Stereoselective synthesis of 2,6- cis -substituted tetrahydropyrans: Bronsted acid-catalyzed intramolecular oxa-conjugate cyclization of α,β-unsaturated ester surrogates

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Stereoselective Synthesis of 2,6-Cis-Substituted Tetrahydropyrans:

Brønsted Acid-Catalyzed Intramolecular Oxa-Conjugate Cyclization

of α,β-Unsaturated Ester Surrogates

Haruhiko Fuwa,* Naoki Ichinokawa, Kenkichi Noto, and Makoto Sasaki

Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan

S

* Supporting Information

ABSTRACT: Intramolecular oxa-conjugate cyclization (IOCC) of α,β-unsaturated

carbonyl compounds, triggered by deprotonation with a base, represents a

straightforward method for the synthesis of tetrahydropyrans. However, it has been

known that stereochemical outcome of IOCC depends on the local structure of

substrates and sometimes requires harsh reaction conditions and/or prolonged

reaction times for selective formation of 2,6-cis-substituted tetrahydropyrans. These

shortcomings limit the feasibility of IOCC in the context of complex natural product synthesis. In this paper, we describe

Brønsted acid-catalyzed IOCC of α,β-unsaturated ester surrogates (e.g., α,β-unsaturated thioesters, oxazolidinone imides, and

pyrrole amides) under mild reaction conditions, which affords a series of synthetically versatile 2,6-cis-substituted

tetrahydropyran derivatives with good to excellent stereoselectivity (dr from 7:1 to >20:1). These α,β-unsaturated carbonyl

compounds were found to be more reactive than the corresponding oxoesters that are generally unreactive toward Brønsted acid-

catalyzed intramolecular oxa-conjugate additions. The product tetrahydropyrans could be transformed into various derivatives in

an efficient manner, highlighting the usefulness of our methodology.

Scheme 1. Intramolecular Oxa-Conjugate Cyclization of α,β-

Unsaturated Ketones/Esters

INTRODUCTION

■

There are a growing number of tetrahydropyran-containing

marine natural substances that show potent and diverse

biological activities.¹Their importance at the interface of

chemistry and biology is obvious as they serve as intriguing

medicinal leads as well as powerful molecular probes for

dissecting biological phenomena at the molecular level. As such,

significant efforts have been devoted to development of efficient

methodologies and tactics for the synthesis of tetrahydropyran

derivatives.²

A number of methodologies are currently available for

tetrahydropyran synthesis, e.g., intramolecular oxa-conjugate

cyclization (IOCC),³⁻⁷Prins-type reaction,⁸modified Maitland−

Japp reaction,⁹palladium-catalyzed intramolecular alkoxy-

carbonylation,¹⁰and palladium-catalyzed intramolecular S_N2′

cyclization.^11,12Among these, IOCC of α,β-unsaturated

ketones and esters has served as key transformations in a

number of total syntheses of complex natural products and

related compounds due to the synthetic versatility of the

product tetrahydropyrans.^5,6The cyclization proceeds under

basic conditions to provide, in most cases, 2,6-trans-substituted

tetrahydropyrans as the kinetic product, and the corresponding

2,6-cis isomers can be obtained via a base-catalyzed ring-

opening/recyclization sequence (Scheme 1A).^13,14It should be

noted that the majority of tetrahydropyrans found in naturally

occurring substances have 2,6-cis stereochemistry. Nevertheless,

stereoselective formation of 2,6-cis-substituted tetrahydropyrans

is in some cases difficult to achieve even under thermodynamic

conditions.¹⁵It appears that this is particularly true when

α,β-unsaturated esters were employed as substrates, probably

because the α-hydrogens of esters are less acidic than those

of ketones. The difficulty in controlling stereoselectivity limits

the usefulness of IOCC in tetrahydropyran synthesis. A

complementary means to catalyze IOCC is the activation of

Received: October 21, 2011

Published: December 12, 2011

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the conjugate acceptor by acids. It has been known that α,β-

unsaturated ketones also participate in IOCC under acid catalysis

to give 2,6-cis-substituted tetrahydropyrans (Scheme 1B),¹⁶but

intrinsically less reactive α,β-unsaturated esters generally do not

(Scheme 1C).¹⁷

Recent studies on the biosynthesis of several tetrahydropyran-

containing polyketides, such as pederin, ambruticin, bryosta-

tins, jerangolid, and sorangicin, have suggested that the

tetrahydropyrans embedded within the structures of those

natural products would be forged via IOCC of α,β-unsaturated

thioesters.¹⁸Illustrated in Scheme 2 is the postulated

conditions. In this paper, we detail our investigations into

Brønsted acid-catalyzed IOCC of α,β-unsaturated ester

surrogates for stereoselective synthesis of 2,6-cis-substituted

tetrahydropyrans.

RESULTS AND DISCUSSION

■

Brønsted Acid-Catalyzed IOCC of α,β-Unsaturated

Thioesters. To probe the reactivity of α,β-unsaturated

thioesters toward IOCC under acid catalysis, we first prepared

a series of thioesters from olefin ( )-1 via an olefin cross-

metathesis (CM) reaction,²²as reported by Feringa and co-

workers²³(Table 1). Thus, olefin ( )-1, prepared from 3-(4-

methoxybenzyloxy)propanal (4-pentenylmagnesium bromide,

THF, 0 °C, 78%), was coupled with an appropriate thioacrylate

by the action of the second-generation Hoveyda−Grubbs

catalyst (HG-II)²⁴in CH₂Cl₂at 35 °C, giving rise to α,β-

unsaturated thioesters 2a−f in good yields with high E/Z

Scheme 2. Proposed Biosynthesis of 2,6-Substituted

Tetrahydropyrans of Polyketide Natural Products

1

selectivity (E/Z > 20:1 by 600 MHz H NMR analysis).

We next examined IOCC of α,β-unsaturated thioesters 2a-f

(Table 1). Our preliminary experiments on IOCC of α,β-

unsaturated S-ethyl thioester ( )-2a in the presence of various

acids showed that Brønsted acids including p-TsOH·H₂O,

(+)-10-camphorsulfonic acid (CSA), CH₃SO₃H, and

CF₃CO₂H promoted the cyclization and that CSA was found

to be the acid of choice. On the other hand, Lewis acids, such as

MgBr₂, InCl₃, Sc(OTf)₃, Zn(OTf)₂, Cu(OTf)₂, and Yb(OTf)₃,

are uniformly ineffective and resulted only in no reaction or

material decomposition.²⁵Accordingly, IOCC of α,β-unsatu-

rated thioesters 2b-f was examined by using CSA as a catalyst.

In all cases, the cyclization had to be performed at room

temperature and stopped before reaching to completion due to

partial cleavage of the MPM ether as a side reaction.

Nonetheless, information on the reactivity of α,β-unsaturated

thioesters could be sufficiently gathered. Clearly, S-ethyl

thioester ( )-2a (entry 1) was less reactive than S-aryl

thioesters 2b-f (entries 2−6). In addition, the presence of an

electron-donating substituent at the para position of the

benzene ring was beneficial for increasing the reactivity (entries

3 and 4), while p-nitro group was obviously detrimental (entry 5).

For each product, the stereochemistry was determined on the

basis of an NOE enhancement observed between two axial

hydrogen atoms flanking the ether oxygen atom. Since ( )-2c

displayed the highest reactivity among others, further investiga-

tions were carried out using S-(p-tolyl) thioesters.

biosynthetic formation of the bryostatin tetrahydropyran ring,

according to Haygood and co-workers.^18bThey proposed that

the tetrahydropyran ring would be formed during polyketide

synthesis via IOCC of the intermediary acyl carrier protein

(ACP)-bounded α,β-unsaturated thioester by the action of

“pyran synthase”. It seems that the cyclization would be

facilitated by the activation of the carbonyl group of the α,β-

unsaturated thioester, presumably through hydrogen bonding-

(s). We thought that the feasibility of the biosynthetic

formation of tetrahydropyrans would be, at least in part, due

to the enhanced reactivity of α,β-unsaturated thioesters.¹⁹

Inspired by the biosynthetic proposal, we have recently

reported on IOCC of α,β-unsaturated thioesters under

Brønsted acid catalysis, which gives access to 2,6-cis-sub-

stituted tetrahydropyrans with high stereocontrol (Scheme 3;

To probe the scope of Brønsted acid-catalyzed IOCC, a

variety of olefins were prepared as the precursors of α,β-

unsaturated thioesters (Table 2 and Scheme 4). Olefin ( )-4

was prepared from 3-(tert-butyldiphenylsilyloxy)propanal in

69% yield by reacting with 4-pentenylmagnesium bromide.

Olefins (−)-5, (−)-6, (+)-7, and (+)-8 are the known

compounds.^6e,26The preparation of olefins (+)-9 and (+)-10

started with the known alcohol (+)-11,²⁷which was oxidized

and then reacted with allylmagnesium bromide to give a

separable mixture of homoallylic alcohols (+)-12 and (+)-13,

and these products were individually desilylated to deliver

olefins (+)-9 and (+)-10.

A series of α,β-unsaturated thioesters 14−20 were

synthesized uneventfully by means of CM (Table 2). The

cyclization of ( )-14 proceeded only sluggishly in CH₂Cl₂at

room temperature (78% conversion after 40 h) and gave 2,6-cis-

substituted tetrahydropyran ( )-21 in 66% yield with greater

than 20:1 diastereoselectivity. Gratifyingly, the reaction could

be completed within 30 h by performing in 1,2-dichloroethane

Scheme 3. Brønsted Acid Catalyzed IOCC of α,β-

Unsaturated Thioesters

Tol = p-tolyl).^20,21It is significant that acid-catalyzed IOCC of

α,β-unsaturated thioesters predominantly leads to synthetically

useful 2,6-cis-substituted tetrahydropyrans. Furthermore, the

products can be easily transformed into a variety of derivatives

by exploiting the unique reactivity of the thioester functionality.

However, the acid-catalyzed cyclization under high temperature

conditions is imcompatible with sensitive substrates. To address

the shortcoming of our methodology, we strove to seek for α,β-

unsaturated ester surrogates with sufficiently high reactivity that

enable Brønsted acid-catalyzed IOCC under room temperature

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Table 1. Preparation and IOCC of α,β-Unsaturated Thioesters

a

b

CM

IOCC

c

d

entry

R

yield (%)

time (h)

yield (rsm ) (%)

cis/trans

e

1

Et

( )-2a: 93

( )-2b: 94

( )-2c: 92

( )-2d: 82

( )-2e: 94

( )-2f: 87

21

40

44

45

73

( )-3a: 43 (26)

( )-3b: 56 (41)

( )-3c: 72 (12)

( )-3d: 69 (16)

( )-3e: 29 (65)

15:1

>20:1

2

3

4

5

6

Ph

p-MeC₆H₄

p-MeOC₆H₄

p-NO₂C₆H₄

1-naphthyl

( )-3f: 56 (35)

a

b

CM reactions were performed using HG-II (10 mol %) and thioacrylate (3 equiv) in CH₂Cl₂at 35 °C. IOCCs were performed using CSA (20

mol %) in CH₂Cl₂at room temperature unless otherwise noted and quenched when cleavage of the p-methoxyphenylmethyl (MPM) ether was

c

d

e

observed by TLC analysis. rsm = recovered starting material. Determined by 600 MHz ¹H NMR analysis. IOCC was performed using 70 mol %

of CSA.

(DCE) at 70 °C, giving tetrahydropyran ( )-21 in 88% yield

(entry 1). In a similar manner, IOCC of α,β-unsaturated

thioesters 15−20 was performed by treatment with CSA

(20 mol %) in DCE at 70 °C to provide the respective 2,6-cis-

substituted tetrahydropyrans 22−27 in excellent yields with

high diastereoselectivity (from 14:1 to >20:1) (entries 2−7).

The stereochemistry of the cyclization products was established

temperature (entry 1). This result was not unanticipated because

the low reactivity of simple α,β-unsaturated amides toward

conjugate additions is well documented.²⁹By contrast, imide

( )-28b underwent cyclization to afford 2,6-cis-substituted

tetrahydropyran ( )-29b in 94% yield with moderate diaster-

eoselectivity (dr 8:1, estimated by ¹H NMR analysis), indicating

the importance of the electron-withdrawing carbonyl group

of the pyrrolidine ring (entry 2). A slight improvement of

stereoselectivity was observed upon changing the nitrogen

heterocycle to oxazolidinone (entry 3). Thus, acid treatment of

2-oxazolidinone imide ( )-28c led to tetrahydropyran ( )-29c

in 94% yield with satisfactory diastereoselectivity (dr 13:1).

Cyclization of 2-benzoxazolidinone imide ( )-28d gave

tetrahydropyran ( )-29d in a highly stereoselective manner

(dr >20:1), although the reaction did not complete even after

40 h (entry 4). Indole amide ( )-28e showed good reactivity

toward cyclization and provided tetrahydropyran ( )-29e in

90% yield (93% conversion) after 25 h with 15:1

diastereoselectivity (entry 5). On the other hand, indoline

amide ( )-28f was much less reactive than ( )-28e, giving

tetrahydropyran ( )-29f in 49% yield (62% conversion) after

25 h (entry 6). Finally, we found that the cyclization of 2,5-

dimethylpyrrole amide ( )-28g completed within 24 h at room

temperature to deliver tetrahydropyran ( )-29g in 90% yield as a

single diastereomer (entry 7). In each case, the stereochemistry of

the major diastereomer of the cyclization product was determined

on the basis of NOE enhancement observed between axial protons

flanking the ether oxygen (see the Supporting Information for

details). From the results summarized in Table 3, it seems that the

reactivity of the substrates would be inversely correlated with the

electron-donating ability of the nitrogen lone pair toward the

conjugate acceptor³⁰and that α,β-unsaturated 2-oxazolidinone

imides and 2,5-dimethylpyrrole amides³¹would be suitable

candidates for Brønsted acid-catalyzed IOCC in terms of their

reactivity and stereoselectivity.

3

on the basis of NOE experiments and/or J_H,Hanalysis (see

Supporting Information for details). The cyclization of δ-

substituted α,β-unsaturated thioesters [i.e., (−)-15, (−)-16,

(+)-17, (+)-19, and (−)-20] proceeded more rapidly than that

of unsubstituted ones [i.e., ( )-14 and (+)-18]. It is likely that

the conformation of δ-substituted α,β-unsaturated thioesters

would avoid unfavorable steric repulsions between the bulky δ-

substituent and the carbon chain as much as possible, thereby

bringing the hydroxy group in close proximity to the α,β-

unsaturated thioester group.

As shown above, Brønsted acid-catalyzed IOCC of α,β-

unsaturated thioesters provides synthetically useful 2,6-cis-

substituted tetrahydropyran derivatives in a highly stereo-

selective fashion. However, from a practical point of view, the

cyclization has to be performed under elevated temperature

conditions, making it difficult to apply to acid-sensitive

substrates. To broaden the scope of our methodology, we

strove to investigate additional α,β-unsaturated ester surrogates

that exhibit enhanced reactivity toward IOCC.

Brønsted Acid-Catalyzed IOCC of α,β-Unsaturated

Amides/Imides. Among the possible α,β-unsaturated ester

equivalents, we chose to examine amide and imide derivatives

due to their ready availability and ease of subsequent

transformation.²⁸A variety of α,β-unsaturated amides/imides

28a−g were readily prepared via CM, as summarized in Table 3.

Olefin ( )-4 was coupled with an appropriate acryloyl amide/

imide by the action of HG-II (5−10 mol %) in CH₂Cl₂at 35 °C

to provide 28a−g in good to excellent yields with high E/Z

selectivity (E/Z > 20:1).

To investigate the substrate scope, we synthesized a series of

α,β-unsaturated 2-oxazolidinone imides and 2,5-dimethylpyrrole

amides as summarized in Table 4. CM of olefins 1, 5−7, 9, and

10 with 3-(2-propenoyl)-2-oxazolidinone in the presence of

We next investigated Brønsted acid-catalyzed IOCC of

28a−g (Table 3). Cyclization of amide ( )-28a did not take

place at all in the presence of CSA in CH₂Cl₂at room

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Table 2. Substrate Scope

a

b

CM reactions were performed using HG-II (10 mol %) and thioacrylate (3 equiv) in CH₂Cl₂at 35 °C. IOCCs were performed using CSA (20

c

1

mol %) in DCE at 70 °C. For reaction time, see the Experimental Section. Determined by 600 MHz H NMR analysis.

Scheme 4. Synthesis of Olefins (+)-9 and (+)-10

( )-43 in 86% yield with 14:1 diastereoselectivity (entry 1).

Importantly, the IOCC of the corresponding α,β-unsaturated

thioesters under the same reaction conditions proceeded quite

sluggishly and resulted in lower product yields due to partial cleavage

of the MPM ether as a side reaction (see Table 1). Cyclization of a

series of α,β-unsaturated 2-oxazolidinone imides 31−35 in the

presence of 20 mol % of CSA in CH₂Cl₂at room temperature

completed within reasonable reaction times to provide the

corresponding 2,6-cis-substituted tetrahydropyrans 44−48 in

excellent yields with a synthetically useful level of diastereoselectivity

(dr from 9:1 to >20:1) (entries 2−6). Moreover, α,β-unsaturated

2,5-dimethylpyrrole amides 36−42 underwent clean cyclization

upon exposure to 20 mol % of CSA (CH₂Cl₂, room temperature),

giving rise to 2,6-cis-substituted tetrahydropyrans 49−55, respec-

tively, in high yields (entries 7−13). Most notably, all the products

were isolated as single diastereomers (dr >20:1) except for (−)-52

(entry 10). The olefin geometry of 40, used as a 6:1 mixture of E/Z

isomers, did not affect the diastereoselectivity of the cyclization, since

HG-II afforded the respective α,β-unsaturated 2-oxazolidinone

imides 30−35 in high yields (entries 1−6). In a similar manner,

α,β-unsaturated 2,5-dimethylpyrrole amides 36−42 were

prepared from 1 and 5−10 via CM (entries 7−13), although

their yields were uniformly lower than those of oxazolidinone

derivatives. Next, Brønsted acid-catalyzed cyclization of α,β-

unsaturated 2-oxazolidinone imides was examined (Table 4).

Treatment of ( )-30 with 20 mol % of CSA in CH₂Cl₂at room

temperature for 23 h gave 2,6-cis-substituted tetrahydropyran

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isomers occurred even under the low temperature conditions,

due to the high acidity of the α-hydrogens of pyrrole amides.

Indeed, exposure of (−)-trans-52 to the cyclization conditions

(KOt-Bu, THF, −78 °C) gave an approximately 1:1 mixture of

2,6-cis and 2,6-trans isomers.

Table 3. Preparation and IOCC of α,β-Unsaturated Amides/

Imides

Stereoselectivity of IOCC of (E)-α,β-Unsaturated Ester

Surrogates. It has been known that Brønsted base-catalyzed

IOCC of (E)-α,β-unsaturated esters provides 2,6-trans-substituted

tetrahydropyrans under kinetic conditions.³²On the basis

́

of theoretical and experimental studies, Martın and co-

workers^13b,chave proposed a chelate-controlled model to

account for the selective formation of 2,6-trans isomers.

Schneider and Schuffenhauer have shown that IOCC of (E)-

α,β-unsaturated oxazolidinone imides catalyzed by KOt-Bu

provided 2,6-trans-substituted tetrahydropyrans in a stereo-

selective fashion. Supported by semiempirical molecular orbital

calculations, they reasoned the observed stereoselectivity by a

stereoelectronic effect.^13e,33Coupled with our results summa-

́

rized in Table 5, the Martın’s chelate-controlled transition

structure model would also be viable for understanding the

stereoselectivity of Brønsted base-catalyzed kinetic cyclization

of (E)-α,β-unsaturated ester surrogates (Scheme 5A). Thus, in

transition state B (TS-B), chelation of the potassium cation

between the alkoxide and the conjugate acceptor is well

accommodated, whereas in TS-A, the conjugate acceptor has to

adopt energetically unfavorable s-trans conformation³⁴to

accommodate the chelation.^13cMoreover, according to the

́

theoretical calculations by the Martın and Schneider group-

s,^13c,ethe attack angle ∠(O−C(β)C(α)) of TS-B would be

nearly tetrahedral (the Burgi−Dunitz trajectory) so as to

̈

maximize stabilizing HOMO/LUMO interaction, while the

attack angle of TS-A would be smaller than that of TS-B

(around 100°).³⁵Accordingly, TS-B would be energetically

preferred over TS-A.

a

CM reactions were performed using HG-II (5−10 mol %) in CH₂Cl₂at

b

35 °C. IOCCs were performed using CSA (20 mol %) in CH₂Cl₂at

c

room temperature. Reaction times were not optimized. Determined

d

by 600 MHz ¹H NMR analysis. ( )-28a was recovered in 92% yield.

Houk and Strozier have shown that protonation of acrolein

results in significant changes in the energy levels and

coefficients of the frontier molecular orbitals (FMO). Thus,

the FMO of protonated acrolein are more like “those of an

allylic cation mixed with a lone-pair orbital on oxygen”.³⁶In line

with the theoretical study by Houk and Strozier, it has been

proposed that acid-catalyzed hydration of aliphatic α,β-

unsaturated ketones I, such as 3-buten-2-one derivatives,

involves protonation of the carbonyl oxygen followed by

addition of H₂O to the β-carbon atom (Scheme 6). Because

of the contribution of the canonical structures II and III, the

transition structure of the reaction would have an allylic

cationic character.³⁷On the basis of these previous studies, we

propose that Brønsted acid-catalyzed IOCC of (E)-α,β-

unsaturated ester surrogates would involve an allylic cationic

transition structure³⁸and proceed via an S_N1-type mechanism

(Scheme 5B). In this context, two possible chairlike TS-C and

TS-D could be considered, and their conformation would be

basically similar to that of TS-A and TS-B, respectively. TS-D

suffers from the 1,3-diaxial interactions as shown, while such an

unfavorable steric repulsion does not exist in TS-C. Moreover,

in contrast to the arguments on TS-A/TS-B, the stabilizing

HOMO/LUMO interaction in TS-C would be greater than

that in TS-D by considering the attack angle and the

coefficients of the LUMO. Thus, TS-C would be energetically

favored over TS-D by both steric and stereoelectronic reasons.

