Total synthesis, stereochemical assignment, and biological evaluation of L-755,807

Tetrahedron 75 (2019) 1085e1097

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Total synthesis, stereochemical assignment, and biological evaluation of L-755,807 Kosaku Tanaka III, Yusuke Honma, Chihiro Yamaguchi, Lina Aoki, Minami Saito, Momoko Suzuki, Kazuhiro Arahata, Kaoru Kinoshita, Kiyotaka Koyama, Kenichi Kobayashi*, Hiroshi Kogen** Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan

a r t i c l e i n f o

a b s t r a c t

Article history: Received 9 November 2018 Received in revised form 10 January 2019 Accepted 10 January 2019 Available online 16 January 2019

The relative and absolute configurations of L-755,807 were established through total synthesis. All four possible stereoisomers were prepared via a convergent synthetic strategy, including a novel diastereoselective Darzens reaction of an a-alkoxy aldehyde with di-tert-butyl bromomalonate, an E-selective HornereWadswortheEmmons reaction, and late-stage coupling of the ring and side-chain segments. Additionally, biological evaluation of the synthesized compounds revealed their potent inhibitory activities (IC50 ¼ 5e21 mM) against amyloid-b aggregation for the treatment of Alzheimer's disease. © 2019 Elsevier Ltd. All rights reserved.

1. Introduction In 1996, ()-L-755,807 (originally proposed structure 1, Fig. 1) was isolated from an endophytic fungus, Microsphaeropsis sp., and reported to display bradykinin B2 receptor antagonist activity with an IC50 of 71 mM [1]. Bradykinin receptor antagonist activity is effective for the treatment of not only inflammatory diseases but also neurodegenerative disorders such as Alzheimer's disease (AD) [2]. In addition, some related natural products containing an epoxyg-lactam ring exhibit a broad range of biological activities, [3e7] which presumably originate from the highly oxygenated ring structure. Therefore, L-755,807 is considered a potential lead compound for natural product drug discovery. L-755,807 (1) structurally consists of a characteristic epoxy-glactam ring and a conjugated tetraene side chain. The ring contains three contiguous chiral centers, and the side chain possesses two chiral centers at C18 and C20 in addition to a trisubstituted C16eC17 olefin moiety. The planar structure of L-755,807 was determined by an extensive NMR study. However, the stereochemistry could be only partially deduced from the NOESY experiment, in which the correlation between H4 and H7/H8 indicated only the relative configuration of the epoxy-g-lactam moiety as

* Corresponding author. ** Corresponding author. E-mail addresses: [email protected] (K. Kobayashi), [email protected] (H. Kogen). https://doi.org/10.1016/j.tet.2019.01.020 0040-4020/© 2019 Elsevier Ltd. All rights reserved.

depicted in Fig. 1 [1]. In addition, the stereochemistries of C18 and C20 in the flexible side chain remained uncertain. Thus, the entire stereostructure should be unambiguously assigned by total synthesis of the natural product. Recently, we accomplished the asymmetric total synthesis of L755,807 (2, revised structure) and its stereoisomers (3, 4, and 5) by means of a novel diastereoselective Darzens reaction, [8] permitting the relative and absolute configurations of natural L-755,807 to be established [9]. In this paper, we report a full account of our synthetic studies on L-755,807. In addition, biological evaluation of the synthetic compounds 2e5 revealed their potent inhibitory activity against amyloid-b (Ab) aggregation at low micromolar concentrations for effective AD therapy. 2. Results and discussion 2.1. Stereochemical considerations of L-755,807 Concerning the above-mentioned stereochemical issues, two research groups have synthesized model compounds for the sidechain and epoxy-g-lactam ring moieties of L-755,807 to elucidate its stereochemistry. In 1998, Clark and Ellard deduced the relative configuration of C18 and C20 in the side-chain moiety of 1 (Fig. 2) [10]. In particular, synthetic syn-6 exhibited quite a similar 13C NMR spectrum to that of L-755,807, whereas anti-7 displayed slight differences compared to the natural product, suggesting a syn relationship between the

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Fig. 1. Originally proposed (1) and revised (2) structures of L-755,807 and synthetic compounds 3e5.

epoxy-g-lactam ring in 1 were deduced as shown in Fig. 1. From these results, compounds 3 and 5 were tentatively proposed as putative structures of natural L-755,807. 2.2. Initial synthetic strategy and synthetic studies of L-755,807

Fig. 2. Synthetic model compounds for the side-chain and epoxy-g-lactam ring moieties of L-755,807.

two methyl groups C23 and C24 in 1. Additional 13C NMR data obtained from MM3/SOS-DFPT/IGLO calculations for the two compounds (syn-6 and anti-7) also supported the presence of syn1,3-dimethyl groups in 1 [11]. Following this report, our research group prepared the optically active L-755,807 derivative 8 to examine the absolute configuration of the lactam ring portion in the natural product [12]. The NMR data of synthetic 8 were in good agreement with those of L-755,807, and the signs of the optical rotations of synthetic 8 and natural L-755,807 were also identical; consequently, the relative and absolute configurations of the

Our initial retrosynthetic strategy for 3 and 5 was as follows (Scheme 1). Late-stage coupling of the ring and side-chain segments was expected to enable the efficient preparation of both compounds 3 and 5. Thus, we initially planned the coupling of amide 9 with vinyl iodides (R,R)- and (S,S)-10. Amide 9 could be prepared from epoxide 12 via lactone 11. Epoxide 12 would be stereoselectively synthesized by a syn-selective Darzens condensation between di-tert-butyl bromomalonate and an O-protected ahydroxy aldehyde, [8] which can be derived from alcohol 13. For the preparation of tetraene 10, stereoselective construction of the trisubstituted C16eC17 olefin is necessary. Thus, disconnection of the conjugated vinyl iodides (R,R)- and (S,S)-10 at the C15eC16 position (carbon numbering based on L-755,807) provides boronic acid 14 [13] and (E)-vinyl bromides (R,R)- and (S,S)-15, respectively. The vinyl bromides (R,R)- and (S,S)-15 could be obtained from alcohols (R,R)and (S,S)-16, respectively, by HornereWadswortheEmmons (HWE) reactions using our original phosphonate reagent [14] and conversion of an ester group to a methyl group. Our investigation began with the preparation of amide 9 from Dvaline. According to a known procedure, [12,15] D-valine was converted to alcohols 13a and 13b in four steps (Table 1). Subsequent ParikheDoering oxidation of alcohols 13a and 13b afforded the corresponding aldehydes 17a and 17b, which were then subjected to the Darzens reaction with di-tert-butyl bromomalonate. After extensive experimentation, we found the optimum conditions for each of the substrates 17a and 17b, providing the desired epoxides 12a and 12b in high yield and diastereoselectivity (Table 1, entries 1 and 2). In our previous paper, we proposed a plausible reaction

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mechanism in which a metal cation was presumed to be important for high diastereoselectivity [8]. To verify the proposed role of the metal cation during this reaction, further experiments were conducted using crown ethers or a polar solvent (THF) as additives (entries 3e5). These additives dramatically lowered the syn/anti selectivity, and most of the unreacted aldehyde 17b was recovered (73% yield) when 12-crown-4 was employed with LHMDS. Based on these observations, the formation of a metal-cation-mediated rigid structure during the reaction is supposed to be essential for high diastereoselectivity and yield. Thus, the additives trapped the metal cation from the aldol adduct to make the transition state leading to the epoxide more flexible and induce the retro-aldol reaction, which resulted in low diastereoselectivity and yield. We believe that the present results clearly support the previously proposed reaction mechanism (Scheme 2) [8]. With these excellent conditions for the Darzens reaction in hand, syn-epoxide 12b was converted to amide 9 (Scheme 3). Treatment of epoxide 12b with formic acid afforded mono acid 19 with spontaneous lactonization after removal of the tert-butyl and TBDPS groups. Condensation between mono acid 19 and N,Odimethylhydroxylamine using (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) furnished Weinreb amide 11 in 84% yield from 12b. Weinreb amide 11 was then reacted with 7 N NH3 in methanol to afford amide 20, the hydroxyl group of which was protected by forming the TMS or TES ether (9a and 9b). When TESOTf was used as the silylating agent, the major product displayed a higher Rf value than expected, which suggested that both the amide and hydroxyl groups were silylated to form the bisTES ether. To selectively cleave the SieO bond in the amide group, the crude product was heated with silica gel in EtOAc at 40  C to afford the desired mono-TES ether 9b in 86% yield over two steps. The preparation of side-chain segments (R,R)- and (S,S)-26 is summarized in Scheme 4. Alcohols (R,R)- and (S,S)-16 were conveniently synthesized from commercially available methyl (R)()-3-hydroxy-2-methylpropionate ((R)-21) and its enantiomer (S)-21, respectively, via a known procedure [16]. Swern oxidation of

Scheme 1. Initial retrosynthetic analysis for 3 and 5.

Table 1 Optimization of reaction conditions for the Darzens Reaction.

Entry

R (aldehyde)

Solvent

Base

Additive

Temp ( C)

Yield (%)

syn:antia (12:18)

1 2 3 4 5

MEM (17a) TBDPS (17b) TBDPS (17b) TBDPS (17b) MEM (17a)

Toluene Toluene Toluene Toluene Toluene

t-BuOK LHMDS LHMDS LHMDS t-BuOK

e e THF 12-Crown-4 18-Crown-6$CH3CN

78 to 45 40 40 40 78 to 45

92b 94b Quant.b 6c,d 82b

17:1 syn only 3: 1 N.D. 2.1:1

a b c d

The syn/anti ratio was determined by 1H NMR analysis of the crude mixture. Isolated yield. NMR yield. Unreacted aldehyde 17b was recovered in 73% yield.

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Scheme 4. Synthesis of side-chain segments (R,R)- and (S,S)-26.

Scheme 2. Proposed reaction mechanism.

