Article pubs.acs.org/OPRD
Lab-Scale Preparation of a Novel Cyclopenta[b]furan Chemokine Receptor Antagonist Christopher A. Teleha,*,† Shawn Branum,† Yongzheng Zhang,† Michael E. Reuman,† Luc Van Der Steen,‡ Marc Verbeek,‡ Nagy Fawzy,§ Gregory C. Leo,∥ Michael P. Winters,⊥ Fu-An Kang,⊥ Michael Kolpak,∥ Derek A. Beauchamp,† James C. Lanter,⊥ Ronald K. Russell,† Zhihua Sui,⊥ and Hilde Vanbaelen‡ †
High Output Synthesis, §Pharmaceutical Sciences, ∥Analytical Research, ⊥Cardiovascular and Metabolic Disease Research, Janssen Pharmaceutical Research and Development, Welsh and McKean Roads, P.O. Box 776, Spring House, Pennsylvania 19477, United States ‡ Preparative Separation Techniques, API Small, Janssen Research and Development, 30 Turnhoutseweg, Beerse, B-2340, Belgium S Supporting Information *
ABSTRACT: The preparation of a chemokine receptor type 2 (CCR-2) antagonist bearing a cyclopenta[b]furan core is described on a 600 g scale. Compared to our previously reported synthesis of the all-carbon core CCR-2 antagonist with a similar peripheral 3-methoxypyran appendage, our work required a redesign of the original Discovery Chemistry route and took advantage of a side product seen in the diastereoselective alkylation reaction. Elaboration by reduction and oxy-cyclization eventually led to the required N-Boc acid method. After amidation using a traditional coupling reaction, a reductive amination using enantiomerically enriched 3-methoxy-4-pyranone led to the final compound. Although several steps of the syntheses involved reagents such as selenium and chromium that would not be used in a large-scale process setting, the overall route went through intermediates that could certainly be used for future scale-up campaigns. The synthesis provided a method to make labscale quantities of the final succinate salt to support tox/toleration studies. Relative to the Discovery Chemistry route, this labscale route featured novel intermediates that could open new avenues for future research in this area.
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INTRODUCTION
The Discovery Chemistry team required a 600 g preparation of target 1 for tox/toleration studies. In conjunction with a rapid, “just-scale-it-up” approach to quickly access the molecule on scale, we felt confident that the parallels of the chemistry to the all-carbon 2 would allow easy technical transfer to this new molecule of interest. We hoped to take advantage of the process innovations from this earlier published route3 and embarked on the scale-up of target 1 reported herein. The Discovery Chemistry synthesis of 1 worked back to intermediates 3−5 in a similar fashion to the earlier report route to 2 (Figure 2). The general strategy was sound for discovery scale-up and entailed: (1) amide formation between 5 and fused piperidine 6; (2) deprotection of the NHBoc protecting group; (3) reductive amination of the newly revealed amine with the chiral ketone 4; (4) chiral separation of the reductive amination products to provide diastereomerically pure 3; and (5) salt formation with succinic acid to give final compound 1. This general synthesis strategy of these final steps was locked due to the time constraints of the project, and more importantly the plan for chiral chromatography of the reductive amination product 3 was the only sure-fire way to obtain a diastereomerically pure product. Methods for the preparation of chiral ketone 4 (or its enantiomer) have been generally described in the literature.4,5 Although the chiral purity of these ketones by the earlier reported methods was high (∼90−95% ee), because we did not have access to the enzymatic method,
Antagonists of the CC-chemokine receptor 2 (CCR2) have been vigorously pursued by a number of pharmaceutical companies as a target for drug discovery, in that compounds could have the potential for use in the acute and chronic conditions of inflammatory and autoimmune diseases associated with infiltration of monocytes, macrophages, lymphocytes, dendritic cells, NK cells, eosinophils, basophils, natural killer (NK cells), and memory T-cells. Several compounds of interest that were discovered in the Janssen laboratories that met the initial criteria set out during the in vitro screening phase of drug discovery. Structurally similar in that both possessed a chiral methoxypyran on the periphery, target 11 and previously reported 22 were distinct in their core portions of the molecules differed only by the one atom replacement of an oxygen (in 1) for a carbon (in 2) (Figure 1).
