Consecutive Ireland–Claisen Enyne-Metathesis Strategy Enables Rapid Assembly of Cyclic Imine Core Cyclohexene Motif

Abstract

An efficient strategy for rapid assembly of the complex substituted cyclohexene core that is present in several cyclic imine marine toxins is presented. Several of these toxins, including pinnatoxin A and recently discovered portimine A, have been the focus of much attention due to their fascinating biological activities. We demonstrate that the substituted cyclohexene-diene motif, which is a challenging feature to access synthetically, can be prepared through a stepwise Ireland–Claisen rearrangement/enyne metathesis procedure beginning from chiral esters. This approach enables a divergent strategy that can be implemented in syntheses of cyclic imines or derivatives thereof.

The cyclic imine family of marine natural products is well-known for the fascinating biological activity of its members as well as the exceptional total syntheses that have been accomplished to access them.[1] [2] The spiroimine motif is a hallmark of the family and is thought to be the biological warhead responsible for the toxicological profile of this class of compounds.[3] This feature is composed of a 5–8 membered cyclic imine with a 6-membered cyclohexene spirocycle. The cyclohexene fragment has a variety of substitution patterns, however, the cyclohexene diene is prominent in some of the most interesting members of the family, including the recently discovered portimines and karbirimine,[4,5] as well as pinnatoxin G and pinnatoxin H (Scheme [1]A).[6] [7] The 1,2-position of the 3,4-cyclohexene typically bears contiguous quaternary and tertiary stereocenters, the construction of which presents a meaningful challenge in any synthesis of a cyclic imine natural product.

While the cyclohexene has been accessed by many different approaches,[2] [8] a diastereoselective method for directly accessing this motif as a starting point has remained difficult.

Herein we report a general strategy for quickly accessing this fragment with high diastereocontrol via consecutive Ireland–Claisen/enyne metathesis starting from simple chiral α-substituted allylic esters bearing δ-chiral acetonides. The Ireland–Claisen rearrangement (ICR) of allylic esters controlled by δ-alkoxy group was recently reported,[9] [10] and this method enables efficient access to chiral carboxylic acids with contiguous quaternary and tertiary stereocenters. The products also bear a terminal olefin that is immediately accessible for olefin metathesis, which leads to the simplicity of this tandem application (Scheme [1]B). The chiral esters are prepared from allylic alcohols bearing a cis-alkene and chiral acetonide, as well as branched acids with a chiral center at the α-position. Pairing of the chiral acid with the correct chiral lithium amide allows for efficient control of stereochemistry in the resulting acid.[11] Subsequent conversion of the acid into the methyl ester with (CH₃)₃SiCHN₂, followed by desilylation of the terminal alkyne with potassium methoxide affords an enyne that may be submitted directly to metathesis conditions. To the best of our knowledge, this is the first report that details the use of enyne metathesis to forge the cyclohexene fragment of a cyclic imine.

This strategy was developed organically in our lab to quickly access the cyclohexene fragment with adequate functionality to allow for synthetic flexibility. The following is an example from our current ongoing synthesis of portimine A. Preparation of the chiral acid may be accomplished by a variety of methods, however, diastereoselective alkylation with Myers’ auxiliary provides the most expedient route (Scheme [2]A).[12] Alkylation of amide 1 (prepared in three steps from commercially available 5-hexyn-1-ol) provides the chiral amide 2 following Myers’ protocol in high yield as a single diastereomer. Removal of the auxiliary is achieved by reduction with lithium-amidoborane, and subsequent oxidation with TEMPO provides the chiral acid 3.

The synthesis of the allylic alcohol begins with naturally abundant l-ribose following a routine procedure to obtain lactol 4 (Scheme [2]B).[13] Olefination of 4 with (ethoxycarbonylmethyledene)triphenylphosphorane gives 5 in a nearly quantitative yield as a 4:1 mixture of Z:E isomers that is difficult to separate by chromatography. Silylation and subsequent reduction with i-Bu₂AlH of the isolated Z isomer of 5 provides the allylic alcohol 6. Although telescoping the olefination product into the silylation provides the desired product in high yield without the need for intermittent purification, the separation of these esters is challenging on decagram scale. Finally, the desired chiral ester 7 was obtained by esterification of 6 with 3 in the presence of EDC without erosion of stereochemistry.