Scheme 3. Synthesis of epoxy-g-lactam precursor segments 9a and 9b.

alcohols (R,R)- and (S,S)-16 was followed by HWE reaction of the resulting aldehydes with bromide-containing phosphonate 22 [14]

to afford (E)-a-bromoacrylate derivatives (R,R)- and (S,S)-23 with complete stereoselectivity. The ester groups in (R,R)- and (S,S)-23 were then converted into methyl groups by reduction with DIBALH, tosylation, and reduction with LiAlH4, affording vinyl bromides (R,R)- and (S,S)-15 in 78% and 90% yield, respectively. SuzukieMiyaura coupling of vinyl bromides (R,R)- and (S,S)-15 with boronic acid 14 [13] under Roush conditions [17] delivered the triene alcohols (R,R)- and (S,S)-25, which were oxidized with MnO2 to yield triene aldehydes (R,R)- and (S,S)-26 in 79% and 75% yield, respectively. To convert aldehyde 26 to the side-chain segment 10, Takai olefination of (S,S)-26 was initially attempted (Scheme 5) [18]. Although vinyl iodide 10 was obtained in 60% yield, the tetraene moiety underwent isomerization to afford an inseparable mixture of products. A two-step reaction sequence for the preparation of (S,S)-10 from (S,S)-26 was next examined. SeyfertheGilbert homologation [19] of (S,S)-26 furnished the requisite alkyne (S,S)-27 without isomerization; nevertheless, hydrozirconation of terminal alkyne (S,S)-27 and the subsequent iodination also afforded (S,S)-10 as a mixture of isomers. As our initial attempts to obtain vinyl iodide 10 as a sole product had proved unsuccessful, an alternative route involving nucleophilic addition of acetylide 29 to amide 9a via CoreyeFuchs alkynylation was investigated [20]. Thus, dibromide (S,S)-28, derived from aldehyde (S,S)-26 in 89% yield, was treated with n-BuLi to generate lithium acetylide (S,S)-29 in situ, which was immediately reacted with amide 9a (Scheme 6). Unfortunately, this reaction did not afford the coupling product (S,S)-30, and (S,S)-27 was recovered in 65% yield. To test the acetylide anion as a nucleophile, a small or large excess of lithium acetylide (S,S)-29, prepared from (S,S)-27 with n-BuLi, was reacted with amide 9a, but these reactions also failed to afford the desired coupling product (S,S)-30 (Table 2, entries 1 and 2). LieCe exchange to increase the nucleophilicity of the acetylide anion was also ineffective for achieving the coupling reaction (entry 3).

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Scheme 5. Unsuccessful preparation of side-chain segment (S,S)-10. Scheme 7. New retrosynthetic analysis.

2.3. Second-generation synthetic strategy and total synthesis of L755,807 and its stereoisomers

Scheme 6. Attempted synthesis of (S,S)-30.

Having obtained little success in the coupling of an electrophilic ring segment and a nucleophilic side-chain segment, we reversed the roles of these segments based on a dipole inversion strategy. Thus, in our new retrosynthetic analysis for L-755,807, the ring segment 31 and the side-chain segment 26 were expected to serve as the nucleophile and electrophile, respectively, in the HWE coupling (Scheme 7). Amides 9a and 9b were reacted with dimethyl methylphosphonate pretreated with n-BuLi to deliver phosphonates 31a and 31b in 90% and 89% yield, respectively. For the crucial HWE coupling of ring segment 31 and side-chain segment 26, various bases and solvents were screened (Table 3). The HWE reaction of aldehyde (S,S)-26 and TMS-protected HWE reagent 31a with tBuOK in THF proceeded under reflux conditions to afford the desired coupling product 32a with complete stereoselectivity, albeit in only 19% yield, whereas no reaction occurred at 0  C to room temperature (Table 3, entries 1 and 2). The use of LHMDS as the base led to a diminished product yield (entry 3). TES-protected HWE reagent 31b gave better results than did TMS derivative 31a, although this reaction suffered from poor reproducibility (entry 4). After some experiments, we discovered that the product yield was dependent on the reaction scale; a comparatively high yield of the coupling product 32b was obtained on a small scale, which was probably attributable to rapid evaporation of the solvent during small-scale reactions. As expected, high-concentration conditions

Table 2 Unsuccessful coupling reaction between 9a and (S,S)-27.

Entry

Conditions

1 2 3

(S,S)-27 (3.0 eq), n-BuLi (2.5 eq), THF, 78  C (S,S)-27 (6.0 eq), n-BuLi (5.0 eq), THF, 78  C (S,S)-27 (1.0 eq), n-BuLi (1.0 eq), CeCl3, (2.0 eq), THF, 78 to 40  C

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Table 3 HWE Reaction between the ring and side-chain segments.

Entry

Si

Conditionsa

Temp ( C)

Yield (%)

1 2 3 4 5 6 7 8

TMS TMS TMS TES TES TES TES TES

t-BuOK (1.2 eq), THF (0.1 M) t-BuOK (1.2 eq), THF (0.1 M) LHMDS (1.2 eq), THF (0.1 M) t-BuOK (1.2 eq), THF (0.1 M) t-BuOK (1.2 eq), THF (1.0 M) t-BuOK (2.4 eq), THF (0.1 M) t-BuOK (1.2 eq), 1,4-dioxane (0.1 M) i-Pr2NEt (1.3 eq), LiCl (3.2 eq), CH3CN (0.1 M)

0 to rt rt to reflux rt to reflux rt to reflux rt to reflux rt to reflux rt to reflux rt

No reaction 19 8 14e38 43 Decomposition 14 No reaction

a

1.4 eq of HWE reagent (31a or 31b) was used in all reactions.

Scheme 8. Completion of the total synthesis of L-755,807 (2) and its stereoisomers 3e5.

(1.0 M) reproducibly afforded a moderate yield of 32b (entry 5). Increasing the number of equivalents of t-BuOK (entry 6) or using 1,4-dioxane as the solvent (entry 7) did not improve the yield, and the reaction did not proceed under MasamuneeRoush conditions

(entry 8) [21]. Aldehyde (R,R)-26 and 31b were similarly coupled under the optimized conditions to afford tetraene (R,R)-32b (structure not shown) in 65% yield. Following the deprotection of (R,R)- and (S,S)-32b with

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3HF$Et3N to obtain (R,R)- and (S,S)-33, the final task required to complete the total synthesis was oxidation of the secondary alcohol, which turned out to be challenging (Scheme 8). Based on a model experiment reported by Kogen, [12] DesseMartin oxidation of 33 was initially attempted. Although the reaction proceeded smoothly, isomerization of the tetraene moiety was observed in the 1H NMR spectrum of the product. Other methods of oxidation using SO3$py, PDC, BaMnO4, or TPAP resulted in a low yield or decomposition. To our delight, AZADOL oxidation [22] at low temperature afforded the desired products in good yield without isomerization. Thus, oxidation of secondary alcohol (R,R)33 with concomitant hemiaminal formation furnished 2 and 3 in 63% and 21% yield, respectively. Alcohol (S,S)-33 was similarly oxidized to afford 4 and 5 in 26% and 38% yield, respectively.

Table 4 Ab aggregation inhibitory activity of the synthetic compounds.

2.4. Stereochemical assignment of L-755,807

In conclusion, we have accomplished the convergent synthesis of L-755,807 (2, revised structure) and its stereoisomers (3, 4, and 5) via a syn-selective Darzens reaction and a late-stage HWE coupling between the ring and side-chain segments. This work has established the relative and absolute configurations of natural L755,807, correcting the previous structural assignment of L755,807 reported by Merck. In addition, it is notable that the synthetic compounds displayed potent Ab aggregation inhibitory activity with IC50 values of 5e21 mM, which is the first reported example of a structureeactivity relationship (SAR) study for L755,807. For further SAR studies, the synthesis and biological evaluation of the other stereoisomers and structurally simplified analogues of L-755,807 are currently underway in our laboratory, and the results will be reported in due course.

Among the synthetic compounds 2e5, comparison of the 1H and C NMR spectra indicated that either of compounds 2 or 4 was a plausible candidate for L-755,807 (see Supporting Information). These two compounds were hardly distinguishable because their NMR data were very similar. However, their specific optical rotation values permitted a clear distinction between 2 and 4. Compound 2  ([a]20 D 96.1 (c 0.65, MeOH)) exhibited a similar optical rotation to  L-755,807 ([a]22 D 87.3 (c 0.65, MeOH)), [1] whereas compound 4  ([a]24 D 15.6 (c 0.71, MeOH)) had a clearly different value. Thus, the structure of L-755,807 was assigned to be identical to that of the synthetic compound 2. At this stage, NOESY experiments were performed on compounds 2 and 3 to verify the configuration at C5 in synthetic 2. In the report from the group at Merck, the relative configuration of the lactam ring in 1 (originally proposed structure of L-755,807) was assigned as depicted in Fig. 1 based on NOESY correlations between H4 and H7/8;1 however, correlations at the same position were also unexpectedly observed for our synthetic 3 as well as for 2. Hence, further analysis of the NOESY spectra was necessary for the stereochemical assignment. For compound 3, the methyl protons H7/ H8 correlated with the vinyl proton H10, which proved a cis relationship between the isopropyl group and H4. On the other hand, compound 2 did not show the corresponding NOESY correlation. In addition, steric compression shifts at C6 in 2 and C7/C8 and C9 in 3 were observed in the 13C NMR spectra, further confirming the structures of these compounds [23]. Consequently, the structure of natural L-755,807 can be revised from 1 to 2, and we have unambiguously established the relative and absolute configurations of the natural product. 13

