Synthesis of chiral building blocks for oxygenated terpenoids through a simultaneous and stereocontrolled construction of contiguous quaternary stereocenters by an ireland-claisen rearrangement

Article

pubs.acs.org/joc

Synthesis of Chiral Building Blocks for Oxygenated Terpenoids

through a Simultaneous and Stereocontrolled Construction of

Contiguous Quaternary Stereocenters by an Ireland−Claisen

Rearrangement

Yoshihiro Akahori,^†Hiroyuki Yamakoshi,^†Yuki Sawayama,^†Shunichi Hashimoto,^‡

and Seiichi Nakamura*^,†

^†Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan

^‡Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan

S

* Supporting Information

ABSTRACT: Methods for highly stereocontrolled syntheses

of chiral building blocks with a triad of contiguous stereo-

centers, including two quaternary ones, have been developed.

Ireland−Claisen rearrangement of the (Z)-silyl ketene acetal

generated stereoselectively from the (R)-3-methylcyclohex-2-

enyl ester derived from an acyclic carboxylic acid proceeded

through a chairlike transition state to give the rearranged

product with an S conﬁguration at the position α to the carboxyl group. Introduction of a cyclic conformational constraint in the

acid component completely switched the transition state of the rearrangement to a boatlike one, leading to the predominant

formation of a product with an R conﬁguration, from which pseudodiastereomeric α-hydroxy esters were obtained in a four-step

sequence. The enyne obtained through a base-mediated double eliminative ring-opening reaction was successfully converted into

advanced intermediates for the synthesis of 9-oxygenated labdane diterpenoids through a Heck reaction and a regioselective

transformation of the resultant diene.

polycyclic compound having an angular methyl group as the

starting material and created an oxygen-substituted quaternary

center by either a nucleophilic or an electrophilic addition to an

sp²carbon in a stereoselective manner.¹³

INTRODUCTION

■

Terpenes with various carbon skeletons undergo oxidation

during the biosynthetic process to provide a wide variety of

terpenoids. Since the C17 position of triterpenes and the C9

position of diterpenes are prone to oxygenation, C17-

oxygenated steroids¹and C9-oxygenated labdane diterpenoids²

constitute representative subclasses of this family (Figure 1).

Some of these natural products, including the OSWs (1)

(antitumor),³withanone (2) (LTB₄inhibitor),⁴17,20-

dihydroxyvitamin D₂(3) (transcriptional activity stimulator),⁵

scillascillosides (4) (antitumor),⁶scillasaponins (5) (cyto-

toxic),⁷physagulins (6) (trypanocidal),⁸kadcoccilactones (7)

(cytotoxic),⁹jaborosalactone P (8) (antifeedant),¹⁰marruliba-

cetal (9) (antispasmodic),¹¹and isopreleoheterins (10)

(cytoprotective),¹²have been reported to display remarkable

biological activities. An inspection of these structures reveals

that motifs 11α and 11β, which contain a cyclohexane ring and

a triad of contiguous stereocenters, including two quaternary

ones, and diﬀer only in the stereochemistry of the oxygen-

substituted quaternary stereocenter, are embedded in all of

these natural products. In view of the important biological

activities and structural complexity of these classes of natural

products, compounds including motifs 11α and 11β are

expected to be valuable building blocks for the synthesis of

these natural products and their analogues, whereas all of the

reported approaches to these molecules have employed a

Because of the ease of substrate preparation, mild reaction

conditions, and predictability in the stereochemistry of the

products, the Ireland−Claisen rearrangement has been

extensively utilized in natural product synthesis.¹⁴This reaction

can be applied for the assembly of contiguous tetrasubstituted

carbon atoms,¹⁵and stereoselective transformations have been

realized in some cases.¹⁶It is well-recognized that the

stereoselectivity of the reaction can be controlled by the silyl

ketene acetal geometry and the selectivity of the chairlike versus

boatlike transition state;¹⁷however, attempts to synthesize two

possible diastereomeric products bearing contiguous quaternary

centers in a stereoselective manner have been limited.^18,19In

this article, we describe procedures for the stereodivergent

syntheses of chiral building blocks including either motif 11α or

11β by an Ireland−Claisen rearrangement.

RESULTS AND DISCUSSION

■

We envisioned compounds such as 12α and 12β as promising

building blocks for oxygenated terpenoids with the expectation

Received: November 15, 2013

Published: December 17, 2013

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Figure 1. Structures of bioactive C17-oxygenated steroids and C9-oxygenated labdane diterpenoids that contain either 11α or 11β as a common

motif.

Scheme 1. Retrosynthetic Analysis of Building Blocks 12α and 12β

that an oleﬁn and either an ester or a functional group in the

substituent R, which could be varied depending on the target

molecule, would serve as handles for the construction of a ﬁve-

or six-membered ring (Scheme 1). It is known that the

Ireland−Claisen rearrangement of silyl ketene acetals derived

from glycolates of cyclic alcohols frequently proceeds through a

boatlike transition state.²⁰In contrast, Zakarian and co-workers

have concluded that the rearrangement of α,α-disubstituted

silyl ketene acetals derived from esters of cyclic alcohols shows

a preference for a chairlike transition state.¹⁸Despite the lack of

precedent for the reaction of α-substituted glycolates of cyclic

alcohols, we surmised that compounds 12α and 12β would be

obtained by the rearrangement of α,α-disubstituted silyl ketene

acetals 14a and 14b through chairlike transition states 13a and

13b, respectively. We also considered that stereoselective

formation of silyl ketene acetals 14a and 14b from ester 15

could be accomplished by the proper choice of either the

protecting group at the hydroxyl group or the reaction

conditions.²¹

At the outset of this study, a benzyl group was selected as the

protecting group R′ so that (Z)-silyl ketene acetal 14a would be

formed predominantly through metal chelate organization. The

preparation of substrate 15a (R = OTBDPS, R′ = Bn) was

initiated by regioselective ring opening of known epoxy alcohol

16²²(prepared with 95% ee through a Sharpless asymmetric

epoxidation²³) with Me₃Al under Oshima−Nozaki conditions²⁴

to give 1,2-diol 17 in 86% yield (Scheme 2). The resultant

secondary alcohol was selectively protected as its benzyl ether

in a two-step sequence involving benzylidene acetal formation

with benzaldehyde dimethyl acetal in the presence of a catalytic

amount of PPTS (93% yield) and regioselective reductive ring

opening with DIBALH (88% yield). The primary alcohol 19

was then converted into carboxylic acid 21 by two successive

oxidations (Dess−Martin periodinane;²⁵NaClO₂²⁶), and acid

21 was coupled with chiral alcohol 22^27,28in the presence of

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Scheme 2. Preparation of Ester 15a

Scheme 3. Ireland−Claisen Rearrangement of Ester 15a and the Stereochemical Correlation

EDCI, Et₃N, and DMAP in CH₂Cl₂to yield ester 15a along

with a trace amount of 23 in a combined yield of 68% for the

three steps.²⁹

hydrogenation.³¹After considerable experimentation, puriﬁca-

tion by preparative TLC enabled the isolation of a small

amount of slightly impure 24b, which could be converted to

iodolactone 26b as with 24a. The equatorial proton H_a1adjacent

to the quaternary carbon in 26b exhibited signiﬁcant H NOE

interactions with the side-chain protons H_band H_c, indicating

an R conﬁguration of the oxygen-substituted stereocenter of

24b.

With precursor 15a in hand, we then proceeded to construct

the contiguous quaternary stereocenters by an Ireland−Claisen

rearrangement (Scheme 3). Treatment of ester 15a, contami-

nated with a small amount of isomer 23, with LDA at −78 °C

followed by the addition of TMSCl produced the correspond-

ing silyl ketene acetal, which upon warming to room

temperature underwent rearrangement to provide a mixture

of three stereoisomers 24 in a 94:5:1 ratio.³⁰Esteriﬁcation of

the major isomer 24a, which could be separated by silica gel

column chromatography, with MeI in the presence of K₂CO₃in

DMF gave methyl ester 25 in 41% yield in two steps. The

stereochemical assignment of the major isomer 24a was

In accordance with established precedents,³²the metal

chelate organization in lithium enolate 28 led to the exclusive

formation of (Z)-silyl ketene acetal 29 from ester 15a (Scheme

4). Rearrangement of 29 preferentially proceeded through an

energetically favorable chairlike transition state to give isomer

24a as the major product, whereas the formation of the minor

isomer 24b can be attributed to the reaction via a

thermodynamically less favored boatlike transition state.

Since structural motif 11α is involved in the molecule,

carboxylic acid 24a and methyl ester 25 can be employed as

building blocks for the synthesis of α-type natural products

illustrated in Figure 1 through construction of a ﬁve-membered

ring.³³Since the 1-oxaspiro[4.4]nonane ring system is a

fragment of some α-type C17-oxygenated triterpenoids (e.g.,

4 and 5 in Figure 1), our attention was next focused on the

1

established by H NOE experiments using iodolactone 26a,

obtained from 24a by the reaction with I₂and NaHCO₃in

aqueous MeCN at 0 °C. On the other hand, the isomers 24b

and 24c were diﬃcult to separate, but the two isomers were

found to possess the opposite conﬁgurations at the methyl-

bearing and oxygen-substituted stereocenters because of the

formation of an enantiomerically enriched racemic mixture

upon esteriﬁcation of the mixture with TMSCHN₂followed by

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Scheme 4. Plausible Reaction Pathways for the Rearrangement of Ester 15a

Scheme 5. Preparation of Tetrahydrofuran-2-carboxylate 36

Scheme 6. Ireland−Claisen Rearrangement of Tetrahydrofuran-2-carboxylate 36 and the Stereochemical Correlation

Ireland−Claisen rearrangement of tetrahydrofuran-2-carboxy-

late 36. The preparation of substrate 36 commenced with the ^L-

glutamic acid-derived lactone 30³⁴and proceeded along the

path delineated in Scheme 5. Lithiation of thioanisole under

Corey−Seebach conditions³⁵followed by addition of lactone

30 furnished hemiacetal 31, which was subjected to BF₃·OEt₂-

promoted reduction with Et₃SiH³⁶to aﬀord 2,5-trans-

tetrahydrofuran 32 as a single diastereomer in 86% yield in

two steps. After oxidation of the sulﬁde in tetrahydrofuran 32

using m-CPBA, treatment of the resultant sulfoxide 33 with

TFAA eﬀected a Pummerer rearrangement,³⁷providing

aldehyde 34 in 73% yield for the three-step sequence after

hydrolysis of the corresponding triﬂuoroacetate intermediate

with aqueous NaHCO₃and concomitant epimerization. With

regard to the conversion of aldehyde 34 to ester 36, a two-step

sequence involving oxidation to the corresponding carboxylic

acid and subsequent esteriﬁcation with alcohol 22 using a

dehydrating agent such as DCC led to irreproducible results,

probably because of self-decomposition of the carboxylic acid.

Considerable experimentation showed that this problem could

be avoided by employing a Tollens oxidation³⁸and isolation of

the product as the potassium salt 35, which upon treatment

with oxalyl chloride in the presence of a catalytic amount of

DMF and subsequent condensation with alcohol 22 reprodu-

cibly aﬀorded ester 36 in 65% yield for the three-step sequence

on a 23 g scale.

Under the foregoing conditions, the Ireland−Claisen

rearrangement of tetrahydrofuran-2-carboxylate 36 furnished

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Scheme 7. Plausible Reaction Pathways for the Rearrangement of Tetrahydrofuran-2-carboxylate 36

Scheme 8. Ring Opening of Tetrahydrofuran 38b

ously established by X-ray crystallography, as shown in Figure

2.

Since (Z)-silyl ketene acetal 40 would be exclusively formed

from ester 36 via the corresponding chelated enolate,^40,41the

stereochemical outcome of the rearrangement indicates that the

reaction of the Z isomer 40 did not proceed through chairlike

transition state A, which suﬀers from severe steric interaction

resulting from the methyl group on the tetrahydrofuran ring

(Scheme 7). No such nonbonded destabilization could be

observed in boatlike transition state B, thus leading to the

predominant formation of isomer 37b. This result suggests that

the contiguous quaternary stereocenters should be created prior

to construction of the tetrahydrofuran ring in order to apply

this method for the synthesis of α-type C17-oxygenated

triterpenoids like 4 and 5.

While the rearrangement of ester 36 provided an unexpected

result, we considered that the product 37b having an R

conﬁguration at the α position of the carboxyl group is a

potential intermediate for the synthesis of β-type natural

products. We therefore turned our attention to the ring

opening of methyl ester 38b. In this regard, it is known that

both hydroxyalkenes⁴²and hydroxyalkynes⁴³can be obtained

from tetrahydrofuran-2-methanol derivatives by proper choice

of the reaction conditions. As a prelude, the TBDPS group was

removed with NH₄F⁴⁴to give primary alcohol 41 in 94% yield

(Scheme 8). After iodination of primary alcohol 41 with I₂in

the presence of Ph₃P and imidazole in THF at 50 °C, treatment

of the resultant iodide 42 with activated zinc in AcOH at 110

°C eﬀected fragmentation to provide alkene 43 in 78% yield in

two steps. On the other hand, primary alcohol 41 was

converted to chloride 44 by the reaction with PPh₃in reﬂuxing

CCl₄in preparation for the base-induced double eliminative

ring-opening reaction. While LDA proved to be an ineﬀective

base in the reaction of 44, the desired product 45 could be

Figure 2. X-ray crystal structure of iodolactone 39b, rendered in

Chem3D. For the purpose of clarity, only protons attached to

stereocenters are shown.

an inseparable mixture of rearranged products 37a and 37b in

74% yield (Scheme 6). O-Alkylation of the mixture with MeI

under basic conditions provided a 94:6 mixture of esters,³⁹

from which esters 38a and 38b were isolated in yields of 5%

and 94%, respectively, after chromatographic separation. To

determine the relative stereochemical relationship between the

quaternary stereocenters, the mixture of carboxylic acids 37a

and 37b was subjected to iodolactonization to give isomers 39a

and 39b in yields of 4% and 81%, respectively. Surprisingly, a

NOESY experiment performed on the major isomer 39b

revealed a diagnostic cross-peak supporting the stereochemical

assignment of the R conﬁguration at the position α to the

carbonyl group, whereas the expected interaction between

methyl protons was observed in minor isomer 39a. Finally, the

stereochemistry of the crystalline isomer 39b was unambigu-

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a

the remaining oleﬁn could be achieved by employing the two-

step protocol reported by Narasaka and co-workers⁴⁸(OsO₄-

catalyzed dihydroxylation with NMO in the presence of

PhB(OH)₂and exposure of the resultant boronate 50 to

NaIO₄), providing ketone 51 in 71% yield in three steps.

Finally, epimerization of cis-1-decalone 51 upon brief exposure

to NaOMe in THF completed the synthesis of trans-1-decalone

derivative 52.⁴⁹

We next considered that the double bond in the ring system

could be used for further functionalization if selective cleavage

of the exocyclic oleﬁn in diene 47 could be realized.

Fortunately, further experimentation with diene 47 led to the

discovery that the exocyclic oleﬁn was stereoselectively

oxidized, with the internal oleﬁn remaining intact, upon

exposure to m-CPBA in CH₂Cl₂at 0 °C to give epoxide 53

in 87% yield (Scheme 10). However, all attempts to convert

epoxide 53 to the corresponding diol met with failure due to

the propensity of epoxide 53 to undergo desilylative trans-

annular cyclization under either acidic or basic conditions to

give alcohol 54.

Table 1. Base-Induced Double Eliminative Ring Opening

entry

base

LDA

solvent

temp (°C) time (h) yield (%)

1

2

3

4

5

THF

−20

−78

−40

1

2

0

15

42

52

96

LDA

20:1 THF/HMPA

2:1 NH₃/THF

LTMP

BuLi

NaNH₂

a

The reaction was carried out on a 0.1 mmol scale.

obtained by the use of HMPA as a cosolvent, albeit in low yield

(Table 1, entries 1 and 2). Of the lithium amides surveyed,

LTMP gave the best result, but the reaction suﬀered from

reproducibility issues and the formation of many byproducts

(entry 3). Because of the steric bulk in the vicinity of the

carbonyl group, the ester functionality was unaﬀected upon

treatment with 5 equiv of BuLi at −78 °C, and α-hydroxy ester

45 was obtained in 52% yield (entry 4). Finally, we were

gratiﬁed to ﬁnd that the use of NaNH₂as the base in liquid

NH₃aﬀorded a signiﬁcantly improved yield (96%; entry 5).