Ireland–Claisen rearrangement of 7 with the appropriately matched chiral lithium amide affords the acid 8 in 98% yield with 9:1 d.r. (Scheme [3]).[11] [14] It is worth noting that all 4 diastereomers are readily accessible through interchange of the chiral amine and/or alteration of the double-bond geometry. This strategy circumvents the need for additional steps to install a chiral secondary alcohol at the α-position of the allylic alcohol to direct the stereochemistry of the rearrangement, while conveniently setting the stage for ring-closing metathesis by directly furnishing a terminal alkene. The δ-alkoxy stereodirecting chiral acetonide provides a synthetic handle for various modifications, making this a convenient and broadly applicable approach that may be employed for various synthetic applications.

Two brief modifications are required to prepare the substrate for enyne metathesis following the formation of the contiguous C1 and C2 stereocenters. Treatment of 8 with (CH₃)₃SiCHN₂, followed by desilylation of the alkyne, provides the enyne 9.[15] Several conditions were screened to determine the optimal conditions for enyne metathesis (Table [1]). A variety of ruthenium catalysts were screened for the metathesis, however, in all cases Grubbs catalysts proved to be superior.

Table 1 Optimization of the Enyne-Metathesis Conditions To Form Cyclohexene-Diene 10

Entry	Catalyst	Solvent	Temperature	Yield (%)	10/11
1	HG II (15 mol%)	CH2Cl2	rt	64	5:1
2	G II (15 mol%)	CH2Cl2	rt	50	5:1
3	HG II (15 mol%)	PhMe	rt	43	4:1
4	HG II (15 mol%)	PhMe	110 °C	47	5:1
5	HG II (15 mol%) CH2CH2 (1 atm)	PhMe	110 °C	66	5:1
6	HG II (8 mol%) CH2CH2 (1 atm)	PhMe	110 °C	86	7:1

Low yields were obtained at first, and the product was isolated as an inseparable mixture of the desired product and several minor byproducts (Table [1], entries 1–3). The dominant byproduct of the mixture was identified as the triene 11. Performing the reaction at a higher temperature in toluene did not lead to an improvement in yield or distribution of byproducts (Table [1], entry 4).

Replacing inert atmosphere with ethylene, a procedure first introduced by Mori,[16] led to higher yields with both HG II and G II catalysts, and significantly cleaner reactions with only the triene 11 observed as a byproduct (Table [1], entry 5). Furthermore, decreasing the catalyst loading increased the cyclic diene/triene ratio and further improved the yield (Table [1], entry 6).[17]

The reaction most likely proceeds through an ‘yne-then-ene’ pathway to provide the exo product exclusively (Scheme [4]).[18] Although both the ‘yne-then-ene’ as well as the ‘ene-then-yne’ pathway may produce the desired exo product (none of the endo product was observed), mixtures containing large portions of the triene 11 were resubmitted to reaction conditions without improvement in the ratio of 10/11. This suggests that the presence of less hindered alkyne functionality is necessary for the reaction to be productive. We suggest that the congested steric environment that the alkene portion of the ene-yne resides in most likely hinders initial addition to the C3 olefin, while the C8 alkene of the triene outcompetes the C7 olefin for ruthenacyclobutane formation thus leading to unproductive metathesis when mixtures of triene are resubmitted to reaction conditions.

In conclusion, we have developed a strategy for rapidly accessing the fully functionalized cyclohexene motif that is ubiquitous in the cyclic imine family of marine natural products. The consecutive Ireland–Claisen enyne metathesis approach leverages recent advances in ICR methodology and inherits chirality from chiral pool materials.[9] [11] The strategy is general and has been applied to several substrates in our efforts to access cyclic imine natural products in our lab. To the best of our knowledge, this is the only example of enyne metathesis as a method for accessing the cyclic imine cyclohexene motif, which is obtainable in excellent yield and diastereoselectivity following this procedure. Although the challenging to separate triene byproduct was observed in all cases where this strategy was employed, removal of any alkoxy protecting group typically allows for efficient purification of the products.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

Dr. Hongjun Zhou is acknowledged for assistance with NMR spectroscopy. Dr. Dmithry Uchenik and MRL Shared Experimental Facilities at UCSB are acknowledged for assistance with mass spectral analysis.

