Convergent Total Synthesis of Paecilomycin B and 6â²-epi

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Convergent Total Synthesis of Paecilomycin B and 6´-epi-Paecilomycin B by Barbier-type Reaction Using 2,4,6-Triisopropylphenyllithium Kiyomi Ohba, and Masaya Nakata J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 08 Feb 2018 Downloaded from http://pubs.acs.org on February 8, 2018

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The Journal of Organic Chemistry

Convergent Total Synthesis of Paecilomycin B and 6´-epiPaecilomycin B by Barbier-type Reaction Using 2,4,6Triisopropylphenyllithium Kiyomi Ohba*,† and Masaya Nakata‡ †

Research Unit, Innovative Medical Science, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan ‡ Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan Supporting Information Placeholder

ABSTRACT: The convergent total synthesis of the natural product paecilomycin B and its 6´-epimer was investigated. The aryl-Cglycoside skeleton was constructed by an intramolecular Barbier-type reaction using 2,4,6-triisopropylphenyllithium and subsequent deoxygenation of the resulting anomeric hydroxy group. Starting from aryl iodide 24, the addition reaction afforded the thermodynamically stable C-β macrocyclic adduct 41a in 29% yield and the C-α adduct 41b in 1 % yield. Meanwhile, aryl iodide 43 (6´-epimer of 24) gave only the C-α adduct 44 in 76 % yield. The stereoselectivities of these nucleophilic addition reactions are also discussed.

INTRODUCTION Resorcylic acid lactones (RALs) and dihydroxyphenylacetic acid lactones (DALs) are a family of polyketide-derived macrolides.1 These macrolides exhibit various biological activities including anti-tumor, anti-inflammatory, anti-bacterial, and anti-oxidant properties. For example, radicicol (1)2 inhibits heat shock protein 90 and possesses antiplasmodial activities (Figure 1). Hypothemycin (2)3 irreversibly inhibits mitogenactivated protein kinases, and curvularin (3)4 exhibits antiinflammatory effects. Paecilomycins A–F (4–9) were isolated by Chen and Wei5 in 2010 from mycelial solid cultures of Paecilomyces sp. SC0924 and showed high to moderate antiplasmodial activities (Figure 2). Subsequently, paecilomycins G–M (10–16) were isolated.6 To date, total syntheses of paecilomycins B, E, F, and G have been achieved.7 Many practical synthetic procedures for the macrolactone ring formation have been employed and developed over the years, such as macrolactonization,8 cross-coupling reaction9 and ring closing metathesis (RCM).10 With regard to nucleophilic addition reactions, Nozaki–Hiyama–Kishi (NHK) coupling11 has been used preferentially due to its mild reaction conditions. Meanwhile, there are a few reports that mention macrolactonization via intramolecular nucleophilic additions using lithium, sodium, or Grignard reagents possessing high reactivity for the ester groups. For example, Tsuji12a reported a

synthetic method for macrolides based on an intramolecular alkylation of the dianions generated from a phenylthiomethyl group and a protected cyanohydrin, and Banwell12b reported an intramolecular addition reaction of the lithium acetylide generated in situ using LiHMDS to the pendant Weinreb amide. Recently, we reported a novel synthetic method of aryl-β-Cglycosides having an ester, cyano, or carbonyl group on the aromatic ring using 2,4,6-triisopropylphenyllithium (TIPPLi) as a chemoselective halogen–lithium exchange reagent under Barbier-type reaction conditions.13 Additionally, we have already reported the first total synthesis of paecilomycin B (5) via this functionalized aryl-β-C-glycoside synthetic methodolOH O

OH O O

O

O

OH

MeO

HO

O O

Cl

O Radicicol, 1

OH

Hypothemycin, 2 O

O

HO

OH

O

Curvularin, 3

Figure 1. Structures of radicicol, hypothemycin, and curvularin, 1–3.

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ogy and RCM as the key steps with the longest linear sequence of 22 steps.7a Herein, we describe two new syntheses of paecilomycin B (5) and 6´-epi-paecilomycin B (34) (vide infra). The key macrocyclization reactions are NHK coupling and the Barbier-type reaction using TIPPLi.

OH O

OH O 3

O MeO

MeO

OH

O

1

O O

6'

1'

HO

OH OH Paecilomycin A, 4

OH

5'

OH

Paecilomycin B, 5

OH O

OH O O

OH

O

MeO

R1

MeO OH OH R2 R1 Paecilomycin C, 6 (R1 = H, R2 = OH) Paecilomycin D, 7 (R1 = OH, R2 = H)

OH

R3 R2

OH Paecilomycin E, 8 (R1, R2 = OH, R3 = H) 1 Paecilomycin F, 9 (R , R3 = OH, R2 = H) Paecilomycin G, 10 (R1, R2 = H, R3 = OH) OH O

OH O

O

O MeO

HO

OEt OH

O

O

O O

OH

Paecilomycin H, 11

Paecilomycin I, 12

OH O

OH O O OH

MeO

H

MeO O

OH

O

O OH R3 R2

H

O OH HO

H

O OH

H H R1 Paecilomycin J, 13 (R1, R3 = OH, R2 = H) Paecilomycin K, 15 Paecilomycin L, 14 (R1, R3 = H, R2 = OH)

O H

OH

Paecilomycin M, 16

Figure 2. Structures of paecilomycins A–M, 4–16.

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RESULTS AND DISCUSSION Our retrosynthetic routes for the synthesis of paecilomycin B (5) are shown in Scheme 1, including the previously reported route (route A-1) where the key macrocyclization was achieved through the RCM approach.7a The key intermediate diene 17 was obtained from the coupling product 19, which was synthesized from aryl bromide 20 and δ-lactone 21 by the intermolecular Barbier-type reaction using TIPPLi. Segments 20 and 21 were prepared from 1-bromo-3,5-dimethoxybenzene (22a) and p-methoxyphenyl (PMP) β-D-glucopyranoside 23, respectively. Starting from lactone 19, we designed a new synthetic route (route A-2) in which the intramolecular NHK reaction of vinyl iodide 18 would be employed for the macrocyclization process. Vinyl iodide 18 would be synthesized from lactone 19 through several steps including Mitsunobu esterification14 and Dess–Martin periodinane (DMP) oxidation15 of the primary alcohol. The intramolecular nucleophilic addition route (route B), the main issue in this report, is illustrated in the lower part of Scheme 1. We designed aryl iodide 24 as the key intermediate containing the six-membered lactone ring. Aryl iodide 24 would be synthesized from vinyl iodide 25 and aldehyde 26 by NHK coupling and subsequent scission of the anomeric PMP-ether followed by oxidation. Vinyl iodide 25 could be obtained from 2-iodo-4,6dimethoxybenzoic acid derived from 22b and chiral alcohol 27 by Mitsunobu esterification. Aldehyde 26 could be accessed from glucopyranoside 23 through deoxygenation of the C-3 hydroxy group followed by oxidation of the C-6 hydroxy group. The key aryl-C-glycoside synthesis of the previously reported RCM synthetic route (route A-1) is shown in Scheme 2. The coupling reaction of aryl bromide 20 and δ-lactone 21 using TIPPLi under Barbier-type reaction conditions afforded spiroketal 28 in 89% yield. After the conversion to methyl glycoside 29 under acidic conditions (methanol/methanesulfonic acid) in 67% yield, the deoxygenation of the anomeric position was achieved using Et3SiH and BF3·Et2O in a stereoselective manner16 to afford the corresponding aryl-Cglycoside 30 in 89% yield.

Scheme 1. Retrosynthesis of Paecilomycin B, 5


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Scheme 2. Construction of the Aryl-C-glycoside Skeleton (Route A-1) iPr

PG = N,N-dimethylcarbamoyl O

iPr

iPr Li

20

+

BnO

21 THF, –78 °C, 20 min 89%

O

OPG MeSO3H MeOH

O

BnO

OMe 50 °C, 64 h 67%

OTBS 28

OMe

OMe

BnO

Et3SiH, BF3Et2O TFA, CH2Cl2

MeO O

BnO

O 29

BnO

OPG O

–30 °C, 2 h 89%

O

BnO

H OPG O

O

30

Next, starting from intermediate 19 which was prepared from 30 by a selective debenzylation, we conducted the synthesis of paecilomycin B (5) using the intramolecular NHK reaction as the key macrocyclization step (route A-2, Scheme 3). The removal of the N,N-dimethylcarbamoyl group and hydrolysis of the lactone ring of 19 were achieved using aqueous NaOH to afford triol carboxylic acid in 71% yield, which was treated with excess TBSCl/imidazole to yield a persilylated compound. Subsequent hydrolysis using aqueous NaOH gave disilylated product 31 in 84% yield. Subjection of carboxylic acid 31 and alcohol 27 to the Mitsunobu reaction using N,N´-diisopropylcarbodiimide (DIAD)/PPh3 afforded ester 32 with inversion of configuration in 72% yield. The chiral alcohol 27 was synthesized based on a known method (Scheme 4).1d,17 Namely, the known E-vinylboronic acid pinacol ester 36 derived from commercially available chiral alco hol 35 was converted into iodide 37 followed by deprotection under acidic conditions to afford 27 in 71% yield over two steps. After the protection of the phenol group in 32 as its

MOM ether, selective desilylation of the TBS group of the primary hydroxy protecting group was achieved using (±)-10camphorsulfonic acid (CSA) in MeOH to produce a primary alcohol in 96% yield, which was oxidized with DMP to afford the corresponding aldehyde 18 in 90% yield. With the precursor 18 in hand, this was subjected to the intramolecular NHK coupling reaction using CrCl2/NiCl2 to produce the desired coupling product 33a in 42% yield, accompanied by its C6´ epimer 33b in 37% yield. Unfortunately, our efforts for increasing the ratio of the desired isomer using chiral sulfonamide ligand11b-d did not improve the ratio drastically. Furthermore, our attempts for the DMP oxidation and subsequent stereoselective reduction using Zn(BH4)2 reduction,18a,b Luche reduction,18c or Corey–Bakshi–Shibata reduction18d failed to afford the desired epimer 33a selectively (data not shown). The TBS and MOM groups of the obtained macrolactone 33a were removed with methanesulfonic acid to produce the triol in 89% yield, whose analytical NMR and MS data were identical with our previously reported data.7a Subsequent debenzylation using TiCl4 led to paecilomycin B (5). Additionally, 6′-epi-paecilomycin B (34) was prepared according to the same scheme above. The treatment of 6′-epimer 33b with methanol/methanesulfonic acid afforded the triol in 83% yield, subsequent exposure of which to TiCl4 furnished 6′-epipaecilomycin B (34) in 84% yield. Thus, we accomplished the total synthesis of paecilomycin B (5) through the RCM route or the intramolecular NHK coupling route mentioned above. In these synthetic routes, an isomerization step from 28 to 29 was required after the intermolecular nucleophilic coupling reaction due to the spontaneous spirolactonization between the generated alkoxide and methyl ester moieties (Scheme 2). Our attempts for direct deoxygenation at the anomeric position of this spiroketal using several reducing reagents failed to afford the desired deoxygenated product. Therefore, we examined the applicability of our functionalized aryl-β-C-glycoside synthetic method using

Scheme 3. Synthesis of Paecilomycin B and 6´-epi- Paecilomycin B (Intramolecular NHK Coupling Route)



Scheme 4. Synthesis of Alcohol 27

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Scheme 7. Synthesis of Paecilomycin B (Intramolecular Nucleophilic Addition Route)

TIPPLi for the macrocyclization step (Scheme 1, route B). This approach would avoid the spirolactonization due to steric restrictions, and hence could lead to more effective and convergent synthesis of paecilomycin B (5). The synthetic routes for the vinyl iodide 25 and aldehyde 26 intermediates are shown in Schemes 5 and 6, respectively. 1Iodo-3,5-dimethoxybenzene (22b) was subjected to the Vilsmeier reaction, and the resulting aldehyde was converted to the known carboxylic acid 3819 by Kraus–Pinnick oxidation. Ester 25 was obtained by Mitsunobu esterification between benzoic acid 38 and the chiral alcohol 27 in 95% yield. Precursor 26 was obtained from the known 3-deoxy glucoside 3920. The benzylidene moiety of 39 was reduced with the combination of LiAlH4/AlCl321 in 57% yield, and the generated primary hydroxy group was oxidized with DMP to afford aldehyde 26 in 85% yield. Scheme 5. Synthesis of Vinyl Iodide 25

Scheme 6. Synthesis of Aldehyde 26

With vinyl iodide 25 and aldehyde 26 in hand, we conducted the NHK coupling reaction using CrCl2/NiCl2 in DMF to give the desired coupling product 40a in 16% yield along with its C6´ epimer 40b in 40% yield (Scheme 7). We presumed that this stereoselectivity was induced by the Si-face attack of the nucleophiles due to the chelation of chromium between the oxygen of the carbonyl group and the oxygen of the pyran ring. Our attempt to improve the stereoselectivity using chiral sulfonamide ligand11b-d failed; therefore, the epimer 40b was converted into 40a by oxidation and subsequent stereoselective reduction using Zn(BH4)218a,b in 79% yield over two steps. The hydroxy group of the obtained coupling product 40a was protected with TBSCl/imidazole to afford the silylether in 95% yield, whose p-methoxyphenyl group was removed by treatment with CAN22 in toluene–CH3CN–H2O to give an anomeric mixture in 72% yield. DMP oxidation of the generated hydroxy group furnished lactone 24 in 91% yield. With precursor 24 in hand, we performed the key intramolecular nucleophilic addition reaction using TIPPLi for the

macrolactone ring formation. As expected, the desired adducts 41a (C-β: 29%) and 41b (C-α: 1%) were isolated without spontaneous spiroketalization between the generated alkoxide and the ester group on the aromatic ring, though the yields were not high. It should be noted that the isomerization of 41b to 41a occurred during extraction and column chromatography on silica gel, while only 41b was initially detected by TLC. Subsequently, the deoxygenation of 41a using Et3SiH and BF3·Et2O proceeded in a stereoselective manner via the forNOE

NOE H

H O

TBSO H

OMe

O

H

TBSO BnO

O

O

BnO

H H

H

OTBS O H

H

OMe

OH O O OTBS H

H MeO

41a

OMe

41b

NOE H O

HO H

OMe

O O

BnO H H

OH H

OMe

42

Figure 3. Determination of the configurations of 41a, 41b, and 42.