This transition state model well explains the observed

stereoselectivity of the cyclization.³⁹

e

f

g

Not applicable. ( )-28d was recovered in 17% yield. ( )-28e was

h

recovered in 7% yield. ( )-28f was recovered in 38% yield.

its acid treatment provided 53 in 93% yield as a single stereoisomer

(entry 11). It is clear from these results that α,β-unsaturated 2-

oxazolidinone imides and 2,5-dimethylpyrrole amides exhibit much

higher reactivity than the corresponding thioesters and give 2,6-cis-

substituted tetrahydropyrans in a highly stereoselective fashion.

Brønsted Base-Catalyzed IOCC of α,β-Unsaturated

Ester Surrogates. Having investigated the reactivity of α,β-

unsaturated ester surrogates toward Brønsted acid-catalyzed

IOCC, we briefly examined Brønsted base-catalyzed IOCC of

α,β-unsaturated thioester (+)-17 and 2,5-dimethylpyrrole

amide (+)-39 (Table 5). As a control experiment, α,β-

unsaturated ester (+)-56 was treated with KOt-Bu (20 mol %)

in THF at −78 °C to give 2,6-trans-substituted tetrahydropyran

(−)-trans-57 in 81% yield with good diastereoselectivity

(dr 4:1) (entry 1). IOCC of (+)-17 under the identical condi-

tions afforded (−)-trans-24 in 85% yield, and the observed

diastereoselectivity was exactly the same as that of the

corresponding oxoester (+)-56 (entry 2). Thus, the stereo-

selectivity of base-catalyzed IOCC of α,β-unsaturated thioesters

may be similar to that of α,β-unsaturated esters. On the other

hand, cyclization of (+)-39 under the same conditions as those

used for (+)-17 and (+)-56 gave tetrahydropyran (−)-52 as a

1:1 mixture of diastereomers (entry 3). In this case, it is likely

that thermodynamic equilibration between 2,6-cis and 2,6-trans

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Table 4. Application to a Variety of Substrates

a

b

CM reactions were performed using HG-II (10 mol %) in CH₂Cl₂at 35 °C. IOCCs were performed using CSA (20 mol %) in CH₂Cl₂at room

c

d

1

temperature. For reaction time (not optimized), see the Experimental Section. Determined by 600 MHz H NMR analysis. Isolated as a 6:1

mixture of E/Z isomers. Isolated as a 9:1 mixture of E/Z isomers.

e

Another important point of Brønsted acid-catalyzed IOCC of (E)-

α,β-unsaturated ester surrogates is that the stereoselective formation

of 2,6-cis-substituted tetrahydropyrans is kinetically controlled and is

not a result of thermodynamic equilibration. We confirmed that

resubjection of thermodynamically less stable (−)-trans-24 to the

cyclization conditions (20 mol % CSA, DCE, 70 °C, 6 h) did not

induce any isomerization to thermodynamically more stable (−)-cis-

24 and resulted in almost quantitative (96%) recovery of (−)-trans-

24 (Scheme 7). Similarly, treatment of ( )-trans-29c⁴⁰with CSA

(20 mol %) in CH₂Cl₂at room temperature for 24 h cleanly

returned the starting material (95% recovery). We also confirmed

that 2,5-dimethylpyrrole amide derivative (−)-trans-52 did not iso-

merize to (−)-52 under the cyclization conditions (CSA (20 mol %),

CH₂Cl₂, room temperature, 8.5 h).

Reactivity of α,β-Unsaturated Ester Surrogates.

Although α,β-unsaturated esters are generally unreactive toward

IOCC under acidic conditions, we have shown that α,β-

unsaturated thioesters, 2-oxazolidinone imides, and 2,5-

dimethylpyrrole amides underwent Brønsted acid-catalyzed

IOCC to provide 2,6-cis-substituted tetrahydropyran derivatives.

The reactivity of α,β-unsaturated ester surrogates (−)-15, (−)-31,

and (−)-37 was compared by monitoring their cyclization by

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a

Table 5. Brønsted Base-Catalyzed IOCC of α,β-Unsaturated Ester and Its Surrogates

b

entry

substrate

X

product

yield (%)

trans/cis

1

2

3

(+)-56

(+)-17

(+)-39

OMe

STol

(−)-trans-57

(−)-trans-24

(−)-trans-52

81

85

92

4:1

1:1

2,5-dimethylpyrrolyl

a

b

All reactions were performed using KOt-Bu (20−50 mol %) in THF at −78 °C. Determined by 600 MHz ¹H NMR analysis of a purified mixture

of diastereomers.

Scheme 5. (A) Transition-State Model for Brønsted Base-Catalyzed IOCC of (E)-α,β-Unsaturated Ester Surrogates. (B)

Transition-State Model for Brønsted Acid-Catalyzed IOCC of (E)-α,β-Unsaturated Ester Surrogates

carbonyl group and reduces the acidity of the α-hydrogens.⁴¹In

contrast, acid-catalyzed keto−enol tautomerism of aliphatic

thioesters, 2-oxazolidinone imides, and 2,5-dimethylpyrrole

amides would be more facile than that of esters, due to the

low electron donating ability of the sulfur or nitrogen atom and

sufficient Lewis basicity of the carbonyl oxygen.⁴¹Analogously,

protonation of α,β-unsaturated ester surrogates, such as 15,

31, and 37, would easily generate the corresponding allylic

cationic intermediates that subsequently react intramolecularly

with the pendant hydroxy group, while such a reaction would

be difficult to occur in the case of less reactive α,β-unsaturated

esters.

¹H NMR spectroscopy (20 mol % CSA, CD₂Cl₂, room

temperature), and the results are depicted in Figure 1. Thus, we

established that the reactivity order is: 2,5-dimethyl-

pyrrole amide (−)-37 > 2-oxazolidinone imide (−)-31 > S-

(p-tolyl) thioester (−)-15.

On the basis of our proposed reaction mechanism of

Brønsted acid-catalyzed IOCC, the high reactivity of α,β-

unsaturated ester surrogates (e.g., 15, 31, and 37) could be

reasoned by their propensity to form the corresponding allylic

cationic intermediates upon protonation. It is well-known that

aliphatic esters do not undergo keto−enol tautomerism easily,

because the lone pair of the ester oxygen delocalizes to the

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Scheme 6. Mechanism of Acid-Catalyzed Hydration of

3-Buten-2-one Derivatives

Scheme 8. One-Step Transformation of S-(p-Tolyl)

Thioester ( )-21

Scheme 7. Isomerization Experiments

Scheme 9. One-Step Transformation of 2-Oxazolidinone

Imide ( )-29c

Transformation of the Product Tetrahydropyrans.

Finally, we evaluated the synthetic versatility of the cyclization

products ( )-21, ( )-29c, and ( )-29g (Schemes 8−10).

It is well accepted that a diverse set of carbonyl compounds is

available from thioesters in one step (Scheme 8). Fukuyama

reduction⁴²of ( )-21 provided aldehyde ( )-58 in 86% yield.

Amidation of ( )-21 could be efficiently performed in the pre-

sence of AgOCOCF₃⁴³to give amide ( )-59 in 99% yield. Moreover,

thioester ( )-21 is amenable to a series of palladium-catalyzed

Figure 1. Comparison of reactivity of α,β-unsaturated thioester 15

(•), 2-oxazolidinone imide 31 (■), and 2,5-dimethylpyrrole amide 37

1

(◆) by H NMR spectroscopy.

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coupling reactions,⁴⁴⁻⁴⁸leading to asymmetric ketones ( )-60,

( )-61, and ( )-62 in moderate to good yields.

EXPERIMENTAL SECTION

■

General Remarks. All reactions sensitive to moisture and/or air

were carried out under an atmosphere of argon in dry, freshly distilled

solvents under anhydrous conditions using oven-dried glassware unless

otherwise noted. Commercially available anhydrous dichloromethane

(CH₂Cl₂) was used directly without further drying. Anhydrous diethyl

ether (Et₂O), tetrahydrofuran (THF), and toluene were purified by

a Glass Contour solvent purification system under an atmosphere

of argon immediately prior to use. 1,2-Dichloroethane (DCE) and

triethylamine (Et₃N) were distilled from calcium hydride under an

atmosphere of argon. N,N-dimethylformamide (DMF) was distilled

from magnesium sulfate under reduced pressure. Degassed solvents

were obtained by repeating freeze−thaw cycle for three times. All

other chemicals were purchased at the highest commercial grade and

used directly. ¹H and ¹³C NMR spectra were recorded at 22 °C unless

otherwise noted. Chemical shift values of ¹H and ¹³C NMR spectra are

reported in ppm (δ) downfield from tetramethylsilane with reference

to internal solvent [¹H NMR, CHCl₃(7.24), C₆HD₅(7.15); ¹³C

NMR, CDCl₃(77.0), C₆D₆(128.0)] unless otherwise noted. Coupling

constants (J) are reported in hertz (Hz). The following abbreviations

were used to designate the multiplicities: s = singlet; d = doublet; t =

triplet; m = multiplet; br = broad.

Similarly, 2-oxazolidinone imide ( )-29c could be readily

elaborated to the corresponding carboxylic acid ( )-63, ester

( )-64 or aldehyde ( )-58 in one step (Scheme 9).^49,50

Transformation of 2,5-dimethylpyrrole amide ( )-29g to

carboxylic acid ( )-63 or ester ( )-64 proceeded without

incident (Scheme 10). On the other hand, DIBALH reduction

Scheme 10. Transformation of 2,5-Dimethylpyrrole Amide

( )-29g

Olefin ( )-1. To a solution of 3-(4-methoxybenzyloxy)propanal⁵²

(4.80 g, 24.7 mmol) in THF (90 mL) at 0 °C was added a solution of

4-pentenylmagnesium bromide (ca. 1.0 M solution in THF, 33.8 mL,

ca. 33.8 mmol), and the resultant mixture was stirred at 0 °C for

70 min. The reaction was quenched with saturated aqueous NH₄Cl

solution. The resultant mixture was extracted with EtOAc, and the

organic layer was washed with brine, dried (Na₂SO₄), filtered, and

concentrated under reduced pressure. Purification of the residue by

flash chromatography on silica gel (5−10% EtOAc/hexanes) gave

olefin ( )-1 (5.07 g, 78%) as a colorless oil: IR (film) 3436, 2935,

1

2859, 1613, 1514, 1460, 1248, 1092, 1036, 821 cm⁻¹; H NMR (600

MHz, CDCl₃) δ 7.26−7.23 (m, 2H), 6.89−6.86 (m, 2H), 5.80 (dddd,

J = 17.2, 8.9, 6.9, 6.5 Hz, 1H), 5.00 (dddd, J = 17.2, 2.1, 1.7, 1.7 Hz,

1H), 4.94 (dddd, J = 8.9, 2.1, 1.4, 1.4 Hz, 1H), 4.45 (s, 2H), 3.82−3.77

(m, 4H), 3.69 (ddd, J = 9.3, 5.2, 5.2 Hz, 1H), 3.61 (ddd, J = 9.3, 6.2,

6.2 Hz, 1H), 2.93 (br s, 1H), 2.11−2.02 (m, 2H), 1.74−1.70 (m, 2H),

1.57−1.39 (m, 4H); ¹³C NMR (150 MHz, CDCl₃) δ 159.2, 138.7,

129.9, 129.2 (2C), 114.4, 113.8 (2C), 72.9, 71.2, 68.9, 55.2, 36.8, 36.3,

33.7, 24.8; HRMS (ESI) calcd for C₁₆H₂₄O₃Na [(M + Na)⁺]

287.1618, found 287.1624.

of ( )-29g gave pyrrolyl carbinol ( )-65 as a 1:1 mixture of

diastereomers.⁵¹It was necessary to treat ( )-65 with a

catalytic amount of CaCO₃in MeOH at 60 °C to obtain

aldehyde ( )-58 in good yield.

Olefin

( )-4. Prepared in 69% yield from 3-(tert-

CONCLUSION

■

butyldiphenylsilyloxy)propanal⁵³in the same way as that described

for ( )-1. Data for ( )-4: IR (film) 2914, 1357, 1314, 1275, 1102

cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 7.72−7.62 (m, 4H), 7.45−7.32

(m, 6H), 5.80 (m, 1H), 5.00 (d, J = 17.2 Hz, 1H), 4.94 (d, J = 8.9 Hz,

1H), 3.90−3.78 (m, 3H), 3.24 (s, 1H), 2.08−2.04 (m, 2H), 1.73−1.62

(m, 2H), 1.58−1.38 (m, 4H), 1.03 (s, 9H); ¹³C NMR (150 MHz,

CDCl₃) δ 138.8 (2C), 135.5 (2C), 134.8, 133.0, 132.9, 129.8 (2C),

129.5, 127.8 (2C), 127.6, 114.5, 71.7, 63.6, 38.3, 36.9, 33.7, 26.8 (3C),

24.8, 19.0; HRMS (ESI) calcd for C₂₄H₃₄O₂SiNa [(M + Na)⁺]

405.2220, found 405.2221.

We have demonstrated that stereoselective synthesis of 2,6-cis-

substituted tetrahydropyrans could be efficiently achieved by

means of Brønsted acid-catalyzed IOCC of α,β-unsaturated

ester surrogates. The cyclization precursor α,β-unsaturated ester

surrogates were readily accessible via olefin cross-metathesis.

A “biomimetic” IOCC of α,β-unsaturated thioesters under

Brønsted acid catalysis was demonstrated to give access to 2,6-

cis-substituted tetrahydropyrans in a highly stereoselective

fashion, although elevated temperature conditions were

required. Among the other α,β-unsaturated carboxylic acid deri-

vatives examined, α,β-unsaturated 2-oxazolidinone imides

and 2,5-dimethylpyrrole amides showed satisfactory re-

activity toward Brønsted acid-catalyzed IOCC and afforded

2,6-cis-substituted tetrahydropyran derivatives in a synthetically

useful level of diastereoselectivity. Because of the mild reaction

conditions, our methodology would be applicable to a broad

range of substrates. In addition, the product tetrahydropyrans

could be easily transformed into various derivatives. The

chemistry described in this paper would significantly broaden

the scope of IOCC for tetrahydropyran synthesis. We believe

that our methodology would find its use in the synthesis of

complex tetrahydropyran-containing natural products.

Olefins (−)-5, (−)-6, (+)-7, and (+)-8. These compounds were

previously prepared.^6e,26

Olefins (+)-12 and (+)-13. To a solution of alcohol (+)-11

(601.1 mg, 2.442 mmol) and Et₃N (1.35 mL, 9.74 mmol) in CH₂Cl₂/

DMSO (1:1, v/v, 20 mL) at 0 °C were added SO₃·pyridine complex

(1.17 g, 7.35 mmol), and the resultant mixture was stirred at 0 °C for

40 min. The reaction was quenched with H₂O, and the resultant

mixture was diluted with Et₂O. The organic layer was washed with

H₂O and brine, dried (Na₂SO₄), filtered, and concentrated under

reduced pressure. The residual crude aldehyde was immediately used

in the next reaction without further purification.

To a solution of the above material in THF (16 mL) at 0 °C were

added allylmagnesium bromide (1.0 M solution in Et₂O, 4.90 mL, 4.90

mmol), and the resultant mixture was stirred at 0 °C for 50 min. The

reaction was quenched with saturated aqueous NH₄Cl solution, and

the resultant mixture was extracted with EtOAc. The organic layer was

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washed with brine, dried (Na₂SO₄), filtered, and concentrated under

reduced pressure. Purification of the residue by flash chromatography

on silica gel (5 to 10% Et₂O/hexanes) followed by preparative HPLC

(CHCl₃) gave olefin (+)-12 (258.1 mg, 37% for the two steps) as a

colorless oil, along with olefin (+)-13 (290.7 mg, 42% for the two

hexanes) to give α,β-unsaturated thioester ( )-2a (421.4 mg, 93%) as

a brown oil.

( )-2a: IR (film) 3460, 2932, 2862, 1669, 1513, 1248, 1091, 1034,

820 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 7.23−7.21 (m, 2H), 6.88−

6.83 (m, 3H), 6.08 (ddd, J = 15.9, 1.7, 1.7 Hz, 1H), 4.32 (s, 2H),

3.81−3.75 (m, 4H), 3.68 (m, 1H), 3.60 (m, 1H), 2.99 (br d, J = 2.4

Hz, 1H), 2.91 (q, J = 7.6 Hz, 2H), 2.22−2.17 (m, 2H), 1.74−1.67 (m,

2H), 1.61 (m, 1H), 1.53−1.38 (m, 3H), 1.25 (t, J = 7.6 Hz, 3H); ¹³C

NMR (150 MHz, CDCl₃) δ 190.1, 159.2, 144.9, 129.9, 129.3 (2C),

128.8, 113.8 (2C), 72.9, 71.2, 68.9, 55.2, 36.7, 36.3, 32.0, 23.9, 23.0,

14.8; HRMS (ESI) calcd for C₁₉H₂₈O₄SNa [(M + Na)⁺] 375.1601,

found 375.1593.

steps) as a pale yellow oil. Data for (+)-12: [α]³¹+38.1 (c 1.00,

D

CHCl₃); IR (film) 3482, 2936, 2857, 1472, 1252, 1096, 837, 777 cm⁻¹;

¹H NMR (600 MHz, CDCl₃) δ 5.82 (dddd, J = 17.2, 10.0, 7.2, 6.9 Hz,

1H), 5.09 (dddd, J = 17.2, 2.0, 1.7, 1.7 Hz, 1H), 5.06 (dddd, J = 10.0,

2.0, 1.0, 1.0 Hz, 1H), 3.90 (dddd, J = 8.9, 4.1, 2.0, 1.4 Hz, 1H), 3.84

(m, 1H), 3.67 (ddd, J = 13.7, 8.9, 4.8 Hz, 1H), 3.32 (m, 1H), 2.93 (dd,

J = 8.9, 1.4 Hz, 1H), 2.36 (m, 1H), 2.27 (m, 1H), 2.03 (m, 1H), 1.89

(d, J = 8.9 Hz, 1H), 1.65−1.58 (m, 2H), 1.41 (m, 1H), 0.86 (s, 9H),

0.08 (s, 3H), 0.06 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 135.4,

117.1, 82.7, 68.3, 67.8, 66.8, 38.9, 33.4, 25.8 (3C), 25.4, 17.9, −4.1,

−4.9; HRMS (ESI) calcd for C₁₅H₃₀O₃SiNa [(M + Na)⁺] 309.1856,

( )-2b. According to GP1, ( )-2b was prepared from ( )-1 and S-

phenyl 2-propenthioate:⁵⁵IR (film) 3457, 2936, 2861, 1685, 1513,

1

1248, 1089, 1034, 820, 747 cm⁻¹; H NMR (600 MHz, CDCl₃) δ

7.43−7.37 (m, 5H), 7.25−7.21 (m, 2H), 6.96 (ddd, J = 15.4, 6.9, 6.8

Hz, 1H), 6.88−6.84 (m, 2H), 6.17 (ddd, J = 15.4, 1.4, 1.3 Hz, 1H),

4.44 (s, 2H), 3.81−3.77 (m, 4H), 3.68 (m, 1H), 3.61 (m, 1H), 3.01

(br d, J = 2.4 Hz, 1H), 2.27−2.19 (m, 2H), 1.76−1.60 (m, 3H), 1.57−

1.40 (m, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 188.0, 159.3, 146.5,

134.6 (2C), 134.5, 129.9, 129.3 (2C), 129.1 (2C), 127.9, 127.6, 113.8

(2C), 73.0, 71.3, 68.9, 55.2, 36.7, 36.3, 32.2, 23.9; HRMS (ESI) calcd

for C₂₃H₂₈O₄SNa [(M + Na)⁺] 423.1601, found 423.1603.