• References and Notes

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• 10 General Procedure for Ireland–Claisen Rearrangement A solution of chiral lithium amide (2.930 g, 10.23 mmol, 3.3 equiv) was dissolved in THF (30 mL) and cooled to –78 °C under an atmosphere of argon. n-Butyl lithium (3.7 mL, 9.3 mmol, 3.0 equiv, 2.5 M in hexanes) was added dropwise, and the solution stirred at this temperature for 15 min was warmed to 0 °C for 15 min and cooled back to –78 °C. A solution of allylic ester (3.10 mmol) was added dropwise as a solution in THF (6 mL + 2 × 2 mL rinses) and stirring continued for 1 h, at which point TMSCl (1.2 mL, 9.76 mmol, 3.15 equiv) was added dropwise. After stirring for an additional 1 h at –78 °C, the reaction was warmed to rt, and then heated to 50 °C. After 48 h, the reaction was cooled to 0 °C and quenched with DI H₂O and diluted with EtOAc. The mixture was transferred into a separatory funnel containing a 1:1 mixture of hexanes and 1 M HCl (the chiral amine was later recovered from this acidic aqueous phase by basification with NaOH and extraction with CH₂Cl₂). The biphasic mixture was extracted with EtOAc, and the organic extracts were dried over anhydrous Na₂SO₄, concentrated, and the crude material was purified by column chromatography on silica gel.
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• 14 Preparation of Acid 8 The acid 8 was prepared according to the general procedure.¹⁰ After purification by column chromatography (5% EtOAc in hexanes to 30% EtOAc in hexanes + 1% AcOH), the acid 8 was obtained as a colorless oil (1.916 g, 3.02 mmol, 98% yield, 9:1 d.r. The d.r. was determined by ¹H NMR spectroscopy). [α]_D ²¹ 0.5978° (c 0.100, CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 7.20–7.18 (m, 4 H), 6.86–6.78 (m, 2 H), 5.58 (ddd, J = 17.2, 10.7, 9.2 Hz, 1 H), 5.22–5.14 (m, 2 H), 4.40 (s, 2 H), 4.12 (dd, J = 10.7, 5.5 Hz, 1 H), 3.90 (q, J = 5.3 Hz, 1 H), 3.73 (s, 3 H), 3.61 (dt, J = 6.7, 4.1 Hz, 2 H), 3.50 (dd, J = 10.7, 5.6 Hz, 1 H), 3.05 (t, J = 10.1 Hz, 1 H), 2.26–2.10 (m, 3 H), 1.87 (dt, J = 14.2, 6.5 Hz, 1 H), 1.78 (dt, J = 11.4, 5.6 Hz, 2 H), 1.30 (d, J = 5.9 Hz, 3 H), 1.23 (s, 3 H), 0.83 (s, 9 H), 0.07 (d, J = 4.2 Hz, 9 H), 0.00 (d, J = 3.1 Hz, 6 H). ¹³C NMR (126 MHz, CDCl₃): δ = 181.38, 159.33, 134.00, 130.37, 129.41, 129.36, 129.30, 120.98, 113.94, 108.08, 108.02, 106.83, 84.48, 78.68, 77.41, 77.16, 76.91, 76.34, 72.86, 66.91, 62.78, 55.37, 49.81, 46.56, 34.58, 31.07, 27.75, 26.19, 26.07, 25.50, 18.65, 15.38, 0.27, –5.09, –5.12. HRMS (TOF MS ES): m/z calcd for C₃₄H₅₅O₇Si₂ [M – H]^–: 631.3486; found: 631.3505.