2.5. Amyloid b aggregation inhibitory activity of the synthetic compounds With L-755,807 and its stereoisomers in hand, our attention next turned to their biological activities. As part of our ongoing research project concerning dementia drug resource development, [24] synthetic compounds 2e5 were biologically evaluated for inhibitory activity against amyloid-b (Ab) aggregation. To date, a number of small-molecule inhibitors of Ab aggregation have been developed and these have gained considerable attention in the AD drug discovery field [25]. Therefore, the screening of small molecules is highly important for identifying potential lead compounds. Gratifyingly, all of the compounds 2e5 exhibited potent inhibitory activity against Ab aggregation with IC50 values of 21, 17, 12, and 5 mM, respectively (Table 4). Among them, (5R,18S,20S)-5, with opposite configurations to the natural product at C5, C18, and C20, displayed the most potent activity. Considering the present Ab aggregation inhibitory activity in addition to the bradykinin B2

compound

Ab aggregation inhibitory activity (IC50)

2 (L-755,807) 3 4 5

21 mM 17 mM 12 mM 4 mM

receptor antagonist activity of L-755,807, this natural product and related compounds could represent promising lead compounds for developing therapeutic agents against AD. 3. Conclusion

4. Experimental section 4.1. General 1 H NMR spectra were recorded on JEOL JNM-AL300 (300 MHz) or JEOL JNM-AL400 (400 MHz) instruments. The chemical shifts are expressed in ppm relative to tetramethylsilane (d ¼ 0) as an internal standard (CDCl3 or CD2Cl2 solution). Splitting patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak. 13C NMR spectra were measured at 100 MHz. The chemical shifts are reported in ppm relative to the central line of the triplet at 77.0 ppm for CDCl3. Infrared spectra (IR) were measured on a JASCO VALOR-III and are reported in wavenumbers (cm1). High-resolution mass spectra (HRMS) were obtained using a JEOL JMS 700 instrument with a direct inlet system. Optical rotations were measured on a JASCO P-2200 polarimeter using a cell with an optical path length of 100 mm. Melting points (m.p.) were measured on a Yanaco Micro Melting Point apparatus. Column chromatography was performed on silica gel (40e100 mesh). Analytical thin-layer chromatography (TLC) was conducted using 0.25 mm silica gel 60-F plates.

4.2. Synthesis of L-755,807 and its stereoisomers 4.2.1. Di-tert-butyl (S)-3-((R)-1-((tert-butyldiphenylsilyl)oxy)-2methylpropyl)oxirane-2,2-dicarboxylate (12b) To a stirred solution of alcohol 13b (2.01 g, 5.87 mmol) in CH2Cl2 (30 mL) were successively added DMSO (4.2 mL, 59 mmol), iPr2NEt (4.1 mL, 24 mmol), and SO3$Py (1.96 g, 12.3 mmol) at 0  C. After stirring at room temperature for 30 min, the reaction was quenched by addition of saturated aqueous NaHCO3. The mixture was extracted with Et2O (three times). The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was used in the following reaction without further purification.

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To a stirred solution of di-tert-butyl bromomalonate (2.60 g, 8.81 mmol) in toluene (50 mL) was added LHMDS (0.5 M solution in toluene, 16.5 mL, 8.3 mmol) at room temperature. After 30 min, the crude aldehyde 17b in toluene (10 mL) was added. The reaction was warmed to 40  C, stirred for 12 h, and subsequently quenched by addition of saturated aqueous NH4Cl. The mixture was extracted with EtOAc (three times). The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (20:1 hexane:EtOAc) to afford epoxide 12b (3.07 g, 94% yield over two steps, single diastereomer) as a  colorless oil. [a]20 D e13.7 (c 1.01, CHCl3); IR (CHCl3) 2977, 1743, 1369, 1250, 1114, 702 cm1; 1H NMR (400 MHz, CDCl3) d 7.73e7.68 (m, 4H), 7.41e7.31 (m, 6H), 3.61 (d, J ¼ 8.2 Hz, 1H), 3.30 (dd, J ¼ 8.2, 2.8 Hz, 1H), 1.83e1.71 (m, 1H), 1.45 (s, 9H), 1.30 (s, 9H), 1.09 (s, 9H), 0.95 (d, J ¼ 6.8 Hz, 3H), 0.78 (d, J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 164.9, 163.6, 136.2 (2C), 136.1 (2C), 133.9, 133.3, 129.5, 129.4, 127.4 (2C), 127.3 (2C), 83.4, 83.0, 75.9, 63.8, 61.5, 31.9, 27.8 (3C), 27.7 (3C), 27.1 (3C), 19.8, 19.1, 16.4; HRMS (FABþ) m/z calcd for C32H46O6Si [MþH]þ: 555.3142 found 555.3141. 4.2.2. (1R,4R,5S)-4-isopropyl-N-methoxy-N-methyl-2-oxo-3,6dioxabicyclo[3.1.0]hexane-1-carboxamide (11) Epoxide 12b (3.07 g, 5.53 mmol) was dissolved in formic acid (30 mL) and the resulting solution was stirred at 40  C for 12 h. The reaction mixture was then concentrated in vacuo. The crude product was used in the following reaction without further purification. To a stirred solution of crude carboxylic acid 19 in CH2Cl2 (50 mL) were successively added N,O-dimethylhydroxylamine hydrochloride (1.14 g, 11.6 mmol), iPr2NEt (3.9 mL, 22 mmol), and PyBOP (5.86 g, 11.3 mmol) at 0  C. After stirring at room temperature for 1 h, the reaction was quenched by addition of water. The mixture was extracted with CH2Cl2 (three times). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (1:1 hexane:EtOAc). The combined fractions containing 11 were washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated in vacuo to afford Weinreb amide 11 (1.06 g, 84% yield over two steps) as a colorless solid. m.p. 65e70  C;  [a]17 D e33.6 (c 1.01, CHCl3); IR (CHCl3) 3033, 2982, 2936, 2878, 1739, 1371, 1209, 1165, 769, 763, 753, 749, 745 cm1; 1H NMR (400 MHz, CDCl3) d 4.28 (s, 1H), 4.16 (d, J ¼ 9.0 Hz, 1H), 3.74 (s, 3H), 3.27 (s, 3H), 2.13e2.03 (m, 1H), 1.10 (d, J ¼ 6.6 Hz, 3H), 1.08 (d, J ¼ 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 167.1, 161.5, 83.7, 61.2, 60.9, 58.9, 32.2, 29.2, 19.3, 17.8; HRMS (FABþ) m/z calcd for C10H16NO5 [MþH]þ: 230.1028 found 230.1033. 4.2.3. (2S,3S)-N-methoxy-N-methyl-3-((R)-2-methyl-1((trimethylsilyl)oxy)propyl)oxirane-2,2-dicarboxamide (9a) To a stirred solution of Weinreb amide 11 (744 mg, 3.24 mmol) in MeOH (25 mL) was added NH3 (7N solution in MeOH, 25 mL, 175 mmol) at 0  C. The resulting solution was stirred at 0  C for 30 min and then concentrated in vacuo. The crude product was used in the following reaction without further purification. To a stirred solution of crude alcohol 20 in CH2Cl2 (55 mL) were sequentially added 2,6-lutidine (1.9 mL, 16 mmol) and TMSOTf (1.8 mL, 9.7 mmol) at 0  C. After stirring at 0  C for 30 min, the reaction mixture was quenched by addition of saturated aqueous NaHCO3. The mixture was extracted with EtOAc (three times). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (1:2 hexane:EtOAc) to afford amide 9a  (609 mg, 59% yield over two steps) as a colorless oil. [a]18 D e56.5 (c 2.38, CHCl3); IR (CHCl3): 3675, 3518, 3475, 3401, 3213, 3023, 3012,

2964, 2943, 3903, 2878, 1701, 1674, 1570, 1252, 1214, 1060, 876, 843, 759, 735 cm1; 1H NMR (400 MHz, CDCl3) d 6.54 (br s, 1H), 6.19 (br s, 1H), 3.77 (s, 3H), 3.57 (br d, J ¼ 8.4 Hz, 1H), 3.34 (dd, J ¼ 8.4, 5.6 Hz, 1H), 3.23 (s, 3H), 1.80 (octet, J ¼ 6.8 Hz, 1H), 0.97 (d, J ¼ 6.8 Hz, 3H), 0.92 (d, J ¼ 6.8 Hz, 3H), 0.15 (s, 9H); 13C NMR (100 MHz, CDCl3) d 168.3, 165.4, 75.0, 65.5, 63.2, 61.5, 32.4, 32.3, 18.5, 17.3, 0.4 (3C); HRMS (EIþ) m/z calcd for C13H26N2O5Si [M]þ: 318.1611 found 318.1618. 4.2.4. (2S,3S)-N-methoxy-N-methyl-3-((R)-2-methyl-1((triethylsilyl)oxy)propyl)oxirane-2,2-dicarboxamide (9b) To a stirred solution of Weinreb amide 11 (2.56 g, 11.2 mmol) in MeOH (30 mL) was added NH3 (7 M solution in MeOH, 30 mL, 210 mmol) at 0  C. The resulting solution was stirred at 0  C for 1 h and then concentrated in vacuo. The crude product was used in the following reaction without further purification. To a stirred solution of crude alcohol 20 in CH2Cl2 (110 mL) were sequentially added 2,6-lutidine (6.0 mL, 56 mmol) and TESOTf (6.0 mL, 28 mmol) at 0  C. After stirring at 0  C for 1 h, the reaction mixture was quenched by addition of water. The mixture was extracted with EtOAc (three times). The combined organic layers were washed successively with 0.5N HCl, saturated aqueous NaHCO3, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was then redissolved in EtOAc and silica gel was added. After stirring at 40  C for 36 h, the mixture was filtered through Celite and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (1:1 hexane:EtOAc) to afford amide 9b (3.46 g, 86% yield over two steps) as a  colorless solid. m.p. 121e128  C; [a]22 D e32.0 (c 1.15, CHCl3); IR (CHCl3) 3519, 3402, 2961, 2878, 1702, 1674, 1571, 1462, 1390, 1062 cm1; 1H NMR (400 MHz, CDCl3) d 6.43 (br s, 1H), 6.15 (br s, 1H), 3.74 (s, 3H), 3.54 (d, J ¼ 8.6 Hz, 1H), 3.35 (dd, J ¼ 8.6, 4.8 Hz, 1H), 3.19 (s, 3H), 1.83e1.66 (m, 1H), 0.94 (t, J ¼ 9.0 Hz, 9H), 0.94 (d, J ¼ 6.4 Hz, 3H), 0.90 (d, J ¼ 6.8 Hz, 3H), 0.68e0.52 (m, 6H); 13C NMR (100 MHz, CDCl3) d 168.3, 165.5, 74.8, 65.6, 63.0, 61.5, 32.6, 32.3, 18.7, 16.8, 6.8 (3C), 5.1 (3C); HRMS (FABþ) m/z calcd for C16H33N2O5Si [MþH]þ: 361.2159 found 361.2160. 4.2.5. Methyl (4R,6R,E)-2-bromo-4,6-dimethyloct-2-enoate ((R,R)23) To a stirred solution of (COCl)2 (0.52 mL, 6.1 mmol) in CH2Cl2 (10 mL) was slowly added DMSO (0.64 mL, 9.01 mmol) in CH2Cl2 (10 mL) via syringe at 78  C. The resulting mixture was stirred for 30 min, and alcohol (R,R)-16 (391 mg, 3.00 mmol) in CH2Cl2 (10 mL) was then carefully added dropwise. After stirring for 30 min, Et3N (2.1 mL, 15 mmol) was added in a single portion. The cooling bath was removed and the reaction was allowed to warm to room temperature. After 30 min, the reaction mixture was diluted with pentane and brine and then extracted with pentane (three times). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was used in the following reaction without further purification. A solution of 18-crown-6$CH3CN (1.20 g, 3.93 mmol) in THF (40 mL) was added to methyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)-2-bromoacetate (22, 1.55 g, 3.90 mmol) in THF (10 mL) at room temperature. The mixture was cooled to 78  C and t-BuOK (1.0 M solution in THF, 3.9 mL, 3.9 mmol) was added. After stirring for 30 min, the crude aldehyde in THF (10 mL) was added dropwise. After the addition was complete, the reaction mixture was allowed to warm to 0  C and stirred for 1 h. The reaction was then quenched by addition of saturated aqueous NH4Cl, and the mixture was extracted with EtOAc (three times). The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (50:1 hexane:EtOAc) to afford (E)-a-

