CC BY-ND-NC 4.0 · Synthesis 2019; 51(01): 285-295
DOI: 10.1055/s-0037-1610387
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Copyright with the author

Synthesis of the C1–C12 Fragment of Calyculin C

a  Aalto University School of Chemical Engineering, Department of Chemistry and Materials Science, Kemistintie 1, P.O. Box 16100, 02150 Espoo, Finland   Email: ari.koskinen@aalto.fi
b  Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006, Riga, Latvia
,
a  Aalto University School of Chemical Engineering, Department of Chemistry and Materials Science, Kemistintie 1, P.O. Box 16100, 02150 Espoo, Finland   Email: ari.koskinen@aalto.fi
› Author Affiliations
This work was supported by the Academy of Finland (project number 266369) and (to O.V.K.) the FP7 InnovaBalt project (contract Nr.316149). The authors would like to acknowledge the networking contribution by COST Action CM1407 “Challenging organic syntheses inspired by nature – from natural products chemistry to drug discovery”.
Further Information

Publication History

Received: 26 September 2018

Accepted after revision: 26 October 2018

Publication Date:
22 November 2018 (online)

 

Dedicated to the memory of Professor István E. Markó.

Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue

Abstract

Calyculins are a class of highly cytotoxic metabolites originally isolated from the marine sponge Discodermia calyx. To date, a total of twelve different calyculins (A–J) and calyculinamides (A, B and F) have been described, the most abundant (in D. calyx) being calyculins A and C. Herein, we demonstrate a concise route to access the C1–C12 tetraene fragment of calyculin C using transition-metal-catalyzed coupling reactions (Suzuki–Miyaura, Stille, Negishi and Heck) for the key connections. The synthesis starts from propionaldehyde and proceeds in 10 steps with 7.5% overall yield. We also describe an efficient route for the preparation of (Z)-3-iodobut-2-enenitrile in four steps and 68% yield.


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Calyculins are a class of highly cytotoxic metabolites originally isolated from the marine sponge Discodermia calyx by Fusetani et al.[1] Later, other marine sponges containing calyculins and calyculinamides were found.[2] To date, a total of twelve different calyculins (A–J) and calyculinamides (A, B and F) have been described, the most abundant (in D. calyx) being calyculins A and C (Scheme [1]), which differ from each other only by methyl substitution at C32. The remaining calyculins are either geometric isomers of the calyculins A or C, or close derivatives of calyculin A: calyculinamides,[3] dephosphonocalyculin A,[4] geometricin and swinhoeiamide,[5] and clavosines A–C.[6] Structure–activity relationships and biosyntheses of these sponge-derived cytotoxins have been reviewed.[7]

These intriguing structures have inspired several research groups to devote significant synthetic efforts toward the calyculins,[8] and these are summarized in Table [1].

Table 1 Overview of the Reported Total Syntheses of Calyculins

Group

Target

No. of steps

Overall yield

Remarks

Ref.

Evans

ent-calyculin A

33

0.54%

total synthesis

 9

Masamune

calyculin A

43

0.31%

total synthesis

10

Shioiri

calyculin A

32

0.092%

formal synthesis

11

Smith

ent-calyculin A

35

0.89%

formal synthesis

12

Armstrong

calyculin C

30

0.018%

total synthesis

13

Barrett

ent-calyculin A

34

0.9%

formal synthesis

14

We have been involved in the development of a synthetic access to calyculins and their analogues, and our chosen retrosynthesis is shown in Scheme [1]. We have so far completed the syntheses of fragments A–C,[15] and have reported a synthesis of a tetraene fragment D,[16] but which unfortunately is not attractive for large-scale efforts. Previous syntheses of the tetraene fragment D have been reported by Barrett,[17] Shioiri[18] and Armstrong.[19]

Transition-metal-catalyzed alkenyl–alkenyl cross-coupling reactions have proven to be effective in stereoselective syntheses of di- and polyenes and have been successfully applied to the total syntheses of a wide variety of natural products.[20] [21] [22] [23]

Zoom Image
Scheme 1 Structures and retrosynthesis of calyculins A and C

Herein, we describe our recent results on the application of Pd-catalyzed cross-coupling reactions to the synthesis of the C1–C12 tetraene fragment D of calyculin C. We tested the effectiveness of Stille,[24] Negishi,[25] Heck[26] and Suzuki­–Miyaura[27] coupling strategies for the key connections of three precursors: iodonitrile 1, an appropriate component 2, 3 or 4 and alcohol 5 (Scheme [2]).

Zoom Image
Scheme 2 Retrosynthetic analysis of the tetraene fragment D of calyculin C
Zoom Image
Scheme 3 Synthesis of iodonitrile 1 in four steps and 68% overall yield from 2-butyn-1-ol (6)

The synthesis of iodonitrile 1 started with a one-pot Red-Al reduction of readily available 2-butyn-1-ol (6) followed by iodination to give alcohol 7.[28] Oxidation of the primary alcohol 7 with MnO2 gave aldehyde 8, which was converted into oxime 9 (as a mixture of isomers) in 85% yield over the three steps. Initial attempts to convert 9 into iodonitrile 1 using (CF3CO)2O and imidazole or N-chlorosuccinimide and triphenylphosphine in CH2Cl2 proved unsuccessful. However, the desired conversion was achieved by treatment of 9 with thionyl chloride at 0 °C, providing (Z)-3-iodobut-2-enenitrile (1) as the only isomer in 68% overall yield in four steps (Scheme [3]). The oximes 9 and iodonitrile 1 were found to be light- and temperature-sensitive but could be stored in a freezer in darkness for a long time (a year or more).

A Stille coupling was initially attempted in order to obtain adduct 11 (Scheme [4]). Stannyl derivative 2 was prepared from propargylic alcohol (3) by several methods: a direct stannylcupration reaction[29] with in situ generated Bu3Sn(Bu)CuCNLi2, a radical hydrostannylation reaction[30] with Bu3SnH and AIBN at 80 °C, or a Pd(0)-catalyzed hydrostannylation reaction.[31] Due to the formation of isomer mixtures, the yield of 2 obtained by these different methods varied from low to moderate, the best being obtained through direct stannylcupration. The large excess of toxic Bu3SnH required for full conversion of substrate 3, the low yield and the necessity to separate isomers made this approach unattractive. Therefore, the Stille coupling of iodonitrile 1 with 2, although giving 11 stereoselectively in 39% yield, was not optimized further.

Zoom Image
Scheme 4 Synthesis of conjugated aldehyde 12 by Stille and Negishi cross-coupling reactions

The next attempt to prepare adduct 11 was through a Negishi coupling procedure.[32] This alternative shorter route included a one-pot Schwartz hydrozirconation of 3, transmetalation from Zr to Zn and a Pd-catalyzed cross-coupling of the vinylzinc intermediate 10 with iodonitrile 1 to provide 11 in 60% yield as a single isomer. Oxidation of 11 with MnO2 afforded the conjugated aldehyde 12 in an excellent 90% yield (Scheme [4]).

Table 2 Conditions Screened for the Mizoroki–Heck Cross-Coupling of Iodonitrile 1 with Acrolein (4) Affording Conjugated Aldehyde 12

Entry

Cat.

Base

12:13

Conversion (%)a

Yield (%)b

Time (d)

 1c

PdCl2

K2CO3

53:47

full

36

1

 2

Ag2CO3

73:27

15

NE

1

 3

KOAc

75:25

80

NE

1

 4d

AgOAc

95:5

12

NE

1

 5

95:5

80

40

1

 6

Pd2(dba)3

AgOAc

94:6

18

NE

1

 7

Pd(acac)2

NR

2

 8e

Pd(OAc)2

95:5

95

65

2

9

95:5

95

85

2

10

CsOAc

82:18

99

NE

1

a Conversions determined from the 1H NMR spectra. NR = no reaction.

b Yield of isolated product 12. NE = not estimated.

c Bu4NF (1 equiv) was added to the reaction mixture.

d Instead of acetonitrile the same amount of acrolein was added.

e 10 mol% Pd(OAc)2 was used.

The Mizoroki–Heck cross-coupling reaction[33a] [b] is a much more attractive method providing conjugated aldehyde 12 directly from 1 in one step (Scheme [5]). Unfortunately, initial experiments showed that the reaction of iodonitrile 1 with acrolein (4) at room temperature yielded an inseparable mixture of two isomeric compounds 12 and 13 (Table [2], entries 1–3). The isomeric compound was likely to be diene 13 because of the typical trans double bond coupling constant (J = 15.8 Hz) in the 1H NMR spectrum and the low possibility of the formation of branched Heck coupling products with olefins containing an electron-withdrawing carbonyl group, as found in acrolein. The only remaining possibility is the isomerization of the cyano group, which has been described previously.[33c]

Zoom Image
Scheme 5 Mizoroki–Heck cross-coupling of iodonitrile 1 with acrolein (4) affording conjugated aldehyde 12

Some reactions (Table [2], entries 1 and 5) gave high conversions (determined from the 1H NMR spectral data), but low isolated yields. A possible explanation is base-initiated iodine elimination in 1 and removal of volatile but-2-ynenitrile from the reaction mixture. Reaction times that were too long led to contamination of the product with polymerization or Diels–Alder cyclization by-products. After screening different catalysts and bases, we were fortunate to find conditions delivering the desired isomer 12 with 95% isomeric purity and 85% yield (entry 9). The NMR data of this product were identical with those previously obtained for compound 12 prepared via different methods (Scheme [4]).