( )-2c. According to GP1, ( )-2c was prepared from ( )-1 and S-

(4-methylphenyl) 2-propenthioate.⁵⁵IR (film) 3464, 2935, 2861,

1685, 1513, 1248, 1091, 1034, 809 cm⁻¹; ¹H NMR (600 MHz,

CDCl₃) δ 7.30−7.28 (m, 2H), 7.24−7.19 (m, 4H), 7.95 (ddd, J = 15.5,

6.9, 6.8 Hz, 1H), 6.87−6.85 (m, 2H), 6.16 (ddd, J = 15.5, 1.7, 1.4 Hz,

1H), 4.44 (s, 2H), 3.81−3.76 (m, 4H), 3.68 (m, 1H), 3.61 (m, 1H),

3.01 (br d, J = 3.2 Hz, 1H), 2.36 (s, 3H), 2.25−2.21 (m, 2H), 1.76−

1.60 (m, 3H), 1.56−1.40 (m, 3H); ¹³C NMR (150 MHz, CDCl₃) δ

188.5, 159.3, 146.3, 139.5, 134.6 (2C), 129.94 (2C), 129.87, 129.3

(2C), 128.0, 124.1, 113.8 (2C), 73.0, 71.2, 68.9, 52.2, 36.7, 36.3, 32.2,

23.9, 21.3; HRMS (ESI) calcd for C₂₄H₃₀O₄SNa [(M + Na)⁺]

437.1757, found 437.1744.

found 309.1861. Data for (+)-13: [α]³⁰+65.3 (c 1.00, CHCl₃); IR

D

1

(film) 3502, 2930, 1472, 1254, 1098, 837, 776 cm⁻¹; H NMR (600

MHz, CDCl₃) δ 5.90 (m, 1H), 5.12 (dddd, J = 17.2, 2.0, 1.4, 1.4 Hz,

1H), 5.08 (dddd, J = 10.3, 2.0, 1.0, 1.0 Hz, 1H), 3.92−3.84 (m, 2H),

3.53 (ddd, J = 10.6, 8.9, 4.4 Hz, 1H), 3.30 (m, 1H), 3.12 (dd, J = 8.9,

4.8 Hz, 1H), 2.75 (d, J = 5.2 Hz, 1H), 2.35 (m,1H), 2.23 (m, 1H), 2.02

(m, 1H), 1.65−1.60 (m, 2H), 1.65 (m, 1H), 0.86 (s, 9H), 0.080 (s,

3H), 0.076 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 135.5, 117.1,

83.8, 71.6, 70.8, 68.0, 36.1, 33.8, 25.7 (3C), 25.5, 17.9, −3.6, −4.8;

HRMS (ESI) calcd for C₁₅H₃₀O₃SiNa [(M + Na)⁺] 309.1856, found

309.1860.

Olefin (+)-9. To a solution of olefin (+)-12 (242.2 mg, 0.845

mmol) in MeOH (8 mL) was added CSA (39.3 mg, 0.169 mmol), and

the resultant solution was stirred at room temperature for 6.5 h. The

reaction was quenched with Et₃N, and the resultant mixture was

concentrated under reduced pressure. Purification of the residue by

flash chromatography on silica gel (60% EtOAc/hexanes) gave olefin

(+)-9 (144.9 mg, 100%) as a colorless solid: mp 70.4−70.6 °C

(EtOAc/hexanes); [α]²⁵+40.5 (c 1.00, CHCl₃); IR (film) 3339,

D

2938, 2855, 1430, 1098, 1058, 639 cm⁻¹; ¹H NMR (600 MHz,

CDCl₃) δ 5.84 (dddd, J = 17.5, 10.3, 7.2, 7.2 Hz, 1H), 5.13 (m, 1H),

5.10 (m, 1H), 3.89−3.94 (m, 2H), 3.70 (dddd, J = 10.3, 9.2, 5.5, 4.5

Hz, 1H), 3.32 (m, 1H), 3.01 (dd, J = 9.2, 2.0 Hz, 1H), 2.38−2.32 (m,

2H), 2.26 (m, 1H), 2.14−2.09 (m, 2H), 1.68−1.62 (m, 2H), 1.42 (m,

1H); ¹³C NMR (150 MHz, CDCl₃) δ 135.1, 117.7, 82.4, 69.4, 67.8,

66.2, 38.1, 32.5, 25.4; HRMS (ESI) calcd for C₉H₁₆O₃Na [(M + Na)⁺]

195.0992, found 195.0994.

( )-2d. According to GP1, ( )-2d was prepared from ( )-1 and

S-(4-methoxyphenyl) 2-propenthioate:⁵⁵IR (film) 3481, 2936, 2860,

1

1682, 1495, 1290, 1031, 826 cm⁻¹; H NMR (600 MHz, CDCl₃) δ

7.33−7.30 (m, 2H), 7.24−7.21 (m, 2H), 6.94 (ddd, J = 15.5, 1.7, 1.4

Hz, 1H), 6.93−6.91 (m, 2H), 6.87−6.84 (m, 2H), 6.12 (ddd, J = 15.5,

1.7, 1.4 Hz, 1H), 4.44 (s, 2H), 3.81 (s, 3H), 3.80−3.76 (m, 4H), 3.68

(m, 1H), 3.60 (m, 1H), 3.01 (br d, J = 2.7 Hz, 1H), 2.25−2.20 (m,

2H), 1.76−1.60 (m, 3H), 1.55−1.40 (m, 3H); ¹³C NMR (150 MHz,

CDCl₃) δ 189.0, 160.6, 159.3, 146.3, 136.2 (2C), 129.9, 129.3 (2C),

127.9, 118.2, 114.8 (2C), 113.8 (2C), 73.0, 71.3, 69.0, 55.3, 55.2, 36.7,

36.3, 32.2, 23.9; HRMS (ESI) calcd for C₂₄H₃₀O₅SNa [(M + Na)⁺]

453.1706, found 453.1710.

Olefin (+)-10. To a solution of olefin (+)-13 (239.5 mg, 0.836

mmol) in MeOH (8 mL) was added CSA (38.8 mg, 0.167 mmol), and

the resultant solution was stirred at room temperature for 6.5 h. The

reaction was quenched with Et₃N, and the resultant mixture was

concentrated under reduced pressure. Purification of the residue by

flash chromatography on silica gel (15% acetone/hexanes then 20%

EtOAc/benzene) gave olefin (+)-10 (130.9 mg, 91%) as a colorless

( )-2e. According to GP1, ( )-2e was prepared from ( )-1 and S-

(4-nitrophenyl) 2-propenthioate:⁵⁵IR (film) 3446, 2936, 2860, 1687,

1

1517, 1343, 1089, 852, 819 cm⁻¹; H NMR (600 MHz, CDCl₃) δ

oil: [α]³¹+24.0 (c 1.00, CHCl₃); IR (film) 3365, 2940, 2856, 1436,

D

1

8.24−8.22 (m, 2H), 7.62−7.60 (m, 2H), 7.23−7.20 (m, 2H), 7.02

(ddd, J = 15.5, 6.9, 6.8 Hz, 1H), 6.87−6.84 (m, 2H), 6.18 (ddd, J =

15.5, 1.7, 1.4 Hz, 1H), 4.43 (s, 2H), 3.81−3.78 (m, 4H), 3.69 (ddd, J =

9.6, 5.5, 5.2 Hz, 1H), 3.61 (ddd, J = 9.6, 4.4, 4.1 Hz, 1H), 3.05 (br d,

J = 2.8 Hz, 1H), 2.32−2.23 (m, 2H), 1.77−1.62 (m, 3H), 1.58−1.40

(m, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 185.6, 159.3, 148.3, 148.0,

136.4, 134.8 (2C), 129.8, 129.3 (2C), 127.6, 123.8 (2C), 113.8 (2C),

73.0, 71.3, 69.0, 55.2, 36.7, 36.3, 32.3, 23.9; HRMS (ESI) calcd for

C₂₃H₂₇NO₆SNa [(M + Na)⁺] 468.1451, found 468.1447.

1097, 1031, 913, 591 cm⁻¹; H NMR (600 MHz, CDCl₃) δ 5.82

(dddd, J = 16.9, 10.7, 8.2, 6.2 Hz, 1H), 5.21−5.15 (m, 2H), 3.88

(dddd, J = 11.3, 3.8, 2.0, 1.4 Hz, 1H), 3.75 (ddd, J = 8.2, 7.9, 2.7 Hz,

1H), 3.60 (ddd, J = 10.6, 8.3, 4.8 Hz, 1H), 3.50 (br s, 1H), 3.29 (m,

1H), 2.92 (dd, J = 8.3, 8.2 Hz, 1H), 2.60 (ddddd, J = 14.0, 6.2, 3.1,

1.4, 1.4 Hz, 1H), 2.41 (br s, 1H), 2.21 (ddd, J = 14.0, 8.6, 8.2 Hz, 1H),

2.11 (m, 1H), 1.67−1.62 (m, 2H), 1.41 (m, 1H); ¹³C NMR (150

MHz, CDCl₃) δ 134.2, 119.0, 81.9, 74.2, 70.8, 67.6, 38.4, 32.0, 25.1;

HRMS (ESI) calcd for C₉H₁₆O₃Na [(M + Na)⁺] 195.0992, found

195.0998.

α,β-Unsaturated Thioesters 2a−f and 14−20. General

Procedure for Olefin Cross-Metathesis Reaction (GP1). To a

solution of olefin ( )-1 (341.7 mg, 1.29 mmol) and S-ethyl 2-

propenthioate⁵⁴(0.450 mL, 3.88 mmol) in CH₂Cl₂(5 mL) was added

a solution of the Hoveyda−Grubbs second-generation catalyst (32.3

mg, 0.0515 mmol) in CH₂Cl₂(1.5 mL), and the resultant solution was

stirred at 35 °C for 18 h. After complete consumption of 1, the

reaction mixture was cooled to room temperature and directly purified

by flash chromatography on silica gel (10 to 20 to 30% EtOAc/

( )-2f. According to GP1, ( )-2f was prepared from ( )-1 and S-

(1-naphthyl) 2-propenthioate:^21aIR (film) 3462, 2935, 2860, 1629,

1

1457, 1090, 850, 747 cm⁻¹; H NMR (600 MHz, CDCl₃) δ 7.95 (s,

1H), 7.87−7.79 (m, 3H), 7.52−7.45 (m, 3H), 7.25−7.21 (m, 2H),

6.99 (ddd, J = 15.5, 6.9, 6.8 Hz, 1H), 6.88−6.85 (m, 2H), 6.21 (ddd,

J = 15.5, 1.7, 1.4 Hz, 1H), 4.44 (s, 2H), 3.82−3.77 (m, 4H), 3.69 (m,

1H), 3.61 (m, 1H), 3.03 (br s, 1H), 2.28−2.23 (m, 2H), 1.77−1.62

(m, 3H), 1.59−1.41 (m, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 188.2,

159.3, 146.7, 134.4, 133.5, 133.3, 131.1, 129.9, 129.3 (2C), 128.7,

128.0, 127.9, 127.7, 127.0, 126.5, 125.0, 113.8 (2C), 73.0, 71.3, 69.0,

2597

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The Journal of Organic Chemistry

Featured Article

55.2, 36.7, 36.3, 32.2, 23.9; HRMS (ESI) calcd for C₂₇H₃₀O₄SNa

[(M + Na)⁺] 473.1757, found 473.1767.

HRMS (ESI) calcd for C₁₇H₂₂O₃SNa [(M + Na)⁺] 329.1182, found

329.1173.

(+)-19. According to GP1, (+)-19 was prepared from (+)-9 and S-

( )-14. According to GP1, ( )-14 was prepared from ( )-4 and S-

(4-methylphenyl) 2-propenthioate: IR (film) 3510, 2930, 2857, 1686,

1631, 1427, 1112, 1016, 808, 703 cm⁻¹; ¹H NMR (600 MHz, CDCl₃)

δ 7.68−7.65 (m, 4H), 7.45−7.41 (m, 2H), 7.41−7.37 (m, 4H), 7.31−

7.29 (m, 2H), 7.22−7.19 (m, 2H), 6.96 (ddd, J = 15.5, 6.9, 6.8 Hz,

1H), 6.18 (ddd, J = 15.5, 1.4, 1.4 Hz, 1H), 3.92−3.82 (m, 3H), 3.35

(br d, J = 2.4 Hz, 1H), 2.36 (s, 3H), 2.27−2.22 (m, 2H), 1.74−1.60

(m, 3H), 1.59−1.50 (m, 2H), 1.45 (m, 1H), 1.04 (s, 9H); ¹³C NMR

(150 MHz, CDCl₃) δ 188.5, 146.3, 139.5, 135.5 (3C), 134.6 (2C),

132.9, 132.8, 129.95 (2C), 129.87 (2C), 129.85, 128.0, 127.8 (4C),

124.1, 71.6, 63.6, 38.3, 36.9, 32.2, 26.8 (3C), 23.9, 21.3, 19.0; HRMS

(ESI) calcd for C₃₂H₄₀O₃SSiNa [(M + Na)⁺] 555.2360, found

555.2363.

(4-methylphenyl) 2-propenthioate: [α]²⁵+40.5 (c 1.00, CHCl₃); IR

D

(film) 3352, 2938, 2855, 1682, 1632, 1093, 1042, 808 cm⁻¹; ¹H NMR

(600 MHz, CDCl₃) δ 7.31−7.28 (m, 2H), 7.22−7.18 (m, 2H), 7.00

(ddd, J = 15.5, 7.2, 7.2 Hz, 1H), 6.25 (ddd, J = 15.5, 1.4, 1.4 Hz, 1H),

4.04 (m, 1H), 3.92 (m, 1H), 3.68 (m, 1H), 3.33 (m, 1H), 2.96 (dd, J =

8.9, 2.0 Hz, 1H), 2.55 (dddd, J = 14.4, 8.2, 7.2, 1.4 Hz, 1H), 2.48

(dddd, J = 14.4, 7.2, 5.8, 1.4 Hz, 1H), 2.36 (s, 3H), 2.17 (br s, 1H),

2.12 (m, 1H), 1.70−1.59 (m, 3H), 1.42 (m, 1H); ¹³C NMR (150

MHz, CDCl₃) δ 188.5, 142.9, 139.6, 134.6 (2C), 130.0 (2C), 129.8,

124.0, 82.5, 68.9, 67.8, 66.2, 36.9, 32.7, 25.3, 21.3; HRMS (ESI) calcd

for C₁₇H₂₂O₄SNa [(M + Na)⁺] 345.1131, found 345.1144.

(−)-20. According to GP1, (−)-20 was prepared from (+)-10 and

S-(4-methylphenyl) 2-propenthioate: [α]²⁶_D−6.9 (c 1.00, CHCl₃); IR

(film) 3364, 2938, 2853, 1673, 1632, 1437, 1096, 1029, 967, 808 cm⁻¹;

¹H NMR (600 MHz, CDCl₃) δ 7.32−7.28 (m, 2H), 7.23−7.19 (m,

2H), 7.01 (ddd, J = 15.5, 8.2, 6.8 Hz, 1H), 6.27 (ddd, J = 15.5, 1.4, 1.4

Hz, 1H), 3.94−3.87 (m, 2H), 3.59 (dddd, J = 14.1, 8.6, 4.5, 4.5 Hz,

1H), 3.30 (m, 1H), 2.96 (dd, J = 8.6, 7.9 Hz, 1H), 2.88 (m, 1H), 2.74

(m, 1H), 2.67 (dddd, J = 14.4, 6.8, 3.4, 1.7 Hz, 1H), 2.42 (ddd, J =

15.1, 8.3, 7.9 Hz, 1H), 2.36 (s, 3H), 2.10 (m, 1H), 1.68−1.63 (m, 2H),

1.44 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 188.5, 142.5, 139.7,

134.6 (2C), 130.3, 130.0 (2C), 123.9, 81.9, 73.7, 70.9, 67.7, 36.5, 32.6,

25.2, 21.3; HRMS (ESI) calcd for C₁₇H₂₂O₄SNa [(M + Na)⁺]

345.1131, found 345.1139.

2,6-cis-Substituted Tetrahydropyrans 3a−f and 21−27. Gen-

eral Procedure for Intramolecular Oxa-Conjugate Cyclization of

α,β-Unsaturated Thioesters (GP2). To a solution of α,β-unsaturated

thioester ( )-14 (36.3 mg, 0.0681 mmol) in DCE (1.0 mL) was added

CSA (3.2 mg, 0.014 mmol), and the resultant solution was stirred at

70 °C for 30 h. After complete consumption of ( )-14, the reaction

mixture was cooled to room temperature. The reaction was quenched

with Et₃N, and the resultant mixture was concentrated under reduced

pressure. Purification of the residue by flash chromatography on silica

gel (2 to 20% EtOAc/hexanes) gave 2,6-cis-substituted tetrahydropyr-

an ( )-21 (32.1 mg, 88%) as a colorless oil.

(−)-15. According to GP1, (−)-15 was prepared from (−)-5 and S-

(4-methylphenyl) 2-propenthioate: [α]²⁸−16.6 (c 1.00, CHCl₃); IR

D

(film) 3519, 2942, 2865, 1687, 1464, 1112, 1015, 807, 702, 505 cm⁻¹;

¹H NMR (600 MHz, CDCl₃) δ 7.68−7.63 (m, 4H), 7.44−7.40 (m,

2H), 7.40−7.35 (m, 4H), 7.31−7.28 (m, 2H), 7.22−7.19 (m, 2H),

6.97 (ddd, J = 15.5, 7.6, 7.2 Hz, 1H), 6.20 (ddd, J = 15.5, 1.4, 1.4 Hz,

1H), 4.30 (dddd, J = 6.9, 6.5, 4.5, 3.8 Hz, 1H), 4.17 (m, 1H), 3.88−

3.79 (m, 2H), 3.50 (br d, J = 2.1 Hz, 1H), 2.57 (dddd, J = 14.4, 7.2,

3.8, 1.4 Hz, 1H), 2.50 (dddd, J = 14.4, 7.6, 4.5, 1.4 Hz, 1H), 2.36 (s,

3H), 1.75−1.65 (m, 2H), 1.62 (m, 1H), 1.54 (ddd, J = 14.4, 6.5, 2.5

Hz, 1H), 1.12−1.05 (m, 21H), 1.04 (s, 9H); ¹³C NMR (150 MHz,

CDCl₃) δ 188.3, 142.3, 139.6, 135.5 (4C), 134.6 (2C), 134.5, 133.2,

133.1, 130.03, 129.98 (2C), 129.8, 127.7 (4C), 124.0, 69.4, 67.3, 62.7,

43.7, 40.5, 39.4, 26.8 (3C), 21.3, 19.0, 18.2 (6C), 12.6 (3C); HRMS

(ESI) calcd for C₄₁H₆₀O₄SSi₂Na [(M + Na)⁺] 727.3643, found

727.3649.

(−)-16. According to GP1, (−)-16 was prepared from (−)-6 and S-

(4-methylphenyl) 2-propenthioate: [α]²⁷−1.4 (c 1.00, CHCl₃); IR

D

(film) 3484, 2943, 2865, 1686, 1632, 1463, 1097, 1014, 807, 679 cm⁻¹;

¹H NMR (600 MHz, CDCl₃) δ 7.36−7.26 (m, 7H), 7.22−7.19 (m,

2H), 7.02 (ddd, J = 14.4, 7.9, 6.9 Hz, 1H), 6.21 (ddd, J = 14.4, 1.4, 1.4

Hz, 1H), 4.54 (s, 2H), 4.25 (m, 1H), 3.93 (m, 1H), 3.45 (dd, J = 9.6,

3.8 Hz, 1H), 3.33 (dd, J = 9.6, 7.6 Hz, 1H), 2.64 (br d, J = 2.4 Hz,

1H), 2.57 (dddd, J = 14.1, 12.7, 6.9, 1.4 Hz, 1H), 2.46 (dddd, J = 14.1,

7.9, 4.8, 1.4 Hz, 1H), 2.36 (s, 3H), 1.69 (ddd, J = 14.1, 9.6, 5.5 Hz,

1H), 1.59 (ddd, J = 14.1, 7.2, 2.8 Hz, 1H), 1.08−1.04 (m, 21H); ¹³C

NMR (150 MHz, CDCl₃) δ 188.3, 142.5, 139.6, 137.9, 134.6 (2C),

130.1, 130.0 (2C), 128.5 (2C), 127.79, 127.76 (2C), 124.0, 74.7, 73.3,

69.3, 67.8, 39.8, 39.6, 21.3, 18.1 (6C), 12.6 (3C); HRMS (ESI) calcd

for C₃₁H₄₆O₄SSiNa [(M + Na)⁺] 565.2778, found 565.2764.

( )-3a. Synthesized from ( )-2a according to GP2 except that

the reaction was performed in CH₂Cl₂at room temperature: IR

(film) 2932, 2858, 1685, 1513, 1247, 1089, 1037, 820 cm⁻¹; ¹H NMR

(600 MHz, CDCl₃) δ 7.25−7.22 (m, 2H), 6.87−6.84 (m, 2H), 4.38 (s,

2H), 3.79−3.74 (m, 4H), 3.55−3.48 (m, 2H), 3.45 (m, 1H), 2.89−

2.80 (m, 2H), 2.74 (dd, J = 14.5, 7.6 Hz, 1H), 2.55 (dd, J = 14.5, 5.2

Hz, 1H), 1.79 (m, 1H), 1.74−1.64 (m, 2H), 1.59 (m, 1H), 1.56−1.46

(m, 2H), 1.22, (t, J = 7.6 Hz, 3H), 1.23−1.14 (m, 2H); ¹³C NMR (150

MHz, CDCl₃) δ 197.4, 159.1, 130.8, 129.2 (2C), 113.7 (2C), 74.9,

74.5, 72.7, 66.6, 55.2, 50.8, 36.5, 31.3, 31.2, 23.4, 23.3, 14.8; HRMS

(ESI) calcd for C₁₉H₂₈O₄SNa [(M + Na)⁺] 375.1601, found 375.1605.