• 15 Preparation of Enyne 9 A solution of 8 (0.568 g, 0.897 mmol) in a 4:1 mixture of benzene (7.2 mL) to methanol (1.8 mL) was cooled to 0 °C, and TMSCHN₂ (1.0 mL, 1.07 mmol, 1.2 equiv, 1.05 M in hexanes) was added dropwise. The solution was warmed to rt and stirred for 30 min, at which point the reaction was concentrated in vacuo and redissolved in methanol (9 mL). Potassium carbonate (0.495 g, 3.58 mmol, 4.0 equiv) was added and the solution stirred at rt for 18 h. Upon completion, the mixture was diluted with DI H₂O and extracted with EtOAc. The organic extracts were dried over anhydrous Na₂SO₄, concentrated, and the crude material was purified by column chromatography on silica gel (10% EtOAc in hexanes) to afford the product 9 (0.489 g, 0.850 mmol, 95% yield). [α]_D ¹⁸ 5.6540° (c 1.00, CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 7.26 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 5.71–5.58 (m, 1 H), 5.28–5.18 (m, 2 H), 4.42 (s, 2 H), 4.16 (dd, J = 10.8, 5.3 Hz, 1 H), 3.93 (d, J = 5.3 Hz, 1 H), 3.80 (s, 3 H), 3.74 (dd, J = 10.7, 4.8 Hz, 1 H), 3.69–3.59 (m, 5 H), 3.53 (dd, J = 10.7, 5.9 Hz, 1 H), 3.11–3.02 (m, 1 H), 2.23 (d, J = 2.5 Hz, 1 H), 2.19–2.11 (m, 1 H), 2.07 (d, J = 2.6 Hz, 1 H), 2.00–1.79 (m, 4 H), 1.35 (s, 3 H), 1.28 (s, 5 H), 0.91 (s, 9 H), 0.07 (d, J = 3.8 Hz, 6 H). ¹³C NMR (126 MHz, CDCl₃): δ = 175.56, 175.17, 159.22, 135.13, 134.26, 134.10, 130.58, 130.48, 129.33, 129.26, 129.09, 120.80, 120.69, 118.94, 113.83, 107.84, 107.79, 107.72, 85.07, 84.27, 78.63, 76.39, 72.79, 72.73, 68.42, 68.35, 68.27, 66.98, 66.49, 66.46, 62.70, 61.58, 55.31, 51.68, 51.41, 51.35, 50.58, 49.51, 49.48, 47.22, 47.13, 46.73, 34.77, 33.09, 32.54, 31.65, 31.57, 31.39, 28.11, 28.07, 27.10, 26.13, 26.00, 25.42, 24.84, 22.72, 18.61, 18.33, 14.72, 14.19, 14.08, 13.97, –5.17, –5.18. HRMS (TOF MS ES): m/z calcd for C₃₂H₅₀O₇SiNa [M + Na]⁺: 597.3224; found: 597.3245.
• 16 Mori M, Sakakibara N, Kinoshita A. J. Org. Chem. 1998; 63: 6082
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• 17 Preparation of Cyclohexene 10 A 100 mL round-bottom flask equipped with a stir bar was flame-dried under vacuum and cooled under argon, and 9 (0.378 g, 0.657 mmol) was added, followed by HG II (27 mg, 0.032 mmol, 0.08 equiv). Toluene (34 mL, freshly distilled over Na and degassed by sparging with argon for 1 h) was added to the flask, and the mixture was sparged with ethylene gas (1 party balloon full of ethylene). The reaction was fitted with a reflux condenser and a full balloon of ethylene gas