Oxidative rearrangement of 2-alkoxy-3,4-dihydro-2H-pyrans: stereocontrolled synthesis of 4,5-cis-disubstituted tetrahydrofuranones including whisky and cognac lactones and crobarbatic acid

Tetrahedron 65 (2009) 4490–4504

Contents lists available at ScienceDirect

Tetrahedron

journal homepage: w ww.elsevier.com/locate/tet

Oxidative rearrangement of 2-alkoxy-3,4-dihydro-2H-pyrans: stereocontrolled

synthesis of 4,5-cis-disubstituted tetrahydrofuranones including whisky

and cognac lactones and crobarbatic acid

,

a

b

Alan Armstrong ^a, Cassim Ashraff , Hunsuk Chung , Lorraine Murtagh

*

^aDepartment of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK

^bPﬁzer Global Research & Development, Sandwich, Kent CT13 9NJ, UK

a r t i c l e i n f o

a b s t r a c t

Article history:

Oxidation of 2-alkoxy-3,4-dihydro-2H-pyrans 3 with dimethyldioxirane or MTO/urea–H₂O₂followed by

Jones oxidation leads to rearrangement and stereocontrolled formation of 4,5-cis-disubstituted tetra-

hydrofuranones. The method is applied to the synthesis of the whisky lactone 9, cognac lactone 10 and

crobarbatic acid 17.

Received 4 November 2008

Received in revised form 16 March 2009

Accepted 2 April 2009

Available online 10 April 2009

1. Introduction

investigated microwave conditions (conditions B), which allowed

completion in much shorter times (2–3 h). Where applicable, the

Tetrahydrofurans (THFs) are key motifs of several classes of bi-

ologically important natural product,¹and methods for their ster-

eocontrolled synthesis are therefore important and actively sought.²

In 1970, Hall and co-workers reported that oxidation of some simple

2-alkoxy-3,4-dihydro-2H-pyrans 3 (R²–R⁴¼H) with m-CPBA afforded

the THFs 4, presumably via the intermediate epoxide 5 (Scheme 1).³

Since then, this rearrangement has been exploited in the speciﬁc case

of spiroketal synthesis, by Ireland⁴and Rizzacasa and McRae.⁵Be-

cause awide range of the starting pyrans 3 may be readilyaccessed by

Lewis-acid promoted hetero-Diels–Alder reaction between an enone

and an enol ether, we wished to explore the generality of the oxi-

dative rearrangement process, particularly with regard to diaster-

eoselectivity issues, which had not previously been addressed. Our

recent demonstration that diastereoselective aziridination of 3 leads

to substituted pyrrolidines with a high level of stereocontrol provided

encouragement in this regard.⁶In this paper, we report in full our

studies on the oxidative rearrangement of pyrans 3.

cycloadditions afforded predominantly one diastereomer. Litera-

ture precedent⁷suggests that the major diastereomer is the endo-

cycloadduct, with the C2-alkoxy group and the C4-substituent R³in

a cis-relationship. Analysis of ¹H NMR coupling constants for the

major product supported by molecular mechanics analysis (MMFF,

Spartan) suggested that H2 is pseudoaxial (J_H2–H37.0–9.5 Hz) and

thus both the C2-alkoxy substituent and the C4-substituent R³are

likely to be pseudoequatorial. On standing in CDCl₃, the major endo-

diastereomer underwent epimerisation to the minor exo-isomer,

having a pseudoaxial alkoxy group (J_H2–H32.5–3.0 Hz), preferred

due to the anomeric effect.

2.2. Oxidative rearrangement of 6-substituted pyrans

With a convenient synthesis of substrates 3 in hand, we were now

in a position to test their epoxidation/rearrangement. Initially, we

employed the least substituted substrate 3a to screen several com-

mon epoxidation reagents (Table 2). Reaction of 3a with commercial

m-CPBA in CH₂Cl₂(entry 1) afforded only a low yield (14%) of the

desired THF 4a, along with the lactol 6 (ca. 10%), presumably arising

from hydrolysis of 4a. Concerns that the low yield of 4a may be partly

due to its volatility led us also to test the ⁿBu-substrate 3b under these

conditions (entry 2). A higher yield of 4 (39%) was indeed obtained,

and smaller quantities of hydrolysis product 6. Next, we tested iso-

lated solutions of dimethyldioxirane (DMDO)⁸(entries 3 and 4).

Surprisingly, the major reaction product in this case was the lactol 6,

even when the acetone solutions of DMDO solutions were dried over

K₂CO₃prior to use. The combined product yield (yield of 4þyield of 6)

was, however, better with DMDO than with m-CPBA. Potential difﬁ-

culties in preparing DMDO solutions on large scale prompted us to

2. Results and discussion

2.1. Synthesis of dihydropyrans 3

We aimed to prepare a wide range of substrates 3 bearing a va-

riety of substitution patterns. Initially, we employed thermal cy-

cloaddition between enones 1 and enol ethers 2 under Yb(FOD)

catalysis (Table 1, conditions A).⁷However, these conditions gen-

erally required long reaction times (1–10 days). Therefore, we

* Corresponding author. Tel.: þ44 (0)20 7594 5876.

E-mail address: a.armstrong@imperial.ac.uk (A. Armstrong).

doi:10.1016/j.tet.2009.04.013

A. Armstrong et al. / Tetrahedron 65 (2009) 4490–4504

4491

R⁴

R³

R⁴

R³

R²

R¹

R²

R¹

R⁴

R¹

"O"

+

OR⁵

O

OR⁵

O

1

OR⁵

2

O

3

4

R³R⁴

R³

R⁴

O

R²

O

R²

R¹

OR⁵

O

R¹

O

OR⁵

5

Scheme 1.

attempt in situ formation of DMDO⁹from acetone and Oxone (entries

5 and 6). The reaction with the less volatile substrate 3b afforded

a highly promising combined product yield (76%, entry 6), but the

longer reaction times meant that we preferred to use isolated DMDO

solutions in subsequent investigations. An attempt at using the more

reactive triﬂuoroacetone/Oxone system¹⁰with 3b did not provide

any of the desired product.

In order to simplify product analysis and puriﬁcation, and also to

facilitate eventual stereochemical analysis, we wished to convert

the mixture of lactol ethers 4 and lactols 6 into a common product.

Table 1

Enone/enol ether hetero Diels–Alder reaction

R³

R⁴

2

R²

R¹

R²

R⁴

+

4

A or B

OR⁵

R¹

O

3

O

1

OR⁵

2

Entry

R¹

R²

R³

R⁴

1

R⁵

Et

2

3

Yieldⁱ

dr^j

1^a

Me

H

Ph

H

Me

ⁿBu

Ph

H

Me

ⁱPr

Me

Ph

H

Me

H

Me

Et

1a

1b

1c

1d

1e

1f

1g

1h

1i

1j

1k

1l

1m

1n

1o

1p

1q

1r

2a^c

2b^d

2b^e

2a^e

2a^f

3a

3b

3c

3d

3e

3f

3g

3h

3i

3j

3k

3l

3m

3n

3o

3p

3q

3r

70

55

40

75

54

50

67

56

100

89

88

66

99

58

98

91

90

93

85

13

26

85

91

48

41

12

30

27

40

44

58

41

N/A

6:1

2^a

ⁿBu

Et

3^a

4^a

5^a

N/A

6^a

ꢀ99:1

4:1

7^a

CH₂OBn

(CH₂)₄CH]CHEt

Ph

Me

CH₂OBn

ⁱPr

p-MeO C₆H₄

Et

H

Me

Et

Ph

Furyl

OEt

H

Me

H

Me

Et

CyHex

Me

8^a

2a^f

9^a

2a^g

2a^h

2a^e

ꢀ99:1

N/A

ꢀ99:1

N/A

3:1

N/A

10^b

11^a

12^b

13^a

14^b

15^b

16^a

17^a

18^a

19^a

20^a

21^b

22^b

23^b

24^b

25^b

26^b

27^b

28^b

29^b

30^b

31^b

32^b

33^b

3s

3t

1s

1t

3u

3v

3w

3x

3y

3z

3aa

3ab

3ac

3ad

3ae

1u

1v

1w

1x

1y

1z

1aa

1ab

1ac

1ad

p-MeO C₆H₄

p-Me C₆H₄

p-Cl C₆H₄

p-NO₂C₆H₄

2-Naphthyl

Me

H

N/A

a

Conditions A: pressure tube, 45–100 ^ꢁC, YbFOD catalyst (2–5 mol %), 1–10 days.

b

c

d

e

f

Conditions B: microwave, 55–80 ^ꢁC, YbFOD catalyst (5 mol %), 2–6 h.

7 equiv of 2 to 1.

2 equiv of 2 to 1.

5 equiv of 2 to 1.

10 equiv of 2 to 1.

12 equiv of 2 to 1.

6 equiv of 2 to 1.

Combined yield of diastereoisomers (%).

The ratio of endo to exo determined by ¹H NMR.

g

h

i

j

4492

A. Armstrong et al. / Tetrahedron 65 (2009) 4490–4504

Table 2

1. 1 eq DMDO,

Preliminary screen of oxidants

acetone/CH₂Cl₂

+

R

[O]

O

R

O

OEt

2. Jones

oxidation

OR⁵

OH

+

3af R=ⁿPr, 70%

3ag R=ⁿBu, 65%

O

3

OR⁵

7h R=ⁿPr, 58%

7i R=ⁿBu, 48%

8h R=ⁿPr, 12%

8i R=ⁿBu, 6%

O

4

6

Entry R⁵

3

Reagent

Time

4

Yield 4^ddr 4^eYield 6^hdr 6ⁱ

1. NaBH₄, MeOH

7h R=ⁿPr

7i R=ⁿBu

1

2

3

4

5

6

Et

ⁿBu 3b m-CPBA^a

Et

3a DMDO^b

ⁿBu 3b DMDO^b

3a m-CPBA^a

2 h

3 h

4a 14

4b 39

2:1^f

2:1^g<5

53

2:1^g64

2:1^f

2:1^g30

10

1:1

R

O

2. (Im)₂CS, DCE, 80 °C

3. ⁿBu₃SnH, AIBN,

toluene

d

9 R=ⁿBu, 36% (over 3 steps)

10 R=ⁿPent, 49% (over 3 steps)

4b

9

Et

3a Acetone/Oxone^Òc24 h 4a 13

d

ⁿBu 3b Acetone/Oxone^Òc24 h 4b 46

Scheme 2.

a

b

c

d

e

f

m-CPBA (1.0 equiv), CH₂Cl₂, 0 ^ꢁC to rt.

DMDO (1.0 equiv), CH₂Cl₂, 0 ^ꢁC to rt.

Acetone/Oxone^Ò, NaHCO₃, Na₂EDTA (pH¼7.5), CH₂Cl₂, 0 ^ꢁC to rt.

Combined yield of diastereoisomers (%).

The ratio determined by ¹H NMR.

Inseparable diastereoisomers.

Separable diastereoisomers.

In order to demonstrate the application of the oxidative rear-

rangement chemistry to natural product synthesis, we were

attracted to the Quercus lactones, in particular the lactones 9 and 10

(Scheme 2) partly responsible for aroma and ﬂavour in whisky and

cabernet sauvignon wine.¹¹Oxidative rearrangement of the ap-

propriate substrates with DMDO followed by Jones oxidation pro-

ceeded to give a mixture of diastereomers (5:1 for 7h/8h; 8:1 for 7i/

8i by ¹H NMR analysis), from which the desired cis-isomers could

be separated (58% for 7h; 48% for 7i). The superﬂuous ketone

moiety was removed by reduction (NaBH₄) followed by Barton–

McCombie deoxygenation, providing the cis-lactones 9 and 10, the

spectroscopic data of which matched those reported for the natural

products.^12,13

g

h

i

Combined yield of inseparable diastereoisomers (%).

The ratio determined by ¹H NMR.

Reduction was considered for this purpose, but initial attempts

(Et₃SiH, BF₃$Et₂O) led to reduction of the ketone as well as the

lactol ether/lactol, thus further complicating the product mixture.

Turning instead to oxidation, we discovered that Jones oxidation

would convert the mixture of 4 and 6 cleanly into a common lac-

tone product 7. The DMDO/Jones procedure was applied to several

pyrans 3 and the results are displayed in Table 3. The substrate 3c

bearing a CH₃-substituent at C4 provided the ﬁrst evidence for

diastereoselective THF formation (3:1 diastereoselectivity, entry 2).

The major isomer was shown to have the cis-relative conﬁguration

7 by NOE studies (notably, NOE between H4 and H5), while the

minor, trans-isomer showed NOE interactions between H5 and the

C4-methyl group. This stereochemical outcome is consistent with

predominant epoxidation on the less hindered face of 3c, trans- to

the C4-methyl substituent. With larger C4-substituents, the levels

of diastereoselectivity were higher (entries 3–6), with NOE studies

again indicating the cis-conﬁguration in the major product. As in

our earlier aziridination studies on 3, we found that this oxidative

rearrangement chemistry tolerated the presence of an oxygen

functionality (entry 3), an isolated alkene (entry 6), and a quater-

nary centre in the substrate (entry 7).

2.3. Oxidative rearrangement of 6-unsubstituted pyrans

The chemistry described above successfully accomplished the

stereoselective synthesis of lactones 7 containing a ketone func-

tionality in the product (R¹sH). We were keen to extend the

method to substrates 3 with R¹¼H, because an effective catalytic

enantioselective hetero-Diels–Alder reaction has been reported¹⁴

for the synthesis of these speciﬁc substrates. This would allow us to

prepare our lactone products in enantiomerically pure form. Dis-

appointingly, we were not able to effect DMDO-mediated epoxi-

dation/rearrangement on these substrates. Reaction of 3 (R¹¼H)

with DMDO instead afforded the acetonide 11 as the major iden-

tiﬁed product (Table 4). A similar outcome has been reported in the

reaction of glycals with DMDO.¹⁵In one case (entry 3), a further

product, ketone 12, was also isolated. Both 11 and 12 could con-

ceivably arise from the desired intermediate epoxide 13 (Scheme

3). Opening of epoxide 13 with acetone solvent would lead to 11.

Unimolecular ring opening to 14 and hydride shift would convert

13 into ketone 12.

Table 3

Conversion of pyrans 3 to lactones 7; (a) DMDO (1.0 equiv), CH₂Cl₂, 0 ^ꢁC to rt/Jones

reagent (3.0 equiv), acetone, 0 ^ꢁC to rt

R⁴

R³R⁴

R³

O

Experiments using m-CPBA with 6-unsubstituted substrates 3

(R¹¼H) also failed to provide the desired oxidation/rearrangement,

with ring opening of the intermediate epoxide by solvent or carb-

oxylic acid co-product again being suspected. Seeking epoxidation

4

a

O

5

O

OR⁵

3

7

R³

R⁴

R⁵

7

Yield 7^a

dr^b

Table 4

Entry

3

1

2

3

4

5

6

7

3b

3c

3g

3d

3f

H

Me

H

Me

ⁿBu

Et

7a

7b

7c

7d

7e

7f

69

53

48

63

65

64

50

d

3:1^c

95:5

9:1

R₃

CH₂OBn

O

1 eq. DMDO

O

ⁱPr

Ph

ⁿBu

Et

+

>95:5^d

d

O

3

OEt

O

OEt

O

11

OEt

3h

3e

(CH₂)₄CH]CHEt

Me

Et

ⁿBu

7g

12

a

Isolated yield of 7 over two steps from 3 (%).

b

The ratio of cis to trans determined by ¹H NMR spectrum of the crude reaction

Entry

3

R³

11

Yield 11

12

Yield 12

mixture.

1

2

3

3i

3l

3m

Ph

11a

11b

11c

30

25

31

d

14

c

Isomers separable by column chromatography: cis-lactone 32%, trans-lactone

10%.

ⁱPr

p-MeO Ph

12a

d

Only the cis product observed by ¹H NMR.

A. Armstrong et al. / Tetrahedron 65 (2009) 4490–4504

4493

trans- to R³. Speciﬁcally, for 4e, we observed NOESY correlations

between the C-2 methyl and H3, and between the aldehyde proton

and the C3–Et substituent. The acetal centre was tentatively

assigned due to the absence of a NOESY interaction between the 2-

Me and the acetal proton. Despite these encouraging results, the

method appeared to be rather substrate-speciﬁc. Attempted oxi-

dative rearrangement (not shown in Table 5) of substrates 1k and

1m (R²¼H; R³¼ⁱPr or Et) was not successful.

R³

H

^-O

DMDO

O

12

O⁺OEt

14

O

13

OEt

O

3

OEt

Scheme 3.