Aldehyde 12 was next subjected to the Ramirez reaction[34] by treatment with the ylide formed in situ from triphenylphosphine and tetrabromomethane to give dibromide 14 (Scheme [6]).

A Negishi-type reaction of dibromide 14 would require iodide 15, which was synthesized according to Scheme [7]. Thus, alcohol 6 was reacted with Schwarz’s reagent and then iodinated leading to iodide 21. Silylation then gave the protected iodide 15. However, attempts to couple 14 with the Zn reagent derived from iodide 15 in the presence of Pd(PPh3)4 failed.

Zoom Image
Scheme 6 Synthesis of tetraene 20 synthesis according to the first strategic plan

Alternatively, the Suzuki–Miyaura coupling of dibromide 14 and olefin 16 gave the corresponding tetraene 17 (Scheme [6]).[35] The synthesis of 16 is shown later in Scheme [11]. Treatment of 17 with t-BuMe2SiOTf and 2,6-lutidine in dichloromethane at –85 °C led to the protected compound 18 in 91% yield along with a small amount of cyclized compound 19. Unfortunately, compound 18 showed a tendency to undergo spontaneous cyclization to give compound 19 during column chromatography or on standing in solution at room temperature. This type of Pd-catalyzed cyclization of conjugated tetraenes has been reported by Parker,[36] Trauner[37] and Baldwin.[38] Finally, the bromotetraene 18 was subjected to a Negishi cross-coupling using ZnMe2 and [Pd(t-Bu3P)2][39] to give tetraene 20.

Zoom Image
Scheme 7 Synthesis of iodide 15

As the approach to tetraene 20 was significantly complicated by the undesired formation of the cyclic compound 19, modifications according to Scheme [8] were undertaken to avoid the undesired cyclization.

Zoom Image
Scheme 8 Modified retrosynthetic analysis of tetraene fragment D

The synthesis of the key compound 5 started with self-aldol condensation of propionaldehyde (23) catalyzed by 4-trans-hydroxy-l-proline in DMSO[40] to give 24 as a 6:1 anti/syn diastereomeric mixture (determined by 1H NMR) (Scheme [9]). Unfortunately, the next step, silylation with tert-butyldimethylsilyl triflate and diisopropylethylamine in dichloromethane at 0 °C, was accompanied by partial racemization at the labile α-stereogenic center leading to compound 25 in 76% yield (2 steps from 23), but a diastereomeric ratio of 2:1 (anti/syn). The protected compound 25 was subjected to the Ramirez reaction and the dibromoolefins 26 and 27 were separated through column chromatography on silica gel to afford the desired diastereomer 26 as the major product. Dibromide 26 was then subjected to a Corey–Fuchs alkynylation step.[41] Thus, elimination with n-butyllithium and methylation with iodomethane gave intermediate 28 in excellent yield. Sequential hydrozirconation of 28 with Schwartz’s reagent[42] (obtained in situ from Cp2ZrCl2 and DIBAL-H) and iodination afforded iodide 29 in 65% yield.

Zoom Image
Scheme 9 Synthetic route to 29 representing key compound 5

The enantiomeric composition of the obtained chiral compounds was determined according to the Mosher method.[43] Deprotection of 26 with n-Bu4NF at 45–50 °C proceeded with dehydrobromination leading to monobromo-substituted 30. Improved results were obtained when 28 was deprotected under the same conditions to give the more stable compound 31 (Scheme [10]), which was then subjected to derivatization with Mosher’s acid chlorides.[44] NMR analysis established a 70% enantiomeric excess for alkyne 28 (see the Supporting Information).

Zoom Image
Scheme 10 Synthesis of compounds for derivatization with Mosher’s acid chlorides to establish the enantiomeric excesses of their precursors

Only a few approaches to the anti diastereomer of 24 or its precursors with high de and ee values, requiring multistep syntheses, are described.[45] When we first tested the key steps of the approach (see Scheme [8]), we gave preference to the shorter synthetic route to compound 29 with lower ee over the longer synthetic route with higher ee.

In multistep syntheses a convergent strategy is much more advantageous over a linear one. We therefore prepared three compounds, 32,[29] 16 [46] and 21, and planned to modify them according to Scheme [11]. A further intention was the Heck coupling of the obtained diene with 1 and final assembly of the resulting triene with key compound 5 (i.e., vinyl iodide 29) in the last step.

Only the tin derivative 34 was obtained with a satisfactory yield according to this scheme. All attempts to convert 34 into compound 37 by metathesis with 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane led to complex reaction mixtures with low yields of 37 (Scheme [12]). The reaction of 34 with 1 resulted in formation of the Stille coupling product instead of the desired Heck coupling product.

Zoom Image
Scheme 11 Syntheses of the components for transition-metal-catalyzed cross-coupling reactions with iodide 29
Zoom Image
Scheme 12 Screened conditions for metathesis reactions of 34 with 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane

The Pd(PPh3)4-catalyzed Suzuki–Miyaura coupling of vinylboronate 16 with iodide 29 proceeded stereoselectively with 95% yield to give the conjugated diene 38 with two trisubstituted double bonds (Scheme [13]). Oxidation with MnO2 afforded aldehyde 39, which was subjected to Wittig olefination to yield the conjugated triene 40.

Zoom Image
Scheme 13 Synthetic route to triene 40
Zoom Image
Scheme 14 Mizoroki–Heck cross-coupling reaction of triene 40 with iodide 1

Inspired by the successful Mizoroki–Heck coupling of 1 with acrolein (4) (see Scheme [5]), we first tried to apply the same conditions to couple triene 40 with iodonitrile 1 (Scheme [14]). As AgOAc had demonstrated the best stereoselectivity in this reaction, we opted for AgOAc as the base again and no other bases were tested. However, the best conditions from Table [2] were not a guarantee of the desired result for the reaction of iodonitrile 1 with triene 40. All experiments yielded a mixture of isomers, which were not separated into individual components. One of the components was tetraene 41, the 1H NMR data of which were identical to those of the same compound obtained later through Suzuki–Miyaura coupling according to Scheme [15]. Analysis of the spectral data of the second component most likely showed the formation of isomer 42 instead of 43.

Despite the lack of high stereoselectivity this reaction is interesting because, to the best of our knowledge, it is one of only a few examples of the Heck coupling of vinyl halides with nonaromatic trienes.[47]

Metathesis of 40 with 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane in dichloromethane at room temperature gave triene 45 (Scheme [15]), which was reacted with iodonitrile 1 via a Suzuki–Miyaura coupling to afford the desired tetraene 41. The chemical shifts and coupling constants in the 1H NMR of the obtained tetraene 41 matched very well with the same parameters described previously for an analogous tetraene fragment.[48]

In summary, we have demonstrated a concise route to access the C1–C12 tetraene fragment 41 of calyculin C. The synthesis starts from propionaldehyde (23) and proceeds in 10 steps with 7.5% overall yield. We have also described an efficient route for the preparation of (Z)-3-iodobut-2-enenitrile (1) in four steps and 68% overall yield.

Zoom Image
Scheme 15 Final steps in the synthesis of tetraene 41 according to the second strategic plan

Moisture-sensitive reactions were carried out under an argon atmosphere, and glassware was flame-dried under high vacuum or in an oven. Dry solvents (THF, Et2O, toluene, MeCN, CH2Cl2) were obtained using an MBraun MB-SPS 800 solvent drying system. Commercial reagents were used without further purification. Ph3P was recrystallized from hot ethanol and was dried over P2O5 under vacuum. n-BuLi was titrated with N-benzylbenzamide. Other solvents and reagents were used as received. Analytical TLC was performed using Merck silica gel (60, F254 230–400 mesh) precoated aluminum plates and samples were made visual by UV light (λ = 250 nm) and/or staining upon heating with standard KMnO4, anisaldehyde or PMA solutions. Flash chromatography was carried out using Merck silica gel (60, F254 230–400 mesh) and p.a. grade solvents. IR spectra were recorded with Perkin-Elmer ONE FTIR or Bruker ALPHA ECO ATR FTIR spectrometers. 1H and 13C NMR spectra were recorded with a Bruker Avance DPX-400 spectrometer (1H: 400 MHz; 13C: 101 MHz). The chemical shifts are reported in ppm relative to TMS as the internal standard (δ = 0.00) or the residual solvent signal (1H NMR: CDCl3, δ = 7.26; 13C NMR: CDCl3, δ = 77.16). Multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad). HRMS were obtained using a Waters Micromass LCT Premier (ESI) spectrometer.


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(Z)-3-Iodobut-2-enenitrile (1)

To a solution of oxime 9 (0.5 g, 2.4 mmol) in THF (8 mL) cooled to –5 °C under an inert atmosphere was added dropwise SOCl2 (0.26 mL, 3.6 mmol) and the resulting mixture was stirred for 30 min. It was then poured into a saturated aqueous solution of ice-cold NaHCO3 and extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure (140 mbar) without heating. The residue was purified by column chromatography on silica gel (PE/Et2O, 40:1 to 15:1) to give compound 1 (0.36 g, 80%) as a colorless oil.

IR (thin film): 3397, 2975, 2937, 2226, 1614, 1461, 1364, 1272, 1178, 1101, 838, 793 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.13 (q, J = 1.6 Hz, 1 H), 2.68 (d, J = 1.6 Hz, 3 H).