Figure 1. Cyclopenta[b]furan CCR2 compound 1 and a previously reported analogue 2. © 2014 American Chemical Society
Received: August 18, 2014 Published: November 10, 2014 1630
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crystallizable solid in 82% yield. Retrospective analysis of the alkylation reaction revealed that 16 was present in the crude alkylation mixture before chromatography, up to 40% depending on the reaction conditions. Attempts to hydrolyze the ester in 13, with the idea of working on the ester-to-amide formation before bicycle formation, was described earlier by Discovery. Their work was plagued by desilylation and lactone formation and was only useful to make analogues on a small scale. It was believed that the lactone 16 was a thermodynamic sink for this arrangement of a γ-hydroxy ester. The ease of lactone formation was also demonstrated with the minor alkylation isomer 14, which under the same conditions, provided lactone 17 as a solid in 74% yield. Despite the crystallinity of 16 and 17, they were not separable by selective crystallization and thus validated the need to separate the alkylation products with the TBS group intact. The generality of the lactonization was also shown for pyrrole 1812 with an alternative nitrogen protecting group; when carried through the analogous sequence, it provided lactone 19 as a solid in 56% yield. Foiled by the propensity of the hydroxyester 13 to cyclize to lactone 16, even in the alkylation reaction, we questioned whether any cyclization strategy with the ester in place could work. It seemed as if lactone 16 was favored thermodynamically, so we reasoned that we should take advantage of its ease of formation. It is noteworthy that the desilylation reaction was not as trivial as we expected. Two technical issues became apparent during our investigations. The precipitated product 16 was contaminated with tetrabutylammonium salts when using EtOAc during the water wash. An adjustment of the polarity of the organic layer (EtOAc) by addition of heptane and an inprocess check (NMR of evaporated aliquot) of the organic layer after washing to verify the absence of this impurity alleviated this problem. Additionally we found that, if the crystallized slurry of 16 was cooled below 10 °C, TBS-F coprecipitated with the lactone, and so the complete recovery of the product was compromised by this restriction. Naturally the next step towards providing a cyclization precursor required reduction of the lactone to provide the tethered hydroxyl group for cyclization. We found lactone 16 was surprisingly resistant to reduction with NaBH4 in THF according to a prescribed method13 but found it did succumb to reduction when the solvent was changed to MeOH and provided 20 in 99% yield (Scheme 2). With diol 20 in hand, we had some confidence in knowing that any cyclization event would probably favor the [3.3.0] ether we wanted, since the alternative cyclization products were more strained and did not have much precedent. We initially tried to cyclize 20 using a Pt-catalyzed method that was recently reported14 but did not find any of the expected 21. We next turned to the use of an oxy-selenation protocol15 whereby a transient association of an electrophilic selenium could induce cyclization. Treatment of 20 with PhSe-phthalimide/cat. BF3
Figure 2. Retrosynthesis of CCR-2 compound 1.
our chemical method provided chiral 4 in only ∼85−90% ee. Hence, the higher amount of the ketone enantiomer solidified the strategy to use chiral chromatography to arrive at diastereomerically pure 3. The preparation of the [3.3.0] ether system of 5 presented a unique challenge. With the knowledge that our earlier work3 using radical cyclization to enter the all-carbon framework not directly applicable here, there were few literature precedents for [3.3.0] bicyclic ethers. As shown in Figure 3, Smith and coworkers rationalized the 7 of an intramolecular Michael addition of the deacetylated alcohol of 8 to the acrylonitrile component.6 Others have utilized the Michael addition to enones7 or lactol formations8 as a method to construct more complex ring [3.3.0] systems. If we were interested in the 9 (X= CN), the chemistry might be very similar to the literature. But we were interested in 10 (X = H), and so any electronic force driving the reaction to form the new ring is not present. As shown in Figure 3, 11 would not be expected to provide a Michael addition product since it did not have the benefit of the electrophilic β-carbon. Therefore, we needed to investigate alternative methodology for the preparation of N-Boc bicyclic acid 5. We felt that the preparation of 5 would start with the wellunderstood alkylation chemistry from our earlier studies, using the dianion of 129 (Scheme 1) with the appropriate electrophile. Alkylation with TBS-protected 2-iodoethanol10 provided the logical unit as an alkylation synthon which worked better than the corresponding TBS-protected bromoethanol. The alkylation provided a mixture of 13/14 in the same 6:1 mixture as seen in our earlier work (with 3-chloro-1iodopropane), again with predominance of the alkylation occurring on the face opposite the NHBoc group.11 The separation was challenging, with the two isomers closely eluting on silica gel, and provided the desired diastereomer in 56% yield. Desilylation of 13 using TBAF/THF failed to give the desired alcohol 15; rather it afforded lactone 16 as a
Figure 3. Background of ethers. 1631
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Scheme 1. Initial alkylation results and observation of lactone side product
a
I(CH2)2OTBS, LiHMDS, THF, −70 to 0 °C (56−65%); b) TBAF, 60 °C (71−82%).
Scheme 2. Oxyselenation and oxyhalogenation approach
a
NaBH4, MeOH, rt (75−99%). bPhSe-phthalimide, BF3 Et2O, DCM (85−93%). cI2, MeCN, NaHCO3 (37%). dNBS, DCM or EtOAc (68−91%).
Figure 4. X-ray transition state for oxyselenation of 20 to form 22a.
etherate/DCM gave a gratifying cyclization product 22a in 75− 93% yield. The structure of 22a was confirmed first by NMR and later by small-molecule X-ray spectrum of crystals formed from nitromethane (Figure 4). We were pleased at the high yield for the process and the lack of other diastereomers.