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bromoacrylate (R,R)-23 (624 mg, 79% yield over two steps) as a  colorless oil. [a]23 D e18.8 (c 1.15, CHCl3); IR (CHCl3) 3025, 2963, 2928, 2875, 1720, 1236, 1224, 1222, 1216, 778, 775, 740 cm1; 1H NMR (300 MHz, CDCl3) d 6.39 (d, J ¼ 10.2 Hz, 1H), 3.82 (s, 3H), 3.34e3.24 (m, 1H), 1.37e1.22 (m, 3H), 1.18e1.06 (m, 2H), 1.02 (d, J ¼ 6.6 Hz, 3H), 0.86 (t, J ¼ 6.9 Hz, 3H), 0.82 (d, J ¼ 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 163.5, 154.5, 109.2, 52.8, 44.2, 33.7, 32.4, 29.9, 20.5, 18.9, 11.2; HRMS (EIþ) m/z calcd for C11H19BrO2 [M]þ: 262.0568 found 262.0565. 4.2.6. Methyl (4S,6S,E)-2-bromo-4,6-dimethyloct-2-enoate ((S,S)23) (E)-a-Bromoacrylate (S,S)-23 (436 mg, 55% yield over two steps, colorless oil) was obtained from alcohol (S,S)-16 (391 mg, 3.00 mmol) by a similar procedure to that used for the (R,R)-isomer. The spectroscopic data for (S,S)-23 were identical to those for (R,R)23, and this compound exhibited an optical rotation of similar  magnitude with the opposite sign ([a]23 D þ17.9 (c 0.75, CHCl3)). 4.2.7. (4R,6R,E)-2-bromo-4,6-dimethyloct-2-en-1-ol ((R,R)-24) To a stirred solution of (E)-a-bromoacrylate (R,R)-23 (1.07 g, 4.07 mmol) in toluene (40 mL) was added DIBAL-H (1.02 M solution in hexane, 10 mL, 10 mmol) at 78  C, and the reaction mixture was allowed to warm to 0  C. After stirring for 1 h, the reaction was quenched by addition of MeOH and saturated aqueous Rochelle salt and then vigorously stirred for 1 h. The mixture was extracted with EtOAc (three times). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (20:1 hexane:EtOAc) to afford alcohol (R,R)-24 (865 mg,  90% yield) as a colorless oil. [a]23 D e28.9 (c 1.15, CHCl3); IR (CHCl3) 3592, 2963, 2928, 2875, 1462, 1454, 1380, 1039, 988, 751, 739, 671 cm1; 1H NMR (300 MHz, CDCl3) d 5.76 (d, J ¼ 10.5 Hz, 1H), 4.31 (d, J ¼ 6.6 Hz, 2H), 2.62e2.53 (m, 1H), 1.83 (t, J ¼ 6.6 Hz, 1H), 1.33e1.22 (m, 3H), 1.19e1.04 (m, 2H), 1.00 (d, J ¼ 6.6 Hz, 3H), 0.86 (t, J ¼ 7.2 Hz, 3H), 0.83 (d, J ¼ 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 141.3, 123.2, 62.9, 44.2, 32.6, 32.0, 29.9, 21.6, 18.8, 11.2; HRMS (EIþ) m/z calcd for C10H19BrO [M]þ: 234.0619 found 234.0615. 4.2.8. (4S,6S,E)-2-bromo-4,6-dimethyloct-2-en-1-ol ((S,S)-24) Alcohol (S,S)-24 (1.39 g, 95% yield, colorless oil) was obtained from (S,S)-23 (1.64 g, 6.24 mmol) by a similar procedure to that used for the (R,R)-isomer. The spectroscopic data for (S,S)-24 were identical to those for (R,R)-24, and this compound exhibited an optical rotation of similar magnitude with the opposite sign  ([a]23 D þ29.3 (c 0.38, CHCl3)). 4.2.9. (4R,6R,E)-2-bromo-4,6-dimethyloct-2-ene ((R,R)-15) To a stirred solution of alcohol (R,R)-24 (2.61 g, 11.1 mmol) in THF (110 mL) was added t-BuOK (1.0 M solution in THF, 13.3 mL, 13.3 mmol) dropwise via syringe at 78  C. The resulting solution was stirred at 78  C for 30 min, and TsCl (2.54 g, 13.3 mmol) was then added in small portions. After 10 min, the cooling bath was removed and the reaction was allowed to warm to room temperature. The reaction was then quenched by addition of water and stirred for 5 min, and the mixture was extracted with Et2O (three times). The combined organic layers were washed successively with 0.5N HCl, saturated aqueous NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was used in the following reaction without further purification. To a stirred suspension of LiAlH4 (687 mg, 16.7 mmol) in THF (100 mL) was added the crude tosylate in THF (10 mL) at 0  C. The resulting mixture was allowed to warm to room temperature and stirred for 30 min. The reaction was quenched by addition of cold saturated aqueous Na2SO4 (100 mL). After stirring for 1 h, the

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mixture was extracted with pentane (three times). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (pentane) to afford vinyl bromide (R,R)-15 (1.90 g, 78%  yield over two steps) as a colorless oil. [a]23 D e31.7 (c 1.32, CHCl3); IR (CHCl3) 3676, 3023, 3013, 2963, 2927, 2874, 2360, 1740, 1652, 1458, 1381, 1223, 1218, 1214, 1209, 789, 783, 773, 748, 736, 668 cm1; 1H NMR (300 MHz, CDCl3) d 5.58 (dq, J ¼ 10.2, 1.2 Hz, 1H), 2.48e2.38 (m, 1H), 2.23 (d, J ¼ 1.2 Hz, 3H), 1.35e1.21 (m, 3H), 1.17e0.99 (m, 2H), 0.95 (d, J ¼ 6.6 Hz, 3H), 0.86 (t, J ¼ 7.5 Hz, 3H), 0.83 (d, J ¼ 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 138.6, 117.9, 44.3, 32.5, 32.1, 30.0, 23.4, 21.2, 19.0, 11.2; HRMS (EIþ) m/z calcd for C10H19Br [M]þ: 218.0670 found 218.0669. 4.2.10. (4S,6S,E)-2-bromo-4,6-dimethyloct-2-ene ((S,S)-15) Vinyl bromide (S,S)-15 (1.13 g, 90% yield over two steps, colorless oil) was obtained from (S,S)-24 (1.39 g, 5.91 mmol) by a similar procedure to that used for the (R,R)-isomer. The spectroscopic data for (S,S)-15 were identical to those for (R,R)-15, and this compound exhibited an optical rotation of similar magnitude with the oppo site sign ([a]19 D þ54.3 (c 1.25, CHCl3)). 4.2.11. (2E,4E,6E,8R,10R)-6,8,10-trimethyldodeca-2,4,6-trien-1-ol ((R,R)-25) All of the following operations were performed in the dark. A solution of vinyl bromide (R,R)-15 (1.04 g, 4.75 mmol) and boronic acid 14 (3.04 g, 23.8 mmol) in THF (36 mL) and water (12 mL) was thoroughly degassed by the freezeepumpethaw technique. Pd(PPh3)4 (549 mg, 0.475 mmol) was then added, and the reaction mixture was stirred at 50  C for 5 min. Subsequently, TlOEt (0.6 mL, 8.5 mmol) was added and the stirring was continued for 30 min. The reaction mixture was diluted with Et2O and 1N aqueous NaHSO4 (20 mL) and filtered through Celite. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (5:1 hexane:EtOAc) to afford triene alcohol (R,R)-25 (691 mg, 65% yield) as a colorless oil. [a]22 D e21.2 (c 1.03, CHCl3); IR (CHCl3) 3613, 3013, 2963, 2925, 2874, 1457, 1379, 1213, 987, 888, 739, 734, 730 cm1; 1H NMR (300 MHz, CDCl3) d 6.34e6.09 (m, 3H), 5.84 (dt, J ¼ 5.9, 7.8 Hz, 1H), 5.26 (d, J ¼ 9.6 Hz, 1H), 4.20 (t, J ¼ 5.9 Hz, 2H), 2.65e2.55 (m, 1H), 1.78 (s, 3H), 1.31e1.24 (m, 3H), 1.18e1.03 (m, 2H), 0.95 (d, J ¼ 6.3 Hz, 3H), 0.84 (t, J ¼ 7.2 Hz, 3H), 0.81 (d, J ¼ 6.3 Hz, 3H). A signal due to one proton (OH) was not observed; 13C NMR (100 MHz, CDCl3) d 141.1, 138.7, 132.5, 132.0, 130.4, 125.2, 63.6, 44.9, 32.2, 30.4, 30.1, 21.5, 19.1, 12.5, 11.3; HRMS (EIþ) m/z calcd for C15H26O [M]þ: 222.1984 found 222.1978. 4.2.12. (2E,4E,6E,8S,10S)-6,8,10-trimethyldodeca-2,4,6-trien-1-ol ((S,S)-25) Alcohol (S,S)-25 (136 mg, 59% yield, colorless oil) was obtained from (S,S)-15 (229 mg, 1.04 mmol) by a similar procedure to that used for the (R,R)-isomer. The spectroscopic data for (S,S)-25 were identical to those for (R,R)-25, and this compound exhibited an optical rotation of similar magnitude with the opposite sign  ([a]18 D þ36.1 (c 1.00, CHCl3)). 4.2.13. (2E,4E,6E,8R,10R)-6,8,10-trimethyldodeca-2,4,6-trienal ((R,R)-26) All of the following operations were performed in the dark. To a stirred solution of triene alcohol (R,R)-25 (660 mg, 2.99 mmol) in CH2Cl2 (30 mL) was added MnO2 (7.86 g, 89.8 mmol) at 0  C. After 1 h at room temperature, the reaction mixture was filtered through Celite and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (20:1 hexane:EtOAc) to afford