13C NMR (101 MHz, CDCl3): δ = 122.84, 118.21, 110.28, 34.72.

HRMS (ESI): m/z [M + Na]+ calcd for C4H4NNaI: 215.9286; found: 215.9283.


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(E)-3-(Tributylstannyl)prop-2-en-1-ol (2)

Stannylcupration of propargylic alcohol (3) with in situ generated Bu3Sn(Bu)CuCNLi2 was performed according to the reported procedure.[29]


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(Z)-3-Iodobut-2-en-1-ol (7)

A solution of Red-Al® (65% in toluene, 9 mL, ≈ 3.5 M, 31.5 mmol) was added dropwise over 1 h to a solution of 2-butyn-1-ol (6) (1.59 g, 22.7 mmol) in dry Et2O (35 mL) at 0 °C under an inert atmosphere. The reaction mixture was allowed to warm slowly to r.t. and was stirred at ambient temperature overnight. After the starting material had been completely consumed (TLC monitoring), the mixture was cooled to 0 °C and EtOAc (1.8 mL) was added dropwise. The mixture was then cooled to –78 °C and a solution of I2 (8.65 g, 34.1 mmol) in THF (25 mL) was added dropwise over 1.5 h. After 30 min, the cooling bath was removed and stirring was continued at r.t. for 1 h. The mixture was then poured into an ice-cold saturated aqueous solution of Na2S2O3 and extracted with Et2O. The combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure (50 mbar) without heating to give 4.5 g (quant.) of crude compound 7 as a colorless oil, which was used in the next step without purification. Pure compound 7 was obtained by column chromatography on silica gel (hexane/EtOAc, 5:1). The spectroscopic data are consistent with reported literature data.[49,50]


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(2Z)-3-Iodobut-2-enal Oxime (9)

To a solution of alcohol 7 (4.5 g) in CH2Cl2 (100 mL) was added MnO2 (22 g, 253 mmol) portionwise. When the reaction was complete, the MnO2 was removed by filtration through a pad of Celite® and the pad was rinsed with CH2Cl2. The filtrate was concentrated under reduced pressure (250 mbar) without heating. The residue was dissolved in THF (30 mL) and NH2OH·HCl (1.9 g, 27.3 mmol), H2O (7 mL) and NaHCO3­ (1.9 g, 22.7 mmol) were added portionwise. The reaction mixture was stirred at r.t. for 20 min and then poured into a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2. The combined organic fractions were dried over Na2SO4, filtered, and concentrated under vacuum without heating. The residue was purified by column chromatography on silica gel (hexane/Et2O, 40:1 to 20:1) to give 9 as a slightly yellow solid [4.0 g, 84% from 2-butyn-1-ol (6)]. This compound was very light-sensitive and should be stored in a freezer at –18 °C in the dark.

IR (thin film): 3160, 3042, 2865, 2772, 1633, 1478, 1423, 1309, 1261, 1080, 1015, 974, 934, 839, 726 cm–1.

1H NMR (400 MHz, CDCl3): δ = 9.92 (br s, 1 H), 7.87 (d, J = 9.1 Hz, 0.62 H), 7.20 (d, J = 8.5 Hz, 0.34 H), 6.87 (d, J = 8.5 Hz, 0.34 H), 6.28 (dd, J = 9.1, 1.4 Hz, 0.64 H), 2.71 (d, J = 1.5 Hz, 1.05 H), 2.66 (s, 1.93 H).

13C NMR (101 MHz, CDCl3): δ = 154.96, 150.91, 127.86, 122.84, 113.02, 109.22, 35.33, 34.95.

HRMS (ESI): m/z [M + Na]+ calcd for C4H6NONaI: 233.9392; found: 233.9383.


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(2Z,4E)-6-Hydroxy-3-methylhexa-2,4-dienenitrile (11) (1st Method)

A mixture of iodide 1 (80 mg, 0.4146 mmol), stannyl derivative 2 (140 mg, 0.4146 mmol) and Pd(CH3CN)2Cl2 (11 mg, 0.0414 mmol, 0.1 equiv) in THF (1.5 mL) and DMF (1.5 mL) was heated at 80 °C under argon for 22 h. The reaction mixture was poured into a saturated solution of brine and extracted with EtOAc. The combined organic fractions were dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (hexane/EtOAc, 10:1 to 1:3) to give adduct 11 as a colorless oil (20 mg, 39%).


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(2Z,4E)-6-Hydroxy-3-methylhexa-2,4-dienenitrile (11) (2nd Method)

The adduct 11 was also obtained by a slightly modified procedure.[32] Under argon at 0 °C, DIBAL-H (0.62 mL, 1 M in hexane, 0.62 mmol, 1.5 equiv) was added slowly via syringe to a solution of alcohol 3 (35 mg, 0.62 mmol, 1.5 equiv) in THF (0.3 mL) and the resulting solution was allowed to warm to r.t. and stirred for 1 h. In another flask covered with aluminum foil under argon were added Cp2ZrCl2 (363 mg, 1.24 mmol, 3 equiv) and THF (2 mL). To this mixture was added dropwise DIBAL-H (1.24 mL, 1 M in hexane, 1.24 mmol, 3 equiv) at 0 °C. After 30 min, the pretreated alcohol mixture was transferred via cannula into the second reaction flask and the resulting mixture was stirred at r.t. for 2 h until all the solid had dissolved. Next, a solution of ZnBr2 (280 mg, 1.24 mmol, 3 equiv) in THF (1.5 mL) was added via cannula. After 15 min, a solution of 1 (80 mg, 0.41 mmol, 1 equiv) and Pd(PPh3)4 (48 mg, 0.04 mmol, 0.1 equiv) in THF (0.9 mL) was transferred via cannula and the reaction mixture was left stirring overnight. The mixture was diluted with Et2O and quenched with saturated NH4Cl solution. The mixture was then extracted with Et2O and the combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (PE/Et2O, 30:1 to 1:10) to give 11 as a colorless oil (37 mg, 60%).

IR (thin film): 3412, 2212, 1643, 1585, 1436, 1097, 965 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.86 (dt, J = 15.7, 1.7 Hz, 1 H), 6.27 (dtd, J = 15.7, 5.1, 0.5 Hz, 1 H), 5.20–5.14 (m, 1 H), 4.34 (dd, J = 5.1, 1.3 Hz, 2 H), 2.02 (d, J = 1.4 Hz, 3 H).

13C NMR (101 MHz, CDCl3): δ = 156.06, 137.92, 127.44, 116.80, 96.53, 62.84, 19.61.

HRMS (ESI): m/z [M + Na]+ calcd for C7H9NONa: 146.0582; found: 146.0582.


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(2Z,4E)-3-Methyl-6-oxohexa-2,4-dienenitrile (12) (1st Method)

To a solution of alcohol 11 (18 mg, 0.15 mmol, 1 equiv) in CH2Cl2 (1 mL) was added MnO2 (190 mg, 2.19 mmol, 15 equiv) portionwise and the resulting mixture was stirred at r.t. When the reaction was complete, MnO2 was removed by filtration through a pad of Celite® and the pad was rinsed with CH2Cl2. The filtrate was concentrated under vacuum to give 12 as a colorless oil (16 mg, 90%).


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(2Z,4E)-3-Methyl-6-oxohexa-2,4-dienenitrile (12) (2nd Method)

To a solution of 1 (97 mg, 0.50 mmol, 1 equiv) in MeCN (2 mL) covered with aluminum foil were added acrolein (4) (0.33 ml, 5.03 mmol, 10 equiv), Pd(OAc)2 (6 mg, 0.025 mmol, 5 mol%) and AgOAc (100 mg, 0.60 mmol, 1.2 equiv) and reaction mixture was stirred under argon in the dark for 48 h at r.t. The mixture was filtered through a pad of SiO2, the pad was rinsed with Et2O and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on SiO2 (hexane/Et2O, 15:1 to 1:1) to give 12 (52 mg, 85%).

IR (thin film): 2217, 1682, 1132, 985, 862 cm–1.

1H NMR (400 MHz, CDCl3): δ = 9.77 (d, J = 7.6 Hz, 1 H), 7.63 (dd, J = 15.9, 0.5 Hz, 1 H), 6.43 (ddd, J = 15.8, 7.6, 0.4 Hz, 1 H), 5.56–5.57 (m, 1 H), 2.13 (d, J = 1.5 Hz, 3 H).

13C NMR (101 MHz, CDCl3): δ = 193.26, 153.77, 146.04, 134.39, 115.47, 104.55, 19.36.

HRMS (ESI): m/z [M + Na]+ calcd for C7H7NONa: 144.0425; found: 144.0422.


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(2Z,4E)-7,7-Dibromo-3-methylhepta-2,4,6-trienenitrile (14)

To a solution of Ph3P (2.2 g, 8.59 mmol, 8 equiv) in dry CH2Cl2 (20 mL) cooled to 0 °C under an inert atmosphere was added a solution of CBr4 (306 mg, 4.29 mmol, 4 equiv) in dry CH2Cl2 (5 mL). After 10 min, the mixture turned yellow and was cooled to –50 °C. A solution of aldehyde 12 (130 mg, 1.07 mmol, 1 equiv) in dry CH2Cl2 (1 mL) was added dropwise at the same temperature. The mixture was then allowed to warm to r.t. over 2 h until the reaction was complete. Hexane was added and the obtained precipitate was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified by column chromatography on silica gel (hexane) to give dibromide 14 (180 mg, 61%) as a white solid.