Commenting on the stereochemical features of the X-ray spectrum of selenide 22a, it was easy to see the transrelationship of the newly formed oxygen ether relative to the anchoring −NHBoc group. What was puzzling was the positioning of the −SePh group on the same side of the 1632
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4). It was disappointing that the aqueous precipitation did not bring down a clean product, and so we regressed to the use of the less desirable DCM for the solvent and chromatography for purification (Scheme 4). The only satisfaction from this step was the isolated yield for 25 was 89%, which was higher than in DMAc, but the product needed to be purified by chromatography and the thick foamy product trapped EtOAc used in the purification. Deprotection of the Boc group in amide 25 was performed with HCl in MeOH conditions and carefully heated from 40 to 60 °C. The bis HCl salt 26 was isolated by solvent switching the MeOH for i-PrOH, followed by addition of heptane to facilitate recovery in the ensuing filtration. Here too we were able to isolate 26 as an ivory solid in 85% yield. Similar to the earlier work on the reductive amination reaction and the complications of base instability of ketone 4, our strategy for using the free-base 27 in dichloroethane (DCE) as a way to eliminate dichloromethane (DCM) from the process did not transition smoothly from our earlier experience. The initial partitioning between the organic phase containing 27 and the aqueous NaOH used for the neutralization did not work well; in this case, it appeared that the heavy rag layer actually entrained some precipitated 27 at the interface. As an in-process change to the earlier procedure, we found that the free-base 27 was not as soluble in DCE as it was in DCM, so the extraction was marred by the need to back-extract the basic aqueous fraction with DCM. The mixed DCE/DCM solution of 27 was carried in a through-process as done earlier, in reductive amination using glacial AcOH (2 equiv)20 and STAB (1.5 equiv) followed by charging a DCE solution of 4 (92% ee, 1.3 equiv) at 0 °C, in portions over several hours. Despite the superstoichiometric amounts of 4 present in the reaction, full conversion of 27 was difficult to achieve. Relative to our earlier experience with this kind of reaction, where diastereomers were also detected, the pairing of this chiral ketone 4 was the only change that would account for the subtle changes in reaction rate and diastereomer ratios. We were fortunate to find that the aqueous bicarbonate workup of the reaction was heavily enriched in unreacted 27 which aided in the eventual chiral chromatography. Similar to earlier investigation, the presence of a ∼5% trans-reductive amination product (not shown) and small amount of diastereomers from the enantiomer contamination (of 4) were also seen in the crude isolated product. Chiral chromatography of the batch using a Chiralpak AD column rendered the desired diastereomer 3 in 97.7% de and in 75% yield as an oil that retained about 9% w/w EtOH. The succinate salt 1 was prepared using the chromatographically purified 3 in a similar manner as done for 2, but for this final product, recrystallization from methyl isobutyl ketone (MIBK) was required to give the desired polymorph. The decolorization was required to meet a color specification on visual inspection of the succinate 1, and with the earlier experience of recrystallization, we implemented the charcoal treatment during the salt formation in MeOH and eliminated an isolation step. The method entailed dissolving 3 (reddish oil) in warm MeOH, addition of a stoichiometric amount of succinic acid, and direct treatment of the salt in solution with Darco-60. Filtration and concentration provided 1 as an ivory foam (with trapped MeOH), which was dissolved in hot MIBK for the final crystallization. Slow cooling, chilling and filtration provided 1 in 92% yield. We were surprised to find that 1 had developed some browning on the surface of the filter cake after
bicyclic ring as the NH-Boc group, that had previously shielded the bottom face of the cyclopentene ring during alkylation. An explanation for the observed diastereoselectivity seen in 22a could be the result of an equilibrium between the two different cationic selenium species 23 and 24, formed by the association of the reagent on the top and bottom face of the olefin 20, respectively. In the case of transient 24, the −NHBoc has shielded the top face of 20, minimizing any unfavorable interactions with the −SePh group. However, this transient intermediate 24 cannot be captured by either hydroxyl group. The only hydroxyl properly aligned for SN2 opening is the −CH2OH, which would lead to a strained four-membered ether. Hence, the reversible nature of the cationic selenium formation goes back to 20, and reassociation with the more sterically encumbered α-face leads to transient 23. In this intermediate, although there is a disfavored repulsion of the NHBoc and PhSe groups being on the same side of the cyclopentane ring, the −CH2CH2OH group is now positioned for a productive (and irreversible) attack, leading to product 22a. We were equally gratified to find that cyclization of 20 induced by the action of I2/NaHCO3/DCM gave 22b in 37% and by NBS/DCM gave 22c in 68−91% yield. Both products retained the same stereochemistry for the cyclization as seen for 22a (confirmed by 1H-NMR) and reinforced our understanding of the cyclization mechanism. Towards advancing products 22a/c to our goal of 5, we next investigated the reduction of the newly installed SePh/Br groups. Selenide 22a was easily removed using tin-free silane radical reduction conditions and provided 21 in quantitative yield (Scheme 3). Equally useful was the reduction of 22c Scheme 3. Reduction and re-oxidation of alcohol 21 to carboxylic acid 5
a
HSi(SiMe3)3, AIBN, toluene, reflux (100%). bH2 (40 psi), Pd/C, TEA, EtOAc (100%). cCrO3, Celite, acetone (85%).