( )-3b. Synthesized from ( )-2b according to GP2 except that the

reaction was performed in CH₂Cl₂at room temperature: IR (film)

(+)-17. According to GP1, (+)-17 was prepared from (+)-7 and S-

(4-methylphenyl) 2-propenthioate: [α]²⁹+14.6 (c 1.00, CHCl₃); IR

D

(film) 3511, 2929, 2857, 1685, 1427, 1255, 1110, 1015, 776, 703 cm⁻¹;

¹H NMR (600 MHz, CDCl₃) δ 7.67−7.61 (m, 4H), 7.42−7.32 (m,

6H), 7.30−7.26 (m, 2H), 7.22−7.18 (m, 2H), 6.84 (ddd, J = 15.5, 7.9,

7.6 Hz, 1H), 6.17 (d, J = 15.5 Hz, 1H), 3.96 (m, 1H), 3.88 (ddd, J =

7.2, 5.8, 3.4 Hz, 1H), 3.72−3.62 (m, 2H), 3.23 (br s, 1H), 2.58−2.46

(m, 2H), 2.36 (s, 3H), 1.65 (m, 1H), 1.60−1.47 (m, 3H), 1.43 (m,

1H), 1.02 (s, 9H), 0.96 (d, J = 7.2 Hz, 3H), 0.89 (s, 9H), 0.090 (s,

3H), 0.088 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 188.1, 141.8,

139.7, 135.5 (4C), 134.5 (2C), 133.89, 133.86, 130.0 (2C), 129.9,

129.5 (2C), 127.6 (4C), 123.8, 76.6, 70.2, 63.9, 40.1, 38.1, 31.3, 29.2,

26.8 (3C), 25.8 (3C), 21.3, 19.2, 17.9, 10.7, −4.4, −4.7; HRMS (ESI)

calcd for C₄₀H₅₈O₄SSi₂Na [(M + Na)⁺] 713.3487, found 713.3490.

(+)-18. According to GP1, (+)-18 was prepared from (+)-8 and S-

1

2934, 2857, 1705, 1513, 1247, 1089, 820, 745 cm⁻¹; H NMR (600

MHz, CDCl₃) δ 7.38 (m, 5H), 7.23−7.20 (m, 2H), 6.85−6.82 (m,

2H), 4.39 (s, 2H), 3.80 (m, 1H), 3.76 (s, 3H), 3.59−3.52 (m, 2H),

3.48 (m, 1H), 2.84 (dd, J = 14.5, 7.8 Hz, 1H), 2.65 (dd, J = 14.5, 5.2

Hz, 1H), 1.81 (m, 1H), 1.78−1.67 (m, 2H), 1.63 (m, 1H), 1.57−1.48

(m, 2H), 1.28−1.16 (m, 2H); ¹³C NMR (150 MHz, CDCl₃) δ

192.3, 159.0, 134.4 (2C), 130.7, 129.3, 129.2 (2C), 129.1 (2C), 127.9,

113.7 (2C), 75.0, 74.5, 72.7, 66.6, 55.2, 50.3, 36.6, 31.3, 31.2, 23.4;

HRMS (ESI) calcd for C₂₃H₂₈O₄SNa [(M + Na)⁺] 423.1601, found

423.1598.

(4-methylphenyl) 2-propenthioate: [α]²²+35.2 (c 1.00, CHCl₃); IR

( )-3c. Synthesized from ( )-2c according to GP2 except that the

D

(film) 2848, 1703, 999, 960, 807 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ

7.31−7.28 (m, 2H), 7.21−7.19 (m, 2H), 6.99 (ddd, J = 15.5, 6.8, 6.8

Hz, 1H), 6.19 (ddd, J = 15.5, 1.4, 1.4 Hz, 1H), 3.88 (dddd, J = 11.3,

4.1, 2.1, 1.7 Hz, 1H), 3.33−3.25 (m, 2H), 2.98 (ddd, J = 9.3, 8.9, 2.4

Hz, 1H), 2.44 (m, 1H), 2.36 (s, 3H), 2.29 (m, 1H), 2.09 (m, 1H),

2.03 (m, 1H), 1.70−1.64 (m, 2H), 1.57 (m, 1H), 1.42−1.35 (m, 2H);

¹³C NMR (150 MHz, CDCl₃) δ 188.7, 146.4, 139.5, 134.6 (2C),

129.9 (2C), 127.9, 124.0, 81.3, 70.3, 67.5, 33.1, 30.3, 28.1, 25.6, 21.3;

reaction was performed in CH₂Cl₂at room temperature: IR (film)

1

2932, 2857, 1704, 1513, 1089, 1036, 808 cm⁻¹; H NMR (600 MHz,

CDCl₃) δ 7.27−7.17 (m, 6H), 6.86−6.82 (m, 2H), 4.39 (s, 2H),

3.82−3.76 (m, 4H), 3.59−3.51 (m, 2H), 3.47 (m, 1H), 2.83 (dd, J =

14.8, 7.9 Hz, 1H), 2.63 (dd, J = 14.8, 5.2 Hz, 1H), 2.35 (s, 3H), 1.81

(m, 1H), 1.78−1.67 (m, 2H), 1.63 (m, 1H), 1.56−1.47 (m, 2H),

1.27−1.16 (m, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 195.8, 159.0,

139.6, 134.5 (2C), 130.7, 129.9 (2C), 129.2 (2C), 124.4, 113.7 (2C),

2598

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1

75.0, 74.5, 72.7, 66.6, 55.2, 50.2, 36.6, 31.3, 31.2, 23.3, 21.3; HRMS

(ESI) calcd for C₂₄H₃₀O₄SNa [(M + Na)⁺] 437.1757, found 437.1757.

( )-3d. Synthesized from ( )-2d according to GP2 except that the

reaction was performed in CH₂Cl₂at room temperature: IR (film)

2865, 1707, 1463, 1106, 1068, 1044, 687 cm⁻¹; H NMR (600 MHz,

CDCl₃) δ 7.34−7.29 (m, 4H), 7.27−7.22 (m, 3H), 7.18−7.15 (m,

2H), 4.61 (d, J = 12.4 Hz, 1H), 4.57 (d, J = 12.4 Hz, 1H), 4.36 (dddd,

J = 12.0, 7.2, 6.2, 2.1 Hz, 1H), 4.32 (dddd, J = 3.2, 3.1, 2.8, 2.4 Hz,

1H), 4.13 (dddd, J = 11.7, 5.2, 4.8, 2.1 Hz, 1H), 3.48−3.45 (m, 2H),

2.93 (dd, J = 14.4, 7.2 Hz, 1H), 2.66 (dd, J = 14.4, 6.2 Hz, 1H), 2.34

(s, 3H), 1.74 (dddd, J = 13.4, 3.2, 2.1, 1.4 Hz, 1H), 1.60 (dddd, J =

13.4, 3.1, 2.1, 1.4 Hz, 1H), 1.51 (ddd, J = 13.4, 11.7, 2.8 Hz, 1H), 1.48

(ddd, J = 13.4, 12.0, 2.4, Hz, 1H), 1.04 (s, 18H), 1.03 (s, 3H); ¹³C

NMR (150 MHz, CDCl₃) δ 195.4, 139.5, 138.6, 134.4 (2C), 129.9

(2C), 128.3 (2C), 127.6 (2C), 127.4, 124.4, 73.34, 73.27, 71.7, 69.0,

64.7, 50.0, 38.9, 35.6, 21.3, 18.1 (6C), 12.2 (3C); HRMS (ESI) calcd

for C₃₁H₄₆O₄SSiNa [(M + Na)⁺] 565.2778, found 565.2761.

1

2935, 2857, 1703, 1513, 1249, 1089, 826 cm⁻¹; H NMR (600 MHz,

C₆D₆) δ 7.37−7.34 (m, 2H), 7.27−7.24 (m, 2H), 6.82−6.79 (m, 2H),

6.69−6.67 (m, 2H), 4.39 (s, 2H), 3.78 (m, 1H), 3.66 (m, 1H), 3.57

(m, 1H), 3.43 (m, 1H), 3.29 (s, 3H), 3.16 (s, 3H), 2.79 (dd, J = 14.8,

7.9 Hz, 1H), 2.43 (dd, J = 14.8, 4.8 Hz, 1H), 1.83 (m, 1H), 1.74 (m,

1H), 1.47 (m, 1H), 1.30−1.23 (m, 2H), 1.18 (m, 1H), 1.07−0.95 (m,

2H); ¹³C NMR (150 MHz, CDCl₃) δ 196.3, 160.5, 159.0, 136.0 (2C),

130.7, 129.2 (2C), 118.6, 114.8 (2C), 113.7 (2C), 75.0, 74.5, 72.6,

66.6, 55.3, 55.2, 50.1, 36.6, 31.3, 31.2, 23.4; HRMS (ESI) calcd for

C₂₄H₃₀O₅SNa [(M + Na)⁺] 453.1706, found 453.1708.

(−)-24. According to GP2, (−)-24 was synthesized from (+)-17

(reaction time: 4.5 h): [α]³⁰−1.5 (c 1.00, CHCl₃); IR (film) 2928,

( )-3e. Synthesized from ( )-2e according to GP2 except that the

reaction was performed in CH₂Cl₂at room temperature: IR (film)

D

1

2856, 1706, 1389, 1252, 1110, 741, 702 cm⁻¹; H NMR (600 MHz,

1

2933, 2856, 1709, 1517, 1343, 1088, 852, 743 cm⁻¹; H NMR (600

CDCl₃) δ 7.67−7.64 (m, 4H), 7.42−7.38 (m, 2H), 7.37−7.34 (m,

4H), 7.26−7.23 (m, 2H), 7.18−7.15 (m, 2H), 3.79 (ddd, J = 11.0, 9.7,

4.8 Hz, 1H), 3.73 (dddd, J = 12.7, 7.6, 5.2, 2.4 Hz, 1H), 3.68 (ddd, J =

10.3, 6.2, 5.9 Hz, 1H), 3.63 (ddd, J = 10.3, 6.2, 5.9 Hz, 1H), 3.25 (m,

1H), 2.87 (dd, J = 14.8, 7.6 Hz, 1H), 2.62 (dd, J = 14.8, 5.2 Hz, 1H),

2.34 (s, 3H), 1.72−1.65 (m, 2H), 1.63−1.52 (m, 3H), 1.45−1.39 (m,

2H), 1.04 (s, 9H), 0.87 (s, 9H), 0.83 (d, J = 6.8 Hz, 3H), 0.04 (s, 3H),

0.03 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 195.9, 139.7, 135.7

(4C), 134.6 (2C), 134.1 (2C), 130.1 (2C), 129.6 (2C), 127.7 (4C),

124.4, 78.8, 72.8, 71.4, 64.0, 49.7, 39.0, 35.7, 29.19, 29.15, 27.0 (3C),

25.9 (3C), 21.4, 19.3, 18.2, 5.2, −4.5, −4.6; HRMS (ESI) calcd for

C₄₀H₅₈O₄SSi₂Na [(M + Na)⁺] 713.3487, found 713.3499.

MHz, C₆D₆) δ 7.71−7.68 (m, 2H), 7.23−7.20 (m, 2H), 7.08−7.05 (m,

2H), 6.81−6.78 (m, 2H), 4.36 (s, 2H), 3.67 (dddd, J = 12.7, 8.6, 4.1,

2.0 Hz, 1H), 3.61 (m, 1H), 3.51 (m, 1H), 3.42 (dddd, J = 12.7, 8.3,

4.1, 1.7 Hz, 1H), 3.29 (s, 3H), 2.63 (dd, J = 14.8, 8.6 Hz, 1H), 2.30

(dd, J = 14.8, 4.1 Hz, 1H), 1.82 (m, 1H), 1.72 (m, 1H), 1.48 (m, 1H),

1.26 (m, 1H), 1.12−1.20 (m, 2H), 1.02 (m, 1H), 0.95 (m, 1H); ¹³C

NMR (150 MHz, CDCl₃) δ 193.2, 159.1, 148.0, 136.5, 134.6 (2C),

130.6, 129.0 (2C), 123.9 (2C), 113.7 (2C), 75.0, 74.4, 72.6, 66.5, 55.2,

50.7, 36.5, 31.2 (2C), 23.3; HRMS (ESI) calcd for C₂₃H₂₇NO₆SNa

[(M + Na)⁺] 468.1451, found 468.1449.

( )-3f. Synthesized from ( )-2f according to GP2 except that the

reaction was performed in CH₂Cl₂at room temperature: IR (film)

(+)-25. According to GP2, (+)-25 was synthesized from (+)-18

1

2933, 2856, 1703, 1512, 1247, 1088, 814, 746 cm⁻¹; H NMR (600

(reaction time: 23 h): [α]²²+23.7 (c 1.00, CHCl₃); IR (film) 3444,

D

2936, 2851, 1683, 1630, 1439, 1094, 1043, 807 cm⁻¹; H NMR (600

1

MHz, CDCl₃) δ 7.91 (s, 1H), 7.84−7.82 (m, 2H), 7.78 (d, J = 7.9 Hz,

1H), 7.52−7.46 (m, 2H), 7.42 (dd, J = 8.6, 1.7 Hz, 1H), 7.21 (m, 2H),

6.82 (m, 2H), 4.41 (d, J = 11.3 Hz, 1H), 4.38 (d, J = 11.3 Hz, 1H),

3.84 (dddd, J = 13.0, 7.9, 5.2, 2.0 Hz, 1H), 3.74 (s, 3H), 3.62−3.54 (m,

2H), 3.50 (dddd, J = 12.7, 8.2, 4.1, 1.7 Hz, 1H), 2.89 (dd, J = 14.4, 7.9

Hz, 1H), 2.69 (dd, J = 14.4, 5.2 Hz, 1H), 1.83 (m, 1H), 1.79−1.68 (m,

2H), 1.66 (m, 1H), 1.58−1.49 (m, 2H), 1.30−1.18 (m, 2H); ¹³C

NMR (150 MHz, CDCl₃) δ 195.5, 159.0, 134.1, 133.5, 133.3, 130.9,

130.7, 129.2 (2C), 128.7, 127.9, 127.7, 127.1, 126.5, 125.3, 113.7 (2C),

75.0, 74.5, 72.7, 66.6, 55.2, 50.4, 36.6, 31.3, 31.2, 23.3; HRMS (ESI)

calcd for C₂₇H₃₀O₄SNa [(M + Na)⁺] 473.1757, found 473.1751.

( )-21: IR (film) 2931, 2856, 1705, 1427, 1110, 996, 806, 703

MHz, C₆D₆) δ 7.34−7.32 (m, 2H), 6.88−6.85 (m, 2H), 3.80 (dddd,

J = 12.7, 7.6, 5.2, 2.4 Hz, 1H), 3.66 (apparent dd, J = 11.3, 4.8 Hz,

1H), 3.05 (ddd, J = 12.0, 11.3, 2.4, Hz, 1H), 2.90 (ddd, J = 10.6, 8.9,

4.5 Hz, 1H), 2.78 (ddd, J = 10.6, 8.9, 4.8 Hz, 1H), 2.77 (dd, J = 15.1,

7.6 Hz, 1H), 2.37 (dd, J = 15.1, 5.2 Hz, 1H), 1.96 (s, 3H), 1.88−1.82

(m, 2H), 1.45−1.27 (m, 4H), 1.19−1.12 (m, 2H); ¹³C NMR (150

MHz, CDCl₃) δ 195.5, 139.7, 134.4 (2C), 130.0 (2C), 124.1, 78.3,

78.0, 74.0, 68.0, 49.4, 30.9, 29.5, 29.4, 25.7, 21.3; HRMS (ESI) calcd

for C₁₇H₂₂O₃SNa [(M + Na)⁺] 329.1182, found 329.1172.

(+)-26. According to GP2, (+)-26 was synthesized from (+)-19

(reaction time: 10.5 h): [α]²⁹_D+20.2 (c 1.00, CHCl₃); IR (film) 3450,

1

cm⁻¹; H NMR (600 MHz, C₆D₆) δ 7.82 (m, 4H), 7.32−7.21 (m,

1

2943, 2865, 1703, 1100, 959, 808, 767 cm⁻¹; H NMR (600 MHz,

8H), 6.88−6.86 (m, 2H), 3.95 (m, 1H), 3.88 (ddd, J = 11.0, 6.2, 5.8

Hz, 1H), 3.74 (apparent ddd, J = 11.3, 7.3, 5.9 Hz, 1H), 3.41 (dddd,

J = 12.4, 9.2, 3.7, 1.7 Hz, 1H), 2.77 (dd, J = 14.5, 7.3 Hz, 1H), 2.43

(dd, J = 14.5, 5.9 Hz, 1H), 1.98 (s, 3H), 1.81 (m, 1H), 1.69 (m, 1H),

1.46 (m, 1H), 1.33 (m, 1H), 1.25−1.12 (m, 11H), 1.05−0.95 (m, 2H);

¹³C NMR (150 MHz, CDCl₃) δ 195.8, 139.5, 135.5 (4C), 134.4 (2C),

134.1, 134.0, 129.9 (2C), 129.5 (2C), 127.6 (4C), 124.3, 74.8, 74.3,

60.4, 50.2, 39.4, 31.3, 31.2, 26.9 (3C), 23.4, 21.3, 19.2; HRMS (ESI)

calcd for C₃₂H₄₀O₃SSiNa [(M + Na)⁺] 555.2360, found 555.2375.

(−)-22.: According to GP2, (−)-22 was synthesized from (−)-15

CDCl₃) δ 7.27−7.25 (m, 2H), 7.20−7.17 (m, 2H), 4.31 (dddd, J =

13.4, 7.6, 5.2, 2.4 Hz, 1H), 4.08 (ddd, J = 3.1, 2.8, 2.8 Hz, 1H), 3.92

(m, 1H), 3.60 (ddd, J = 11.3, 9.3, 2.8 Hz, 1H), 3.44 (m, 1H), 3.00 (dd,

J = 9.3, 2.8 Hz, 1H), 2.84 (dd, J = 15.1, 7.6 Hz, 1H), 2.64 (dd, J = 15.1,

5.2 Hz, 1H), 2.35 (s, 3H), 2.29 (br s, 1H), 2.04 (m, 1H), 1.96 (ddd,

J = 14.1, 3.1, 2.4 Hz, 1H), 1.72−1.58 (m, 3H), 1.42 (m, 1H); ¹³C

NMR (150 MHz, CDCl₃) δ 195.1, 139.6, 134.4 (2C), 130.0 (2C),

124.2, 79.7, 70.8, 68.8, 68.2, 65.7, 49.1, 37.2, 29.3, 25.5, 21.3; HRMS

(ESI) calcd for C₁₇H₂₂O₄SNa [(M + Na)⁺] 345.1131, found 345.1139.

(+)-27. According to GP2, (+)-27 was synthesized from (−)-20

(reaction time: 7.5 h): [α]²⁹−3.2 (c 1.00, CHCl₃); IR (film) 2942,

(reaction time: 10 h): [α]²⁷+31.5 (c 1.00, CHCl₃); IR (film) 3446,

D

1

2864, 1463, 1112, 806, 702 cm⁻¹; H NMR (600 MHz, CDCl₃) δ

1

2942, 2920, 1700, 1100, 963, 808, 756 cm⁻¹; H NMR (600 MHz,

7.64−7.61 (m, 4H), 7.39−7.36 (m, 2H), 7.35−7.31 (m, 4H), 7.20−

7.19 (m, 2H), 7.16−7.13 (m, 2H), 3.84 (dddd, J = 11.3, 11.3, 4.8, 4.8

Hz, 1H), 3.80−3.75 (m, 2H), 3.72 (dddd, J = 12.1, 7.6, 5.5, 2.4 Hz,

1H), 3.49 (dddd, J = 11.3, 8.3, 4.1, 2.4 Hz, 1H), 2.85 (dd, J = 14.8, 7.6

Hz, 1H), 2.64 (dd, J = 14.8, 5.5 Hz, 1H), 2.35 (s, 3H), 1.96 (ddd, J =

12.7, 4.8, 2.4 Hz, 1H), 1.88 (ddd, J = 12.7, 4.8, 2.4 Hz, 1H), 1.80 (m,

1H), 1.69 (m, 1H), 1.26 (ddd, J = 12.7, 12.1, 11.3 Hz, 1H), 1.24 (ddd,

J = 12.7, 11.3, 11.3 Hz, 1H), 1.04−1.02 (m, 21H), 1.01 (s, 9H); ¹³C

NMR (150 MHz, CDCl₃) δ 195.6, 139.6, 135.5 (4C), 134.4 (2C),

133.98, 133.96, 123.0 (2C), 129.52, 129.50, 127.6 (4C), 124.2, 72.6,

72.1, 68.4, 60.5, 49.7, 41.7, 41.4, 38.9, 26.9 (3C), 21.3, 19.2, 18.1 (6C),

12.3 (3C); HRMS (ESI) calcd for C₄₁H₆₀O₄SSi₂Na [(M + Na)⁺]

727.3643, found 727.3665.

CDCl₃) δ 7.27−7.25 (m, 2H), 7.21−7.18 (m, 2H), 3.96 (dddd, J =

12.7, 7.2, 5.5, 1.7 Hz, 1H), 3.92 (m, 1H), 3.70 (ddd, J = 11.3, 8.9, 5.2

Hz, 1H), 3.37 (m, 1H), 3.04 (ddd, J = 11.3, 8.9, 4.2 Hz, 1H), 2.93 (dd,

J = 15.1, 7.2 Hz, 1H), 2.83 (dd, J = 8.9, 8.9 Hz, 1H), 2.70 (dd, J = 15.1,

5.5 Hz, 1H), 2.57 (br s, 1H), 2.35 (s, 3H), 2.09 (ddd, J = 12.7, 5.2, 1.7

Hz, 1H), 2.03 (m, 1H), 1.70−1.65 (m, 2H), 1.50−1.42 (m, 2H); ¹³C

NMR (150 MHz, CDCl₃) δ 195.2, 139.8, 134.4 (2C), 130.0 (2C),

123.4, 83.7, 75.0, 72.0, 70.1, 67.9, 49.0, 38.4, 29.0, 25.4, 21.3; HRMS

(ESI) calcd for C₁₇H₂₂O₄SNa [(M + Na)⁺] 345.1131, found 345.1140.