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mation of a carbocation intermediate along with the elimination of the TBS groups to give macrolactone 42 in 84% yield. The configurations of 41a, 41b, and 42 were confirmed by NOE measurements (Figure 3). Finally, deprotections of the methoxy group on the aromatic ring and the benzyl group of the 4′-position of the pyran ring were achieved simultaneously by boron tribromide to furnish paecilomycin B (5) in 54% yield, whose analytical data including MS, 1H NMR, and 13C NMR spectra were identical with the previously reported data.7a Furthermore, to evaluate the potency of our methodology, we attempted the synthesis of 6′-epi-paecilomycin B (34) starting from 6′-epimer 40b by the intramolecular nucleophilic addition reaction using TIPPLi as the key macrocyclization step. The synthesis of 6′-epi-paecilomycin B (34) was achieved using a similar procedure as that for paecilomycin B (5) described in Scheme 7. Namely, the hydroxy group of 40b was protected as its TBS ester, and the anomeric position was hydrolyzed using CAN in an aqueous medium. The resulting anomeric mixture was treated with DMP to afford δ-lactone 43 as the macrocyclization precursor in 60% yield over three steps (Scheme 8). The obtained aryl iodide 43 including the δlactone moiety was exposed to TIPPLi in THF at −78 °C to Scheme 8. Synthesis of 6´-epi- Paecilomycin B (Intramolecular Nucleophilic Addition Route) O

OMe

6' HO

I OPMP

O

BnO

O

1) TBSCl, imidazole, DMF 80 °C, 3 h 92%

O

I O

OMe O

2) CAN TBSO toluene-CH3CN-H2O 0 °C, 0.5 h BnO 68% 3) DMP, CH2Cl2 rt, 16 h 96%

OTBS 40b

OMe

O OMe

OTBS

produce the macrocyclized adduct 44 as a single C-α isomer in 76% yield. The reduction of the anomeric hydroxy group of 44 was conducted using Et3SiH and BF3·Et2O to afford the arylβ-C-glycoside 45 with inversion of configuration in 39% yield. In this case, though the deoxygenation proceeded at low temperature, only partial removal of the TBS groups was observed. Hence, treatment of the crude mixture with methanol/methanesulfonic acid was required. The configurations of 44 and 45 were confirmed by NOE measurements (Figure 4). Subsequent exposure of 45 to boron tribromide furnished 6′epi-paecilomycin B (34) in 61% yield. Many previous studies23 showed that the nucleophilic addition reaction to aldonolactone by an aryllithium afforded predominantly aryl C-β adducts after usual workup using a saturated aqueous solution of ammonium chloride. As an isomerization of the obtained hemiketal could occur, it is unclear whether α-attack or β-attack of aryllithium to the δ-lactone preferentially occurs under kinetic control conditions. Meanwhile, in this study, it seems that α-attack preferentially occurred to form C-α macrocyclized adducts 41b and 44, though the coupling reaction of 20 and 21 using TIPPLi afforded C-β spiroketal 28 (see Scheme 2 and note 9b of ref 7a). We observed similar C-α stereoselectivities in intermolecular nucleophilic addition reactions between the perbenzylated or persilylated δ-gluconolactone and methyl 2-halobenzoate to form C-α spiroketals.13a For instance, the coupling reaction between methyl 2-iodobenzoate (46) and the perbenzylated gluconolactone 47 using TIPPLi under Barbier-type conditions afforded spiroketal 48 with spontaneous lactonization in 69% yield as an anomeric mixture (C-α:β = 7:1) (Scheme 9). Scheme 9. Barbier-type Reaction with 46 and 47 iPr

43

O O

iPr

+ CO2Me iPr Li (3 equiv) THF, –78 °C, 0.5 h 76%

TBSO

O OH O

BnO

Et3SiH, BF3Et2O CH2Cl2 –20 °C, 4 h

OMe

O

iPr

OMe

then MeSO3H, MeOH rt, 2 h 39%

OTBS 44 C-alpha

O

HO

OMe

BnO

OMe OH

45 C-beta

O

BBr3, CH2Cl2

O O

0 °C, 0.5 h 61%

HO HO

OH

O O

OMe OH

6'-epi-Paecilomycin B, 34

iPr OBn

O BnO

I 46

OBn OBn 47

O

iPr Li

O

OBn

BnO THF, –78 °C, 1 h 69%

OBn OBn 48 C-alpha : C-beta = 7 : 1

Two similar findings were reported in the cases the generated alkoxide could trap spontaneously by acylation or alkylation. Dondoni24a revealed that the coupling reaction between 2lithiothiazole and aldonolactones 49 afforded only C-β adducts after usual acidic workup, while trapping of the generated alkoxide by acetic anhydride gave preferentially C-α adducts 50 (Scheme 10). Schweizer24b also showed that Claisen condensation between aldonolactones 49 and tert-butyl bromoacetate led to C-α exocyclic epoxides 51 (Scheme 11). Scheme 10. Nucleophilic Addition Reactions by 2lithiothiazole to aldonolactones (Dondoni et al.) N

O OBn

O BnO

Li

(1.2 equiv)

49 (1.0 equiv)

Et2O-THF, –78 °C, 45 min then Ac2O (10 equiv), –65 °C then –65 °C, 1 h

perbenzylated aldono-1,5-lactones (D-glucono-, D-mannono-, D-galactono-)


S OAc OBn

O BnO

OBn OBn

Figure 4. Determination of the configurations of 44 and 45.

N

S

OBn OBn 50

D-glucoC-alpha : beta = 7:1 D-manno- C-alpha only D-galacto- C-alpha : beta = 10:1


Scheme 11. Claisen Condensation between Aldonolactones 49 and tert-Butyl Bromoacetate (Schweizer et al.)

Page 6 of 14

tem.26 Estimated transition states of α-attack versus β-attack are depicted in Figure 6. We presumed that the effect of torsional strain contributes for the α-attack of the nucleophile more than that of the steric repulsions between the nucleophile and the 3,5-axial protons. Moreover, there may be the influence of the electrostatic repulsion between the negative nucleophile and lone pair of the oxygen of the pyran ring. This may be advantageous to α-attack.

To confirm these C-α stereoselectivities, we undertook an additional experiment to trap the generated alkoxide by acetic anhydride (Scheme 12). We previously reported that the coupling reaction between tert-butyl 4-iodobenzoate (52) and the perbenzylated gluconolactone 47 using TIPPLi under Barbiertype conditions afforded aryl C-β glucoside 53 in 93% yield after the usual aqueous acidic quenching operations. In contrast, quenching with excess acetic anhydride resulted in the formation of the acetylated aryl C-α glucoside 54 in 80% yield accompanied by C-β glucoside 53 in 5% yield, which would be obtained from the non-acetylated C-α glucoside via epimerization during workup or purification. The C-α configurations of 48 and 55 were confirmed by NOE measurements shown in Figure 5. Scheme 12. Nucleophilic Addition Reactions with Perbenzylated Lactone 47

Figure 6. Stereoselectivity in nuclephillic addition to aldonolacton.

Based on the above discussion, in the cases of aldono-1,5lactones (glucono-, mannono-, galactono-), it seems that the generated aryllithium attacked the δ-lactone moiety preferentially from the α-face under kinetically-controlled conditions, and the isomerization to the thermodynamically stable C-β isomer occurred during acidic aqueous workup. In the case of intramolecular nucleophilic additions for the syntheses of paecilomycin B (5) and 6′-epi-paecilomycin (34), α-attack of the generated aryllithium to the δ-lactone moieties seemed to occur preferentially, though some difference was observed in the isolated yields. The exposure of aryl iodide 24 to TIPPLi afforded the corresponding coupling product in low total 30% yield. We presumed that steric repulsion between the 4′-OBn group and the 6′-OTBS group of the lithiated 24 (24′) might interfere with the desired α-attack conformation to diminish the yield of the cyclized adduct 41b, while the reaction of the lithiated 43 (43′) yielded the coupling product 44 in 76% yield since the desired conformation was more accessible to the nucleophilic addition (Figure 7). The same reasoning would be applicable to the observation that 41b (C-α) easily isomerized to 41a (C-β) but 44 (C-α) does not.

Figure 5. Determination of the configurations of 48 and 54. We presumed that these C-α stereoselectivities were derived from less torsional strain in the transition structure of the axial attack than that of the equatorial attack on the basis of the Felkin torsional strain theory25 and the computational studies of the nucleophilic additions to cyclohexanone and related sys-

Figure 7. The α-attacks of aryl lithiums to the lactone moieties.


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CONCLUSION In conclusion, we accomplished the total synthesis of paecilomycin B (5) and 6′-epi-paecilomycin B (34) based on our functionalized aryl-β-C-glycoside synthetic method using TIPPLi for the construction of the 2-aryltetrahydropyran skeleton. We developed three routes for the synthesis of paecilomycin B (5) with different macrocyclization methods, i.e., the RCM route via the longest linear sequence of 22 steps in 2.4% overall yield (24 steps, 3.7%, including recovery), the intramolecular NHK coupling route via the longest linear sequence of 22 steps in 2.1% overall yield, and the intramolecular nucleophilic addition route via the longest linear sequence of 14 steps in 0.44% overall yield (16 steps, 1.3%, including recovery). Thus, direct macrocyclization with TIPPLi enabled convergent synthesis of paecilomycin B and shortened the synthetic steps. The synthetic methods for paecilomycin B developed here would be useful for the syntheses of new derivatives.

EXPERIMENTAL SECTION General Information. Optical rotations were measured on a polarimeter. IR spectra were measured by attenuated total reflection infrared spectroscopy (ATR-IR). Chemical shifts of 1H and 13C NMR spectra were expressed in ppm relative to tetramethylsilane = 0.00 in CDCl3, CD3OD, or pyridine-d5 unless noted. Low-resolution mass spectra were measured by eluting with 10 mM AcONH4/MeOH (APCI-MS: atmospheric pressure chemical ionization mass spectrometry). High-resolution mass spectra were measured by eluting with 10 mM HCOONH4/CH3CN (APCI-MS). Analytical thin layer chromatography (TLC) was performed using 60F-254 plates (0.25 mm), and visualization was accomplished with UV light or ethanolic phosphomolybdic acid. All reagents and solvents were purchased from commercial suppliers and used without further purification unless otherwise noted. Experimens requiring anhydrous conditions were performed under nitrogen atmosphere. Experimental procedures and compound characterization data in Scheme 2 were already reported in Supporting Information of ref. 7a. Structure Determination. COSY, NOESY, HSQC, and HMBC of all new compounds were measured in addition to 1H and 13 C NMR spectra. The α- or β-configuration of the products was determined by NOE measurement in 1H NMR experiments. 2-[(2S,3R,5S,6R)-5-Benzyloxy-3-[tert-butyl(dimethyl)silyl]oxy-6-[[tert-butyl-(dimethyl)silyl]oxymethyl]tetrahydropyran-2-yl]-6-hydroxy-4-methoxybenzoic acid (31). To a solution of [(2R,3S,4aR,10bS)-3-benzyloxy-2-(hydroxymethyl)-9methoxy-6-oxo-3,4,4a,10b-tetrahydro-2H-pyrano[3,2-c]isochromen7-yl] N,N-dimethylcarbamate (19)7a (1.50 g, 3.28 mmol) in EtOH (20.0 mL) was added 2 M aqueous NaOH (8.20 mL, 16.4 mmol) at rt, and then the mixture was refluxed for 30 min. After cooling in an ice– bath, to the mixture were added H2O (40 mL) and CHCl3 (40 mL), and the new mixture was acidified with 1 M aqueous HCl (20 mL). The organic layer was separated and the aqueous layer was extracted with CHCl3 (40 mL × 2). The extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residual solid was triturated with Et2O (10 mL) and filtered to give 2-[(2S,3R,5S,6R)-5-benzyloxy3-hydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]-6-hydroxy-4methoxybenzoic acid (S1) (935 mg, 71%) as a colorless amorphous solid; Rf = 0.24 (4:1 CHCl3–MeOH); IR (ATR, cm–1) 3446 (OH), 2941 , 2512 , 1610 (C═O), 1206, 1021; 1H NMR (400 MHz, CD3OD) δ 1.57 (1H, q, J = 11.3 Hz), 2.64 (1H, dt, J = 11.8, 4.6 Hz), 3.39 (1H, ddd, J = 9.3, 5.1, 2.1 Hz), 3.50–3.63 (2H, m), 3.69 (1H, dd, J = 12.1, 5.4 Hz), 3.80 (3H, s), 3.86 (1H, dd, J = 12.1, 2.3 Hz), 4.54 (1H, d, J = 11.3 Hz), 4.67 (1H, d, J = 11.8 Hz), 5.16 (1H, d, J = 9.3 Hz), 6.41 (1H, d, J = 2.6 Hz), 6.77 (1H, d, J = 2.6 Hz), 7.21–7.41 (5H, m); 13C NMR (100 MHz, CD3OD) δ 40.3, 55.9, 62.8, 71.8, 72.2, 73.8, 81.3, 83.2, 101.5, 107.9, 108.9, 128.8, 129.0 (2C), 129.4 (2C), 139.9, 144.8, 164.3, 165.2, 174.1; LRMS (APCI) m/z 405 [M + H]+; Anal. Calcd for C21H24O8: C, 62.37; H, 5.98. Found: C, 62.45; H, 5.87; [α]25D +64.2