While our earlier studies with DMDO epoxidations suggested

that at least partial hydrolysis of the lactol ether products to the

corresponding lactols was likely, we were unable to isolate any

lactols from these MTO reactions. In order to converge any alter-

native diastereomers and lactols to a common product, we sub-

jected the crude product of the epoxidation/rearrangement step to

Jones oxidation, as in our earlier studies. Since the resultant mix-

ture of carboxylic acids was not readily separable, we transformed

the resulting product mixture into the corresponding PMB-esters.

The yields of the desired lactone products 15 were disappointing

(Table 6), with the moderate diastereoselectivities suggesting that

the earlier isolation of single diastereomers of 4 was indeed due to

incomplete rearrangement of the minor epoxide diastereomer and/

or the chromatographic puriﬁcation. The low yield of 15 was

explained partly by the formation of the ketoester 16, the result of

oxidative decarboxylation,¹⁷as a signiﬁcant by-product. To probe

the origin of 16, a sample of 15 was hydrolysed to the corresponding

carboxylic acid, which when submitted to Jones conditions indeed

underwent oxidative decarboxylation. Attempts to minimise this

side-reaction by reducing the time period of exposure to Jones

reagent after the epoxidation rearrangement, were not successful

in improving the yield of 15.

Although the low yields, moderate diastereoselectivities and

narrow substrate scope were disappointing, we aimed to prove

the relative conﬁguration of the major diastereomer of 15 by

conversion to crobarbatic acid, a component of a natural prod-

uct.¹⁸Cleavage of the PMB-ester of 15a, derived from oxidative

rearrangement/Jones oxidation of 3p, gave (ꢂ)-crobarbatic acid 17

as an inseparable 2:1 mixture of diastereoisomers (Scheme 4).

The major isomer had the depicted conﬁguration as indicated by

comparison to ¹H NMR data for the two diastereomers reported

by Donohoe.¹⁸

Table 5

4 mol% MTO

3.0 eq. UHP

0.5 eq. ImH

CH₂Cl₂

R³

R²

H

OEt

O

OEt

then CSA, 18 h

R²

O

3

4

Entry

3

R₂

R₃

4

Yield 4

1

2

3o

3p

3q

3r

3t

3u

Me

ⁿBu

H

Me

Et

Ph

OEt

H

4c

13

4d

4e

4f

4g

4h

28

35

10^b

54

63

3

4^a

5

6

a

MTO (8 mol %) and 6 equiv UHP used.

4-Oxo-3-phenylpentenal (5%) also isolated.

b

processes that could be performed in the absence of nucleophilic

solvents or additives, we were attracted to reports¹⁶of glycal ep-

oxidations using urea/H₂O₂under methyltrioxorhenium catalysis

in the presence of imidazole ligands. Early attempts using these

conditions with a range of substrates 3 suggested that the desired

aldehyde products 4 were not formed in more than trace amounts.

For some substrates 3 (R¹¼H; R²sH), resonances were observed in

the ¹H NMR spectrum of the crude product at ca. 4.0–4.5 ppm,

which were tentatively assigned to the epoxide intermediate 13.

Addition of CSA to the reaction mixture to promote rearrangement

of 13, following consumption of 3 in the epoxidation step, pleas-

ingly led to isolable quantities of the desired product 4 (Table 5,

entries 1–5), albeit in low-to-moderate yields. The products 4

prepared under the stated conditions were isolated after column

chromatography as single diastereomers. When longer reaction

times were employed, the isolated products were in some cases

obtained in higher yields but lower diastereoselectivity. While the

reasons for this were not examined in detail, we believe that this is

due partly to epimerisation at the acetal centre and partly to slower

rearrangement of the minor diastereomer of the intermediate ep-

oxide. The shorter reaction times provided products, which could

be isolated as essentially single diastereomers, which greatly

facilitated product characterisation.

2.4. Enantioselective THF synthesis

We next turned to the synthesis of enantiomerically enriched

products. The disappointing oxidative rearrangement results with

6-unsubstituted substrates (R¹¼H), required for Jacobsen’s catalytic

asymmetric hetero-Diels–Alder reaction,¹⁴led us to focus instead

on enantioselective epoxidation. Since there is as yet no effective

enantioselective MTO-catalysed epoxidation, we concentrated ﬁrst

on the use of chiral dioxiranes.¹⁹In view of the low enantiose-

lectivities observed for enol ether epoxidation using chiral ketone

NOESY experiments suggested the depicted conﬁguration for

the isolated isomers, which is again in accord with epoxidation

Table 6

1. 4 mol% MTO, 3.0 eq. UHP

R³

O

0.5 eq. ImH, CH₂Cl₂,

R²

then Amberlyst 15

2. Jones oxidation

O

PMBO

R²

+

O

R³OPMB

R²

O

3. PMB-OH, DCC, cat. DMAP

O

OEt

3

15

16

Entry

3

R₂

R₃

15

Yield 15

dr 15

Yield 16

1

2

3

3p

3t

3v

Me

Ph

Me

OEt

Me

15a

15b

15c

23

21

0

2:1

9:1

d

9

48

21

4494

A. Armstrong et al. / Tetrahedron 65 (2009) 4490–4504

1. 4 mol% MTO, 3.0 eq. UHP

0.5 eq. ImH, CH₂Cl₂, then CSA

2. Jones oxidation

O

3. PMB-OH, DCC, cat. DMAP

RO

+

O

OPMB

O

OEt

O

23%

9%

3p

TFA / phenol

15 R=PMB

17 R=H: ( )-crobarbatic acid

45 ^oC (93%)

Scheme 4.

effect of para-substituents on the aromatic ring (entries 7–10).

Electron donating substituents led to increased ee (compare entries

4, 7 and 8) while the electron-withdrawing nitro group gave lower

enantioselectivity (entry 10). The p-Cl-substituent also led to im-

proved ee (entry 9), as did replacement of the phenyl group with

napthyl group (entry 11). In order to check whether differing levels

of background epoxidation could be responsible for the substituent

effects on enantioselectivity, we subjected substrates 3x, 3aa and

3ad to the Jacobsen conditions in the absence of the Mn(salen)

catalyst. No reaction was observed for the latter. While disappear-

ance of the former two substrates was noted, none of the product 7

was observed. Thus differing levels of background reaction is not

likely to explain the enantioselectivity trends. Electronic effects in

Jacobsen epoxidations have been observed previously, and have

been quantiﬁed using Hammett correlations. Jacobsen studied the

effect on epoxide ee of tuning the effect of substituents in the

catalyst.²⁴Additionally, there are reports of Hammett studies of

substituent effects in the substrate on the ratio of cis/trans epoxides

obtained from cinnamates and stilbenes.²⁵However, we were not

aware of any study of Hammett correlation of substituent effects in

the substrate to product enantiomeric excess. A Hammett plot us-

ing log (% S product/% R product) based on the enantiomeric ex-

cesses in Table 7 (entries 4, 7–10) was found to give poor correlation

to the substituent s_paravalues (r²¼0.563) or s_p^þ_ara(r²¼0.796). As

noted in the qualitative analysis of the results in Table 7, the data

point for the p-Cl substituent was noticeably off the best-ﬁt line for

the Hammett correlation: omission of this data point gave a good

correlation to s_p^þ_ara(r²¼0.967, slope ꢃ0.32). The s^þ_paraparameter is

derived from a study of the rates of S_N1 hydrolysis of substituted

aryl halides, which proceed via a benzylic carbocation.²⁶A good

correlation of ee to this parameter suggests that the transition state

leading to the major enantiomer has a larger degree of benzylic

cation character than the transition state leading to the minor

enantiomer.

Table 7

Epoxidation of DHPs with Jacobsen’s catalyst 19; (a) 4-phenyl pyridine N-oxide

(0.2 equiv), (R,R)-Jacobsen’s cat 19 (0.05 equiv), NaOCl (1.5 equiv), CH₂Cl₂, 0 ^ꢁC to rt,

(b) Jones reagent (3.0 equiv), acetone, 0 ^ꢁC to rt

Entry

Substrate

R¹

R³(]R⁴)

R⁵

7

Yield^a(%)

ee (%)

1

2

3

4

5

6

7

8

3a

3e

3w

3x

3y

Me

Ph

p-MeO ph

p-Me ph

p-Cl ph

p-NO₂ph

2-Naph

H

Me

H

Me

Et

CyHex

Me

Et

ⁿBu

Et

7j

7k

40

16

55

49

45

40

35

43

40

64

41

0^b

(S)-7l

(S)-7m

(S)-7n

(S)-7o

(S)-7p

(S)-7q

(S)-7r

(S)-7s

(S)-7t

38^c

58^c

69^c

80^c

79^c

70^c

76^c

46^c

71^c

3z

3aa

3ab

3ac

3ad

3ae

9

10

11

a

Yield over two steps.

Based on the optical rotation.

By chiral HPLC analysis.

b

c

catalysts developed in our own laboratories,²⁰we chose to test Shi’s

fructose-derived chiral ketone 18.²¹Disappointingly, 18/Oxone did

not afford any of the desired product from substrates 3a, 3d, or 3w,

even under higher reaction pH conditions (pH 10). Next, we ex-

plored Jacobsen’s Mn(salen) catalyst (R,R)-19, in conjunction with

1.5 equiv of NaOCl as co-oxidant and 0.2 equiv of pyridine oxide as

additive (Table 7, Fig. 1). Pleasingly, Jacobsen epoxidation of 3a in-

deed afforded the desired rearrangement product 7j (entry 1).

However, optical rotation analysis suggested that this material was

racemic. In order to provide greater steric differentiation of the two

sides of the alkene, we studied the C4-disubstituted substrate 3e,

but again racemic product was obtained (entry 2). Since aromatic

alkenes are generally superior substrates in Jacobsen epoxidation,

we examined substrate 3w. Pleasingly, this led to the ﬁrst obser-

vation of signiﬁcant asymmetric induction (38% ee, entry 3). The

absolute conﬁguration of the major enantiomer of product 7l was

found to be S by chiral HPLC comparison to an authentic sample

prepared by a literature route.²²This outcome is also in accord with

that observed by Jacobsen for enantioselective epoxidation of tri-

substituted alkenes.²³Addition of C4-substituents led to higher

enantioselectivity (entries 4–6) with larger substituents affording

higher levels of enantiocontrol. Next, we explored the electronic

3. Conclusions

We have investigated the oxidative rearrangement of a wide

range of 2-alkoxypyrans 3 using several common epoxidation

reagent systems. Substrates with 6-substitution generally react

effectively: they undergo oxidative rearrangement using DMDO,

and this process proceeds with good to excellent levels of ster-

eocontrol when a 4-substituent is present. The high cis-selectivity

of this process has been exploited in the synthesis of whisky and

cognac lactones. Substrates lacking 6-substitution generally gave

poorer results: a narrow range of these were found to undergo

oxidative rearrangement using MTO/urea–H₂O₂, but yields and

diastereoselectivities were generally moderate-to-poor. This

O

N

O

N

O

Mn

Cl

O

^tBu

O

chemistry allowed synthesis of crobarbatic acid as

a di-

^tBu

astereomeric mixture. Finally, 6-phenyl-substituted substrates

were found to undergo Jacobsen epoxidation with enantiose-

lectivities of up to 79% ee, with highest ee values for electron-rich

aromatic substrates.

18

19

Figure 1. Shi’s fructose-derived chiral ketone 18 and Jacobsen’s Mn(salen) catalyst

(R,R)-19.

A. Armstrong et al. / Tetrahedron 65 (2009) 4490–4504

4495

4. Experimental

4.3. General procedure for the preparation of enones

(1ab–1ad) by Grignard reaction/MnO₂oxidation

4.1. General experimental

To a 0.05 M solution of aryl aldehyde (1.0 equiv) in dried Et₂O

at room temperature under N₂was added 0.5 M (2-methylprop-

1-enyl)magnesium bromide (in THF, 1.2 equiv). After stirring for

5 h, the reaction was quenched with NH₄Cl (aq). It was then

extracted with Et₂O and NaHCO₃(aq) followed by brine. The

organic layer was dried by MgSO₄and the solvent was evapo-

rated under reduced pressure. The crude product was dissolved

in acetone and MnO₂(20.0 equiv) was added to the mixture.

After stirring at room temperature overnight, Mn residues were

removed by ﬁltration and the resulting product was concen-

trated to give the crude product. Column chromatography,

eluting with Et₂O/petrol (1:9) gave the corresponding pure

product.

Reactions were run under a positive pressure of nitrogen. Unless

otherwise stated, organic layers were dried using MgSO₄. Flash

column chromatography was performed using BDH F₂₅₄silica gel.

Analytical thin layer chromatography was performed on pre-coated

Merck silica gel 60 F₂₅₄glass backed plates and visualised by either

UV light (254 nm) or reactive stain reagents as appropriate. NMR

analyses were performed on Bruker AC 250 MHz, AV 400 MHz or DX

400 MHz instruments; Chemical shifts are quoted in parts per mil-

lion relative toTMS (asreferenced toresidual CHCl₃d_H¼7.26 orCDCl₃

d_C¼77.0). Infrared analyses were recorded on NaCl plates. A Mattson

Satellite FTIR spectrometer was employed in the absorption range of

4000–600 cm^ꢃ1. Microwave reactions were carried out using a CEM

Discover instrument. Chemical Ionisation Mass Spectrometry was

carried out with ammonia reagent gas using a Micromass Autospec-

Q spectrometer. Melting points were determined using a Reichert

hot stage microscope apparatus. Optical rotations were recorded on

an Optical-Activity AA-5 Polarimeter, with a path length of 10 cm in

4.3.1. 1-(4-Chlorophenyl)-3-methylbut-2-en-1-one 1ab

Prepared by the general procedure (34 mL of Grignard reagent,

2.00 g of aldehyde and 30.00 g of MnO₂) to give a corresponding

product 1ab as a yellow oil (1.45 g, 53%). n_max(CHCl₃)/cm^ꢃ12976–

chloroform unless stated otherwise. [

a

]

values are given in

2913 (CH), 1662 (a, b-unsaturated C]O); d_H(400 MHz, CDCl₃) 7.89

D

10^ꢃ1deg cm²g^ꢃ1. Concentrations (c) are given in grams per 100 cm³.

(2H, d, J 8.5, 2ꢄCH in Ph), 7.43 (2H, d, J 8.5, 2ꢄCH in Ph), 6.72 (1H, s,

CH), 2.23 (3H, s, CH₃), 2.04 (3H, s, CH₃); d_C(100 MHz, CDCl₃) 190.1

(C), 157.7 (CH), 138.6 (C), 137.6 (C), 129.6 (2ꢄCH), 128.7 (2ꢄCH),

120.7 (C), 28.1 (CH₃), 21.3 (CH₃); m/z (CI) 195 (MH^þ,100%). Found:

MH^þ, 195.0577; C₁₁H₁₁OCl requires: MH^þ, 195.0577.

Chiral HPLC was performed on Hewlett Packard Series 1100 HPLC

i

system with Chiralcel columns using PrOH/hexane as eluent. For

HPLC, retention times are quoted in minutes.

4.2. Preparation of enones 1

4.3.2. 1-(4-Nitrophenyl)-3-methylbut-2-en-1-one 1ac

4.2.1. (E)-5-Benzyloxy-pent-3-en-2-one 1f²⁷

Prepared by the general procedure (31 mL of Grignard reagent,

2.00 g of aldehyde and 29.00 g of MnO₂) to give a corresponding

product 1ac as a yellow solid (0.35 g, 13%). Mp 114–116 ^ꢁC; n_max

Compound 1f was prepared by literature procedure.²⁷

4.2.2. (3E,9Z)-Dodecadien-2-one 1g

(CHCl₃)/cm^ꢃ12947–2903 (CH), 2853, 1656 (

a, b-unsaturated C]O),

To a solution of LiCl (0.50 g, 12.0 mmol) in MeCN (90 mL) at

room temperature under N₂was added diethyl(2-oxopropyl)-

phosphonate (2.70 g, 12.0 mmol) in MeCN (20 mL). To the reaction

mixture was added DBU (1.50 g, 10.0 mmol) dropwise and then

a solution of cis-6-nonenal (1.40 g, 10.0 mmol) in THF/MeCN (1:1,

40 mL) was added. After stirring overnight, the reaction mixture

was quenched with water/brine (1:1, total volume 200 mL). The

phases were separated and extracted with EtOAc (2ꢄ50 mL). The

combined organic layers were washed with brine (50 mL), dried

over MgSO₄and concentrated to afford the crude product. Column

chromatography eluting with EtOAc/petrol (3:7) gave 1g (1.20 g,

66%) as a colourless oil. n_max/cm^ꢃ12932, 1677, 1360, 1254, 980; d_H

(250 MHz, CDCl₃) 6.79 (1H, dt, J 16.0, 7.0, CH]CHC(O)CH₃), 6.05

1613 (NO₂); d_H(400 MHz, CDCl₃) 8.32 (2H, d, J 9.0, 2ꢄCH in Ph), 8.08

(2H, d, J 9.0, 2ꢄCH in Ph), 6.78 (1H, s, CH), 2.30 (3H, s, CH₃), 2.10 (3H,

s, CH₃); d_C(100 MHz, CDCl₃) 189.3 (C), 160.4 (CH), 149.8 (C), 144.1

(C), 129.1 (2ꢄCH), 123.7 (2ꢄCH), 120.4 (C), 28.3 (CH₃), 21.6 (CH₃);

m/z (CI) 206 (MH^þ,100%). Found: MH^þ, 206.0816; C₁₁H₁₁NO₃re-

quires: MH^þ, 206.0817.