α,β-Unsaturated Amide/Imide Derivatives 28a−g and 30−

42. ( )-28a. According to GP1, ( )-28a was prepared from ( )-4

and 1-(2-propenoyl)-pyrrolidine:⁵⁶IR (film) 3420, 2951, 2873, 1651,

1

1609, 1437, 1375, 1111, 981 cm⁻¹; H NMR (600 MHz, CDCl₃) δ

(+)-23. According to GP2, (+)-23 was synthesized from (−)-16

7.67−7.64 (m, 4H), 7.44−7.34 (m, 5H), 6.85 (ddd, J = 15.0, 7.2,

6.6 Hz, 1H), 6.08 (d, J = 15.0 Hz, 1H), 3.90−3.80 (m, 3H), 3.52−3.46

(reaction time: 6 h): [α]²⁷+14.7 (c 1.00, CHCl₃); IR (film) 2942,

D

2599

dx.doi.org/10.1021/jo202179s | J. Org. Chem. 2012, 77, 2588−2607

The Journal of Organic Chemistry

Featured Article

(m, 4H), 3.35 (br s, 1H), 2.23−2.19 (m, 2H), 1.97−1.90 (m, 2H),

1.87−1.82 (m, 2H), 1.72−1.42 (m, 8H), 1.03 (s, 9H); ¹³C NMR (150

MHz, CDCl₃) δ 164.8, 145.4, 135.5 (4C), 132.9, 129.8 (2C), 128.3,

121.8, 71.8, 63.7, 46.5, 45.8, 38.2, 37.0, 32.3, 26.8 (9C), 24.3, 19.0;

HRMS (ESI) calcd for C₂₉H₄₂NO₃Si [(M + H)⁺] 480.2928, found

480.2938.

( )-30. According to GP1, ( )-30 was prepared from ( )-1 and 3-

(2-propenoyl)-2-oxazolidinone: IR (film) 2927, 1793, 1684, 1542,

1508, 1362 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 7.23−7.18 (m, 3H),

7.13 (m, 1H), 6.85 (d, J = 8.6 Hz, 2H), 4.42 (s, 2H), 4.38 (dd, J = 8.6,

7.9 Hz, 2H), 4.03 (dd, J = 8.6, 7.9 Hz, 2H), 3.81−3.73 (m, 4H), 3.66

(m, 1H), 3.59 (m, 1H), 2.98 (s, 1H), 2.32−2.23 (m, 2H), 1.75−1.40

(m, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 165.3, 159.3, 153.5, 151.4,

129.9, 129.3, 120.2 (2C), 113.8 (2C), 73.0, 71.3, 69.0, 62.0, 55.3, 42.7,

36.8, 36.3, 32.6, 24.1; HRMS (ESI) calcd for C₂₀H₂₇NO₆Na [(M +

Na)⁺] 400.1731, found 400.1735.

( )-28b. According to GP1, ( )-28b was prepared from ( )-4 and

1-(3-propenoyl)-2-pyrrolidinone:⁵⁷IR (film) 3648, 2931, 1735, 1683,

1361, 1111, 704 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 7.67−7.64 (m,

4H), 7.44−7.34 (m, 6H), 7.23 (d, J = 13.8 Hz, 1H), 7.15 (ddd, J =

15.6, 7.2, 7.2 Hz, 1H), 3.90−3.80 (m, 5H), 3.32 (s, 1H), 2.58 (dd, J =

8.4, 7.8 Hz, 2H), 2.30−2.25 (m, 2H), 2.04−1.98 (m, 2H), 1.72−1.42

(m, 6H), 1.03 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 175.5, 166.2,

150.3 (2C), 135.5 (4C), 132.9, 132.8, 129.8 (2C), 127.7 (4C), 71.5,

63.5, 45.7, 38.3, 36.9, 33.9, 32.5, 26.8 (3C), 24.1, 19.0, 17.1; HRMS

(ESI) calcd for C₂₉H₄₀NO₄Si [(M + H)⁺] 494.2721, found 494.2709.

( )-28c. According to GP1, ( )-28c was prepared from ( )-4 and

3-(2-propenoyl)-2-oxazolidinone:⁵⁸IR (film) 3473, 2930, 1777, 1686,

(−)-31. According to GP1, (−)-31 was prepared from (−)-5 and 3-

(2-propenoyl)-2-oxazolidinone: [α]²²−15.7 (c 1.00, CHCl₃); IR

D

(film) 3566, 2942, 1781, 1684, 1387, 1223, 1111, 1038, 704 cm⁻¹; ¹H

NMR (600 MHz, CDCl₃) δ 7.66−7.63 (m, 4H), 7.43−7.35 (m, 6H),

7.26 (d, J = 15.5 Hz, 1H), 7.15 (ddd, J = 15.5, 7.3, 7.3 Hz, 1H), 4.39

(dd, J = 8.2, 7.9 Hz, 2H), 4.29 (dddd, J = 7.2, 7.2, 4.4, 4.4 Hz, 1H),

4.15 (m, 1H), 4.03 (dd, J = 8.2, 7.9 Hz, 2H), 3.85−3.77 (m, 2H), 3.44

(d, J = 2.4 Hz, 1H), 2.64−2.54 (m, 2H), 1.74−1.51 (m, 4H), 1.11−

1.01 (m, 30H) ;¹³C NMR (150 MHz, CDCl₃) δ 164.8, 153.4, 147.1,

135.5 (4C), 133.3, 133.2, 129.7 (2C), 127.7 (4C), 122.2, 69.4, 67.3,

62.7, 62.0, 43.7, 42.6, 40.7, 39.5, 26.8 (3C), 19.0, 18.1 (6C), 12.6 (3C);

HRMS (ESI) calcd for C₃₇H₅₇NO₆Si₂Na [(M + Na)⁺] 690.3617,

found 690.3590.

1

1386, 1360, 1111, 823, 704 cm⁻¹; H NMR (600 MHz, CDCl₃) δ

7.67−7.64 (m, 4H), 7.44−7.36 (m, 6H), 7.22 (d, J = 16.8 Hz, 1H),

7.15 (dt, J = 16.8, 6.9 Hz, 1H), 4.39 (dd, J = 8.3, 7.9 Hz, 2H), 4.04 (dd,

J = 8.3, 7.9 Hz, 2H), 3.92−3.80 (m, 3H), 3.30 (m, 1H), 2.29 (dt, J =

8.6, 6.9 Hz, 2H), 1.73−1.59 (m, 3H), 1.58−1.41 (m, 3H), 1.03 (s,

9H); ¹³C NMR (150 MHz, CDCl₃) δ 165.2, 153.5, 151.4, 135.5 (4C),

132.9, 132.8, 129.8 (2C), 127.8 (4C), 120.1, 71.5, 63.6, 62.0, 42.7,

38.3, 36.9, 32.6, 26.8 (3C), 24.0, 19.0; HRMS (ESI) calcd for

C₂₈H₃₇NNaO₅Si [(M + Na)⁺] 518.2333, found 518.2338.

(−)-32. According to GP1, (−)-32 was prepared from (−)-6 and 3-

(2-propenoyl)-2-oxazolidinone: [α]²⁴−10.3 (c 0.30, CHCl₃); IR

D

(film) 3566, 1772, 1716, 1684, 1362 cm⁻¹; ¹H NMR (600 MHz,

CDCl₃) δ 7.34−7.16 (m, 6H), 7.18 (ddd, J = 15.1, 8.2, 8.2 Hz, 1H),

4.53 (s, 2H), 4.40 (dd, J = 8.3, 7.6 Hz, 2H), 4.25 (m, 1H), 4.04 (dd,

J = 8.3, 7.6 Hz, 2H), 3.94 (m, 1H), 3.44 (dd, J = 9.7, 3.4 Hz, 1H), 3.31

(dd, J = 9.7, 7.2 Hz, 1H), 2.67 (s, 1H), 2.62 (m, 1H), 2.54 (m, 1H),

1.67 (ddd, J = 14.1, 9.6, 5.5 Hz, 1H), 1.59 (ddd, J = 14.1, 6.8, 3.1 Hz,

1H), 1.08−1.01 (m, 21H); ¹³C NMR (150 MHz, CDCl₃) δ 165.0,

153.5, 147.3, 138.1, 128.5 (2C), 127.8 (3C), 122.4, 74.8, 73.4, 69.6,

68.0, 62.1, 42.7, 40.1, 39.9, 18.2 (6C), 12.7 (3C); HRMS (ESI) calcd

for C₂₇H₄₃NNaO₆Si [(M + Na)⁺] 528.2752, found 528.2745.

( )-28d. According to GP1, ( )-28d was prepared from ( )-4

and 3-(2-propenoyl)-2-benzoxazolidinone:⁵⁸IR (film) 3402, 2939,

1

2907, 1860, 1816, 1478, 1111, 702, 503 cm⁻¹; H NMR (600 MHz,

CDCl₃) δ 8.08 (m, 1H), 7.69−7.64 (m, 4H), 7.45−7.32 (m, 8H),

7.25−7.18 (m, 3H), 3.94−3.81 (m, 3H), 3.34 (s, 1H), 2.41−2.34 (m,

2H), 1.77−1.45 (m, 6H), 1.04 (s, 9H); ¹³C NMR (150 MHz, CDCl₃)

δ 164.2, 154.0, 151.3 (2C), 142.3, 135.5 (2C), 132.9, 132.8, 129.8

(2C), 128.1, 127.8 (2C), 125.1 (2C), 124.7 (2C), 120.6 (2C), 116.1,

109.7, 71.5, 63.6, 38.3, 36.9, 32.9, 26.8 (3C), 24.0, 19.0; HRMS (ESI)

calcd for C₃₂H₃₇NNaO₅Si [(M + Na)⁺] 566.2333, found 566.2354.

( )-28e. According to GP1, ( )-28e was prepared from ( )-4 and

1-(2-propenoyl)indole:⁵⁸IR (film) 3502, 2931, 1685, 1636, 1451,

(+)-33. According to GP1, (+)-33 was prepared from (+)-7 and 3-

(2-propenoyl)-2-oxazolidinone: [α]²⁴_D+7.9 (c 0.10, CHCl₃); IR (film)

1

3088, 1797, 1713, 742 cm⁻¹; H NMR (600 MHz, CDCl₃) δ 7.65−

7.63 (m, 4H), 7.41−7.33 (m, 6H), 7.27 (d, J = 15.1 Hz, 1H), 7.06

(ddd, J = 15.1, 7.9, 7.7 Hz, 1H), 4.43−4.31 (m, 2H), 4.06−3.95 (m,

3H), 3.89 (m, 1H), 3.72−3.61 (m, 2H), 3.24 (s, 1H), 2.63 (ddd, J =

14.1, 7.7, 1.4 Hz, 1H), 2.56 (ddd, J = 14.1, 7.9, 1.1 Hz, 1H), 1.66 (m,

1H), 1.58−1.48 (m, 3H), 1.41 (m, 1H), 1.02 (s, 9H), 0.95 (d, J = 7.2

Hz, 3H), 0.88 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H); ¹³C NMR (150

MHz, CDCl₃) δ 164.8, 153.5, 146.8 (2C), 135.6 (4C), 134.0, 129.5

(2C), 127.6 (4C), 122.3, 77.2, 70.2, 64.0, 62.0, 42.6, 40.0, 38.5, 31.2,

29.3, 26.8 (3C), 25.8 (3C), 19.2, 17.9, 10.9, −4.4, −4.7; HRMS (ESI)

calcd for C₃₆H₅₅NO₆Si₂Na [(M + Na)⁺] 676.3460, found 676.3452.

(−)-34. According to GP1, (−)-34 was prepared from (+)-9 and

1

1111, 703 cm⁻¹; H NMR (600 MHz, CDCl₃) δ 8.48 (d, J = 7.8 Hz,

1H), 7.68−7.64 (m, 4H), 7.55 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 3.6 Hz,

1H), 7.45−7.32 (m, 8H), 7.27 (m, 1H), 6.68−6.62 (m, 2H),

3.96−3.82 (m, 3H), 3.45 (d, J = 1.8 Hz, 1H), 2.42−2.36 (m, 2H),

1.80−1.68 (m, 2H), 1.66−1.46 (m, 4H), 1.04 (s, 9H); ¹³C NMR (150

MHz, CDCl₃) δ 164.2, 151.2 (2C), 135.8, 135.5 (4C), 132.9, 132.8,

130.5, 129.9, 129.8, 127.8 (4C), 124.9, 124.7, 123.6, 120.9, 120.8,

116.8, 71.6, 63.6, 38.3, 36.9, 32.7, 26.8 (3C), 24.0, 19.0; HRMS (ESI)

calcd for C₃₃H₃₉NNaO₃Si [(M + Na)⁺] 548.2591, found 548.2592.

( )-28f. According to GP1, ( )-28f was prepared from ( )-4 and

1-(2-propenoyl)indoline:⁵⁸IR (film) 3648, 2921, 1653, 1541, 1112,

3-(2-propenoyl)-2-oxazolidinone: [α]²⁴−3.3 (c 0.50, CHCl₃); IR

D

1

669 cm⁻¹; H NMR (600 MHz, CDCl₃) δ 8.27 (m, 1H), 7.67−7.64

(film) 3424, 2926, 1774, 1682, 1363, 1039, 707 cm⁻¹; H NMR (600

(m, 4H), 7.44−7.37 (m, 7H), 7.20−7.13 (m, 2H), 6.99 (dd, J = 7.8,

7.2 Hz, 1H), 6.22 (d, J = 14.4 Hz, 1H), 4.13 (dd, J = 9.0, 8.4 Hz, 2H),

3.92−3.81 (m, 3H), 3.40 (br s, 1H), 3.22−3.14 (m, 2H), 2.32−2.24

(m, 2H), 1.74−1.44 (m, 6H), 1.03 (s, 9H); ¹³C NMR (150 MHz,

CDCl₃) δ 164.4, 147.4, 143.1, 135.5 (4C), 132.9, 132.8, 131.4, 129.9,

129.8, 127.8 (4C), 127.5, 124.4, 123.6, 122.1, 117.4, 71.7, 63.7, 48.0,

38.3, 37.0, 32.5, 28.0, 26.8 (3C), 24.3, 19.0; HRMS (ESI) calcd for

C₃₃H₄₂NO₃Si [(M + H)⁺] 528.2928, found 528.2914.

MHz, CDCl₃) δ 7.26 (d, J = 15.5 Hz, 1H), 7.17 (ddd, J = 15.5, 7.3, 6.9

Hz, 1H), 4.41 (dd, J = 8.6, 7.6 Hz, 2H), 4.07−4.02 (m, 3H), 3.92 (m,

1H), 3.68 (m, 1H), 3.33 (m, 1H), 2.98 (dd, J = 8.9, 2.0 Hz, 1H), 2.61

(dddd, J = 14.8, 8.3, 7.3, 1.0 Hz, 1H), 2.55 (dddd, J = 14.8, 6.9, 5.2, 1.0

Hz, 1H), 2.41 (m, 1H), 2.26 (br s, 1H), 2.12 (m, 1H), 1.71−1.62 (m,

2H), 1.41 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 165.1, 153.5,

147.7, 122.2, 82.5, 69.0, 67.8, 66.2, 62.1, 42.7, 37.1, 32.7, 25.4; HRMS

(ESI) calcd for C₁₃H₁₉NO₆Na [(M + Na)⁺] 308.1105, found

308.1104.

( )-28g. According to GP1, ( )-28g was prepared from ( )-4 and

1-(2-propenoyl)-2,5-dimethylpyrrole:^28bIR (film) 3749, 2929, 1696,

(+)-35. According to GP1, (+)-35 was prepared from (+)-10 and

1

1636, 1427, 1366, 1253 cm⁻¹; H NMR (600 MHz, CDCl₃) δ 7.67−

3-(2-propenoyl)-2-oxazolidinone: [α]²³+23.1 (c 0.20, CHCl₃); IR

D

1

7.64 (m, 4H), 7.45−7.34 (m, 6H), 7.03 (m, 1H), 6.34 (d, J = 15.5 Hz,

1H), 5.82−5.80 (m, 2H), 3.92−3.81 (m, 3H), 3.38 (br d, J = 2.4 Hz,

1H), 2.33−2.29 (m, 6H), 1.74−1.66 (m, 2H), 1.63−1.43 (m, 6H), 1.04

(s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 167.4, 150.9, 151.4, 135.5 (4C),

132.9, 132.8, 129.9 (2C), 129.8, 127.8 (4C), 125.5, 120.1, 110.6, 71.6,

63.7, 38.3, 37.0, 32.6, 26.8 (3C), 23.9, 19.0, 15.5 (2C); HRMS (ESI)

calcd for C₃₁H₄₁NO₃SiNa [(M + Na)⁺] 526.2748, found 526.2730.

(film) 3420, 2926, 1772, 1683, 1362, 1038, 706 cm⁻¹; H NMR (600

MHz, CDCl₃) δ 7.27 (d, J = 15.5 Hz, 1H), 7.16 (ddd, J = 15.5, 7.3, 6.9

Hz, 1H), 4.41 (dd, J = 8.2, 7.9 Hz, 2H), 4.05 (dd, J = 8.2, 7.9 Hz, 2H),

3.94−3.86 (m, 2H), 3.59 (m, 1H), 3.30 (m, 1H), 2.96 (dd, J = 8.3, 7.9

Hz, 1H), 2.73 (m, 1H), 2.73 (m, 1H), 2.49 (m, 1H), 2.10 (m, 1H),

1.71−1.57 (m, 3H), 1.43 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ

165.0, 153.6, 147.2, 122.8, 81.9, 73.8, 70.7, 67.7, 62.1, 42.7, 36.8, 32.4,

2600

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Featured Article

25.2; HRMS (ESI) calcd for C₁₃H₁₉NO₆Na [(M + Na)⁺] 308.1105,

found 308.1099.

(2C), 82.7, 68.9, 67.8, 66.2, 37.2, 32.7, 25.3, 15.5 (2C); HRMS (ESI)

calcd for C₁₆H₂₃NO₄Na [(M + Na)⁺] 316.1519, found 316.1521.

(+)-42. According to GP1, (+)-42 was prepared from (+)-10 and

1-(2-propenoyl)-2,5-dimethylpyrrole: [α]²⁹_D+9.1 (c 1.00, CHCl₃); IR

( )-36. According to GP1, ( )-36 was prepared from ( )-1 and

1-(2-propenoyl)-2,5-dimethylpyrrole: IR (film) 3482, 2927, 1692, 1635,

1538, 1366, 1249 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 7.25−7.21 (m,

2H), 7.13 (ddd, J = 13.7, 6.9, 6.8 Hz, 1H), 6.88−6.84 (m, 2H), 7.13 (d,

J = 13.7 Hz, 1H), 5.82−5.79 (m, 2H), 4.43 (s, 2H), 3.83−3.77 (m,

4H), 3.68 (m, 1H), 3.60 (m, 1H), 3.04 (br s, 1H), 2.32−2.26 (m, 8H),

1.75−1.40 (m, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 167.4, 159.3,

150.8, 129.8 (2C), 129.3 (2C), 125.5 (2C), 113.8 (2C), 110.5 (2C),

73.0, 71.3, 69.0, 55.2, 36.8, 36.3, 32.5, 23.9, 15.5 (2C); HRMS (ESI)

calcd for C₂₃H₃₁NO₄Na [(M + Na)⁺] 408.2145, found 408.2156.

(−)-37. According to GP1, (−)-37 was prepared from (−)-5 and

1-(2-propenoyl)-2,5-dimethylpyrrole: [α]²⁸_D−4.1 (c 1.00, CHCl₃); IR

1

(film) 3649, 1698, 1653, 1457, 1362, 668 cm⁻¹; H NMR (600 MHz,

CDCl₃) δ 7.08 (ddd, J = 14.8, 7.9, 6.5 Hz, 1H), 6.46 (d, J = 14.8 Hz,

1H), 5.85−5.78 (m, 2H), 4.00−3.85 (m, 2H), 3.60 (m, 1H), 3.29 (m,

1H), 2.98 (m, 1H), 2.73 (m, 1H), 2.50 (m, 1H), 2.34−2.28 (m, 6H),

2.10 (m, 1H), 1.69−1.61 (m, 4H), 1.44 (m, 1H); ¹³C NMR (150

MHz, CDCl₃) δ 167.2, 147.0, 130.0 (2C), 127.9, 110.8 (2C), 82.0,

73.7, 70.9, 67.8, 36.8, 32.7, 25.2, 15.6 (2C); HRMS (ESI) calcd for

C₁₆H₂₃NO₄Na [(M + Na)⁺] 316.1519, found 316.1530.

2,6-Cis-Substituted Tetrahydropyrans 29b−g and 43−55. Gen-

eral Procedure for Intramolecular Oxa-Conjugate Cyclization of

α,β-Unsaturated 2-Oxazolidinone Imides and 2,5-Dimethylpyrrole

Amides (GP3). To a solution of α,β-unsaturated 2,5-dimethylpyrrole

amides ( )-28g (39.0 mg, 0.0770 mmol) in CH₂Cl₂(1.4 mL) was

added CSA (3.6 mg, 0.015 mmol), and the resultant solution was

stirred at room temperature for 24 h. The reaction was quenched

with Et₃N, and the resultant mixture was concentrated under reduced

pressure. Purification of the residue by flash chromatography on silica

gel (5 to 10% EtOAc/hexanes) gave tetrahydropyran ( )-29g (34.6

mg, 90%) as a colorless oil.