IR (thin film): 2211, 1603, 1548, 1440, 1354, 1211, 962, 806 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.13 (dd, J = 10.4, 0.6 Hz, 1 H), 6.94 (d, J = 15.4 Hz, 1 H), 6.58 (ddd, J = 15.3, 10.4, 0.4 Hz, 1 H), 5.29 (d, J = 0.5 Hz, 1 H), 2.08 (d, J = 1.2 Hz, 3 H).

13C NMR (101 MHz, CDCl3): δ = 155.43, 136.30, 132.47, 131.87, 116.69, 98.91, 97.29, 19.28.

HRMS (ESI): m/z [M + Na]+ calcd for C8H7NNaBr2: 297.8843; found: 297.8854.


#

(E)-tert-Butyl[(3-iodobut-2-en-1-yl)oxy]dimethylsilane (15)

To a solution of iodide 21 (156 mg, 0.79 mmol, 1 equiv) in dry CH2Cl2 (3 mL) at –78 °C were added dropwise t-BuMe2SiOTf (0.27 mL, 1.18 mmol, 1.5 equiv) and 2,6-lutidine (0.27 mL, 1.18 mmol, 3 equiv) and the resulting mixture was stirred for 1 h. The reaction was quenched with saturated NaHCO3 solution, allowed to warm to r.t. and extracted with CH2Cl2. The combined organic fractions were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/Et2O, 30:1) to give 15 (236 mg, 96%) as a colorless oil.

1H NMR (400 MHz, CDCl3): δ = 6.30 (tq, J = 6.5, 1.5 Hz, 1 H), 4.12 (ddd, J = 6.5, 1.8, 0.8 Hz, 2 H), 2.41 (dt, J = 1.6, 0.9 Hz, 3 H), 0.90 (s, 9 H), 0.07 (s, 6 H).

13C NMR (101 MHz, CDCl3): δ = 140.80, 96.14, 60.82, 28.23, 26.03, 18.49, –5.06.

The data are consistent with those reported in the literature.[51]

(Z)-3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)but-2-en-1-ol (16)

The product 16 (0.5 g, 69% yield) was obtained from 2-butyn-1-ol (6) (253 mg, 3.58 mmol) according to the literature procedure.[46]


#

(2Z,4E,6Z,8E)-7-Bromo-10-hydroxy-3,8-dimethyldeca-2,4,6,8-tetraenenitrile (17)

To a solution of 16 (56 mg, 0.28 mmol, 1.1 equiv) in degassed THF (0.45 mL) under an argon atmosphere was added TlOEt (0.018 mL, 0.25 mmol, 1 equiv) followed by H2O (0.04 mL) and the resulting mixture was stirred at r.t. for 5 min. A solution of 14 (70 mg, 0.25 mmol, 1 equiv) and Pd(PPh3)4 (15 mg, 0.013 mmol, 0.05 equiv) in THF (1 mL) was added and the mixture was stirred at r.t. for 4 h. After filtration through a pad of Celite® and Na2SO4, the filtrate was concentrated under vacuum and the residue purified by column chromatography on SiO2 (hexane/Et2O, 60:1 to 2:1) to give: (1) dibromide 14 (22 mg, 31%), and (2) adduct 17 (43 mg, 63%), which was isolated crude and used in the next step without purification.


#

(2Z,4E,6Z,8E)-7-Bromo-10-[(tert-butyldimethylsilyl)oxy]-3,8-dimethyldeca-2,4,6,8-tetraenenitrile (18) and (2Z,4Z,6E)-6-Bromo-8-{[(tert-butyldimethylsilyl)oxy]methyl}-2,7-dimethylcycloocta-2,4,6-triene-1-carbonitrile (19)

A solution of 17 (40 mg, 0.15 mmol, 1 equiv) in CH2Cl2 (1.5 mL) was cooled to –85 °C under an argon atmosphere and 2,6-lutidine (0.05 mL, 0.45 mmol, 3 equiv) was added, followed by the addition of t-BuMe2SiOTf (0.05 mL, 0.22 mmol, 1.5 equiv). The mixture was stirred at this temperature for 1 h and then quenched by the addition of brine. The mixture was allowed to warm to r.t. and then extracted with Et2O, dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (hexane/Et2O, 100:1 to 35:1) to give tetraenenitrile 18 (52 mg, 91%) and cyclized compound 19 (5 mg, 8%).


#

Compound 18

IR (thin film): 2952, 2929, 2884, 2856, 2209, 1595, 1253, 1105, 1070, 834, 769 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.04 (dt, J = 29.7, 12.5 Hz, 2 H), 6.71 (d, J = 9.7 Hz, 1 H), 6.31 (t, J = 5.6 Hz, 1 H), 5.20 (d, J = 1.1 Hz, 1 H), 4.40 (d, J = 5.9 Hz, 2 H), 2.10 (d, J = 1.4 Hz, 3 H), 1.92 (d, J = 0.9 Hz, 3 H), 0.91 (s, 9 H), 0.09 (s, 6 H).

13C NMR (101 MHz, CDCl3): δ = 156.17, 136.57, 135.30, 134.05, 132.80, 132.13, 127.02, 117.05, 97.39, 61.13, 26.05, 19.39, 18.47, 15.39, –5.01.

HRMS (ESI): m/z [M + Na]+ calcd for C18H28NONaSiBr: 404.1021; found: 404.1035.


#

Compound 19

IR (thin film): 2954, 2929, 2885, 2857, 1471, 1256, 1100, 837, 778 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.65 (dd, J = 14.1, 11.2 Hz, 1 H), 6.28 (d, J = 14.0 Hz, 1 H), 6.04 (d, J = 11.1 Hz, 1 H), 4.02 (t, J = 9.8 Hz, 1 H), 3.94 (dd, J = 10.1, 5.1 Hz, 1 H), 3.79–3.68 (m, 2 H), 2.00 (s, 6 H), 0.93 (s, 9 H), 0.14 (s, 3 H), 0.13 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 133.75, 132.28, 131.59, 130.21, 128.69, 127.06, 119.46, 62.33, 50.93, 39.44, 25.99, 19.65, 18.38, 17.21, –5.19, –5.25.

HRMS (ESI): m/z [M + Na]+ calcd for C18H28NONaSiBr: 404.1021; found: 404.1031.


#

(2Z,4E,6E,8E)-10-[(tert-Butyldimethylsilyl)oxy]-3,7,8-trimethyldeca-2,4,6,8-tetraenenitrile (20)

To solution of Pd(t-Bu3P)2 (4 mg, 0.008 mmol, 0.1 equiv) in THF (0.4 mL) at 0 °C was added ZnMe2 (0.16 mL, 0.32 mL, 4 equiv). The obtained solution was transferred via cannula to neat 18 (31 mg, 0.08 mmol, 1 equiv) which had been cooled to 0 °C under argon. The resulting mixture was stirred at 0 °C for 4 h and then quenched with a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2. The combined organic fractions were dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (hexane/Et2O, 60:1 to 40:1) to give 20 (11 mg, 42%).

IR (thin film): 2954, 2929, 2856, 2209, 1593, 1255, 1094, 1050, 960, 836 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.99 (dd, J = 15.0, 11.0 Hz, 1 H), 6.85 (d, J = 15.0 Hz, 1 H), 6.38 (d, J = 11.0 Hz, 1 H), 5.86 (t, J = 5.6 Hz, 1 H), 5.09 (s, 1 H), 4.40 (d, J = 5.8 Hz, 2 H), 2.07 (d, J = 1.3 Hz, 3 H), 2.02 (s, 3 H), 1.84 (d, J = 0.8 Hz, 3 H), 0.92 (s, 9 H), 0.09 (s, 6 H).

13C NMR (101 MHz, CDCl3): δ = 156.64, 143.16, 135.98, 133.59, 130.57, 129.45, 125.30, 117.50, 95.44, 61.43, 26.13, 19.57, 18.56, 14.69, 14.31, –4.95.

HRMS (ESI): m/z [M + Na]+ calcd for C19H31NONaSi: 340.2073; found: 340.2077.


#

(E)-3-Iodobut-2-en-1-ol (21)

Under argon at 0 °C, DIBAL-H (4.28 mL, 1 M in hexane, 4.28 mmol, 1 equiv) was added slowly via syringe to a solution of but-2-yn-1-ol (6) (300 mg, 4.28 mmol, 1 equiv) in THF (0.3 mL) and the solution was then allowed to warm to r.t. and stirred for 1 h. To another flask covered with aluminum foil under argon were added Cp2ZrCl2 (2.5 g, 8.56 mmol, 2 equiv) and THF (15 mL). To this suspension was added dropwise DIBAL-H (8.6 mL, 1 M in hexane, 8.6 mmol, 2 equiv) at 0 °C. After 30 min, the pretreated alcohol mixture was transferred via cannula into the second reaction flask and the resulting mixture was stirred at 40 °C for 3.5 h until all the solid had dissolved. Next, the mixture was cooled to 0 °C and treated with a solution of I2 (2.4 g, 9.42 mmol, 2.2 equiv) in THF (5 mL). After stirring at 0 °C for 15 min, the mixture was diluted with Et2O and quenched with saturated Na2S2O3 solution. The mixture was extracted with Et2O and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on SiO2 (hexane/Et2O, 40:1 to 3:1) to give 21 (402 mg, 47%).