As stated earlier, motif 11β can be found in many labdane-

type natural products such as marrulibacetal (9) and

isopreleoheterins (10). To demonstrate the potential utility

of ring-opening product 45 as a building block, we then

addressed the construction of the decaline skeleton from 45

(Scheme 9). While protection of tertiary alcohol 45 as its TMS

ether served to set the stage for a cyclization reaction, the

attempted Pd₂(dba)₃-catalyzed cycloisomerization of enyne 46

according to the procedure of Trost⁴⁵aﬀorded only a trace of

the desired diene 47 and led to the formation of a dimerization

product. Therefore, enyne 46 was converted to vinyl iodide 48

by iodoboration under Hara−Suzuki conditions⁴⁶in prepara-

tion for an intramolecular Heck reaction.⁴⁷With regard to the

cyclization reaction, the use of AgNO₃as an additive was found

to be eﬀective in providing cis-decaline 47 in good yield. At this

stage, we were faced with the task of oleﬁn diﬀerentiation. After

some experimentation, we found that the 1,2-disubstituted (Z)-

oleﬁn present in the six-membered ring is slightly more reactive

and prone to hydrogenation with the aid of Lindlar catalyst

than the exocyclic 1,1-disubstituted oleﬁn. Oxidative cleavage of

Given the lability of the tertiary TMS ether under a variety of

reaction conditions tested, a decision was made to switch the

protecting group to a Boc group with the expectation that the

carbonate group could participate in a transannular cyclization.

Deprotection of TMS ether 47 with Bu₄NF in THF was

followed by protection with (Boc)₂O under basic conditions,

producing diene 56 in 95% yield in two steps. Although

epoxidation of Boc-protected diene 56 proved less selective

(5.4:1 selectivity) even at −20 °C, at which temperature the

reaction did not go to completion, the desired epoxide 57 was

obtained in 58% yield (66% based on recovered starting

material) after one recycle of recovered starting material. As

expected, epoxide 57 underwent transannular cyclization when

treated with BF₃·OEt₂in CH₂Cl₂at −60 °C⁵¹to provide cyclic

carbonate 59 in 74% yield; upon exposure to NaOMe in

MeOH, 59 furnished triol 60 in 93% yield. The superﬂuous

one-carbon unit was successfully removed by oxidative cleavage

1

with Pb(OAc)₄in CH₂Cl₂at 0 °C. While the H and ¹³C

spectra clearly revealed that product 61 existed exclusively in

the hydroxy ketone form, the carbonyl group and tertiary

alcohol in 61 could be masked as a lactol TBS ether by the

reaction with TBSOTf in the presence of Et₃N in CH₂Cl₂,

producing 62 in 94% yield.

Scheme 9. Conversion of Alkyne 45 to trans-Decalone 52

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Scheme 10. Conversion of Diene 47 to Tricyclic Compound 62

puriﬁed by ﬂash column chromatography (silica gel 100 g, 10:1

CH₂Cl₂/Et₂O) to give diol 17 (1.67 g, 86%) as a colorless oil. R_f0.40

(1:1 n-hexane/AcOEt); [α]_D¹⁷−11.0 (c 1.06, CHCl₃); IR (neat) 3401,

2960, 2931, 2859, 1472, 1427, 1123, 1113 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ 0.80 (d, J = 7.0 Hz, 3H), 1.06 (s, 9H), 1.94 (m, 1H), 2.33 (t,

J = 5.9 Hz, 1H), 3.60 (m, 1H), 3.66 (dd, J = 8.4, 10.3 Hz, 1H), 3.68−

3.74 (m, 2H), 3.74 (dd, J = 4.0, 10.3 Hz, 1H), 4.00 (d, J = 2.5 Hz, 1H),

7.40−7.47 (m, 6H), 7.66−7.69 (m, 4H); ¹³C NMR (125.7 MHz,

CDCl₃) δ 13.1 (CH₃), 19.0 (C), 26.8 (CH₃), 37.0 (CH), 64.9 (CH₂),

68.8 (CH₂), 76.5 (CH), 127.8 (CH), 127.9 (CH), 129.9 (CH), 130.0

(CH), 132.5 (C), 132.6 (C), 135.52 (CH), 135.54 (CH); HRMS

(FAB) m/z [M + H]⁺calcd for C₂₁H₃₁O₃Si 359.3043; found

359.3047.

CONCLUSION

■

We have developed stereocontrolled methods to access chiral

building blocks with a triad of contiguous stereocenters,

including two quaternary ones, through an Ireland−Claisen

rearrangement. While the use of 2-(benzyloxy)butyrate as a

substrate gave the rearranged product resulting from a chairlike

transition state in accord with the precedent provided by

Zakarian,¹⁸the introduction of a cyclic conformational

constraint in the acid component switched the transition

state to a boatlike one because of severe steric repulsion

resulting from a methyl group on the ring in the chairlike

transition state, leading to the predominant formation of a

product with the opposite stereochemistry at the position α to

the carboxyl group. Subsequent conversion of the product

through a sequence involving base-induced double eliminative

ring opening, intramolecular Heck reaction, and oleﬁn

diﬀerentiation provided bicyclo[4.4.0]decane derivatives having

potential for the syntheses of labdane diterpenes. This is the

ﬁrst report of an Ireland−Claisen rearrangement using an α-

substituted glycolate derived from a cyclic alcohol wherein both

the enolate geometry and the conformation of the transition

state have been successfully controlled. Further studies toward

the total syntheses of such bioactive natural products are

currently underway in our laboratory and will be reported in

due course.

[4R,4(1R)]-4-[[2-(tert-Butyldiphenylsilyl)oxy-1-methyl]ethyl]-

2-phenyl-1,3-dioxolane (18). Pyridinium p-toluenesulfonate (116

mg, 0.461 mmol) was added to a mixture of diol 17 (1.66 g, 4.63

mmol) and benzaldehyde dimethyl acetal (1.55 mL, 10.4 mmol) in

CH₂Cl₂(46 mL), and the mixture was stirred for 48 h. Triethylamine

(1.0 mL) was added to the mixture, and the solvent was removed in

vacuo. The residual pale-yellow oil (2.95 g) was puriﬁed by ﬂash

column chromatography (silica gel 120 g, 30:1 n-hexane/AcOEt) to

give benzylidene acetal 18 (1.92 g, 93%, dr = 1.6:1) as a colorless oil.

R_f0.42 (10:1 n-hexane/AcOEt); [α]¹_D⁷−3.6 ( c 0.95, CHCl₃); IR

1

(neat) 2961, 2932, 2859, 1427, 1113 cm⁻¹; H NMR (500 MHz,

CDCl₃) δ 1.01 (d, J = 6.9 Hz, 1.2H), 1.03 (d, J = 6.9 Hz, 1.8H), 1.06

(s, 3.5H), 1.07 (s, 5.5H), 1.97 (m, 0.38H), 2.03 (m, 0.62H), 3.73 (dd,

J = 4.3, 10.0 Hz, 0.62H), 3.76 (dd, J = 3.8, 9.9 Hz, 0.38H), 3.75−3.82

(m, 1.38H), 3.84 (t, J = 7.6 Hz, 0.62H), 4.07 (dd, J = 7.1, 7.6 Hz,

0.62H), 4.20−4.27 (m, 1.38H), 5.78 (s, 0.62H), 5.86 (s, 0.38H),

7.32−7.47 (m, 11H), 7.66−7.70 (m, 4H); ¹³C NMR (125.7 MHz,

CDCl₃) δ 12.6 (CH₃), 12.7 (CH₃), 19.31 (C), 19.32 (C), 26.8 (CH₃),

26.9 (CH₃), 38.89 (CH), 38.94 (CH), 65.6 (CH₂), 65.7 (CH₂), 68.0

(CH₂), 69.1 (CH₂), 77.4 (CH), 78.4 (CH), 103.4 (CH), 103.6 (CH),

126.3 (CH), 126.56 (CH), 127.57 (CH), 127.59 (CH), 127.61 (CH),

127.62 (CH), 128.25 (CH), 128.26 (CH), 128.9 (CH), 129.1 (CH),

129.52 (CH), 129.55 (CH), 129.57 (CH), 129.58 (CH), 133.59 (C),

133.65 (C), 133.67 (C), 133.71 (C), 135.59 (CH), 135.60 (CH),

137.8 (C), 138.6 (C); HRMS (ESI) m/z [M + Na]⁺calcd for

C₂₈H₃₄O₃SiNa 469.2175; found 469.2152.

EXPERIMENTAL SECTION

■

(2R,3R)-4-(tert-Butyldiphenylsilyl)oxy-3-methylbutane-1,2-

diol (17). Trimethylaluminum in n-heptane (2.0 M, 8.15 mL, 16.3

mmol) was added to a solution of epoxy alcohol 16²²(1.87 g, 5.44

mmol) in n-pentane (60 mL) at 0 °C. After 3 h of stirring, the reaction

was quenched with MeOH (2 mL), and 10% aqueous potassium

sodium tartrate (100 mL) was added to the solution. The mixture was

vigorously stirred at room temperature for 29 h and extracted with

AcOEt (3 × 300 mL). The combined organic extracts were washed

with brine (100 mL) and dried over anhydrous Na₂SO₄. Filtration and

evaporation in vacuo furnished the crude product (2.19 g), which was

(2R,3R)-2-Benzyloxy-4-(tert-butyldiphenylsilyl)oxy-3-meth-

ylbutan-1-ol (19). DIBALH in n-hexane (1.0 M, 15.0 mL, 15.0

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mmol) was added to a solution of benzylidene acetal 18 (1.92 g, 4.30

mmol) in CH₂Cl₂(43 mL) at −78 °C. After 9 h of stirring at −20 °C,

the reaction was quenched with MeOH (2 mL), and 20% aqueous

potassium sodium tartrate (50 mL) was added to the solution. The

mixture was vigorously stirred for 16 h and extracted with AcOEt (2 ×

200 mL). The combined organic extracts were washed with brine (50

mL) and dried over anhydrous Na₂SO₄. Filtration and evaporation in

vacuo furnished the crude product (2.20 g), which was puriﬁed by

ﬂash column chromatography (silica gel 60 g, 5:1 n-hexane/AcOEt) to

give alcohol 19 (1.70 g, 88%) as a colorless oil. R_f0.42 (3:1 n-hexane/

AcOEt); [α]¹_D⁷−2.4 (c 1.05, CHCl₃); IR (neat) 3435, 2959, 2857,

1427, 1113 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.96 (d, J = 6.9 Hz,

3H), 1.07 (s, 9H), 2.06 (m, 1H), 2.16 (t, J = 5.3 Hz, 1H), 3.61−3.66

(m, 2H), 3.68−3.74 (m, 2H), 3.80 (m, 1H), 4.54 (d, J = 11.6 Hz, 1H),

4.57 (d, J = 11.6 Hz, 1H), 7.27−7.43 (m, 11H), 7.65−7.67 (m, 4H);

¹³C NMR (125.7 MHz, CDCl₃) δ 13.2 (CH₃), 19.3 (CH), 26.9

CDCl₃) δ 1.37 (d, J = 6.5 Hz, 1H), 1.54−1.61 (m, 2H), 1.69 (s, 3H),

1.69−1.81 (m, 2H), 1.85−1.96 (m, 2H), 4.17 (m, 1H), 5.49 (m, 1H).

(R)-3-Methylcyclohex-2-en-1-yl Benzoate. Benzoyl chloride

(0.07 mL, 0.57 mmol) was added to a mixture of (R)-alcohol 22

(18.2 mg, 0.16 mmol) and DMAP (99.1 mg, 0.81 mmol) in CH₂Cl₂

(1.6 mL) at 0 °C. After 2 h of stirring at room temperature, the

mixture was partitioned between CH₂Cl₂(10 mL) and saturated

aqueous NaHCO₃(2 mL), and the aqueous layer was extracted with

CH₂Cl₂(8 mL). The combined organic extracts were washed with

brine (4 mL) and dried over anhydrous Na₂SO₄. Filtration and

evaporation in vacuo furnished the crude product (31.0 mg), which

was puriﬁed by column chromatography (silica gel 15 g, 20:1 n-

hexane/AcOEt) to give the corresponding benzoate (26.3 mg, 75%) as

a colorless oil. The enantiomeric excess was determined to be >99% ee

by HPLC analysis (column, Chiralpak IC-3; eluent, 200:1 n-hexane/2-

propanol; ﬂow rate, 0.5 mL/min; t_R= 26.4 min for the R enantiomer,

t_R= 29.2 min for the S enantiomer). R_f0.72 (5:1 n-hexane/AcOEt);

[α]²_D³+211.8 (c 1.09, CHCl₃); IR (neat) 3061, 2936, 1713, 1450, 1271

(CH₃), 37.1 (CH), 61.6 (CH₂), 65.5 (CH₂), 72.1 (CH₂), 80.9 (CH),

127.65 (CH), 127.66 (CH), 127.70 (CH), 128.4 (CH), 129.6 (CH),

129.7 (CH), 133.4 (C), 133.5 (C), 135.6 (CH), 135.7 (CH), 138.4

(C); HRMS (ESI) m/z [M + Na]⁺calcd for C₂₈H₃₆O₃SiNa 471.2331;

found 471.2311.

1

cm⁻¹; H NMR (500 MHz, CDCl₃) δ 1.70 (m, 1H), 1.84−1.89 (m,

3H), 1.94−2.06 (m, 2H), 1.74 (s, 3H), 5.49 (m, 1H), 5.60 (m, 1H),

7.41−7.44 (m, 2H), 7.54 (m, 1H), 8.05−8.06 (m, 2H); ¹³C NMR

(125.7 MHz, CDCl₃) δ 19.1 (CH₂), 23.8 (CH₃), 28.1 (CH₂), 29.9

(CH₂), 69.3 (CH), 120.0 (CH), 128.2 (CH), 129.5 (CH), 130.9 (C),

132.6 (CH), 141.2 (C), 166.3 (C); HRMS (EI) m/z [M]⁺calcd for

C₁₄H₁₆O₂216.1150; found 216.1145.

(R)-3-Methylcyclohex-2-en-1-yl (2R,3R)-2-Benzyloxy-4-(tert-

butyldiphenylsilyl)oxy-3-methylbutanoate (15a). To a mixture

of aldehyde 20 (1.67 g, 3.74 mmol) and 2-methyl-2-butene (8.0 mL,

75.5 mmol) in t-BuOH/H₂O (4:1, 35 mL) was added NaH₂PO₄(672

mg, 5.60 mmol) followed by NaClO₂(507 mg, 5.61 mmol). After 3 h

of stirring, the mixture was partitioned between AcOEt (100 mL) and

10% aqueous NaHSO₄(40 mL), and the aqueous layer was extracted

with AcOEt (3 × 100 mL). The combined organic extracts were

washed with brine (40 mL) and dried over anhydrous Na₂SO₄.

Filtration and evaporation in vacuo furnished the crude product 21

(1.94 g), which was used without further puriﬁcation.

To an ice-cooled mixture (0 °C) of crude carboxylic acid 21 (1.94

g) and alcohol 22 (461 mg, 4.11 mmol) in CH₂Cl₂(37 mL) was

added 1-ethyl-3-(dimethylamino)propylcarbodiimide (1.00 g, 5.22

mmol) followed by DMAP (639 mg, 5.23 mmol). After 18 h of

stirring at room temperature, the reaction was quenched with H₂O (40

mL), and the resulting mixture was extracted with AcOEt (2 × 200

mL). The combined organic extracts were washed with brine (40 mL)

and dried over anhydrous Na₂SO₄. Filtration and evaporation in vacuo

furnished the crude product (3.20 g), which was puriﬁed by column

chromatography (silica gel 200 g, 20:1 n-hexane/AcOEt) to give ester

15a (1.49 g, 72% for two steps) as a colorless oil. R_f0.61 (5:1 n-

hexane/AcOEt); [α]²_D⁷+79.1 (c 1.48, CHCl₃); IR (neat) 3069, 2932,

2859, 1738, 1454, 1427, 1255, 1188, 1111 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ 0.93 (d, J = 7.0 Hz, 3H), 1.04 (s, 9H), 1.59−1.79 (m, 4H),

1.69 (s, 3H), 1.87−1.99 (m, 2H), 2.17 (dddq, J = 4.7, 5.6, 7.1, 7.0 Hz,

1H), 3.68 (dd, J = 4.7, 9.9 Hz, 1H), 3.75 (dd, J = 5.6, 9.9 Hz, 1H), 3.97

(d, J = 7.1 Hz, 1H), 4.39 (d, J = 11.6 Hz, 1H), 4.63 (d, J = 11.6 Hz,

1H), 5.30 (m, 1H), 5.43 (m, 1H), 7.28−7.42 (m, 11H), 7.63−7.65 (m,

4H); ¹³C NMR (125.7 MHz, CDCl₃) δ 13.3 (CH₃), 19.0 (CH₂), 19.3

(C), 23.7 (CH₃), 26.8 (CH₃), 28.0 (CH₂), 29.9 (CH₂), 39.1 (CH),

64.7 (CH₂), 69.4 (CH), 72.4 (CH₂), 80.1 (CH), 119.7 (CH), 127.56

(CH), 127.57 (CH), 127.7 (CH), 128.0 (CH), 128.3 (CH), 129.49

(CH), 129.51 (CH), 133.7 (C), 133.8 (C), 135.57 (CH), 135.62

(CH), 137.7 (C), 141.3 (C), 172.0 (C); HRMS (ESI) m/z [M + Na]⁺

calcd for C₃₅H₄₄O₄SiNa 579.2907; found 579.2892. Anal. Calcd for

C₃₅H₄₄O₄Si: C, 75.50; H, 7.97. Found: C, 75.30; H, 8.02.