1

(film) 3750, 2941, 1698, 1541, 1457, 1363, 702 cm⁻¹; H NMR (600

MHz, CDCl₃) δ 7.66−7.62 (m, 4H), 7.43−7.34 (m, 6H), 7.04 (ddd,

J = 15.1, 7.3, 7.2 Hz, 1H), 6.38 (d, J = 15.1 Hz, 1H), 5.82−5.80 (m,

2H), 4.32 (dddd, J = 7.2, 7.2, 4.1, 4.1 Hz, 1H), 4.16 (m, 1H), 3.85−

3.77 (m, 2H), 3.52 (br s, 1H), 2.67−2.54 (m, 2H), 2.30 (s, 6H), 1.74−

1.67 (m, 2H), 1.61−1.53 (m, 2H), 1.12−1.00 (m, 30H); ¹³C NMR

(150 MHz, CDCl₃) δ 166.9, 146.8, 135.5 (4C), 133.1 (2C), 129.9,

129.8, 127.7 (4C), 127.5, 110.7 (2C), 69.4, 67.4, 62.8, 43.8, 40.8, 39.5,

26.8 (3C), 19.0, 18.2 (6C), 18.1, 15.5 (3C), 12.6 (3C); HRMS (ESI)

calcd for C₄₀H₆₁NO₄Si₂Na [(M + Na)⁺] 698.4031, found 698.4054.

(−)-38. According to GP1, (−)-38 was prepared from (−)-6 and

1-(2-propenoyl)-2,5-dimethylpyrrole: [α]²⁸_D−5.0 (c 1.00, CHCl₃); IR

(film) 3649, 2942, 1697, 1366, 1059 cm⁻¹; ¹H NMR (600 MHz,

CDCl₃) δ 7.35−7.26 (m, 5H), 7.08 (ddd, J = 15.1, 7.9, 7.9 Hz, 1H),

6.39 (d, J = 15.1 Hz, 1H), 5.81 (s, 2H), 4.53 (s, 2H), 4.27 (m, 1H),

3.95 (m, 1H), 3.42 (m, 1H), 3.31 (m, 1H), 2.68−2.52 (m, 2H), 2.29

(s, 6H), 1.69 (m, 1H), 1.62−1.53 (m, 2H), 1.08−1.01 (m, 21H); ¹³C

NMR (150 MHz, CDCl₃) δ 166.9, 147.3, 137.8, 129.8 (2C), 128.5

(2C), 127.8 (3C), 127.6, 110.6 (2C), 74.7, 73.4, 69.3, 67.8, 39.9, 39.6,

18.1 (6C), 15.5 (2C), 12.5 (3C); HRMS (ESI) calcd for

C₃₀H₄₇NO₄SiNa [(M + Na)⁺] 536.3167, found 536.3163.

( )-29b. According to GP3, ( )-29b was prepared from ( )-28b:

1

IR (film) 3648, 2930, 1734, 1698, 1362, 1110, 703 cm⁻¹; H NMR

(600 MHz, CDCl₃) δ 7.66−7.62 (m, 4H), 7.41−7.33 (m, 6H), 3.81

(dddd, J = 13.2, 7.2, 5.5, 1.8 Hz, 1H), 3.77−3.66 (m, 4H), 3.49 (m,

1H), 3.11 (dd, J = 16.1, 7.2 Hz, 1H), 2.97 (dd, J = 16.1, 5.5 Hz, 1H),

2.58 (dd, J = 8.3, 7.9 Hz, 2H), 1.95−1.87 (m, 2H), 1.81−1.71 (m,

2H), 1.67−1.60 (m, 2H), 1.56−1.47 (m, 2H), 1.26−1.11 (m, 2H),

1.01 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 175.2, 171.8, 135.5

(4C), 134.1 (2C), 129.5 (2C), 127.6 (4C), 74.7, 73.8, 60.6, 45.4, 43.5,

39.3, 33.7, 31.4, 31.3, 26.8 (3C), 23.5, 19.2, 17.1; HRMS (ESI) calcd

for C₂₉H₃₉NO₄SiNa [(M + Na)⁺] 516.2541, found 516.2541.

( )-29c. According to GP3, ( )-29c was prepared from ( )-28c:

(+)-39. According to GP1, (+)-39 was prepared from (+)-7 and

1

IR (film) 2931, 2857, 1782, 1702, 1388, 1196, 1110, 704 cm⁻¹; H

1-(2-propenoyl)-2,5-dimethylpyrrole: [α]²⁸_D+1.3 (c 1.00, CHCl₃); IR

NMR (600 MHz, CDCl₃) δ 7.65−7.62 (m, 4H), 7.41−7.34 (m, 6H),

4.28−4.20 (m, 2H), 3.86−3.79 (m, 3H), 3.75 (ddd, J = 13.7, 7.6, 6.2

Hz, 1H), 3.69 (ddd, J = 13.7, 6.9, 5.5 Hz, 1H), 3.49 (m, 1H), 3.14 (dd,

J = 15.8, 7.9 Hz, 1H), 2.95 (dd, J = 15.8, 5.2 Hz, 1H), 1.80 (m, 1H),

1.73 (m, 1H), 1.68−1.61 (m, 2H), 1.60−1.48 (m, 2H), 1.28−1.12 (m,

2H), 1.02 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 170.9, 153.4, 135.5

(4C), 134.1, 134.0, 129.5 (2C), 127.6 (4C), 74.7, 73.8, 61.9, 60.5, 42.4,

41.8, 39.3, 31.3, 31.2, 26.8 (3C), 23.5, 19.8; HRMS (ESI) calcd for

C₂₈H₃₇NO₅SiNa [(M + Na)⁺] 518.2333, found 518.2318.

1

(film) 3649, 1698, 1541, 1404, 1365, 1263, 996 cm⁻¹; H NMR (600

MHz, CDCl₃) δ 7.66−7.62 (m, 4H), 7.41 − 7.33 (m, 6H), 6.94 (ddd,

J = 15.1, 7.6, 7.6 Hz, 1H), 6.37 (d, J = 15.1 Hz, 1H), 5.82 (s, 2H),

4.00−3.91 (m, 2H), 3.72−3.61 (m, 2H), 3.29 (br s, 1H), 2.67 (m,

1H), 2.58 (m, 1H), 2.30 (s, 6H), 1.71−1.49 (m, 3H), 1.41 (m, 1H),

1.25 (m, 1H), 1.02 (s, 9H), 0.98 (d, J = 7.2 Hz, 3H), 0.89 (s, 9H), 0.11

(s, 3H), 0.10 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 166.7, 146.3

(2C), 135.5 (4C), 133.9, 129.8 (2C), 129.5 (2C), 127.6 (4C), 127.4,

110.9 (2C), 76.7, 70.2, 64.0, 40.2, 38.5, 31.5, 29.3, 26.8 (3C), 25.8

(3C), 19.2, 17.9, 15.5 (2C), 10.8, −4.4, −4.8; HRMS (ESI) calcd for

C₃₉H₅₉NO₄Si₂Na [(M + Na)⁺] 684.3875, found 684.3886.

( )-29d. According to GP3, ( )-29d was prepared from ( )-28d:

1

IR (film) 2965, 1859, 1739, 1479, 820, 747 cm⁻¹; H NMR (600

MHz, CDCl₃) δ 7.99 (m, 1H), 7.65−7.57 (m, 4H), 7.42−7.30 (m,

6H), 7.25−7.14 (m, 3H), 3.93 (m, 1H), 3.72 (ddd, J = 16.5, 6.2, 4.1

Hz, 1H), 3.66 (ddd, J = 16.5, 6.5, 4.8 Hz, 1H), 3.52 (m, 1H), 3.29 (dd,

J = 16.5, 7.6 Hz, 1H), 3.16 (dd, J = 16.5, 5.2 Hz, 1H), 1.84 (m, 1H),

1.74−1.68 (m, 2H), 1.67−1.51 (m, 3H), 1.31 (m, 1H), 1.20 (m, 1H),

0.99 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 170.0, 151.3, 142.3,

135.5 (4C), 134.1, 129.4 (2C), 127.7 (2C), 127.5 (4C), 125.1, 124.7,

116.0, 109.7, 74.8, 73.3, 60.4, 43.4, 39.3, 31.3, 26.8 (3C), 26.5, 23.5,

19.2; HRMS (ESI) calcd for C₃₂H₃₇NNaO₅Si [(M + Na)⁺] 566.2333,

found 566.2323.

(+)-40. According to GP1, (+)-40 was prepared from (+)-8 and

1-(2-propenoyl)-2,5-dimethylpyrrole: [α]²³+17.8 (c 1.00, CHCl₃);

D

1

IR (film) 3445, 1694, 1540, 1366, 1257, 1096 cm⁻¹; H NMR (600

MHz, CDCl₃, a 6:1 mixture of E/Z isomers) δ 7.05 (ddd, J = 15.1, 6.9,

6.8 Hz, 6/7H), 6.40 (m, 1/7H), 6.35 (d, J = 15.5 Hz, 6/7H), 6.23 (d,

J = 11.3 Hz, 1/7H), 5.80 (s, 2H), 3.87 (m, 1H), 3.35 (m, 2/7H),

3.32−3.25 (m, 12/7H), 2.99 (ddd, J = 8.9, 8.9, 2.4 Hz, 1H), 2.74 (m,

1/7H), 2.59 (m, 1/7H), 2.51 (m, 6/7H), 2.37 (m, 6/7H), 2.33−2.29

(m, 6H), 2.12−2.03 (m, 13/7H), 1.99 (m, 1/7H), 1.72−1.51 (m, 4H),

1.38 (m, 1H); ¹³C NMR (150 MHz, CDCl₃, signals with asterisk

diagnostic for Z isomer) δ 167.5, 150.9, 150.1*, 130.0 (2C)*, 129.9

(2C), 125.4, 124.4*, 110.8 (2C)*, 110.6 (2C), 81.8*, 81.4, 70.4, 69.9*,

67.6, 33.2, 30.3, 28.6, 25.6, 15.7 (2C)*, 15.5 (2C); HRMS (ESI) calcd

for C₁₆H₂₃NO₃Na [(M + Na)⁺] 300.1570, found 300.1581.

( )-29e. According to GP3, ( )-29e was prepared from ( )-28e:

1

IR (film) 2931, 1699, 1454, 1351, 1206, 1110, 702 cm⁻¹; H NMR

(600 MHz, CDCl₃) δ 8.45 (d, J = 7.8 Hz, 1H), 7.61−7.57 (m, 4H),

7.52 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 3.6 Hz, 1H), 7.39−7.25 (m, 8H),

6.49 (d, J = 3.6 Hz, 1H), 3.91 (m, 1H), 3.72−3.61 (m, 2H), 3.56 (m,

1H), 3.07 (dd, J = 15.0, 6.0 Hz, 1H), 2.87 (dd, J = 15.0, 6.0 Hz, 1H),

1.86−1.78 (m, 2H), 1.72−1.62 (m, 2H), 1.62−1.52 (m, 2H), 1.32−

1.14 (m, 2H), 0.99 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 169.6,

135.6, 135.5 (4C), 134.1, 133.9, 130.4, 129.5 (2C), 127.5 (4C), 125.5,

124.9, 123.6, 120.7, 116.7, 108.7, 74.8, 74.3, 60.2, 43.1, 39.3, 31.6, 31.4,

26.8 (3C), 23.4, 19.2; HRMS (ESI) calcd for C₃₃H₃₉NO₃SiNa [(M +

Na)⁺] 548.2591, found 548.2600.

(+)-41. According to GP1, (+)-41 was prepared from (+)-9 and

1-(2-propenoyl)-2,5-dimethylpyrrole: [α]²⁵_D+6.2 (c 0.50, CHCl₃); IR

1

(film) 3649, 2925, 1698, 1541, 1457, 1363, 567 cm⁻¹; H NMR (600

MHz, CDCl₃) δ 7.06 (ddd, J = 15.1, 7.2, 7.2 Hz, 1H), 6.43 (d, J = 15.1

Hz, 1H), 5.83−5.78 (m, 2H), 4.08 (m, 1H), 3.93 (m, 1H), 3.69 (m,

1H), 2.98 (dd, J = 9.2, 1.7 Hz, 1H), 2.65 − 2.51 (m, 2H), 2.34−2.29

(m, 6H), 2.23−2.08 (m, 2H), 1.72− 1.61 (m, 4H), 1.42 (m, 1H); ¹³C

NMR (150 MHz, CDCl₃) δ 167.2, 147.7, 130.0 (2C), 127.4, 110.7

2601

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Featured Article

( )-29f. According to GP3, ( )-29f was prepared from ( )-28f:

(+)-47. According to GP3, (+)-47 was prepared from (−)-34

1

IR (film) 3647, 2930, 1652, 1264, 1360, 1111, 702 cm⁻¹; H NMR

(reaction time: 23 h): [α]²²+6.2 (c 1.00, CHCl₃); IR (film) 3549,

D

1

2939, 1779, 1697, 1389, 1227, 1099, 959, 708 cm⁻¹; H NMR (600

(600 MHz, CDCl₃) δ 8.21 (d, J = 7.8 Hz, 1H), 7.62−7.59 (m, 4H),

7.40−7.29 (m, 6H), 7.20−7.11 (m, 2H), 7.00 (dd, J = 7.8, 7.2 Hz,

1H), 4.12−3.96 (m, 2H), 3.88 (m, 1H), 3.76−3.66 (m, 2H), 3.55 (m,

1H), 3.12−3.01 (m, 2H), 2.64 (dd, J = 15.0, 6.6 Hz, 1H), 2.44 (dd, J =

15.0, 6.0 Hz, 1H), 1.84−1.78 (m, 2H), 1.75−1.62 (m, 2H), 1.62−1.52

(m, 2H), 1.25−1.12 (m, 2H), 0.99 (s, 9H); ¹³C NMR (150 MHz,

CDCl₃) δ 169.3, 142.9, 135.5 (4C), 134.0, 133.9, 131.3, 129.5, 128.3,

127.5 (4C), 127.4, 124.5, 123.6, 117.1, 75.0, 74.8, 60.4, 48.3, 43.1, 39.4,

31.7, 31.5, 27.9, 26.8 (3C), 23.4, 19.2; HRMS (ESI) calcd for

C₃₃H₄₂NO₃Si [(M + H)⁺] 528.2928, found 528.2938.

MHz, CDCl₃) δ 4.46−4.35 (m, 2H), 4.06−3.96 (m, 3H), 3.92 (m,

1H), 3.73 (dddd, J = 11.0, 6.5, 4.8, 2.1 Hz, 1H), 3.37 (m, 1H), 3.30

(dd, J = 16.9, 7.9 Hz, 1H), 3.07 (ddd, J = 13.4, 8.6, 4.4 Hz, 1H), 2.95

(dd, J = 16.9, 4.4 Hz, 1H), 2.83 (dd, J = 11.0, 8.6 Hz, 1H), 2.44 (d, J =

2.1 Hz, 1H), 2.08 (ddd, J = 12.7, 5.2, 2.0 Hz, 1H), 2.01 (m, 1H),

1.71−1.65 (m, 2H), 1.51 (m, 1H), 1.42 (m, 1H); ¹³C NMR (150

MHz, CDCl₃) δ 170.3, 153.4, 83.8, 74.9, 71.2, 70.2, 67.8, 62.1, 42.4,

41.0, 38.5, 29.1, 25.4; HRMS (ESI) calcd for C₁₃H₁₉NO₆Na [(M +

Na)⁺] 308.1105, found 308.1098.

1

( )-29g. IR (film) 2930, 1715, 1540, 1364, 1111, 702 cm⁻¹; H

(−)-48. According to GP3, (−)-48 was prepared from (+)-35

(reaction time: 22 h): [α]²³−6.5 (c 1.00, CHCl₃); IR (film) 3566,

NMR (600 MHz, CDCl₃) δ 7.66−7.61 (m, 4H), 7.41−7.31 (m, 6H),

5.80−5.76 (m, 2H), 3.89 (m, 1H), 3.77−3.66 (m, 2H), 3.52 (m, 1H),

2.96 (dd, J = 16.9, 6.2 Hz, 1H), 2.75 (dd, J = 16.9, 6.5 Hz, 1H), 2.34−

2.31 (m, 6H), 1.81 (m, 1H), 1.74−1.51 (m, 5H), 1.24−1.11 (m, 2H),

1.02 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 172.6, 135.5 (4C),

134.1, 134.0, 130.3 (2C), 129.5 (2C), 127.5 (4C), 111.3, 111.2, 74.9,

74.6, 60.4, 45.8, 39.4, 31.4 (2C), 26.9 (3C), 23.4, 19.2, 16.5 (2C);

HRMS (ESI) calcd for C₃₁H₄₁NO₃SiNa [(M + Na)⁺] 526.2748, found

526.2754.

D

1

2923, 1773, 1698, 1388, 1226, 1098, 959, 701 cm⁻¹; H NMR (600

MHz, CDCl₃) δ 4.42−4.33 (m, 3H), 4.08 (m, 1H), 4.00 (m, 1H), 3.91

(m, 1H), 3.61 (ddd, J = 10.3, 9.3, 3.8 Hz, 1H), 3.44 (ddd, J = 10.7,

10.7, 4.5 Hz, 1H), 3.25 (dd, J = 16.8, 8.3 Hz, 1H), 2.99 (dd, J = 9.3, 2.1

Hz, 1H), 2.84 (dd, J = 16.8, 3.4 Hz, 1H), 2.44 (m, 1H), 2.01 (m, 1H),

1.93 (m, 1H), 1.73−1.60 (m, 4H), 1.39 (dddd, J = 11.3, 11.3, 10.3, 5.5

Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 170.3, 153.5, 79.7, 70.6,

68.2, 67.8, 65.8, 62.0, 42.4, 40.8, 37.3, 29.4, 25.5; HRMS (ESI) calcd

for C₁₃H₁₉NO₆Na [(M + Na)⁺] 308.1105, found 308.1097.

( )-43. According to GP3, ( )-43 was prepared from ( )-30

(reaction time: 23 h): IR (film) 2924, 1780, 1702, 1510, 1388, 1248,

( )-49. According to GP3, ( )-49 was prepared from ( )-36

(reaction time: 30 h): IR (film) 2931, 1714, 1513, 1365, 1248, 1089

1

1038 cm⁻¹; H NMR (600 MHz, C₆D₆) δ 7.25 (d, J = 8.2 Hz, 2H),

1

cm⁻¹; H NMR (600 MHz, CDCl₃) δ 7.22 (d, J = 8.6 Hz, 2H), 6.84

6.81 (d, J = 8.2 Hz, 2H), 4.37 (s, 2H), 3.99 (m, 1H), 3.62 (m, 1H),

3.56−3.50 (m, 2H), 3.42 (dd, J = 16.1, 7.6 Hz, 1H), 3.30 (s, 3H),

3.06−2.91 (m, 5H), 1.87 (m, 1H), 1.75 (m, 1H), 1.57−1.48 (m, 2H),

1.34−1.26 (m, 2H), 1.17 (m, 1H), 1.09 (m, 1H); ¹³C NMR (150 MHz,

CDCl₃) δ 170.9, 159.1, 153.5, 130.8, 129.2 (2C), 113.7 (2C), 74.9,

73.8, 72.6, 66.6, 61.9, 55.3, 42.5, 41.9, 36.5, 31.3, 31.2, 23.5; HRMS

(ESI) calcd for C₂₀H₂₇NO₆Na [(M + Na)⁺] 400.1731, found 400.1727.

(+)-44. According to GP3, (+)-44 was prepared from (−)-31

(d, J = 8.6 Hz, 2H), 5.80 (s, 2H), 4.38 (s, 2H), 3.93 (m, 1H), 3.77 (s,

3H), 3.51−3.44 (m, 3H), 3.42 (dd, J = 15.8, 7.2 Hz, 1H), 2.76 (dd, J =

15.8, 5.5 Hz, 1H), 2.37 (s, 6H), 1.82 (m, 1H), 1.73−1.51 (m, 5H),

1.27−1.13 (m, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 172.6, 159.1,

130.7, 130.3 (2C), 129.3 (2C), 113.7 (2C), 111.2 (2C), 75.1, 74.6,

72.6, 66.5, 55.2, 45.7, 36.5, 31.4 (2C), 23.4, 16.5 (2C); HRMS (ESI)

calcd for C₂₃H₃₁NO₄Na [(M + Na)⁺] 408.2145, found 408.2136.

(+)-50. According to GP3, (+)-50 was prepared from (−)-37

(reaction time: 9 h): [α]²⁴+4.8 (c 1.00, CHCl₃); IR (film) 3567,

D

1

2942, 1784, 1700, 1387, 1225, 1111, 882, 703 cm⁻¹; H NMR (600

(reaction time: 5.5 h): [α]²⁶+7.6 (c 0.50, CHCl₃); IR (film) 2928,

D

MHz, CDCl₃) δ 7.66−7.62 (m, 4H), 7.41−7.33 (m, 6H), 4.30−4.21

(m, 2H), 3.90−3.83 (m, 3H), 3.79 (m, 1H), 3.76−3.67 (m, 2H), 3.49

(m, 1H), 3.21 (dd, J = 16.4, 7.9 Hz, 1H), 2.95 (dd, J = 16.4, 4.8 Hz,

1H), 1.98−1.85 (m, 2H), 1.81−1.63 (m, 2H), 1.31−1.19 (m, 2H),

1.05−0.99 (m, 30H); ¹³C NMR (150 MHz, CDCl₃) δ 170.7, 153.4,

135.5 (4C), 134.0 (2C), 129.5 (2C), 127.5 (4C), 72.5, 71.4, 68.5, 61.9,

60.8, 60.5, 42.4, 41.5, 38.8, 26.8 (3C), 19.2, 18.1 (6C), 12.3 (3C), 12.2;

HRMS (ESI) calcd for C₃₇H₅₇NO₆Si₂Na [(M + Na)⁺] 690.3617,

found 690.3607.