(c 0.50, MeOH). To a solution of S1 (891 mg, 2.20 mmol) in DMF (17.8 mL) were added imidazole (1.20 g, 17.6 mmol) and TBSCl (2.66 g, 17.6 mmol) at rt and the mixture was heated at 80 °C for 30 min. After cooling, the mixture was diluted with EtOAc (80 mL), and to this was added H2O (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (50 mL). The extracts were washed with H2O (100 mL) and saturated aqueous NaCl (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude colorless syrup, which was dissolved in MeOH (26.7 mL) and the solution was treated with 2 M aqueous NaOH (8.81 mL, 17.6 mmol) at rt and stirred at the same temperature for 30 min. The reaction mixture was treated with 10% aqueous citric acid (100 mL) and extracted with CHCl3 (50 mL × 2). The extracts were washed with H2O (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane only to 2:1 hexane–EtOAc to 4:1 CHCl3–MeOH) to afford 31 (1.17 g, ca. 84%, unstable, impure) as a slightly yellow syrup; Rf = 0.29 (20:1 CHCl3–MeOH); 1H NMR (400 MHz, CD3OD) δ −0.54, −0.24, 0.01, 0.04 (each 3H, s), 0.65, 0.86 (each 9H, s), 1.49 (1H, q, J = 11.3 Hz), 2.35 (1H, dt, J = 11.8, 4.4 Hz), 3.28–3.39 (2H, m), 3.55– 3.65 (1H, m), 3.74 (3H, s), 3.84 (1H, dd, J = 10.8, 4.1 Hz), 3.89 (1H, dd, J = 10.8, 1.0 Hz), 4.52 (1H, d, J = 11.3 Hz), 4.59 (1H, d, J = 11.3 Hz), 5.40 (1H, d, J = 8.7 Hz), 6.33 (1H, d, J = 2.6 Hz), 6.66 (1H, d, J = 3.1 Hz), 7.19–7.33 (5H, m); 13C NMR (100 MHz, CD3OD) δ −5.2, −4.8, −4.73, −4.67, 18.7, 19.3, 26.4 (3C), 26.7 (3C), 41.8, 56.0, 64.1, 72.8, 73.4, 74.8, 81.4, 83.4, 101.5, 107.9, 108.0, 129.0, 129.2 (2C), 129.5 (2C), 140.0, 146.4, 165.5, 173.1, 174.5; (APCI) m/z 631 [M – H]–. tert-Butyl-[(E,1R)-4-iodo-1-methyl-but-3-enoxy]-dimethylsilane (37). To a solution of tert-butyldimethyl-[(E,1R)-1-methyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enoxy]silane (36)1d (20.5 g, 62.8 mmol) in THF (62.8 mL) was added 1.0 M aqueous NaOH (314 mL, 314 mmol) at rt. To this mixture was added iodine (31.9 g, 126 mmol) in THF (126 mL) at rt, and the mixture was stirred at the same temperature for 30 min. To the mixture was added hexane (200 mL) and the organic layer was separated. The aqueous layer was extracted with hexane (100 mL). The extracts were washed with 10% aqueous Na2S2O3 (200 mL) and saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane only) to afford 37 (15.6 g, 76%) as a colorless oil; Rf = 0.33 (hexane only); IR (ATR, cm–1) 1082, 833, 773; 1H NMR (400 MHz, CDCl3) δ 0.05 (6H, s), 0.88 (9H, s), 1.13 (3H, d, J = 6.1 Hz), 2.10–2.20 (2H, m), 3.84 (1H, sxt, J = 5.9 Hz), 6.02 (1H, dt, J = 14.3, 1.3 Hz), 6.52 (1H, dt, J = 14.8, 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ −4.7, −4.6, 18.1, 23.5, 25.8 (3C), 46.0, 67.5, 76.4, 143.6; LRMS (APCI) m/z 327 [M + H]+, 195 [M − OTBS]+ base peak; HRMS (APCI-Ion Trap) m/z: [M + H]+ Calcd for C12H24IOSi 327.0636; Found 327.0624; [α]25D −10.7 (c 1.05, CHCl3). (E)-(R)-5-Iodo-pent-4-en-2-ol (27). To a solution of 37 (11.1 g, 34.0 mmol) in MeOH (45.0 mL) was added methanesulfonic acid (0.220 mL, 3.39 mmol) at rt, and the mixture was stirred at the same temperature for 18 h. The mixture was treated with Et3N (0.95 mL, 6.82 mmol) and the solution was concentrated in vacuo. The residue was diluted with CHCl3 (30 mL), and the mixture was treated with saturated aqueous NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with CHCl3 (20 mL). The extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (4:1 to 2:1 hexane–EtOAc) to afford 27 (6.75 g, 94%) as a colorless syrup; Rf = 0.29 (4:1 hexane–EtOAc); IR (ATR, cm–1) 3337 (OH), 946; 1H NMR (400 MHz, CDCl3) δ 1.21 (3H, d, J = 6.1 Hz), 1.49 (1H, d, J = 4.6 Hz), 2.11–2.29 (2H, m), 3.78–3.95 (1H, m), 6.14 (1H, dt, J = 14.3, 1.5 Hz), 6.56 (1H, dt, J = 14.6, 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 22.9, 45.5, 66.6, 77.5, 142.6; LRMS (APCI) m/z 195 [M − OH]+; HRMS (APCI-Ion Trap) m/z: [M + H −H2O]+ Calcd for C5H8I 194.9665; Found 194.9660; [α]25D −15.4 (c 1.06, CHCl3). [(E,1S)-4-Iodo-1-methyl-but-3-enyl] 2-[(2S,3R,5S,6R)-5benzyloxy-3-[tert-butyl(dimethyl)silyl]oxy-6-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydropyran-2-yl]-6-hydroxy-4-



methoxybenzoate (32). To a solution of 31 (1.13 g, 1.79 mmol, impure), (E)-(R)-5-iodo-pent-4-en-2-ol (27) (568 mg, 2.68 mmol) and PPh3 (750 mg, 2.86 mmol) in THF (22.6 mL) was added DIAD (1.50 mL, 2.86 mmol, 40 wt% toluene solution) at rt. The mixture was stirred at the same temperature for 30 min, and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (wako NH-SiO2, 20:1 to 1:1 hexane–EtOAc) to give the crude mixture. The mixture was purified by column chromatography on silica gel (SiO2, hexane only to 20:1 hexane–EtOAc) to afford 32 (1.03 g, 72%) as a colorless syrup; Rf = 0.29 (20:1 hexane–EtOAc); IR (ATR, cm–1) 1648, 1615, 1250, 1071, 833; 1H NMR (400 MHz, CDCl3) δ −0.49, −0.24, 0.08, 0.11 (each 3H, s), 0.69, 0.93 (each 9H, s), 1.41 (3H, d, J = 6.2 Hz), 1.57 (1H, q, J = 12.3 Hz), 2.31–2.51 (3H, m), 3.24 (1H, ddd, J = 10.9, 8.6, 4.1 Hz), 3.38 (1H, dt, J = 9.3, 2.6 Hz), 3.61–3.73 (1H, m), 3.80 (3H, s), 3.89–4.01 (2H, m), 4.60 (1H, d, J = 11.3 Hz), 4.65 (1H, d, J = 11.8 Hz), 5.22 (1H, sxt, J = 6.2 Hz), 5.43 (1H, d, J = 8.7 Hz), 6.16 (1H, d, J = 14.4 Hz), 6.40 (1H, d, J = 2.6 Hz), 6.52 (1H, dt, J = 14.9, 7.2 Hz), 6.76 (1H, d, J = 3.1 Hz), 7.27–7.42 (5H, m), 11.50 (1H, s); 13C NMR (100 MHz, CDCl3) δ −5.6, −5.4, −5.1, −5.0, 17.7, 18.4, 19.3, 25.6 (3C), 26.0 (3C), 40.6, 42.2, 55.4, 62.6, 70.7, 71.8, 71.9, 74.0, 78.3, 79.6, 82.2, 100.7, 106.2, 106.4, 127.8, 127.9 (2C), 128.4 (2C), 138.4, 140.7, 145.0, 164.1, 164.3, 170.9; LRMS (APCI) m/z 844 [M + NH4]+; HRMS (APCI-Ion Trap) m/z: [M + H]+ Calcd for C38H60IO8Si2 827.2866; Found 827.2871; [α]25D +62.5 (c 0.50, CHCl3). [(E,1S)-4-Iodo-1-methyl-but-3-enyl] 2-[(2S,3R,5S,6S)-5benzyloxy-3-[tert-butyl(dimethyl)silyl]oxy-6-formyl-tetrahydropyran-2-yl]-4-methoxy-6-(methoxymethoxy)benzoate (18). To a solution of 32 (967 mg, 1.17 mmol) in CH3CN (20.0 mL) were added tetrabutylammonium iodide (432 mg, 1.17 mmol), iPr2NEt (0.611 mL, 3.51 mmol), and chloromethyl methyl ether (0.266 mL, 3.51 mmol) at rt, and then the mixture was heated at 80 °C for 30 min. To the mixture were added iPr2NEt (0.611 mL, 3.51 mmol) and chloromethyl methyl ether (0.266 mL, 3.51 mmol) at rt, and then the mixture was stirred at 80 °C for 30 min. To the mixture were added iPr2NEt (0.611 mL, 3.51 mmol) and chloromethyl methyl ether (0.266 mL, 3.51 mmol) at rt, and then the mixture was stirred at 80 °C for 1 h. After cooling, to the mixture was added saturated aqueous NaHCO3 (30 mL) and the solution was extracted with CHCl3 (30 mL × 2). The extracts were dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane only to 9:1 hexane–EtOAc) to afford [(E,1S)-4-iodo-1-methyl-but-3-enyl] 2-[(2S,3R,5S,6R)-5benzyloxy-3-[tert-butyl-(dimethyl)silyl]oxy-6-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydropyran-2-yl]-4-methoxy-6-(methoxymethoxy)benzoate (S2) (950 mg, 93%) as a colorless syrup; Rf = 0.33 (9:1 hexane–EtOAc); IR (ATR, cm–1) 1731 (C═O), 1607, 1091, 834; 1H NMR (400 MHz, CDCl3) δ −0.39, −0.18, 0.03, 0.06 (each 3H, s), 0.71, 0.90 (each 9H, s), 1.31 (3H, d, J = 6.2 Hz), 1.59 (1H, q, J = 11.8 Hz), 2.29–2.49 (3H, m), 3.32 (1H, dt, J = 9.3, 2.6 Hz), 3.45 (3H, s), 3.57– 3.70 (2H, m), 3.78 (3H, s), 3.83–3.94 (2H, m), 4.16 (1H, d, J = 8.7 Hz), 4.57 (1H, d, J = 11.3 Hz), 4.64 (1H, d, J = 11.3 Hz), 5.12 (1H, d, J = 6.7 Hz), 5.15–5.23 (2H, m), 6.13 (1H, dt, J = 14.4, 1.5 Hz), 6.57 (1H, dt, J = 14.4, 7.2 Hz), 6.58 (1H, d, J = 2.1 Hz), 6.65 (1H, d, J = 2.1 Hz), 7.27–7.40 (5H, m); 13C NMR (100 MHz, CDCl3) δ −5.3, −5.2, −5.0 (2C), 17.9, 18.4, 19.5, 25.7 (3C), 26.0 (3C), 40.1, 42.0, 55.4, 56.0, 62.7, 70.0, 71.48, 71.51, 71.8, 77.5, 82.0, 82.1, 94.7, 101.8, 105.5, 118.5, 127.7, 127.8 (2C), 128.4 (2C), 138.6, 139.7, 141.5, 155.1, 160.9, 166.3; LRMS (APCI) m/z 888 [M + NH4]+; HRMS (APCI-Ion Trap) m/z: [M + H]+ Calcd for C40H64IO9Si2 871.3128; Found 871.3132; [α]25D +26.8 (c 0.50, CHCl3). To a solution of S2 (302 mg, 0.347 mmol) in MeOH (6.00 mL) was added (±)-10camphorsulfonic acid (40.3 mg, 0.173 mmol) at 0 °C. The mixture was stirred at the same temperature for 1 h, and to the mixture was added saturated aqueous NaHCO3 (30 mL). The solution was extracted with CHCl3 (30 mL × 3). The extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (4:1 to 2:1 hexane–EtOAc) to afford [(E,1S)-4-iodo-1-methyl-but-3-enyl] 2-[(2S,3R,5S,6R)-5benzyloxy-3-[tert-butyl(dimethyl)silyl]oxy-6-(hydroxylmethyl)tetrahydropyran-2-yl]-4-methoxy-6-(methoxymethoxy) benzoate (S3)