(2R,3R)-2-Benzyloxy-4-(tert-butyldiphenylsilyl)oxy-3-meth-

yl-1-butanal (20). Dess−Martin periodinane (136 mg, 0.321 mmol)

was added to a solution of alcohol 19 (120 mg, 0.267 mmol) in

CH₂Cl₂(2.7 mL) at 0 °C. After 1 h of stirring at room temperature,

the reaction was quenched with a mixture of 1 M aqueous Na₂S₂O₃(1

mL) and saturated aqueous NaHCO₃(1 mL), and the resulting

mixture was vigorously stirred for 30 min. The mixture was partitioned

between AcOEt (30 mL) and H₂O (5 mL), and the aqueous layer was

extracted with AcOEt (30 mL). The combined organic extracts were

washed with brine (10 mL) and dried over anhydrous Na₂SO₄.

Filtration and evaporation in vacuo furnished the crude product (245

mg), which was puriﬁed by column chromatography (silica gel 15 g,

10:1 n-hexane/AcOEt) to give aldehyde 20 (112 mg, 94%) as a

colorless oil. R_f0.57 (5:1 n-hexane/AcOEt); [α]¹_D⁵+33.3 (c 0.99,

CHCl₃); IR (neat) 3071, 2961, 2930, 2856, 1732, 1472, 1427, 1389,

1113, 1074 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.93 (d, J = 7.0 Hz,

3H), 1.02 (s, 9H), 2.30 (dddq, J = 4.3, 4.9, 8.4, 7.0 Hz, 1H), 3.54 (dd, J

= 4.9, 10.0 Hz, 1H), 3.73 (dd, J = 8.4, 10.0 Hz, 1H), 3.78 (dd, J = 2.2,

4.3 Hz, 1H), 4.54 (d, J = 11.6 Hz, 1H), 4.75 (d, J = 11.6 Hz, 1H),

7.32−7.42 (m, 11H), 7.62−7.67 (m, 4H), 9.83 (d, J = 2.2 Hz, 1H);

¹³C NMR (125.7 MHz, CDCl₃) δ 13.4 (CH₃), 19.1 (CH), 26.7

(CH₃), 39.2 (CH), 64.3 (CH₂), 73.2 (CH), 85.5 (CH₂), 127.6 (CH),

127.7 (CH), 127.88 (CH), 127.92 (CH), 128.4 (CH), 129.6 (CH),

129.7 (CH), 133.3 (C), 135.59 (CH), 135.60 (CH), 137.58 (C),

204.5 (CH); HRMS (ESI) m/z [M + Na]⁺calcd for C₂₈H₃₄O₃SiNa

469.2174; found 469.2160.

(R)-3-Methylcyclohex-2-en-1-ol (22). A mixture of racemic 3-

methylcyclohex-2-en-1-ol (50.0 g, 444 mmol), vinyl butyrate (112 mL,

881 mmol), and Novozym 435 (1.11 g, 2.2 wt %) in n-heptane (450

mL) was stirred for 3 h. The resulting yellow suspension was ﬁltered,

and the ﬁltrate was concentrated in vacuo. The residual oil (127 g) was

passed through silica gel (800 g, CH₂Cl₂) to give a mixture of the

butyrate of 22 and vinyl butyrate (34.7 g) along with ent-22 (26.7 g).

The mixture of the butyrate and vinyl butyrate was dissolved in MeOH

(300 mL), and 4 M aqueous NaOH (110 mL, 440 mmol) was added

at 0 °C. After 1 h of stirring at room temperature, the mixture was

partitioned between CH₂Cl₂(200 mL) and H₂O (250 mL), and the

aqueous layer was extracted with CH₂Cl₂(175 and 150 mL). The

combined organic extracts were washed with brine (200 mL) and

dried over anhydrous Na₂SO₄. Filtration and evaporation in vacuo

furnished the crude product (22.9 g), which was used without further

puriﬁcation.

[2R,2(1S),3R]-2-Benzyloxy-4-(tert-butyldiphenylsilyl)oxy-3-

methyl-2-(1-methylcyclohex-2-en-1-yl)butanoic acid (24a). To

a cooled solution (−78 °C) of ester 15a (245 mg, 0.440 mmol) in

THF (6 mL) was added a solution of LDA [prepared from

diisopropylamine (0.10 mL, 0.70 mmol) and BuLi in n-hexane (1.56

M, 0.43 mL, 0.67 mmol)] in THF (3 mL) followed by

chlorotrimethylsilane (85 μL, 0.67 mmol). After 5 min of stirring at

−78 °C, the mixture was allowed to warm to room temperature and

This sequence was repeated, employing vinyl butyrate (52.0 mL,

409 mmol), Novozym 435 (504 mg, 2.2 wt %), n-heptane (200 mL), 4

M aqueous NaOH (83 mL, 332 mmol), and MeOH (230 mL). The

crude product (17.5 g) was puriﬁed by column chromatography (silica

gel 200 g, CH₂Cl₂) to give (R)-alcohol 22 (17.3 g, 76%, >99% ee) as a

colorless oil. R_f0.49 (2:1 n-hexane/AcOEt); [α]²_D²+95.1 (c 2.88,

CHCl₃) {lit.⁵²[α]_D+96.0 (c 0.423, CHCl₃)}; H NMR (500 MHz,

1

727

dx.doi.org/10.1021/jo402537u | J. Org. Chem. 2014, 79, 720−735

The Journal of Organic Chemistry

Article

stirred for 12 h. The reaction was quenched with saturated aqueous

NH₄Cl (10 mL), and the resulting mixture was extracted with AcOEt

(3 × 40 mL). The combined organic extracts were washed with brine

(10 mL) and dried over anhydrous Na₂SO₄. Filtration and evaporation

in vacuo furnished the crude product (297 mg), which was subjected

to ﬂash chromatography (silica gel 70 g, 5:1 n-hexane/AcOEt with

0.2% TFA) to provide a mixture of rearranged products. Separation by

column chromatography (silica gel 30 g, 9:1 n-hexane/AcOEt) yielded

carboxylic acid 24a (117 mg, 48%) as a colorless foam along with a

mixture of other products (6.0 mg) as a colorless oil. R_f0.47 (3:1 n-

hexane/AcOEt); [α]²_D⁹+14.2 (c 1.21, CHCl₃); IR (neat) 3088, 2932,

2859, 1703, 1427, 1113 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.05 (s,

9H), 1.13 (s, 3H), 1.22 (d, J = 6.8 Hz, 3H), 1.54 (m, 1H), 1.57−1.62

(m, 2H), 1.72−1.81 (m, 2H), 1.89 (m, 1H), 2.62 (m, 1H), 3.86−3.87

(m, 2H), 4.71 (s, 2H), 5.54 (m, 1H), 5.78 (d, J = 10.5 Hz, 1H), 7.28−

7.41 (m, 11H), 7.65−7.67 (m, 4H); ¹³C NMR (125.7 MHz, CDCl₃) δ

13.3 (CH₃), 19.2 (C), 19.3 (CH₂), 24.3 (CH₂), 25.1 (CH₃), 26.9

(CH₃), 31.3 (CH₂), 40.3 (CH), 42.9 (C), 66.3 (CH₂), 67.7 (CH₂),

88.8 (C), 126.4 (CH), 127.2 (CH), 127.5 (CH), 127.6 (CH), 127.7

(CH), 128.4 (CH), 129.64 (CH), 129.647 (C), 129.653 (CH), 133.2

(CH), 133.4 (C), 135.62 (CH), 135.63 (CH), 138.5 (C), 174.2 (C);

HRMS (ESI) m/z [M + Na]⁺calcd for C₃₅H₄₄O₄SiNa 579.2907;

found 579.2893.

MHz, C₆D₆) δ 13.0 (CH₃), 19.1 (C), 19.8 (CH₂), 21.9 (CH₂), 25.9

(CH₃), 26.7 (CH₃), 30.5 (CH₂), 32.4 (CH₂), 38.1 (CH), 47.6 (C),

65.3 (CH₂), 67.0 (CH₂), 84.2 (CH), 85.6 (C), 127.4 (CH), 127.6

(CH), 127.8 (CH), 127.9 (CH), 128.2 (CH), 129.78 (CH), 129.83

(CH), 133.3 (C), 133.4 (C), 135.7 (CH), 135.8 (CH), 138.3 (C),

173.1 (C); HRMS (ESI) m/z [M + Na]⁺calcd for C₃₅H₄₃IO₄SiNa

705.1873; found 705.1858.

Methyl [2S,3R]-2-Benzyloxy-4-(tert-butyldiphenylsilyl)oxy-3-

methyl-2-(1-methylcyclohexyl)butanoate (27a). Platinum(IV)

oxide (3.0 mg, 0.013 mmol) was added to a solution of ester 25

(27.7 mg, 0.049 mmol) in EtOH (1.5 mL), and the mixture was

vigorously stirred under hydrogen (1 atm) for 29 h. The catalyst was

ﬁltered through a Celite pad, and the ﬁltrate was evaporated in vacuo.

Puriﬁcation of the crude product (42.2 mg) by preparative thin-layer

chromatography (200 mm × 200 mm × 0.25 mm preparative silica gel

plate and elution with 20:1 n-hexane/AcOEt twice) gave hydrogenated

compound 27a (21.2 mg, 77%) as a colorless oil. R_f0.59 (5:1 n-

hexane/AcOEt); [α]²_D⁶−10.3 (c 1.02, CHCl₃); IR (neat) 2930, 2859,

1736, 1427, 1240, 1217, 1113, 1028 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ 1.05 (s, 9H), 1.14 (s, 3H), 1.25−1.31 (m, 2H), 1.28 (d, J =

6.7 Hz, 3H), 1.40−1.61 (m, 6H), 1.68 (m, 1H), 1.78 (dt, J = 4.3, 13.1

Hz, 1H), 2.61 (m, 1H), 3.47 (s, 3H), 3.56 (dd, J = 2.1, 9.4 Hz, 1H),

3.70 (t, J = 9.4 Hz, 1H), 4.64 (s, 2H), 7.22 (m, 1H), 7.28−7.29 (m,

4H), 7.37−7.42 (m, 6H), 7.64−7.66 (m, 4H); ¹³C NMR (125.7 MHz,

CDCl₃) δ 14.0 (CH₃), 18.8 (CH₃), 19.3 (C), 22.1 (CH₂), 22.4 (CH₂),

25.8 (CH₂), 26.8 (CH₃), 32.6 (CH₂), 33.8 (CH₂), 41.8 (CH), 42.6

(C), 50.8 (CH₃), 67.9 (CH₂), 68.3 (CH₂), 89.7 (CH₂), 126.8 (CH),

127.58 (CH), 127.64 (CH), 128.0 (CH), 129.5 (CH), 129.6 (CH),

133.6 (C), 133.8 (C), 135.59 (CH), 135.61 (CH), 140.0 (C), 173.9

(C); HRMS (ESI) m/z [M + Na]⁺calcd for C₃₆H₄₈O₄SiNa 595.3220;

found 595.3231.

Methyl [2S,2(1S),3R]-2-Benzyloxy-4-(tert-butyldiphenylsilyl)-

oxy-3-methyl-2-[1-methylcyclohex-2-en-1-yl]butanoate (25).

Potassium carbonate (87.1 mg, 0.63 mmol) was added to an ice-

cooled mixture (0 °C) of carboxylic acid 24a (117 mg, 0.21 mmol)

and iodomethane (40 μL, 0.64 mmol) in DMF (2 mL). After 1 h of

stirring, H₂O (40 mL) was added to the yellow mixture, and the

resulting mixture was extracted with n-hexane/AcOEt (3:1, 2 × 50

mL). The combined organic extracts were washed with brine (40 mL)

and dried over anhydrous Na₂SO₄. Filtration and evaporation in vacuo

furnished the crude product (143 mg), which was puriﬁed by column

chromatography (silica gel 15 g, 9:1 n-hexane/AcOEt) to give methyl

ester 25 (103 mg, 85%) as a colorless oil. R_f0.64 (5:1 n-hexane/

AcOEt); [α]²_D⁷−12.1 (c 1.05, C₆H₆); IR (neat) 3071, 2932, 2856,

Methyl (2R*,3R*)-2-Benzyloxy-4-(tert-butyldiphenylsilyl)-

oxy-3-methyl-2-(1-methylcyclohexyl)butanoate (27b). Trime-

thylsilyldiazomethane in n-hexane (1.7 M, 35 μL, 0.06 mmol) was

added to a 1.6:1 mixture of the minor isomers 24b and 24c (15.1 mg)

in benzene/MeOH (1:1, 1.5 mL) at 0 °C. After 5 min of stirring, the

mixture was concentrated in vacuo, and the residual pale-yellow oil

(16.0 mg) was used without further puriﬁcation.

1

1738, 1429, 1219, 1113, 1028 cm⁻¹; H NMR (500 MHz, CDCl₃) δ

1.05 (s, 9H), 1.14 (s, 3H), 1.22 (d, J = 7.0 Hz, 3H), 1.63−1.72 (m,

3H), 1.85 (dt, J = 5.1, 12.7 Hz, 1H), 1.92−1.98 (m, 2H), 2.63 (ddq, J

= 3.1, 9.6, 7.0 Hz, 1H), 3.49 (s, 3H), 3.59 (dd, J = 3.1, 9.6 Hz, 1H),

3.69 (t, J = 9.6 Hz, 1H), 4.68 (s, 2H), 5.55 (ddd, J = 2.9, 4.4, 10.3 Hz,

1H), 5.83 (d, J = 10.3 Hz, 1H), 7.22 (m, 1H), 7.28−7.29 (m, 4H),

7.35−7.44 (m, 6H), 7.64−7.66 (m, 4H); ¹³C NMR (125.7 MHz,

CDCl₃) δ 13.0 (CH₃), 19.2 (C), 19.3 (CH₂), 24.6 (CH₂), 25.5 (CH₃),

26.9 (CH₃), 31.4 (CH₂), 42.0 (CH), 43.1 (C), 51.0 (CH₃), 67.5

(CH₂), 67.9 (CH₂), 89.0 (C), 125.3 (CH), 126.8 (CH), 127.58 (CH),

127.62 (CH), 128.0 (CH), 129.5 (CH), 129.6 (CH), 133.6 (C), 133.8

(C), 134.7 (CH), 135.58 (CH), 135.60 (CH), 139.9 (C), 173.5 (C);

HRMS (ESI) m/z [M + Na]⁺calcd for C₃₆H₄₆O₄SiNa 593.3063;

found 593.3050.

[ 1 S , 5 S , 6 S , 9 S , 9 ( 1 R ) ] - 9 - B e n z y l o x y - 9 - [ 2 - ( t e r t -

butyldiphenylsilyl)oxy-1-methyl]ethyl-5-iodo-1-methyl-7-

oxabicyclo[4.3.0]nonan-8-one (26a). Iodine (14.3 mg, 0.056

mmol) was added to an ice-cooled solution (0 °C) of carboxylic

acid 24a (26.1 mg, 0.047 mmol) in MeCN/saturated aqueous

NaHCO₃(1:1, 1 mL). After 1 h of stirring at 0 °C, the reaction was

quenched with 1 M aqueous Na₂S₂O₃(4 mL), and the mixture was

extracted with AcOEt (2 × 30 mL). The combined organic extracts

were washed with brine (4 mL) and dried over anhydrous Na₂SO₄.