4.3.3. 3-Methyl-1-(naphthalen-2-yl)but-2-en-1-one 1ad³⁵

Prepared by the general procedure (40 mL of Grignard reagent,

2.00 g of aldehyde and 32.00 g of MnO₂) to give the corresponding

product 1ad as a yellow solid (1.38 g, 69%).

(1H, dt,

J

16.0, 1.5, CH]CHC(O)CH₃), 5.42–5.22 (2H, m,

4.4. Typical procedure for hetero Diels–Alder reaction

CH₂CH]CHCH₂), 2.26–2.16 (2H, m, CH₂), 2.22 (3H, s, COCH₃), 2.08–

1.95 (4H, m, 2ꢄCH₂), 1.54–1.29 (4H, m, 2ꢄCH₂), 0.94 (3H, t, J 7.5,

CH₂CH₃); d_C(63 MHz, CDCl₃) 198.7 (C), 148.4 (CH), 132.0 (CH), 131.3

(CH), 128.6 (CH), 32.3 (CH₂), 29.2 (CH₂), 27.6 (CH₂), 26.8 (CH₃), 26.7

(CH₂), 20.5 (CH₂), 14.3 (CH₃); m/z (CI) 198 (MþNH₄)^þ, 181 (MþH)^þ;

m/z calcd for C₁₂H₂₁O (MþH)^þ, 181.1592; found: 181.1594.

4.4.1. Conditions A

To vinyl ether 2 (2.0–10.0 equiv) at room temperature in

a pressure tube was added enone 1 (1.0 equiv) and YbFOD (0.02–

0.05 equiv). The tube was sealed and the solution was then stirred

at the appropriate temperature (45–100 ^ꢁC) for 1–10 days. After

allowing the mixture to cool to room temperature, column chro-

matography, eluting with diethyl ether/petrol, gave the alkoxy-

dihydropyran product.

4.2.3. 1-Phenylprop-2-en-1-one 1v²⁸

Compound 1v was prepared according to literature procedure.

4.2.4. 3-Methyl-1-phenylbut-2-en-1-one 1w,²⁹3-ethyl-1-

phenylpent-2-en-1-one 1x³⁰and 2-cyclohexylidene-1-

phenylethanone 1y³¹

4.4.2. Conditions B

To vinyl ether 2 (5.0 equiv) was added enone 1 (1.0 equiv) and

YbFOD (0.05 equiv). After reaction under microwave conditions

(300 W, 24 psi) at 65 ^ꢁC for 2-3 h, column chromatography, eluting

with diethyl ether/petrol (5:95 to 1:9), gave the product 2-

alkoxydihydropyrans.

The following dihydropyrans gave spectroscopic data in accord

with those in the literature, 3a,³⁶3c,⁶3d,³⁷3f,³⁸3i,¹⁴3j,¹⁴3k,¹⁴3l,¹⁴

3m,¹⁴3n,¹⁴3p.¹⁴

Compounds 1w, 1x and 1y were prepared according to a litera-

ture procedure.³²

4.2.5. 1-(4-Methoxyphenyl)-3-methylbut-2-en-1-one 1z³³

Compound 1z was prepared according to

a literature

procedure.³⁴

4496

A. Armstrong et al. / Tetrahedron 65 (2009) 4490–4504

4.4.3. 2-Butoxy-6-methyl-3,4-dihydro-2H-pyran 3b

(CH₂), 26.7 (CH₂), 21.9 (CH₂), 18.4 (CH₃), 15.1 (CH₃); m/z (CI) 143

(MþH)^þ, 160 (MþNH₄)^þ. Found: 143.1067 (MþH)^þ; C₈H₁₅O₂re-

quires: 143.1072.

Prepared by the general procedure (conditions A, 1.0 equiv of

diene 1a, 2.0 equiv of vinyl ether 2b, 0.05 equiv of Yb catalyst, 90 ^ꢁC,

6 days) to give 3ac (2.80 g, 55%) as a pale yellow oil. n_max(CHCl₃)/

cm^ꢃ12958–2936 (CH), 1721, 1687 (C]C); d_H(250 MHz, CDCl₃) 4.97

(1H, t, J 3.5, OCHO), 4.52 (1H, t, J 3.5, C]CH), 3.78 (1H, dt, J 9.5, 6.5,

OCH₂), 3.50 (1H, dt, J 9.5, 6.5, OCH₂), 2.20–1.69 (4H, m, CH₂CH₂),

1.68–1.48 (2H, m, CH₂), 1.42–1.24 (2H, m, CH₂), 1.71 (3H, s, CCH₃),

0.90 (3H, t, J 7.5, CH₂CH₃); d_C(125 MHz, CDCl₃) 147.4 (C), 97.4 (CH),

96.1 (CH), 67.9 (CH₂), 31.8 (CH₂), 26.4 (CH₂), 19.9 (CH₃), 19.3 (CH₂),

17.0 (CH₂), 13.8 (CH₃); m/z (CI) 140, 171 (MH^þ), 197. Found: MH^þ,

171.1387; C₁₀H₁₈O₂requires: MH^þ, 171.1385.

4.4.8. (2S

*

,4S )-2-Ethoxy-4-ethyl-5-methyl-3,4-dihydro-

*

2H-pyran 3q

Prepared by the general procedure (conditions A, 20.0 mmol,

1.0 equiv trans-2-methyl-2-pentenal 1p, 5.0 equiv of vinyl ether 2a,

0.02 equiv of Yb catalyst, 55 ^ꢁC, 10 days) to afford the title com-

pound 3q (3.17 g, 93%) as a colourless oil. n_max(CH₂Cl₂)/cm^ꢃ12964,

1664, 1458, 1378, 1140, 1082, 1059; d_H(400 MHz, CDCl₃) 6.08 (1H, s,

OCH]C), 4.83 (1H, dd, J 8.3, 2.1, OCHCH₂), 3.90 (1H, dq, J 9.5, 7.1,

OCHHCH₃), 3.54 (1H, dq, J 9.5, 7.1, OCHHCH₃), 2.18–2.11 (1H, m,

CCHCH₂), 1.98 (1H, ddd, 13.2, 6.7, 2.1, CHCHHCH), 1.71–1.61 (2H, m,

CHCH₂CH₃), 1.36–1.24 (1H, m, CHCHHCH), 1.23 (3H, t, J 7.1,

OCH₂CH₃), 0.87 (3H, t, J 7.1, CHCH₂CH₃); d_C(100 MHz, CDCl₃) 136.3

(CH), 112.5 (C), 99.2 (CH), 64.1 (CH₂), 35.8 (CH), 33.1 (CH₂), 24.7

(CH₂), 15.6 (CH₃), 15.2 (CH₃), 10.5 (CH₃); m/z (CI) 171 (MþH)^þ, 188

(MþNH₄)^þ. Found: 171.1385 (MþH)^þ; C₁₀H₁₉O₂requires: 171.1385.

4.4.4. 2-Butoxy-4,4,6-trimethyl-3,4-dihydro-2H-pyran 3e

Prepared by the general procedure (conditions A, 1.0 equiv of

diene 1d, 5.0 equiv of vinyl ether 2b, 0.05 equiv of Yb catalyst,

100 ^ꢁC, 5 days) to give 3e (1.60 g, 54%) as a pale yellow oil. n_max

(CHCl₃)/cm^ꢃ12958–2872 (CH), 1676 (C]C); d_H(250 MHz, CDCl₃)

4.88 (1H, dd, J 7.5, 3.0, OCHO), 4.32 (1H, s, C]CH), 3.88 (1H, dt, J 9.5,

6.5, OCH₂), 3.48 (1H, dt, J 9.5, 6.5, OCH₂), 1.76–1.25 (6H, m, CH₂,

CH₂CH₂), 1.71 (3H, s, C]CCH₃), 1.02, 1.00 (6H, s, C(CH₃)₂), 0.92 (3H,

t, J 7.5, CH₂CH₃); d_C(63 MHz, CDCl₃) 145.9 (C), 107.4 (CH), 98.4 (CH),

68.6 (CH₂), 41.7 (CH₂), 31.8 (CH₂), 31.4 (CH₃), 30.5 (CH₃), 29.6 (C),

19.7 (CH₃), 19.3 (CH₂), 13.8 (CH₃); m/z (CI) 199 (MH^þ, 100%). Found:

MH^þ, 199.1695; C₁₂H₂₂O₂requires: MH^þ, 199.1698.

4.4.9. (2S

*

,4R )-2-Ethoxy-5-methyl-4-phenyl-3,4-dihydro-

*

2H-pyran 3r

Prepared by the general procedure (conditions A, 8.0 mmol,

1.0 equiv trans-2-methyl-cinnamaldehyde 1q, 5.0 equiv of vinyl

ether 2a, 0.04 equiv of Yb catalyst, 65 ^ꢁC, 10 days) to afford the

title compound 3r (1.57 g, 90%) as a colourless oil. n_max(CH₂Cl₂)/

cm^ꢃ13201, 1384, 1348, 1107, 1034; d_H(250 MHz, CDCl₃) 7.16–7.33

(5H, m, ArH), 6.28 (1H, s, OCH]C), 4.95 (1H, dd, J 8.5, 2.1,

OCHCH₂), 3.92 (1H, dq, J 9.5, 7.1, OCHHCH₃), 3.56 (1H, dq, J 9.5, 7.1,

OCHHCH₃), 3.42 (1H, br t, J 8.4, CCHCH₂), 2.26 (1H, ddd, 13.5, 7.5,

2.1, CHCHHCH), 1.97 (1H, ddd, 13.5, 9.7, 8.5, CHCHHCH), 1.32 (3H,

s, HC]CCH₃), 1.22 (3H, t, J 7.1, OCH₂CH₃); d_C(63 MHz, CDCl₃)

143.2 (C), 137.8 (CH), 128.4 (CH), 128.1 (CH), 126.4 (CH), 111.4 (C),

98.8 (CH), 64.1 (CH₂), 42.5 (CH), 38.1 (CH₂), 16.1 (CH₃), 15.2 (CH₃);

m/z (CI) 219 (MþH)^þ, 236 (MþNH₄)^þ. Found: 219.1389 (MþH)^þ;

C₁₄H₁₉O₂requires: 219.1385.

4.4.5. (2S

*

,4S )-2-Benzyloxymethyl-2-ethoxy-6-methyl-3,4-

*

dihydro-2H-pyran 3g

Prepared by the general procedure (conditions A, 1.0 equiv of

diene 1f, 10.0 equiv of vinyl ether 2a, 0.05 equiv of Yb catalyst,

55 ^ꢁC, 1 day) to give 3g (0.60 g, 67%) as a pale yellow oil. n_max

(CHCl₃)/cm^ꢃ12976–2857 (CH), 1714, 1643 (C]C); d_H(250 MHz,

CDCl₃) 7.38–7.23 (5H, m, Ph), 5.01 (1H, dd, J 7.5, 1.0, OCHO), 4.55–

4.51 (3H, CH₃C]CH, PhCH₂), 4.00 (1H, dq, J 9.5, 7.0, OCH₂CH₃), 3.60

(1H, dq, J 9.5, 7.0, OCH₂CH₃), 3.43 (2H, d, J 7.0, BnOCH₂), 2.73–2.55

(1H, m, BnOCH₂CH), 2.09 (1H, ddd, J 13.0, 6.5, 2.0, CHCH₂CH), 1.77

(3H, s, CCH₃), 1.67 (1H, ddd, J 13.0, 6.5, 2.0, CHCH₂CH), 1.26 (3H, t, J

7.0, CH₂CH₃); m/z (CI) 263 (MH^þ, 100%), 280 (MNH₄^þ). Found: MH^þ,

263.1652; C₁₆H₂₂O₃requires: MH^þ, 263.1647.

4.4.10. (2S

*

,4S )-2-Ethoxy-4-(furan-2-yl)-5-methyl-3,4-dihydro-

*

2H-pyran 3s

Prepared by the general procedure (conditions B, 5.0 mmol,

1.0 equiv 2-methyl-3-(2-furyl)-propenal 1r, 5.0 equiv of vinyl ether

2a, 0.05 equiv of Yb catalyst, 65 ^ꢁC, 4 h) to give 3s (137 mg, 13%) as

a pale yellow oil. n_max(CH₂Cl₂)/cm^ꢃ12975, 1666, 1379, 1134, 1004,

934, 731; d_H(250 MHz, CDCl₃) 7.31 (1H, dd, J 1.8, 0.8, ArH), 6.29 (1H,

J 3.2, 1.8, ArH), 6.18 (1H, s, OCH]C), 6.08 (d, J 3.0, ArH), 4.94 (1H, dd,

J 5.8, 4.2, OCHCH₂), 3.89 (1H, dq, J 9.8, 7.1, OCHHCH₃), 3.61–3.47 (2H,

m, OCHHCH₃and CCHCH₂), 2.21–2.14 (2H, m, CHCH₂CH),1.42 (3H, s,

HC]CCH₃), 1.20 (3H, t, J 7.1, OCH₂CH₃); d_C(100 MHz, CDCl₃) 155.9

(C), 141.0 (CH), 137.0 (CH), 110.1 (CH), 109.5 (C), 105.9 (CH), 98.2

(CH), 64.0 (CH₂), 35.1 (CH), 33.5 (CH₂), 16.1 (CH₃), 15.1 (CH₃); m/z

(CI) 209 (MþH)^þ, 226 (MþNH₄)^þ. Found: 209.1182 (MþH)^þ;

C₁₂H₁₇O₃requires: 209.1178.

4.4.6. (2S

*

,4S )-2-Ethoxy-6-methyl-4-(Z-octen-5-yl)-3,4-dihydro-

*

2H-pyran 3h

Prepared by the general procedure (conditions A, 1.0 equiv of

diene 1g, 10.0 equiv of vinyl ether 2a, 0.05 equiv of Yb catalyst,

55 ^ꢁC, 5 days) to give 3h (0.55 g, 56%) in a 4:1 inseparable mixture

as a pale yellow oil. Data in accordance with the literature.⁶n_max

(CHCl₃)/cm^ꢃ13002–2855 (CH), 1719, 1652 (C]C); d_H(250 MHz,

CDCl₃) 5.40–5.24 (2H_both, m, CH]CH), 5.01 (1H_minor, t, J 3.0, OCHO),

4.88 (1H_major, dd, J 9.0, 2.0, OCHO), 4.51–4.48 (1H_minor, m, C]CH),

4.49–4.36 (1H_major, m, C¼CH), 4.01–3.77 (1H_both, dt, J 9.5, 7.0,

OCH₂), 3.63–3.50 (1H_both

, m, OCH₂), 2.32–1.80 (5H_both, m,

C]CHCHCH₂, CH₂, CH₂), 1.72 (3H_both, s, CH]CCH₃), 1.52–1.12

(11H_both, m, 4ꢄCH₂and OCH₂CH₃), 0.94 (3H_both, t, J 7.5, CH₂CH₃);

m/z (CI) 253 (MH^þ, 100%), 270 (MNH^þ₄, 100%). Found: MH^þ,

253.2172; C₁₆H₂₈O₂requires: MH^þ, 253.2168.