1H NMR (400 MHz, CDCl3): δ = 6.44–6.38 (m, 1 H), 4.09 (t, J = 6.0 Hz, 2 H), 2.45 (d, J = 0.7 Hz, 3 H), 1.46 (br s, 1 H).

13C NMR (101 MHz, CDCl3): δ = 139.85, 98.71, 60.10, 28.16.

The data are consistent with those reported in the literature.[52]


#

3-Hydroxy-2-methylpentanal (24)

The product was obtained by the 4-trans-hydroxy-l-proline-catalyzed aldol reaction of propionaldehyde in DMSO at 4 °C.[40]


#

3-[(tert-Butyldimethylsilyl)oxy]-2-methylpentanal (25)

To a solution of aldehyde 24 (0.5 g, 4.3 mmol) and DIPEA (3.2 mL, 18.4 mmol) in dry CH2Cl2 (20 mL) cooled to –5 °C was added t-BuMe2SiOTf (3 mL, 13.1 mmol) dropwise and stirring was continued for 1 h. During this time the temperature rose to 0 °C, and at this point the reaction was quenched with saturated NaHCO3 solution and extracted with CH2Cl2. The combined organic fractions were dried over Na2SO4, filtered, and concentrated under reduced pressure without heating. The residue was purified by column chromatography on silica gel (hexane/Et2O, 40:1 to 16:1) to give 25 (0.97 g, 98%) as a colorless oil.

IR (thin film): 2958, 2931, 2858, 1726, 1463, 1253, 833, 773, 668 cm–1.

1H NMR (400 MHz, CDCl3): δ = 9.74 (dd, J = 7.3, 1.7 Hz, 1 H), 4.02 (td, J = 6.6, 3.7 Hz, 0.5 H), 3.85 (q, J = 5.5 Hz, 0.5 H), 2.55–2.40 (m, 1 H), 1.63–1.42 (m, 2 H), 1.05 (d, J = 7.0 Hz, 1.5 H), 1.04 (d, J = 6.9 Hz, 1.5 H), 0.92–0.87 (m, 3 H), 0.86 (s, 4.5 H), 0.85 (s, 4.5 H), 0.05 (s, 3 H), 0.04 (s, 1.5 H), 0.02 (s, 1.5 H).

13C NMR (101 MHz, CDCl3): δ = 205.50, 205.27, 74.65, 73.49, 50.93, 50.71, 27.58, 27.53, 25.89, 25.88, 18.16, 18.14, 10.61, 10.22, 9.03, 7.66, –4.11, –4.16, –4.68.


#

tert-Butyl[(6,6-dibromo-4-methylhex-5-en-3-yl)oxy]dimethylsilane (anti-26) and tert-Butyl[(6,6-dibromo-4-methylhex-5-en-3-yl)oxy]dimethylsilane (syn-27)

To a solution of Ph3P (11.4 g, 43.4 mmol) in dry CH2Cl2 (40 mL) cooled to –15 °C under an inert atmosphere was added a solution of CBr4 (1.55 g, 21.7 mmol, 5.6 equiv) in dry CH2Cl2 (5 mL). After 5 min, the reaction mixture turned yellow and a solution of aldehyde 25 (0.9 g, 3.9 mmol) in dry CH2Cl2 (5 mL) was added dropwise. Over the next 2 h the mixture was allowed to warm to r.t. until the reaction was complete. Hexane was added and the obtained precipitate was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified by column chromatography on silica gel (hexane) to give a mixture of two diastereomers 26 and 27 (1.00 g, 67%) as a colorless oil. These two diastereomers were partly separated by consecutive column chromatography on silica gel (hexane) to give the individual diastereomers.


#

anti-26

IR (thin film): 2958, 2930, 2857, 1461, 1255, 1109, 1079, 1038, 872, 834, 773 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.37 (d, J = 9.5 Hz, 1 H), 3.49 (ddd, J = 6.7, 5.9, 3.5 Hz, 1 H), 2.61 (m, 1 H), 1.51–1.31 (m, 2 H), 1.01 (d, J = 6.9 Hz, 3 H), 0.90 (s, 9 H), 0.87 (t, J = 7.5 Hz, 3 H), 0.06 (s, 3 H), 0.05 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 140.96, 88.04, 76.27, 42.86, 28.14, 26.05, 18.25, 15.97, 10.01, –4.06, –4.38.

HRMS (ESI): m/z [M + Na]+ calcd for C13H26ONaSiBr2: 407.0017; found: 407.0003.


#

syn-27

IR (thin film): 2957, 2929, 2857, 1462, 1377, 1255, 1014, 873, 833, 773.

1H NMR (400 MHz, CDCl3): δ = 6.32 (d, J = 9.5 Hz,1 H), 3.56 (dd, J = 11.1, 5.5 Hz, 1 H), 2.64–2.49 (m, 1 H), 1.58–1.37 (m, 2 H), 0.97 (d, J = 6.8 Hz, 3 H), 0.90 (s, 9 H), 0.88 (m, 3 H), 0.05 (s, 3 H), 0.05 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 142.65, 87.58, 75.45, 42.37, 27.64, 26.03, 18.27, 13.25, 9.63, –4.09, –4.50.

HRMS (ESI): m/z [M + Na]+ calcd for C13H26ONaSiBr2: 407.0017; found: 407.0000.


#

tert-Butyldimethyl{[(3S,4R)-4-methylhept-5-yn-3-yl]oxy}silane (28)

To a solution of dibromide 26 (0.4 g, 1.0 mmol) in THF (5 mL) at –78 °C was added n-BuLi (1.66 mL, 2 M in hexane, 3.3 mmol, 3.3 equiv) dropwise. The reaction mixture was allowed to warm to –50 °C over 20 min at which point TLC indicated that no dibromide 26 remained. The mixture was cooled to –78 °C and MeI (0.2 mL, 3.1 mmol, 3.1 equiv) was added dropwise. The mixture was allowed to warm to –45 °C over 15 min at which point the reaction was complete. The cooling bath was removed and the mixture was allowed to warm to r.t., poured into saturated NH4Cl solution and extracted with CH2Cl2. The combined organic fractions were dried over Na2SO4, filtered, and concentrated under reduced pressure without heating. The residue was purified by column chromatography on silica gel (PE/Et2O, 90:1) to give 28 (230 mg, 92%).

IR (thin film): 2958, 2930, 2857, 1253, 1107, 1063, 871, 832, 771 cm–1.

1H NMR (400 MHz, CDCl3): δ = 3.56 (dt, J = 8.2, 4.1 Hz, 1 H), 2.49–2.57 (m, 1 H), 1.78 (d, J = 2.4 Hz, 3 H), 1.72–1.60 (m, 1 H), 1.47–1.35 (m, 1 H), 1.08 (d, J = 7.1 Hz, 3 H), 0.95–0.84 (m, 12 H), 0.05 (s, 6 H).

13C NMR (101 MHz, CDCl3): δ = 81.79, 76.82, 76.35, 32.25, 26.02, 25.61, 18.28, 15.30, 10.63, 3.70, –4.35.

HRMS (ESI): m/z [M + Na]+ calcd for C14H28ONaSi: 263.1807; found: 263.1795.


#

tert-Butyl{[(3S,4R,E)-6-iodo-4-methylhept-5-en-3-yl]oxy}dimethylsilane (29)

Under argon at 0 °C, DIBAL-H (0.07 mL, 1 M in cyclohexane, 0.07 mmol, 0.3 equiv) was added slowly via syringe to a solution of 28 (60 mg, 0.25 mmol, 1 equiv) in THF (1 mL). The solution was allowed to warm to r.t. and stirred for 1 h. To another flask covered with aluminum foil under argon were added Cp2ZrCl2 (182 mg, 0.62 mmol, 2.5 equiv) and THF (1.5 mL). To this suspension was added dropwise DIBAL-H (0.62 mL, 1 M in cyclohexane, 0.62 mmol, 2.5 equiv) at 0 °C. After 50 min, the pretreated solution of 28 was transferred via cannula into the second reaction flask, the cooling bath was removed and the mixture was allowed to warm to r.t. and then stirred at 40 °C for 1 h until all the solid had dissolved. The mixture was cooled to –78 °C and treated with a solution of I2 (158 mg, 0.62 mmol, 2.5 equiv) in THF (1 mL) until the iodine color was persistent. After 5 min, the cooling bath was removed, and the mixture was allowed to warm to r.t. and then quenched with a minimum amount of aqueous Na2S2O3 solution, dried over Na2SO4 and filtered through a Celite® pad. The pad was rinsed with Et2O and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel (hexane) to give 29 (60 mg, 65%) as a colorless oil.

IR (thin film): 2958, 2929, 2856, 1377, 1251, 1023, 1005, 832, 772 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.07 (d, J = 10.0 Hz, 1 H), 3.37–3.45 (m, 1 H), 2.57–2.46 (m, 1 H), 2.38 (d, J = 1.4 Hz, 3 H), 1.50–1.37 (m, 2 H), 0.94 (d, J = 6.9 Hz, 3 H), 0.89 (s, 9 H), 0.84 (t, J = 7.4 Hz, 3 H), 0.05 (s, 3 H), 0.04 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 144.09, 93.64, 76.49, 40.12, 28.01, 27.28, 26.06, 18.24, 16.60, 9.61, –4.15, –4.26.