to maintain the atmosphere of ethylene, and the temperature was increased to 110 °C. After 24 h, completion was observed by TLC, and the reaction was concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (10% EtOAc in hexanes) to provide 10 (0.322 g, 0.560 mmol, 86%) as a 7:1 mixture of the desired cyclohexene 10 to the triene 11 (ratio of 10/11 was determined by ¹H NMR spectroscopy). Cyclohexene 10 [α]_D ²² 23.4716° (c 1.00, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 7.26 (d, J = 8.8 Hz, 2 H), 6.87 (d, J = 8.8 Hz, 2 H), 6.28 (dd, J = 17.5, 10.7 Hz, 1 H), 5.45 (s, 1 H), 5.06 (d, J = 17.0 Hz, 1 H), 4.96 (d, J = 10.3 Hz, 1 H), 4.53–4.38 (m, 2 H), 4.16 (dt, J = 8.6, 4.3 Hz, 1 H), 4.01–3.87 (m, 2 H), 3.80 (s, 4 H), 3.73 (dd, J = 10.4, 8.6 Hz, 1 H), 3.67–3.55 (m, 5 H), 3.48 (dd, J = 10.1, 4.0 Hz, 1 H), 3.35 (d, J = 11.4 Hz, 1 H), 2.32–2.09 (m, 4 H), 1.90 (dd, J = 10.7, 6.6 Hz, 1 H), 1.87–1.79 (m, 1 H), 1.79–1.68 (m, 1 H), 1.28 (d, J = 9.2 Hz, 6 H), 0.88 (s, 9 H), 0.06 (d, J = 7.0 Hz, 6 H). ¹³C NMR (126 MHz, CDCl₃): δ = 177.81, 159.22, 139.11, 138.70, 135.55, 134.49, 133.75, 130.95, 129.39, 129.36, 127.49, 120.59, 116.01, 113.90, 113.88, 113.82, 113.50, 111.60, 107.75, 107.59, 78.78, 77.99, 77.34, 76.66, 72.74, 67.47, 67.22, 66.79, 62.79, 62.43, 55.39, 51.57, 47.71, 45.76, 42.73, 41.98, 34.80, 31.72, 31.52, 29.15, 28.43, 28.33, 27.74, 26.63, 26.51, 26.19, 26.13, 26.06, 25.97, 25.55, 25.41, 25.18, 22.79, 21.18, 20.83, 18.39, 14.25, –5.10, –5.44. HRMS (TOF MS ES): m/z calcd for C₃₂H₅₀O₇SiNa [M + Na]⁺: 597.3224; found: 597.3206. Triene 11 [α]_D ²¹ –19.3102° (c 0.8, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 7.24 (d, J = 8.4 Hz, 3 H), 6.86 (d, J = 8.0 Hz, 3 H), 6.34 (dt, J = 17.7, 8.9 Hz, 1 H), 5.66 (d, J = 3.5 Hz, 1 H), 5.25–4.89 (m, 5 H), 4.39 (s, 2 H), 3.80 (s, 5 H), 3.67–3.59 (m, 3 H), 3.57 (s, 3 H), 3.55–3.43 (m, 3 H), 3.03 (s, 1 H), 2.23–3.59 (m, 3 H), 2.13–2.07 (m, 3 H), 2.01–1.98 (m, 4 H), 1.89–1.83 (m, 4 H), 1.25 (s, 19 H), 0.89 (s, 17 H), 0.07 (s, 17 H). ¹³C NMR (126 MHz, CDCl₃): δ = 176.83, 159.23, 139.70, 136.21, 132.29, 132.22, 130.74, 129.38, 128.79, 128.61, 113.84, 110.92, 108.36, 107.85, 75.58, 72.82, 66.95, 61.94, 55.42, 51.90, 47.19, 41.25, 32.08, 31.77, 29.85, 29.52, 28.25, 27.96, 26.86, 26.64, 26.08, 26.01, 25.20, 24.97, 22.84, 21.65, 21.13, 18.39, 14.27, 1.17, –2.77, –5.28, –5.30. HRMS (TOF MS ES): m/z calcd for C₃₄H₅₄O₇SiNa [M + Na]⁺: 625.3536; found: 625.3516.
• 18 Villar H, Frings M, Bolm C. Chem. Soc. Rev. 2007; 36: 55
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Corresponding Author