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(251 mg, 96%) as a colorless syrup; Rf = 0.30 (3:1 hexane–EtOAc); IR (ATR, cm–1) 3528 (OH), 1720 (C═O), 1608, 1066; 1H NMR (400 MHz, CDCl3) δ −0.40, −0.19 (each 3H, s), 0.76 (9H, s), 1.27 (3H, d, J = 6.7 Hz), 1.58 (1H, q, J = 11.3 Hz), 2.27 (1H, dd, J = 8.7, 5.1 Hz), 2.36–2.47 (3H, m), 3.36 (1H, dt, J = 9.3, 3.3 Hz), 3.45 (3H, s), 3.56 (1H, ddd, J = 11.3, 9.5, 4.4 Hz), 3.73 (1H, ddd, J = 12.3, 8.7, 3.6 Hz), 3.79 (3H, s), 3.80–3.91 (2H, m), 4.14 (1H, d, J = 8.7 Hz), 4.55 (1H, d, J = 11.3 Hz), 4.64 (1H, d, J = 11.3 Hz), 5.07–5.20 (3H, m), 6.15 (1H, d, J = 14.3 Hz), 6.47 (1H, d, J = 2.6 Hz), 6.56 (1H, dt, J = 14.9, 7.2 Hz), 6.67 (1H, d, J = 2.6 Hz), 7.28–7.40 (5H, m); 13C NMR (100 MHz, CDCl3) δ −5.5, −5.1, 17.9, 19.2, 25.7 (3C), 39.5, 41.8, 55.4, 56.1, 61.8, 69.9, 70.2, 71.3, 71.5, 77.8, 80.4, 84.2, 94.7, 101.3, 107.8, 116.8, 127.9 (3C), 128.5 (2C), 138.0, 138.3, 141.1, 155.6, 160.3, 168.1; LRMS (APCI) m/z 774 [M + NH4]+; HRMS (APCI-Ion Trap) m/z: [M + H]+ Calcd for C34H50IO9Si 757.2263; Found 757.2262; [α]25D +19.3 (c 0.50, CHCl3). To a solution of S3 (240 mg, 0.317 mmol) in CH2Cl2 (4.80 mL) was added DMP (175 mg, 0.413 mmol) at rt, and the mixture was stirred at the same temperature for 4 h. The mixture was diluted with EtOAc (40 mL), and the new mixture was washed with 1:1 saturated aqueous NaHCO3–saturated aqueous Na2S2O3 (40 mL), saturated aqueous NaHCO3 (40 mL × 2) and saturated aqueous NaCl (40 mL) successively. The extract was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (4:1 to 2:1 hexane– EtOAc) to afford 18 (215 mg, 90%) as a colorless syrup; Rf = 0.24 (2:1 hexane–EtOAc); IR (ATR, cm–1) 1721 (C═O), 1608, 1068, 835; 1 H NMR (400 MHz, CDCl3) δ −0.40, −0.16 (each 3H, s), 0.74 (9H, s), 1.31 (3H, d, J = 6.2 Hz), 1.67 (1H, q, J = 11.3 Hz), 2.31–2.57 (3H, m), 3.45 (3H, s), 3.69 (1H, ddd, J = 10.8, 9.3, 4.1 Hz), 3.79 (3H, s), 3.87 (1H, dd, J = 9.8, 1.0 Hz), 3.93 (1H, ddd, J = 10.9, 9.1, 4.6 Hz), 4.17 (1H, d, J = 8.7 Hz), 4.55 (1H, d, J = 11.8 Hz), 4.64 (1H, d, J = 12.3 Hz), 5.06 (1H, sxt, J = 6.2 Hz), 5.11 (1H, d, J = 6.7 Hz), 5.17 (1H, d, J = 7.2 Hz), 6.16 (1H, dt, J = 14.9, 1.0 Hz), 6.51 (1H, d, J = 2.1 Hz), 6.56 (1H, dt, J = 14.4, 7.2 Hz), 6.66 (1H, d, J = 2.6 Hz), 7.28–7.42 (5H, m), 9.70 (1H, d, J = 1.0 Hz); 13C NMR (100 MHz, CDCl3) δ −5.5, −5.0, 17.8, 19.2, 25.7 (3C), 40.0, 42.0, 55.5, 56.1, 69.6, 70.2, 71.5, 72.2, 77.8, 83.1, 83.5, 94.6, 101.7, 107.4, 117.5, 127.99, 128.03 (2C), 128.5 (2C), 137.6, 137.9, 141.4, 155.7, 160.6, 167.1, 197.4; (APCI) m/z 772 [M + NH4]+; HRMS (APCI-Ion Trap) m/z: [M + H]+ Calcd for C34H48IO9Si 755.2107; Found 755.2113; [α]25D +18.5 (c 0.50, CHCl3). (4S,6E,8R,9S,10S,12R,13S)-10-Benzyloxy-12-[tert-butyl(dimethyl)silyl]oxy-9,13-epoxy-8-hydroxy-16-methoxy-18(methoxymethoxy)-4-methyl-3-oxabicyclo[12.4.0]octadecane-1(14),6,15,17-tetraene-2-one (33a) and (4S,6E,8S,9S,10S,12R,13S)-10-benzyloxy-12-[tert-butyl(dimethyl)silyl]oxy-9,13-epoxy-8-hydroxy-16-methoxy-18(methoxymethoxy)-4-methyl-3-oxabicyclo[12.4.0]octadecane-1(14),6,15,17-tetraene-2-one (33b). Under nitrogen atmosphere, to a solution of 18 (430 mg, 0.570 mmol) in DMF (57.0 mL) were added CrCl2 (280 mg, 2.28 mmol) and NiCl2 (3.00 mg, 0.0231 mmol) at rt, and the mixture was stirred at rt for 20 h. To the mixture was added saturated aqueous NH4Cl (150 mL) and EtOAc (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (50 mL × 2). The extracts were washed with H2O (100 mL) and saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (4:1 to 2:1 hexane–EtOAc) to afford 33a (150 mg, 42%) as a colorless syrup and 33b (132 mg, 37%) as a colorless syrup. 33a: Rf = 0.34 (2:1 hexane–EtOAc); IR (ATR, cm–1) 3477 (OH), 1711 (C═O), 1607, 1057, 835; 1H NMR (400 MHz, CDCl3) δ −0.45, −0.18 (each 3H, s), 0.77 (9H, s), 1.34 (3H, d, J = 6.2 Hz), 1.52 (1H, q, J = 11.3 Hz), 2.02 (1H, d, J = 7.7 Hz), 2.24 (1H, ddd, J = 14.4, 11.6, 7.5 Hz), 2.39 (1H, dt, J = 14.4, 4.1 Hz), 2.48 (1H, dt, J = 11.8, 4.4 Hz), 3.35 (1H, td, J = 11.8, 3.6 Hz), 3.41–3.48 (1H, m), 3.44 (3H, s), 3.77 (3H, s), 4.03 (1H, d, J = 9.3 Hz), 4.23 (1H, ddd, J = 10.9, 8.9, 4.9 Hz), 4.48 (1H, d, J = 11.3 Hz), 4.56 (1H, dd, J = 6.2, 4.6 Hz), 4.68 (1H, d, J = 11.3 Hz), 5.11 (2H, s), 5.34–5.46 (1H, m), 5.54 (1H, dd, J = 15.4, 4.1 Hz), 5.58–5.68 (1H, m), 6.44 (1H, d, J = 2.6 Hz), 6.63 (1H, d, J = 2.1 Hz), 7.27–7.43 (5H, m); 13C NMR (100


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MHz, CDCl3) δ −5.7, −5.3, 17.9, 20.6, 25.8 (3C), 36.8, 39.5, 55.4, 56.0, 69.3, 70.3, 70.8, 71.3, 73.2, 84.6, 85.2, 94.7, 101.4, 109.3, 116.6, 125.2, 127.9 (3C), 128.5 (2C), 130.9, 138.0, 139.2, 156.0, 159.8, 168.3; LRMS (APCI) m/z 646 [M + NH4]+; HRMS (APCI-Ion Trap) m/z: [M + H]+ Calcd for C34H49O9Si 629.3140; Found 629.3141; [α]25D +90.6 (c 0.50, CHCl3). 33b: Rf = 0.55 (2:1 hexane–EtOAc); IR (ATR, cm–1) 3488 (OH), 1712 (C═O), 1607, 1043, 835; 1H NMR (400 MHz, CDCl3) δ −0.45, −0.16 (each 3H, s), 0.78 (9H, s), 1.35 (3H, d, J = 6.2 Hz), 1.55 (1H, q, J = 11.8 Hz), 2.18 (1H, ddd, J = 13.7, 11.2, 6.9 Hz), 2.30–2.43 (1H, m), 2.54 (1H, dt, J = 11.4, 4.6 Hz), 3.44 (3H, s), 3.59 (1H, dd, J = 9.5, 4.4 Hz), 3.69–3.83 (4H, m), 4.09 (1H, d, J = 8.7 Hz), 4.18–4.30 (2H, m), 4.40 (1H, ddd, J = 11.1, 9.0, 5.1 Hz), 4.50 (1H, d, J = 11.3 Hz), 4.70 (1H, d, J = 11.3 Hz), 5.02–5.17 (2H, m), 5.31 (1H, sxt, J = 5.1 Hz), 5.40 (1H, dd, J = 15.7, 8.0 Hz), 5.69 (1H, dt, J = 14.9, 8.2 Hz), 6.46 (1H, d, J = 2.6 Hz), 6.63 (1H, d, J = 2.1 Hz), 7.29–7.43 (5H, m); 13C NMR (100 MHz, CDCl3) δ −5.7, −5.2, 17.8, 20.6, 25.8 (3C), 35.6, 39.2, 55.4, 56.1, 69.0, 70.4, 72.9, 73.7, 76.2, 77.8, 85.6, 94.8, 101.7, 109.5, 116.7, 128.3 (3C), 128.7 (2C), 130.0, 131.6, 137.0, 139.1, 155.9, 159.9, 168.4; LRMS (APCI) m/z 646 [M + NH4]+; HRMS (APCI-Ion Trap) m/z: [M + H]+ Calcd for C34H49O9Si 629.3140; Found 629.3144; [α]25D +123.5 (c 0.50, CHCl3). The stereochemistry of the new chiral center of 33a was confirmed by conversion into 4´-O-benzyl paecilomycin B (S4). To a solution of 33a (100 mg, 0.159 mmol) in MeOH (3.20 mL) was added methanesulfonic acid (0.0420 mL, 0.647 mmol), and the mixture was stirred at 60 °C for 1.5 h. After cooling, to the mixture was added saturated aqueous NaHCO3 (20 mL), and extracted with EtOAc (30 mL × 2). The extracts were washed with saturated aqueous NaCl (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (1:1 to 1:3 hexane–EtOAc) to afford (4S,6E,8R,9S,10S,12R,13S)-10-benzyloxy-9,13-epoxy8,12,18-trihydroxy-16-methoxy-4-methyl-3-oxabicyclo[12.4.0]octadecane-1(14),6,15,17-tetraene-2-one (S4) (66.2 mg, 89%) as a colorless solid; Rf = 0.38 (1:2 hexane–EtOAc); IR (ATR, cm–1) 3288 (OH), 1708 (C═O), 1614, 1589, 1026; 1H NMR (400 MHz, CDCl3) δ 1.43 (3H, d, J = 6.7 Hz), 1.56 (1H, q, J = 11.3 Hz), 1.82 (1H, d, J = 4.6 Hz), 2.14–2.33 (1H, m), 2.45 (1H, br. s.), 2.52 (1H, dt, J = 14.1, 5.0 Hz), 2.72 (1H, dt, J = 11.6, 4.5 Hz), 3.35 (1H, dd, J = 9.8, 3.1 Hz), 3.49 (1H, td, J = 10.1, 3.9 Hz), 3.79 (3H, s), 4.17 (1H, d, J = 9.2 Hz), 4.37– 4.47 (2H, m), 4.50 (1H, d, J = 11.8 Hz), 4.73 (1H, d, J = 11.3 Hz), 5.45–5.55 (1H, m), 5.59 (1H, dd, J = 15.4, 3.6 Hz), 5.65–5.76 (1H, m), 6.41 (1H, d, J = 2.6 Hz), 6.51 (1H, d, J = 2.1 Hz), 7.28–7.49 (5H, m), 8.02 (1H, br. s.); 13C NMR (100 MHz, CDCl3) δ 20.5, 37.1, 37.6, 55.5, 67.9, 70.7, 70.8, 71.2, 73.4, 83.7, 85.2, 101.2, 109.4, 110.1, 124.5, 127.96 (2C), 128.01, 128.6 (2C), 133.3, 137.7, 140.6, 159.0, 162.0, 167.1; LRMS (APCI) m/z 471 [M + H]+; HRMS (APCI-Ion Trap) m/z: [M + H]+ Calcd for C26H31O8 471.2013; Found 471.2007; [α]25D +128.8 (c 0.56, CHCl3). These spectral data were identical with previously reported data7a (from RCM route). Synthesis of 6´-epi-paecilomycin B (34) (intramolecular NHK route). To a solution of 33b (100 mg, 0.159 mmol) in MeOH (3.20 mL) was added methanesulfonic acid (0.0420 mL, 0.647 mmol) and the mixture was stirred at 60 °C for 1.5 h. After cooling, to the mixture was added saturated aqueous NaHCO3 (20 mL), and the new mixture was extracted with EtOAc (30 mL × 2). The extracts were washed with saturated aqueous NaCl (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (1:1 hexane–EtOAc) to afford (4S,6E,8S,9S,10S,12R,13S)-10-benzyloxy-9,13-epoxy-8,12,18trihydroxy-16-methoxy-4-methyl-3-oxabicyclo[12.4.0]octadecane1(14),6,15,17-tetraene-2-one (S5) (61.7 mg, 83%) as a colorless amorphous powder; Rf = 0.38 (1:1 hexane–EtOAc); IR (ATR, cm–1) 3397 (OH), 1708 (C═O), 1612, 1252, 1024; 1H NMR (400 MHz, CDCl3) δ 1.38 (3H, d, J = 6.1 Hz), 1.62 (1H, q, J = 11.8 Hz), 1.73 (1H, d, J = 4.1 Hz), 2.25 (1H, dt, J = 13.2, 3.7 Hz), 2.49 (1H, br. s), 2.63– 2.81 (2H, m), 3.28 (1H, dd, J = 9.2, 2.6 Hz), 3.70 (1H, td, J = 10.8, 4.6 Hz), 3.80 (3H, s), 4.24–4.33 (1H, m), 4.41 (1H, d, J = 9.2 Hz), 4.47–4.54 (1H, m), 4.60 (1H, d, J = 11.3 Hz), 4.71 (1H, d, J = 12.3 Hz), 5.28–5.48 (1H, m), 5.52–5.71 (2H, m), 6.44 (1H, d, J = 2.6 Hz), 6.62 (1H, d, J = 2.6 Hz), 7.28–7.55 (5H, m), 10.43 (1H, br. s); 13C