4.4.11. (2S

*

,4S )-2,4-Diethoxy-5-methyl-3,4-dihydro-2H-pyran 3t

*

Prepared by the general procedure (conditions B, 5.0 mmol,

1.0 equiv 2-methyl-3-(2-furyl)-propenal 1s, 5.0 equiv of vinyl

ether 2a, 0.05 equiv of Yb catalyst, 65 ^ꢁC, 3 h) to afford the title

compound 3t (248 mg, 26%) as a colourless oil. n_max(CH₂Cl₂)/

cm^ꢃ12975, 1668, 1456, 1379, 1139, 1096; d_H(400 MHz, CDCl₃) 6.10

(1H, s, OCH]C), 4.90 (1H, dd, J 7.1, 2.7, OCHCH₂), 3.92–1.94 (7H, br

m, 2ꢄOCH₂CH₃, CHCH₂CH, and CCHCH₂), 1.59 (3H, s, HC]CCH₃),

1.21 (3H, t, J 7.1, OCH₂CH₃), 1.10 (3H, d, J 7.0, OCH₂CH₃); d_C

(63 MHz, CDCl₃) 138.0 (CH), 110.7 (C), 97.7 (CH), 71.4 (CH), 64.4

(CH₂), 63.3 (CH₂), 33.6 (CH₂), 15.5 (CH₃), 15.0 (CH₃), 14.6 (CH₃);

m/z (CI) 204 (MþNH₄)^þ. Found: 204.1600 (MþNH₄)^þ; C₁₀H₂₂NO₃

requires: 204.1600.

4.4.7. 2-Ethoxy-5-methyl-3,4-dihydro-2H-pyran 3o

Prepared by the general procedure (conditions B, 5.0 mmol,

1.0 equiv of methacrolein 1n, 5.0 equiv of vinyl ether 2a, 0.05 equiv

of Yb catalyst, 65 ^ꢁC, 2 h) to afford the title compound 3o (646 mg,

91%) as a colourless oil. n_max(CH₂Cl₂)/cm^ꢃ13210, 1384, 1106, 1034;

d_H(400 MHz, CDCl₃) 6.05 (1H, s, OCH]C), 4.93–4.90 (1H, m,

OCHCH₂), 3.82 (1H, dq, J 9.7, 7.0, OCHHCH₃), 3.55 (1H, dq, J 9.8, 7.0,

OCHHCH₃), 2.15–2.03 (1H, m, OCHHCH₂), 1.89–1.79 (3H, m,

CCH₂CH₂and OCHHCH₂), 1.56 (3H, s, HC]CCH₃), 1.22 (3H, t, J 7.1,

OCH₂CH₃); d_C(63 MHz, CDCl₃) 134.9 (CH), 109.3 (C), 96.2 (CH), 63.5

A. Armstrong et al. / Tetrahedron 65 (2009) 4490–4504

4497

4.4.12. 5-Butyl-2-ethoxy-3,4-dihydro-2H-pyran 3u

catalyst, 70–80 ^ꢁC, 4 h) to give alkoxydihydropyran 3y (0.20 g, 12%)

as a pale yellow oil. n_max(CHCl₃)/cm^ꢃ12968 (CH), 2254, 1713, 1650

(C]C); d_H(400 MHz, CDCl₃) 7.58–7.61 (2H, m, 2ꢄCH in Ph), 7.24–

7.35 (3H, m, 3ꢄCH in Ph), 5.20 (1H, s, CCHC), 5.06 (1H, dd, J 2.5, 8.5,

OCHO), 4.14 (1H, dt, J 9.5, 7.0, OCHH), 3.70 (1H, dt, J 9.5, 7.0, OCHH),

1.68–1.80 (2H, m, CH₂), 1.39–1.54 (4H, 2ꢄCCH₂CH₃), 1.32 (3H, t, J 7.0,

OCH₂CH₃), 0.88 (3H, t, J 7.5, CH₃), 0.85 (3H, t, J 7.5, CH₃); d_C

(125 MHz, CDCl₃) 147.9 (C), 135.8 (C), 128.1, 127.9, 124.6 (5ꢄCH),

106.1 (CH), 98.9 (CH), 64.6 (CH₂), 37.5 (CH₂), 36.7 (C), 33.6 (CH₂),

31.5 (CH₂), 15.4 (CH₃), 8.3 (2ꢄCH₃); m/z (CI) 261 (MH^þ, 100%).

Found: MH^þ, 261.1851; C₁₇H₂₄O₂requires: MH^þ, 261.1854.

Prepared by the general procedure (conditions B, 5.0 mmol,

1.0 equiv 2-methylenehexanal 1t, 5.0 equiv of vinyl ether 2a,

0.05 equiv of Yb catalyst, 65 ^ꢁC, 2 h) to afford the title compound 3u

(743 mg, 81%) as a colourless oil. n_max(CH₂Cl₂)/cm^ꢃ12962, 1671,

1456, 1376, 1144, 1074; d_H(250 MHz, CDCl₃) 6.05 (1H, s, OCH]C),

4.92 (1H, t, J 3.3, OCHCH₂), 3.82 (1H, dq, J 9.7, 7.1, OCHHCH₃), 3.55

(1H, dq, J 9.7, 7.0, OCHHCH₃),1.98–1.40 (10H, br m, 5ꢄCH₂),1.21 (3H,

t, J 7.1, OCH₂CH₃), 0.89 (3H, t, J 7.0, OCH₂CH₃); d_C(63 MHz, CDCl₃)

135.0 (CH), 113.4 (C), 96.3 (CH), 63.4 (CH₂), 32.5 (CH₂), 29.9 (CH₂),

26.8 (CH₂), 22.1 (CH₂),19.9 (CH₂),15.2 (CH₃),13.9 (CH₃); m/z (CI) 185

(MþH)^þ, 202 (MþNH₄)^þ. Found: 185.1539 (MþH)^þ; C₁₁H₂₁O₂re-

quires: 185.1542.

4.4.17. 4-Ethoxy-2-phenyl-3-oxa-spiro[5,5]undec-1-ene 3z

Prepared by the general procedure (conditions B, 9.2 mmol,

1.0 equiv of diene 1y, 5.0 equiv of vinyl ether 2a, 0.05 equiv of Yb

catalyst, 65 ^ꢁC, 6 h) to give alkoxydihydropyran 3z (0.75 g, 30%) as

a pale yellow oil. n_max(CHCl₃)/cm^ꢃ12927 (CH), 2251, 1648 (C]C);

d_H(400 MHz, CDCl₃) 7.58–7.62 (2H, m, CH in Ph), 7.24–7.34 (3H, m,

CH in Ph), 5.38 (1H, s, CCHC), 5.07 (1H, dd, J 8.5, 2.5, OCHO), 4.12

(1H, dt, J 9.5, 7.0, OCHH), 3.69 (1H, dt, J 9.5, 7.0, OCHH), 2.00 (1H, d, J

13.0, 1H in CH₂), 1.38–1.68 (11H, m, 1H in CH₂, 5ꢄCH₂in CyHex),

1.31 (3H, t, J 7.0, CH₂CH₃); d_C(100 MHz, CDCl₃) 146.8 (C), 135.8 (C),

128.6, 128.0, 124.6 (5ꢄCH), 107.1 (CH), 98.5 (CH), 64.5 (CH₂), 39.4

(CH₂), 39.3 (CH₂), 36.6 (C), 33.6 (CH₂), 26.0 (CH₂), 22.0 (CH₂), 21.5

(CH₂), 15.3 (CH₃); m/z (CI) 273 (MH^þ,100%). Found: MH^þ, 273.1849;

C₁₈H₂₄O₂requires: MH^þ, 273.1854.

4.4.13. (2S

*

,4S )-2-Ethoxyethoxy-4-methyl-5-phenyl-3,4-dihydro-

*

2H-pyran 3v

Prepared by the general procedure (conditions B, 5.0 mmol,

1.0 equiv 2-phenyl-2-butenal 1u, 5.0 equiv of vinyl ether 2a, 0.05 equiv

of Yb catalyst, 65 ^ꢁC, 2 h) to afford the title compound 3v (995 mg, 91%,

3:1 dr) as a pale yellow oil. n_max(CH₂Cl₂)/cm^ꢃ12976, 2929, 1639, 1445,

1156,1137, 1097, 976, 851, 760, 698; d_H(250 MHz, CDCl₃) 7.35–7.16 (5H,

m, ArH), 6.53 (1H, s, OCH]C), 5.08 (1H_major, dd, J 5.9, 2.6, OCHCH₂), 5.02

(1H_minor, dd, J 6.6, 2.3, OCHCH₂), 3.92 (1H, dq, J 9.5, 7.1, OCHHCH₃), 3.64

(1H_minor, dq, J 9.6, 7.1, OCHHCH₃), 3.59 (1H_major, dq, J 9.5, 7.0, OCHHCH₃),

3.06–2.83 (1H, m, CCHCH₂), 2.17 (1H_major, ddd, J 13.6, 6.9, 2.6,

CHCHHCH), 2.05 (1H_minor, dd, J 13.2, 6.6, CHCHHCH), 1.88–1.75 (1H, m,

CHCHHCH), 1.27 (3H_minor, t, J 7.1, OCH₂CH₃), 1.26 (3H_major, t, J 7.1,

OCH₂CH₃),1.05 (3H_major, d, J7.1, CHCH₃),1.02 (3H_minor, d, J7.1, CHCH₃); d_C

(63 MHz, CDCl₃) 138.5 (C)_minor, 138.3 (C)_major, 128.3 (CH), 126.2 (CH),

126.0 (CH), 119.7 (C), 98.1 (CH)_major, 96.6 (CH)_minor, 64.1 (CH₂), 35.4

4.4.18. 2-Ethoxy-6-(4-methoxyphenyl)-4,4-dimethyl-3,4-dihydro-

2H-pyran 3aa

Prepared by the general procedure (conditions B, 5.3 mmol,

1.0 equiv of diene 1z, 5.0 equiv of vinyl ether 2a, 0.05 equiv of Yb

catalyst, 60 ^ꢁC, 5 h) to give alkoxydihydropyran 3aa (0.38 g, 27%) as

a yellow oil. n_max(CHCl₃)/cm^ꢃ13380, 2960 (CH), 2360, 2054, 1646

(C]C), 1622; d_H(400 MHz, CDCl₃) 7.55 (2H, d, J 8.5, 2ꢄCH in Ph),

6.89 (2H, d, J 8.5, 2ꢄCH in Ph), 5.11–5.13 (2H, m, CCHC, OCHO), 4.14

(1H, dt, J 15.0, 7.5, 1H in OCHH), 3.84 (3H s, OCH₃), 3.73 (1H, dt, J

15.0, 7.5, 1H in OCHH), 1.89–1.70 (2H, m, CH₂), 1.34 (3H, t, J 7.0,

CH₂CH₃), 1.18 (3H, s, CCH₃), 1.16 (3H, s, CCH₃); d_C(100 MHz, CDCl₃)

159.4 (C), 146.4 (C), 128.4 (C), 125.9 (2ꢄCH), 113.5 (2ꢄCH), 107.0

(CH), 98.7 (CH), 64.5 (CH₂), 55.3 (CH₃), 42.1 (CH₂), 31.6 (CH₃), 30.7

(CH₃), 30.4 (C), 15.4 (CH₃); m/z (CI) 263 (MH^þ,100%). Found: MH^þ,

263.1642; C₁₆H₂₂O₃requires: MH^þ, 263.1647.

(CH₂), 26.4 (CH₂)_major, 25.3 (CH₂)_minor, 20.4 (CH₃)_minor, 19.9 (CH₃)_major

,

15.2 (CH₃); m/z (CI) 219 (MþH)^þ, 236 (MþNH₄)^þ. Found: 219.1377

(MþH)^þ; C₁₄H₁₉O₂requires: 219.1385.

4.4.14. 2-Ethoxy-6-phenyl-3,4-dihydro-2H-pyran 3w

Prepared by the general procedure (conditions B, 3.1 mmol,

1.0 equiv of diene 1v, 5.0 equiv of vinyl ether 2a, 0.05 equiv of Yb

catalyst, 55 ^ꢁC, 2 h) to give alkoxydihydropyran 3w (0.30 g, 48%) as

a pale yellow oil. n_max(CHCl₃)/cm^ꢃ12974 (CH),1722,1684 (C]C); d_H

(400 MHz, CDCl₃) 7.60 (2H, d, J 8.0, 2ꢄCH in Ph), 7.37–7.27 (3H, m,

3ꢄCH in Ph), 5.45 (1H, dd, J 3.5, 4.5, OCHO), 5.26 (1H, t, J 3.5, C]CH),

4.01 (1H, dq, J 9.5, 7.0, OCHH), 3.72 (1H, dq, J 9.5, 7.0, OCHH), 2.44–

2.15 (2H, m, CH₂), 1.97–1.90 (2H, m, CH₂), 1.28 (3H, t, J 7.0, CH₃); d_C

(125 MHz, CDCl₃) 148.1 (C), 136.0 (C), 128.1, 127.7, 124.3 (5ꢄCH),

98.0 (CH), 97.6 (CH), 63.8 (CH₂), 26.5 (CH₂), 17.6 (CH₂), 15.3 (CH₃);

m/z (CI) 205 (MH^þ,100%). Found: MH^þ, 205.1225; C₁₃H₁₆O₂re-

quires: MH^þ, 205.1228.

4.4.19. 2-Ethoxy-4,4-dimethyl-6-p-tolyl-3,4-dihydro-2H-pyran 3ab

Prepared by the general procedure (conditions B, 11.5 mmol,

1.0 equiv of diene 1aa, 5.0 equiv of vinyl ether 2a, 0.05 equiv of Yb

catalyst, 65 ^ꢁC, 3 h) to give alkoxydihydropyran 3ab (1.13 g, 40%) as

a yellow oil. n_max(CHCl₃)/cm^ꢃ12956–2926 (CH), 2867, 1649 (C]C);

d_H(400 MHz, CDCl₃) 7.50 (2H, d, J 8.0, 2ꢄCH in Ph), 7.15 (2H, d, J 8.0,

2ꢄCH in Ph), 5.19 (1H, s, C]CH), 5.11 (1H, dd, J 8.0, 2.5, OCHO), 4.13

(1H, dt, J 9.5, 7.0, OCHH), 3.72 (1H, dt, J 9.5, 7.0, OCHH), 2.37 (3H, s,

CH₃Ph), 1.73–1.86 (2H, m, CH₂), 1.33 (3H, t, J 7.0, CH₂CH₃), 1.18 (3H, s,

CH₃),1.16 (3H, s, CH₃); d_C(100 MHz, CDCl₃) 146.6 (C),137.6 (C),132.9

(C), 128.8 (2ꢄCH), 124.4 (2ꢄCH), 107.8 (CH), 98.6 (CH), 64.5 (CH₂),

42.0 (CH₂), 31.5, 30.6 (2ꢄCH₃), 30.5 (C), 21.2 (CH₃), 15.4 (CH₃); m/z

(CI) 247 (MH^þ,100%). Found: MH^þ, 247.1689; C₁₆H₂₂O₂requires:

MH^þ, 247.1685.

4.4.15. 2-Ethoxy-4,4-dimethyl-6-phenyl-3,4-dihydro-2H-pyran 3x

Prepared by the general procedure (conditions B, 6.2 mmol,

1.0 equiv of diene 1w, 5.0 equiv of vinyl ether 2a, 0.05 equiv of Yb

catalyst, 55 ^ꢁC, 4 h) to give alkoxydihydropyran 3x (0.60 g, 41%) as

a yellow oil. n_max(CHCl₃)/cm^ꢃ13058–2957 (CH), 2250, 1649 (C]C);

d_H(500 MHz, CDCl₃) 7.62–7.65 (2H, m, 2ꢄCH in Ph), 7.28–7.39 (3H,

m, 3ꢄCH in Ph), 5.26 (1H, s, CCHC), 5.14 (1H, dd, J 2.5, 8.0, OCHO),

4.15 (1H, dt, J 9.5, 7.0, OCHH), 3.74 (1H, dt, J 9.5, 7.0, OCHH), 1.85–

1.89 (1H, m, CH₂), 1.77–1.81 (1H, m, CH₂), 1.35 (3H, t, J 7.0, CH₂CH₃),

1.21 (3H, s, CH₃), 1.19 (3H, s, CH₃); d_C(125 MHz, CDCl₃) 146.6 (C),

135.7 (C), 128.1, 127.8, 124.6 (5ꢄCH), 108.6 (CH), 98.7 (CH), 64.6

(CH₂), 42.0 (CH₂), 31.5 (CH₃), 30.6 (CH₃), 30.5 (C), 15.4 (CH₃); m/z

(CI) 233 (MH^þ,100%). Found: MH^þ, 233.1537; C₁₅H₂₀O₂requires:

MH^þ, 233.1542.