under more benign conditions (H2, Pd/C, TEA, EtOAc), which employed a neutralizing base for the HBr produced in the reaction, and gave 21 also in quantitative yield. Returning the alcohol in 21 to its original oxidation state was initially attempted using several catalytic RuCl3 methods,16 but they were less favorable than using Jones oxidation17,18 that provided acid 5 in 85% yield. On a multigram scale, we found it convenient to run this reaction using 3 g of Celite/g of 21 to provide a smooth suspension, which was easy to stir and to filter at the end of the reaction. If the reaction were run by the normal method without Celite, the chromium salts coagulated and were very difficult to stir. We were surprised at the compatibility of the NHBoc group to what is traditionally viewed as a very acidic reaction condition. Having completed the preparation of the similar CCR-2 antagonist 2 and aware of the issues for the final steps, the final steps for preparation of 1 were generally the same with several nuances described below. Initial trials of the amide formation between acid 5 and fused piperidine 619 with EDC/HOBt/ DIEA did not work as well in DMAc as found earlier (Scheme 1633
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Scheme 4. Steps to final compound 1
within an aggressive timeline. Our procedures stand as an achievement in balancing the issues that were present at the onset of the project. We delivered the CCR-2 Antagonist of interest by developing safe, fit-for-purpose experimental procedures that allowed for their multihundred gram amounts without incident. We redesigned the original Discovery Chemistry route for the preparation of 1 and took advantage of a side-product 16 from the alkylation reaction that became the featured intermediate in the synthesis of N-Boc acid 5 by an oxy-cyclization method. Hopefully our work will be of value for future exploration of cyclization strategies for more complex ring systems.
air-drying overnight. The discoloration was not pervasive through the entire filter cake but was found only on the top and heal of the filtered solid. We did not observe this in the earlier prepared all-carbon core CCR-2 antagonist 2, and so this phenomenon remains a mystery. For the delivery, we carefully scraped away the brown solid from the white bulk solid and stored this part of the batch separately. Retrospectively we noticed this browning on retained samples of 1 (>6 months), again only of the surface.21 To the level of detection of our analytical HPLC method, we could not detect any appreciable differences of the brown-tinged part of the batch, which affected only 3% of the total weight of product and did not appreciably impact the 600 g of 1 that we obtained in 92% yield, 97% HPLC purity, and 99.5% chiral HPLC purity.
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EXPERIMENTAL SECTION Alkylation of Ester 12 with tert-Butyl(2-iodoethoxyl)dimethylsilane. LHMDS in THF (1 M, 6.97 L, 6.97 mol) cooled to −70 °C was treated with a solution of 12 (763.5 g, 3.16 mol) in THF (800 mL) over a 2 h period at < −68 °C. The resulting solution was stirred for 45 min at < −68 °C. A solution of tert-butyl(2-iodoethoxyl)dimethylsilane (1.267 kg, 4.426 mol) in THF (800 mL) added over 1 h 50 min at ∼ −66 °C. The reaction was stirred at ∼ −66 °C for 45 min. The reaction was warmed to −15 °C by addition of r.t. IPA to the cooling bath. Once the reaction reached this temperature, it was checked by NMR and HPLC and found to be complete (tlc, 20% EtOAc in heptane, KMnO4 stain, absence of 12 at Rf 0.2). The reaction was poured into a mixture of aqueous HCl (conc., 500 mL) and ∼4 L of ice. While stirring the mixture, additional conc. HCl (250 mL) and ice (2 L) were added (pH now 8), and finally conc. HCl (250 mL) was added to achieve an aqueous pH of 2. The lower aqueous layer was separated and extracted with toluene (1.5 L). The combined organic layers were washed with 1 L brine, and the organic layer was diluted with toluene (∼7.5 L) until two layers were evident when washed with water (1.5 L). The organic layer was washed with brine (1 L), and the resulting organic layer was clear. The organic layer was washed with brine (1 L) and dried over MgSO4. The combined aqueous and brine washings were back-
