dt, J=10.96, 7.1, 7.0 Hz, 1H), 2.64 (d, J=18.5 Hz, 1H), 2.54 (d, J=18.7 Hz, 1H), 2.28–2.23 (m, 1H), 2.07 (d, J=17.9 Hz, 1H), 2.01–1.87 (d, J=19.0 Hz, 1H and m, 2H), 1.75–1.67 (m, 1H), 1.46 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz) δ 157.6, 124.4, 123.6, 80.5, 74.3, 69.8, 64.6, 48.2, 32.2. 32.0, 28.6, 27.7, 24.7; IR (thin film, NaCl) 3426(m), 2970(m), 2904(m), 1664(s), 1398(s), 1362(m), 1168(s), 1106(w), 1024(w), 906(m), 878(w), 727(m), 650(w); HRMS (ESI-APCI) m/z calcd. for C₁₅H₂₆NO₄ [M+H]⁺:284.1856, found: 284.1855. [α]²²_D = −80.9 (c = 1.12, CHCl₃)

(+)-35b (α-OH): R_f = 0.21 70:30 hexanes:EtOAc; ¹H NMR (CDCl₃, 400 MHz) δ 5.61 (br s, 1H), 5.52 (br s, 2H), 4.13 (app d, J=8.8 Hz, 1H), 3.70–3.67 (m, 1H), 3.55–3.52 (m, 1H), 3.31–3.26 (m, 1H), 2.37–2.20 (m, 5H), 2.10–1.99 (m, 4H), 1.45 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz) δ 157.5, 124.7, 123.1, 80.6, 74.9, 67.3, 60.5, 48.2, 30.7, 29.4, 28.3, 25.5, 24.2; IR (thin film, NaCl) 3392(m), 3027(w), 2976(m), 2902(m), 1667(s), 1395(s), 1345(w), 1255(w), 1168(m), 1119(m), 1078(m), 890(m), 774(w), 732(w), 668(w); HRMS (ESI-APCI) m/z calcd. for C₁₅H₂₆NO₄ [M+H]⁺: 284.1856, found: 284.1860. [α]²²_D = +15.7 (c = 0.74, CHCl₃)

4.2.14 Dibromide 36

To a solution of (−)-35a and (+)-35b (602 mg, 2.12 mmol) in CH₂Cl₂ (42 mL) was added a solution of Br₂ (53.3 uL, 3.18 mmol) in CH₂Cl₂ (5 mL) dropwise at 0 °C. The reaction was stirred for 5 mins before pouring into a 10% solution of Na₂S₂O₃. The aqueous layer was extracted with CH₂Cl₂ (4 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO₄ and concentrated to yield (−)-36a and (+)-36b (893 mg, 95% yield, combined) as a mixture, which was carried forward without further purification. An aliquot of the mixture was purified for characterization purposes.

(−)-36a (β-OH): white powder; R_f = 0.21 70:30 hexanes:EtOAc; ¹H NMR (CDCl₃, 400 MHz) δ 5.34 (br s, 1H), 4.14–4.06 (m, 3H), 3.55 (br s, 2H), 3.32–3.31 (m, 1H), 3.05 (br s, 1H), 2.67–2.63 (m, 2H), 2.21–2.18 (m, 1H), 2.10–1.87 (m, 5H), 1.47 (s, 9H); ³C NMR (CDCl₃, 100 MHz) δ 157.7, 81.6, 76.1, 74.9, 52.9, 52.4, 48.8, 42.1, 40.7, 28.4, 26.8, 24.4; IR (thin film, NaCl) 3376(m), 2975(m), 2894(w), 1662(s), 1477(w), 1448(w), 1392(s), 1367(s), 1257(w), 1166(s), 1066(w), 1032(w), 898(w), 871(w), 680(w); HRMS (ESI-APCI) m/z calcd. for C₁₅H₂₆Br₂NO₄ [M+H]⁺: 442.0223, found: 442.0216. [α]²²_D = −1.53 (c = 1.76, CHCl₃)

(+)-36b (α-OH): white foam; R_f = 0.48 70:30 hexanes:EtOAc ¹H NMR (CDCl₃, 400 MHz) δ 4.91 (br s, 1H), 4.70 (br s, 1H), 4.54 (br s, 1H), 4.02–3.95 (m, 2H), 3.51–3.48 (m, 1H), 3.30–3.24 (m, 1H), 2.81 (s, 1H), 2.62 (ddd, J=14.2, 10.9, 2.9 Hz, 1H), 2.27 (dd, J= 15.3, 4.1 Hz, 1H), 2.14–2.10 (m, 1H), 2.04–1.80 (m, 1H), 1.41 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz) δ 157.5, 80.7, 75.7, 65.9, 61.2, 53.2, 47.9, 47.49, 31.6, 31.1, 28.2, 25.3, 24.2; IR (thin film, NaCl) 3407(m), 2976(m), 2932(w), 1667(s), 1478(w), 1393(s), 1367(s), 1247(w), 1166(s), 1121(m), 1074(w), 1042(w), 986(w), 938(w), 890(w), 738(m); HRMS (ESI-APCI) m/z calcd. for C₁₅H₂₆Br₂NO₄ [M+H]⁺: 442.0223, found: 442.0210. [α]²²_D = +7.10 (c = 1.62, CHCl₃)