HRMS (ESI): m/z [M + Na]+ calcd for C14H29ONaSiI: 391.0930; found: 391.0919.


#

(2E,4E,6R,7S)-7-[(tert-Butyldimethylsilyl)oxy]-3,4,6-trimethylnona-2,4-dien-1-ol (38)

To a solution of boronic ether 16 (163 mg, 0.81 mmol, 2 equiv) in THF (1.5 mL) under argon was added TlOEt (0.05 mL, 0.73 mmol, 1.8 equiv) and degassed H2O (0.15 mL) at r.t. and the resulting mixture was stirred for 5 min. To this mixture were added a solution of iodide 29 (150 mg, 0.41 mmol, 1 equiv) in THF (0.6 mL) and Pd(PPh3)4 (23 mg, 0.02 mmol, 0.05 equiv) and stirring was continued for 4 h. The mixture was filtered through Celite® and the pad rinsed with Et2O. The filtrate was concentrated under vacuum and the residue purified by column chromatography on silica gel (hexane/Et2O, 30:1 to 6:1) to give adduct 38 (161 mg, 95%) as a colorless oil.

IR (thin film): 3314, 2957, 2929, 2857, 1462, 1377, 1254, 1102, 1073, 1060, 1006, 835, 773 cm–1.

1H NMR (400 MHz, CDCl3): δ = 5.70 (t, J = 6.3 Hz, 1 H), 5.59 (d, J = 9.5 Hz, 1 H), 4.31 (t, J = 6.0 Hz, 2 H), 3.47 (td, J = 6.1, 3.9 Hz, 1 H), 2.64 (dqd, J = 13.6, 6.8, 3.9 Hz, 1 H), 1.83 (s, 3 H), 1.81 (d, J = 1.1 Hz, 3 H), 1.32–1.50 (m, 2 H), 1.22 (t, J = 5.5 Hz, 1 H), 0.97 (d, J = 6.9 Hz, 3 H), 0.90 (s, 9 H), 0.84 (t, J = 7.4 Hz, 3 H), 0.04 (s, 6 H).

13C NMR (101 MHz, CDCl3): δ = 139.64, 135.02, 130.75, 124.05, 77.36, 60.29, 37.74, 27.24, 26.07, 18.28, 16.98, 14.40, 14.27, 10.27, –4.09, –4.32.

HRMS (ESI): m/z [M + Na]+ calcd for C18H36O2NaSi: 335.2382; found: 335.2377.


#

(2E,4E,6R,7S)-7-[(tert-Butyldimethylsilyl)oxy]-3,4,6-trimethylnona-2,4-dienal (39)

To a solution of alcohol 38 (96 mg, 0.31 mmol) in CH2Cl2 (15 mL) was added MnO2 (0.5 g, 6.15 mmol, 20 equiv) portionwise. The reaction was complete after stirring at r.t. for 1 h. The MnO2 was removed by filtration through a pad of Celite® and the pad was rinsed with CH2Cl2. The filtrate was concentrated under reduced pressure and the obtained aldehyde 39 (91 mg, 96%) was used in the next step without purification.

IR (thin film): 2958, 2930, 2857, 1667, 1462, 1378, 1253, 1154, 1078, 1031, 836, 774 cm–1.

1H NMR (400 MHz, CDCl3): δ = 10.15 (d, J = 7.9 Hz, 1 H), 6.11 (dd, J = 27.0, 8.4 Hz, 2 H), 3.51 (td, J = 6.0, 3.9 Hz, 1 H), 2.71 (dqd, J = 13.6, 6.8, 3.8 Hz, 1 H), 2.30 (d, J = 0.8 Hz, 3 H), 1.85 (d, J = 1.1 Hz, 3 H), 1.54–1.29 (m, 2 H), 1.00 (d, J = 6.9 Hz, 3 H), 0.89 (s, 9 H), 0.84 (t, J = 7.5 Hz, 3 H), 0.04 (d, J = 3.0 Hz, 6 H).

13C NMR (101 MHz, CDCl3): δ = 192.36, 158.48, 138.31, 135.10, 125.68, 77.11, 37.90, 27.95, 26.02, 18.23, 17.10, 14.43, 14.28, 9.88, –4.05, –4.39.


#

tert-Butyldimethyl{[(3S,4R,5E,7E)-4,6,7-trimethyldeca-5,7,9-trien-3-yl]oxy}silane (40)

To a solution of Ph3PCH3I (250 mg, 0.61 mmol, 2 equiv) in THF (2 mL) at 0 °C under argon was added NaN(SiMe3)2 (0.55 mL, 1 M in THF, 0.55 mmol, 1.8 equiv). After stirring for 20 min, a solution of aldehyde 39 (91 mg, 0.31 mmol, 1 equiv) in THF (1 mL) was added to the obtained yellow solution and stirring was continued for 2 h. After the reaction was complete, it was quenched by the addition of hexane and evaporated under vacuum until dry. The residue was purified by column chromatography on silica gel (hexane/Et2O, 90:1) to give adduct 40 (76 mg, 84%) as a colorless oil.

IR (thin film): 2957, 2929, 2857, 1462, 1378, 1252, 1102, 1059, 1005, 833, 772 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.74 (ddd, J = 16.7, 10.9, 10.1 Hz, 1 H), 6.18 (d, J = 11.0 Hz, 1 H), 5.68–5.60 (m, 1 H), 5.23 (dd, J = 16.7, 1.8 Hz, 1 H), 5.09 (dd, J = 10.1, 1.9 Hz, 1 H), 3.48 (td, J = 6.1, 3.9 Hz, 1 H), 2.66 (dqd, J = 13.6, 6.8, 3.9 Hz, 1 H), 1.92 (s, 3 H), 1.84 (d, J = 1.1 Hz, 3 H), 1.50–1.33 (m, 2 H), 0.97 (d, J = 6.8 Hz, 3 H), 0.90 (s, 9 H), 0.84 (t, J = 7.4 Hz, 3 H), 0.05 (d, J = 1.0 Hz, 6 H).

13C NMR (101 MHz, CDCl3): δ = 138.79, 135.34, 134.19, 131.25, 125.58, 116.56, 77.40, 37.92, 27.23, 26.07, 18.29, 16.98, 14.41, 14.36, 10.27, –4.09, –4.31.

HRMS (ESI): m/z [M + Na]+ calcd for C19H36ONaSi: 331.2433; found: 331.2448.


#

tert-Butyldimethyl{[(3S,4R,5E,7E,9E)-4,6,7-trimethyl-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)deca-5,7,9-trien-3-yl]oxy}silane (45)

A mixture of 40 (54 mg, 0.17 mmol, 1 equiv), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.059 mL, 0.35 mmol, 2 equiv) and Hoveyda–Grubbs 1st generation catalyst (16 mg, 0.03 mmol, 0.15 equiv) in CH2Cl2 (0.7 mL) was heated at 35–40 °C with stirring under argon for 3 h. After completion, the reaction was loaded onto a silica gel column and eluted with hexane/Et2O (50:1 to 35:1) to give adduct 45 (55 mg, 72%).

IR (thin film): 2976, 2958, 2930, 2857, 1606, 1379, 1350, 1257, 1143, 850 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.43 (dd, J = 17.3, 11.0 Hz, 1 H), 6.24 (d, J = 10.9 Hz, 1 H), 5.71 (d, J = 9.0 Hz, 1 H), 5.56 (d, J = 17.3 Hz, 1 H), 3.48 (td, J = 5.9, 4.1 Hz, 1 H), 2.67 (dqd, J = 13.6, 6.8, 4.1 Hz, 1 H), 1.99 (d, J = 0.6 Hz, 3 H), 1.83 (d, J = 1.0 Hz, 3 H), 1.41 (m, 2 H), 1.28 (s, 12 H), 0.97 (d, J = 6.8 Hz, 3 H), 0.89 (s, 9 H), 0.84 (t, J = 7.4 Hz, 3 H), 0.04 (s, 6 H).

13C NMR (101 MHz, CDCl3): δ = 146.75, 142.34, 135.50, 132.72, 127.13, 83.20, 77.32, 38.00, 27.25, 26.06, 24.92, 18.27, 16.92, 14.81, 14.41, 10.16, –4.10, –4.32.

HRMS (ESI): m/z [M + Na]+ calcd for C25H47O3NaSiB: 457.3285; found: 457.3282.


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(2Z,4E,6E,8E,10R,11S)-11-[(tert-Butyldimethylsilyl)oxy]-3,7,8,10-tetramethyltrideca-2,4,6,8-tetraenenitrile (41)

To a solution of boronic ether 45 (27 mg, 0.06 mmol, 1 equiv) in THF (0.9 mL) under argon was added TlOEt (0.01 mL, 0.14 mmol, 2.3 equiv) and degassed H2O (0.09 mL) at r.t. and the mixture stirred for 5 min. Next, a solution of iodide 1 (16 mg, 0.08 mmol, 1.4 equiv) in THF (1 mL) and Pd(PPh3)4 (7 mg, 0.006 mmol, 0.1 equiv) were added and stirring was continued for 1 h. The reaction mixture was filtered through Celite® and the pad was rinsed with Et2O. The filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel (hexane/Et2O, 100:1 to 80:1) to give adduct 41 (15 mg, 67%) as a colorless oil.