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CONCLUSIONS We have described the scale-up of CCR-2 antagonist succinate salt 1 to a 600 g quantity in sufficient purity to allow for the planned studies to be undertaken. The process for the formation of 1 involved a new strategy that took advantage of a lactone 16 that formed under the alkylation conditions. Lactone reduction provided diol 20 that was subjected to diastereoselective oxyselenation or oxybromination and provided the bicyclic ether core. Our work revealed a detailed explanation for the stereochemical outcome for the oxyselenation/oxyhalogenation reactions, along with an X-ray structure of selenide 22a to confirm our stereochemical assignment. Our oxy-halogenation results also showed that selenium could be removed from the process. Reduction of 22a/c and reoxidation of the alcohol in 21 using the Celitemodified Jones conditions provided the acid 5 in overall 25% yield from 12. The final steps involved coupling of acid 5 with amine 6, Boc deprotection of 26, reductive amination with 4, chromatographic enrichment for the desired diastereomer 3, and succinate salt formation completed the synthesis of final compound 1 in 10 steps (from 12) and 13% overall yield. The overall methods described for the preparation of 1 achieved the goal of making the required amount of material 1634
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drying led to sublimation of the noxious TBS-F in the vacuum oven. The solid was filtered on a Buchner funnel, washed with heptane (3 × 100 mL), and provided 16 (595 g) as a white solid in 82% yield. Mp: 106.3−110.1 °C; 1H NMR (400 MHz, CDCl3) 6.02 (dd, J = 2.2, 5.4 Hz, 1 H), 5.77 (dd, J = 1.1, 5.5 Hz, 1H), 5.17−5.32 (m, 1 H), 4.90 (br. s., 1 H), 4.38 (dd, J = 6.4, 7.6 Hz, 2H), 2.17−2.42 (m, 3 H), 2.06 (dd, J = 2.7, 13.7 Hz, 1 H), 1.44 (s, 9 H); 13C NMR (101 MHz, CDCl3) 180.73, 155.27, 136.07, 133.13, 79.43, 66.29, 55.58, 54.64, 41.80, 34.37, 28.39; Anal. Calcd for C13H19NO4 × 0.08 H2O: C, 61.30; H, 7.58; N, 5.50; Karl Fischer, 0.57. Found: C, 61.05; H, 7.87; N, 5.63; Karl Fischer, 0.56; [α]D25 +9.76° (1.0) (MeOH); LCMS (m/z): 276 (M + Na, 100), 529 (2M + Na, 100). tert-Butyl-(5R,7S)-1-oxo-2-oxaspiro[4.4]non-8-en-7-ylcarbamate (17). A solution of 14 (0.589 g, 1.47 mmol) and THF (28 mL) was treated with TBAF (1 M in THF, 1.5 mL, 1.47 mmol, 1 equiv), and the reaction was stirred for 3 h at r.t. when it was judged complete by TLC and LCMS. The reaction was evaporated to dryness, diluted with a mixture of dichloromethane (25 mL) and water (10 mL), and the layers were separated. The organic layer was washed with water (2 × 10 mL), brine (10 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (17 g) using a mixture of EtOAc and heptane. The collected product (bearing residual heptane) was triturated from a hot mixture of heptane with 5−10% EtOAc. Cooling and filtration provided 17 (0.278 g) as a white solid in 74% yield. Mp: 129.6−132.1 °C; 1H NMR (400 MHz, CDCl3) 5.97 (dd, J = 2.0, 5.4 Hz, 1 H), 5.77 (dd, J = 1.7, 5.4 Hz, 1H), 4.93 (br. s., 1 H), 4.49−4.64 (m, 1 H), 4.33 (qd, J = 2.1, 6.9 Hz, 2 H), 2.81 (dd, J = 7.8, 13.7 Hz, 1 H), 2.32−2.48 (m, 1 H), 2.26 (dt, J = 6.7, 13.0 Hz, 1 H), 1.71 (br. s., 1 H), 1.40−1.53 (m, 9 H), 1.45 (s, 2 H); 13C NMR (101 MHz, CDCl3) 179.8, 154.9, 135.8, 133.3, 79.7, 65.7, 56.4, 54.7, 42.7, 36.3, 28.4; Anal. Calcd for C13H19NO4: C, 61.64; H, 7.56; N, 5.53. Found: C, 61.67; H, 7.96; N, 5.53; [α]D25 −228.3° (c 1.0) (MeOH); LCMS (m/z): 276 (M + Na, 100). (5S,8S)-8-(2,5-Dimethyl-1H-pyrrol-1-yl)-2-oxaspiro[4.4]non-6-en-1-one (19). To a solution of LHMDS (1 M in THF, 65 mL, 65 mmol, 1.6 equiv) cooled to −20 °C was added a solution of 188 (8.9 g, 40.8 mmol) in THF (40 mL) over 20 min. The anion was stirred for 30 min at −20 °C, cooled to −70 °C (dry ice/acetone), and a solution of tert-butyl(2iodoethoxy)dimethylsilane (16.3 g, 57 mmol, 1.4 equiv) in THF (16 mL) was added over 10−15 min and the resulting solution stirred for 30 min at −70 °C. The bath was replaced by an ice bath, and the temperature was allowed to rise quickly to 0 °C and stirred for 1 h at this temperature. The reaction was quenched by addition of aqueous NH4Cl (6%, 40 mL) and isopropyl acetate (iPAc, 40 mL). The organic layer was separated and washed with aqueous NH4Cl (3%, 2 × 40 mL) and half-saturated brine (40 mL). The organic layer was dried (Na2SO4), filtered, and evaporated, and the crude was purified on silica gel (200 g) using a mixture of 0−10% EtOAc in heptane gave (1S, 4S)-methyl 1-(2-(tert-butyldimethylsiloxy)ethyl)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclopent-2-enecarboxylate (12.5 g) as a yellow oil in 81% yield. (The product was contaminated with a small amount of alkylating agent). The above product (10.4 g, 27.5 mmol) and THF (200 mL) was treated with TBAF (1 M in THF, 33 mL, 33 mmol) by syringe, and the reaction was stirred for 1 h at rt when it was judged complete by HPLC. The reaction was evaporated to near dryness and diluted with a mixture of dichloromethane