Filtration and evaporation in vacuo furnished the crude product (41.1

mg), which was puriﬁed by ﬂash column chromatography (silica gel 10

g, 15:1 n-hexane/AcOEt) to give iodolactone 26a (24.7 mg, 77%) as a

colorless oil. R_f0.52 (5:1 n-hexane/AcOEt); [α]¹_D⁷+15.2 (c 1.24,

CHCl₃); IR (neat) 3069, 2932, 2857, 1778, 1472, 1458, 1427, 1113,

613 cm⁻¹; ¹H NMR (500 MHz, C₆D₆) δ 1.03 (s, 3H), 1.14 (d, J = 7.0

Hz, 3H), 1.21 (s, 9H), 1.13−1.63 (m, 6H), 2.31 (ddq, J = 5.1, 6.7, 7.0

Hz, 1H), 3.79 (dd, J = 6.7, 10.3 Hz, 1H), 4.03 (dd, J = 5.1, 10.3 Hz,

1H), 4.15 (d, J = 5.1 Hz, 1H), 4.24 (dd, J = 5.1, 10.0 Hz, 1H), 4.57 (d,

J = 11.2 Hz, 1H), 5.17 (d, J = 11.2 Hz, 1H), 7.08 (m, 1H), 7.14−7.20

(m, 4H), 7.23−7.26 (m, 6H), 7.79−7.82 (m, 4H); ¹³C NMR (125.7

Platinum(IV) oxide (3.0 mg, 0.013 mmol) was added to a solution

of the crude ester (16.0 mg) in EtOH (1.5 mL), and the mixture was

vigorously stirred under hydrogen (1 atm) for 26 h. The catalyst was

ﬁltered through a Celite pad, and the ﬁltrate was evaporated in vacuo.

Puriﬁcation of the crude product (15.5 mg) by preparative thin-layer

chromatography (200 mm × 100 mm × 0.25 mm preparative silica gel

plate and elution with 20:1 n-hexane/AcOEt twice) gave hydrogenated

compound 27b (4.8 mg) as a colorless oil. R_f0.59 (5:1 n-hexane/

1

AcOEt); H NMR (500 MHz, CDCl₃) δ 0.97 (s, 3H), 1.05 (s, 9H),

1.13 (m, 1H), 1.20 (d, J = 7.0 Hz, 3H), 1.25−1.43 (m, 6H), 1.50−1.64

(m, 3H), 2.55 (m, 1H), 3.58 (t, J = 9.9 Hz, 1H), 3.71 (s, 3H), 4.13

(dd, J = 3.9, 9.9 Hz, 1H), 4.79 (d, J = 11.3 Hz, 1H), 4.83 (d, J = 11.3

Hz, 1H), 7.24 (m, 1H), 7.29−7.30 (m, 4H), 7.35−7.42 (m, 6H),

7.65−7.69 (m, 4H); HRMS (ESI) m/z [M + Na]⁺calcd for

C₃₆H₄₈O₄SiNa 595.3220; found 595.3195.

(2S,3R,5S)-5-[(tert-Butyldiphenylsilyl)oxymethyl]-3-methyl-

2-(phenylthiomethyl)tetrahydrofuran (32). BuLi in n-hexane (2.2

M, 12.0 mL, 26.4 mmol) was added to an ice-cooled mixture (0 °C) of

thioanisole (3.10 mL, 26.5 mmol) and DABCO (2.97 g, 26.5 mmol) in

THF (160 mL). After 1 h of stirring, the mixture was cooled to −78

°C, and a solution of lactone 30 (7.50 g, 20.4 mmol) in THF (40 mL)

was added dropwise. After 20 min of stirring, the reaction was

quenched with saturated aqueous NH₄Cl (170 mL), and the resulting

mixture was extracted with AcOEt (350 and 250 mL). The combined

organic extracts were washed with brine (200 mL) and dried over

anhydrous Na₂SO₄. Filtration and evaporation in vacuo furnished the

crude product (12.1 g), which was chromatographed (silica gel 250 g,

4:1 n-hexane/AcOEt) to give a mixture containing hemiketal 31 (8.70

g) as a colorless oil.

To a cooled solution (−78 °C) of hemiketal 31 (8.70 g) in CH₂Cl₂

(180 mL) was added triethylsilane (4.2 mL, 26.5 mmol) followed by

BF₃·OEt₂(3.3 mL, 26.5 mmol). After 1 h of stirring, the reaction was

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Article

quenched with saturated aqueous NaHCO₃(120 mL), and the

resulting mixture was extracted with AcOEt (300 and 200 mL). The

combined organic extracts were washed with brine (80 mL) and dried

over anhydrous Na₂SO₄. Filtration and evaporation in vacuo furnished

the crude product (9.20 g), which was puriﬁed by column

chromatography (silica gel 250 g, 19:1 n-hexane/AcOEt) to give

sulﬁde 32 (7.28 g, 86% for two steps) as a colorless oil. R_f0.36 (10:1 n-

hexane/AcOEt); [α]²_D⁶−21.3 (c 1.36, CHCl₃); IR (neat) 3071, 3049,

suspension was diluted with H₂O (40 mL) and passed through a

Celite pad. The yellow ﬁltrate was extracted with AcOEt (4 × 120

mL), and the combined organic extracts were washed with brine (40

mL) and dried over anhydrous Na₂SO₄. Filtration and evaporation in

vacuo furnished the crude product (3.19 g), which was chromato-

graphed (silica gel 100 g, 3:1 CH₂Cl₂/MeOH) to give potassium

carboxylate 35 (3.19 g) as a pale-yellow solid.

To an ice-cooled solution (0 °C) of crude potassium carboxylate 35

(3.19 g) in CH₂Cl₂(40 mL) was added oxalyl chloride (1.0 mL, 11.8

mmol) followed by DMF (60 μL, 0.77 mmol). After 1 h of stirring at

room temperature, the mixture was concentrated in vacuo, and the

residue was dissolved in CH₂Cl₂(40 mL). A mixture of alcohol 22

(1.06 g, 9.45 mmol), Et₃N (5.5 mL, 39.5 mmol), and DMAP (87.0 mg,

0.712 mmol) in CH₂Cl₂(10 mL) was added to the solution of crude

acyl chloride at 0 °C. After 2 h of stirring, the reaction mixture was

partitioned between AcOEt (200 mL) and H₂O (40 mL), and the

aqueous layer was extracted with AcOEt (200 mL). The combined

organic extracts were washed with brine (40 mL) and dried over

anhydrous Na₂SO₄. Filtration and evaporation in vacuo furnished the

crude product (4.15 g), which was puriﬁed by column chromatography

(silica gel 200 g, 20:1 n-hexane/AcOEt) to give ester 36 (2.52 g, 65%

for three steps) as a colorless oil. R_f0.52 (5:1 n-hexane/AcOEt); [α]_D²⁷

+77.0 (c 1.49, CHCl₃); IR (neat) 3071, 3049, 2932, 2859, 1748, 1458,

1427, 1275, 1198, 1113 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.05 (s,

9H), 1.16 (d, J = 6.8 Hz, 3H), 1.56−1.76 (m, 5H), 1.67 (s, 3H), 1.84−

1.96 (m, 2H), 2.07 (m, 1H), 2.35 (m, 1H), 3.64 (dd, J = 6.8, 10.3 Hz,

1H), 3.83 (dd, J = 4.9, 10.3 Hz, 1H), 3.96 (d, J = 6.6 Hz, 1H), 4.25 (m,

1H), 5.24 (m, 1H), 5.41 (m, 1H), 7.35−7.43 (m, 6H), 7.66−7.69 (m,

4H); ¹³C NMR (125.7 MHz, CDCl₃) δ 18.2 (CH₃), 19.0 (CH₂), 19.2

(C), 23.7 (CH₃), 26.8 (CH₂), 27.9 (CH₂), 29.9 (CH₃), 36.3 (CH),

38.0 (CH₂), 66.1 (CH₂), 69.3 (CH), 80.1 (CH), 84.1 (CH), 119.8

(CH), 127.617 (CH), 127.625 (CH), 129.57 (CH), 129.58 (CH),

133.61 (C), 133.64 (C), 135.61 (CH), 135.63 (CH), 141.1 (C), 172.4

(C); HRMS (ESI) m/z [M + Na]⁺calcd for C₃₀H₄₀O₄SiNa 515.2594;

found 515.2593. Anal. Calcd for C₃₀H₄₀O₄Si: C, 73.13; H, 8.18.

Found: C, 73.10; H, 8.02.

Methyl [2R,2(1S),3R,5S]-5-[(tert-Butyldiphenylsilyl)-

oxymethyl]-3-methyl-2-[1-methylcyclohex-2-en-1-yl]-

tetrahydrofuran-2-carboxylate (38b). To a cooled solution (−78

°C) of ester 36 (1.25 g, 2.54 mmol) in THF (40 mL) was added a

solution of LDA [prepared from diisopropylamine (0.55 mL, 3.92

mmol) and BuLi in n-hexane (1.56 M, 2.50 mL, 3.90 mmol)] in THF

(10 mL) followed by chlorotrimethylsilane (0.48 mL, 0.38 mmol).

After 5 min of stirring at −78 °C, the mixture was allowed to warm to

room temperature and stirred for 10 h. The reaction was quenched

with saturated aqueous NH₄Cl (40 mL), and the resulting mixture was

extracted with AcOEt (3 × 100 mL). The combined organic extracts

were washed with brine (40 mL) and dried over anhydrous Na₂SO₄.

Filtration and evaporation in vacuo furnished the crude product (1.75

g), which was chromatographed (silica gel 150 g, 7:1 n-hexane/

AcOEt) to give an inseparable mixture of carboxylic acids 37a and 37b

(921 mg, 74%) as a colorless oil.

Potassium carbonate (775 mg, 5.61 mmol) was added to an ice-

cooled mixture (0 °C) of carboxylic acids 37a and 37b (921 mg, 1.87

mmol) and iodomethane (0.35 mL, 5.62 mmol) in DMF (19 mL).

After 4 h of stirring, the resulting yellow mixture was partitioned

between n-hexane/AcOEt (3:1, 50 mL) and H₂O (40 mL), and the

aqueous layer was extracted with n-hexane/AcOEt (3:1, 2 × 50 mL).

The combined organic extracts were washed with brine (40 mL) and

dried over anhydrous Na₂SO₄. Filtration and evaporation in vacuo

furnished the crude product (1.41 g), which was subjected to ﬂash

chromatography (silica gel 30 g, 9:1 n-hexane/AcOEt) to give a

mixture of methyl esters 38a and 38b (938 mg, 99%) as a colorless oil.

The diastereomeric ratio (38a:38b) was determined to be 6:94 by

HPLC analysis (column, Zorbax Sil, 4.6 mm × 250 mm; eluent, 50:1

n-hexane/THF; ﬂow rate, 1.5 mL/min; detection, 254 nm; t_R= 10.0

min for the major isomer 38b, t_R= 11.4 min for the minor isomer

38a). Separation of diastereomers 38a and 38b by ﬂash column

chromatography (silica gel 100 g, 50:1 n-hexane/AcOEt) yielded

isomer 38a (61.0 mg, 5%) and isomer 38b (877 mg, 94%) as colorless

1

2959, 2930, 2857, 1427, 1113 cm⁻¹; H NMR (500 MHz, CDCl₃) δ

1.05 (d, J = 4.2 Hz, 3H), 1.06 (s, 9H), 1.64 (dt, J = 11.7, 7.0 Hz, 1H),

2.07−2.16 (m, 2H), 3.05 (dd, J = 6.4, 13.3 Hz, 1H), 3.08 (dd, J = 5.1,

13.3 Hz, 1H), 3.62−3.66 (m, 3H), 4.13 (dt, J = 12.3, 4.7 Hz, 1H), 7.15

(m, 1H), 7.23−7.25 (m, 2H), 7.33−7.43 (m, 8H), 7.66−7.70 (m, 4H);

¹³C NMR (125.7 MHz, CDCl₃) δ 17.6 (CH₃), 19.3 (C), 26.9 (CH₃),

36.3 (CH₂), 37.9 (CH), 38.1 (CH₂), 66.3 (CH₂), 78.6 (CH), 84.7

(CH), 125.7 (CH), 127.64 (CH), 127.65 (CH), 128.8 (CH), 128.9

(CH), 129.59 (CH), 129.62 (CH), 133.6 (C), 135.64 (CH), 135.65

(CH), 136.9 (C); HRMS (ESI) m/z [M + Na]⁺calcd for

C₂₉H₃₆O₂SSiNa 499.2103; found 499.2087. Anal. Calcd for

C₂₉H₃₆O₂SSi: C, 73.06; H, 7.61. Found: C, 72.89; H, 7.68.

(2R,3R,5S)-5-[(tert-Butyldiphenylsilyl)oxymethyl]-3-methyl-

tetrahydrofuran-2-carbaldehyde (34). m-CPBA (ca. 70%, 21.1 g,

ca. 85.6 mmol) was added to an ice-cooled (0 °C) solution of sulﬁde

32 (40.0 g, 83.9 mmol) in CH₂Cl₂(420 mL). After 1 h of stirring, the

reaction mixture was quenched with solid Na₂S₂O₃·5H₂O (20.0 g),

and saturated aqueous NaHCO₃(500 mL) was added. The resulting

mixture was extracted with AcOEt (3 × 500 mL), and the combined

organic extracts were washed with brine (400 mL) and dried over

anhydrous Na₂SO₄. Filtration and evaporation in vacuo furnished the

crude product 33 (43.8 g), which was used without further

puriﬁcation.

TFAA (35.0 mL, 249 mmol) was added to an ice-cooled mixture (0

°C) of crude sulfoxide 33 (43.8 g) and 2,6-lutidine (29 mL, 249

mmol) in CH₂Cl₂(400 mL). After 1 h of stirring, the reaction was

quenched with saturated aqueous NaHCO₃(400 mL), and the

resulting mixture was extracted with AcOEt (3 × 600 mL). The

combined organic extracts were successively washed with saturated

aqueous NaHCO₃(400 mL) and brine (400 mL) and then dried over

anhydrous Na₂SO₄. Filtration and evaporation in vacuo furnished the

crude product (69.1 g), which was used without further puriﬁcation.

NaHCO₃(70.5 g, 839 mmol) was added to a solution of the crude

triﬂuoroacetate (69.1 g) in acetone/H₂O (1:1, 400 mL). After 24 h of

stirring, the mixture was diluted with AcOEt (200 mL), and acetone

was removed in vacuo. The residue was passed through a Celite pad,

and the ﬁltrate was partitioned between AcOEt (600 mL) and H₂O

(200 mL). The aqueous layer was extracted with AcOEt (3 × 600

mL), and the combined organic extracts were washed with brine (200

mL) and dried over anhydrous Na₂SO₄. Filtration and evaporation in

vacuo furnished the crude product (65.2 g), which was puriﬁed by

column chromatography (silica gel 500 g, 5:1 n-hexane/AcOEt) to

give aldehyde 34 (26.3 g, 82% for three steps) as a colorless oil. R_f0.45

(3:1 n-hexane/AcOEt); [α]_D¹⁶+39.4 (c 1.03, CHCl₃); IR (neat) 3071,

2961, 2930, 2859, 1734, 1472, 1460, 1427, 1112 cm⁻¹; ¹H NMR (500

MHz, CDCl₃) δ 1.06 (s, 9H), 1.14 (d, J = 6.8 Hz, 3H), 1.70 (dt, J =

12.4, 7.8 Hz, 1H), 2.12 (ddd, J = 5.0, 7.8, 12.4 Hz, 1H), 2.40 (dtq, J =

7.3, 7.8, 6.8 Hz, 1H), 3.67 (dd, J = 4.2, 10.9 Hz, 1H), 3.74 (dd, J = 4.7,

10.9 Hz, 1H), 3.76 (dd, J = 2.5, 7.3 Hz, 1H), 4.32 (dddd, J = 4.2, 4.7,

5.0, 7.8 Hz, 1H), 7.38−7.45 (m, 6H), 7.67−7.71 (m, 4H), 9.63 (d, J =

2.5 Hz, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 17.2 (CH₃), 19.2 (C),

26.8 (CH₃), 35.9 (CH₂), 36.0 (CH), 66.1 (CH₂), 80.5 (CH), 89.6

(CH), 127.70 (CH), 127.72 (CH), 129.7 (CH), 129.8 (CH), 133.26

(C), 133.28 (C), 135.58 (CH), 135.61 (CH), 203.0 (CH); HRMS

(ESI) m/z [M + Na]⁺calcd for C₂₃H₃₀O₃SiNa 405.1862; found

405.1871.