IR (thin film): 2957, 2929, 2856, 2209, 1591, 1378, 1360, 1252, 1078, 1029, 961, 835, 773 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.00 (dd, J = 15.0, 11.1 Hz, 1 H), 6.84 (d, J = 15.0 Hz, 1 H), 6.35 (d, J = 11.1 Hz, 1 H), 5.79 (d, J = 9.5 Hz, 1 H), 5.07 (s, 1 H), 3.50 (td, J = 6.0, 3.9 Hz, 1 H), 2.69 (dqd, J = 13.6, 6.8, 3.9 Hz, 1 H), 2.07 (d, J = 1.3 Hz, 3 H), 2.00 (s, 3 H), 1.87 (d, J = 1.0 Hz, 3 H), 1.33–1.51 (m, 2 H), 0.99 (d, J = 6.8 Hz, 3 H), 0.90 (s, 9 H), 0.85 (t, J = 7.4 Hz, 3 H), 0.05 (s, 6 H).

13C NMR (101 MHz, CDCl3): δ = 156.82, 144.25, 135.41, 133.96, 133.73, 128.79, 124.49, 117.63, 94.91, 77.32, 38.02, 27.50, 26.06, 19.59, 18.28, 17.09, 14.78, 14.40, 10.13, –4.07, –4.32.

HRMS (ESI): m/z [M + Na]+ calcd for C23H39NONaSi: 396.2699; found: 396.2695.


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Acknowledgment

The authors would like to acknowledge Tiia Seppä for HRMS measurements.

Supporting Information

  • References

    • 1a Kato Y, Fusetani N, Matsunaga S, Hashimoto K. J. Am. Chem. Soc. 1986; 108: 2780
    • 1b Kato Y, Fusetani N, Matsunaga S, Hashimoto K, Koseki K. J. Org. Chem. 1988; 53: 3930
    • 1c Calyculins E–H: Matsunaga S, Fujiki H, Sakata D, Fusetani N. Tetrahedron 1991; 47: 2999
  • 2 Dumdei EJ, Blunt JW, Munro MH. G, Pannell LK. J. Org. Chem. 1997; 62: 2636
  • 3 Matsunaga S, Wakimoto T, Fusetani N. J. Org. Chem. 1997; 62: 2640
  • 4 Matsunaga S, Wakimoto T, Fusetani N, Suganuma M. Tetrahedron Lett. 1997; 38: 3763
  • 5 Steube KG, Meyer C, Proksch P, Supriyono A, Sumaryono W, Drexler HG. Anticancer Res. 1998; 18: 129
  • 6 Fu X, Schmitz FJ, Kelly-Borges M, McCready TL, Holmes CF. B. J. Org. Chem. 1998; 63: 7957
  • 7 Wakimoto T, Egami Y, Abe I. Nat. Prod. Rep. 2016; 33: 751
  • 8 Fagerholm AE, Habrant D, Koskinen AM.P. Mar. Drugs 2010; 8: 122
  • 9 Evans DA, Gage JR, Leighton JL. J. Am. Chem. Soc. 1992; 114: 9434
  • 10 Tanimoto N, Gerritz SW, Sawabe A, Noda T, Filla SA, Masamune S. Angew. Chem., Int. Ed. Engl. 1994; 33: 673
  • 11 Yokokawa F, Hamada Y, Shioiri T. Chem. Commun. 1996; 871
  • 12 Smith AB. III, Friestad GK, Duan JJ.-W, Barbosa J, Hull KG, Iwashima M, Qiu Y, Spoors PG, Bertounesque E, Salvatore BA. J. Org. Chem. 1998; 63: 7596
  • 13 Ogawa AK, Armstrong RW. J. Am. Chem. Soc. 1998; 121: 12435
  • 14 Anderson OP, Barrett AG. M, Edmunds JJ, Hachiya S.-I, Hendrix JA, Horita K, Malecha JW, Parkinson CJ, VanSickle A. Can. J. Chem. 2001; 79: 1562

    • Fragment A:
    • 15a Koskinen AM.P, Chen J. Tetrahedron Lett. 1991; 32: 6977
    • 15b Passiniemi M, Koskinen AM. P. Synthesis 2010; 2816

    • Fragment B:
    • 15c Koskinen AM.P, Pihko PM. Tetrahedron Lett. 1994; 35: 7417
    • 15d Pihko PM, Koskinen AM. P. J. Org. Chem. 1998; 63: 92

    • Fragment C:
    • 15e Habrant D, Koskinen AM. P. Org. Biomol. Chem. 2010; 8: 4364
  • 16 Pihko PM, Koskinen AM. P. Synlett 1999; 1966
  • 17 Barrett AG. M, Edmunds JJ, Hendrix JA, Horita K, Parkinson CJ. J. Chem. Soc., Chem. Commun. 1992; 1238
    • 18a Yokokawa F, Hamada Y, Shioiri T. Tetrahedron Lett. 1993; 34: 6559
    • 18b Matsubara J, Nakao K, Shioiri T. Tetrahedron Lett. 1992; 33: 4187
  • 19 Scarlato GR, DeMattei JA, Chong LS, Ogawa AK, Lin MR, Armstrong RW. J. Org. Chem. 1996; 61: 6139
  • 20 Negishi E. Bull. Chem. Soc. Jpn. 2007; 80: 233
  • 21 Ronson TO, Taylor RJ. K, Fairlamb IJ. S. Tetrahedron 2015; 71: 989
  • 22 Heravi MM, Hashemi E, Azimian F. Tetrahedron 2014; 70: 7
  • 23 Heravi MM, Hashemi E. Tetrahedron 2012; 68: 9145
  • 24 Kosugi M, Fugami K. J. Organomet. Chem. 2002; 653: 50
  • 25 Negishi E. Angew. Chem. Int. Ed. 2011; 50: 6738
  • 26 Beletskaya IP, Cheprakov AV. Chem. Rev. 2000; 100: 3009
  • 27 Miyaura N, Yamada K, Suzuki A. Tetrahedron Lett. 1979; 20: 3437
  • 28 Corey EJ, Katzenellenbogen JA, Posner GH. J. Am. Chem. Soc. 1967; 89: 4245
  • 29 Betzer J.-F, Delaloge F, Muller B, Pancrazi A, Prunet J. J. Org. Chem. 1997; 62: 7768
  • 30 Jung ME, Light LA. Tetrahedron Lett. 1982; 23: 3851
  • 31 Zhang HX, Guibe F, Balavoine G. J. Org. Chem. 1990; 55: 1857
  • 32 Huang Z, Negishi E. Org. Lett. 2006; 8: 3675
    • 33a Cornil J, Echeverria P.-G, Phansavath P, Ratovelomanana-Vidal V, Guérinot A, Cossy J. Org. Lett. 2015; 17: 948
    • 33b Madden KS, David S, Knowles JP, Whiting A. Chem. Commun. 2015; 51: 11409
    • 33c Jeffery T. Tetrahedron Lett. 1985; 26: 2667
  • 34 Desai NB, McKelvie N, Ramirez F. J. Am. Chem. Soc. 1962; 84: 1745
  • 35 Roush WR, Moriarty KJ, Brown BB. Tetrahedron Lett. 1990; 31: 6509
  • 36 Kim K, Lauher JW, Parker KA. Org. Lett. 2012; 14: 138
  • 37 Sofiyev V, Navarro G, Trauner D. Org. Lett. 2008; 10: 149
  • 38 Jacobsen MF, Moses JE, Adlington RM, Baldwin JE. Tetrahedron 2006; 62: 1675
  • 39 Zeng X, Qian M, Hu Q, Negishi E. Angew. Chem. Int. Ed. 2004; 43: 2259
  • 40 Källström S, Erkkilä A, Pihko PM, Sjöholm R, Sillanpää R, Leino R. Synlett 2005; 751
  • 41 Corey EJ, Fuchs PL. Tetrahedron Lett. 1972; 13: 3769
  • 42 Hart DW, Blackburn TF, Schwartz J. J. Am. Chem. Soc. 1975; 97: 679
  • 43 Dale JA, Dull DL, Mosher HS. J. Org. Chem. 1969; 34: 2543
  • 44 Ward DE, Rhee CK. Tetrahedron Lett. 1991; 32: 7165
    • 45a Crossman JS, Perkins MV. J. Org. Chem. 2006; 71: 117
    • 45b Brown HC, Bhat KS. J. Am. Chem. Soc. 1986; 108: 5919
    • 45c Kalaitzakis D, Smonou I. Eur. J. Org. Chem. 2012; 43
  • 46 Moure AL, Gómez Arrayás R, Cárdenas DJ, Alonso I, Carretero JC. J. Am. Chem. Soc. 2012; 134: 7219
  • 47 Mitsudo T, Fischetti W, Heck RF. J. Org. Chem. 1984; 49: 1640
  • 48 Okada A, Watanabe K, Umeda K, Miyakado M. Agric. Biol. Chem. 1991; 55: 2765
  • 49 Zurwerra D, Gertsch J, Altmann K.-H. Org. Lett. 2010; 12: 2302
  • 50 Yang Q, Draghici C, Njardarson JT, Li F, Smith BR, Das P. Org. Biomol. Chem. 2014; 12: 330
  • 51 Placzek AT, Gibbs RA. Org. Lett. 2011; 13: 3576
  • 52 Paterson I, Anderson EA, Dalby SM, Lim JH, Maltas P, Loiseleur O, Genovino J, Moessner C. Org. Biomol. Chem. 2012; 10: 5861