Publication History

Received: 23 October 2023

Accepted after revision: 21 November 2023

Accepted Manuscript online:
21 November 2023

Article published online:
20 December 2023

© 2023. Thieme. All rights reserved

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• References and Notes

• 1a Kita M, Uemura D. Chem. Lett. 2005; 34: 454
  CrossrefSearch in Google Scholar
• 1b Hellyer SD, Selwood AI, Rhodes L, Kerr DS. Toxicon 2011; 58: 693
  CrossrefPubMedSearch in Google Scholar
• 1c Bourne Y, Radic Z, Araoz R, Talley TT, Benoit E, Servent D, Taylor P, Molgo J, Marchot P. Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 6076
  CrossrefPubMedSearch in Google Scholar
• 1d Munday R. In Seafood and Freshwater Toxins: Pharmacology, Physiology and Detection . Botana LM. CRC Press; Boca Raton: 2008: 581 I Cuddihy S. L., Drake S., Harwood D. T., Selwood A. I., McNabb P. S., Hampton M. B.; Apoptosis; 2016, 21: 1447
  CrossrefSearch in Google Scholar
• 1e Izumida M, Suga K, Ishibashi F, Kubo Y. Mar. Drugs 2019; 17: 495
  CrossrefPubMedSearch in Google Scholar
• 2a Tang J, Li W, Chiu TY, Luo Z, Chong C, Wei Q, Martínez-Peña F, Gazaniga N, Yang SeeY, Lairson L, Parker C, Baran P. Nature 2023; 662: 507
  CrossrefPubMedSearch in Google Scholar
• 2b Nakamura S, Kikuchi F, Hashimoto S. Angew. Chem. Int. Ed. 2008; 47: 7091
  CrossrefPubMedSearch in Google Scholar
• 2c Stivala CE, Zakarian A. J. Am. Chem. Soc. 2008; 130: 3774
  CrossrefPubMedSearch in Google Scholar
• 2d Sakamoto S, Sakazaki H, Hagiwara K, Kamada K, Ishii K, Noda T, Inoue M, Hirama M. Angew. Chem. Int. Ed. 2004; 43: 6505
  CrossrefPubMedSearch in Google Scholar
• 2e McCauley JA, Nagasawa K, Lander PA, Mischke SG, Semones MA, Kisi Y. J. Am. Chem. Soc. 1998; 120: 7647
  CrossrefSearch in Google Scholar
• 3 Araoz R, Servent D, Molgo J, Iorga BI, Fruchart-Gaillard C, Benoit E, Gu Z, Stivala CE, Zakarian A. J. Am. Chem. Soc. 2011; 133: 10499
  CrossrefPubMedSearch in Google Scholar
• 4a Selwood AI, Wilkins AL, Munday R, Shi F, Rhodes LL, Hollad PT. Tetrahedron Lett. 2013; 54: 4705
  CrossrefSearch in Google Scholar
• 4b Fribley AM, Xi Y, Makris C, Alves-de-Souza C, York R, Tomas C, Wright JL. C, Strangman WK. ACS Med. Chem. Lett. 2019; 10: 175
  CrossrefPubMedSearch in Google Scholar
• 5 Hermawan I, Higa M, Hutabarat PU. B, Fujiwara T, Akiyama K, Kanamoto A, Haruyama T, Kobayashi N, Higashi M, Suda S, Tanaka J. Mar. Drugs 2019; 17: 353
  CrossrefPubMedSearch in Google Scholar
• 6 Selwood AI, Miles CO, Wilkins AL, van Ginkel R, Munday R, Rise F, McNabb P. J. Agric. Food Chem. 2010; 58: 6532
  CrossrefPubMedSearch in Google Scholar
• 7 Selwood AI, Wilkins AL, Munday R, Gu H, Smith KF, Rhodes LL, Rise F. Tetrahedron Lett. 2014; 55: 5508
  CrossrefSearch in Google Scholar
• 8 Saito T, Fujiwara K, Kondo Y, Akiba U, Suzuki T. Tetrahedron Lett. 2019; 60: 386
  CrossrefSearch in Google Scholar
• 9 Lee H, Gladfelder JJ, Zakarian A. J. Org. Chem. 2023; 88: 7560
  CrossrefPubMedSearch in Google Scholar
• 10 General Procedure for Ireland–Claisen Rearrangement A solution of chiral lithium amide (2.930 g, 10.23 mmol, 3.3 equiv) was dissolved in THF (30 mL) and cooled to –78 °C under an atmosphere of argon. n-Butyl lithium (3.7 mL, 9.3 mmol, 3.0 equiv, 2.5 M in hexanes) was added dropwise, and the solution stirred at this temperature for 15 min was warmed to 0 °C for 15 min and cooled back to –78 °C. A solution of allylic ester (3.10 mmol) was added dropwise as a solution in THF (6 mL + 2 × 2 mL rinses) and stirring continued for 1 h, at which point TMSCl (1.2 