NMR (100 MHz, CDCl3) δ 19.4, 36.0, 38.9, 55.5, 67.4, 71.4, 71.5, 71.9, 73.1, 81.8, 88.0, 101.0, 107.8, 108.8, 123.4, 128.1 (3C), 128.6 (2C), 137.8, 138.5, 140.2, 163.0, 163.3, 169.6; LRMS (APCI) m/z 488 [M + NH4]+; HRMS (APCI-Ion Trap) m/z: [M + H]+ Calcd for C26H31O8 488.2279; Found 488.2283; [α]25D +19.8 (c 0.20, CHCl3). To a solution of S5 (38.0 mg, 0.0808 mmol) in CH2Cl2 (7.60 mL) was added TiCl4 (0.404 mL, 0.404 mmol, 1.0 M CH2Cl2 solution) at rt, and the mixture was stirred at rt for 2 h. To the mixture was added saturated aqueous NaHCO3 (10 mL), and the new mixture was extracted with EtOAc (30 mL × 2). The extracts were washed with saturated aqueous NaCl (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (15:1 CHCl3–MeOH) to afford 34 (25.7 mg, 84%) as a colorless amorphous solid; Rf = 0.28 (9:1 CHCl3–MeOH); IR (ATR, cm–1) 3330 (OH), 1695 (C═O), 1613, 1591, 1256, 1019; 1H NMR (400 MHz, pyridine-d5) δ 1.44 (3H, d, J = 6.1 Hz), 2.16–2.23 (1H, m), 2.23 (1H, q, J = 11.0 Hz), 2.42–2.54 (1H, m), 3.03 (1H, dt, J = 11.8, 4.6 Hz), 3.57 (3H, s), 3.93 (1H, dd, J = 9.5, 5.4 Hz), 4.53 (1H, td, J = 10.8, 5.1 Hz), 4.61 (1H, d, J = 8.7 Hz), 4.85–5.10 (1H, m), 5.16 (1H, ddd, J = 11.1, 9.1, 4.9 Hz), 5.67 (1H, sxt, J = 6.7 Hz), 5.99 (1H, dt, J = 14.3, 7.2 Hz), 6.18 (1H, dd, J = 15.9, 8.7 Hz), 6.41 (1H, br. s), 6.63 (1H, d, J = 2.6 Hz), 6.85 (1H, br. s.), 6.89 (1H, d, J = 2.6 Hz), 7.63 (1H, br. s.), 11.92 (1H, br. s.); 1H NMR (400 MHz, CDCl3) δ 1.42 (3H, d, J = 6.7 Hz), 1.59 (1H, q, J = 11.8 Hz), 1.85 (1H, br. s), 2.26 (1H, ddd, J = 13.4, 7.8, 5.4 Hz), 2.49 (1H, br. s), 2.54 (1H, dt, J = 11.6, 4.7 Hz), 2.62 (1H, ddd, J = 13.7, 7.0, 4.9 Hz), 3.23 (1H, br. s.), 3.31 (1H, dd, J = 9.5, 4.4 Hz), 3.79 (3H, s), 3.87–3.99 (1H, m), 4.23 (1H, d, J = 9.2 Hz), 4.39–4.49 (1H, m), 4.49–4.54 (1H, m), 5.49–5.60 (1H, m), 5.62–5.73 (1H, m), 5.73 (1H, dd, J = 16.4, 6.7 Hz), 6.42 (1H, d, J = 2.6 Hz), 6.57 (1H, d, J = 2.1 Hz), 8.76 (1H, br. s.); 13C NMR (100 MHz, pyridine-d5) δ 20.8, 36.0, 44.0, 55.1, 67.1, 68.2, 72.7, 76.3, 81.6, 87.1, 101.6, 108.1, 115.7, 130.1, 132.7, 141.3, 158.4, 160.6, 169.6; 13C NMR (100 MHz, CDCl3) δ 20.3, 36.0, 41.1, 55.5, 65.3, 67.5, 72.2, 74.0, 83.3, 83.8, 101.2, 109.1, 109.4, 127.0, 134.6, 140.5, 160.3, 162.3, 167.8; LRMS (APCI) m/z 381 [M + H]+; HRMS (APCIIon Trap) m/z: [M + H]+ Calcd for C19H25O8 398.1809; Found 398.1812; [α]25D +122.7 (c 0.30, MeOH). [(E,1S)-4-Iodo-1-methyl-but-3-enyl] 2-iodo-4,6-dimethoxybenzoate (25). To a solution of 2-iodo-4,6-dimethoxybenzoic acid (38)19 (5.00 g, 16.2 mmol), (E)-(R)-5-iodo-pent-4-en-2-ol (27) (3.61 g, 17.0 mmol), and PPh3 (6.39 g, 24.4 mmol) in THF (100 mL) was added DIAD (12.8 mL, 24.3 mmol, 40 wt% toluene solution) at rt. The mixture was stirred at the same temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (9:1 to 6:1 hexane– EtOAc) to afford 25 (7.71 g, 95%) as a colorless syrup; Rf = 0.28 (6:1 hexane–EtOAc); IR (ATR, cm–1) 1722 (C═O), 1594, 1558, 1261, 1028; 1H NMR (400 MHz, CDCl3) δ 1.37 (3H, d, J = 6.2 Hz), 2.28– 2.52 (2H, m), 3.79 (3H, s), 3.81 (3H, s), 5.21 (1H, sxt, J = 6.2 Hz), 6.17 (1H, dt, J = 14.4, 1.5 Hz), 6.44 (1H, d, J = 2.6 Hz), 6.61 (1H, dt, J = 14.8, 7.3 Hz), 6.90 (1H, d, J = 2.1 Hz); 13C NMR (100 MHz, CDCl3) δ 19.5, 41.8, 55.7, 56.1, 70.8, 77.8, 92.5, 99.0, 115.1, 123.5, 141.5, 157.7, 161.5, 167.0; LRMS (APCI) m/z 502.9 [M + H]+; HRMS (APCI-Ion Trap) m/z: [M + H]+ Calcd for C14H17I2O4 502.9211; Found 502.9214; [α]25D +14.5 (c 0.50, CHCl3). (2S,3S,5R,6S)-3-Benzyloxy-5-[tert-butyl(dimethyl)silyl]oxy-6-(4-methoxyphenoxy)tetrahydropyran-2-carbaldehyde (26). To a suspension of LiAlH4 (400 mg, 10.6 mmol) in 2:1 CH2Cl2– Et2O (75.0 mL) were added 4-methoxyphenyl 2-O-tert-butyldimethylsilyl-3-deoxy-β-D-glucopyranoside (39)20 (5.00 g, 10.6 mmol) and AlCl3 (1.41 g, 10.6 mmol) at rt. The mixture was stirred at the same temperature for 1.5 h. To the mixture was added EtOAc (10 mL) dropwise. After addition, the mixture was poured into 1 M aqueous HCl (250 mL), and to the new mixture was added EtOAc (200 mL). The organic layer was separated and washed with 1 M aqueous HCl (100 mL), saturated aqueous NaHCO3 (100 mL), and saturated aqueous NaCl (100 mL) successively. The aqueous layers were reextracted with EtOAc (150 mL). The extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (9:1 to 3:1 hexane–EtOAc to



EtOAc only) to afford [(2R,3S,5R,6S)-3-benzyloxy-5-[tertbutyl(dimethyl)silyl]-oxy-6-(4-methoxyphenoxy)tetrahydropyran-2yl]methanol (S6a) (2.87 g, 57%) as a colorless solid and (2R,3S,5R,6S)-2-(benzyloxymethyl)-6-(4-methoxyphenoxy)tetrahydropyran-3,5-diol (S6b) (1.50 g, 39%) as a colorless solid. S6a: Rf = 0.34 (3:1 hexane–EtOAc); IR (ATR, cm–1) 3513 (OH), 1505, 1221, 1078, 822; 1H NMR (400 MHz, CDCl3) δ 0.10, 0.14 (each 3H, s), 0.89 (9H, s), 1.58–1.70 (1H, m), 1.97 (1H, t, J = 6.7 Hz), 2.40–2.50 (1H, m), 3.47–3.59 (2H, m), 3.65–3.76 (2H, m), 3.77 (3H, s), 3.90 (1H, ddd, J = 11.8, 6.2, 2.6 Hz), 4.50 (1H, d, J = 11.3 Hz), 4.65 (1H, d, J = 11.8 Hz), 4.79 (1H, d, J = 7.2 Hz), 6.82 (2H, d, J = 9.3 Hz), 6.94 (2H, d, J = 8.7 Hz), 7.27–7.39 (5H, m); 13C NMR (100 MHz, CDCl3) δ −4.8, −4.4, 18.1, 25.8 (3C), 37.7, 55.7, 62.5, 69.1, 71.4, 72.2, 78.4, 103.5, 114.6 (2C), 117.6 (2C), 127.8 (2C), 128.0, 128.5 (2C), 137.9, 151.3, 155.0; LRMS (APCI) m/z 492 [M + NH4]+; HRMS (APCI-Ion Trap) m/z: [M + NH4]+ Calcd for C26H42NO6Si 492.2776; Found 492.2780; [α]25D −38.4 (c 0.50, CHCl3). S6b: Rf = 0.36 (1:3 hexane– EtOAc); IR (ATR, cm–1) 3396 (OH), 1506, 1217, 1048; 1H NMR (400 MHz, CDCl3) δ 1.65 (1H, dt, J = 12.3, 11.3 Hz), 2.46 (1H, dt, J = 12.5, 4.8 Hz), 2.53 (1H, d, J = 3.1 Hz), 2.91 (1H, d, J = 3.1 Hz), 3.53–3.63 (1H, m), 3.68–3.90 (4H, m), 3.77 (3H, s), 4.54 (1H, d, J = 11.8 Hz), 4.58 (1H, d, J = 12.3 Hz), 4.76 (1H, d, J = 7.2 Hz), 6.77– 6.84 (2H, m), 6.95–7.02 (2H, m), 7.27–7.39 (5H, m); 13C NMR (100 MHz, CDCl3) δ 37.1, 55.7, 68.07, 68.10, 71.3, 73.8, 77.0, 103.6, 114.6 (2C), 118.2 (2C), 127.8 (2C), 128.0, 128.6 (2C), 137.4, 151.0, 155.4; LRMS (APCI) m/z 378 [M + NH4]+; HRMS (APCI-Ion Trap) m/z: [M + NH4]+ Calcd for C20H28NO6 378.1911; Found 378.1911; [α]25D −90.7 (c 0.50, CHCl3). The structure of S6a was confirmed by HMBC measurement between C-4 and benzylic protons. The structure of S6b was confirmed by HMBC measurement between C-6 and benzylic protons. To a solution of S6a (4.00 g, 8.43 mmol) in CH2Cl2 (80.0 mL) was added DMP (4.29 g, 10.1 mmol) at rt, and the mixture was stirred at the same temperature for 1 h. The mixture was diluted with EtOAc (300 mL), and the new mixture was washed successively with 2:1 saturated aqueous NaHCO3–saturated aqueous Na2S2O3 (300 mL), saturated aqueous NaHCO3 (200 mL), and saturated aqueous NaCl (200 mL). The aqueous layers were extracted with EtOAc (100 mL). The extracts were dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (9:1 to 3:1 hexane–EtOAc) to afford the crude syrup. This was dissolved in toluene (60.0 mL), and to the solution was added molecular sieves 4 Å (3.00 g). The mixture was heated at 80 °C for 30 min. After cooling, the mixture was filtered through a pad of Celite. The filtrate was evaporated under reduced pressure to afford 26 (3.37 g, 85%) as a colorless syrup; Rf = 0.24 (3:1 hexane– EtOAc); IR (ATR, cm–1) 1741 (C═O) , 1506, 1217, 1072, 826; 1H NMR (400 MHz, CDCl3) δ 0.10, 0.12 (each 3H, s), 0.89 (9H, s), 1.74 (1H, dt, J = 12.8, 10.5 Hz), 2.42 (1H, dt, J = 13.9, 4.6 Hz), 3.69–3.79 (2H, m), 3.77 (3H, s), 3.98 (1H, dd, J = 8.7, 1.5 Hz), 4.53 (1H, d, J = 11.8 Hz), 4.63 (1H, d, J = 11.8 Hz), 4.85 (1H, d, J = 7.2 Hz), 6.82 (2H, d, J = 9.3 Hz), 6.97 (2H, d, J = 9.3 Hz), 7.26–7.38 (5H, m), 9.65 (1H, d, J = 1.5 Hz); 13C NMR (100 MHz, CDCl3) δ −4.9, −4.5, 18.1, 25.8 (3C), 36.7, 55.6, 68.3, 71.4, 71.5, 80.9, 103.4, 114.6 (2C), 118.2 (2C), 127.9 (2C), 128.0, 128.5 (2C), 137.4, 151.1, 155.3, 197.5; LRMS (APCI) m/z 490 [M + NH4]+; HRMS (APCI-Ion Trap) m/z: [M + NH4]+ Calcd for C26H40NO6Si 490.2619; Found 490.2624; [α]25D −53.1 (c 0.50, CHCl3). [(E,1S,5R)-5-[(2R,3S,5R,6S)-3-Benzyloxy-5-[tert-butyl(dimethyl)silyl]oxy-6-(4-methoxyphenoxy)tetrahydropyran2-yl]-5-hydroxy-1-methyl-pent-3-enyl] 2-iodo-4,6-dimethoxybenzoate (40a) and [(E,1S,5S)-5-[(2R,3S,5R,6S)-3benzyloxy-5-[tert-butyl(dimethyl)silyl]oxy-6-(4-methoxyphenoxy)tetrahydropyran-2-yl]-5-hydroxy-1-methyl-pent-3enyl] 2-iodo-4,6-dimethoxybenzoate (40b). Under nitrogen atmosphere, to a solution of vinyl iodide 25 (2.04 g, 4.06 mmol) and aldehyde 26 (1.60 g, 3.39 mmol) in DMF (33.9 mL) were added CrCl2 (1.50 g, 12.2 mmol) and NiCl2 (15.8 mg, 0.122 mmol) at 0 °C. The mixture was stirred at the same temperature for 10 min, and then the mixture was allowed to warm to rt. The mixture was stirred at rt for 1.5 h. The mixture was diluted with EtOAc (150 mL), and the new