4.2.15 Enone (−)-38

Anhydrous DMSO (900 μL, 22.7 mmol) in CH₂Cl₂ (1 mL) was added to a solution of oxalyl chloride (805 μL, 5.27 mmol) in CH₂Cl₂ (12 mL) at −78 °C. The mixture was stirred for 10 mins before adding a solution of (−)-36a and (+)-36b (940 mg, 2.11 mmol) in CH₂Cl₂ (7 mL) dropwise. This mixture was stirred for 10 mins before adding Et₃N (2.90 mL, 21.1 mmol) and allowing the reaction to warm to room temperature. After 1 hour the reaction was diluted with CH₂Cl₂ and washed with commercial bleach solution (12% NaClO₄, 2 × 15 mL). The combined aqueous layers were back extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layers were dried over Na₂SO₄ and concentrated. The residue was purified by flash chromatography (90:10 hexanes:EtOAc) to yield (−)-38 (760 mg, 75% yield) as a viscous orange oil. R_f = 0.53, 70:30 hexanes:EtOAc; ¹H NMR (CDCl₃, 400 MHz) δ 7.02 (d, J=10.0 Hz, 1H), 6.01 (d, J=9.86 Hz, 1H), 5.88 (br s, 1H), 4.09 (br s, 1H), 3.78 (s, 1H), 3.54 (br s, 1H), 3.39–3.27 (m, 1H). 2.92–2.89 (m, 1H), 2.26 (app t, J=12.0, 11.0 Hz, 1H), 2.00–1.92 (m, 1H), 1.72–1.62 (m, 3H), 1.45 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz) δ 200.5, 156.2, 151.8, 125.7, 80.5, 79.9, 59.3, 47.7, 44.3, 42.2, 28.3, 25.1, 24.6; IR (thin film, NaCl) 3477(w), 2975(m), 1685(s), 1398(s), 1229(w), 1163(s), 1106(m), 1065(w), 917(w), 819(w), 768(w); HRMS (ESI-APCI) C₁₅H₂₂BrNNaO₄ [M+Na]⁺: 382.0624, found: 382.0624. [α]²²_D = −132.3 (c = 3.12, CHCl₃)

4.2.16 (+)-Norsecurinine, 2

To a solution of (−)-38 (250mg, 0.69 mmol) in dry CH₂Cl₂ (7 mL) was added trifluoroacetic acid (550 μL, 6.9 mmol). The solution was refluxed until TLC showed complete consumption of starting material. The reaction was concentrated in vacuo and then rediluted with dry CH₂Cl₂ (5 mL). Triethylamine (142 μL, 1.04 mmol) was added and the reaction was stirred at room temperature for 15 mins. The brown solution was concentrated in vacuo and triturated with EtOAc. The mixture was filtered through a fritted funnel and the filter cake washed with EtOAc (2 × 5 mL). The brownish liquid was concentrated and redissolved in dry CH₂Cl₂ (6 mL). To this solution was added diethylphosphonoacetic acid (255 mg, 1.3 mmol) and DCC (268 mg, 1.3 mmol) as a solution in dry CH₂Cl₂ (3 mL). The mixture was refluxed for 1 hour before being filtered through a fritted funnel. The crude filtrate was concentrated in vacuo and redissolved in dry THF (6 mL). The solution was cooled to 0 °C before adding NaH (31.2 mg, 1.3 mmol, washed with hexanes). The mixture was stirred at 0 °C for 15 mins then at room temperature for 10 mins. After quenching with H₂O (5 mL) the aqueous layer was extracted with EtOAc (6 × 5 mL). The combined organic layers were dried over MgSO₄ and concentrated. The resulting residue was purified by flash chromatography using gradient elution (95:5 to 90:10 CH₂Cl₂/MeOH) to yield (+)-2 (54 mg, 38% yield, 3 steps) as a yellow oil. R_f = 0.10 90:10 CH₂Cl₂:MeOH; ¹H NMR (CDCl₃, 400 MHz) δ 6.73 (dd, J=8.9, 6.5 Hz, 1H), 6.47 (d, J=8.9 Hz, 1H), 5.65 (s, 1H), 3.61 (app t, J=5.6 Hz, 1H), 3.27 (app dd, J=8.0, 6.0 Hz, 1H), 3.19–3.16 (m, 1H), 2.57 (dd, J=10.5, 4.7 Hz, 1H), 2.54–2.50 (m, 1H), 2.00–1.94 (m, 2H), 1.81–1.74 (m, 2H), 1.71 (d, J=10.5 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz) δ 172.9, 168.5, 143.9, 120.6, 108.0, 92.0, 65.3, 59.9, 55.4, 35.9, 29.5, 26.9;[α]²²_D = +183 (c = 1.36, EtOH)

4.2.17 (+)-Allonorsecurinine 40

yellow oil; R_f = 0.24, 90:10 CH₂Cl₂:MeOH; ¹H NMR (CDCl₃, 400 MHz) δ 6.86 (dd, J=9.1, 5.4 Hz, 1H), 6.71 (dd, J=9.1, 0.7 Hz, 1H), 5.79 (s, 1H), 4.16 (t, J= 7.4 Hz, 1H), 3.98 (app t, J=4.9 Hz, 1H), 2.95–2.89 (m, 2H), 2.87–2.81 (m, 1H), 2.04 (d, J=10.0 Hz, 1H), 1.91–1.62 (m, 3H), 1.30–1.21 (m, 1H); ¹³C NMR (CDCl₃, 100 MHz) δ 172.4, 167.1, 149.2, 124.0, 110.1, 90.8, 69.2, 57.8, 49.4, 47.0, 27.9, 25.5; [α]²²_D = +738 (c=1.30, EtOH).