4.4.20. 6-(4-Chlorophenyl)-2-ethoxy-4,4-dimethyl-3,4-dihydro-

2H-pyran 3ac

Prepared by the general procedure (conditions B, 5.2 mmol,

1.0 equiv of diene 1ab, 5.0 equiv of vinyl ether 2a, 0.05 equiv of Yb

catalyst, 65 ^ꢁC, 5 h) to give alkoxydihydropyran 3ac (0.60 g, 44%) as

a yellow oil. n_max(CHCl₃)/cm^ꢃ12958–2926 (CH), 2867, 1648 (C]C);

d_H(400 MHz, CDCl₃) 7.54 (2H, d, J 8.5, 2ꢄCH in Ph), 7.31 (2H, d, J 8.5,

2ꢄCH in Ph), 5.23 (1H, s, CCHC), 5.12 (1H, dd, J 8.0, 2.5, OCHO), 4.11

4.4.16. 2-Ethoxy-4,4-diethyl-6-phenyl-3,4-dihydro-2H-pyran 3y

Prepared by the general procedure (conditions B, 6.4 mmol,

1.0 equiv of diene 1x, 5.0 equiv of vinyl ether 2a, 0.05 equiv of Yb

4498

A. Armstrong et al. / Tetrahedron 65 (2009) 4490–4504

(1H, dt, J 9.5, 7.0, OCHH), 3.71 (1H, dt, J 9.5, 7.0, OCHH), 1.72–1.87

(2H, m, CH₂), 1.33 (3H, t, J 7.0, CH₂CH₃), 1.19 (3H, s, CCH₃), 1.17 (3H, s,

CCH₃); d_C(100 MHz, CDCl₃) 145.7 (C), 134.2 (C), 133.5 (C), 128.2

(2ꢄCH), 125.8 (2ꢄCH), 109.0 (CH), 98.8 (CH), 64.6 (CH₂), 41.8 (CH₂),

31.4 (CH₃), 30.5 (C, CH₃), 15.4 (CH₃); m/z (CI) 267 (MH^þ,100%).

Found: MH^þ, 267.1149; C₁₅H₁₉O₂Cl requires: MH^þ, 267.1152.

(2H_major, m, CH₂), 1.51–1.18 (18H_both, m, 2ꢄCH₂, 2ꢄCH₂, 2ꢄCH₂,

2ꢄOCH₂CH₃), 1.01 (3H_minor, d, J 7.0, CHCH₃), 1.00 (3H_major, d, J 7.0,

CHCH₃), 0.92 (3H_major, t, J 7.0, CHCH₃); d_C(125 MHz, CDCl₃) 151.2

(C)_minor, 149.8 (C)_major, 102.7 (CH)_major, 102.0 (CH)_minor, 96.7 (CH)_major

,

99.8 (CH)_minor, 64.1 (CH₂)_minor, 63.5 (CH₂)_major, 36.7 (CH₂)_minor, 35.2

(CH2)_major, 33.7 (CH₂)_minor, 33.4 (CH₂)_major, 29.2 (CH₂)_major, 29.1

(CH₂)_minor, 26.4 (CH)_minor, 22.1 (CH)_major, 21.7 (CH₂)_major, 21.6

4.4.21. 6-(4-Nitrophenyl)-2-ethoxy-4,4-dimethyl-3,4-dihydro-2H-

pyran 3ad

(CH₂)_minor, 15.3 (CH₃)_major, 15.2 (CH₃)_major, 13.9 (CH₃)_major, 13.9

(CH₃)_minor[22 out of 24 carbons observed]; m/z (CI) 199 (MH^þ,100%).

Found: MH^þ, 199.1697; C₁₂H₂₂O₂requires: MH^þ, 199.1698.

Prepared by the general procedure (conditions B, 1.6 mmol,

1.0 equiv of diene 1ac, 5.0 equiv of vinyl ether 2a, 0.05 equiv of Yb

catalyst, 65 ^ꢁC, 5 h) to give alkoxydihydropyran 3ad (0.25 g, 58%) as

a yellow oil. n_max(CHCl₃)/cm^ꢃ13466, 2254,1640 (C]C), 1518 (NO₂);

d_H(400 MHz, CDCl₃) 8.20 (2H, d, J 9.0, 2ꢄCH in Ph), 7.74 (2H, d, J 9.0,

2ꢄCH in Ph), 5.46 (1H, s, CCHC), 5.16 (1H, dd, J 7.5, 2.5, OCHO), 4.05–

4.15 (1H, m, OCHH), 3.68–3.77 (1H, m, OCHH), 1.90–1.77 (2H, m,

CH₂), 1.32 (3H, t, J 7.0, CH₂CH₃), 1.22 (3H, s, CH₃), 1.19 (3H, s, CH₃); d_C

(100 MHz, CDCl₃) 147.1 (C), 145.0 (C), 141.8 (C), 125.0 (2ꢄCH), 123.5

(2ꢄCH), 112.8 (CH), 98.9 (CH), 64.8 (CH₂), 41.5 (CH₂), 31.2 (CH₃),

30.6 (C), 30.2 (CH₃), 15.3 (CH₃); m/z (CI) 278 (MH^þ,100%). Found:

MH^þ, 278.1405; C₁₅H₁₉NO₄requires: MH^þ, 278.1392.

4.5. Oxidation methods

4.5.1. Conditions A

To a 0.02 M solution of 2-alkoxydihydropyrans 3 (1.0 equiv) in

CH₂Cl₂, 55% m-CPBA (1.0 equiv) in CH₂Cl₂(0.16–0.30 M) at 0 ^ꢁC

under N₂was added dropwise. After stirring at room temperature,

the white precipitate was ﬁltered off from the reaction mixture and

then phosphate buffer solution was added to the ﬁltered solution.

The CH₂Cl₂layer was separated off from the aqueous layer. The

organic layer was washed with aqueous saturated NaHCO₃solution,

dried with MgSO₄and ﬁltered. Column chromatography, eluting

with EtOAc/petrol, gave (major product) the lactol ether as a col-

ourless oil and as a mixture of diastereoisomers, along with (minor

product) the volatile lactol, also as a colourless oil and as an in-

separable mixture (1:1) of diastereomers.

4.4.22. 2-Ethoxy-4,4-dimethyl-6-(naphthalen-2-yl)-3,4-dihydro-

2H-pyran 3ae

Prepared by the general procedure (conditions B, 4.8 mmol,

1.0 equiv of diene 1ad, 5.0 equiv of vinyl ether 2a, 0.05 equiv of Yb

catalyst, 65 ^ꢁC, 5 h) to give alkoxydihydropyran 3ae (0.55 g, 41%) as

a yellow oil. n_max(CHCl₃)/cm^ꢃ13057–2926 (CH), 2868, 1643 (C]C),

1626; d_H(400 MHz, CDCl₃) 8.09 (1H, s, CH in Naph), 7.79–7.90 (3H,

m, 3ꢄCH in Naph), 7.71 (1H, dd, J 8.5, 1.5, CH in Naph), 7.45–7.51

(2H, m, 2ꢄCH in Naph), 5.41 (1H, s, CCHC), 5.21 (1H, dd, J 2.5, 8.0,

OCHO), 4.22 (1H, dt, J 9.5, 7.0, OCHH), 3.79 (1H, dt, J 9.5, 7.0, OCHH),

1.82–1.94 (2H, m, CH₂), 1.38 (3H, t, J 7.0, CH₂CH₃), 1.24 (3H, s, CH₃),

1.21 (3H, s, CH₃); d_C(100 MHz, CDCl₃) 146.6 (C), 133.3 (C), 133.0 (C),

132.9 (C), 128.4 (CH), 127.63 (CH), 127.55 (CH), 126.1 (CH), 125.9

(CH), 123.3 (CH), 122.8 (CH), 109.4 (CH), 98.8 (CH), 64.7 (CH₂), 42.0

(CH₂), 31.5 (CH₃), 30.65 (CH₃), 30.63 (C), 15.4 (CH₃); m/z (CI) 283

(MH^þ,100%). Found: MH^þ, 283.1691; C₁₉H₂₂O₂requires: MH^þ,

283.1698.

4.5.2. Conditions B

To a 0.02 M solution of 2-alkoxydihydropyran 3 in CH₂Cl₂

(10 mL) at 0 ^ꢁC was added a DMDO/acetone solution (1.0 equiv,

0.01–0.04 M).⁹The reaction mixture was kept in the ice-bath for

30 min and then allowed to stir at rt. After the solution was con-

centrated, column chromatography, eluting with diethyl ether/

petrol, gave lactols as major products and lactol ethers as minor

products.

4.5.3. Conditions C

To a degassed, oven dried vessel was added dry pre-heated 4 Å

molecular sieves (1 g), urea hydrogen peroxide (3.0–6.0 equiv),

imidazole (0.5 equiv) and distilled CH₂Cl₂(10 mL). The mixture was

cooled to 0–5 ^ꢁC under an inert atmosphere of Ar and MTO (4–

8 mol %) was then added to give a deep yellow colour. The dihy-

dropyran 3 (1.0 equiv) was added dropwise and the reaction

warmed to rt. On consumption of the starting material (TLC anal-

ysis), CSA (0.2 equiv) was added and the reaction mixture stirred

for 18 h. On completion, the mixture was ﬁltered, washed with

CH₂Cl₂, concentrated under reduced pressure and then puriﬁed via

ﬂash column chromatography to give the required epoxidation-

rearrangement product.

4.4.23. (2S

*

,4S )-2-Ethoxy-4-methyl-6-propyl-3,4-dihydro-2H-

*

pyran 3af

Prepared by the general procedure (conditions B, 4.3 mmol,

1.0 equiv of diene 1, 5.0 equiv of vinyl ether 2a, 0.05 equiv of Yb cat-

alyst, 55 ^ꢁC, 5 days) to give 3af (0.55 g, 70%) in a 4:1 inseparable

mixture as a colourless oil. n_max(CHCl₃)/cm^ꢃ12961–2873 (CH), 1675

(C]C); d_H(250 MHz, CDCl₃) 5.00 (1H_minor, t, J 3.0, OCHO), 4.88

(1H_major, dd, J 8.5, 2.0, OCHO), 4.44 (1H_minor, d, J 1.0, C]CH), 4.33

(1H_major, d, J 1.0, C]CH), 3.93 (1H_major, dq, J 9.5, 7.0, OCHH), 3.56

(1H_major, dq, J 9.5, 7.0, OCHH), 2.48–2.28 (2H_both, m, 2ꢄCHCH₃), 2.03–

1.90 (4H_both, m, 2ꢄCH₂), 1.55–1.14 (8H_both, 2ꢄCH₂, 2ꢄCH₂), 1.23

4.5.4. Conditions D (in situ DMDO formation)

(3H_major, t, J 7.0, OCH₂CH₃), 0.99(3H_major, d, J 7.0, CHCH₃), 0.89(3H_major

,

To a 0.02 M solution of acetone (20.0 equiv) and 2-alkoxydihy-

t, J 7.5, CH₂CH₂CH₃); ¹³C could not be obtained due to the rapid de-

composition of the sample in CDCl₃; m/z (CI) 185 (MH^þ,100%). Found:

MH^þ, 185.1550; C₁₁H₂₀O₂requires: MH^þ, 185.1542.

dropyran 3 (1.0 equiv) in CH₂Cl₂at 0 ^ꢁC was added 0.4 mM

Na₂EDTA (aq, adjusting to pHw7.5).

A

mixture of Oxone^Ò

(2.5 equiv) and NaHCO₃(4.0 equiv) was ground together before

being added to the reaction mixture over 30 min. After stirring

vigorously at room temperature overnight, the organic layer was

washed with aqueous saturated NaHCO₃solution, dried with

MgSO₄, ﬁltered and concentrated. Column chromatography, eluting

with diethyl ether/petrol (3:2), gave lactol ethers as the major

products and lactols as minor products.

4.4.24. (2S

*

,4S )-6-Butyl-2-ethoxy-4-methyl-3,4-dihydro-2H-

*

pyran 3ag

Prepared by the general procedure (conditions B, 7.8 mmol,

1.0 equiv of diene 1, 5.0 equiv of vinyl ether 2a, 0.05 equiv of Yb cat-

alyst, 55 ^ꢁC, 3 h, microwave) to give 3ag (1.01 g, 65%) in a 4:1 in-

separable mixture as a colourless oil. n_max(CHCl₃)/cm^ꢃ12957–2872

(CH), 1673 (C]C); d_H(250 MHz, CDCl₃) 5.02 (1H_major, t, J 3.0, OCHO),

4.90 (1H_minor, dd, J 8.5, 2.0, OCHO), 4.45 (1H_major, d, J 0.5, C]CH), 4.35

(1H_minor, d, J 1.0, C]CH), 3.85 (1H_major, dq, J 9.5, 7.0, OCHH), 3.58

(1H_major, dq, J 9.5, 7.0, OCHH), 2.48–2.33 (1H_major, m CHCH₃), 2.09–1.95

4.5.5. (2R

*

,5R

*

)-1-(5-Hydroxy-tetrahydro-furan-2-yl)-ethanone

and (2R ,5S

*

)-1-(5-hydroxy-tetrahydro-furan-2-yl)-ethanone 6³⁹

Prepared by the oxidation method (conditions B, 3 h) to give 6

(263 mg, dr 1:1, 53%). n_max(CHCl₃)/cm^ꢃ12959 (CH), 1716 (C]O),

A. Armstrong et al. / Tetrahedron 65 (2009) 4490–4504

4499

1649; d_H(250 MHz, CDCl₃) 5.60 (1H_a, t, J 2.5, CHOH), 5.53 (1H_b, t, J

2.5, CHOH), 5.11 (2H_both, s, 2ꢄOH), 4.53 (1H_a, dd, J 9.0, 5.0, C(O)CH),

4.36 (1H_b, t, J 8.0, C(O)CH), 2.53–1.72 (8H_both, m, 4ꢄCH₂), 2.15 (3H_a,

s, CH₃), 2.08 (3H_b, s, CH₃); d_C(125 MHz, CDCl₃) 210.5, 209.2 (C), 99.4,

99.2 (CH), 84.0, 82.5 (CH), 33.3, 32.2 (CH₂), 26.5, 25.9 (CH₃), 25.5,

25.1 (CH₂); m/z (CI) 148 (MNH^þ₄, 100%). Found: MNH₄^þ, 148.0975;

C₆H₁₀O₃requires: MNH^þ₄, 148.0974.

25%) as a colourless oil. n_max(CH₂Cl₂)/cm^ꢃ12975, 1379, 1131; d_H

(500 MHz, CDCl₃) 5.38 (1H, d, J 3.9, OCHO), 4.94 (1H, dd, J 8.2, 6.3,

OCHCH₂), 3.97 (1H, dd, J 7.4, 3.9, OCHCH), 3.92 (1H, dq, J 9.7, 7.1,

OCHHCH₃), 3.52 (1H, dq, J 9.7, 7.1, OCHHCH₃), 1.94 (1H, ddd, J 14.1,

6.2, 3.6, CHCHHCH), 1.81–1.73 (1H, m, CHCHCH₂), 1.64–1.61–1.54

(1H, m, CHCHCH₃), 1.54 (3H, s, OCCH₃), 1.37 (3H, s, OCCH₃), 1.20 (3H,

t, J 7.1, OCH₂CH₃), 1.13 (1H, ddd, J 13.9, 8.3, 8.3, CHCHHCH), 0.98 (3H,

d, J 6.8, CHCH₃), 0.91 (3H, d, J 6.7, CHCH₃); d_C(125 MHz, CDCl₃) 110.8

(C), 97.8 (CH), 95.3 (CH), 79.5 (CH), 63.3 (CH₂), 41.9 (CH), 29.9 (CH),

28.6 (CH₂), 28.1 (CH₃), 26.4 (CH₃), 20.5 (CH₃), 19.1 (CH₃), 15.2 (CH₃);

m/z (CI) 245 (MþH)^þ, 262 (MþNH₄)^þ. Found: 262.2024, (MþNH₄)^þ;

C₁₃H₂₈NO₄requires: 262.2018.