mL, 9.76 mmol, 3.15 equiv) was added dropwise. After stirring for an additional 1 h at –78 °C, the reaction was warmed to rt, and then heated to 50 °C. After 48 h, the reaction was cooled to 0 °C and quenched with DI H₂O and diluted with EtOAc. The mixture was transferred into a separatory funnel containing a 1:1 mixture of hexanes and 1 M HCl (the chiral amine was later recovered from this acidic aqueous phase by basification with NaOH and extraction with CH₂Cl₂). The biphasic mixture was extracted with EtOAc, and the organic extracts were dried over anhydrous Na₂SO₄, concentrated, and the crude material was purified by column chromatography on silica gel.
• 11 Qin Y, Stivala CE, Zakarian A. Angew. Chem. Int. Ed. 2007; 46: 746
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• 14 Preparation of Acid 8 The acid 8 was prepared according to the general procedure.¹⁰ After purification by column chromatography (5% EtOAc in hexanes to 30% EtOAc in hexanes + 1% AcOH), the acid 8 was obtained as a colorless oil (1.916 g, 3.02 mmol, 98% yield, 9:1 d.r. The d.r. was determined by ¹H NMR spectroscopy). [α]_D ²¹ 0.5978° (c 0.100, CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 7.20–7.18 (m, 4 H), 6.86–6.78 (m, 2 H), 5.58 (ddd, J = 17.2, 10.7, 9.2 Hz, 1 H), 5.22–5.14 (m, 2 H), 4.40 (s, 2 H), 4.12 (dd, J = 10.7, 5.5 Hz, 1 H), 3.90 (q, J = 5.3 Hz, 1 H), 3.73 (s, 3 H), 3.61 (dt, J = 6.7, 4.1 Hz, 2 H), 3.50 (dd, J = 10.7, 5.6 Hz, 1 H), 3.05 (t, J = 10.1 Hz, 1 H), 2.26–2.10 (m, 3 H), 1.87 (dt, J = 14.2, 6.5 Hz, 1 H), 1.78 (dt, J = 11.4, 5.6 Hz, 2 H), 1.30 (d, J = 5.9 Hz, 3 H), 1.23 (s, 3 H), 0.83 (s, 9 H), 0.07 (d, J = 4.2 Hz, 9 H), 0.00 (d, J = 3.1 Hz, 6 H). ¹³C NMR (126 MHz, CDCl₃): δ = 181.38, 159.33, 134.00, 130.37, 129.41, 129.36, 129.30, 120.98, 113.94, 108.08, 108.02, 106.83, 84.48, 78.68, 77.41, 77.16, 76.91, 76.34, 72.86, 66.91, 62.78, 55.37, 49.81, 46.56, 34.58, 31.07, 27.75, 26.19, 26.07, 25.50, 18.65, 15.38, 0.27, –5.09, –5.12. HRMS (TOF MS ES): m/z calcd for C₃₄H₅₅O₇Si₂ [M – H]^–: 631.3486; found: 631.3505.
• 15 Preparation of Enyne 9 A solution of 8 (0.568 g, 0.897 mmol) in a 4:1 mixture of benzene (7.2 mL) to methanol (1.8 mL) was cooled to 0 °C, and TMSCHN₂ (1.0 mL, 1.07 mmol, 1.2 equiv, 1.05 M in hexanes) was added dropwise. The solution was warmed to rt and stirred for 30 min, at which point the reaction was concentrated in vacuo and redissolved in methanol (9 mL). Potassium carbonate (0.495 g, 3.58 mmol, 4.0 equiv) was added and the solution stirred at rt for 18 h. Upon completion, the mixture was diluted with DI H₂O and extracted with EtOAc. The organic extracts were dried over anhydrous Na₂SO₄, concentrated, and the crude material was purified by column chromatography on silica gel (10% EtOAc in hexanes) to afford the product 9 (0.489 g, 0.850 mmol, 95% yield). [α]_D ¹⁸ 5.6540° (c 1.00, CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 7.26 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 5.71–5.58 (m, 1 H), 5.28–5.18 (m, 2 H), 4.42 (s, 2 H), 4.16 (dd, J = 10.8, 5.3 Hz, 1 H), 3.93 (d, J = 5.3 Hz, 1 H), 3.80 (s, 3 H), 3.74 (dd, J = 10.7, 4.8 Hz, 1 H), 3.69–3.59 (m, 5 H), 3.53 (dd, J = 10.7, 5.9 Hz, 1 H), 3.11–3.02 (m, 1 H), 2.23 (d, J = 2.5 Hz, 1 H), 2.19–2.11 (m, 1 H), 2.07 (d, J = 2.6 Hz, 1 H), 2.00–1.79 (m, 4 H), 1.35 (s, 3 H), 1.28 (s, 5 H), 0.91 (s, 9 H), 0.07 (d, J = 3.8 Hz, 6 H). ¹³C NMR (126 MHz, CDCl₃): δ = 175.56, 175.17, 159.22, 135.13, 134.26, 134.10, 130.58, 130.48, 129.33, 129.26, 129.09, 120.80, 120.69, 118.94, 113.83, 107.84, 107.79, 107.72, 85.07, 84.27, 78.63, 76.39, 72.79, 72.73, 68.42, 68.35, 68.27, 66.98, 66.49, 66.46, 62.70, 61.58, 55.31, 51.68, 51.41, 51.35, 50.58, 49.51, 49.48, 47.22, 47.13, 46.73, 34.77, 33.09, 32.54, 31.65, 31.57, 31.39, 28.11, 28.07, 27.10, 26.13, 26.00, 25.42, 24.84, 22.72, 18.61, 18.33, 14.72, 14.19, 14.08, 13.97, –5.17, –5.18. HRMS (TOF MS ES): m/z calcd for C₃₂H₅₀O₇SiNa [M + Na]⁺: 597.3224; found: 597.3245.