(R)-3-Methylcyclohex-2-en-1-yl (2R,3R,5S)-5-[(tert-

Butyldiphenylsilyl)oxymethyl]-3-methyltetrahydrofuran-2-car-

boxylate (36). To an ice-cooled solution (0 °C) of aldehyde 34 (3.00

g, 7.84 mmol) in EtOH (10 mL) was added a solution of AgNO₃(5.30

g, 31.2 mmol) in H₂O (5 mL) followed by a solution of KOH (3.50 g,

62.4 mmol) in H₂O (5 mL). After 1 h of stirring, the resulting black

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Article

oils. Data for 38b: R_f0.31 (10:1 n-hexane/AcOEt); [α]²_D⁶+7.1 (c 1.08,

133.4 (C), 135.5 (CH), 135.6 (CH), 175.9 (C); HRMS (ESI) m/z [M

+ Na]⁺calcd for C₃₀H₃₉IO₄SiNa 641.1560; found 641.1568.

CHCl₃); IR (neat) 3071, 2932, 2859, 1732, 1456, 1427, 1227, 1113

1

cm⁻¹; H NMR (500 MHz, CDCl₃) δ 1.04 (d, J = 7.1 Hz, 3H), 1.05

Methyl [2R,2(1S),3R,5S]-5-(Hydroxymethyl)-3-methyl-2-(1-

methylcyclohex-2-en-1-yl)tetrahydrofuran-2-carboxylate (41).

NH₄F (249 mg, 6.72 mmol) was added to a solution of TBDPS ether

38b (341 mg, 0.673 mmol) in MeOH/EtOH (5:2, 7 mL). After 24 h

of stirring, the mixture was partitioned between AcOEt (70 mL) and

H₂O (15 mL), and the aqueous layer was extracted with AcOEt (70

mL). The combined organic extracts were washed with brine (20 mL)

and dried over anhydrous Na₂SO₄. Filtration and evaporation in vacuo

furnished the crude product (391 mg), which was puriﬁed by column

chromatography (silica gel 10 g, 2:1 n-hexane/AcOEt) to give alcohol

41 (170 mg, 94%) as a colorless oil. R_f0.31 (3:1 n-hexane/AcOEt);

[α]²_D²+19.5 (c 1.17, CHCl₃); IR (neat) 3442, 2937, 1732, 1456, 1227,

1101, 1051 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.06 (d, J = 7.0 Hz,

3H), 1.20 (s, 3H), 1.52−1.71 (m, 4H), 1.81 (dt, J = 3.3, 12.5 Hz, 1H),

1.92−1.94 (m, 2H), 2.04 (ddd, J = 5.6, 9.0, 12.5 Hz, 1H), 2.55 (m,

1H), 3.47 (dd, J = 5.1, 11.6 Hz, 1H), 3.73 (s, 3H), 3.74 (dd, J = 3.4,

11.6 Hz, 1H), 4.32 (m, 1H), 5.75 (m, 1H), 5.84 (m, 1H); ¹³C NMR

(125.7 MHz, CDCl₃) δ 18.0 (CH₃), 19.2 (CH₂), 23.2 (CH₃), 24.8

(CH₂), 31.1 (CH₂), 36.5 (CH₂), 37.0 (CH), 42.0 (C), 51.3 (CH₃),

65.0 (CH₂), 78.0 (CH), 94.1 (C), 127.8 (CH), 132.4 (CH), 173.2

(C); HRMS (ESI) m/z [M + Na]⁺calcd for C₁₅H₂₄O₄Na 291.1572;

found 291.1555.

(s, 9H), 1.08 (s, 3H), 1.49−1.62 (m, 4H), 1.80−1.89 (m, 3H), 2.16

(ddd, J = 5.0, 8.6, 13.5 Hz, 1H), 2.46 (m, 1H), 3.66 (dd, J = 4.3, 10.6

Hz, 1H), 3.69 (dd, J = 5.2, 10.6 Hz, 1H), 3.71 (s, 3H), 4.29 (m, 1H),

5.65 (m, 1H), 5.95 (m, 1H), 7.36−7.43 (m, 6H), 7.67 (m, 4H); ¹³C

NMR (125.7 MHz, CDCl₃) δ 18.0 (CH₃), 19.49 (C), 19.51 (CH₂),

23.6 (CH₃), 25.1 (CH₂), 27.1 (CH₃), 30.8 (CH₂), 36.9 (CH), 37.3

(CH₂), 42.1 (C), 51.4 (CH₃), 66.0 (CH₂), 78.3 (CH), 94.2 (C), 127.3

(CH), 127.87 (CH), 127.89 (CH), 129.8 (CH), 129.9 (CH), 133.0

(CH), 133.7 (C), 133.9 (C), 135.85 (CH), 135.90 (CH), 173.9 (C);

HRMS (ESI) m/z [M + Na]⁺calcd for C₃₁H₄₂O₄SiNa 529.2750;

found 529.2769.

Data for the [2S,2(1S),3R,5S] isomer 38a: R_f0.28 (10:1 n-hexane/

AcOEt); [α]²_D⁶−14.2 (c 0.16, CHCl₃); IR (neat) 3028, 2932, 2856,

1

1732, 1460, 1427, 1227, 1113 cm⁻¹; H NMR (500 MHz, CDCl₃) δ

1.056 (s, 9H), 1.063 (d, J = 6.7 Hz, 3H), 1.10 (s, 3H), 1.51−1.66 (m,

3H), 1.72 (dt, J = 3.4, 13.1 Hz, 1H), 1.86 (m, 1H), 1.90−1.93 (m,

2H), 2.20 (ddd, J = 7.0, 9.1, 12.2 Hz, 1H), 2.48 (m, 1H), 3.69 (dd, J =

3.8, 10.7 Hz, 1H), 3.71 (s, 3H), 3.80 (dd, J = 4.9, 10.7 Hz, 1H), 4.29

(m, 1H), 5.68 (dt, J = 10.0, 3.3 Hz, 1H), 5.76 (dd, J = 1.6, 10.0 Hz,

1H), 7.36−7.43 (m, 6H), 7.66−7.70 (m, 4H); ¹³C NMR (125.7 MHz,

CDCl₃) δ 18.6 (CH₃), 19.1 (CH₂), 19.3 (CH), 23.3 (CH₃), 24.9

(CH₂), 26.8 (CH₃), 31.3 (CH₂), 36.8 (C), 37.4 (CH₂), 42.5 (C), 51.2

(CH₃), 65.2 (CH₂), 78.4 (CH), 94.8 (C), 127.63 (CH), 127.65 (CH),

129.56 (CH), 129.61 (CH), 132.6 (CH), 133.5 (C), 133.6 (C), 135.6

(CH), 135.7 (CH), 173.4 (C); HRMS (ESI) m/z [M + Na]⁺calcd for

C₃₁H₄₂O₄SiNa 529.2750, found 529.2730.

Methyl [2R,2(1S),3R,5S]-5-(Iodomethyl)-3-methyl-2-(1-meth-

ylcyclohex-2-en-1-yl)tetrahydrofuran-2-carboxylate (42). Io-

dine (103 mg, 0.405 mmol) was added to a mixture of alcohol 41

(72.4 mg, 0.270 mmol), triphenylphosphine (106 mg, 0.405 mmol),

and imidazole (55.1 mg, 0.809 mmol) in toluene (2.7 mL). After 1 h

of stirring at 50 °C, the reaction was quenched with 1 M aqueous

Na₂S₂O₃(5 mL), and the resulting mixture was extracted with AcOEt

(2 × 30 mL). The combined organic extracts were washed with brine

(5 mL) and dried over anhydrous Na₂SO₄. Filtration and evaporation

in vacuo furnished the crude product (247 mg), which was puriﬁed by

column chromatography (silica gel 10 g, 20:1 n-hexane/AcOEt) to

give iodide 42 (96.3 mg, 94%) as a colorless oil. R_f0.42 (10:1 n-

hexane/AcOEt); [α]²_D⁰−15.5 (c 1.20, CHCl₃); IR (neat) 2936, 2876,

(1S,3S,5R,3a′S,4′S,7a′S)-3-[(tert-Butyldiphenylsilyl)-

oxymethyl]-4′-iodo-5,7a′-dimethyl-2,3′-dioxaspiro-

[cyclopentane-1,1′-hexahydroindan]-2′-one (39b). Iodine (453

mg, 1.78 mmol) was added to a solution of carboxylic acids 37a and

37b (797 mg, 1.62 mmol) in MeCN/saturated aqueous NaHCO₃

(1:1, 20 mL) at 0 °C. After 90 min of stirring, the reaction was

quenched with 1 M aqueous Na₂S₂O₃(30 mL), and the resulting

mixture was extracted with AcOEt (2 × 100 mL). The combined

organic extracts were washed with brine (30 mL) and dried over

anhydrous Na₂SO₄. Filtration and evaporation in vacuo furnished the

crude product (977 mg), which was puriﬁed by ﬂash column

chromatography (silica gel 70 g, 20:1 n-hexane/AcOEt) to give

isomer 39b (802 mg, 81%) as a white solid along with isomer 39a

(35.5 mg, 4%) as a colorless oil. Data for 39b: R_f0.54 (5:1 n-hexane/

AcOEt); mp 139−140 °C (colorless prisms from n-hexane); [α]_D²⁵

+53.7 (c 1.08, CHCl₃); IR (KBr) 3071, 2934, 2857, 1780, 1460, 1233,

1

1732, 1454, 1433, 1229, 1061 cm⁻¹; H NMR (500 MHz, CDCl₃) δ

1.04 (d, J = 6.7 Hz, 3H), 1.11 (s, 3H), 1.57−1.62 (m, 2H), 1.67 (m,

1H), 1.76 (ddd, J = 8.0, 8.8, 12.9 Hz, 1H), 1.82 (dt, J = 3.2, 12.5 Hz,

1H), 1.90−1.94 (m, 2H), 2.02 (ddd, J = 4.8, 8.7, 12.9 Hz, 1H), 2.52

(ddq, J = 8.7, 8.8, 6.7 Hz, 1H), 3.12 (dd, J = 8.4, 9.7 Hz, 1H), 3.29 (dd,

J = 4.4, 9.7 Hz, 1H), 3.72 (s, 3H), 4.35 (dddd, J = 4.4, 4.8, 8.0, 8.4 Hz,

1H), 5.59 (m, 1H), 5.91 (m, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ

9.8 (CH₂), 17.6 (CH₃), 19.3 (CH₂), 23.4 (CH₃), 24.9 (CH₂), 30.8

(CH₂), 36.2 (CH₂), 40.6 (CH), 41.8 (C), 51.3 (CH₃), 77.5 (CH),

95.2 (C), 127.5 (CH), 132.3 (CH), 173.0 (C); HRMS (ESI) m/z [M

+ Na]⁺calcd for C₁₅H₂₃IO₃Na 401.0590; found 401.0587.

Methyl [2R,2(1S),3R]-2-(1-Methylcyclohex-2-en-1-yl)-3-

methyl-2-hydroxyhex-5-enoate (43). Activated zinc powder

(80.0 mg, 1.22 mmol) was added to a solution of iodide 42 (92.6

mg, 0.245 mmol) in AcOH (1.2 mL). After 1 h of stirring at 110 °C,

the suspension was ﬁltered through a Celite pad, and the ﬁltrate was

concentrated in vacuo. The residue was azeotropically dried with

toluene (3 × 5 mL) to furnish the crude product (127 mg), which was

puriﬁed by column chromatography (silica gel 5 g, 20:1 n-hexane/

AcOEt) to give diene 43 (51.3 mg, 83%) as a colorless oil. R_f0.42

(10:1 n-hexane/AcOEt); [α]_D²³+27.4 (c 1.06, CHCl₃); IR (neat) 3510,

2938, 1720, 1639, 1437, 1229, 1153 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ 0.77 (d, J = 6.7 Hz, 3H), 1.09 (s, 3H), 1.51−1.71 (m, 3H),

1.91−2.01 (m, 4H), 2.19 (m, 1H), 2.57 (m, 1H), 3.36 (s, 1H), 3.77 (s,

3H), 4.96−5.03 (m, 2H), 5.67 (m, 1H), 5.70−5.79 (m, 2H); ¹³C

NMR (125.7 MHz, CDCl₃) δ 14.8 (CH₃), 19.4 (CH₂), 24.0 (CH₃),

24.5 (CH₂), 30.7 (CH₂), 35.8 (CH₂), 37.8 (CH), 41.9 (C), 52.4

(CH₃), 83.9 (C), 115.9 (CH₂), 126.5 (CH), 133.0 (CH), 137.5 (CH),

177.4 (C); HRMS (ESI) m/z [M + Na]⁺calcd for C₁₅H₂₄O₃Na

275.1623; found 275.1642.

1

1113, 970, 702 cm⁻¹; H NMR (500 MHz, C₆D₆) δ 0.79 (m, 1H),

0.95−1.04 (m, 2H), 1.14 (d, J = 6.7 Hz, 3H), 1.16 (s, 9H), 1.28 (s,

3H), 1.33 (m, 1H), 1.48−1.60 (m, 2H), 1.83 (m, 1H), 1.93 (m, 1H),

2.10 (m, 1H), 3.51 (dd, J = 4.8, 10.7 Hz, 1H), 3.58 (dd, J = 4.7, 10.7

Hz, 1H), 4.19 (m, 1H), 4.28 (m, 1H), 4.72 (s, 1H), 7.25−7.26 (m,

6H), 7.75−7.79 (m, 4H); ¹³C NMR (125.7 MHz, C₆D₆) δ 15.9

(CH₃), 17.4 (CH₂), 17.8 (CH₃), 19.4 (C), 23.5 (CH), 27.0 (CH₃),

29.3 (CH₂), 30.6 (CH₂), 32.8 (CH), 36.7 (CH₂), 43.9 (C), 66.0

(CH₂), 77.7 (CH), 83.7 (CH), 91.4 (C), 128.11 (CH), 128.14 (CH),

128.3 (CH), 130.06 (CH), 130.10 (CH), 133.8 (C), 133.9 (C), 136.0

(CH), 172.0 (C); HRMS (ESI) m/z [M + Na]⁺calcd for

C₃₀H₃₉IO₄SiNa 641.1560; found 641.1549. Anal. Calcd for

C₃₀H₃₉IO₄Si: C, 58.25; H, 6.35. Found: C, 58.17; H, 6.35.

Data for the (1R,3S,5R,3a′S,4′S,7a′S) isomer 39a: R_f0.52 (5:1 n-

hexane/AcOEt); [α]²_D⁷+2.5 (c 1.19, CHCl₃); IR (neat) 3071, 2932,

1

2859, 1782, 1456, 1236, 1113, 970, 702 cm⁻¹; H NMR (500 MHz,

CDCl₃) δ 1.06 (s, 9H), 1.10 (d, J = 7.1 Hz, 3H), 1.36 (s, 3H), 1.55−

1.63 (m, 3H), 1.75 (m, 1H), 1.88−2.00 (m, 3H), 2.15 (ddd, J = 4.7,

8.1, 12.5 Hz, 1H), 2.50 (m, 1H), 3.60 (dd, J = 4.0, 10.9 Hz, 1H), 3.70

(dd, J = 4.4, 10.9 Hz, 1H), 4.43 (m, 1H), 4.50 (d, J = 3.1 Hz, 1H), 4.62

(dt, J = 3.1, 3.3 Hz, 1H), 7.37−7.45 (m, 6H), 7.65−7.69 (m, 4H); ¹³C

NMR (125.7 MHz, CDCl₃) δ 15.7 (CH₃), 18.1 (CH₂), 19.2 (C), 20.1

(CH₃), 24.3 (CH), 26.8 (CH₃), 30.0 (CH₂), 31.2 (CH₂), 35.3 (CH₂),

35.5 (CH), 43.2 (C), 65.7 (CH₂), 78.1 (CH), 83.5 (CH), 93.2 (C),

127.68 (CH), 127.72 (CH), 129.67 (CH), 129.74 (CH), 133.2 (C),

Methyl [2R,2(1S),3R,5S]-5-(Chloromethyl)-3-methyl-2-(1-

methylcyclohex-2-en-1-yl)tetrahydrofuran-2-carboxylate (44).