4.5.6. (2R

(2R ,5S

)-1-(5-ethoxy-tetrahydro-furan-2-yl)-ethanone 4a³

Prepared using oxidation method A, on 3a (1.0 equiv, 1.6 mmol)

*

,5R

*

)-1-(5-Ethoxy-tetrahydro-furan-2-yl)-ethanone and

*

for 2 h to give 4a (32 mg, 14%) in an inseparable mixture (2:1) as

a colourless oil. n_max(CHCl₃)/cm^ꢃ12979 (CH), 2254, 1716 (C]O); d_H

(250 MHz, CDCl₃) 5.25 (1H_minor, t, J 3.5, OCHO), 5.18 (1H_major, t, J 3.5,

OCHO), 4.45 (1H_minor, dd, J 9.0, 5.5, C(O)CH), 4.32 (1H_major, t, J 8.0,

C(O)CH), 3.85 (2H_both, dq, J 9.5, 7.0, 2ꢄOCHH), 3.46 (2H_both, dq, J 9.5,

7.0, 2ꢄOCHH), 2.42–1.80 (8H_both, m, 4ꢄCH₂), 2.22 (3H_major, s,

C(O)CH₃), 2.18 (3H_minor, s, C(O)CH₃), 1.17 (3H_minor, t, J 7.0, CH₂CH₃),

1.20 (3H_major, t, J 7.0, CH₂CH₃); d_C(125 MHz, CDCl₃) 105.0, 104.6

(CH), 84.7, 82.4 (CH), 63.2, 61.2 (CH₂), 32.9, 31.6 (CH₃), 26.9, 26.7

(CH₂), 25.5, 19.1 (CH₂), 15.0, 15.2 (CH₃).

4.5.10. (3aR

dimethyl-tetrahydro-3aH-[1,3]dioxolo[4,5-b]pyran 11c and

(4R ,6S )-6-ethoxy-4-(4-methoxyphenyl)-dihydro-2H-pyran-

*

,5S

*

,7R

*

,7aR )-5-Ethoxy-7-(4-methoxyphenyl)-2,2-

*

3(4H)-one 12a

Prepared using oxidation method B (0.5 mmol, 1.0 equiv 3m,

1.0 equiv DMDO, rt, 18 h) to afford the title compounds 11c (48 mg,

31%) and 12a (16 mg, 14%) as colourless oils. Compound (11c); n_max

(CH₂Cl₂)/cm^ꢃ12973, 1379, 1131; d_H(400 MHz, CDCl₃) 7.21 (2H, d, J

8.6, ArH), 6.88 (2H, d, J 8.6, ArH), 5.55 (1H, d, J 4.1, OCHO), 5.09 (1H,

dd, J 7.8, 6.6, OCHCH₂), 4.16 (1H, dd, J 8.0, 4.1, OCHCH), 3.96 (1H, dq, J

9.6, 7.1, OCHHCH₃), 3.79 (3H, s, OCH₃), 3.57 (1H, dq, J 9.6, 7.1,

OCHHCH₃), 2.91 (1H, ddd, J 13.8, 8.0, 3.7, CHCHCH₂), 2.17 (1H, ddd, J

14.1, 6.4, 3.7, CHCHHCH), 1.67 (1H, dt, J 14.0, 7.9, CHCHHCH), 1.60

(3H, s, OCCH₃), 1.34 (3H, s, OCCH₃), 1.24 (3H, t, J 7.1, OCH₂CH₃); d_C

(100 MHz, CDCl₃) 158.5 (C), 134.0 (C), 128.3 (CH), 114.0 (CH), 111.2

(C), 97.3 (CH), 95.2 (CH), 63.4 (CH₂), 55.2 (CH₃), 41.2 (CH), 32.9

(CH₂), 28.1 (CH₃), 26.5 (CH₃), 15.5 (CH₃); m/z (CI) 326 (MþNH₄)^þ.

Found: 326.1976 (MþNH₄)^þ; C₁₇H₂₈NO₅requires: 326.1967.

Compound (12a); n_max(CH₂Cl₂)/cm^ꢃ11735 (C]O),1379,1131; d_H

(250 MHz, CDCl₃) 7.05 (2H, d, J 8.7, ArH), 6.89 (2H, d, J 8.8, ArH), 5.22

(1H, t, J 6.6, OCHO), 4.37 (1H, d, J 17.6, OCHH(O)), 4.06 (1H, d, J 17.6,

OCHH(O)), 3.92–3.78 (5H, OCHHCH₃, CCHCH₂and OCH₃), 3.57 (1H,

dq, J 9.6, 7.1, OCHHCH₃), 2.64 (1H, td, J 6.3, 14.3, CHCHHCH), 2.13

(1H, dt, J 6.4, 14.2, CHCHHCH), 1.26 (3H, t, J 7.1, OCH₂CH₃); d_C

(100 MHz, CDCl₃) 210.5 (C), 158.8 (C), 129.6 (CH), 128.3 (C), 114.0

(CH), 97.5 (CH), 66.6 (CH₂), 63.4 (CH₂), 55.2 (CH₃), 48.6 (CH), 34.9

(CH₂), 15.1 (CH₃); m/z (CI) 251 (MþH)^þ, 268 (MþNH₄)^þ. Found:

268.1548, (MþNH₄)^þ; C₁₄H₂₂NO₄requires: 268.1549.

4.5.7. (2R

(2R ,5S )-1-(5-butoxy-tetrahydro-furan-2-yl)-ethanone 4b

Prepared using oxidation method A, on 3b (1.0 equiv, 3.0 mmol)

for 3 h to give major compounds 4b_minor(13%) and 4b_major(26%) as

separable mixture (2:1) in colourless oil (220 mg,

4b_minorþ4b_major¼39%), 4b_major

n_max(CHCl₃)/cm^ꢃ12962–2876 (CH),

*

,5R

*

)-1-(5-Butoxy-tetrahydro-furan-2-yl)-ethanone and

*

a

:

1722 (C]O), 1644; d_H(250 MHz, CDCl₃) 5.28 (1H, t, J 2.0, OCHO),

4.49 (1H, dd, J 9.0, 6.0, C(O)CH), 3.70 (1H, dt, J 9.5, 6.5, OCHH), 3.42

(1H, dt, J 9.5, 6.5, OCHH), 2.40–1.79 (4H, m, CH₂, CH₂), 2.19 (3H, s,

CCH₃), 1.62–1.42 (2H, m, CH₂), 1.42–1.25 (2H, m, CH₂), 0.91 (3H, t, J

7.5, CH₂CH₃); d_C(125 MHz, CDCl₃), 209.0 (C), 104.8 (CH), 82.4 (CH),

67.4 (CH₂), 31.7 (CH₂), 31.6 (CH₂), 26.9 (CH₂), 26.1 (CH₃), 19.3 (CH₂),

13.8 (CH₃); m/z (CI) 171 (MH^þ). Found: MNH₄^þ, 204.1595; C₁₀H₁₈O₃

requires: MNH^þ₄, 204.1560; 4b_minorn_max(CHCl₃)/cm^ꢃ12962–2876

:

(CH), 1721 (C]O), 1642; d_H(250 MHz, CDCl₃) 5.19 (1H, dd, J 4.5, 1.5,

OCHO), 4.34 (1H, t, J 8.0, C(O)CH), 3.80 (1H, dt, J 9.5, 6.5, OCHH), 3.43

(1H, dt, J 9.5, 6.5, OCHH), 2.25 (3H, s, CH₃), 2.22–1.87 (4H, m, CH₂,

CH₂), 1.62–1.43 (2H, m, CH₂), 1.42–1.22 (2H, m, CH₂), 0.92 (3H, t, J

6.5, CH₂CH₃); d_C(125 MHz, CDCl₃), 211.0 (C), 105.3 (CH), 84.7 (CH),

67.7 (CH₂), 32.8 (CH₂), 31.7 (CH₂), 26.7 (CH₂), 25.5 (CH₃), 19.4 (CH₂),

13.9 (CH₃); m/z (CI) 171 (MH^þ). Found: MNH₄^þ, 204.1595; C₁₀H₁₈O₃

requires: MNH^þ₄, 204.1560.

4.5.11. (2R

*

,5R )-5-Ethoxy-2-methyl-tetrahydrofuran-2-

*

carbaldehyde 4c

Prepared using oxidation method C (1.0 mmol, 1.0 equiv 3o) to

afford the title compound 4c (21 mg, 13%) as a colourless oil. n_max

(CH₂Cl₂)/cm^ꢃ12977, 2932, 2801, 1735 (C]O), 1451, 1375, 1339,

1209, 1109, 1083, 1042, 1008, 976, 877; d_H(400 MHz, CDCl₃) 9.54

(1H, s, CCH(O)), 5.21 (1H, d, J 4.8, OCHO), 3.80 (1H, dq, J 9.5, 7.1,

OCHHCH₃), 3.47 (1H, dq, J 9.5, 7.1, OCHHCH₃), 2.33 (1H, app td, J 9.0,

12.6, CCHHCH₂), 2.09–1.99 (1H, m, CCHHCH₂),1.91 (1H, dddd, J 12.8,

8.8, 3.3, 0.7, CH₂CHHCH), 1.67 (1H, ddd, J 12.8, 9.7, 3.3, CH₂CHHCH),

1.27 (3H, s, CCH₃), 1.16 (3H, t, J 7.1, OCH₂CH₃); d_C(100 MHz, CDCl₃)

203.2 (CH), 104.7 (CH), 87.0 (C), 63.0 (CH₂), 32.3 (CH₂), 30.7 (CH₂),

20.8 (CH₃), 15.0 (CH₃); m/z (CI) 176 (MþNH₄)^þ. Found: 176.1286

(MþNH₄)^þ; C₈H₁₈NO₃requires: 176.1287.

4.5.8. (3aR

*

,5S

*

,7R

*

,7aR )-5-Ethoxy-2,2-dimethyl-7-phenyl-

*

tetrahydro-3aH-[1,3]dioxolo[4,5-b]pyran 11a

Prepared using oxidation method B (0.5 mmol, 1.0 equiv 3i,

1.0 equiv DMDO, rt, 18 h) to afford the title compound 11a (42 mg,

30%) as a colourless oil. n_max(CH₂Cl₂)/cm^ꢃ12977, 1371, 1117, 1043,

1009, 699; d_H(400 MHz, CDCl₃) 7.39–7.19 (5H, m, ArH), 5.57 (1H, d, J

4.1, OCHO), 5.10 (1H, dd, J 7.8, 6.6, OCHCH₂), 4.21 (1H, dd, J 8.0, 4.1,

OCHCH), 3.97 (1H, dq, J 9.6, 7.1, OCHHCH₃), 3.57 (1H, dq, J 9.6, 7.1,

OCHHCH₃), 2.96 (1H, ddd, J 13.7, 7.9, 3.7, OCHCH₂), 2.20 (1H, ddd, J

14.2, 6.4, 3.7, CHCHHCH), 1.71 (1H, dt, J 7.9, 14.0, CHCHHCH), 1.61

(3H, s, OCCH₃), 1.35 (3H, s, OCCH₃), 1.24 (3H, t, J 7.0, OCH₂CH₃); d_C

(100 MHz, CDCl₃) 141.9 (C), 128.7 (CH), 127.4 (CH), 126.9 (CH), 111.3

(C), 97.3 (CH), 95.2 (CH), 82.7 (CH), 63.5 (CH₂), 42.0 (CH), 32.8 (CH₂),

28.1 (CH₃), 26.5 (CH₃), 15.2 (CH₃); m/z (CI) 279 (MþH)^þ, 296

(MþNH₄)^þ. Found: 296.1864, (MþNH₄)^þ; C₁₆H₂₆NO₄requires:

296.1862.

4.5.12. (2R ,3S

* *

,5R )-5-Ethoxy-2,3-dimethyl-tetrahydrofuran-2-

*

carbaldehyde 4d

Prepared using oxidation method C (1.0 mmol, 1.0 equiv 3p) to

afford the title compound 4d (48 mg, 28%) as a colourless oil. n_max

(CH₂Cl₂)/cm^ꢃ11730, 1662, 1548, 1444, 1379, 1132, 922; d_H

(400 MHz, CDCl₃) 9.85 (1H, s, CCH(O)), 5.31 (1H, dd, J 5.7, 3.7,

OCHO), 3.89 (1H, dq, J 9.5, 7.1, OCHHCH₃), 3.52 (1H, dq, J 9.6, 7.1,

OCHHCH₃), 2.47 (1H, ddd, J 13.3, 8.2, 5.7, CHCHHCH), 2.24–2.06 (1H,

m, CCHCH₂), 1.73–1.60 (1H, m, CHCHHCH), 1.26 (3H, s CCH₃), 1.22

4.5.9. (3aR

*

,5S

*

,7R

*

,7aR )-5-Ethoxy-7-isopropyl-2,2-dimethyl-

*

tetrahydro-3aH-[1,3]dioxolo[4,5-b]pyran 11b

Prepared using oxidation method B (0.5 mmol, 1.0 equiv 3l,

1.0 equiv DMDO, rt, 18 h) to afford the title compound 11b (31 mg,

4500

A. Armstrong et al. / Tetrahedron 65 (2009) 4490–4504

(3H, t, J 7.1, OCH₂CH₃),1.06 (3H, d, J 7.2, CHCH₃); d_C(100 MHz, CDCl₃)

205.6 (CH), 104.8 (CH), 89.6 (C), 63.8 (CH₂), 43.3 (CH), 41.2 (CH₂),

20.7 (CH₃), 15.2 (CH₃), 14.5 (CH₃); m/z (CI) 173 (MþH)^þ, 190

(MþNH₄)^þ. Found: 190.1441 (MþNH₄)^þ; C₉H₂₀NO₃requires:

190.1443.

oil. (63%). n_max(CH₂Cl₂)/cm^ꢃ12958, 1735 (C]O), 1460, 1373, 1112,

1043; d_H(400 MHz, CDCl₃) 9.56 (1H_major, s, CC(O)H), 9.54 (1H_minor, s,

CC(O)H), 5.21–5.19 (1H, m, OCHO), 3.79 (1H, dq, J 9.4, 7.1,

OCHHCH₃), 3.46 (1H, dq, J 9.4, 7.1, OCHHCH₃), 2.32–1.18 (10H, m,

5ꢄCH₂), 1.19 (3H_minor, t, J 7.1, OCH₂CH₃), 1.15 (3H_major, t, J 7.1,

OCH₂CH₃), 0.89–86 (3H, m, CH₂CH₃); d_C(100 MHz, CDCl₃) 204.4

(CH)_major, 203.4 (CH)_minor, 104.6 (CH)_major, 104.3 (CH)_minor, 90.7

4.5.13. (2R

*

,3S

*

,5R )-5-Ethoxy-3-ethyl-2-methyl-tetrahydrofuran-

*

2-carbaldehyde 4e

(C)_minor, 89.7 (C)_major, 63.0 (CH₂)_major, 62.7 (CH₂)_minor, 36.2

Prepared using oxidation method C (1.0 mmol, 1.0 equiv 3q) to

afford the title compound 4e (65 mg, 35%) as a colourless oil. n_max

(CH₂Cl₂)/cm^ꢃ13055, 1728 (C]O), 1384, 1260, 1142, 1015; d_H

(400 MHz, CDCl₃) 9.83 (1H, s, CCH(O)), 5.31 (1H, dd, J 5.7, 4.0,

OCHO), 3.86 (1H, dq, J 9.5, 7.1, OCHHCH₃), 3.51 (1H, dq, J 9.5, 7.1,

OCHHCH₃), 2.48 (1H, ddd, J 13.5, 8.9, 5.8, CHCHHCH), 1.97–1.87 (1H,

m, CCHCH₂), 1.66 (1H, ddd, J 13.5, 9.5, 3.9, CHCHHCH), 1.56–1.46

(1H, m, CHCHHCH₃), 1.34–1.27 (1H, m, CHCHHCH₃), 1.27 (3H, s,

CCH₃), 1.20 (3H, t, J 7.1, OCH₂CH₃), 0.90 (3H, t, J 7.4, CCH₂CH₃); d_C

(63 MHz, CDCl₃) 205.0 (CH), 104.8 (CH), 89.4 (C), 63.7 (CH₂), 51.1

(CH), 39.2 (CH₂), 22.6 (CH₃), 20.9 (CH), 15.2 (CH₃), 13.3 (CH₃); m/z

(CI) 204 (MþNH₄)^þ. Found: 204.1603 (MþNH₄)^þ; C₁₀H₂₂NO₃re-

quires: 204.1600.

(CH₂)_minor, 34.6 (CH₂)_major, 32.5 (CH₂)_minor, 32.4 (CH₂)_major, 29.8

(CH₂)_minor, 28.8 (CH₂)_major, 25.9 (CH₂)_minor, 25.3 (CH₂)_major, 23.0

(CH₂), 15.1 (CH₃)_minor, 14.9 (CH₃)_major, 13.9 (CH₃); m/z (CI) 218

(MþNH₄)^þ. Found: 218.1755, (MþNH₄)^þ; C₁₁H₂₄NO₃requires:

218.1756.

4.6. General procedure for rearrangement/Jones oxidation of

alkoxydihydropyrans

To a 0.02 M solution of the 2-alkoxydihydropyran 3 in CH₂Cl₂at

0 ^ꢁC was added DMDO/acetone (1 equiv of a 0.02–0.045 M solu-

tion). The reaction mixture was kept in the ice-bath for 30 min and

then allowed to stir at rt. After the acetone was evaporated, the

crude material was washed with saturated aqueous NaHCO₃solu-

tion and concentrated to give a mixture of lactol and lactol ether.