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triene aldehyde (R,R)-26 (521 mg, 79% yield) as a yellow oil. [a]21 D e37.8 (c 1.13, CHCl3); IR (CHCl3) 3027, 3014, 2964, 2926, 2874, 2741, 1673, 1603, 1218, 1160, 1132, 985, 776, 741, 671, 480 cm1; 1H NMR (300 MHz, CDCl3) d 9.55 (d, J ¼ 8.0 Hz, 1H), 7.15 (dd, J ¼ 15.3, 11.0 Hz, 1H), 6.68 (d, J ¼ 15.3 Hz, 1H), 6.36 (dd, J ¼ 15.3, 11.0 Hz, 1H), 6.16 (dd, J ¼ 15.3, 8.0 Hz, 1H), 5.55 (d, J ¼ 10.2 Hz, 1H), 2.72e2.59 (m, 1H), 1.83 (d, J ¼ 0.9 Hz, 3H), 1.37e1.20 (m, 3H), 1.17e1.10 (m, 2H), 0.98 (d, J ¼ 6.6 Hz, 3H), 0.85 (t, J ¼ 8.4 Hz, 3H), 0.83 (d, J ¼ 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 193.7, 153.3, 148.4, 147.4, 132.3, 130.4, 123.8, 44.6, 32.4, 30.9, 30.1, 21.7, 19.1, 12.4, 11.3; HRMS (FABþ) m/z calcd for C15H25O [MþH]þ: 221.1905 found 221.1902. 4.2.14. (2E,4E,6E,8S,10S)-6,8,10-trimethyldodeca-2,4,6-trienal ((S,S)-26) Aldehyde (S,S)-26 (100 mg, 75% yield, yellow oil) was obtained from (S,S)-25 (136 mg, 0.454 mmol) by a similar procedure to that used for the (R,R)-isomer. The spectroscopic data for (S,S)-26 were identical to those for (R,R)-26, and this compound exhibited an optical rotation of similar magnitude with the opposite sign  ([a]16 D þ56.0 (c 0.97, CHCl3)). 4.2.15. (1E,3E,5E,7E,9S,11S)-1-iodo-7,9,11-trimethyltrideca-1,3,5,7tetraene ((S,S)-10) 4.2.15.1. Preparation by takai olefination. For this reaction, THF was degassed using the freezeepumpethaw technique and all operations were performed in a glove box. To a suspension of CrCl2 (10 mg, 0.082 mmol) in THF (0.1 mL) was added CHI3 (10 mg, 0.027 mmol), and the resulting solution was stirred at room temperature for 1 h. A solution of (S,S)-26 (3.0 mg, 0.014 mmol) in THF (0.1 mL) was then added. After stirring for 1 h, the reaction was diluted with Et2O and saturated aqueous NH4Cl, filtered through Celite, and extracted with Et2O. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (nhexane) to afford iodo olefin (S,S)-10 (4.0 mg, 60%) as a mixture of isomers. 4.2.15.2. Preparation via alkyne (S,S)-27. For this reaction, THF was degassed using the freezeepumpethaw technique and the operations involving ZrCp2HCl were performed in a glove box. A solution of alkyne (S,S)-27 (6.0 mg, 0.028 mmol; the preparation of (S,S)-27 is described below) in THF (0.3 mL) was added to a suspension of ZrCp2HCl (15 mg, 0.058 mmol) in THF (0.3 mL). After stirring for 1 h, I2 (14.2 mg, 0.056 mmol) was then added at 0  C. After stirring for a further 2 h, the reaction was quenched by addition of 5% aqueous Na2S2O3, stirred for 5 min, filtered through Celite, and extracted with Et2O. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (n-hexane) to afford iodo olefin (S,S)-10 (3 mg, 31%) as a mixture of isomers. 1H NMR (300 MHz, CDCl3) d 7.06 (dd, J ¼ 14.1, 10.5 Hz, 1H), 6.76 (dd, J ¼ 14.7, 10.2 Hz, 1H), 6.52 (dd, J ¼ 14.7, 9.9 Hz, 1H), 6.39e6.11 (m, 3H), 5.33 (d, J ¼ 9.3 Hz, 1H), 2.68e2.56 (m, 1H), 1.81 (d, J ¼ 1.2 Hz, 3H), 1.35e1.19 (m, 3H), 1.17e1.08 (m, 2H), 0.95 (d, J ¼ 6.0 Hz, 3H), 0.84 (t, J ¼ 6.6 Hz, 3H), 0.82 (d, J ¼ 6.3 Hz, 3H); EI-LRMS m/z (%) 344 (Mþ, 100). 4.2.16. (3E,5E,7E,9S,11S)-7,9,11-trimethyltrideca-3,5,7-trien-1-yne ((S,S)-27) To a stirred solution of dimethyl diazomethylphosphonate (16 mg, 0.11 mmol) in THF (0.1 mL) was added t-BuOK (1.0 M solution in THF, 0.1 mL, 0.1 mmol) at 78  C. After stirring for 1 h, a solution of aldehyde (S,S)-26 (9 mg, 0.041 mmol) in THF (0.3 mL) was added dropwise. After stirring for a further 1 h, the reaction mixture was allowed to warm to 30  C and stirred for 30 min. The

reaction was then quenched by addition of saturated aqueous NH4Cl and the mixture was extracted with EtOAc (three times). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (n-hexane) to afford (S,S)-27 (2.0 mg,  23%) as a yellow oil. [a]17 D þ54.5 (c 0.75, CHCl3); IR (CHCl3): 3307, 3012, 2963, 2926, 2873, 2093, 1607, 983, 647, 600 cm1; 1H NMR (300 MHz, CDCl3) d 6.71 (dd, J ¼ 15.6, 15.3 Hz, 1H), 6.33 (d, J ¼ 15.3 Hz, 1H), 6.16 (dd, J ¼ 15.3, 10.8 Hz, 1H), 5.54 (dd, J ¼ 15.6, 2.4 Hz, 1H), 5.34 (d, J ¼ 9.6 Hz, 1H), 3.04 (d, J ¼ 2.4 Hz, 1H), 2.65e2.55 (m, 1H), 1.77 (d, J ¼ 1.2 Hz, 3H), 1.32e1.23 (m, 3H), 1.15e1.05 (m, 2H), 0.95 (d, J ¼ 6.6 Hz, 3H), 0.84 (t, J ¼ 6.9 Hz, 3H), 0.81 (d, J ¼ 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 144.3, 143.3, 141.3, 132.0, 124.9, 108.1, 79.2, 44.8, 32.3, 30.1, 21.4, 19.1, 12.4, 11.3; HRMS (EIþ) m/z calcd for C16H24 [M]þ: 216.1878 found 216.1876.