extracted with EtOAc (1 L) and used for rinsing the drying agent during filtration. The organic layer was concentrated (10 mm Torr, 40 °C) and provided a crude brown oil (1.67 kg). ∼241 g aliquots of this crude oil in a minimum amount of dichloromethane and heptane were purified on silica gel using the following conditions: 5 kg of silica gel (prewetted with 8 L heptane), eluted in turn with 8 L heptane, 24 L of 8% EtOAc in heptane, and 32 L of 9% EtOAc in heptane. For a typical run, ∼106 g of product was collected. This purification was repeated six times, and provided 13 (725 g) for a combined isolated yield of 56%. The yield of 14 was not determined from this large run, but the 1H NMR confirmed the ratio of ∼6/1 by comparison of the methyl ester signals. (1S,4S)-Methyl-4-(tert-butoxycarbonylamino)-1-(2(tert-butyldimethylsilyloxy)ethyl)cyclopent-2-enecarboxylate (13). 1H NMR (400 MHz, CDCl3) 5.71−5.85 (m, 2 H), 4.81−4.93 (m, 1 H), 4.70−4.81 (m, 1H), 3.67 (s, 3 H), 3.58 (td, J = 3.1, 6.7 Hz, 2 H), 2.20 (d, J = 8.1 Hz, 1 H), 2.02− 2.17 (m, 2 H), 1.70−1.82 (m, 1 H), 1.41 (s, 9 H), 0.81−0.90 (m, 9 H), 0.00 (s, 6 H); 13C NMR (101 MHz, CDCl3) 176.2, 155.2, 136.6, 133.1, 79.2, 60.2, 57.3, 55.6, 52.2, 40.5, 40.2, 31.9, 29.0, 28.4, 25.9, 22.7, 18.3, 14.1; Anal. Calcd for C20H37NO5Si: C, 60.11; H, 9.33; N, 3.51. Found: C, 60.54; H, 9.79; N, 3.17; Karl Fischer, 0.17; [α]D25 −21.16° (1.0) (MeOH), HPLC (BetaHI, 210 nm only): 10.88 min. (1R,4S)-Methyl 4-(tert-butoxycarbonylamino)-1-(2(tert-butyldimethylsilyloxy)ethyl)cyclopent-2-enecarboxylate (14). 1H NMR (400 MHz, CDCl3) 5.74 (s, 2 H), 4.73 (br. s., 2 H), 3.57−3.63 (m, 5 H), 2.83 (dd, J = 8.1, 13.9 Hz, 1 H), 2.03 (m, 1 H), 1.54−1.65 (m, 1 H), 1.39 (s, 9 H), 0.84 (m, 9 H), −0.03 to 0.03 (m, 6 H); 13C NMR (101 MHz, CDCl3) 175.5, 155.2, 136.0, 133.6, 79.3, 60.0, 57.8, 56.3, 52.1, 41.2, 40.9, 31.9, 29.0, 28.4, 26.0, 22.7, 18.3, 14.2; Anal. Calcd for C20H37NO5Si × 0.12 C7H16: C, 60.23; H, 9.44; N, 3.37; Karl Fischer, 0.11. Found: C, 60.63; H, 9.65; N, 3.22; [α]D25 −110.63° (1.0) (MeOH), HPLC (BetaHi, 210 nm only): 10.47 min. tert-Butyl-(5S,7S)-1-oxo-2-oxaspiro[4.4]non-8-en-7-ylcarbamate (16). A solution of 13 (1149 g, 2.875 mol) and THF (5.75 L) was treated with TBAF (1 M in THF, 2.875 L, 1 equiv) dropwise over ∼1 h. The temperature increased from 17 to 21 °C, and the reaction was clear orange at the end. The reaction was stirred for 1 h at r.t., when it was judged complete by TLC and HPLC. The reaction was poured into EtOAc (4 L) and separated, and the organic layer was washed with brine (2 L). (A white solid was present in the aqueous layer.) The organic layer was washed with additional brine (3 × 2 L), and these aqueous fractions were discarded. Heptane (4 L) was added (The heptane was critical for the removal of the n-Bu4N debris by washing with water. If this heptane addition was not done, the product 16, even after repeated washings, was contaminated with n-Bu4N salts), and the organic layer was washed with water (3 × 2 L) and brine (2 × 2 L), and the clear organic layer was checked by NMR for removal of n-Bu4N (in the expected regions). The organic layer was evaporated at 45 °C to about 750 mL when the solution became hazy, heptane (800 mL) was added, and instant crystallization of a white solid resulted. More heptane (300 mL) was added, and the mixture was swirled at 40 °C for 10 min on the rotovap bath. Ice was added to the bath, and the suspension was stirred at 13 °C for 10 min. NOTE: If the cooling was lowered below this point in an attempt to increase the yield, TBS-F coprecipitated with 16; this coprecipitate was extremely difficult to work with, in that 1635