A mixture of alcohol 41 (170 mg, 0.632 mmol) and triphenylphos-

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phine (829 mg, 3.16 mmol) in CCl₄(6 mL) was heated at reﬂux for 12

h. After cooling, the resulting brown suspension was concentrated in

vacuo. Puriﬁcation of the residue (1.12 g) by column chromatography

(silica gel 50 g, 20:1 n-hexane/AcOEt) gave chloride 44 (177 mg,

98%) as a colorless oil. R_f0.47 (5:1 n-hexane/AcOEt); [α]²_D³−5.2 (c

1.03, CHCl₃); IR (neat) 2940, 2876, 1732, 1458, 1229, 1076, 739

1 h of stirring at room temperature in the dark, AcOH (230 μL, 4.0

mmol) was added at 0 °C. After 10 min, a mixture of 1 M aqueous

Na₂S₂O₃(15 mL) and saturated aqueous NaHCO₃(15 mL) was

added, and the resulting mixture was extracted with AcOEt (2 × 60

mL). The combined organic extracts were washed with brine (30 mL)

and dried over anhydrous Na₂SO₄. Filtration and evaporation in vacuo

furnished the crude product (652 mg), which was puriﬁed by column

chromatography (silica gel 20 g, 40:1 n-hexane/Et₂O) to give vinyl

iodide 48 (568 mg, 93%) as a colorless oil. R_f0.76 (20:1 n-hexane/

Et₂O); [α]²_D⁶+31.7 (c 1.17, CHCl₃); IR (neat) 3028, 2972, 2949, 2835,

1746, 1616, 1456, 1435, 1248, 1173 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ 0.19 (s, 9H), 0.67 (d, J = 6.7 Hz, 3H), 1.04 (s, 3H), 1.44 (m,

1H), 1.62 (m, 1H), 1.71 (m, 1H), 1.88−2.00 (m, 3H), 2.05 (dd, J =

11.3, 13.5 Hz, 1H), 2.44 (ddq, J = 3.4, 11.3, 6.7 Hz, 1H), 2.87 (dd, J =

3.4, 13.5 Hz, 1H), 3.79 (s, 3H), 5.69 (m, 1H), 5.74 (s, 1H), 5.76 (m,

1H), 6.04 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 2.8 (CH₃), 15.1

(CH₃), 19.9 (CH₂), 24.5 (CH₂), 24.6 (CH₃), 31.1 (CH₂), 38.0 (CH),

42.6 (C), 46.5 (CH₂), 51.5 (CH₃), 88.4 (C), 111.9 (C), 126.3 (CH),

126.8 (CH₂), 133.1 (CH), 175.2 (C); HRMS (DART) m/z [M + H]⁺

calcd for C₁₈H₃₂IO₃Si 451.1165; found 451.1150.

1

cm⁻¹; H NMR (500 MHz, CDCl₃) δ 1.05 (d, J = 6.9 Hz, 3H), 1.11

(s, 3H), 1.54 (m, 1H), 1.60 (m, 1H), 1.67 (m, 1H), 1.71 (ddd, J = 8.4,

9.1, 13.0 Hz, 1H), 1.83 (dt, J = 13.3, 3.9 Hz, 1H), 1.90−1.93 (m, 2H),

2.08 (ddd, J = 4.5, 8.6, 13.0 Hz, 1H), 2.50 (ddq, J = 8.4, 8.6, 6.9 Hz,

1H), 3.46 (dd, J = 7.0, 11.0 Hz, 1H), 3.57 (dd, J = 4.4, 11.0 Hz, 1H),

3.72 (s, 3H), 4.42 (dddd, J = 4.4, 4.5, 7.0, 9.1 Hz, 1H), 5.69 (m, 1H),

5.91 (dd, J = 1.5, 10.6 Hz, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 17.5

(CH₃), 19.3 (CH₂), 23.2 (CH₃), 24.8 (CH₂), 30.5 (CH₂), 36.3 (CH),

38.2 (CH₂), 41.8 (C), 46.7 (CH₂), 51.3 (CH₃), 77.1 (CH), 94.5 (C),

127.4 (CH), 132.3 (CH), 173.1 (C); HRMS (ESI) m/z [M + Na]⁺

calcd for C₁₅H₂₃ClO₃Na 309.1233; found 309.1238.

Methyl [2R,2(1S),3R]-2-Hydroxy-2-(1-methylcyclohex-2-en-

1-yl)-3-methylhex-5-ynoate (45). Sodium (167 mg, 7.26 mmol)

was added to a yellow solution of Fe(NO₃)₃·9H₂O (10.0 mg, 0.025

mmol) in liquid ammonia (10 mL) at −40 °C. After 30 min of stirring,

chloride 44 (139 mg, 0.485 mmol) in THF (5 mL) was added to the

brown-colored suspension, and the reaction mixture was stirred for 2

h. The reaction was quenched with solid NH₄Cl (1.0 g), and ammonia

was evaporated at room temperature. The residue was partitioned

between AcOEt (40 mL) and H₂O (15 mL), and the aqueous layer

was extracted with AcOEt (40 mL). The combined organic extracts

were washed with brine (15 mL) and dried over anhydrous Na₂SO₄.

Filtration and evaporation in vacuo furnished the crude product (150

mg), which was puriﬁed by column chromatography (silica gel 10 g,

20:1 n-hexane/AcOEt) to give alkyne 45 (116 mg, 96%) as a colorless

oil. R_f0.44 (5:1 n-hexane/AcOEt); [α]²_D³+45.8 (c 1.03, CHCl₃); IR

(neat) 3505, 3306, 2934, 2116, 1719, 1458, 1437, 1381, 1369, 1242,

Methyl (1S,2R,3R,6S)-1,3-Dimethyl-5-methylene-2-

(trimethylsilyl)oxybicyclo[4.4.0]dec-7-ene-2-carboxylate (47).

A yellow mixture of vinyl iodide 48 (92.5 mg, 0.205 mmol), palladium

acetate (4.6 mg, 0.021 mmol), 1,3-bis(diphenylphosphino)propane

(10.1 mg, 0.025 mmol), AgNO₃(69.6 mg, 0.410 mmol), and

triethylamine (0.11 mL, 0.787 mmol) in DMSO (21 mL) was

degassed by bubbling a stream of argon for 5 min, and the mixture was

heated at 60 °C for 12 h. After cooling, the resulting black suspension

was ﬁltered through a Celite pad, and the ﬁltrate was partitioned

between n-hexane/AcOEt (5:1, 150 mL) and H₂O (40 mL). The

aqueous layer was extracted with n-hexane/AcOEt (5:1, 2 × 100 mL),

and the combined organic extracts were washed with brine (50 mL)

and dried over anhydrous Na₂SO₄. Filtration and evaporation in vacuo

furnished the crude product (72.3 mg), which was puriﬁed by ﬂash

column chromatography (silica gel 40 g, 40:1 n-hexane/Et₂O) to give

diene 47 (58.3 mg, 88%) as a colorless oil. R_f0.64 (20:1 n-hexane/

Et₂O); [α]²_D⁷−126.2 (c 1.06, CHCl₃); IR (neat) 3022, 2953, 2843,

1

1098, 629 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 0.97 (d, J = 6.7 Hz,

3H), 1.06 (s, 3H), 1.51 (m, 1H), 1.60 (m, 1H), 1.69 (m, 1H), 1.87−

1.95 (m, 3H), 1.97 (t, J = 2.6 Hz, 1H), 2.18 (ddd, J = 2.6, 10.5, 16.3

Hz, 1H), 2.35 (ddq, J = 3.6, 10.5, 6.7 Hz, 1H), 2.64 (ddd, J = 2.6, 3.6,

16.3 Hz, 1H), 3.38 (s, 1H), 3.77 (s, 3H), 5.66−5.72 (m, 2H); ¹³C

NMR (125.7 MHz, CDCl₃) δ 15.4 (CH₃), 19.4 (CH₂), 21.2 (CH₂),

23.9 (CH₃), 24.5 (CH₂), 30.7 (CH₂), 37.3 (CH), 41.9 (C), 52.5

(CH₃), 69.4 (CH), 83.2 (C), 83.5 (C), 126.9 (CH), 132.6 (CH),

176.8 (C); HRMS (DART) m/z [M + H]⁺calcd for C₁₅H₂₃O₃

251.1647; found 251.1658.

1

1735, 1437 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 0.09 (s, 9H), 0.86

(s, 3H), 0.95 (d, J = 6.7 Hz, 3H), 1.31 (m, 1H), 1.60 (dt, J = 6.0, 12.9

Hz, 1H), 1.91 (m, 1H), 1.96 (dd, J = 8.5, 15.0 Hz, 1H), 2.03 (dt, J =

18.3, 6.0 Hz, 1H), 2.32 (ddq, J = 8.3, 15.0, 6.7 Hz, 1H), 2.54 (m, 1H),

2.57 (m, 1H), 3.71 (s, 3H), 4.63 (dd, J = 1.9, 4.0 Hz, 1H), 4.76 (m,

1H), 5.52 (dddd, J = 1.5, 2.6, 4.6, 10.0 Hz, 1H), 5.77 (m, 1H); ¹³C

NMR (125.7 MHz, CDCl₃) δ 1.9 (CH₃), 16.9 (CH₃), 21.3 (CH₂),

23.1 (CH₂), 24.5 (CH₃), 33.8 (CH₂), 38.5 (CH), 42.2 (C), 46.5

(CH), 51.0 (CH₃), 85.9 (C), 109.5 (CH₂), 127.11 (CH), 127.14

(CH), 147.6 (C), 174.0 (C); HRMS (EI) m/z [M]⁺calcd for

C₁₈H₃₀O₃Si 322.1964; found 322.1966.

Methyl (1R,4R,5R,6S)-4,6-Dimethyl-2-oxo-5-(trimethylsilyl)-

oxybicyclo[4.4.0]decane-5-carboxylate (51). Lindlar catalyst

(51.3 mg, 100 wt %) was added to a solution of diene 47 (51.3 mg,

0.159 mmol) in MeOH (3 mL), and the mixture was vigorously stirred

for 6 h under hydrogen (1 atm). The catalyst was ﬁltered through a

Celite pad, and the ﬁltrate was evaporated in vacuo. The crude product

49 (49.2 mg) was used without further puriﬁcation.

To a solution of crude alkene 49 (49.2 mg) and phenylboronic acid

(58.2 mg, 0.477 mmol) in CH₂Cl₂(3 mL) was added a 0.16 M

solution of OsO₄in THF (0.15 mL, 0.024 mmol) followed by NMO

(55.9 mg, 0.477 mmol). After 72 h of stirring, the reaction was

quenched with 1 M aqueous Na₂S₂O₃(5 mL), and the resulting

mixture was extracted with CH₂Cl₂(3 × 30 mL). The combined

organic extracts were washed with brine (5 mL) and dried over

anhydrous Na₂SO₄. Filtration and evaporation in vacuo furnished the

crude product 50 (190 mg), which was used without further

puriﬁcation.

NaIO₄(170 mg, 0.795 mmol) was added to a solution of crude

phenylboronate 50 (190 mg) in THF/pH 7 phosphate buﬀer (1:1, 3

mL). After 3 h of stirring at 50 °C, the reaction was quenched with 1

M aqueous Na₂S₂O₃(15 mL), and the resulting mixture was extracted

with AcOEt (2 × 40 mL). The combined organic extracts were washed

Methyl [2R,2(1S),3R]-3-Methyl-2-(1-methylcyclohex-2-en-1-

yl)-2-(trimethylsilyl)oxyhex-5-ynoate (46). TMSOTf (1.50 mL,

8.29 mmol) was added to a mixture of alcohol 45 (1.01 g, 4.03 mmol)

and 2,6-lutidine (1.40 mL, 12.0 mmol) in CH₂Cl₂(40 mL) at 0 °C.

After 14 h of stirring at room temperature, the reaction was quenched

with saturated aqueous NaHCO₃(40 mL), and the resulting mixture

was extracted with AcOEt (2 × 200 mL). The combined organic

extracts were washed with brine (40 mL) and dried over anhydrous

Na₂SO₄. Filtration and evaporation in vacuo furnished the crude

product (2.91 g), which was puriﬁed by column chromatography

(silica gel 100 g, 40:1 n-hexane/AcOEt) to give TMS ether 46 (1.28 g,

98%) as a colorless oil. R_f0.47 (20:1 n-hexane/AcOEt); [α]²_D³+36.9 (c

1.00, CHCl₃); IR (neat) 3312, 2949, 2118, 1746, 1458, 1435, 1248,

1173 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.17 (s, 9H), 0.92 (d, J =

6.6 Hz, 3H), 0.99 (s, 3H), 1.38 (m, 1H), 1.60 (m, 1H), 1.68 (m, 1H),

1.84−1.93 (m, 3H), 1.94 (t, J = 2.6 Hz, 1H), 2.06 (ddd, J = 2.6, 11.0,

16.2 Hz, 1H), 2.36 (ddq, J = 3.7, 11.0, 6.6 Hz, 1H), 2.62 (ddd, J = 2.6,

3.7, 16.2 Hz, 1H), 3.70 (s, 3H), 5.65 (m, 1H), 5.73 (m, 1H); ¹³C

NMR (125.7 MHz, CDCl₃) δ 2.8 (CH₃), 16.2 (CH₃), 19.9 (CH₂),

20.9 (CH₂), 24.5 (CH₂), 24.6 (CH₃), 31.1 (CH₂), 38.4 (CH), 42.4

(C), 51.4 (CH₃), 69.1 (CH), 83.8 (C), 88.0 (C), 126.2 (CH), 133.1

(CH), 175.0 (C); HRMS (DART) m/z [M + H]⁺calcd for

C₁₈H₃₁O₃Si 323.2043; found 323.2037.

Methyl [2R,2(1S),3R]-5-Iodo-3-methyl-2-(1-methylcyclohex-

2-en-1-yl)-2-(trimethylsilyl)oxyhex-5-enoate (48). B-Iodo-9-

BBN in hexanes (1.0 M, 2.0 mL, 2.0 mmol) was added to a solution

of alkyne 46 (435 mg, 1.35 mmol) in n-pentane (14 mL) at 0 °C. After

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with brine (15 mL) and dried over anhydrous Na₂SO₄. Filtration and

evaporation in vacuo furnished the crude product (133 mg), which was

puriﬁed by ﬂash column chromatography (silica gel 10 g, 10:1 n-

hexane/AcOEt) to give ketone 51 (36.9 mg, 71% for three steps) as a

pale-yellow oil. R_f0.33 (5:1 n-hexane/AcOEt); [α]²_D⁷−65.3 (c 0.95,

The combined organic extracts were washed with brine (20 mL) and

dried over anhydrous Na₂SO₄. Filtration and evaporation in vacuo

furnished the crude product (15.1 mg), which was puriﬁed by column

chromatography (silica gel 10 g, 2:3 n-hexane/AcOEt) to give alcohol

54 (10.0 mg, 90%) as a colorless oil. R_f0.50 (1:1 n-hexane/AcOEt);

[α]²_D⁴−54.9 (c 0.48, CHCl₃); IR (neat) 3493, 3024, 2955, 2878, 1755,

1732, 1458, 1437, 1339, 1321, 1290, 1248, 1109, 1090, 1057 cm⁻¹; ¹H

NMR (500 MHz, CDCl₃) δ 0.94 (d, J = 7.0 Hz, 3H), 1.20 (m, 1H),

1.25 (s, 3H), 1.57 (dd, J = 4.3, 11.7 Hz, 1H), 1.64 (dt, J = 5.3, 11.8 Hz,

1H), 1.78 (br, 1H), 1.84 (dd, J = 8.4, 11.7 Hz, 1H), 1.87 (m, 1H),

1.89−1.99 (m, 2H), 2.73 (ddq, J = 4.3, 8.4, 7.0 Hz, 1H), 3.72 (d, J =

12.2 Hz, 1H), 3.78 (s, 3H), 3.95 (d, J = 12.2 Hz, 1H), 5.56 (d, J = 10.0

Hz, 1H), 5.90 (m, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 18.7 (CH₃),

20.58 (CH₃), 20.60 (CH₂), 28.9 (CH₂), 34.8 (CH), 41.9 (CH₂), 46.8

(C), 51.5 (CH₃), 52.0 (CH), 62.4 (CH₂), 87.8 (C), 94.0 (C), 123.9

(CH), 129.2 (CH), 170.6 (C); HRMS (ESI) m/z [M + Na]⁺calcd for

C₁₅H₂₂O₄Na 289.1416; found 289.1434.