4.2.17. (3E,5E,7E,9S,11S)-1,1-dibromo-7,9,11-trimethyltrideca1,3,5,7-tetraene ((S,S)-28) To a stirred solution of CBr4 (138 mg, 0.42 mmol) in CH2Cl2 (0.5 mL) was added a solution of PPh3 (217 mg, 0.82 mmol) in CH2Cl2 (0.5 mL) at 0  C. After stirring for 15 min, a solution of aldehyde (S,S)-26 (33 mg, 0.15 mmol) in CH2Cl2 (0.2 mL) was added. After stirring for a further 15 min, the reaction was quenched by addition of water and the mixture was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (n-hexane) to afford (S,S)-28 (49 mg,  89%) as a yellow oil. [a]17 D þ12.8 (c 0.97, CHCl3); IR (CHCl3): 2963, 2925, 2874, 1604, 1558, 1457, 1220, 987, 815, 788, 776, 743, 727 cm1; 1H NMR (300 MHz, CDCl3) d 6.96 (d, J ¼ 10.5 Hz, 1H), 6.44 (d, J ¼ 14.7 Hz, 1H) 6.39 (dd, J ¼ 15.0, 8.4 Hz, 1H), 6.22 (dd, J ¼ 10.2, 5.1 Hz, 1H), 6.17 (dd, J ¼ 10.8, 5.4 Hz, 1H), 5.35 (d, J ¼ 9.3 Hz, 1H), 2.68e2.56 (m, 1H), 1.80 (d, J ¼ 1.2 Hz, 3H), 1.33e1.20 (m, 3H), 1.17e1.08 (m, 2H), 0.95 (d, J ¼ 6.6 Hz, 3H), 0.84 (t, J ¼ 6.9 Hz, 3H), 0.82 (d, J ¼ 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 142.9, 141.3, 136.9, 132.4, 128.0, 127.3, 125.6, 44.7, 32.3, 30.6, 30.1, 21.4, 19.1, 19.0, 12.5, 11.3; HRMS (EIþ) m/z calcd for C16H24Br2 [M]þ: 374.0245 found 374.0252.

4.2.18. Dimethyl (2-((2R,3S)-2-carbamoyl-3-((R)-2-methyl-1((trimethylsilyl)oxy)propyl)oxiran-2-yl)-2-oxoethyl)phosphonate (31a) To a stirred solution of dimethyl methylphosphonate (143 mg, 1.15 mmol) in THF (3 mL) was added n-BuLi (1.60 M solution in hexane, 0.63 mL, 1.00 mmol) dropwise via syringe at 78  C. After stirring at 78  C for 30 min, amide 9a (118 mg, 0.37 mmol) in THF (1.5 mL) was added. After 30 min, the reaction was quenched by addition of saturated aqueous NH4Cl and the mixture was extracted with EtOAc (three times). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (EtOAc) to afford  phosphonate 31a (128 mg, 90% yield) as a colorless oil. [a]25 D e8.7 (c 0.33, CHCl3); IR (neat) 3441, 3313, 3262, 3187, 2960, 1714, 1693, 1252, 1055, 1033, 874, 842 cm1; 1H NMR (400 MHz, CDCl3) d 6.94 (br s, 1H), 5.63 (br s, 1H), 3.82 (d, J ¼ 11.2 Hz, 3H), 3.80 (d, J ¼ 11.6 Hz, 3H), 3.47e3.29 (m, 4H), 1.83e1.70 (m, 1H), 0.92 (d, J ¼ 7.2 Hz, 9H), 0.88 (d, J ¼ 6.8 Hz, 3H), 0.17 (s, 9H); 13C NMR (100 MHz, CDCl3) d 196.7*, 165.1, 74.5, 65.4*, 65.1, 53.3*, 53.2*, 36.2*, 32.0, 18.7, 17.1, 0.3 (3C) (*These signals are split into doublets by the phosphorus atom.); HRMS (FABþ) m/z calcd for C14H29NO7PSi [MþH]þ: 382.1451 found 382.1446.

K. Tanaka III et al. / Tetrahedron 75 (2019) 1085e1097

4.2.19. Dimethyl (2-((2R,3S)-2-carbamoyl-3-((R)-2-methyl-1((triethylsilyl)oxy)propyl)oxiran-2-yl)-2-oxoethyl)phosphonate (31b) To a stirred solution of dimethyl methylphosphonate (3.57 g, 28.8 mmol) in THF (150 mL) was added n-BuLi (2.65 M solution in hexane, 9.0 mL, 24 mmol) dropwise via syringe at 78  C. After stirring at 78  C for 30 min, amide 9b (3.46 g, 9.60 mmol) in THF (70 mL) was added. After 30 min, the reaction was quenched by addition of saturated aqueous NH4Cl and the mixture was extracted with EtOAc (three times). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (EtOAc) to afford  phosphonate 31b (3.61 g, 89% yield) as a colorless oil. [a]20 D e20.3 (c 1.02, CHCl3); IR (neat) 3495, 3401, 2960, 2878, 1714, 1210, 1059, 1038 cm1; 1H NMR (400 MHz, CDCl3) d 6.88 (br s, 1H), 5.88 (br s, 1H), 3.78 (d, J ¼ 11.4 Hz, 3H), 3.77 (d, J ¼ 11.4 Hz, 3H), 3.42e3.27 (m, 2H), 3.40 (dd, J ¼ 7.8, 4.4 Hz, 1H), 3.32 (d, J ¼ 7.8 Hz, 1H), 1.77e1.67 (m, 1H), 0.95 (t, J ¼ 8.0 Hz, 9H), 0.89 (d, J ¼ 6.8 Hz, 3H), 0.87 (d, J ¼ 6.8 Hz, 3H), 0.68e0.52 (m, 6H); 13C NMR (100 MHz, CDCl3) d 196.7*, 165.0, 74.3, 65.2*, 65.2, 53.3*, 53.2*, 36.1*, 32.2, 18.9, 16.7, 6.8 (3C), 5.0 (3C) (*These signals are split into doublets by the phosphorus atom.); HRMS (FABþ) m/z calcd for C17H35NO7PSi [MþH]þ: 424.1920 found 424.1911. 4.2.20. (2R,3S)-3-((R)-2-methyl-1-((triethylsilyl)oxy)propyl)-2((2E,4E,6E,8E,10R,12R)-8,10,12-trimethyltetradeca-2,4,6,8tetraenoyl)oxirane-2-carboxamide ((R,R)-32b) All of the following operations were performed in the dark. To a stirred solution of phosphonate 31b (597 mg, 1.41 mmol) in THF (1.0 mL) was added t-BuOK (1.0 M solution in THF, 1.2 mL, 1.2 mmol) at room temperature. After stirring for 30 min, aldehyde (R,R)-26 (222 mg, 1.00 mmol) in THF (1.0 mL) was added dropwise. After the addition was complete, the reaction mixture was heated to reflux for 10 h. The reaction was then quenched by addition of saturated aqueous NH4Cl and the mixture was extracted with EtOAc (three times). The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (5:1 hexane:EtOAc) to afford tetraene amide (R,R)-32b (339 mg,  65% yield) as a yellow amorphous solid. [a]20 D e8.5 (c 0.57, CHCl3); IR (neat) 3417, 3327, 2960, 2876, 1703, 1552, 1462, 1351 cm1; 1H NMR (400 MHz, CDCl3) d 7.53 (br d, J ¼ 3.0 Hz, 1H), 7.51 (dd, J ¼ 15.0, 11.7 Hz, 1H), 6.77 (dd, J ¼ 11.1, 15.0 Hz, 1H), 6.56 (d, J ¼ 15.0 Hz, 1H), 6.50 (d, J ¼ 15.2 Hz, 1H), 6.38 (dd, J ¼ 15.0, 11.7 Hz, 1H), 6.26 (dd, J ¼ 15.2, 11.1 Hz, 1H), 5.69 (br d, J ¼ 3.0 Hz, 1H), 5.44 (d, J ¼ 9.6 Hz, 1H), 3.51 (dd, J ¼ 8.1, 5.0 Hz, 1H), 3.17 (d, J ¼ 8.1 Hz, 1H), 2.69e2.57 (m, 1H), 1.81 (s, 3H), 1.81e1.71 (m, 2H), 1.34e1.20 (m, 3H), 1.16e1.06 (m, 1H), 1.00 (t, J ¼ 7.6 Hz, 9H), 0.96 (d, J ¼ 6.8 Hz, 3H), 0.92 (d, J ¼ 6.8 Hz, 3H), 0.89 (d, J ¼ 6.8 Hz, 3H), 0.84 (t, J ¼ 7.6 Hz, 3H), 0.82 (d, J ¼ 5.6 Hz, 3H), 0.77e0.63 (m, 6H); 13C NMR (100 MHz, CDCl3) d 193.7, 165.8, 147.6, 145.9, 145.3, 144.7, 132.5, 129.0, 125.5, 120.5, 74.2, 65.5, 64.5, 44.7, 32.4, 32.3, 30.8, 30.1, 21.3, 19.1, 18.8, 17.1, 12.4, 11.3, 6.8 (3C), 5.0 (3C); HRMS (EIþ) m/z calcd for C30H51NO4Si [M]þ: 517.3587 found 517.3582. 4.2.21. (2R,3S)-3-((R)-2-methyl-1-((trimethylsilyl)oxy)propyl)-2((2E,4E,6E,8E,10S,12S)-8,10,12-trimethyltetradeca-2,4,6,8tetraenoyl)oxirane-2-carboxamide ((S,S)-32a) Amide (S,S)-32a (3.8 mg, 19% yield, yellow oil) was obtained from 31a (25 mg, 0.065 mmol) and (S,S)-26 (9.2 mg, 0.042 mmol) by a similar procedure to that used for the (R,R)-32b. 1H NMR (300 MHz, CDCl3) d 7.56 (br s, 1H), 7.51 (dd, J ¼ 15.0, 11.7 Hz, 1H), 6.77 (dd, J ¼ 14.4, 10.8 Hz, 1H), 6.58 (d, J ¼ 15.0 Hz, 1H), 6.50 (d, J ¼ 15.3 Hz, 1H), 6.38 (dd, J ¼ 14.4, 11.7 Hz, 1H), 6.26 (dd, J ¼ 15.3, 11.4 Hz, 1H), 5.69e5.56 (m, 1H), 5.41 (br d, J ¼ 9.9 Hz, 1H), 3.45 (dd,