This mixture was dissolved in acetone (4.0 M) at 0 ^ꢁC and 3.0 M

Jones reagent (3.0 equiv relative to initial 2-alkoxydihydropyran)

was added dropwise. After the reaction mixture was allowed to stir

at rt, the excess of oxidants was quenched by the addition of 2-

propanol until the brown colour of the mixture turned to green. The

reaction mixture was diluted with diethyl ether and the pre-

cipitated chromium salts were dissolved by the addition of satu-

rated aqueous NH₄Cl solution. The organic layer was separated and

the aqueous layer was extracted with diethyl ether, dried and

concentrated. Column chromatography gave 4,5-cis-lactones as

major products and 4,5-trans-lactones as minor products. Conﬁg-

urations of 4,5-cis-isomers and 4,5-trans-isomers were assigned by

NOESY experiments. The following dihydrofuranones gave spec-

troscopic data in accord with those in the literature: 7a,⁴¹7b,⁴²

7d,³⁷7g.⁴³

4.5.14. (2R

*

,3R

*

,5R )-5-Ethoxy-2-methyl-3-phenyl-tetrahydro-

*

furan-2-carbaldehyde 4f and 4-oxo-3-phenylpentanal⁴⁰

Prepared using oxidation method C (1.5 mmol, 1.0 equiv 3r) to

afford the title compounds 4f (35 mg, 10%) and 4-oxo-3-phenyl-

pentanal, (10 mg, 4%) as colourless oils. n_max(CH₂Cl₂)/cm^ꢃ12979,

1731 (C]O), 1620, 1496, 1376, 1087, 992, 769, 701; d_H(250 MHz,

CDCl₃) 9.65 (1H, s, CCH(O)), 7.34–7.16 (5H, m, ArH), 5.47 (1H, dd, J

5.7, 3.7, OCHO), 3.95 (1H, dq, J 9.4, 7.1, OCHHCH₃), 3.61 (1H, dq, J 9.4,

7.1, OCHHCH₃), 3.36 (1H, br t, J 9.5, CCHCH₂), 2.74 (1H, ddd, J 14.0,

9.7, 5.7, CHCHHCH), 2.44 (1H, ddd, J 14.0, 9.2, 3.6, CHCHHCH), 1.39

(3H, s, CCH₃), 1.28 (3H, t, J 7.1, OCH₂CH₃); d_C(63 MHz, CDCl₃) 202.6

(CH), 136.3 (C), 128.6 (CH), 128.6 (CH), 127.5 (CH), 104.8 (CH), 89.6

(C), 63.9 (CH₂), 54.5 (CH), 39.2 (CH₂), 21.1 (CH₃), 15.2 (CH₃); m/z (CI)

252 (MþNH₄)^þ. Found: 252.1589 (MþNH₄)^þ; C₁₄H₂₂NO₃requires:

252.1600.

4.5.15. 4-Oxo-3-phenylpentanal⁴⁰

n_max(CH₂Cl₂)/cm^ꢃ12922, 2852,1714 (C]O),1659,1632,1357; d_H

(250 MHz, CDCl₃) 9.77 (1H, s, CH₂CH(O)), 7.39–7.18 (5H, m, ArH),

4.24 (1H, dd, J 9.8, 4.1, CCHCH₂), 3.45 (1H, dd, J 18.6, 9.8, CHCHHCH),

2.65 (1H, dd, J 18.5, 4.1, CHCHHCH), 2.13 (3H, s, CCH₃); d_C(63 MHz,

CDCl₃) 206.4 (C), 199.9 (CH), 137.5 (C), 129.2 (CH), 128.2 (CH), 127.8

(CH), 52.8 (CH), 46.6 (CH₂), 28.7 (CH₃); m/z (CI) 194 (MþNH₄)^þ, 177

(MþH)^þ.

4.6.1. (4R

*

,5R )-5-Acetyl-4-(benzyloxymethyl)-dihydrofuran-

*

2(3H)-one 7c

Prepared by the general procedure (0.8 mmol of 2-alkoxydihy-

dropyran, 0.02 M DMDO 40 mL, 3.0 M Jones reagent 2.4 mL, 3 h for

DMDO oxidation, 30 min for Jones oxidation) to give 7c (>95:5) as

a colourless oil (96 mg, 48% over two steps). n_max(CHCl₃)/cm^ꢃ1

2874 (CH), 2089, 1780 (lactone), 1645; d_H(250 MHz, CDCl₃), 7.39–

7.19 (5H, m, Ph), 4.80 (1H, d, J 8.0, C(O)CH), 4.40 (1H, d, J 21.5,

PhCH₂), 4.36 (1H, d, J 21.5, PhCH₂), 3.53 (1H, dd, J 9.5, 3.0, BnOCH₂),

3.38 (1H, dd, J 9.5, 3.0, BnOCH₂), 3.03 (1H, dtt, J 8.0, 9.5, 3.0,

BnOCH₂CH), 2.72 (1H, dd, J 17.5, 9.5, C(O)CH₂), 2.55 (1H, dd, J 17.5,

4.0, C(O)CH₂), 2.23 (3H, s, C(O)CH₃); d_C(125 MHz, CDCl₃) 206.5 (C),

175.5 (C), 136.9 (C), 128.4 (2ꢄCH), 127.9 (CH), 127.6 (2ꢄCH), 83.1

(CH), 73.1, 68.0 (2ꢄCH₂), 38.1 (CH₂), 32.2 (CH), 28.1 (CH₃); m/z (CI)

266 (MNH^þ₄, 100%). Found: MNH₄^þ, 266.1395; C₁₄H₁₆O₄requires:

MNH^þ₄, 266.1392.

4.5.16. (2R

*

,3S

*

,5R )-3,5-Diethoxy-2-methyl-tetrahydrofuran-2-

*

carbaldehyde 4g

Prepared using oxidation method C (1.0 mmol, 1.0 equiv 3t) to

afford the title compound 4g (105 mg, 54%) as a colourless oil. n_max

(CH₂Cl₂)/cm^ꢃ12979, 1735 (C]O), 1442, 1376, 1182, 1086, 1047; d_H

(400 MHz, CDCl₃) 9.73 (1H, s, CCH(O)), 5.31 (1H, dd, J 5.7, 1.8,

OCHO), 3.91–3.83 (2H, m, OCHHCH₃and CCHCH₂), 3.53 (1H, dq, J

9.6, 7.1, OCHHCH₃), 3.47 (1H, dq, J 9.2, 6.9, OCHHCH₃), 3.36 (1H, dq, J

9.6, 6.9, OCHHCH₃), 2.35 (1H, ddd, J 14.1, 7.5, 5.6, CHCHHCH), 2.13

(1H, ddd, J 14.2, 2.9, 1.8, CHCHHCH), 1.29 (3H, s CCH₃), 1.22 (3H, t, J

7.1, OCH₂CH₃),1.11 (3H, t, J 7.0, OCH₂CH₃); d_C(100 MHz, CDCl₃) 202.3

(CH), 105.0 (CH), 88.9 (C), 86.7 (CH), 66.0 (CH₂), 63.4 (CH₂), 39.0

(CH₂), 20.3 (CH₃), 15.0 (CH₃), 14.9 (CH₃); m/z (CI) 203 (MþH)^þ, 220

(MþNH₄)^þ. Found: 203.1276 (MþH)^þ; C₁₀H₁₉O₄requires: 203.1283.

4.6.2. (4R

*

,5R )-5-Acetyl-4-phenyl-dihydro-furan-2-one 7e

*

Prepared by the general procedure (0.9 mmol of 2-alkoxydihy-

dropyran, 0.045 M DMDO 20 mL, 3.0 M Jones reagent 2.7 mL, 3 h

for DMDO oxidation, 30 min for Jones oxidation) to give 7e as

a white solid (120 mg, 65% over two steps). Mp 92–93 ^ꢁC; n_max

(CHCl₃)/cm^ꢃ13035–2877 (CH),1772 (lactone),1721 (C]O),1650; d_H

(250 MHz, CDCl₃) 7.35–7.13 (5H, m, Ph), 5.09 (1H, d, J 8.0, OCH), 4.05

(1H, dt, J 8.0, 6.0, CH), 2.96 (1H, dd, J 17.5, 8.5, CHH), 2.88 (1H, dd, J

17.5, 6.0, CHH), 1.64 (3H, s, CH₃); d_C(125 MHz, CDCl₃), 205.0 (C),

175.6 (C), 135.8 (C), 129.2 (2ꢄCH), 128.4 (CH), 127.6 (2ꢄCH), 85.6

4.5.17. (2R

*

,5R )-2-Butyl-5-ethoxy-tetrahydrofuran-2-

*

carbaldehyde 4h

Prepared using oxidation method C (1.0 mmol, 1.0 equiv 3u) to

afford the title compound 4h (126 mg, 63%, 2:1 dr) as a colourless

A. Armstrong et al. / Tetrahedron 65 (2009) 4490–4504

4501

(CH), 44.0 (CH), 34.5 (CH₂), 28.0 (CH₃); m/z (CI) 222 (MNH^þ₄, 100%).

4.6.5.2. (4S

*

,5S )-4-Methyl-5-pentanoyl-dihydrofuran-2(3H)-one

*

Found: MNH^þ₄, 222.1127; C₁₂H₁₂O₃requires: MNH^þ₄, 222.1130.

8i. n_max(CHCl₃)/cm^ꢃ12254, 1789 (lactone), 1716 (C]O); d_H

(250 MHz, CDCl₃), 4.33 (1H, d, J 9.5, OCH), 2.69 (1H, dd, J 17.5, 8.5,

C(O)CH₂CH), 2.62–2.48 (3H, m, CH₃CH, CH₂in ⁿBu), 2.20 (1H, dd, J

17.5, 4.5, C(O)CH₂CH), 1.61–1.53 (2H, m, CH₂in ⁿBu), 1.37–1.26 (2H,

m, CH₂in ⁿBu), 1.27 (3H, d, J 6.5, CHCH₃), 0.90 (3H, t, J 7.5, CH₂CH₃);

d_C(125 MHz, CDCl₃), 207.4 (C), 175.3 (C), 88.0 (CH), 38.3, 35.8

(2ꢄCH₂), 33.6 (CH), 24.8, 22.2 (2ꢄCH₂), 18.5, 13.8 (2ꢄCH₃); m/z (CI)

202 (MNH^þ₄, 100%). Found: MNH₄^þ, 202.1438; C₁₀H₁₆O₃requires:

MNH^þ₄, 202.1443.

4.6.3. (4S

*

,5R ,Z)-5-Acetyl-4-(oct-5-enyl)-dihydrofuran-2(3H)-

*

one 7f

Prepared by the general procedure (1.2 mmol of 2-alkoxydihy-

dropyran, 0.03 M DMDO 40 mL, 3.0 M Jones reagent 2.5 mL, 3 h for

DMDO oxidation, 30 min for Jones oxidation) to give 7f as a col-

ourless oil (130 mg, 64% over two steps). n_max(CHCl₃)/cm^ꢃ13007–

2858 (CH), 2358, 2330, 1790 (lactone), 1717 (C]O); d_H(250 MHz,

CDCl₃) 5.47–5.14 (2H, m, CH]CH), 4.82 (1H, d, J 7.5, C(O)CH), 2.86–

2.65 (1H, m, C(O)CHCH), 2.65 (1H, dd, J 17.0, 8.0, C(O)CH₂CH), 2.37

(1H, dd, J 17.0, 6.0, C(O)CH₂CH), 2.26 (3H, s, C(O)CH₃), 2.07–1.96 (2H,

m, CH₂CH₃), 1.52–1.02 (8H, m, 4ꢄCH₂), 0.94 (3H, t, J 7.5, CH₂CH₃); d_C

(125 MHz, CDCl₃) 205.8 (C), 175.5 (C), 132.2, 128.3 (2ꢄCH), 84.9

(CH), 38.7 (CH₂), 33.6 (CH), 29.3, 28.8, 28.7, 27.1, 26.7 (5ꢄCH₂), 20.5

(CH₃), 14.3 (CH₃); m/z (CI) 256 (MNH^þ₄, 100%). Found: MNH₄^þ,

256.1907; C₁₄H₂₂O₃requires: MNH^þ₄, 256.1913.

4.7. Synthesis of Quercus lactones

4.7.1. (4S

*

,5S

)-5-butyl-4-methyl-dihydrofuran-2(3H)-one 9¹³

*

To a solution of ketone 7h (0.87 mmol, 1.0 equiv) in MeOH

(10 mL) was added a solution of NaBH₄(0.87 mmol, 1.0 equiv) in

EtOH (10 mL). After stirring at room temperature under N₂over-

night, the reaction mixture was concentrated, taken up in diethyl

ether and washed with water. The ether layer was dried and con-

centrated to give a colourless oil (130 mg), which was diluted in

DCE (10 mL). To the solution was added thiocarbonyldiimidazole

(1.30 mmol, 1.5 equiv) under N₂. The reaction mixture was stirred

and the temperature was gradually increased to 80 ^ꢁC. After stirring

overnight, the reaction mixture was concentrated, diluted with

diethyl ether and washed with water. The ether layer was dried and

concentrated to give a pale yellow oil (80 mg). To a reﬂuxing so-

lution of ⁿBuSnH (0.96 mmol, 1.1 equiv) and AIBN (0.09 mmol,

0.1 equiv) in toluene (10 mL) under N₂was added dropwise a so-

lution of the crude oil above in toluene (10 mL). After stirring at

reﬂux overnight, the organic layer was washed with water, which

was re-extracted with ether. The combined organics were dried and

concentrated. Column puriﬁcation, eluting with EtOAc/petrol (1:1),

4.6.4. (4S

*

,5R

*

)-4-Methyl-5-pentanoyl-dihydrofuran-2(3H)-one 7h

and (4R ,5R

*

)-4-methyl-5-pentanoyl-dihydrofuran-2(3H)-one 8h

Prepared by the general procedure (2.6 mmol of 2-alkoxy-

dihydropyran, 0.03 M DMDO 90 mL, 3.0 M Jones reagent 3.0 mL,

3 h for DMDO oxidation, 30 min for Jones oxidation) to give a 5:1

mixture; 7h (290 mg, 58%) and 8h (60 mg, 12%) as a pale yellow

oil.

4.6.4.1. (4S

*

,5R )-4-Methyl-5-pentanoyl-dihydrofuran-2(3H)-one

*

7h. n_max(CHCl₃)/cm^ꢃ12255, 1788 (lactone), 1719 (C]O); d_H

(250 MHz, CDCl₃), 4.80 (1H, d, J 7.0, OCH), 3.08–2.82 (1H, m,

CH₃CH), 2.73 (1H, dd, J 17.0, 8.0, C(O)CH₂CH), 2.29 (1H, dd, J 17.0,

4.5, C(O)CH₂CH), 2.78–2.32 (2H, m, CH₂CH₂CH₃), 1.71–1.56 (2H, m,

CH₂CH₂CH₃), 1.00 (3H, d, J 7.0, CHCH₃), 0.94 (3H, t, J 7.5, CH₂CH₃);

d_C(125 MHz, CDCl₃), 207.8 (C), 175.6 (C), 84.9 (CH), 42.9 (CH₂),

36.4 (CH), 33.1, 16.0 (2ꢄCH₂), 14.8, 13.6 (2ꢄCH₃); m/z (CI) 188

(MNH^þ₄, 100%). Found: MNH₄^þ, 188.1289; C₉H₁₄O₃requires: MNH^þ₄,

188.1286.

gave (4S

*

,5S )-5-butyl-4-methyl-dihydrofuran-2(3H)-one 9 (37 mg,

*

36%). Data found in accordance with the literature.¹³

4.7.2. (4S

*

,5S

)-4-Methyl-5-pentyl-dihydrofuran-2(3H)-one 10¹²

*

To a solution of ketone 7i (0.66 mmol, 1.0 equiv) in MeOH

(20 mL) was added a solution of NaBH₄(0.66 mmol, 1.0 equiv) in

EtOH (10 mL). After stirring at room temperature under N₂over-

night, the reaction mixture was concentrated, diluted with diethyl

ether and washed with water. The ether layer was dried and con-

centrated to give a colourless oil (197 mg), which was diluted in

DCE (20 mL). To the solution was added thiocarbonyldiimidazole

(0.99 mmol, 1.5 equiv) under N₂. The reaction mixture was stirred

and the temperature was gradually increased to 80 ^ꢁC. After stirring

overnight, the reaction mixture was concentrated, diluted with

diethyl ether and washed with water. The ether layer was dried and

concentrated to give a pale yellow oil (205 mg). To a reﬂuxing so-

lution of ⁿBuSnH (0.73 mmol, 1.1 equiv) and AIBN (0.07 mmol,

0.1 equiv) in toluene (20 mL) under N₂was added dropwise a so-

lution of the crude oil above in toluene (20 mL). After stirring at

reﬂux overnight, the organic layer was washed with water, which

was re-extracted with ether. The combined organics were dried and

concentrated. Column puriﬁcation, eluting with EtOAc/petrol (1:1),

4.6.4.2. (4R

*

,5R )-4-Methyl-5-pentanoyl-dihydrofuran-2(3H)-one

*

8h. n_max(CHCl₃)/cm^ꢃ12255, 1788 (lactone), 1719 (C]O); d_H

(250 MHz, CDCl₃), 4.32 (1H, d, J 7.0, OCH), 2.68 (1H, dd, J 17.0, 8.5,

C(O)CH₂), 2.19 (1H, dd, J 17.0, 7.5, C(O)CH₂), 2.60–2.43 (3H, m,

CH₂CH₂CH₃,CH₃CH),1.61 (2H, tq, J 11.0, 6.5, CH₂CH₂CH₃),1.26 (3H, d,

J 6.5, CHCH₃), 0.91 (3H, t, J 6.5, CH₂CH₃); d_C(125 MHz, CDCl₃), 207.8

(C), 175.0 (C), 87.9 (CH), 40.4, 35.8 (2ꢄCH₂), 33.6 (CH), 18.5 (CH₂),

16.2, 13.6 (2ꢄCH₃); m/z (CI) 188 (MNH^þ₄, 100%). Found: MNH₄^þ,

188.1284; C₉H₁₄O₃requires: MNH^þ₄, 188.1284.