• 16 Mori M, Sakakibara N, Kinoshita A. J. Org. Chem. 1998; 63: 6082
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• 17 Preparation of Cyclohexene 10 A 100 mL round-bottom flask equipped with a stir bar was flame-dried under vacuum and cooled under argon, and 9 (0.378 g, 0.657 mmol) was added, followed by HG II (27 mg, 0.032 mmol, 0.08 equiv). Toluene (34 mL, freshly distilled over Na and degassed by sparging with argon for 1 h) was added to the flask, and the mixture was sparged with ethylene gas (1 party balloon full of ethylene). The reaction was fitted with a reflux condenser and a full balloon of ethylene gas to maintain the atmosphere of ethylene, and the temperature was increased to 110 °C. After 24 h, completion was observed by TLC, and the reaction was concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (10% EtOAc in hexanes) to provide 10 (0.322 g, 0.560 mmol, 86%) as a 7:1 mixture of the desired cyclohexene 10 to the triene 11 (ratio of 10/11 was determined by ¹H NMR spectroscopy). Cyclohexene 10 [α]_D ²² 23.4716° (c 1.00, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 7.26 (d, J = 8.8 Hz, 2 H), 6.87 (d, J = 8.8 Hz, 2 H), 6.28 (dd, J = 17.5, 10.7 Hz, 1 H), 5.45 (s, 1 H), 5.06 (d, J = 17.0 Hz, 1 H), 4.96 (d, J = 10.3 Hz, 1 H), 4.53–4.38 (m, 2 H), 4.16 (dt, J = 8.6, 4.3 Hz, 1 H), 4.01–3.87 (m, 2 H), 3.80 (s, 4 H), 3.73 (dd, J = 10.4, 8.6 Hz, 1 H), 3.67–3.55 (m, 5 H), 3.48 (dd, J = 10.1, 4.0 Hz, 1 H), 3.35 (d, J = 11.4 Hz, 1 H), 2.32–2.09 (m, 4 H), 1.90 (dd, J = 10.7, 6.6 Hz, 1 H), 1.87–1.79 (m, 1 H), 1.79–1.68 (m, 1 H), 1.28 (d, J = 9.2 Hz, 6 H), 0.88 (s, 9 H), 0.06 (d, J = 7.0 Hz, 6 H). ¹³C NMR (126 MHz, CDCl₃): δ = 177.81, 159.22, 139.11, 138.70, 135.55, 134.49, 133.75, 130.95, 129.39, 129.36, 127.49, 120.59, 116.01, 113.90, 113.88, 113.82, 113.50, 111.60, 107.75, 107.59, 78.78, 77.99, 77.34, 76.66, 72.74, 67.47, 67.22, 66.79, 62.79, 62.43, 55.39, 51.57, 47.71, 45.76, 42.73, 41.98, 34.80, 31.72, 31.52, 29.15, 28.43, 28.33, 27.74, 26.63, 26.51, 26.19, 26.13, 26.06, 25.97, 25.55, 25.41, 25.18, 22.79, 21.18, 20.83, 18.39, 14.25, –5.10, –5.44. HRMS (TOF MS ES): m/z calcd for C₃₂H₅₀O₇SiNa [M + Na]⁺: 597.3224; found: 597.3206. Triene 11 [α]_D ²¹ –19.3102° (c 0.8, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 7.24 (d, J = 8.4 Hz, 3 H), 6.86 (d, J = 8.0 Hz, 3 H), 6.34 (dt, J = 17.7, 8.9 Hz, 1 H), 5.66 (d, J = 3.5 Hz, 1 H), 5.25–4.89 (m, 5 H), 4.39 (s, 2 H), 3.80 (s, 5 H), 3.67–3.59 (m, 3 H), 3.57 (s, 3 H), 3.55–3.43 (m, 3 H), 3.03 (s, 1 H), 2.23–3.59 (m, 3 H), 2.13–2.07 (m, 3 H), 2.01–1.98 (m, 4 H), 1.89–1.83 (m, 4 H), 1.25 (s, 19 H), 0.89 (s, 17 H), 0.07 (s, 17 H). ¹³C NMR (126 MHz, CDCl₃): δ = 176.83, 159.23, 139.70, 136.21, 132.29, 132.22, 130.74, 129.38, 128.79, 128.61, 113.84, 110.92, 108.36, 107.85, 75.58, 72.82, 66.95, 61.94, 55.42, 51.90, 47.19, 41.25, 32.08, 31.77, 29.85, 29.52, 28.25, 27.96, 26.86, 26.64, 26.08, 26.01, 25.20, 24.97, 22.84, 21.65, 21.13, 18.39, 14.27, 1.17, –2.77, –5.28, –5.30. HRMS (TOF MS ES): m/z calcd for C₃₄H₅₄O₇SiNa [M + Na]⁺: 625.3536; found: 625.3516.
• 18 Villar H, Frings M, Bolm C. Chem. Soc. Rev. 2007; 36: 55
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