1

1716, 1684, 1541, 1457, 1112, 701, 538 cm⁻¹; H NMR (600 MHz,

CDCl₃) δ 7.63−7.60 (m, 4H), 7.39−7.31 (m, 6H), 5.78 (s, 2H),

3.91−3.85 (m, 2H), 3.75−3.67 (m, 2H), 3.51 (m, 1H), 3.01 (dd, J =

16.1, 6.9 Hz, 1H), 2.75 (dd, J = 16.1, 5.9 Hz, 1H), 2.32 (s, 6H), 2.00

(m, 1H), 1.88 (m, 1H), 1.73 (m, 1H), 1.65 (m, 1H), 1.25−1.17 (m,

2H), 1.06−0.99 (m, 30H); ¹³C NMR (150 MHz, CDCl₃) δ 172.3,

135.5 (4C), 134.0, 133.9, 130.2 (2C), 129.5 (2C), 127.6 (4C), 111.2

(2C), 72.7, 72.3, 68.4, 60.4, 45.3, 41.8, 41.6, 38.9, 30.9, 26.8 (3C),

19.2, 18.1 (6C), 16.4, 12.3 (3C); HRMS (ESI) calcd for

C₄₀H₆₁NO₄Si₂Na [(M + Na)⁺] 698.4031, found 698.4011

(−)-45. According to GP3, (−)-45 was prepared from (−)-32

(reaction time: 5 h): [α]²⁴−2.9 (c 1.00, CHCl₃); IR (film) 2942,

D

(−)-51. According to GP3, (−)-51 was prepared from (−)-38

1

2865, 1781, 1703, 1387, 1206, 1101, 882, 680 cm⁻¹; H NMR (600

(reaction time: 4.5 h): [α]²⁹−9.0 (c 1.00, CHCl₃); IR (film) 2865,

D

MHz, CDCl₃) δ 7.31−7.29 (m, 3H), 7.26−7.22 (m, 2H), 4.55 (d, J =

12.0 Hz, 1H), 4.53 (d, J = 12.0 Hz, 1H), 4.42 (m, 1H), 4.35−4.27 (m,

3H), 4.12 (m, 1H), 4.00−3.92 (m, 2H), 3.47−3.40 (m, 2H), 3.26 (dd,

J = 16.1, 8.2 Hz, 1H), 2.92 (d, J = 16.1, 4.4 Hz, 1H), 1.72 (m, 1H),

1.59 (m, 1H), 1.53−1.46 (m, 2H), 1.10−1.01 (m, 21H); ¹³C NMR

(150 MHz, CDCl₃) δ 170.8, 153.4, 138.6, 128.3 (2C), 127.5 (2C),

127.4, 73.5, 73.1, 71.4, 68.2, 64.8, 61.9, 42.5, 41.5, 39.1, 35.6, 18.1 (6C),

12.2 (3C); HRMS (ESI) calcd for C₂₇H₄₃NO₆SiNa [(M + Na)⁺]

528.2752, found 528.2754.

1

1715, 1541, 1457, 1364, 1042, 676, 519 cm⁻¹; H NMR (600 MHz,

CDCl₃) δ 7.31−7.27 (m, 3H), 7.26−7.22 (m, 2H), 5.78 (s, 2H),

4.54−4.44 (m, 3H), 4.32 (m, 1H), 4.10 (m, 1H), 3.45−3.39 (m, 2H),

3.08 (dd, J = 15.8, 7.2 Hz, 1H), 2.78 (dd, J = 15.8, 5.8 Hz, 1H), 2.35

(s, 6H), 1.76 (m, 1H), 1.61 (m, 1H), 1.53−1.45 (m, 2H), 1.09−1.02

(m, 21H); ¹³C NMR (150 MHz, CDCl₃) δ 172.4, 138.5, 130.1 (2C),

128.3 (2C), 127.6 (2C), 127.4, 110.0 (2C), 73.4, 73.2, 71.5, 69.3, 64.8,

45.5, 39.1, 35.7, 18.1 (6C), 16.3 (2C), 12.2 (3C); HRMS (ESI) calcd

for C₃₀H₄₇NO₄SiNa [(M + Na)⁺] 536.3167, found 536.3154.

(−)-46. According to GP3, (−)-46 was prepared from (+)-33

(reaction time: 7 h): [α]²⁴−12.5 (c 1.00, CHCl₃); IR (film) 2929,

(−)-52. According to GP3, (−)-52 was prepared from (+)-39

D

(reaction time: 3 h): [α]²⁷−13.7 (c 1.00, CHCl₃); IR (film) 2929,

1

2856, 1785, 1704, 1387, 1224, 1109, 702 cm⁻¹; H NMR (600 MHz,

D

1

2856, 1716, 1540, 1507, 1363, 1110, 775, 505 cm⁻¹; H NMR (600

C₆D₆) δ 7.66−7.62 (m, 4H), 7.42−7.38 (m, 2H), 7.37−7.34 (m, 4H),

4.36−4.29 (m, 2H), 3.95 (dd, J = 8.6, 7.6 Hz, 2H), 3.83−3.77 (m,

2H), 3.66 (ddd, J = 16.1, 10.3, 6.2 Hz, 1H), 3.62 (ddd, J = 16.5, 10.3,

6.5 Hz, 1H), 3.25 (m, 1H), 3.24 (dd, J = 16.5, 8.2 Hz, 1H), 2.92 (dd,

J = 16.4, 4.1 Hz, 1H), 1.66 (m, 1H), 1.62−1.51 (m, 4H), 1.49−1.39

(m, 2H), 1.02 (s, 9H), 0.87 (s, 9H), 0.81 (d, J = 6.9 Hz, 3H), 0.03 (s,

3H), 0.03 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 170.7, 153.4, 135.5

(4C), 134.0 (2C), 129.5 (2C), 127.6 (4C), 78.6, 71.8, 71.4, 63.8, 62.0,

42.5, 41.3, 38.9, 35.6, 29.1 (2C), 26.9 (3C), 25.8, 19.2, 18.0, 5.0 (3C),

−4.6 (2C); HRMS (ESI) calcd for C₃₆H₅₅NO₆Si₂Na [(M + Na)⁺]

676.3460, found 676.3461.

MHz, C₆D₆) δ 7.66−7.61 (m, 4H), 7.41−7.32 (m, 6H), 5.79 (s, 2H),

3.90 (m, 1H), 3.82 (m, 1H), 3.67−3.56 (m, 2H), 3.27 (m, 1H), 3.04

(dd, J = 15.8, 7.2 Hz, 1H), 2.75 (dd, J = 15.8, 4.8 Hz, 1H), 2.35 (s,

6H), 1.67 (m, 1H), 1.63−1.49 (m, 4H), 1.47−1.36 (m, 2H), 1.02 (s,

9H), 0.87 (s, 9H), 0.81 (d, J = 6.8 Hz, 3H), 0.04 (s, 3H), 0.03 (s, 3H);

¹³C NMR (150 MHz, CDCl₃) δ 172.4, 135.6 (4C), 134.0 (2C), 130.2

(2C), 129.5 (2C), 127.6 (4C), 111.2 (2C), 78.8, 72.8, 71.3, 63.8, 42.5,

38.8, 35.7, 29.0 (2C), 26.9 (3C), 25.8, 19.2, 18.0, 16.4 (2C), 5.0 (3C),

−4.6, −4.7; HRMS (ESI) calcd for C₃₉H₅₉NO₄Si₂Na [(M + Na)⁺]

684.3875, found 684.3890.

2602

dx.doi.org/10.1021/jo202179s | J. Org. Chem. 2012, 77, 2588−2607

The Journal of Organic Chemistry

Featured Article

1

(−)-53. According to GP3, (−)-53 was prepared from (+)-40

1252, 1110, 835, 702, 503 cm⁻¹; H NMR (600 MHz, CDCl₃) δ

7.66−7.62 (m, 4H), 7.42−7.32 (m, 6H), 5.76 (s, 2H), 4.42 (m, 1H),

3.92 (m, 1H), 3.65 (m, 1H), 3.61−3.56 (m, 2H), 3.01 (dd, J = 15.4,

7.9 Hz, 1H), 2.79 (dd, J = 15.4, 5.8 Hz, 1H), 2.35−2.31 (m, 5H), 1.93

(m, 1H), 1.84 (m, 1H), 1.77 (m, 1H), 1.67 (m, 1H), 1.53−1.46 (m,

3H), 1.41 (m, 1H), 1.01 (s, 9H), 0.87 (s, 9H), 0.84 (d, J = 6.8 Hz,

3H), 0.020 (s, 3H), 0.019 (s, 3H); ¹³C NMR (150 MHz, CDCl₃,

40 °C, signals with asterisk only weakly observed) δ 172.3, 135.6 (2C),

135.5 (2C), 134.20, 134.16, 130.0 (2C), 129.4 (2C), 127.5 (4C),

111.3 (2C), 76.3, 68.8, 63.9, 63.3*, 44.4, 38.1, 37.6*, 29.7, 29.4, 26.8

(3C), 25.8 (3C), 19.2, 18.0, 16.4 (2C), 11.6*, −4.6, −5.0; HRMS

(ESI) calcd for C₃₉H₆₀O₄Si₂N [(M + H)⁺] 662.4043, found 662.4055.

α,β-Unsaturated Ester (+)-56. To a solution of olefin (+)-7

(65.4 mg, 0.121 mmol) in CH₂Cl₂(0.6 mL) were added methyl

acrylate (0.22 mL, 2.4 mmol) and a solution of the Grubbs second-

generation catalyst (4.1 mg, 0.0048 mmol) in CH₂Cl₂(0.6 mL), and

the resultant solution was stirred at room temperature for 4 h. To the

reaction mixture was added an additional portion of a solution of the

Grubbs second-generation catalyst (4.1 mg, 0.0048 mmol) in CH₂Cl₂

(0.4 mL), and the resultant solution was stirred at room temperature

for 4 h. To the reaction mixture was added an additional portion of a

solution of the Grubbs second-generation catalyst (2.1 mg, 0.0025

mmol) in CH₂Cl₂(0.4 mL), and the resultant solution was stirred at

room temperature for 1 h. After complete consumption of (+)-7, the

reaction mixture was stirred at room temperature for 30 min under air

and then concentrated under reduced pressure. The residue was

purified by flash chromatography on silica gel (0 to 5 to 8 to 10%

EtOAc/hexanes) to give α,β-unsaturated ester (+)-56 (70.8 mg, 98%)

(reaction time: 7 h): [α]²⁴−25.4 (c 1.00, CHCl₃); IR (film) 3734,

D

1716, 1541, 1507, 1457, 1099, 773 cm⁻¹; ¹H NMR (600 MHz,

CDCl₃) δ 5.80 (s, 2H), 4.01 (m, 1H), 3.87 (m, 1H), 3.37 (ddd, J =

11.9, 11.9, 2.8 Hz, 1H), 3.11−3.04 (m, 2H), 2.94 (m, 1H), 2.79 (dd,

J = 16.0, 5.5 Hz, 1H), 2.36 (s, 6H), 2.01−1.88 (m, 3H), 1.76−1.63 (m,

2H), 1.58−1.35 (m, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 172.3,

130.3 (2C), 111.3 (2C), 78.3, 78.1, 74.2, 68.0, 45.1, 31.1, 29.6, 29.4,

25.7, 16.5 (2C); HRMS (ESI) calcd for C₁₆H₂₃NO₃Na [(M + Na)⁺]

300.1570, found 300.1580.

(−)-54. According to GP3, (−)-54 was prepared from (+)-41

(reaction time: 3 h): [α]²⁶−5.9 (c 0.50, CHCl₃); IR (film) 3735,

D

1716, 1541, 1507, 1457, 1102, 960 cm⁻¹; ¹H NMR (600 MHz,

CDCl₃) δ 5.80 (s, 2H), 4.12 (m, 1H), 3.92 (m, 1H), 3.76 (ddd, J =

11.0, 8.9, 5.2 Hz, 1H), 3.36 (m, 1H), 3.14−3.07 (m, 2H), 2.85−2.79

(m, 2H), 2.36 (s, 6H), 2.18 (ddd, J = 12.7, 5.2, 2.0 Hz, 1H), 2.01 (m,

1H), 1.71−1.66 (m, 3H), 1.49−1.38 (m, 2H); ¹³C NMR (150 MHz,

CDCl₃) δ 171.9, 130.3 (2C), 111.5 (2C), 83.8, 74.9, 72.3, 70.2, 67.9,

44.7, 38.5, 29.1, 25.4, 16.6 (2C); HRMS (ESI) calcd for

C₁₆H₂₃NO₄Na [(M + Na)⁺] 316.1519, found 316.1511.

(−)-55. According to GP3, (−)-55 was prepared from (+)-42

(reaction time: 6 h): [α]²⁸−18.9 (c 1.00, CHCl₃); IR (film) 3649,

D

1

1698, 1653, 1363, 1339, 669 cm⁻¹; H NMR (600 MHz, CDCl₃) δ

5.78 (s, 2H), 4.44 (m, 1H), 4.10 (dd, J = 5.8, 3.1 Hz, 1H), 3.92 (m,

1H), 3.62 (dddd, J = 9.6, 5.2, 4.4, 4.1 Hz, 1H), 3.44 (ddd, J = 11.3,

11.3, 3.4 Hz, 1H), 3.03−2.98 (m, 2H), 2.76 (dd, J = 15.8, 5.2 Hz, 1H),

2.36 (s, 6H), 2.05−1.97 (m, 2H), 1.71−1.58 (m, 4H), 1.37 (m, 1H);

¹³C NMR (150 MHz, CDCl₃) δ 172.1, 130.2 (2C), 111.2 (2C), 79.8,

70.8, 69.0, 68.2, 65.8, 44.7, 37.4, 29.4, 25.5, 16.4 (2C); HRMS (ESI)

calcd for C₁₆H₂₃NO₄Na [(M + Na)⁺] 316.1519, found 316.1510.

2,6-Trans-Substituted Tetrahydropyran (−)-trans-24. To a

solution of α,β-unsaturated thioester (+)-17 (52.1 mg, 0.0754 mmol)

in THF (0.5 mL) at −78 °C was added a solution of KOt-Bu (2.0 mg,

0.018 mmol) in THF (0.3 mL + 0.3 mL rinse), and the resultant

solution was stirred at −78 °C for 1.5 h. To the resultant solution was

added a solution of KOt-Bu (2.0 mg, 0.018 mmol) in THF (0.2 mL +

0.2 mL rinse), and the resultant solution was stirred at −78 °C for 0.5

h. The reaction was quenched with saturated aqueous NH₄Cl solution,

and the resultant mixture was extracted with EtOAc. The organic layer

was washed with brine, dried (Na₂SO₄), filtered, and concentrated

under reduced pressure. Purification of the residue by flash

chromatography on silica gel (2 to 6% Et₂O/hexanes) gave 2,6-

trans-substituted tetrahydropyran (−)-trans-24 (35.2 mg, 68%) along

as a pale brown oil: [α]²³+10.1 (c 1.00, CHCl₃); IR (film) 3517,

D

2952, 2857, 1727, 1428, 1257, 1111, 837, 703, 505 cm⁻¹; H NMR

1

(600 MHz, CDCl₃) δ 7.66−7.63 (m, 4H), 7.41−7.34 (m, 6H), 6.85

(ddd, J = 15.6, 7.8, 7.2 Hz, 1H), 5.84 (ddd, J = 15.6, 1.2, 1.2 Hz, 1H),

3.97 (m, 1H), 3.86 (ddd, J = 8.4, 5.4, 2.4 Hz, 1H), 3.72−3.60 (m, 5H),

3.32 (br s, 1H), 2.56 (dddd, J = 14.4, 8.4, 7.8, 1.2 Hz, 1H), 2.47 (dddd,

J = 14.4, 7.2, 5.4, 1.2 Hz, 1H), 1.65 (m, 1H), 1.58−1.46 (m, 3H), 1.40

(m, 1H), 1.02 (s, 9H), 0.95 (d, J = 7.2 Hz, 3H), 0.88 (s, 9H), 0.09

(s, 3H), 0.08 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 166.6, 144.9,

135.6 (4C), 133.91, 133.89, 129.5 (2C), 127.584 (2C), 127.577 (2C),

123.3, 76.9, 70.1, 63.9, 51.5, 39.5, 38.1, 31.2, 29.2, 26.8 (3C), 25.8

(3C), 19.2, 17.9, 10.9, −4.4, −4.7; HRMS (ESI) calcd for

C₃₄H₅₄O₅Si₂Na [(M + Na)⁺] 621.3402, found 621.3387.

2,6-Trans-Substituted Tetrahydropyran (−)-trans-57. Pre-

pared from (+)-56 in the same way as that described for (−)-trans-

24: [α]²²−18.7 (c 1.00, CHCl₃); IR (film) 2953, 2857, 1743, 1428,

with (−)-cis-24 (8.9 mg, 17%). Data for (−)-trans-24: [α]²³−27.1

D

1

1254, 1110, 836, 702, 504 cm⁻¹; H NMR (600 MHz, CDCl₃) δ

(c 1.00, CHCl₃); IR (film) 2929, 2856, 1706, 1467, 1428, 1253, 1110,

994, 835, 702, 506 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 7.67−7.65 (m,

4H), 7.41−7.33 (m, 6H), 7.25−7.22 (m, 2H), 7.16−7.13 (m, 2H), 4.40

(m, 1H), 3.92 (ddd, J = 6.9, 6.8, 3.4 Hz, 1H), 3.72−3.59 (m, 3H), 2.90

(dd, J = 14.4, 8.2 Hz, 1H), 2.66 (dd, J = 14.4, 5.5 Hz, 1H), 2.32 (s, 3H),

1.91 (m, 1H), 1.84 (ddd, J = 7.2, 3.8, 3.4 Hz, 1H), 1.79−1.70 (m, 2H),

1.53−1.46 (m, 3H), 1.02 (s, 9H), 0.88 (s, 9H), 0.85 (d, J = 7.2 Hz, 3H),

0.04 (s, 3H), 0.03 (s, 3H); ¹³C NMR (150 MHz, CDCl₃, 40 °C) δ 195.1,

139.5, 135.6 (4C), 134.36 (2C), 134.29, 134.25, 130.0 (2C), 129.5 (2C),

127.6 (4C), 124.4, 75.3, 68.6, 65.1, 63.9, 48.2, 38.5, 36.4, 29.5, 26.9 (3C),

26.1, 25.9 (3C), 21.3, 19.3, 18.0, 10.1, −4.5, −4.9; HRMS (ESI) calcd for

C₄₀H₅₈O₄SSi₂Na [(M + Na)⁺] 713.3487, found 713.3490.

7.66−7.35 (m, 4H), 7.41−7.35 (m, 6H), 4.31 (m, 1H), 3.90 (ddd, J =

6.9, 3.5, 3.4 Hz, 1H), 3.69 (m, 1H), 3.65−3.59 (m, 5H), 2.58 (dd, J =

14.4, 8.6 Hz, 1H), 2.37 (dd, J = 14.4, 5.8 Hz, 1H), 1.92 (m, 1H), 1.83

(m, 1H), 1.75 (ddd, J = 13.4, 6.5, 3.5 Hz, 1H), 1.69 (m, 1H), 1.52−

1.41 (m, 3H), 1.03 (s, 9H), 0.88 (s, 9H), 0.85 (d, J = 7.2 Hz, 3H),

0.033 (s, 3H), 0.026 (s, 3H); ¹³C NMR (150 MHz, CDCl₃, 45 °C) δ

171.6, 135.61 (2C), 135.59 (2C), 134.33, 134.31, 129.5 (2C), 127.6

(4C), 75.3, 68.8, 64.4, 63.9, 51.5, 39.8, 38.5, 36.7, 29.5, 26.9 (3C), 25.9

(4C), 19.3, 18.1, 10.4, −4.6, −4.9; HRMS (ESI) calcd for

C₃₄H₅₄O₅Si₂Na [(M + Na)⁺] 621.3402, found 621.3402.

Aldehyde ( )-58. To a solution of thioester ( )-21 (56.3 mg,

0.106 mmol) in CH₂Cl₂(0.5 mL) were added 10% Pd/C (5.6 mg)

and Et₃SiH (0.050 mL, 0.31 mmol), and the resultant mixture was

stirred at room temperature for 2 h. Insoluble materials were filtered

off, and the filtrate was concentrated under reduced pressure.

Purification of the residue by flash chromatography on silica gel

(3 to 7 to 10% EtOAc/hexanes) gave aldehyde ( )-58 (37.2 mg, 86%)

as a colorless oil: IR (film) 2932, 2857, 1727, 1428, 1111, 738, 703,

2,6-Trans-Substituted Tetrahydropyran ( )-trans-29c. Pre-

pared from ( )-28c (73% yield) in the same way as that described for

(−)-trans-24: IR (film) 2931, 1782, 1701, 1473, 1387, 1111, 702, 614,

504 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 7.67−7.62 (m, 4H), 7.41−

7.33 (m, 6H), 4.28−4.17 (m, 3H), 3.98 (m, 1H), 3.80−3.66 (m, 4H),

3.31 (dd, J = 15.8, 8.6 Hz, 1H), 2.92 (dd, J = 15.8, 4.8 Hz, 1H), 1.96

(m, 1H), 1.71−1.60 (m, 5H), 1.42−1.30 (m, 2H), 1.01 (s, 9H); ¹³C

NMR (150 MHz, CDCl₃) δ 170.9, 153.4, 135.6, 134.1, 134.0, 129.5

(2C), 129.4 (2C), 128.3, 127.6 (2C), 127.5 (2C), 68.7, 67.2, 61.9,

60.8, 42.4, 39.4, 35.7, 30.0, 29.6, 26.8 (3C), 19.1, 18.6; HRMS (ESI)

calcd for C₂₈H₃₇O₅SiNNa [(M + Na)⁺] 518.2333, found 518.2327.