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mixture was washed with saturated aqueous NH4Cl (200 mL × 2) and saturated aqueous NaCl (100 mL) successively. The aqueous layers were re-extracted with EtOAc (100 mL). The extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (9:1 to 4:1 to 2:1 hexane–EtOAc) to afford 40a (467 mg, 16%) as a colorless syrup and 40b (1.13 g, 40%) as a colorless syrup. 40a: Rf = 0.12 (3:1 hexane–EtOAc); IR (ATR, cm–1) 3476 (OH), 1725 (C═O), 1596, 1506, 1215, 1078, 1030; 1H NMR (400 MHz, CDCl3) δ 0.11, 0.14 (each 3H, s), 0.89 (9H, s), 1.31 (3H, d, J = 6.7 Hz), 1.62 (1H, q, J = 11.3 Hz), 2.36 (1H, dt, J = 14.4, 6.7 Hz), 2.43–2.53 (2H, m), 2.77 (1H, d, J = 6.2 Hz), 3.45–3.56 (2H, m), 3.64–3.71 (1H, m), 3.72 (3H, s), 3.76 (3H, s), 3.78 (3H, s), 4.29–4.37 (1H, m), 4.42 (1H, d, J = 11.3 Hz), 4.63 (1H, d, J = 11.3 Hz), 4.72 (1H, d, J = 7.7 Hz), 5.16 (1H, sxt, J = 6.3 Hz), 5.62–5.81 (2H, m), 6.39 (1H, d, J = 2.1 Hz), 6.82 (2H, d, J = 8.7 Hz), 6.88 (1H, d, J = 2.6 Hz), 6.93 (2H, d, J = 9.3 Hz), 7.27– 7.37 (5H, m); 13C NMR (100 MHz, CDCl3) δ −4.8, −4.4, 18.1, 19.3, 25.8 (3C), 37.5, 38.6, 55.7 (2C), 56.0, 69.0, 70.9, 71.9, 73.1, 74.0, 79.9, 92.5, 99.1, 103.7, 114.6 (2C), 115.1, 117.6 (2C), 123.7, 127.9 (2C), 128.1, 128.6 (2C), 129.1, 131.2, 137.5, 151.3, 155.0, 157.7, 161.4, 167.0; (APCI) m/z 866 [M + NH4]+; HRMS (APCI-Ion Trap) m/z: [M + NH4]+ Calcd for C40H57INO10Si 866.2791; Found 866.2800; [α]25D −29.7 (c 0.50, CHCl3). 40b: Rf = 0.25 (3:1 hexane– EtOAc); IR (ATR, cm–1) 3480 (OH), 1725 (C═O), 1596, 1506, 1215, 1075, 1030; 1H NMR (400 MHz, CDCl3) δ 0.11, 0.14 (each 3H, s), 0.89 (9H, s), 1.33 (3H, d, J = 6.1 Hz), 1.62 (1H, q, J = 12.8 Hz), 2.16 (1H, d, J = 9.7 Hz), 2.31–2.60 (3H, m), 3.42 (1H, dd, J = 9.2, 1.5 Hz), 3.61–3.85 (2H, m), 3.72 (3H, s), 3.77 (3H, s), 3.78 (3H, s), 4.42 (1H, dd, J = 9.7, 5.6 Hz), 4.54 (1H, d, J = 11.8 Hz), 4.65 (1H, d, J = 11.3 Hz), 4.72 (1H, d, J = 7.7 Hz), 5.19 (1H, sxt, J = 6.4 Hz), 5.73 (1H, dd, J = 15.9, 4.6 Hz), 5.78–5.89 (1H, m), 6.39 (1H, d, J = 2.1 Hz), 6.81 (2H, d, J = 9.2 Hz), 6.88 (1H, d, J = 2.1 Hz), 6.92 (2H, d, J = 9.2 Hz), 7.28–7.39 (5H, m); 13C NMR (100 MHz, CDCl3) δ −4.8, −4.4, 18.1, 19.4, 25.8 (3C), 37.7, 38.6, 55.7 (2C), 56.0, 69.0, 70.2, 71.6, 71.8, 72.1, 80.2, 92.5, 99.1, 103.8, 114.5 (2C), 115.1, 117.7 (2C), 123.7, 127.3, 127.9 (3C), 128.5 (2C), 133.1, 137.9, 151.4, 155.0, 157.7, 161.4, 167.0; LRMS (APCI) m/z 866 [M + NH4]+; HRMS (APCI-Ion Trap) m/z: [M + NH4]+ Calcd for C40H57INO10Si 866.2791; Found 866.2793; [α] 25D −29.8 (c 0.50, CHCl3). The stereochemistry of the new chiral center of 40a was confirmed by conversion into paecilomycin B (5). Inversion of 6´-hydroxy group in 40b. To a solution of 40b (1.70 g, 2.00 mmol) in CH2Cl2 (34.0 mL) was added DMP (1.02 g, 2.40 mmol) at rt, and the mixture was stirred at the same temperature for 1 h. The mixture was diluted with EtOAc (100 mL), and the new mixture was washed successively with 4:1 saturated aqueous NaHCO3–saturated aqueous Na2S2O3 (100 mL), and then saturated aqueous NaHCO3 (100 mL). The extract was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (9:1 to 3:1 hexane–EtOAc) to afford [(E,1S)-5-[(2S,3S,5R,6S)-3-benzyloxy-5-[tert-butyl(dimethyl)silyl]oxy-6-(4-methoxyphenoxy)tetrahydropyran-2-yl]-1-methyl-5oxo-pent-3-enyl] 2-iodo-4,6-dimethoxybenzoate (S7) (1.58 g, 93%) as a colorless syrup; Rf = 0.37 (3:1 hexane–EtOAc); IR (ATR, cm–1) 1727 (C═O), 1596, 1506, 1214, 1071, 1029; 1H NMR (400 MHz, CDCl3) δ 0.10, 0.12 (each 3H, s), 0.88 (9H, s), 1.35 (3H, d, J = 6.1 Hz), 1.69 (1H, q, J = 12.3 Hz), 2.41 (1H, dt, J = 12.6, 4.7 Hz), 2.46– 2.65 (2H, m), 3.70–3.80 (2H, m), 3.73, 3.76, 3.77 (each 3H, s), 4.10 (1H, d, J = 8.7 Hz), 4.48 (1H, d, J = 10.8 Hz), 4.55 (1H, d, J = 11.3 Hz), 4.77 (1H, d, J = 7.2 Hz), 5.23 (1H, sxt, J = 6.1 Hz), 6.38 (1H, d, J = 2.1 Hz), 6.44 (1H, d, J = 15.9 Hz), 6.80 (2H, d, J = 9.2 Hz), 6.86 (1H, d, J = 2.1 Hz), 6.93 (2H, d, J = 9.2 Hz), 7.03 (1H, dt, J = 15.4, 7.2 Hz), 7.22–7.36 (5H, m); 13C NMR (100 MHz, CDCl3) δ −4.9, −4.4, 18.1, 19.7, 25.8 (3C), 37.9, 38.7, 55.6, 55.7, 56.0, 68.6, 70.7, 71.7, 72.9, 80.6, 92.5, 98.9, 104.1, 114.5 (2C), 115.0, 118.4 (2C), 123.3, 127.8, 128.0 (2C), 128.4 (2C), 129.3, 137.7, 144.1, 151.3, 155.2, 157.8, 161.5, 167.0, 194.1; LRMS (APCI) m/z 864 [M + NH4]+; HRMS (APCI-Ion Trap) m/z: [M + NH4]+ Calcd for C40H55INO10Si 864.2634; Found 864.2646; [α] 25D −45.1 (c 0.50, CHCl3). To a solution of S7 (1.58 g, 1.87 mmol) in Et2O (93.3 mL)


Page 11 of 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


was added Zn(BH4)2 (5.60 mL, 2.80 mmol, 0.50 M THF solution) at 0 °C. The mixture was stirred at the same temperature for 30 min, and the mixture was quenched with H2O (50 mL). To the mixture was added 1 M aqueous HCl (50 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (100 mL). The extracts were washed with saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (4:1 to 2:1 hexane–EtOAc) to afford 40a (1.35 g, 85%) and 40b (138 mg, 9%) as colorless syrups. [(E,1S,5R)-5-[(2S,3S,5R)-3-Benzyloxy-5-[tert-butyl(dimethyl)silyl]oxy-6-oxo-tetrahydropyran-2-yl]-5-[tert-butyl(dimethyl)silyl]oxy-1-methyl-pent-3-enyl] 2-iodo-4,6-dimethoxybenzoate (24). To a suspension of 40a (1.15 g, 1.35 mmol) in DMF (11.5 mL) were added imidazole (278 mg, 4.08 mmol) and TBSCl (408 mg, 2.71 mmol), and the mixture was stirred at 80 °C for 2 h. After cooling, to the mixture were added TBSCl (204 mg, 1.35 mmol) and imidazole (138 mg, 2.03 mmol), and the mixture was heated at 80 °C for 1 h. After cooling, to the mixture was added H2O (100 mL), and the new mixture was extracted with EtOAc (100 mL × 2). The extracts were washed with H2O (100 mL), saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (9:1 to 6:1, hexane–EtOAc) to afford [(E,1S,5R)-5-[(2S,3S,5R,6S)-3benzyloxy-5-[tert-butyl(dimethyl)silyl]oxy-6-(4-methoxyphenoxy)tetrahydropyran-2-yl]-5-[tert-butyl(dimethyl)silyl]oxy-1-methyl-pent3-enyl] 2-iodo-4,6-dimethoxybenzoate (S8) (1.24 g, 95%) as a colorless syrup; Rf = 0.28 (6:1 hexane–EtOAc); IR (ATR, cm–1) 1728 (C═O), 1597, 1507, 1215, 1095, 1038; 1H NMR (400 MHz, CDCl3) δ 0.00, 0.07, 0.12, 0.13 (each 3H, s), 0.88, 0.91 (each 9H, s), 1.31 (3H, d, J = 6.7 Hz), 1.56 (1H, q, J = 11.3 Hz), 2.26–2.49 (3H, m), 3.31– 3.41 (1H, m), 3.54 (1H, dd, J = 9.3, 2.1 Hz), 3.59–3.68 (1H, m), 3.69 (3H, s), 3.76 (3H, s), 3.77 (3H, s), 4.40 (1H, d, J = 11.8 Hz), 4.44 (1H, dd, J = 8.2, 1.5 Hz), 4.58 (1H, d, J = 11.8 Hz), 4.63 (1H, d, J = 7.7 Hz), 5.08–5.21 (1H, m), 5.45 (1H, dt, J = 14.4, 7.7 Hz), 5.69 (1H, dd, J = 15.9, 8.2 Hz), 6.37 (1H, d, J = 2.1 Hz), 6.78 (2H, d, J = 9.3 Hz), 6.87 (1H, d, J = 2.1 Hz), 7.06 (2H, d, J = 9.2 Hz), 7.27–7.37 (5H, m); 13 C NMR (100 MHz, CDCl3) δ −4.8, −4.7, −4.3, −4.2, 18.1 (2C), 19.2, 25.8 (3C), 25.9 (3C), 37.8, 38.5, 55.6, 55.7, 55.9, 69.1, 70.8, 71.9, 72.2, 73.1, 82.5, 92.5, 99.1, 104.4, 114.4 (2C), 115.1, 117.9 (2C), 123.7, 127.7, 127.8 (3C), 128.4 (2C), 132.4, 138.2, 152.2, 154.7, 157.7, 161.4, 166.9; LRMS (APCI) m/z 980 [M + NH4]+; HRMS (APCI-Ion Trap) m/z: [M + NH4]+ Calcd for C46H71INO10Si2 980.3656; Found 980.3673; [α]25D −38.1 (c 0.50, CHCl3). To a cooled solution of S8 (1.11 g, 1.16 mmol) in 2:3:2 toluene–CH3CN–H2O (39.0 mL) was added CAN (2.53 g, 4.62 mmol) at 0 °C, and the mixture was vigorously stirred at the same temperature for 30 min. The mixture was quenched with saturated aqueous NaHCO3 (100 mL), and the new mixture was extracted with EtOAc (100 mL × 2). The extracts were washed with saturated aqueous NaHCO3 (100 mL × 2), saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (9:1 to 5:1 hexane–EtOAc) to afford [(E,1S,5R)-5-[(2S,3S,5R)-3-benzyloxy-5-[tert-butyl(dimethyl)silyl]oxy-6-hydroxy-tetrahydropyran-2-yl]-5-[tert-butyl(dimethyl)silyl]oxy-1-methyl-pent-3-enyl] 2-iodo-4,6-dimethoxybenzoate (S9) (708 mg, 72%) as a slightly yellow syrup; Rf = 0.24 (4:1 hexane– EtOAc); 1H NMR (400 MHz, CDCl3, 3:2 anomeric mixture) δ 0.02– 0.10 (12H, m), 0.80–0.94 (18H, m), 1.28–1.35 (3H, m), 1.41–1.82 (1H, m), 2.01–2.52 (3H, m), 2.69–2.87 (1H, m), 3.25–3.90 (3H, m), 3.74 (3H, s), 3.78 (3H, s), 4.34–5.02 (4H, m), 5.08–5.20 (1H, m), 5.40–5.55 (1H, m), 5.61–5.73 (1H, m), 6.40 (1H, d, J = 2.1 Hz), 6.88 (1H, d, J = 2.1 Hz), 7.26–7.37 (5H, m); LRMS (APCI) m/z 874 [M + NH4]+. To a solution of S9 (700 mg, 0.817 mmol) in CH2Cl2 (14.0 mL) was added DMP (416 mg, 0.980 mmol) at rt, and the mixture was stirred at the same temperature for 1.5 h. The reaction mixture was diluted with EtOAc (100 mL), and the new mixture was washed successively with 4:1 saturated aqueous NaHCO3–saturated aqueous Na2S2O3 (100 mL) and saturated aqueous NaHCO3 (100 mL). The extract was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (9:1 to 5:1 hexane–EtOAc) to afford 24 (635 mg, 91%) as a colorless sol-