1095

J ¼ 8.1, 6.0 Hz, 1H), 3.16 (d, J ¼ 8.1 Hz, 1H), 2.74e2.50 (m, 1H), 1.81 (s, 3H), 1.80e1.66 (m, 1H), 1.40e1.01 (m, 5H), 0.96 (d, J ¼ 6.6 Hz, 3H), 0.92 (d, J ¼ 6.9 Hz, 3H), 0.87 (d, J ¼ 6.9 Hz, 3H), 0.84 (t, J ¼ 7.2 Hz, 3H), 0.82 (d, J ¼ 6.0 Hz, 3H), 0.20 (s, 9H). 4.2.22. (2R,3S)-3-((R)-2-methyl-1-((triethylsilyl)oxy)propyl)-2((2E,4E,6E,8E,10S,12S)-8,10,12-trimethyltetradeca-2,4,6,8tetraenoyl)oxirane-2-carboxamide ((S,S)-32b) Amide (S,S)-32b (100 mg, 43% yield, yellow amorphous solid) was obtained from 31b (386 mg, 0.911 mmol) and (S,S)-26 (100 mg, 0.454 mmol) by a similar procedure to that used for the (R,R)-iso mer. [a]20 D þ17.3 (c 0.95, CHCl3); IR (neat) 3485, 3346, 2962, 2877, 1701, 1548, 1463, 1352 cm1; 1H NMR (400 MHz, CDCl3) d 7.49 (br d, J ¼ 3.0 Hz, 1H), 7.48 (dd, J ¼ 15.0, 11.6 Hz, 1H), 6.74 (dd, J ¼ 14.7, 10.8 Hz, 1H), 6.53 (d, J ¼ 15.0 Hz, 1H), 6.47 (d, J ¼ 15.2 Hz, 1H), 6.35 (dd, J ¼ 14.7, 11.6 Hz, 1H), 6.23 (dd, J ¼ 15.2, 10.8 Hz, 1H), 5.82 (br d, J ¼ 3.0 Hz, 1H), 5.42 (d, J ¼ 9.6 Hz, 1H), 3.48 (dd, J ¼ 8.4, 5.6 Hz, 1H), 3.14 (d, J ¼ 8.4 Hz, 1H), 2.66e2.55 (m, 1H), 1.78 (s, 3H), 1.78e1.67 (m, 1H), 1.31e1.18 (m, 3H), 1.14e1.05 (m, 2H), 0.97 (t, J ¼ 8.0 Hz, 9H), 0.94 (d, J ¼ 6.8 Hz, 3H), 0.89 (d, J ¼ 6.8 Hz, 3H), 0.87 (d, J ¼ 6.8 Hz, 3H), 0.82 (t, J ¼ 7.2 Hz, 3H), 0.80 (d, J ¼ 6.4 Hz, 3H), 0.75e0.62 (m, 6H); 13C NMR (100 MHz, CDCl3) d 193.6, 165.9, 147.6, 145.8, 145.2, 144.7, 132.5, 129.0, 125.5, 120.5, 74.2, 65.5, 64.5, 44.7, 32.4, 32.3, 30.8, 30.1, 21.3, 19.1, 18.8, 17.1, 12.4, 11.2, 6.8 (3C), 5.0 (3C); HRMS (EIþ) m/z calcd for C30H51NO4Si [M]þ: 517.3587 found 517.3582. 4.2.23. (2R,3S)-3-((R)-1-hydroxy-2-methylpropyl)-2((2E,4E,6E,8E,10R,12R)-8,10,12-trimethyltetradeca-2,4,6,8tetraenoyl)oxirane-2-carboxamide ((R,R)-33) All of the following operations were performed in the dark. To a stirred solution of tetraene amide (R,R)-32b (25 mg, 0.048 mmol) in DMF (5.0 mL) was added 3HF$Et3N (0.03 mL, 0.18 mmol) at room temperature. After stirring at 35  C for 1 h, additional 3HF$Et3N (0.03 mL, 0.18 mmol) was added. After 1 h, the reaction was concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (1:1 hexane:EtOAc) to afford alcohol (R,R)-33 (18 mg, 92% yield) as a yellow amorphous solid. [a]20 D e33.4 (c 0.98, CHCl3); IR (neat) 3416, 3325, 2962, 2874, 1686, 1558, 1463, 1352 cm1; 1H NMR (400 MHz, CDCl3) d 7.72 (br s, 1H), 7.48 (dd, J ¼ 15.2, 11.6 Hz, 1H), 6.74 (dd, J ¼ 14.5, 10.8 Hz, 1H), 6.55 (d, J ¼ 15.2 Hz, 1H), 6.46 (d, J ¼ 15.2 Hz, 1H), 6.44 (br s, 1H), 6.33 (dd, J ¼ 14.5, 11.6 Hz, 1H), 6.22 (dd, J ¼ 15.2, 10.8 Hz, 1H), 5.41 (d, J ¼ 9.6 Hz, 1H), 3.58 (br s, 1H), 3.39 (t, J ¼ 7.8 Hz, 1H), 3.18 (d, J ¼ 7.8 Hz, 1H), 2.64e2.54 (m, 1H), 1.79e1.73 (m, 1H), 1.77 (br s, 3H), 1.30e1.17 (m, 3H), 1.12e1.04 (m, 2H), 0.97 (d, J ¼ 6.8 Hz, 3H), 0.93 (d, J ¼ 7.2 Hz, 3H), 0.90 (d, J ¼ 6.8 Hz, 3H), 0.81 (t, J ¼ 7.2 Hz, 3H), 0.79 (d, J ¼ 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 193.3, 166.7, 147.8, 146.1, 145.3, 144.9, 132.5, 129.0, 125.5, 120.4, 72.7, 65.3, 65.0, 44.6, 32.3, 31.8, 30.7, 30.0, 21.3, 19.0, 18.1, 18.0, 12.4, 11.2; HRMS (EIþ) m/z calcd for C24H37NO4 [M]þ: 403.2723 found 403.2722. 4.2.24. (2R,3S)-3-((R)-1-hydroxy-2-methylpropyl)-2((2E,4E,6E,8E,10S,12S)-8,10,12-trimethyltetradeca-2,4,6,8tetraenoyl)oxirane-2-carboxamide ((S,S)-33) Alcohol (S,S)-33 (79 mg, 99% yield, yellow amorphous solid) was obtained from (S,S)-32b (100 mg, 0.193 mmol) by a similar pro cedure to that used for the (R,R)-isomer. [a]20 D þ9.6 (c 0.68, CHCl3); IR (neat) 3412, 3320, 2961, 2874, 1683, 1557, 1463, 1351 cm1; 1H NMR (400 MHz, CDCl3) d 7.76 (br d, J ¼ 2.6 Hz, 1H), 7.58 (dd, J ¼ 15.1, 11.6 Hz, 1H), 6.78 (dd, J ¼ 14.6, 11.2 Hz, 1H), 6.57 (d, J ¼ 15.0 Hz, 1H), 6.50 (d, J ¼ 15.1 Hz, 1H), 6.37 (dd, J ¼ 14.6, 11.6 Hz, 1H), 6.26 (dd, J ¼ 15.0, 11.2 Hz, 1H), 6.15 (br d, J ¼ 2.6 Hz, 1H), 5.45 (d, J ¼ 10.0 Hz, 1H), 3.43 (t, J ¼ 7.6 Hz, 1H), 3.20 (d, J ¼ 7.6 Hz, 1H), 3.16 (br s, 1H), 2.69e2.58 (m, 1H), 1.85e1.75 (m, 1H), 1.81 (br s, 3H), 1.34e1.20 (m, 3H), 1.11e1.08 (m, 2H), 1.01 (d, J ¼ 6.8 Hz, 3H), 0.96 (d, J ¼ 6.4 Hz,

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K. Tanaka III et al. / Tetrahedron 75 (2019) 1085e1097