2,6-Trans-Substituted Tetrahydropyran (−)-trans-52. Pre-

pared from (+)-39 in the same way as that described for (−)-trans-

504 cm⁻¹; H NMR (600 MHz, C₆D₆) δ 9.47 (dd, J = 3.0, 1.8 Hz,

1

1H), 7.81−7.77 (m, 4H), 7.30−7.23 (m, 6H), 3.87 (ddd, J = 10.2, 8.4,

5.4 Hz, 1H), 3.75 (ddd, J = 10.2, 6.6, 4.8 Hz, 1H), 3.44−3.37 (m, 2H),

2.18 (ddd, J = 16.2, 7.8, 3.0 Hz, 1H), 1.92 (ddd, J = 16.2, 4.8, 1.8 Hz,

1H), 1.75−1.63 (m, 2H), 1.46 (m, 1H), 1.26−1.12 (m, 12H), 0.98

(dddd, J = 12.6, 12.6, 11.4, 4.2 Hz, 1H), 0.89 (m, 1H); ¹³C NMR (150

MHz, C₆D₆) δ 199.9, 135.96 (2C), 135.94 (2C), 134.31, 134.29,

24: [α]²⁶−6.8 (c 1.00, CHCl₃); IR (film) 2928, 1716, 1541, 1457,

D

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130.0, 129.9, 128.1 (2C), 128.0 (2C), 74.4, 72.7, 60.6, 50.1, 39.7, 31.5,

31.4, 27.1 (3C), 23.6, 19.4; HRMS (ESI) calcd for C₂₅H₃₄O₃SiNa

[(M + Na)⁺] 433.2169, found 433.2169.

Ynone ( )-62. To a solution of thioester ( )-21 (59.1 mg, 0.111

mmol), Pd₂(dba)₃·CHCl₃(5.7 mg, 0.0055 mmol), (2-furyl)₃P (10.3

mg, 0.0444 mmol), and CuI (35.9 mg, 0.188 mmol) in degassed DMF

(1.0 mL) were added ethynylbenzene (0.025 mL, 0.23 mmol) and

Et₃N (0.2 mL). The resultant mixture was stirred at 50 °C for 17 h.

After being cooled to room temperature, the reaction mixture was

diluted with Et₂O and H₂O and treated with Celite. The resultant

suspension was stirred at room temperature for a while. Insoluble

materials were filtered off, and the filtrate was washed with brine, dried

(MgSO₄), filtered, and concentrated under reduced pressure. Flash

chromatography on silica gel (3 to 5 to 50% EtOAc/hexanes) followed

by preparative HPLC (CHCl₃) gave ynone ( )-62 (42.9 mg, 76%) as

a yellow oil: IR (film) 2931, 2856, 2204, 1670, 1427, 1110, 1085, 757,

Amide ( )-59. To a solution of thioester ( )-21 (41.9 mg, 0.0786

mmol) in toluene (1 mL) were added piperidine (0.023 mL, 0.23

mmol) and AgOCOCF₃(19.1 mg, 0.0865 mmol), and the resultant

mixture was stirred at 60 °C for 20 min. After being cooled to room

temperature, the resultant mixture was diluted with CH₂Cl₂and 10%

NH₄OH and stirred vigorously for 10 min. Insoluble materials were

filtered off, and the filtrate was extracted with CH₂Cl₂. The combined

organic layers were dried (Na₂SO₄), filtered, and concentrated under

reduced pressure. Purification of the residue by flash chromatography

on silica gel (30% EtOAc/hexanes) gave amide ( )-59 (38.5 mg,

99%) as a colorless oil: IR (film) 2933, 2856, 1639, 1428, 1195, 1111,

1

703, 504 cm⁻¹; H NMR (600 MHz, CDCl₃) δ 7.64−7.61 (m, 4H),

1

703, 504 cm⁻¹; H NMR (600 MHz, CDCl₃) δ 7.65−7.62 (m, 4H),

7.52−7.49 (m, 2H), 7.43−7.31 (m, 9H), 3.93 (dddd, J = 13.2, 7.2, 6.0,

2.4 Hz, 1H), 3.78 (ddd, J = 10.2, 7.8, 6.0 Hz, 1H), 3.69 (ddd, J = 10.2,

6.0, 5.4 Hz, 1H), 3.56 (dddd, J = 12.6, 7.8, 4.8, 2.4 Hz, 1H), 2.86 (dd,

J = 15.6, 7.2 Hz, 1H), 2.67 (dd, J = 15.6, 6.0 Hz, 1H), 1.82 (m, 1H),

1.75−1.61 (m, 3H), 1.60−1.51 (m, 2H), 1.27−1.14 (m, 2H), 1.00 (s,

9H); ¹³C NMR (150 MHz, CDCl₃) δ 185.7, 135.52 (2C), 135.49

(2C), 134.0, 133.9, 133.0 (2C), 130.6, 129.5 (2C), 128.6 (2C), 127.56

(2C), 127.55 (2C), 120.0, 90.8, 88.0, 74.8, 73.9, 60.2, 52.1, 39.2, 31.30,

31.27, 26.8 (3C), 23.5, 19.2; HRMS (ESI) calcd for C₃₃H₃₈O₃SiNa

[(M + Na)⁺] 533.2482, found 533.2478.

7.41−7.34 (m, 6H), 3.77−3.67 (m, 3H), 3.56−3.47 (m, 2H), 3.44−

3.37 (m, 2H), 3.29 (m, 1H), 2.58 (dd, J = 14.4, 6.0 Hz, 1H), 2.31 (dd,

J = 14.4, 6.6 Hz, 1H), 1.80−1.70 (m, 3H), 1.68−1.62 (m, 2H), 1.60−

1.44 (m, 7H), 1.19−1.10 (m, 2H), 1.02 (s, 9H); ¹³C NMR (150 MHz,

CDCl₃) δ 169.2, 135.5 (4C), 134.0, 133.9, 129.5, 128.3, 127.58 (2C),

127.57 (2C), 75.4, 74.8, 60.5, 47.1, 42.6, 40.2, 39.5, 31.7, 31.5, 26.8

(3C), 26.5, 25.6, 24.5, 23.5, 19.2; HRMS (ESI) calcd for C₃₀H₄₄NO₃Si

[(M + H)⁺] 494.3085, found 494.3092.

Enone ( )-60. To a solution of thioester ( )-21 (43.3 mg, 0.0813

mmol), Pd₂(dba)₃(3.7 mg, 0.0040 mmol), and CuDPP (45.6 mg,

0.162 mmol) in degassed THF (1.0 mL) were added a solution of

(EtO)₃P (0.006 mL, 0.03 mmol) in THF (0.1 mL) and tri(n-

butyl)vinylstannane (0.030 mL, 0.10 mmol), and the resultant mixture

was stirred at room temperature overnight (21 h). The resultant

mixture was diluted with CH₂Cl₂and treated with Celite. The

resultant suspension was stirred at room temperature for a while, and

then filtered through a pad of Celite. The filtrate was concentrated

under reduced pressure. Purification of the residue by flash

chromatography on silica gel (3 to 5 to 10% EtOAc/hexanes) gave

enone ( )-60 (28.2 mg, 79%) as a yellow oil, along with recovered

starting material (8.1 mg, 19%). Data for ( )-60: IR (film) 2931,

Carboxylic Acid ( )-63. To a solution of imide ( )-29c (42.3

mg, 0.085 mmol) in THF (1.4 mL) at 0 °C were added a solution of

LiOH·H₂O (7.2 mg, 0.17 mmol) in H₂O (0.5 mL) and H₂O₂(30%

aqueous solution, 38 μL, 0.34 mmol). The resultant solution was

stirred at room temperature for 5 h before it was quenched with

saturated aqueous Na₂SO₃solution. The mixture was diluted with

H₂O and washed with CH₂Cl₂. The aqueous layer was acidified with

1 M aqueous HCl solution and extracted with EtOAc. The organic

layer was dried (Na₂SO₄), filtered, and concentrated under reduced

pressure. Purification of the residue by flash chromatography on silica

gel (20% EtOAc/hexanes) gave carboxylic acid ( )-63 (32.3 mg,

89%) as colorless oil: IR (film) 3647, 2931, 1715, 1541, 1111, 702

cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 7.65−7.61 (m, 4H), 7.43−7.34

(m, 6H), 3.77 (dddd, J = 8.2, 5.5, 5.2, 5.1 Hz, 1H), 3.73−3.62 (m,

3H), 2.54−2.46 (m, 2H), 1.84 (m, 1H), 1.77−1.66 (m, 2H), 1.64−

1.47 (m, 3H), 1.31−1.18 (m, 3H), 1.03 (s, 9H); ¹³C NMR (150 MHz,

CDCl₃) δ 173.7, 135.5 (4C), 133.9, 133.8, 129.6 (2C), 127.6 (4C),

75.4, 73.9, 60.0, 41.0, 39.1, 31.1, 30.9, 26.9 (3C), 23.1, 19.2; HRMS

(ESI) calcd for C₂₅H₃₄O₄SiNa [(M + Na)⁺] 449.2119, found 449.2117.

Ester ( )-64. To a solution of imide ( )-29c (47.2 mg, 0.095

mmol) in CH₂Cl₂(1.0 mL) at −25 °C was treated with a cold (0 °C)

solution of NaOMe (0.5 M solution in MeOH, 0.20 mL, 0.10 mmol)

over 15 min. The resultant solution was stirred at −25 °C for 15 min

before it was quenched with saturated aqueous NH₄Cl solution. The

resultant mixture was extracted with EtOAc. The organic layer was

washed with brine, dried (Na₂SO₄), filtered, and concentrated under

reduced pressure. Purification of the residue by flash chromatography

on silica gel (5% EtOAc/hexanes) gave methyl ester ( )-64 (40.0 mg,

96%) as colorless clear oil: IR (film) 2931, 1742, 1428, 1111, 703

cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 7.66−7.62 (m, 4H), 7.41−7.34

(m, 6H), 3.75 (ddd, J = 13.7, 7.6, 6.2 Hz, 1H), 3.74−3.67 (m, 2H),

3.58 (s, 3H), 3.51 (dddd, J = 12.8, 12.7, 4.5, 1.7 Hz, 1H), 2.48 (dd, J =

15.0, 7.2 Hz, 1H), 2.35 (dd, J = 15.0, 6.6 Hz, 1H), 1.82−1.48 (m, 6H),

1.26−1.12 (m, 2H), 1.02 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ

171.8, 135.5 (4C), 134.1, 134.0, 129.5 (2C), 127.6 (4C), 74.7, 74.3,

60.4, 51.5, 41.6, 39.3, 31.3, 31.2, 26.8 (3C), 23.4, 19.2; HRMS (ESI)

calcd for C₂₆H₃₆O₄SiNa [(M + Na)⁺] 463.2281, found 463.2276.

Aldehyde ( )-58 (from ( )-29c). To a solution of imide

( )-29c (43.6 mg, 0.088 mmol) in CH₂Cl₂(1.0 mL) at −78 °C

was added DIBALH (1.03 M solution in n-hexane, 0.094 mL, 0.097

mmol), and the resultant solution was stirred at −78 °C for 3 h before

it was quenched with MeOH. The reaction mixture was diluted with

saturated aqueous potassium sodium tartrate solution and EtOAc, and

the resultant biphasic mixture was vigorously stirred at room

temperature until the layers become clear. The organic layer was

separated, and the aqueous layer was extracted with EtOAc. The

1

2856, 1685, 1427, 1111, 702, 737, 504 cm⁻¹; H NMR (600 MHz,

C₆D₆) δ 7.81−7.76 (m, 4H), 7.28−7.21 (m, 6H), 6.12 (dd, J = 17.5,

10.7 Hz, 1H), 5.86 (dd, J = 17.5, 1.0 Hz, 1H), 5.15 (dd, J = 10.7, 1.0

Hz, 1H), 3.87 (m, 1H), 3.79 (m, 1H), 3.75 (m, 1H), 3.41 (m, 1H),

2.62 (dd, J = 15.5, 6.5 Hz, 1H), 2.25 (dd, J = 15.5, 5.8 Hz, 1H), 1.77

(m, 1H), 1.69 (m, 1H), 1.50 (m, 1H), 1.43 (m, 1H), 1.28−1.19 (m,

2H), 1.18 (s, 9H), 1.06−0.94 (m, 2H); ¹³C NMR (150 MHz, C₆D₆) δ

197.7, 137.3, 135.99 (2C), 135.96 (2C), 134.5, 134.4, 129.89 (2C),

129.86 (2C), 128.3 (2C), 127.2, 74.6, 74.4, 60.9, 46.7, 40.0, 31.8 (2C),

27.1 (3C), 23.7, 19.5; HRMS (ESI) calcd for C₂₇H₃₆O₃SiNa [(M +

Na)⁺] 459.2326, found 459.2337.

Phenyl Ketone ( )-61. To a solution of thioester ( )-21 (66.9

mg, 0.126 mmol), PhB(OH)₂(23.0 mg, 0.189 mmol), Pd₂(dba)₃(5.8

mg, 0.0063 mmol), and CuTC (35.9 mg, 0.188 mmol) in degassed

THF (1.7 mL) was added a solution of (EtO)₃P (0.0086 mL, 0.050

mmol) in degassed THF (0.1 mL), and the resultant mixture was

stirred at room temperature for 2 h 50 min. The resultant mixture was

diluted with Et₂O, washed with saturated aqueous NaHCO₃solution

and brine, dried (MgSO₄), filtered, and concentrated under reduced

pressure. Flash chromatography on silica gel (5% EtOAc/hexanes)

followed by preparative HPLC (CHCl₃) gave phenyl ketone ( )-61

(34.7 mg, 57%) as a colorless oil: IR (film) 2931, 2856, 1682, 1427,

1111, 702, 502 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 7.93−7.91

(m, 2H), 7.63−7.59 (m, 4H), 7.51 (m, 1H), 7.41−7.31 (m, 8H), 3.89

(dddd, J = 12.6, 7.2, 6.0, 1.8 Hz, 1H), 3.70 (ddd, J = 10.2, 7.8, 6.0 Hz,

1H), 3.64 (ddd, J = 10.2, 6.6, 6.6 Hz, 1H), 3.53 (dddd, J = 12.6, 7.8,

4.8, 1.8 Hz, 1H), 3.19 (dd, J = 16.2, 6.0 Hz, 1H), 2.92 (dd, J = 16.2, 7.2

Hz, 1H), 1.80 (m, 1H), 1.74 (m, 1H), 1.71−1.61 (m, 2H), 1.59−1.51

(m, 2H), 1.24−1.14 (m, 2H), 1.00 (s, 9H); ¹³C NMR (150 MHz,

CDCl₃) δ 198.7, 137.4, 135.52 (2C), 135.51 (2C), 134.1, 134.0, 132.9,

129.4 (2C), 128.4 (2C), 128.2 (2C), 127.54 (2C), 127.53 (2C), 74.7,

74.5, 60.2, 45.5, 39.4, 31.7, 31.5, 26.8 (3C), 23.5, 19.2; HRMS (ESI)

calcd for C₃₁H₃₈O₃SiNa [(M + Na)⁺] 509.2482, found 509.2487.

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combined organic layers were washed with brine, dried (Na₂SO₄),

filtered, and concentrated under reduced pressure. Purification of the

residue by flash chromatography on silica gel (5 to 10% EtOAc/

hexanes) gave aldehyde ( )-58 (28.8 mg, 80%) as a colorless oil. The

spectroscopic data of this material were matched those reported above.

Carboxylic Acid ( )-63 (from ( )-29g). To a solution of amide

( )-29g (34.4 mg, 0.0683 mmol) in THF (1.0 mL) at 0 °C were

added a solution of LiOH·H₂O (5.7 mg, 0.14 mmol) in H₂O (0.3 mL)

and 30% aqueous H₂O₂solution (31 μL, 0.27 mmol). The resultant

mixture was stirred at room temperature for 23 h. After being cooled

to 0 °C, the mixture were treated with a solution of LiOH·H₂O (5.7

mg, 0.14 mmol) in H₂O (0.3 mL) and 30% aqueous H₂O₂solution

(31 μL, 0.27 mmol). The resultant mixture was stirred at room

temperature for 3.5 h before it was quenched with saturated aqueous

Na₂SO₃solution. The resultant mixture was diluted with H₂O and

washed with CH₂Cl₂. The aqueous layer was acidified with 1 M

aqueous HCl solution and extracted with EtOAc. The organic layer

was dried (Na₂SO₄), filtered, and concentrated under reduced

pressure. Purification of the residue by flash chromatography on silica

gel (10% EtOAc/benzene) gave carboxylic acid ( )-63 (27.8 mg,

96%) as a colorless oil. The spectroscopic data of this material

matched those reported above.

ASSOCIATED CONTENT

■

S

* Supporting Information

Stereochemical assignment of the cyclization products and

1

copies of H and ¹³C NMR spectra for all new compounds.

This material is available free of charge via the Internet at

http://pubs.acs.org.

AUTHOR INFORMATION

■

Corresponding Author

*E-mail: hfuwa@bios.tohoku.ac.jp.

ACKNOWLEDGMENTS

■

We thank Professor Tohru Fukuyama (University of Tokyo)

for his kind suggestions and Dr. Kenji Sugimoto (University of

Toyama) for his advice on the preparation of S-ethyl 2-

propenthioate. This work was supported in part by a Grant-in-

Aid for Young Scientists (A) and by a Grant-in-Aid for

Scientific Research (A) from Japan Society for the Promotion

of Science (JSPS).

Ester ( )-64 (from ( )-29g). To a solution of amide ( )-29g

(44.2 mg, 0.088 mmol) in CH₂Cl₂(1.0 mL) at −25 °C was added a

cold (0 °C) solution of NaOMe (0.5 M solution in MeOH, 0.20 mL,

0.10 mmol). The resultant solution was stirred at 0 °C for 17 h before

it was quenched with saturated aqueous NH₄Cl solution. The resultant

mixture was extracted with EtOAc. The organic layer was washed with

brine, dried (Na₂SO₄), filtered, and concentrated under reduced

pressure. Purification of the residue by flash chromatography on silica

gel (10% EtOAc/hexanes) gave methyl ester ( )-64 (36.0 mg, 93%)

as a colorless clear oil. The spectroscopic data of this material matched

those reported above.

Aldehyde ( )-58 (from ( )-29g). To a solution of amide

( )-29g (53.9 mg, 0.11 mmol) in toluene/CH₂Cl₂(1:1, v/v, 1.0 mL)

at 0 °C was added DIBALH (1.03 M solution in n-hexane, 0.12 mL,

0.13 mmol), and the resultant solution was stirred at 0 °C for 10 min

before it was quenched with MeOH. The reaction mixture was diluted

with saturated aqueous potassium sodium tartrate solution and EtOAc,

and the resultant biphasic mixture was vigorously stirred at room

temperature until the layers became clear. The organic layer was

separated, and the aqueous layer was extracted with EtOAc. The

combined organic layers were washed with brine, dried (Na₂SO₄),

filtered, and concentrated under reduced pressure. Purification of the

residue by flash chromatography on silica gel (10% EtOAc/hexanes)

gave pyrrole carbinol ( )-65 (53.4 mg, 99%) as a 1:1 mixture of

diastereomers and as a colorless oil: IR (film) 3420, 3070, 2931, 2857,

1716, 1428, 1392, 1284, 1110, 702 cm⁻¹; ¹H NMR (600 MHz,

CDCl₃) δ 7.66−7.62 (m, 4H), 7.42−7.34 (m, 6H), 5.75 (m, 1H), 5.71

(s, 2H), 3.78−3.68 (m, 2H), 3.53−3.48 (m, 2H), 3.30 (m, 1H), 2.28−

2.24 (m, 7H), 2.18 (m, 1H), 1.91 (ddd, J = 14.5, 5.9, 2.1 Hz, 1H),

1.84−1.75 (m, 2H), 1.66 (m, 1H), 1.45 (m, 1H), 1.29−1.13 (m, 3H),

1.03 ppm (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 135.5 (4C), 133.9,

133.8, 129.6 (2C), 127.9 (2C), 127.6 (4C), 106.7, 106.6, 78.8, 75.6

(1/2C), 74.9 (1/2C), 74.7 (1/2C), 74.5 (1/2C), 60.5, 42.7, 39.4

(1/2C), 39.3 (1/2C), 31.7 (1/2C), 31.5 (1/2C), 31.1 (1/2C), 26.9

(3C), 23.5 (1/2C), 23.2, 19.2, 13.6, 13.5 ppm; HRMS (ESI) calcd for

C₃₁H₄₃NNaO₃Si [(M + Na)⁺] 528.2904, found 528.2892.

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To a solution of pyrrole carbinol ( )-65 (33.6 mg, 0.067 mmol) in

MeOH (1.0 mL) was added CaCO₃(1.0 mg, 10 μmol), and the

resultant solution was stirred at 60 °C for 28.5 h. The reaction mixture

was cooled to room temperature, diluted with EtOAc, washed with

H₂O and brine, dried (Na₂SO₄), filtered, and concentrated under

reduced pressure. Purification of the residue by flash chromatography

on silica gel (benzene) gave aldehyde ( )-58 (20.8 mg, 74%) as a

colorless oil. The spectroscopic data of this material matched those

reported above.

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dx.doi.org/10.1021/jo202179s | J. Org. Chem. 2012, 77, 2588−2607

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Stereoselective synthesis of 2,6- cis -substituted tetrahydropyrans: Bronsted acid-catalyzed intramolecular oxa-conjugate cyclization of α,β-unsaturated ester surrogates

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