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the toluene addition crystallization occurred. The contents were heated to 80 °C until all solids dissolved. The flask was swirled, seeded to induce crystallization, and swirled until the 22a started to crystallize. The contents of the flask was swirled at 15 °C (external temp) for 30 min. The product was filtered, washed with ice-cold toluene, and air-dried for 1 h, and afforded 22a (965 g) in 93% yield. 1H NMR (400 MHz, CDCl3) 7.53 (dd, J = 2.9, 6.6 Hz, 2 H), 7.21−7.34 (m, 3 H), 4.96−5.13 (m, 1 H), 4.39−4.54 (m, 1 H), 4.29 (s, 1 H), 3.83−3.98 (m, 2 H), 3.54−3.73 (m, 3 H), 1.98−2.10 (m, 1 H), 1.92 (d, J = 6.6 Hz, 1 H), 1.73−1.87 (m, 3 H), 1.41 (s, 9 H); 13C NMR (101 MHz, CDCl3) 155.2, 133.1, 129.4, 129.3, 127.4, 90.7, 79.6, 68.2, 68.0, 55.0, 53.2, 52.4, 40.6, 38.3; HPLC (BetaSD): 9.06 min, 88%; Anal. Calc. for C19H27NO4Se: C, 55.34; H, 6.60; N, 3.40; Found: C, 55.46; H, 6.97; N, 3.33; Karl Fischer, < 0.1 (Se analysis was conducted for this sample, and another batch and both were returned >0.4% deviation from expected. It was concluded that there was an error in the analysis method); [α]D25 −22.8° (1.09) (MeOH). Crystals for X-ray were grown from nitromethane. tert-Butyl-(3aR,5S,6S,6aS)-3a-(hydroxymethyl)-6-iodohexahydro-2I-cyclopenta[b]furan-5-yl-carbamate (22b). To a mixture of 20 (0.50 g, 1.94 mmol) in MeCN (12 mL) was added NaHCO3 (0.49 g, 5.83 mmol, 3 equiv) followed iodine (1.48 g, 5.83, 3 equiv) and the reaction was stirred for 60 h at rt. The reaction was quenched by dilution with dichloromethane and aqueous sodium thiosulfate (sat’d.). The organic layer was separated and washed with brine, dried with Na2SO4, filtered, and evaporated. Purification was affected in silica gel (12 g) using the following gradient of EtOAc and heptane (1 CV heptane, 5 CV 25% EtOAc in heptane, 8 CV 50% EtOAc in heptane) and provided 22b (0.28 g) in 37% yield. Mp: 155.5− 158.2 °C; 1H NMR (400 MHz, CDCl3) 4.69−4.82 (m, 1 H), 4.57 (d, J = 4.4 Hz, 1 H), 4.53 (s, 1 H), 3.92 (ddd, J = 4.2, 7.5, 8.7 Hz, 1 H), 3.70−3.83 (m, 2 H), 3.62 (td, J = 6.5, 8.7 Hz, 2 H), 2.09−2.22 (m, 1 H), 1.70−1.90 (m, 4 H), 1.45 (s, 9 H); 13 C NMR (101 MHz, CDCl3) 154.9, 91.8, 80.0, 69.1, 68.3, 53.4, 52.2, 43.2, 40.7, 38.6, 28.4; Anal. Calc. for C13H22INO4: C, 40.74; H, 5.79; I, 33.12; N, 3.65; Found: C, 41.11; H, 5.73; I, 33.08; N, 3.71; Karl Fischer, 0.42; LCMS (m/z): 406 (M + Na). tert-Butyl-(3aR,5S,6S,6aS)-6-bromo-3a-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-5-yl-carbamate (22c). A mixture of 20 (77.70 g, 0.284 mol) in EtOAc (875 mL) was gently warmed until a solution resulted. The mixture was cooled in ice bath down to 3 °C, and solid NBS (50.50 g, 0.284 mol, 1 equiv) was added in one portion. The reaction temperature rose to 8 °C, and the resulting yellow suspension was stirred at 3 °C for 2.75 h. The reaction was complete by TLC [EtOAc, KMnO4 stain, 20 at Rf 0.25 (none present), Rf 0.35 for succinimide (green with KMnO4), 22c at Rf 0.5]. The solid was filtered and washed with a minimal amount of EtOAc (10−20 mL or so). The filtrate was washed with 10% sodium bisulfate (2 × 100 mL), aqueous 10% sodium thiosulfate (1 × 100 mL), and aqueous 10% Na2CO3 (1 × 100 mL), and 400 mL of heptane was added (to decrease the organic polarity). The organic layer was washed with aqueous 10% Na2CO3 (2 × 100 mL) and brine (1 × 100 mL), dried over Na2SO4, filtered, and evaporated. Toward the end of the evaporation (at approximately 200 mL left), a solid formed in the recovery flask. The evaporation was stopped, and the suspension allowed to stand at rt (if heat was used in the bath). The solid was filtered, washed with heptane (20−50 mL), and
(200 mL) and water (100 mL), and the layers were separated. The aqueous layer was back-extracted with dichloromethane (2 × 50 mL), and the combined organic layers were washed with water (2 × 100 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (200 g) using a mixture of EtOAc and heptane. There was collected 19 (4.5 g) as a tan solid in 71% yield. Mp: 154.5−158.5 °C; 1H NMR (400 MHz, CDCl3) 6.14 (dd, J = 2.0, 5.6 Hz, 1 H), 5.86 (dd, J = 2.8, 5.5 Hz, 1 H), 5.76 (s, 2 H), 5.44 (d, J = 2.2 Hz, 1 H), 4.26−4.44 (m, 2 H), 2.47− 2.57 (m, 1 H), 2.27−2.44 (m, 9 H); 13C NMR (101 MHz, CDCl3) 179.1, 136.0, 131.9, 128.4, 106.5, 65.8, 60.5, 54.1, 41.2, 35.5, 14.1; Anal. Calcd for C14H17NO2 × 0.06 H2O: C, 72.36; H, 7.43; N, 6.03; Karl Fischer, 0.47. Found: C, 71.99; H, 7.51; N, 6.07; Karl Fischer, 0.41; [α]D25 −55.3° (1.0) (MeOH); LCMS (m/z): 232 (M + H, 100); Exact Mass calc for C14H18NO2+: 232.1332, found 232.1679. tert-Butyl-(1S,4S)-4-(2-hydroxyethyl)-4-(hydroxymethyl)cyclopent-2-enyl-carbamate (20). A solution of 16 (255.9 g, 1.01 mol) and MeOH (2 L) was chilled to 2 °C. NaBH4 (75 g, 1.98 mol) was added in five equal portions over 2.5 