  • References

    • 1a Kato Y, Fusetani N, Matsunaga S, Hashimoto K. J. Am. Chem. Soc. 1986; 108: 2780
    • 1b Kato Y, Fusetani N, Matsunaga S, Hashimoto K, Koseki K. J. Org. Chem. 1988; 53: 3930
    • 1c Calyculins E–H: Matsunaga S, Fujiki H, Sakata D, Fusetani N. Tetrahedron 1991; 47: 2999
  • 2 Dumdei EJ, Blunt JW, Munro MH. G, Pannell LK. J. Org. Chem. 1997; 62: 2636
  • 3 Matsunaga S, Wakimoto T, Fusetani N. J. Org. Chem. 1997; 62: 2640
  • 4 Matsunaga S, Wakimoto T, Fusetani N, Suganuma M. Tetrahedron Lett. 1997; 38: 3763
  • 5 Steube KG, Meyer C, Proksch P, Supriyono A, Sumaryono W, Drexler HG. Anticancer Res. 1998; 18: 129
  • 6 Fu X, Schmitz FJ, Kelly-Borges M, McCready TL, Holmes CF. B. J. Org. Chem. 1998; 63: 7957
  • 7 Wakimoto T, Egami Y, Abe I. Nat. Prod. Rep. 2016; 33: 751
  • 8 Fagerholm AE, Habrant D, Koskinen AM.P. Mar. Drugs 2010; 8: 122
  • 9 Evans DA, Gage JR, Leighton JL. J. Am. Chem. Soc. 1992; 114: 9434
  • 10 Tanimoto N, Gerritz SW, Sawabe A, Noda T, Filla SA, Masamune S. Angew. Chem., Int. Ed. Engl. 1994; 33: 673
  • 11 Yokokawa F, Hamada Y, Shioiri T. Chem. Commun. 1996; 871
  • 12 Smith AB. III, Friestad GK, Duan JJ.-W, Barbosa J, Hull KG, Iwashima M, Qiu Y, Spoors PG, Bertounesque E, Salvatore BA. J. Org. Chem. 1998; 63: 7596
  • 13 Ogawa AK, Armstrong RW. J. Am. Chem. Soc. 1998; 121: 12435
  • 14 Anderson OP, Barrett AG. M, Edmunds JJ, Hachiya S.-I, Hendrix JA, Horita K, Malecha JW, Parkinson CJ, VanSickle A. Can. J. Chem. 2001; 79: 1562

    • Fragment A:
    • 15a Koskinen AM.P, Chen J. Tetrahedron Lett. 1991; 32: 6977
    • 15b Passiniemi M, Koskinen AM. P. Synthesis 2010; 2816

    • Fragment B:
    • 15c Koskinen AM.P, Pihko PM. Tetrahedron Lett. 1994; 35: 7417
    • 15d Pihko PM, Koskinen AM. P. J. Org. Chem. 1998; 63: 92

    • Fragment C:
    • 15e Habrant D, Koskinen AM. P. Org. Biomol. Chem. 2010; 8: 4364
  • 16 Pihko PM, Koskinen AM. P. Synlett 1999; 1966
  • 17 Barrett AG. M, Edmunds JJ, Hendrix JA, Horita K, Parkinson CJ. J. Chem. Soc., Chem. Commun. 1992; 1238
    • 18a Yokokawa F, Hamada Y, Shioiri T. Tetrahedron Lett. 1993; 34: 6559
    • 18b Matsubara J, Nakao K, Shioiri T. Tetrahedron Lett. 1992; 33: 4187
  • 19 Scarlato GR, DeMattei JA, Chong LS, Ogawa AK, Lin MR, Armstrong RW. J. Org. Chem. 1996; 61: 6139
  • 20 Negishi E. Bull. Chem. Soc. Jpn. 2007; 80: 233
  • 21 Ronson TO, Taylor RJ. K, Fairlamb IJ. S. Tetrahedron 2015; 71: 989
  • 22 Heravi MM, Hashemi E, Azimian F. Tetrahedron 2014; 70: 7
  • 23 Heravi MM, Hashemi E. Tetrahedron 2012; 68: 9145
  • 24 Kosugi M, Fugami K. J. Organomet. Chem. 2002; 653: 50
  • 25 Negishi E. Angew. Chem. Int. Ed. 2011; 50: 6738
  • 26 Beletskaya IP, Cheprakov AV. Chem. Rev. 2000; 100: 3009
  • 27 Miyaura N, Yamada K, Suzuki A. Tetrahedron Lett. 1979; 20: 3437
  • 28 Corey EJ, Katzenellenbogen JA, Posner GH. J. Am. Chem. Soc. 1967; 89: 4245
  • 29 Betzer J.-F, Delaloge F, Muller B, Pancrazi A, Prunet J. J. Org. Chem. 1997; 62: 7768
  • 30 Jung ME, Light LA. Tetrahedron Lett. 1982; 23: 3851
  • 31 Zhang HX, Guibe F, Balavoine G. J. Org. Chem. 1990; 55: 1857
  • 32 Huang Z, Negishi E. Org. Lett. 2006; 8: 3675
    • 33a Cornil J, Echeverria P.-G, Phansavath P, Ratovelomanana-Vidal V, Guérinot A, Cossy J. Org. Lett. 2015; 17: 948
    • 33b Madden KS, David S, Knowles JP, Whiting A. Chem. Commun. 2015; 51: 11409
    • 33c Jeffery T. Tetrahedron Lett. 1985; 26: 2667
  • 34 Desai NB, McKelvie N, Ramirez F. J. Am. Chem. Soc. 1962; 84: 1745
  • 35 Roush WR, Moriarty KJ, Brown BB. Tetrahedron Lett. 1990; 31: 6509
  • 36 Kim K, Lauher JW, Parker KA. Org. Lett. 2012; 14: 138
  • 37 Sofiyev V, Navarro G, Trauner D. Org. Lett. 2008; 10: 149
  • 38 Jacobsen MF, Moses JE, Adlington RM, Baldwin JE. Tetrahedron 2006; 62: 1675
  • 39 Zeng X, Qian M, Hu Q, Negishi E. Angew. Chem. Int. Ed. 2004; 43: 2259
  • 40 Källström S, Erkkilä A, Pihko PM, Sjöholm R, Sillanpää R, Leino R. Synlett 2005; 751
  • 41 Corey EJ, Fuchs PL. Tetrahedron Lett. 1972; 13: 3769
  • 42 Hart DW, Blackburn TF, Schwartz J. J. Am. Chem. Soc. 1975; 97: 679
  • 43 Dale JA, Dull DL, Mosher HS. J. Org. Chem. 1969; 34: 2543
  • 44 Ward DE, Rhee CK. Tetrahedron Lett. 1991; 32: 7165
    • 45a Crossman JS, Perkins MV. J. Org. Chem. 2006; 71: 117
    • 45b Brown HC, Bhat KS. J. Am. Chem. Soc. 1986; 108: 5919
    • 45c Kalaitzakis D, Smonou I. Eur. J. Org. Chem. 2012; 43
  • 46 Moure AL, Gómez Arrayás R, Cárdenas DJ, Alonso I, Carretero JC. J. Am. Chem. Soc. 2012; 134: 7219
  • 47 Mitsudo T, Fischetti W, Heck RF. J. Org. Chem. 1984; 49: 1640
  • 48 Okada A, Watanabe K, Umeda K, Miyakado M. Agric. Biol. Chem. 1991; 55: 2765
  • 49 Zurwerra D, Gertsch J, Altmann K.-H. Org. Lett. 2010; 12: 2302
  • 50 Yang Q, Draghici C, Njardarson JT, Li F, Smith BR, Das P. Org. Biomol. Chem. 2014; 12: 330
  • 51 Placzek AT, Gibbs RA. Org. Lett. 2011; 13: 3576
  • 52 Paterson I, Anderson EA, Dalby SM, Lim JH, Maltas P, Loiseleur O, Genovino J, Moessner C. Org. Biomol. Chem. 2012; 10: 5861

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Scheme 1 Structures and retrosynthesis of calyculins A and C
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Scheme 2 Retrosynthetic analysis of the tetraene fragment D of calyculin C
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Scheme 3 Synthesis of iodonitrile 1 in four steps and 68% overall yield from 2-butyn-1-ol (6)
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Scheme 4 Synthesis of conjugated aldehyde 12 by Stille and Negishi cross-coupling reactions
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Scheme 5 Mizoroki–Heck cross-coupling of iodonitrile 1 with acrolein (4) affording conjugated aldehyde 12
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Scheme 6 Synthesis of tetraene 20 synthesis according to the first strategic plan
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Scheme 7 Synthesis of iodide 15
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Scheme 8 Modified retrosynthetic analysis of tetraene fragment D
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Scheme 9 Synthetic route to 29 representing key compound 5
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Scheme 10 Synthesis of compounds for derivatization with Mosher’s acid chlorides to establish the enantiomeric excesses of their precursors
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Scheme 11 Syntheses of the components for transition-metal-catalyzed cross-coupling reactions with iodide 29
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Scheme 12 Screened conditions for metathesis reactions of 34 with 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane
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Scheme 13 Synthetic route to triene 40
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Scheme 14 Mizoroki–Heck cross-coupling reaction of triene 40 with iodide 1
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Scheme 15 Final steps in the synthesis of tetraene 41 according to the second strategic plan