3H), 0.93 (d, J ¼ 6.8 Hz, 3H), 0.84 (t, J ¼ 7.2 Hz, 3H), 0.82 (d, J ¼ 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 193.5, 166.7, 148.0, 146.2, 145.4, 145.0, 132.5, 128.9, 125.5, 120.2, 72.8, 65.2, 64.9, 44.7, 32.3, 31.9, 30.8, 30.1, 21.3, 19.1, 18.1, 17.9, 12.4, 11.2; HRMS (EIþ) m/z calcd for C24H37NO4 [M]þ: 403.2723 found 403.2717. 4.2.25. (1R,4S,5R)-4-hydroxy-4-isopropyl-1((2E,4E,6E,8E,10R,12R)-8,10,12-trimethyltetradeca-2,4,6,8tetraenoyl)-6-oxa-3-azabicyclo[3.1.0]hexan-2-one (2) and (1R,4R,5R)-4-hydroxy-4-isopropyl-1-((2E,4E,6E,8E,10R,12R)8,10,12-trimethyltetradeca-2,4,6,8-tetraenoyl)-6-oxa-3-azabicyclo [3.1.0]hexan-2-one (3) All of the following operations were performed in the dark. To a stirred solution of alcohol (R,R)-33 (40 mg, 0.099 mmol) in CH2Cl2 (1.0 mL) were successively added AZADOL (3.2 mg, 0.093 mmol) and PhI(OAc)2 (41 mg, 0.13 mmol) at 0  C. The reaction mixture was stirred for 12 h. The reaction was then quenched by addition of saturated aqueous NaHCO3 and Na2S2O3 solution and stirred vigorously for 10 min. The resulting mixture was extracted with CH2Cl2 (three times). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (4:1 hexane:acetone) to afford a 3:1 mixture of 2 and 3 (34.6 mg, 87% yield) as a yellow amorphous solid. Compounds 2 (25.2 mg, 63% yield, yellow amorphous solid) and 3 (8.4 mg, 21% yield, yellow amorphous solid) were separated by repeated column chromatography.  2: [a]20 D e96.1 (c 0.65, MeOH); IR (neat) 3454, 3231, 2962, 2925, 1732, 1708, 1659, 1577, 1407 cm1; 1H NMR (400 MHz, CD2Cl2) d 7.87 (br s, 1H), 7.33 (dd, J ¼ 15.1, 11.6 Hz, 1H), 6.71 (dd, J ¼ 14.6, 10.6 Hz, 1H), 6.48 (d, J ¼ 15.1 Hz, 1H), 6.31 (d, J ¼ 15.1 Hz, 1H), 6.31 (dd, J ¼ 14.6, 11.6 Hz, 1H), 6.23 (dd, J ¼ 15.1, 10.6 Hz, 1H), 5.45 (d, J ¼ 9.2 Hz, 1H), 4.49 (br s, 1H), 4.25 (d, J ¼ 2.8 Hz, 1H), 2.68e2.60 (m, 1H), 2.08e2.01 (m, 1H), 1.77 (br s, 3H), 1.34e1.27 (m, 2H), 1.31e1.22 (m, 1H), 1.18e1.03 (m, 2H), 1.15 (d, J ¼ 6.8 Hz, 3H), 1.09 (d, J ¼ 6.8 Hz, 3H), 0.97 (d, J ¼ 6.8 Hz, 3H), 0.85 (t, J ¼ 7.2 Hz, 3H), 0.83 (d, J ¼ 6.4 Hz, 3H); 13C NMR (100 MHz, CD2Cl2) d 189.9, 170.2, 146.7, 146.2, 145.4, 144.8, 133.0, 129.1, 125.9, 120.9, 87.7, 65.9, 61.0, 45.0, 33.7, 32.7, 31.1, 30.4, 21.4, 19.3, 17.8, 16.3, 12.6, 11.4; HRMS (EIþ) m/z calcd for C24H35NO4 [M]þ: 401.2566 found 401.2567.  3: [a]24 D e39.0 (c 0.67, MeOH); IR (neat) 3305, 2963, 2924, 2875, 1726, 1577, 1560, 1153, 1096, 1006 cm1; 1H NMR (400 MHz, CD2Cl2) d 7.50 (dd, J ¼ 15.0, 11.6 Hz, 1H), 6.82 (dd, J ¼ 14.8, 10.8 Hz, 1H), 6.53 (d, J ¼ 15.0 Hz, 1H), 6.47 (d, J ¼ 15.2 Hz, 1H), 6.39 (dd, J ¼ 14.8, 11.6 Hz, 1H), 6.30 (dd, J ¼ 15.2, 10.8 Hz, 1H), 6.16 (br s, 1H), 5.47 (d, J ¼ 10.0 Hz, 1H), 3.98 (d, J ¼ 2.8 Hz, 1H), 3.26 (br s, 1H), 2.70e2.61 (m, 1H), 2.12e2.06 (m, 1H), 1.81 (d, J ¼ 0.8 Hz, 3H), 1.35e1.21 (m, 3H), 1.19e1.09 (m, 2H), 1.04 (d, J ¼ 6.8 Hz, 3H), 1.00 (d, J ¼ 7.2 Hz, 3H), 0.96 (d, J ¼ 6.4 Hz, 3H), 0.85 (t, J ¼ 7.2 Hz, 3H), 0.83 (d, J ¼ 6.4 Hz, 3H); 13C NMR (100 MHz, CD2Cl2) d 187.5, 167.9, 146.7, 146.3, 145.6, 145.1, 133.0, 129.2, 125.9, 122.4, 87.4, 63.5, 63.2, 45.0, 34.6, 32.8, 31.2, 30.5, 21.4, 19.2, 16.2, 16.0, 12.6, 11.4; HRMS (EIþ) m/z calcd for C24H35NO4 [M]þ: 401.2566 found 401.2565. 4.2.26. (1R,4S,5R)-4-hydroxy-4-isopropyl-1-((2E,4E,6E,8E,10S,12S)8,10,12-trimethyltetradeca-2,4,6,8-tetraenoyl)-6-oxa-3-azabicyclo [3.1.0]hexan-2-one (4) and (1R,4R,5R)-4-hydroxy-4-isopropyl-1((2E,4E,6E,8E,10S,12S)-8,10,12-trimethyltetradeca-2,4,6,8tetraenoyl)-6-oxa-3-azabicyclo[3.1.0]hexan-2-one (5) Compounds 4 (9.4 mg, 26% yield, yellow amorphous solid) and 5 (13.4 mg, 38% yield, yellow amorphous solid) were obtained from (S,S)-33 (35.7 mg, 0.088 mmol) by a similar procedure to that used for the synthesis of compounds 2 and 3.  4: [a]20 D e15.6 (c 0.71, MeOH); IR (neat) 3454, 3235, 2962, 2924, 1732, 1707, 1658, 1578, 1407 cm1; 1H NMR (400 MHz, CD2Cl2) d 8.28 (br s, 1H), 7.24 (dd, J ¼ 14.9, 11.4 Hz, 1H), 6.68 (dd, J ¼ 14.7,

11.0 Hz, 1H), 6.43 (d, J ¼ 14.9 Hz, 1H), 6.29 (dd, J ¼ 14.7, 11.4 Hz, 1H), 6.27 (d, J ¼ 15.1 Hz, 1H), 6.21 (dd, J ¼ 15.1, 11.0 Hz, 1H), 5.41 (d, J ¼ 9.6 Hz, 1H), 4.64 (br s, 1H), 4.30 (d, J ¼ 2.8 Hz, 1H), 2.67e2.59 (m, 1H), 2.07e2.00 (m, 1H), 1.76 (br s, 3H), 1.33e1.23 (m, 2H), 1.29e1.22 (m, 1H), 1.20e1.07 (m, 2H), 1.15 (d, J ¼ 6.8 Hz, 3H), 1.11 (d, J ¼ 6.8 Hz, 3H), 0.95 (d, J ¼ 6.8 Hz, 3H), 0.84 (t, J ¼ 6.8 Hz, 3H), 0.82 (d, J ¼ 6.0 Hz, 3H); 13C NMR (100 MHz, CD2Cl2) d 190.0, 170.1, 146.8, 146.5, 145.3, 145.0, 133.1, 129.1, 125.9, 120.7, 87.7, 66.0, 60.9, 45.1, 33.7, 32.8, 31.2, 30.5, 21.5, 19.3, 17.8, 16.3, 12.7, 11.5; HRMS (EIþ) m/z calcd for C24H35NO4 [M]þ: 401.2566 found 401.2562.  5: [a]24 D e10.7 (c 0.65, MeOH); IR (neat) 3422, 2963, 2926, 2875, 1729, 1577, 1560, 1153, 1097, 1008 cm1; 1H NMR (400 MHz, CD2Cl2) d 7.50 (dd, J ¼ 15.0, 11.6 Hz, 1H), 6.82 (dd, J ¼ 14.8, 10.8 Hz, 1H), 6.53 (d, J ¼ 15.0 Hz, 1H), 6.47 (d, J ¼ 15.2 Hz, 1H), 6.39 (dd, J ¼ 14.8, 11.6 Hz, 1H), 6.30 (dd, J ¼ 15.2, 10.8 Hz, 1H), 5.94 (br s, 1H), 5.47 (d, J ¼ 10.0 Hz, 1H), 3.99 (d, J ¼ 2.4 Hz, 1H), 3.09 (br s, 1H), 2.71e2.59 (m, 1H), 2.14e2.04 (m, 1H), 1.81 (d, J ¼ 1.2 Hz, 3H), 1.36e1.20 (m, 3H), 1.19e1.09 (m, 2H), 1.04 (d, J ¼ 6.8 Hz, 3H), 1.00 (d, J ¼ 6.8 Hz, 3H), 0.96 (d, J ¼ 6.8 Hz, 3H), 0.85 (t, J ¼ 6.8 Hz, 3H), 0.83 (d, J ¼ 6.4 Hz, 3H); 13C NMR (100 MHz, CD2Cl2) d 187.5, 167.7, 146.7, 146.4, 145.7, 145.1, 133.0, 129.2, 125.9, 122.4, 87.3, 63.4, 63.2, 45.0, 34.6, 32.8, 31.2, 30.5, 21.4, 19.2, 16.2, 16.0, 12.6, 11.4; HRMS (EIþ) m/z calcd for C24H35NO4 [M]þ: 401.2566 found 401.2568. 4.3. Inhibitory activity against Ab aggregation The aggregation of Ab was evaluated using a slight modification of the thioflavin-T (Th-T) method developed by Naiki and coworkers [26,27]. Briefly, Ab40 (Peptide Institute, Osaka, Japan) was dissolved to a concentration of 250 mM in 0.02% NH4OH. The sample solution (10 mL) was diluted with 80 mL of 50 mM sodium phosphate containing 100 mM NaCl at pH 7.4, followed by the addition of 10 mL of the peptide solution. All procedures were performed on ice. The mixture (containing 25 mM of Ab40 and the test sample in phosphate buffer solution) was incubated at 37  C for 24 h and then diluted with 300 mL of 5 mM Th-T (Wako Pure Chemical Industries, Ltd., Osaka, Japan) in 50 mM GlyeNaOH buffer (pH 8.5). The solution was transferred to black-bottomed 96-well plates at 100 mL per well and then gently vortexed for 30 min. The fluorescence intensity was measured at excitation and emission wavelengths of 440 nm and 485 nm, respectively, using a Synergy HTX Multi-Mode Reader (BioTek, Winooski, VT). The aggregation of Ab40 was calculated by comparing the fluorescence intensity of each sample to that of a control (25 mM Ab40 and DMSO containing no test sample). Acknowledgments This work was supported by JSPS KAKENHI Grant Number 17K08227 and partially supported by a grant from the Dementia Drug Resource Development Center, Project S1511016, the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.tet.2019.01.020. References [1] Y.-K.T. Lam, O.D. Hensens, R. Ransom, R.A. Giacobbe, J. Polishook, D. Zink, Tetrahedron 52 (1996) 1481e1486. [2] (a) J.N. Sharma, G.J. Al-Sherif, Sci. World J. 6 (2006) 1247e1261; (b) J.N. Sharma, G.J. Al-Sherif, Am. J. Biomed. Sci. 3 (2011) 156e169. [3] H. Kakeya, I. Takahashi, G. Okada, K. Isono, H. Osada, J. Antibiot. 48 (1995)

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