h, wherein the temperature usually went to 17 °C and back to 6 °C before the next addition. The reaction was quenched with the addition of aqueous NH4Cl (sat’d, 1 L), wherein the temperature rose to about 10 °C. The white hazy mixture was concentrated (10 mm Torr, 45 °C) to about 1 L when a white solid with some liquid resulted. The mixture was diluted with water and EtOAc (1 L each), and the layers were separated. The aqueous layer was extracted with EtOAc (3 × 250 mL). The combined organics were washed with brine (125 mL), dried over MgSO4, filtered through Celite, and evaporated at a bath temperature of 55 °C and provided 20 (272.9 g) as a thick oil in 99% yield. The product trapped 6 w/w % EtOAc. A toluene azeotrope was optionally done, but this was also ineffectively removed on high vacuum. The product was used directly in the next reaction without detailed characterization. 1 H NMR (400 MHz, CDCl3) 5.68−5.81 (m, 2H), 4.74 (br. s., 2H), 3.71 (t, J = 6.1 Hz, 2 H), 3.40−3.59 (m, 2 H), 2.50−2.89 (m, 1 H), 2.19 (dd, J = 8.4, 13.6 Hz, 2 H), 1.70 (td, J = 1.6, 6.2 Hz, 3 H), 1.55 (dd, J = 4.3, 13.8 Hz, 1 H), 1.44 (s, 9 H); 13C NMR (101 MHz, CDCl3) 155.6, 138.3, 132.5, 79.4, 69.0, 62.5, 59.3, 55.9, 53.3, 40.6, 39.7, 29.8, 28.5; Anal. Calc for C13H23NO4 × 0.7H2O: C, 57.84; H, 9.11; N, 5.19; Karl Fischer 4.6; Found C, 57.72; H, 8.84; N, 5.10; Karl Fischer, 3.84, HPLC (BetaSD): 6.01 min. tert-Butyl-(3aR,5S,6S,6aS)-3a-(hydroxymethyl)-6(phenylselanyl)hexahydro-2H-cyclopenta[b]furan-5-ylcarbamate (22a). A solution of 20 (382 g, 1.26 mol) and dichloromethane (6.5 L) was treated with N-(phenylseleno)phthalimide (419 g, 1.39 mol) followed by BF3 etherate (16 mL, 0.126 mol) all at once. The reaction steadily climbed from 15 to 24 °C, and within 10 min, the reaction formed a pink precipitate. Ten minutes later, the reaction became thick with a white precipitate, and the temperature began to decrease. The reaction was filtered through Celite (removing the phthalimide impurity), and the filter cake was washed with dichloromethane (750 mL) until the filtrate was no longer orange. The filtrate was washed with aqueous NaOH (0.5 M, 2 × 1350 mL) and brine (2 × 1 L), and the organic layer was dried over Na2SO4. [A second run was conducted with 382 g of 22a, under the same conditions, and was worked up and combined at this point]. With about 3 L organics left, toluene (3 L, ∼4 mL/g SM) was added and the evaporation continued. Shortly after 1636
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still showed a small amount of 21 present. An additional 25 mL of Jones reagent (∼5%) was added, stirring continued for 30 min after which the reaction was complete. i-PrOH (200 mL) was added and stirred at rt for 30 min (to quench the oxidant), and the reaction was filtered through Celite and washed with acetone (6 L). The filtrate was evaporated to about 1 L (mostly water), diluted with water (1 L) and dichloromethane (1 L), and transferred to a separatory funnel. The layers were separated, and the aqueous layer was extracted with dichloromethane (2× 1 L). The combined organics were washed with brine (800 mLthere was about 100 mL of an emulsion that was allowed to stand overnight), dried over Na2SO4, filtered, and evaporated. Towards the end of the evaporation, as the distillation rate slowed, MeCN (500 mL) was added, and the bath temperature was increased to 55 °C. The evaporation was continued, and a crystallization event started. MeCN (1 L) was added; the slurry wasas swirled at 50−55 °C for a short while, and the flask was removed, scraped, and allowed to chill overnight. The next day, the solid was broken up, filtered, and washed with a minimum amount of MeCN, and the white solid (168.1 g, 60%) was dried on the filter funnel. The filtrate that had concentrated provided a second crop of product on filtration/washing (72.8 g) that was comparable to the first crop. There was obtained 5 (240.9 g) as a white solid in 86% yield. Mp: 147.4−149.1 °C; 1H NMR (400 MHz, DMSO-d6) 12.51 (s, 1 H), 6.93 (d, J = 7.8 Hz, 1 H), 4.29 (d, J = 5.6 Hz, 1 H), 3.87−3.99 (m, 1 H), 3.83 (d, J = 5.6 Hz, 1 H), 3.48 (dd, J = 3.3, 8.9 Hz, 1 H), 2.35−2.46 (m, 1 H), 1.80−1.98 (m, 3 H), 1.63−1.72 (m, 1 H), 1.49 (d, J = 4.2 Hz, 1 H), 1.36−1.41 (m, 9 H); 13C NMR (101 MHz, DMSO-d6) 176.7, 155.0, 85.5, 75.5. 67.6, 57.0, 49.5, 41.5, 39.1, 38.5, 28.2; Anal. Calcd for C13H21NO5: C, 57.55; H, 7.80; N, 5.16; Found: C, 57.34; H, 8.18; N, 5.08; Karl Fischer,