id; Rf = 0.34 (4:1 hexane–EtOAc); IR (ATR, cm–1) 1748 (C═O), 1716 (C═O), 1597, 1160, 1096, 833; 1H NMR (400 MHz, CDCl3) δ 0.02, 0.04, 0.10, 0.15 (each 3H, s), 0.86, 0.89 (each 9H, s), 1.30 (3H, d, J = 6.2 Hz), 2.00 (1H, dt, J = 12.8, 9.8 Hz), 2.25–2.37 (2H, m), 2.38–2.50 (1H, m), 3.76 (3H, s), 3.78 (3H, s), 3.96 (1H, ddd, J = 9.3, 7.2, 5.7 Hz), 4.10 (1H, dd, J = 10.3, 5.1 Hz), 4.38 (1H, dd, J = 7.2, 2.1 Hz), 4.40–4.45 (2H, m), 4.57 (1H, d, J = 11.3 Hz), 5.15 (1H, sxt, J = 6.2 Hz), 5.53 (1H, dd, J = 15.9, 6.2 Hz), 5.67 (1H, dt, J = 14.9, 6.2 Hz), 6.41 (1H, d, J = 2.1 Hz), 6.89 (1H, d, J = 2.6 Hz), 7.26–7.38 (5H, m); 13 C NMR (100 MHz, CDCl3) δ −5.4, −4.7, −4.6, −4.5, 18.1, 18.3, 19.2, 25.7 (3C), 25.9 (3C), 34.4, 38.4, 55.7, 56.0, 66.6, 69.5, 70.8, 71.7, 74.1, 85.3, 92.6, 99.1, 115.2, 123.6, 127.7, 127.8, 127.9 (2C), 128.5 (2C), 131.6, 137.6, 157.7, 161.4, 166.9, 170.9; LRMS (APCI) m/z 872 [M + NH4]+; HRMS (APCI-Ion Trap) m/z: [M + NH4]+ Calcd for C39H63INO9Si2 872.3081; Found 872.3082; [α] 25D +21.4 (c 0.50, CHCl3). (4S,6E,8R,9S,10S,12R,13S)-10-Benzyloxy-8,12-bis[[tertbutyl(dimethyl)silyl]oxy]-9,13-epoxy-13-hydroxy-16,18dimethoxy-4-methyl-3-oxabicyclo[12.4.0]octadecane1(14),6,15,17-tetraene-2-one (41a) and (4S,6E,8S,9S,10S,12R,13S)-10-benzyloxy-8,12-bis[[tertbutyl(dimethyl)silyl]oxy]-9,13-epoxy-13-hydroxy-16,18dimethoxy-4-methyl-3-oxabicyclo[12.4.0]octadecane1(14),6, 15,17-tetraene-2-one (41b). In a 50 mL round-bottom flask equipped with a nitrogen balloon, 1-bromo-2,4,6-triisopropylbenzene (720 mg, 2.54 mmol) was placed and the flask was evacuated and backfilled with nitrogen twice. THF (10.0 mL) was charged into the flask, and the mixture was cooled to −78 °C. 1.64 M nBuLi (1.55 mL, 2.55 mmol) was added into the flask, and the mixture was stirred at the same temperature for 30 min. To the solution was added dropwise over 7 min a solution of 24 (724 mg, 0.846 mmol), which was beforehand dried azeotropically with toluene, in THF (5.00 mL) at −78 °C, and then the mixture was stirred at the same temperature for 30 min. The reaction mixture was quenched with saturated aqueous NH4Cl (30 mL), and the new mixture was extracted with EtOAc (30 mL × 2). The extracts were washed with saturated aqueous NaCl (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane only to 9:1 hexane–EtOAc) to afford 41a (180 mg, 29%) as a colorless amorphous powder and 41b (8.5 mg, 1.4%, unstable, impure) as a colorless syrup. 41a: Rf = 0.33 (6:1 hexane–EtOAc); IR (ATR, cm–1) 3519 (OH), 1709 (C═O), 1606, 1258, 1043, 834; 1H NMR (400 MHz, CDCl3) δ −0.49, −0.16, −0.02, 0.00 (each 3H, s), 0.77, 0.83 (each 9H, s), 1.32 (3H, d, J = 6.2 Hz), 1.70 (1H, q, J = 11.3 Hz), 2.10–2.34 (3H, m), 3.31 (1H, td, J = 10.7, 4.4 Hz), 3.72 (1H, s), 3.76, 3.79 (each 3H, s), 3.99 (1H, d, J = 10.3 Hz), 4.45 (1H, d, J = 11.8 Hz), 4.54 (1H, d, J = 6.2 Hz), 4.64 (1H, dd, J = 10.8, 5.7 Hz), 4.68 (1H, d, J = 12.8 Hz), 5.18–5.38 (2H, m), 5.51 (1H, dd, J = 16.4, 6.2 Hz), 6.42 (1H, d, J = 2.6 Hz), 6.85 (1H, d, J = 2.6 Hz), 7.26–7.39 (5H, m); 13C NMR (100 MHz, CDCl3) δ −5.8, −5.1, −4.8, −4.5, 17.7, 18.3, 20.4, 25.7 (3C), 26.0 (3C), 35.4, 37.6, 55.3, 56.2, 69.3, 70.7, 70.8, 71.4, 71.8, 80.0, 97.2, 99.2, 104.8, 115.5, 122.2, 127.6, 127.9 (2C), 128.3 (2C), 135.0, 138.3, 142.9, 158.6, 160.1, 168.8; LRMS (APCI) m/z 746 [M + NH4]+; HRMS (APCI-Ion Trap) m/z: [M + NH4]+ Calcd for C39H64NO9Si2 746.4114; Found 746.4117; [α]25D +77.0 (c 0.50, CHCl3). 41b: Rf = 0.47 (6:1 hexane–EtOAc); 1H NMR (400 MHz, CDCl3) δ – 0.03, –0.01, 0.02, 0.10 (each 3H, s), 0.81, 0.85 (each 9H, s), 1.37 (3H, d, J = 6.2 Hz), 2.06–2.21 (2H, m), 2.26–2.41 (2H, m), 2.99 (1H, t, J = 8.7 Hz), 3.61–3.70 (1H, m), 3.77, 3.78 (each 3H, s), 3.89 (1H, dd, J = 13.1, 4.9 Hz), 4.07 (1H, t, J = 8.5 Hz), 4.48–4.58 (2H, m), 5.31 (1H, dd, J = 15.4, 8.7 Hz), 5.39 (1H, ddd, J = 11.8, 6.2, 3.1 Hz), 5.53 (1H, ddd, J = 15.3, 10.4, 4.6 Hz), 6.42 (1H, d, J = 2.1 Hz), 7.16–7.38 (5H, m), 7.45 (1H, s), 7.48 (1H, d, J = 2.1 Hz); 13C NMR (100 MHz, CDCl3) δ −5.4, −4.4, −4.0, −3.4, 18.0, 18.4, 20.2, 25.8 (3C), 26.2 (3C), 37.3, 39.7, 55.4, 56.4, 68.7, 70.3, 74.4, 76.3, 76.7, 77.5, 98.6, 99.3, 107.2, 113.9, 125.8, 127.3, 127.5 (2C), 128.1 (2C), 138.8, 139.2, 141.7, 160.1, 161.0, 170.7; LRMS (APCI) m/z 746 [M + NH4]+. (4S,6E,8R,9S,10S,12R,13S)-10-Benzyloxy-9,13-epoxy8,12-dihydroxy-16,18-dimethoxy-4-methyl-3-oxabicyclo[12.4.0]octadecane-1(14),6,15,17-tetraene-2-one (42). To a



cooled solution of 41a (193 mg, 0.265 mmol) and Et3SiH (0.212 mL, 1.33 mmol) in CH2Cl2 (6.00 mL) was added BF3·Et2O (0.168 mL, 1.33 mmol) at −20 °C, and the mixture was stirred at the same temperature for 1 h. Then the mixture was allowed to warm to rt, and stirred for 1 h. To the mixture was added saturated aqueous NaHCO3 (30 mL), and the new mixture was extracted with EtOAc (30 mL × 2). The extracts were washed with saturated aqueous NaCl (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (2:1 hexane– EtOAc to EtOAc only) to afford 42 (108 mg, 84%) as a colorless amorphous powder; Rf = 0.38 (1:2 hexane–EtOAc); IR (ATR, cm–1) 3403 (OH), 1707 (C═O), 1606, 1584, 1260, 1105, 1031; 1H NMR (400 MHz, CDCl3) δ 1.34 (3H, d, J = 6.7 Hz), 1.47–1.60 (1H, m), 1.74 (1H, d, J = 4.1 Hz), 2.10 (1H, d, J = 6.7 Hz), 2.18–2.30 (1H, m), 2.38 (1H, dt, J = 13.8, 3.6 Hz), 2.59–2.70 (1H, m), 3.34–3.50 (2H, m), 3.78 (3H, s), 3.80 (3H, s), 4.02–4.17 (2H, m), 4.43–4.48 (1H, d, J = 11.3 Hz), 4.50–4.54 (1H, m), 4.70 (1H, d, J = 11.3 Hz), 5.27–5.41 (1H, m), 5.53 (1H, dd, J = 14.3, 7.7 Hz), 5.57–5.69 (1H, m), 6.40 (1H, d, J = 1.5 Hz), 6.42 (1H, d, J = 2.1 Hz), 7.28–7.43 (5H, m); 13C NMR (100 MHz, CDCl3) δ 20.5, 37.3, 37.4, 55.5, 56.0, 68.8, 70.3, 70.7, 72.3, 73.9, 84.3, 85.0, 98.5, 106.1, 115.8, 126.0, 127.87 (2C), 127.93, 128.6 (2C), 131.1, 137.8, 138.3, 159.0, 160.5, 168.2; LRMS (APCI) m/z 485 [M + H]+; HRMS (APCI-Ion Trap) m/z: [M + H]+ Calcd for C27H33O8 485.2170; Found 485.2172; [α]25D +153.1 (c 0.50, CHCl3). Synthesis of paecilomycin B (5) (intramolecular nucleophilic addition route). To a solution of 42 (10.0 mg, 0.0206 mmol) in CH2Cl2 (2.00 mL) was added BBr3 (0.0410 mL, 0.0410 mmol, 1.0 M CH2Cl2 solution) at 0 °C, and the mixture was stirred at the same temperature for 15 min. To the mixture was added additional BBr3 (0.0410 mL, 0.0410 mmol) at 0 °C, and the mixture was stirred at the same temperature for 15 min. To the mixture was added saturated aqueous NaHCO3 (10 mL), and the new mixture was extracted with 1:1 EtOAc–THF (20 mL × 2). The extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (9:1 to 6:1 CHCl3–MeOH) to afford paecilomycin B (5) (4.2 mg, 54%) as a colorless amorphous solid; Rf = 0.28 (6:1 CHCl3–MeOH); IR (ATR, cm–1) 3336 (OH), 1687 (C═O) , 1612, 1254, 1015; 1H NMR (400 MHz, pyridine-d5) δ 1.45 (3H, d, J = 6.7 Hz), 2.15–2.46 (3H, m), 3.06 (1H, dt, J = 11.6, 4.4 Hz), 3.57 (3H, s), 4.13 (1H, d, J = 9.2 Hz), 4.16–4.28 (1H, m), 4.47 (1H, d, J = 8.7 Hz), 5.09–5.24 (1H, m), 5.54 (1H, d, J = 4.6 Hz), 5.73–5.90 (1H, m), 6.08–6.22 (1H, m), 6.33 (1H, dd, J = 16.4, 5.6 Hz), 6.66 (1H, d, J = 2.6 Hz), 6.71 (1H, d, J = 2.0 Hz), 6.78–6.99 (3H, br), 11.87 (1H, s); 13C NMR (100 MHz, pyridine-d5) δ 21.0, 37.8, 44.7, 55.1, 66.7, 68.9, 69.9, 71.4, 87.2, 89.2, 101.7, 107.6, 116.6, 123.4, 134.9, 141.6, 157.9, 160.3, 169.5; LRMS (APCI) m/z 381 [M + H]+; HRMS (APCI-Ion Trap) m/z: [M + H]+ Calcd for C19H25O8 381.1544; Found 381.1541; [α] 25D +86.7 (c 0.25, MeOH). These spectral data were identical with literature data5,7a. [(E,1S,5S)-5-[(2S,3S,5R)-3-Benzyloxy-5-[tert-butyl(dimethyl)silyl]oxy-6-oxo-tetrahydropyran-2-yl]-5-[tert-butyl(dimethyl)silyl]oxy-1-methyl-pent-3-enyl]2-iodo-4,6-dimethoxybenzoate (43). To a suspension of 40b (2.13 g, 2.51 mmol) in DMF (21.0 mL) were added imidazole (513 mg, 7.54 mmol) and TBSCl (757 mg, 5.02 mmol), and the mixture was stirred at 80 °C for 2 h. After cooling, to the mixture were added additional imidazole (256 mg, 3.76 mmol) and TBSCl (379 mg, 2.51 mmol). The mixture was stirred at 80 °C for 1 h. After cooling, to the mixture were added H2O (100 mL), and the new mixture was extracted with EtOAc (100 mL × 2). The extracts were washed with H2O (100 mL) and saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane only to 6:1 hexane–EtOAc) to afford [(E,1S,5S)-5-[(2S,3S,5R,6S)-3-benzyloxy-5-[tert-butyl(dimethyl)silyl]oxy-6-(4-methoxyphenoxy)tetrahydropyran-2-yl]-5-[tertbutyl(dimethyl)silyl]oxy-1-methyl-pent-3-enyl] 2-iodo-4,6-dimethoxy benzoate (S10) (2.21 g, 92%) as a colorless syrup; Rf = 0.24 (6:1 hexane–EtOAc); IR (ATR, cm–1) 1728 (C═O), 1597, 1561, 1215, 1085, 1039; 1H NMR (400 MHz, CDCl3) δ −0.01, 0.02, 0.11, 0.14 (each 3H, s), 0.88 (18H, s), 1.35 (3H, d, J = 6.2 Hz), 1.57 (1H, q, J =

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11.8 Hz), 2.34 (1H, dt, J = 14.3, 7.0 Hz), 2.44–2.57 (2H, m), 3.34 (1H, dd, J = 9.0, 2.3 Hz), 3.65–3.84 (2H, m), 3.71, 3.76, 3.78 (each 3H, s), 4.42–4.52 (2H, m), 4.58–4.69 (2H, m), 5.17 (1H, sxt, J = 6.4 Hz), 5.64–5.75 (1H, m), 5.80 (1H, dd, J = 18.0, 7.7 Hz), 6.39 (1H, d, J = 2.1 Hz), 6.79 (2H, d, J = 9.3 Hz), 6.89 (1H, d, J = 2.1 Hz), 6.93 (2H, d, J = 8.7 Hz), 7.27–7.40 (5H, m); 13C NMR (100 MHz, CDCl3) δ −4.8, −4.5, −4.3, −3.5, 18.1, 18.3, 19.5, 25.8 (3C), 26.1 (3C), 37.8, 38.5, 55.68, 55.69, 55.9, 69.0, 70.7, 71.7, 72.2 (2C), 82.5, 92.6, 99.0, 104.0, 114.4 (2C), 115.1, 117.6 (2C), 123.7, 126.8, 127.5 (2C), 127.6, 128.3 (2C), 134.5, 138.5, 151.8, 154.7, 157.7, 161.4, 166.9; LRMS (APCI) m/z 980 [M + NH4]+; HRMS (APCI-Ion Trap) m/z: [M + NH4]+ Calcd for C46H71INO10Si2 980.3656; Found 980.3668; [α] 25D −1.89 (c 0.50, CHCl3). To a cooled solution of S10 (2.01 g, 2.09 mmol) in 2:3:2 toluene–CH3CN–H2O (70.0 mL) was added CAN (4.58 g, 8.35 mmol) at 0 °C, and the mixture was vigorously stirred at the same temperature for 30 min. The mixture was quenched by saturated aqueous NaHCO3 (200 mL), and the new mixture was extracted with EtOAc (100 mL × 2). The extracts were washed with saturated aqueous NaHCO3 (100 mL), saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (9:1 to 5:1 hexane–EtOAc) to afford (E,1S,5S)-5-[(2S,3S,5R)-3-benzyloxy-5-[tertbutyl(dimethyl)silyl]oxy-6-hydroxy-tetrahydropyran-2-yl]-5-[tertbutyl(dimethyl)silyl]oxy-1-methyl-pent-3-enyl] 2-iodo-4,6-dimethoxybenzoate (S11) (1.22 g, 68%) as a slightly yellow syrup; Rf = 0.18 (5:1 hexane–EtOAc); 1H NMR (400 MHz, CDCl3, 3:2 anomeric mixture) δ 0.01–0.11 (12H, m), 0.86–0.91 (18H, m), 1.32–1.36 (3H, m), 1.41–1.79 (1H, m), 2.15–2.54 (3H, m), 2.79–2.92 (1H, m), 3.26–3.41 (1H, m), 3.59–3.76 (2 H, m), 3.70 (3H, s), 3.78 (3H, s), 4.39–5.06 (4H, m), 5.12–5.23 (1H, m), 5.63–5.73 (1H, m), 5.75–5.87 (1H, m), 6.38– 6.42 (1H, m), 6.87–6.90 (1H, m), 7.27–7.37 (5H, m); LRMS (APCI) m/z 874 [M + NH4]+. To a solution of S11 (1.16 g, 1.35 mmol) in CH2Cl2 (24.0 mL) was added DMP (689 mg, 1.62 mmol) at rt, and the mixture was stirred at the same temperature for 16 h. The reaction mixture was treated with 4:1 saturated aqueous NaHCO3–saturated aqueous Na2S2O3 (100 mL), and the new mixture was extracted with EtOAc (100 mL × 2). The organic layers were washed with saturated aqueous NaHCO3 (100 mL), saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (9:1 to 6:1 hexane–EtOAc) to afford 43 (1.11 g, 96%) as a colorless syrup; Rf = 0.24 (5:1 hexane–EtOAc); IR (ATR, cm–1) 1757 (C═O), 1728 (C═O), 1597, 1259, 1159, 834; 1H NMR (400 MHz, CDCl3) δ −0.01 (6H, s), 0.10, 0.15 (each 3H, s), 0.84, 0.90 (each 9H, s), 1.34 (3H, d, J = 6.1 Hz), 1.90–2.07 (1H, m), 2.27–2.46 (2H, m), 2.47–2.57 (1H, m), 3.72, 3.79 (each 3H, s), 3.96 (1H, ddd, J = 9.9, 7.6, 5.6 Hz), 4.11 (1H, dd, J = 10.8, 5.1 Hz), 4.23 (1H, dd, J = 7.7, 1.5 Hz), 4.27 (1H, dd, J = 7.7, 1.5 Hz), 4.48 (1H, d, J = 11.3 Hz), 4.65 (1H, d, J = 11.3 Hz), 5.15 (1H, sxt, J = 6.3 Hz), 5.64–5.88 (2H, m), 6.41 (1H, d, J = 2.1 Hz), 6.89 (1H, d, J = 2.1 Hz), 7.28–7.40 (5H, m); 13C NMR (100 MHz, CDCl3) δ −5.5, −4.67, −4.65, −3.7, 18.1, 18.3, 19.3, 25.7 (3C), 25.9 (3C), 34.3, 38.4, 55.7, 55.9, 66.6, 70.9, 71.2, 71.9, 73.2, 86.0, 92.5, 99.0, 115.1, 123.7, 127.8 (2C), 128.0, 128.5, 128.6 (2C), 132.8, 137.6, 157.7, 161.4, 166.9, 171.1; LRMS (APCI) m/z 855 [M + H]+; HRMS (APCI-Ion Trap) m/z: [M + H]+ Calcd for C39H60IO9Si2 855.2815; Found 855.2826; [α]25D +45.1 (c 0.50, CHCl3). (4S,6E,8S,9S,10S,12R,13R)-10-Benzyloxy-8,12-bis[[tertbutyl(dimethyl)silyl]oxy]-9,13-epoxy-13-hydroxy-16,18-dimethoxy-4-methyl-3-oxabicyclo[12.4.0]octadecane-1(14),6,15, 17-tetraene-2-one (44). In a round-bottom flask equipped with a nitrogen balloon, 1-bromo-2,4,6-triisopropylbenzene (200 mg, 0.706 mmol) was placed and the flask was evacuated and backfilled with nitrogen twice. THF (2.82 mL) was charged into the flask, and the mixture was cooled to −78 °C. 1.64 M nBuLi (0.431 mL, 0.706 mmol) was added into the flask, and the mixture was stirred at the same temperature for 30 min. To the mixture was added dropwise over 5 min a solution of 43 (201 mg, 0.235 mmol), which was beforehand dried azeotropically with toluene, in THF (1.41 mL) at −78 °C, and then the mixture was stirred at the same temperature for 30 min. The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL), and the new mixture was extracted with EtOAc (20 mL ×2).