1

CHCl₃); IR (neat) 2951, 1737, 1714, 1462, 1437, 1250 cm⁻¹; H

NMR (500 MHz, CDCl₃) δ 0.11 (s, 9H), 0.87 (d, J = 6.7 Hz, 3H),

0.94 (s, 3H), 1.07 (ddd, J = 3.9, 7.7, 13.9 Hz, 1H), 1.28−1.36 (m, 2H),

1.41 (m, 1H), 1.53 (m, 1H), 1.67 (m, 1H), 1.75 (ddd, J = 3.9, 8.7, 13.9

Hz, 1H), 1.94 (m, 1H), 2.17 (dd, J = 5.5, 15.7 Hz, 1H), 2.17 (m, 1H),

2.26 (dd, J = 11.1, 15.7 Hz, 1H), 2.62 (ddq, J = 5.5, 11.1, 6.7 Hz, 1H),

3.68 (s, 3H); ¹³C NMR (125.7 MHz, CDCl₃) δ 2.6 (CH₃), 17.7

(CH₃), 21.7 (CH₂), 23.1 (CH₂), 24.5 (CH₂), 26.3 (CH₃), 32.2 (CH₂),

35.2 (CH), 43.1 (CH₂), 43.4 (C), 51.5 (CH₃), 55.4 (CH), 86.5 (C),

173.5 (C), 213.3 (C); HRMS (EI) m/z [M]⁺calcd for C₁₇H₃₀O₄Si

326.1913; found 326.1909.

Methyl (1S,4R,5R,6S)-4,6-Dimethyl-2-oxo-5-(trimethylsilyl)-

oxybicyclo[4.4.0]decane-5-carboxylate (52). A 2.0 M solution

of NaOMe in MeOH (0.01 mL, 0.02 mmol) was added to a solution

of cis-decalone 51 (30.1 mg, 92.2 μmol) in THF (1.9 mL) at 0 °C.

After 30 min of stirring, the reaction was quenched with saturated

aqueous NH₄Cl (5 mL), and the resulting mixture was extracted with

AcOEt (2 × 30 mL). The combined organic extracts were washed with

brine (5 mL) and dried over anhydrous Na₂SO₄. Filtration and

evaporation in vacuo furnished the crude product (34.8 mg), which

was puriﬁed by column chromatography (silica gel 10 g, 10:1 n-

hexane/AcOEt) to give trans-decalone 52 (25.4 mg, 85%) as a pale-

yellow solid. R_f0.42 (5:1 n-hexane/AcOEt); mp 88−89 °C (colorless

prisms from MeOH); [α]²_D⁷−25.2 (c 1.15, CHCl₃); IR (neat) 2951,

1738, 1713, 1462, 1252 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.22 (s,

9H), 0.85 (d, J = 6.5 Hz, 3H), 0.90 (s, 3H), 0.98 (m, 1H), 1.08 (tq, J =

4.0, 13.3 Hz, 1H), 1.31 (tq, J = 3.9, 13.5 Hz, 1H), 1.40 (dq, J = 3.7,

13.5 Hz, 1H), 1.53 (m, 1H), 1.67 (m, 1H), 1.72−1.78 (m, 2H), 2.15

(dd, J = 5.3, 14.0 Hz, 1H), 2.21 (dd, J = 12.6, 14.0 Hz, 1H), 2.72 (ddq,

J = 5.3, 12.6, 6.5 Hz, 1H), 2.76 (dd, J = 3.7, 12.6 Hz, 1H), 3.74 (s,

3H); ¹³C NMR (125.7 MHz, CDCl₃) δ 2.7 (CH₃), 15.6 (CH₃), 17.7

(CH₃), 20.3 (CH₂), 21.2 (CH₂), 24.8 (CH₂), 32.4 (CH₂), 35.9 (CH),

45.2 (CH₂), 46.6 (C), 50.0 (CH), 51.6 (CH₃), 86.0 (C), 173.0 (C),

211.8 (C); HRMS (EI) m/z [M]⁺calcd for C₁₇H₃₀O₄Si 326.1913;

found 326.1919.

Methyl (1R,2R,4R,5R,6S)-4,6-Dimethyl-5-(trimethylsilyl)-

oxyspiro[bicyclo[4.4.0]dec-9-en-2,2′-oxirane]-5-carboxylate

(53). m-CPBA (ca. 70%, 7.6 mg, ca. 31.0 μmol) was added to a

solution of 1,4-diene 47 (10.0 mg, 31.0 μmol) in CH₂Cl₂(1.0 mL) at

0 °C. After 3 h of stirring, the reaction was quenched with a mixture of

1 M aqueous Na₂S₂O₃(3 mL) and saturated aqueous NaHCO₃(3

mL), and the resulting mixture was extracted with AcOEt (2 × 30

mL). The combined organic extracts were washed with brine (6 mL)

and dried over anhydrous Na₂SO₄. Filtration and evaporation in vacuo

furnished the crude product (12.7 mg), which was puriﬁed by column

chromatography (silica gel 5 g, 20:1 n-hexane/AcOEt) to give epoxide

53 (9.1 mg, 87%) as a white amorphous solid. R_f0.38 (10:1 n-hexane/

AcOEt); [α]²_D⁷−119.6 (c 1.34, CHCl₃); IR (neat) 3021, 2953, 2884,

2843, 1738, 1647, 1458, 1435, 1248 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ 0.11 (s, 9H), 0.89 (s, 3H), 0.95 (d, J = 6.6 Hz, 3H), 1.29

(dd, J = 9.7, 13.6 Hz, 1H), 1.34 (m, 1H), 1.72 (dt, J = 5.6, 12.0 Hz,

1H), 1.90 (m, 1H), 2.06 (dd, J = 7.6, 13.6 Hz, 1H), 2.09 (m, 1H), 2.26

(m, 1H), 2.46 (ddq, J = 7.6, 9.7, 6.6 Hz, 1H), 2.48 (d, J = 5.1 Hz, 1H),

2.80 (d, J = 5.1 Hz, 1H), 3.73 (s, 3H), 5.42 (dddd, J = 1.3, 2.6, 4.2,

10.1 Hz, 1H), 5.77 (m, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 2.2

(CH₃), 17.4 (CH₃), 22.6 (CH₂), 23.0 (CH₃), 25.6 (CH₂), 32.4 (CH),

37.1 (CH₂), 41.9 (C), 43.7 (CH), 51.1 (CH₃), 54.0 (CH₂), 58.6 (C),

86.1 (C), 124.4 (CH), 128.8 (CH), 173.4 (C); HRMS (EI) m/z [M]⁺

calcd for C₁₈H₃₀O₄Si 338.1913; found 338.1910.

Methyl (1S,2R,3R,6S)-2-Hydroxy-1,3-dimethyl-5-

methylenebicyclo[4.4.0]dec-7-ene-2-carboxylate (55). Bu₄NF

in THF (1.0 M, 0.15 mL, 0.15 mmol) was added to a solution of

TMS ether 47 (22.8 mg, 0.071 mmol) in THF (1 mL) at 0 °C. After 2

h of stirring, the mixture was partitioned between AcOEt (30 mL) and

H₂O (5 mL), and the aqueous layer was extracted with AcOEt (30

mL). The combined organic extracts were washed with brine (5 mL)

and dried over anhydrous Na₂SO₄. Filtration and evaporation in vacuo

furnished the crude product (23.9 mg), which was puriﬁed by column

chromatography (silica gel 5 g, 10:1 n-hexane/AcOEt) to give tertiary

alcohol 55 (17.7 mg, 99%) as a colorless oil. R_f0.41 (5:1 n-hexane/

AcOEt); [α]²_D³−164.7 (c 0.53, CHCl₃); IR (neat) 3536, 2936, 1721,

1458, 1375, 1252, 1234 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.88 (d,

J = 6.3 Hz, 3H), 0.95 (s, 3H), 1.36 (dt, J = 6.8, 13.6 Hz, 1H), 1.79 (dt,

J = 6.4, 13.6 Hz, 1H), 2.02 (m, 1H), 2.11 (m, 1H), 2.27−2.36 (m,

3H), 2.63 (m, 1H), 3.15 (s, 1H), 3.79 (s, 3H), 4.73 (s, 1H), 4.85 (s,

1H), 5.35 (m, 1H), 5.83 (ddd, J = 3.2, 6.3, 9.8 Hz, 1H); ¹³C NMR

(125.7 MHz, CDCl₃) δ 15.9 (CH₃), 24.2 (CH₂), 25.0 (CH₃), 28.2

(CH₂), 34.3 (CH), 36.7 (CH₂), 39.8 (C), 48.8 (CH), 52.0 (CH₃),

83.3 (C), 110.1 (CH₂), 128.1 (CH), 128.8 (CH), 148.2 (C), 175.6

(C); HRMS (ESI) m/z [M + Na]⁺calcd for C₁₅H₂₂O₃Na 273.1467;

found 273.1452.

Methyl (1S,2R,3R,6S)-2-(tert-Butoxycarbonyl)oxy-1,3-di-

methyl-5-methylenebicyclo[4.4.0]dec-7-ene-2-carboxylate

(56). KHMDS in toluene (0.5 M, 1.10 mL, 0.55 mmol) was added to a

solution of tertiary alcohol 55 (70.9 mg, 0.283 mmol) in THF (2 mL)

at −78 °C. After 30 min of stirring, di-tert-butyl dicarbonate (185 mg,

0.85 mmol) in THF (1 mL) was added, and the mixture was stirred at

0 °C for 30 min. The reaction was quenched with saturated aqueous

NH₄Cl (15 mL), and the resulting mixture was extracted with AcOEt

(2 × 50 mL). The combined organic extracts were washed with brine

(15 mL) and dried over anhydrous Na₂SO₄. Filtration and evaporation

in vacuo furnished the crude product (291 mg), which was puriﬁed by

column chromatography (silica gel 30 g, 15:1 n-hexane/AcOEt) to

give carbonate 56 (95.5 mg, 96%) as a colorless oil. R_f0.40 (10:1 n-

hexane/AcOEt); [α]²_D⁸−98.8 (c 1.13, CHCl₃); IR (neat) 2978, 1740,

1

1458, 1369, 1290, 1257, 1163 cm⁻¹; H NMR (500 MHz, CDCl₃) δ

0.92 (s, 3H), 0.99 (d, J = 7.2 Hz, 3H), 1.47 (s, 9H), 1.66−1.75 (m,

2H), 1.94−2.03 (m, 2H), 2.08 (dd, J = 4.1, 13.8 Hz, 1H), 2.69 (d, J =

4.0 Hz, 1H), 3.02 (ddq, J = 4.1, 5.2, 7.2 Hz, 1H), 3.11 (dd, J = 5.2, 13.8

Hz, 1H), 3.72 (s, 3H), 4.77 (s, 1H), 4.89 (s, 1H), 5.56 (m, 1H), 5.74

(m, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 17.1 (CH₃), 20.6 (CH₃),

23.6 (CH₂), 24.4 (CH₂), 27.7 (CH₃), 34.1(CH), 39.2 (CH₂), 41.9

(C), 46.3 (CH), 51.4 (CH₃), 81.6 (C), 88.4 (C), 112.3 (CH₂), 126.8

(CH), 127.0 (CH), 146.3 (C), 152.4 (C), 171.9 (C); HRMS (ESI) m/

z [M + K]⁺calcd for C₂₀H₃₀O₅K 389.1730; found 389.1748.

Methyl (1R,2R,4R,5R,6S)-5-(tert-Butoxycarbonyl)oxy-4,6-

dimethylspiro[bicyclo[4.4.0]dec-9-en-2,2′-oxirane]-5-carboxy-

late (57). m-CPBA (ca. 70%, 60.0 mg, ca. 0.243 mmol) was added to a

solution of 1,4-diene 56 (84.6 mg, 0.241 mmol) in CH₂Cl₂(12 mL) at

−40 °C. After 40 h of stirring at −20 °C, the reaction was quenched

with a mixture of 1 M aqueous Na₂S₂O₃(10 mL) and saturated

aqueous NaHCO₃(10 mL), and the resulting mixture was extracted

Methyl (1R,2S,7R,8S,10R)-8-(Hydroxymethyl)-2,10-dimethyl-

11-oxatricyclo[6.2.1.0^2,7]undec-5-ene-1-carboxylate (54). A sol-

ution of epoxide 53 (14.1 mg, 41.9 μmol) in DMSO/4 M aqueous

NaOH (5:2, 0.7 mL) was heated at 80 °C for 2 h. After cooling, the

reaction mixture was partitioned between AcOEt (20 mL) and H₂O

(20 mL), and the aqueous layer was extracted with AcOEt (20 mL).

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with AcOEt (2 × 50 mL). The combined organic extracts were washed

with brine (20 mL) and dried over anhydrous Na₂SO₄. Filtration and

evaporation in vacuo furnished the crude product (120 mg), which was

puriﬁed by column chromatography (silica gel 15 g, 20:1 → 10:1 →

5:1 n-hexane/AcOEt) to give a mixture of epoxides 57 and 58 (44.4

mg, 50%, 57:58 = 5.4:1) as a colorless oil along with recovered diene

56 (27.1 mg, 32%, colorless oil) and bis-epoxide (11.1 mg, 12%, white

solid).

CHCl₃); [α]²_D⁴−66.0 (c 1.20, CHCl₃); IR (neat) 3462, 2926, 1738,

1

1458, 1250, 1113, 1090, 1049 cm⁻¹; H NMR (500 MHz, CDCl₃) δ

1.06 (s, 3H), 1.14 (d, J = 6.7 Hz, 3H), 1.62 (m, 1H), 1.69 (ddd, J =

5.4, 10.2, 13.8 Hz, 1H), 1.80 (dd, J = 8.1, 15.8 Hz, 1H), 1.98−2.04 (m,

2H), 2.15 (m, 1H), 2.23 (m, 1H), 2.43 (dd, J = 9.8, 15.8 Hz, 1H), 2.70

(ddq, J = 8.1, 9.8, 6.7 Hz, 1H), 3.61 (dd, J = 7.0, 11.1 Hz, 1H), 3.73

(dd, J = 3.6, 11.1 Hz, 1H), 3.81 (s, 3H), 5.59 (m, 1H), 6.02 (m, 1H);

¹³C NMR (125.7 MHz, CDCl₃) δ 16.9 (CH₃), 21.5 (CH₂), 24.5

This sequence was repeated, employing recovered 56 (27.1 mg,

77.3 μmol), m-CPBA (ca. 70%, 19.1 mg, ca. 77.5 μmol), and CH₂Cl₂

(4 mL). The crude product (35.6 mg) was puriﬁed by column

chromatography (silica gel 5 g, 20:1 → 10:1 → 5:1 n-hexane/AcOEt)

to give a mixture of epoxides 57 and 58 (16.5 mg, 58%, 57:58 = 5.4:1)

as a colorless oil along with recovered diene 56 (9.7 mg, 32%, colorless

oil) and bis-epoxide (2.5 mg, 9%, white solid). Separation of epoxides

57 and 58 by ﬂash column chromatography (silica gel 120 g, CHCl₃)

yielded the desired epoxide 57 (51.3 mg, 58%) as a colorless oil and

58 (9.4 mg, 11%) as a white solid. Data for 57: R_f0.44 (5:1 n-hexane/

AcOEt), 0.24 (CHCl₃); [α]²_D⁵−143.6 (c 1.36, CHCl₃); IR (neat) 2978,

2949, 1748, 1458, 1292, 1258, 1161 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ 0.96 (s, 3H), 1.16 (d, J = 7.0 Hz, 3H), 1.46 (s, 9H), 1.47 (br,

1H), 1.67 (m, 1H), 1.99−2.00 (m, 2H), 2.19−2.32 (br, 3H), 2.59 (d, J

= 5.0 Hz, 1H), 2.87 (d, J = 5.0 Hz, 1H), 2.97 (m, 1H), 3.75 (s, 3H),

5.45 (m, 1H), 5.77 (d, J = 10.0 Hz, 1H); ¹³C NMR (125.7 MHz,

CDCl₃) δ 18.2 (CH₃), 23.6 (CH₂), 27.7 (CH₃), 33.4 (CH), 36.5 (C),

51.4 (CH₃), 52.7 (C), 81.7 (C), 88.2 (C), 124.4 (CH), 129.2 (CH),

152.4 (C), 170.5 (C), other peaks too broad to detect; HRMS (ESI)

m/z [M + Na]⁺calcd for C₂₀H₃₀O₆Na 389.1940; found 389.1938.

Data for methyl (1S,2R,3R,6S,7S,8R)-2-(tert-butoxycarbonyl)oxy-

7,8-epoxy-1,3-dimethyl-5-methylenebicyclo[4.4.0]decane-2-carboxy-

late (58): R_f0.44 (5:1 n-hexane/AcOEt), 0.34 (CHCl₃); [α]²_D⁵−60.8

(c 0.38, CHCl₃); IR (neat) 2982, 2955, 1748, 1456, 1283, 1258, 1140

(CH₃), 26.7 (CH₂), 30.5 (CH), 37.5 (CH₂), 39.9 (C), 44.2 (CH),

52.5 (CH₃), 66.4 (CH₂), 84.9 (C), 92.8 (C), 121.3 (CH), 130.8 (CH),

149.5 (C), 168.3 (C); HRMS (EI) m/z [M + Na]⁺calcd for

C₁₆H₂₂O₆Na 333.1314; found 333.1328.

Methyl (1S,2R,3R,5S,6R)-2,5-Dihydroxy-5-(hydroxymethyl)-

1,3-dimethylbicyclo[4.4.0]dec-7-ene-2-carboxylate (60). A 0.9

M solution of NaOMe in MeOH (0.76 mL, 0.69 mmol) was added to

a solution of cyclic carbonate 59 (43.0 mg, 139 μmol) in MeOH (1.4

mL) at 0 °C. After 5 h of stirring at room temperature, the reaction

was quenched with saturated aqueous NH₄Cl (10 mL), and the

resulting mixture was extracted with AcOEt (2 × 40 mL). The

combined organic extracts were washed with brine (30 mL) and dried

over anhydrous Na₂SO₄. Filtration and evaporation in vacuo furnished

the crude product (39.0 mg), which was puriﬁed by column

chromatography (silica gel 15 g, 1:2 n-hexane/AcOEt) to give triol

60 (36.9 mg, 93%) as a white solid. R_f0.42 (1:2 n-hexane/AcOEt); mp

139−140 °C (colorless needles from 3:1 n-hexane/CHCl₃); [α]_D²⁷

−185.8 (c 0.96, CHCl₃); IR (neat) 3397, 3024, 2930, 1719, 1437,

1

1250, 1026 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 0.90 (s, 3H), 0.96

(d, J = 6.4 Hz, 3H), 1.28 (dd, J = 5.0, 12.4 Hz, 1H), 1.47 (dd, J = 10.5,

15.0 Hz, 1H), 1.84 (m, 1H), 1.93−1.98 (m, 2H), 2.06 (dt, J = 12.4, 5.3

Hz, 1H), 2.13 (dd, J = 8.6, 15.0 Hz, 1H), 2.15 (m, 1H), 2.25 (ddq, J =

8.6, 10.5, 6.4 Hz, 1H), 3.47 (dd, J = 4.4, 10.5 Hz, 1H), 3.60 (d, J = 10.5

Hz, 1H), 3.80 (s, 3H), 3.88 (s, 1H), 4.45 (s, 1H), 5.65 (m, 1H), 5.91

(m, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 16.3 (CH₃), 21.9 (CH₂),

23.9 (CH₃), 25.3 (CH₂), 29.6 (CH), 39.8 (C), 40.6 (CH₂), 45.5

(CH), 52.2 (CH₃), 69.3 (CH₂), 73.1 (C), 82.5 (C), 124.3 (CH), 128.8

(CH), 175.1 (C); HRMS (ESI) m/z [M + Na]⁺calcd for C₁₅H₂₄O₅Na

307.1521; found 307.1507.

1

cm⁻¹; H NMR (500 MHz, CDCl₃) δ 0.80 (s, 3H), 1.03 (d, J = 6.7

Hz, 3H), 1.15 (dt, J = 6.8, 14.2 Hz, 1H), 1.45 (s, 9H), 1.89 (m, 2H),

2.12 (dd, J = 3.9, 13.9 Hz, 1H), 2.18−2.25 (m, 2H), 2.27 (s, 1H), 2.45

(m, 1H), 2.99 (d, J = 4.0 Hz, 1H), 3.26 (m, 1H), 3.76 (s, 3H), 4.88 (s,

2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 18.9 (CH₃), 23.1 (CH₂), 26.0

(CH₃), 27.7 (CH₃), 30.8 (CH₂), 36.0 (CH), 37.0 (CH₂), 38.2 (C),

51.5 (CH₃), 52.6 (CH), 54.7 (CH), 56.8 (CH), 81.8 (C), 88.8 (C),

111.8 (CH₂), 145.6 (C), 151.6 (C), 168.9 (C); HRMS (ESI) m/z [M

+ Na]⁺calcd for C₂₀H₃₀O₆Na 389.1940; found 389.1940.

Data for methyl (1S,2R,4R,5R,6S,9R,10S)-5-(tert-butoxycarbonyl)-

oxy-9,10-epoxy-4,6-dimethylspiro[bicyclo[4.4.0]decan-2,2′-oxirane]-5-

carboxylate (bis-epoxide): R_f0.18 (5:1 n-hexane/AcOEt); mp 140−

141 °C (colorless prisms from n-hexane); [α]²_D⁵−77.9 (c 0.80,

CHCl₃); IR (neat) 2982, 2955, 1746, 1458, 1285, 1261, 1144 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ 1.00 (s, 3H), 1.04 (d, J = 6.7 Hz, 3H),

1.09 (dq, J = 14.5, 1.5 Hz, 1H), 1.14 (m, 1H), 1.33 (m, 1H), 1.46 (s,

9H), 1.84 (m, 1H), 1.89 (m, 1H), 2.10 (t, J = 14.5 Hz, 1H), 2.23 (m,

1H), 2.69 (d, J = 4.5 Hz, 1H), 2.78 (m, 1H), 2.82 (d, J = 4.5 Hz, 1H),

3.09 (d, J = 4.2 Hz, 1H), 3.28 (m, 1H), 3.78 (s, 3H); ¹³C NMR (125.7

MHz, CDCl₃) δ 18.8 (CH₃), 22.7 (CH₂), 26.2 (CH₃), 27.7 (CH₃),

30.7 (CH₂), 33.0 (CH), 35.0 (CH₂), 38.4 (C), 50.3 (CH), 50.6

(CH₂), 51.6 (CH₃), 54.3 (CH), 54.5 (CH), 58.5 (C), 81.9 (C), 88.6

(C), 151.5 (C), 168.6 (C); HRMS (ESI) m/z [M + Na]⁺calcd for

C₂₀H₃₀O₇Na 405.1889; found 405.1873.

Methyl (1R,2S,7R,8S,12R)-8-(Hydroxymethyl)-2,12-dimethyl-

10-oxo-9,11-dioxatricyclo[6.3.2.0^2,7]tridec-5-ene-1-carboxylate

(59). A 0.2 M solution of BF₃·OEt₂in CH₂Cl₂(0.20 mL, 40.0 μmol)

was added to a solution of epoxide 57 (11.9 mg, 32.5 μmol) in CH₂Cl₂

(0.7 mL) at −78 °C. After 30 min of stirring at −60 °C, the reaction

was quenched with Et₃N (10 μL), and the resulting mixture was

partitioned between AcOEt (40 mL) and saturated aqueous NaHCO₃

(15 mL). The aqueous layer was extracted with AcOEt (40 mL), and

the combined organic extracts were washed with brine (15 mL) and

dried over anhydrous Na₂SO₄. Filtration and evaporation in vacuo

furnished the crude product (12.1 mg), which was puriﬁed by column

chromatography (silica gel 5 g, 1:1 n-hexane/AcOEt) to give cyclic

carbonate 59 (7.5 mg, 74%) as a white solid. R_f0.45 (1:2 n-hexane/

AcOEt); mp 124−125 °C (colorless prisms from 3:1 n-hexane/

Methyl (1S,2R,5R,6R)-2-Hydroxy-1,3-dimethyl-5-oxobicyclo-

[4.4.0]dec-7-ene-2-carboxylate (61). Pb(OAc)₄(14.8 mg, 33.4

μmol) was added to a solution of triol 60 (7.9 mg, 27.8 μmol) in

CH₂Cl₂(0.6 mL) at 0 °C. After 5 min of stirring, the reaction was

quenched with saturated aqueous NaHCO₃(10 mL), and the resulting

mixture was extracted with AcOEt (2 × 30 mL). The combined

organic extracts were washed with brine (10 mL) and dried over

anhydrous Na₂SO₄. Filtration and evaporation in vacuo furnished the

crude product (11.6 mg), which was puriﬁed by column chromatog-

raphy (Wako gel 5 g, 3:1 n-hexane/AcOEt) to give ketone 61 (6.6 mg,

94%) as a white solid. R_f0.41 (2:1 n-hexane/AcOEt); mp 144−146 °C

(colorless needles from 20:1 n-hexane/CHCl₃); [α]²_D⁵−268.7 (c 0.87,

CHCl₃); IR (neat) 3391, 2930, 2855, 1717, 1433, 1265, 1163, 1045

1

cm⁻¹; H NMR (500 MHz, CDCl₃) δ 1.00 (d, J = 6.5 Hz, 3H), 1.11

(s, 3H), 1.25 (ddd, J = 3.1, 5.0, 12.8 Hz, 1H), 1.75 (ddd, J = 5.4, 11.5,

12.8 Hz, 1H), 1.97 (m, 1H), 2.14 (m, 1H), 2.22 (dd, J = 10.8, 17.4 Hz,

1H), 2.45 (dd, J = 7.3, 17.4 Hz, 1H), 2.78 (m, 1H), 2.83 (ddq, J = 7.3,

10.8, 6.5 Hz, 1H), 3.09 (s, 1H), 3.83 (s, 3H), 5.64 (m, 1H), 5.94 (m,

1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 15.7 (CH₃), 22.1 (CH₂), 24.0

(CH₃), 26.0 (CH₂), 32.2 (CH), 43.6 (C), 43.7 (CH₂), 52.3 (CH₃),

53.9 (CH), 81.4 (C), 122.6 (CH), 128.8 (CH), 174.8 (C), 210.7 (C);

HRMS (ESI) m/z [M + Na]⁺calcd for C₁₄H₂₀O₄Na 275.1259; found

275.1265.

Methyl (1R,2S,7R,8R,10R)-8-(tert-Butyldimethylsilyl)oxy-

2,10-dimethyl-11-oxatricyclo[6.2.1.0^2,7]undec-5-ene-1-carbox-

ylate (62). To a cooled solution (−78 °C) of hydroxy ketone 61 (3.4

mg, 13.5 μmol) in CH₂Cl₂(1 mL) was added Et₃N (10 μL, 72 μmol)

followed by a 0.5 M solution of TBSOTf in CH₂Cl₂(60 μL, 30 μmol).

After 15 min of stirring at 0 °C, the reaction was quenched with

saturated aqueous NaHCO₃(10 mL), and the resulting mixture was

extracted with AcOEt (2 × 30 mL). The combined organic extracts

were washed with brine (10 mL) and dried over anhydrous Na₂SO₄.

Filtration and evaporation in vacuo furnished the crude product (6.8

733

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mg), which was puriﬁed by ﬂash column chromatography (silica gel 3

g, 30:1 n-hexane/AcOEt) to give lactol TBS ether 62 (4.6 mg, 94%) as

a colorless oil. R_f0.50 (5:1 n-hexane/AcOEt); [α]²_D³−67.7 (c 1.07,

CHCl₃); IR (neat) 3032, 2953, 2930, 2857, 1763, 1732, 1462, 1335,

1298, 1107, 1069, 920, 833 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.17

(s, 3H), 0.18 (s, 3H), 0.91 (s, 9H), 0.95 (d, J = 6.9 Hz, 3H), 1.18 (m,

1H), 1.21 (s, 3H), 1.28 (dd, J = 4.4, 11.7 Hz, 1H), 1.59 (m, 1H),

1.81−1.88 (m, 2H), 1.94 (m, 1H), 2.08 (dd, J = 8.3, 11.7 Hz, 1H),

2.61 (ddq, J = 4.4, 8.3, 6.9 Hz, 1H), 3.73 (s, 3H), 5.73 (d, J = 10.3 Hz,

1H), 5.90 (m, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ −3.2 (CH₃),

−3.0 (CH₃), 18.1 (C), 19.0 (CH₃), 20.6 (CH₂), 21.2 (CH₃), 25.9

(CH₃), 29.6 (CH₂), 34.7 (CH), 46.40 (CH), 46.43 (CH₂), 51.2

(CH₃), 52.9 (C), 88.7 (C), 107.6 (C), 125.7 (CH), 128.0 (CH), 170.6

(C); HRMS (ESI) m/z [M + Na]⁺calcd for C₂₀H₃₄O₄SiNa 389.2124;

found 389.2117.

(11) Rigano, D.; Aviello, G.; Bruno, M.; Formisano, C.; Rosselli, S.;

Capasso, R.; Senatore, F.; Izzo, A. A.; Borrelli, F. J. Nat. Prod. 2009, 72,

1477−1481.

(12) Moon, H.-I. Phytother. Res. 2010, 24, 1256−1259.

(13) For examples, see: (a) Corey, E. J.; Das, J. J. Am. Chem. Soc.

1982, 104, 5551−5553. (b) Corey, E. J.; Da Silva Jardine, P.; Rohloff,

J. C. J. Am. Chem. Soc. 1988, 110, 3672−3673. (c) Perez-Medrano, A.;

Grieco, P. A. J. Am. Chem. Soc. 1991, 113, 1057−1059. (d) Paquette, L.

A.; Wang, H.-L. J. Org. Chem. 1996, 61, 5352−5357. (e) Yu, W.; Jin, Z.

J. Am. Chem. Soc. 2002, 124, 6576−6583. (f) Shi, B.; Tang, P.; Hu, X.;

Liu, J. O.; Yu, B. J. Org. Chem. 2005, 70, 10354−10367. (g) Tapia, R.;

Cano, M. J.; Bouanou, H.; Alvarez, E.; Alvarez-Manzaneda, R.;

Chahboun, R.; Alvarez-Manzaneda, E. Chem. Commun. 2013, 49,

10257−10259.

(14) For reviews of Ireland−Claisen rearrangements, see: (a) Chai,

Y.; Hong, S.-P.; Lindsay, H. A.; McFarland, C.; McIntosh, M. C.

Tetrahedron 2002, 58, 2905−2928. (b) Ilardi, E. A.; Stivala, C. E.;

Zakarian, A. Chem. Soc. Rev. 2009, 38, 3133−3148.

ASSOCIATED CONTENT

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S

* Supporting Information

(15) For recent examples, see: (a) Srikrishna, A.; Ramesh Babu, R.

Tetrahedron 2008, 64, 10501−10506. (b) Hirai, G.; Watanabe, T.;

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15420−15421.

¹H and ¹³C NMR spectra for all new compounds and X-ray

crystallographic data for iodolactone 39b (CIF). This material

is available free of charge via the Internet at http://pubs.acs.org.

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Chem. Commun. 1983, 499−501. (b) Gilbert, J. C.; Selliah, R. D.

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AUTHOR INFORMATION

■

Corresponding Author

*E-mail: nakamura@phar.nagoya-cu.ac.jp.

Franca̧ is, A.; Haudrechy, A. Synlett 2005, 2313−2316 and references

cited therein. (e) Bunte, J. O.; Cuzzupe, A. N.; Daly, A. M.; Rizzacasa,

M. A. Angew. Chem., Int. Ed. 2006, 45, 6376−6380.

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3572−3582.

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2007, 46, 7466−7469. (b) Gu, Z.; Herrmann, A. T.; Stivala, C. E.;

Zakarian, A. Synlett 2010, 1717−1722.

(19) Yang, Y.; Fu, X.; Chen, J.; Zhai, H. Angew. Chem., Int. Ed. 2012,

51, 9825−9828.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

This research was supported in part by the Japan Society for the

Promotion of Science (Grant-in-Aid for Scientiﬁc Research),

the Uehara Memorial Foundation, and the Naito Foundation.

We thank Ms. Toshiko Naito and Ms. Kana Iwasawa of the

Instrument Center, Nagoya City University, and Dr. Shinobu

Aoyagi of the Graduate School of Natural Sciences, Nagoya

City University, for technical assistance in elemental, mass

spectral, and X-ray analyses, respectively. We are grateful to the

Fukuyama group of Nagoya University for the use of their mass

spectrometer.

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̈

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The Journal of Organic Chemistry

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Synthesis of chiral building blocks for oxygenated terpenoids through a simultaneous and stereocontrolled construction of contiguous quaternary stereocenters by an ireland-claisen rearrangement

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