Page 13 of 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


The extracts were washed with saturated aqueous NaCl (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane only to 9:1 hexane–EtOAc) to afford 44 (131 mg, 76%) as a colorless amorphous solid; Rf = 0.42 (6:1 hexane–EtOAc); IR (ATR, cm–1) 3265 (OH), 1680 (C═O), 1601, 1090, 835; 1H NMR (400 MHz, CDCl3) δ 0.01, 0.03, 0.04, 0.17 (each 3H, s), 0.90, 0.93 (each 9H, s), 1.36 (3H, d, J = 6.2 Hz), 2.00–2.21 (2H, m), 2.29–2.41 (1H, m), 2.54 (1H, dt, J = 12.0, 5.1 Hz), 2.85 (1H, dd, J = 9.3, 1.0 Hz), 3.76 (3H, s), 3.78–3.85 (1H, m), 3.80 (3H, s), 3.90 (1H, dd, J = 13.4, 4.6 Hz), 4.42 (1H, d, J = 11.3 Hz), 4.49–4.55 (1H, m), 4.65 (1H, d, J = 11.3 Hz), 5.24–5.43 (2H, m), 5.62–5.79 (1H, m), 6.41 (1H, d, J = 2.1 Hz), 7.13 (1H, s), 7.19–7.37 (5H, m), 7.51 (1H, d, J = 2.6 Hz); 13C NMR (100 MHz, CDCl3) δ −5.5, −4.9, −4.3, −3.7, 18.1, 18.5, 20.2, 25.9 (3C), 26.2 (3C), 36.1, 38.6, 55.4, 56.3, 68.7, 69.3, 69.6, 72.3, 74.8, 77.6, 99.0, 99.1, 107.1, 114.2, 124.4, 127.3 (2C), 127.5, 128.3 (2C), 135.8, 138.4, 142.2, 159.8, 160.7, 170.8; LRMS (APCI) m/z 711 [M − OH]+; HRMS (APCI-Ion Trap) m/z: [M + H]+ Calcd for C39H61O9Si2 729.3849; Found 729.3839; [α]25D +78.8 (c 0.50, CHCl3). (4S,6E,8S,9S,10S,12R,13S)-10-Benzyloxy-9,13-epoxy8,12-dihydroxy-16,18-dimethoxy-4-methyl-3-oxabicyclo[12.4.0]octadecane-1(14),6,15,17-tetraene-2-one (45). To a cooled solution of 44 (50.0 mg, 0.0686 mmol) and Et3SiH (0.0550 mL, 0.344 mmol) in CH2Cl2 (5.00 mL) was added BF3·Et2O (0.0440 mL, 0.347 mmol) at −20 °C, and the mixture was stirred at the same temperature for 4 h. To the mixture was added saturated aqueous NaHCO3 (20 mL), and the new mixture was extracted with EtOAc (20 mL × 2). The extracts were washed with saturated aqueous NaCl (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The obtained syrup was dissolved with MeOH (3.00 mL), and to the mixture was added methanesulfonic acid (0.0100 mL, 0.154 mmol) at rt, and the new mixture was stirred at the same temperature for 2 h. To the mixture was added saturated aqueous NaHCO3 (20 mL), and the mixture was extracted with EtOAc (20 mL× 2). The extracts were washed with saturated aqueous NaCl (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (4:1 to 1:1 hexane–EtOAc) to afford 45 (12.9 mg, 39%) as a colorless solid; Rf = 0.26 (1:1 hexane– EtOAc); IR (ATR, cm–1) 3434 (OH), 1697 (C═O), 1604, 1247, 1050; 1 H NMR (400 MHz, CDCl3) δ 1.35 (3H, d, J = 6.2 Hz), 1.58 (1H, q, J = 11.3 Hz), 1.84 (1H, d, J = 4.6 Hz), 2.21 (1H, ddd, J = 13.4, 11.1, 7.5 Hz), 2.33–2.43 (1H, m), 2.71 (1H, dt, J = 11.6, 4.5 Hz), 3.58 (1H, dd, J = 9.3, 4.6 Hz), 3.76–3.85 (1H, m), 3.78, 3.80 (each 3H, s), 4.07 (1H, d, J = 9.2 Hz), 4.11 (1H, d, J = 9.3 Hz), 4.22–4.36 (2H, m), 4.50 (1H, d, J = 11.3 Hz), 4.71 (1H, d, J = 10.8 Hz), 5.20–5.34 (1H, m), 5.42 (1H, dd, J = 15.9, 8.2 Hz), 5.70 (1H, dt, J = 15.4, 7.2 Hz), 6.42 (1H, d, J = 2.1 Hz), 6.44 (1H, d, J = 2.1 Hz), 7.29–7.42 (5H, m); 13C NMR (100 MHz, CDCl3) δ 20.5, 36.0, 37.4, 55.5, 56.1, 68.5, 70.5, 72.9, 73.6, 75.6, 78.2, 85.3, 98.6, 106.5, 115.8, 128.2 (2C), 128.3, 128.7 (2C), 130.2, 131.1, 136.9, 138.4, 158.9, 160.6, 168.4; LRMS (APCI) m/z 485 [M + H]+; HRMS (APCI-Ion Trap) m/z: [M + H]+ Calcd for C27H33O8 485.2170; Found 485.2169; [α]25D +215.1 (c 0.50, CHCl3). Synthesis of 6´-epi-paecilomycin B (34) (intramolecular nucleophilic addition route). To a solution of 45 (10.0 mg, 0.0206 mmol) in CH2Cl2 (2.00 mL) was added BBr3 (0.0410 mL, 0.0410 mmol, 1.0 M CH2Cl2 solution) at 0 °C. The mixture was stirred at the same temperature for 15 min. To the mixture was added additional BBr3 (0.0410 mL, 0.0410 mmol), and the solution was stirred at 0 °C for 15 min. To the mixture was added saturated aqueous NaHCO3 (10 mL), and the new mixture was extracted with EtOAc (20 mL × 2). The extracts were washed with saturated aqueous NaCl (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (15:1 CHCl3–MeOH) to afford 6´-epipaecilomycin B (34) (4.8 mg, 61%) as a colorless amorphous solid; Rf = 0.28 (9:1 CHCl3–MeOH); IR (ATR, cm–1) 3305 (OH), 1687 (C═O), 1612, 1254, 1015; 1H NMR (400 MHz, pyridine-d5) δ 1.44 (3H, d, J = 6.2 Hz), 2.07–2.31 (2H, m), 2.41–2.57 (1H, m), 2.90–3.11 (1H, m), 3.57 (3H, s), 3.93 (1H, dd, J = 9.2, 5.1 Hz), 4.43–4.57 (1H, m), 4.61 (1H, d, J = 8.7 Hz), 4.95–5.03 (1H, m), 5.08–5.27 (1H, m), 5.67 (1H,

dquin, J = 11.0, 5.6, 5.6, 5.6, 5.6 Hz), 5.88–6.08 (1H, m), 6.18 (1H, dd, J = 15.9, 8.7 Hz), 6.39 (1H, s), 6.62 (1H, d, J = 2.1 Hz), 6.82 (1H, d, J = 5.7 Hz), 6.89 (1H, d, J = 2.1 Hz), 7.61 (1H, br), 11.89 (1H, s); 13 C NMR (100 MHz, pyridine-d5) δ 20.8, 36.1, 44.1, 55.1, 67.1, 68.2, 72.7, 76.3, 81.6, 87.1, 101.6, 108.1, 115.7, 130.1, 132.8, 141.3, 158.4, 160.6, 169.6; LRMS (APCI) m/z 381 [M + H]+; HRMS (APCI-Ion Trap) m/z: [M + H]+ Calcd for C19H25O8 381.1544; Found 381.1541; [α]25D +119.9 (c 0.20, MeOH). These spectral data were identical with those of 6´-epi-paecilomycin B (34) from intramolecular NHK route. tert-Butyl 4-(1-acetoxy-2,3,4,6-tetra-O-benzyl-α α-D-glucopyranosyl)benzoate (54). In a flame-dried 50 mL round-bottom flask equipped with a nitrogen balloon, 1-bromo-2,4,6-triisopropylbenzene (693 mg, 2.45 mmol) was placed and the flask was evacuated and backfilled with nitrogen twice. THF (10.0 mL) was charged into the flask and cooled to −78 °C. To the solution was added 1.63 M nBuLi (1.50 mL, 2.45 mmol) and the mixture was stirred at the same temperature for 0.5 h. To the mixture was added dropwise over a period of 10 min a solution of tert-butyl 4-iodobenzoate (52) (496 mg, 1.63 mmol) and tetra-O-benzyl-D-glucono-1,5-lactone (47) (878 mg, 1.63 mmol), which were beforehand combined and the new mixture was dried azeotropically with toluene, in THF (4.00 mL) at −78 °C. The mixture was stirred at the same temperature for 5 min, and then to the reaction mixture was added acetic anhydride (1.54 mL, 16.3 mmol). The mixture was allowed to warm to −30 °C, and stirred at the same temperature for 0.5 h. The mixture was allowed to warm to 0 °C, and was quenched with saturated aqueous NaHCO3 (30 mL). The mixture was extracted with EtOAc (20 mL × 2). The extracts were washed with saturated aqueous NaCl (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20:1 to 6:1 to 4:1 hexane−EtOAc) to afford 54 (990 mg, 80%) as a colorless syrup and 1-C(4-tert-butoxycarbonylphenyl)-2,3,4,6-tetra-O-benzyl-α-D-glucopyranose (53)13a (60 mg, 5%) as a colorless syrup. 54: Rf = 0.28 (6:1 hexan−EtOAc); IR (ATR, cm–1) 1757 (C═O), 1710 (C═O), 1089, 1074, 696; 1H NMR (400 MHz, CDCl3) δ 1.60 (9H, s), 1.81 (3H, s), 3.82 (1H, dd, J = 10.8, 1.5 Hz), 3.84−3.91 (2H, m), 3.98 (1H, d, J = 1.5 Hz), 4.06 (1H, d, J = 11.3 Hz), 4.11 (1H, dt, J = 10.8, 2.3 Hz), 4.16 (1H, d, J = 11.8 Hz), 4.36 (1H, dd, J = 11.0, 6.9 Hz), 4.51 (1H, d, J = 11.8 Hz), 4.55 (1H, d, J = 10.8 Hz), 4.60 (1H, d, J = 11.8 Hz), 4.64 (1H, d, J = 11.8 Hz), 4.69 (1H, d, J = 10.8 Hz), 4.81 (1H, d, J = 10.8 Hz), 6.82−6.91 (2H, m), 7.11−7.39 (18H, m), 7.59 (2H, d, J = 8.7 Hz), 7.94 (2H, d, J = 8.7 Hz); 13C NMR (100 MHz, CDCl3) δ 22.3, 28.2 (3C), 68.8, 72.0, 72.6, 73.5, 74.3, 74.4, 76.8, 80.9, 81.0, 83.7, 102.3, 126.2 (2C), 127.5, 127.6 (2C), 127.7 (2C), 127.8, 127.88 (2C), 127.93 (2C), 128.0 (2C), 128.2 (2C), 128.3 (2C), 128.38 (2C), 128.41 (2C), 129.2 (2C), 131.5, 136.9, 138.25, 138.28, 138.5, 144.1, 165.6, 167.6; (APCI) m/z 699 [M − OAc]+; HRMS (APCI-Ion Trap) m/z: [M + H]+ Calcd for C45H47O7 699.3316; Found 699.3314; [α]25D −16.4 (c 1.01, CHCl3).

ASSOCIATED CONTENT Supporting Information Spectral data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]

ORCID Kiyomi Ohba: 0000-0003-1707-6530

Notes The authors declare no competing financial interest.

REFERENCES



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