4.6.5. (4S

*

,5R

*

)-4-Methyl-5-pentanoyl-dihydrofuran-2(3H)-one 7i

and (4S ,5S

*

)-4-methyl-5-pentanoyl-dihydrofuran-2(3H)-one 8i

Prepared by above general procedure (2.8 mmol of 2-alkoxy-

dihydropyran, 0.07 M DMDO 40 mL, 3.0 M Jones reagent 3.0 mL, 3 h

for DMDO oxidation, 30 min for Jones oxidation) to give an 8:1

mixture; 7i (250 mg, 48%) and 8i (31 mg, 6%) in an 8:1 ratio in a pale

yellow oil.

gave

(4S

*

,5S

*

)-4-methyl-5-pentyl-dihydrofuran-2(3H)-one

10

(108 mg, 49%). Data found in accordance with the literature.¹²

4.6.5.1. (4S

*

,5R )-4-Methyl-5-pentanoyl-dihydrofuran-2(3H)-one

*

7i. n_max(CHCl₃)/cm^ꢃ12254, 1789 (lactone), 1716 (C]O); d_H

(250 MHz, CDCl₃), 4.80 (1H, d, J 10.0, OCH), 2.93–2.95 (1H, m,

CH₃CH), 2.72 (1H, dd, J 17.5, 8.0, C(O)CH₂CH), 2.73–2.40 (2H, m, CH₂

in ⁿBu), 2.28 (1H, dd, J 17.5, 4.5, C(O)CH₂CH), 1.62–1.54 (2H, m, CH₂

in ⁿBu), 1.38–1.28 (2H, m, CH₂in ⁿBu), 0.99 (3H, d, J 7.0, CHCH₃), 0.91

(3H, t, J 7.5, CH₂CH₃); d_C(125 MHz, CDCl₃), 207.8 (C), 175.6 (C), 84.9

(CH), 40.7 (CH₂), 36.4 (CH₂), 36.4 (CH), 24.6, 22.2 (2ꢄCH₂), 14.8, 13.8

(2ꢄCH₃); m/z (CI) 202 (MNH^þ₄, 100%). Found: MNH^þ₄, 202.1447;

C₁₀H₁₆O₃requires: MNH^þ₄, 202.1443.

4.8. General procedure for the synthesis of compounds

15a–15c and 16a–16c

4.8.1. Conditions E

To a degassed, dry vessel was added dry pre-heated 4 Å molec-

ular sieves (1 g), urea hydrogen peroxide (3.0 equiv), imidazole

(0.5 equiv)and distilled CH₂Cl₂(10 mL). The mixturewas stirredat rt

in an inert atmosphere and MTO (4 mol %) was then added to give

a deep yellow reaction mixture. 2-Alkoxydihydropyran (1.0 equiv)

4502

A. Armstrong et al. / Tetrahedron 65 (2009) 4490–4504

was subsequently added and the reactionwas monitored via TLC. On

consumption of the starting material, the product mixture was then

passed through a small pad of CeliteÔ. The ﬁltrate was then diluted

further in dry CH₂Cl₂(10 mL) and Amberlyst 15^Ò(30 mg) was added.

The reaction mixture was left to stir under an inert atmosphere for

4 h and monitored via TLC analysis. The product mixture was sub-

sequently concentrated under reduced pressure and the crude ma-

terial diluted in acetone (3 mL) and reacted with 10.0 equiv of Jones

reagentfor 1.5 h. On completion, the reaction mixturewas quenched

with IPA and the inorganic chromium salts removed by ﬁltration.

NaHCO₃was added to the ﬁltrate until the pH was moderately basic.

The unwanted organics wereremovedbyextraction (2ꢄ30 mL) with

EtOAc. The aqueous fractions were collected, acidiﬁed with 3 M HCl

and re-extracted (2ꢄ20 mL) with EtOAc. The organic layers were

subsequently collected, dried over MgSO₄and then concentrated

under reduced pressure. To a separate oven dried vessel was added

1.0 equivof p-nitrobenzylalcohol, in dry CH₂Cl₂, (5–10 mL), 0.1 equiv

of DMAP, 1.1 equiv of DCC and the reaction was stirred under an at-

mosphere of Ar for 15 min. The crude material from the Jones re-

action was subsequently dissolved in CH₂Cl₂(2 mL) and added

dropwise to the DCC coupling mixture and left to stir for 18 h. On

completion, the reaction mixturewas ﬁltered and washed with Et₂O.

The ﬁltrate was concentrated under reduced pressure and puriﬁed

by column chromatography (start 90% PE/10% EtOAc, end 60% PE/

40% EtOAc) to give the desired esters.

21%, 9:1 dr) and 16c (97 mg, 48%). Compound (15b); n_max(CH₂Cl₂)/

cm^ꢃ12978, 1792 (C]O), 1746 (C]O), 1613, 1515, 1456, 1379, 1248,

1172, 1104, 1032, 957, 825; d_H(400 MHz, CDCl₃) 7.33 (2H, d, J 8.7,

ArH), 6.92 (2H, d, J 8.6, ArH), 5.24 (1H, d, J 11.9, OCHHPh), 5.14 (1H, d,

J 11.9, OCHHPh), 4.06 (1H, dd, J 7.2, 6.7, CCHCH₂), 3.83 (3H, s, OCH₃),

3.52–3.49 (2H, m, OCH₂CH₃), 2.82 (1H, dd, J 17.6, 7.3, CCHHCH), 2.73

(1H, dd, J 17.6, 6.7, CCHHCH), 1.69 (3H, s, CCH₃), 1.09 (3H, t, J 7.0,

OCH₂CH₃); d_C(100 MHz, CDCl₃) 173.3 (C), 169.1 (C), 159.7 (C), 130.2

(CH), 127.3 (C), 113.9 (CH), 86.9 (C), 81.5 (CH), 67.3 (CH₂), 66.5 (CH₂),

55.3 (CH₃), 34.9 (CH₂), 22.2 (CH₃), 15.0 (CH₃); m/z (CI) 326

(MþNH₄)^þ. Found: 326.1601 (MþNH₄)^þ; C₁₆H₂₄NO₆requires:

326.1604.

Compound (16b); n_max(CH₂Cl₂)/cm^ꢃ12951, 2360, 1733, 1614,

1516, 1462, 1353, 1461, 1249, 1174, 1163, 1033, 823; d_H(400 MHz,

CDCl₃) 7.32 (2H, d, J 8.6, ArH), 6.91 (2H, d, J 8.7, ArH), 5.11 (2H, s,

OCH₂Ph), 4.11 (1H, dd, J 7.3, 5.0, CCHCH₂), 3.84 (3H, s, OCH₃), 3.58

(2H, m, OCH₂CH₃), 2.77 (1H, dd, J 15.9, 5.0, CHCHHC), 2.71 (1H, dd, J

16.0, 7.3, CHCHHC), 2.54 (3H, s, CCH₃), 1.22 (3H, t, J 7.0, OCH₂CH₃); d_C

(100 MHz, CDCl₃) 209.0 (C),170.3 (C),159.7 (C), 130.1 (CH), 127.7 (C),

113.9 (CH), 81.5 (CH), 66.7 (CH₂), 66.5 (CH₂), 55.3 (CH₃), 37.0 (CH₂),

26.0 (CH₃), 15.3 (CH₃); m/z (CI) 298 (MþNH₄)^þ. Found: 298.1657

(MþNH₄)^þ; C₁₅H₂₄NO₅requires: 298.1654.

4.8.4. 4-Methoxybenzyl-3-methyl-4-oxo-4-phenylbutanoate 16c

Prepared by the general MTO oxidation method (conditions E,

1.0 mmol, 1.0 equiv 3v) to afford the title compound 16c (66 mg,

21%) as a colourless oil. n_max(CH₂Cl₂)/cm^ꢃ11730 (C]O), 1682, 1611,

1514, 1454, 1341, 1247, 1167, 1033, 976, 822, 705; d_H(400 MHz,

CDCl₃) 7.97 (2H, d, J 7.2, ArH), 7.59–7.54 (1H, m, ArH), 7.49–7.44 (2H,

m, ArH), 7.23 (2H, d, J 8.6, ArH), 6.85 (2H, d, J 8.7, ArH), 5.04 (1H, d, J

12.0, OCHHPh), 4.99 (1H, d, J 12.0, OCHHPh), 4.00–3.90 (1H, m,

CCHCH₂), 3.80 (3H, s, OCH₃), 3.00 (1H, dd, J 16.8, 8.5, CHCHHC), 2.48

(1H, dd, J 16.8, 5.7, CHCHHC), 1.21 (3H, d, J 7.2, CCH₃); d_C(100 MHz,

CDCl₃) 202.7 (C), 172.2 (C), 159.6 (C), 133.0 (CH), 130.0 (CH), 128.6

(CH), 128.4 (CH), 127.9 (C), 113.9 (CH), 66.2 (CH₂), 55.2 (CH₃), 37.5

(CH₂), 37.2 (CH), 17.8 (CH₃); m/z (CI) 330 (MþNH₄)^þ. Found:

330.1712 (MþNH₄)^þ; C₁₉H₂₄NO₄requires: 330.1705.

4.8.2. (2R

*

,3S )-4-Methoxybenzyl-2,3-dimethyl-5-oxo-

*

tetrahydrofuran-2-carboxylateacid 15a and 4-methoxybenzyl

3-methyl-4-oxopentanoate 16a

Prepared by the general MTO oxidation method (conditions E,

1.0 mmol, 1.0 equiv 3p) to afford the title compounds 15a (64 mg,

23%, 2:1 dr) and 16a (23 mg, 9%) as colourless oils. Compound

(15a); n_max(CH₂Cl₂)/cm^ꢃ12935, 2856, 1789 (C]O), 1739 (C]O),

1614, 1516, 1462, 1282, 1245, 1173, 1090, 960, 823; d_H(400 MHz,

CDCl₃) 7.29 (2H_both, d, J 8.6, ArH), 6.89 (2H_minor, d, J 8.6, ArH), 6.88

(2H_major, d, J 8.6, ArH), 5.20 (1H_major, d, J 11.9, OCH₂Ph), 5.18 (1H_minor

,

d, J 11.8, OCH₂Ph), 5.11 (1H_minor, d, J 11.9, OCHHPh), 5.07 (1H_major, d, J

11.9, OCHHPh), 3.83 (3H_both, s, OCH₃), 2.66 (1H_minor, dd, J 17.4, 8.3,

CCHHCH), 2.61 (1H_major, dd, J 16.7, 8.1, CCHHCH), 2.52–2.42 (1H_minor

,

4.8.5. (2R

*

,3S

)-Crobarbatic acid 17¹⁸

*

m, CCHCH₂), 2.38–2.28 (1H_minor, m, CCHCH₂), 2.31 (1H_minor, dd, J

16.7, 12.0, CCHHCH), 2.25 (1H_major, dd, J 17.5, 7.5, CCHHCH), 1.65

(3H_major, s, CCH₃),1.61 (3H_minor, s, CCH₃), 0.91 (3H_major, t, J 7.5, CCH₃),

To a degassed, dry vessel was added the tetrahydrofuranone

ester 15a (30 mg, 0.14 mmol), phenol (250 mg, 2.8 mmol,

20.0 equiv), TFA (10 mL, 0.14 mmol) and the mixture was stirred at

0.87 (3H_minor, t, J 7.5, CHCH₃); d_C(100 MHz, CDCl₃) 177.2 (C)_minor

175.5 (C)_major, 171.9 (C)_minor, 170.2 (C)_minor, 161.3 (C)_minor, 159.9

(C)_major, 130.5 (CH)_major, 130.1 (CH)_minor, 127.1 (C)_minor, 127.0 (C)_major

114.0 (CH), 87.2 (C)_major86.1 (C)_minor67.4 (CH₂)_minor67.3

(CH₂)_major, 55.3 (CH₃), 41.0 (CH)_major, 36.7 (CH)_minor, 36.2 (CH₂)_minor

,

45 ^ꢁC under an atmosphere of Ar for 1 h. The reaction was then

quenched with NaHCO₃and the organics were extracted with

EtOAc (2ꢄ20 mL). The aqueous phase was acidiﬁed with 3 M HCl

and re-extracted with EtOAc (2ꢄ20 mL). The organics were dried

over MgSO₄, and concentrated under reduced pressure to afford the

title compound 17 (22 mg, 93%, 2:1 dr) as an off-white crystalline

solid. Data of both diastereoisomers in accordance with the

literature.¹⁸

,

35.8 (CH₂)_major, 21.9 (CH₃)_major, 18.2 (CH₃)_minor, 15.1 (CH₃)_minor, 14.0

(CH₃)_major; m/z (CI) 296 (MþNH₄)^þ. Found: 296.1491 (MþNH₄)^þ;

C₁₅H₂₂NO₅requires: 296.1498.

Compound (16a); n_max(CH₂Cl₂)/cm^ꢃ11731 (C]O), 1713 (C]O),

1613, 1515, 1461, 1452, 1248, 1161, 1033; d_H(400 MHz, CDCl₃) 7.27

(2H, d, J 8.2, ArH), 6.88 (2H, d, J 8.7, ArH), 5.05 (1H, d, J 12.0,

OCHHPh), 5.00 (1H, d, J 12.0, OCHHPh), 3.80 (3H, s, OCH₃), 3.06–

2.96 (1H, m, CCHCH₂), 2.79 (1H, dd, J 16.8, 8.7, CHCHHC), 2.32 (1H,

dd, J 16.8, 5.4, CHCHHC), 2.19 (3H, s, CCH₃), 1.14 (3H, t, J 7.3, CHCH₃);

d_C(100 MHz, CDCl₃) 210.7 (C), 172.2 (C), 159.6 (C), 130.0 (CH), 127.9

(C), 113.9 (CH), 66.2 (CH₂), 55.3 (CH₃), 42.7 (CH), 36.9 (CH₂), 28.4

(CH₃), 16.5 (CH₃); m/z (CI) 268 (MþNH₄)^þ. Found: 268.1553

(MþNH₄)^þ; C₁₄H₂₂NO₄requires: 268.1549.

4.9. General procedure for enantioselective rearrangement/

Jones oxidation of alkoxydihydropyrans using Jacobsen’s

catalyst

A mixture of alkoxydihydropyran (0.32–1.35 mmol, 1.0 equiv)

pre-dissolved in CH₂Cl₂(0.07 M), Jacobsen catalyst 19 (0.1 equiv)

and 4-phenyl pyridine N-oxide (0.2 equiv) was cooled down to 0 ^ꢁC.

Buffered bleach (1.5–3.0 equiv, pHw11.5) pre-cooled to 0 ^ꢁC was

added to the mixture and the reaction was stirred at 0 ^ꢁC. The re-

action mixture was diluted with CH₂Cl₂, extracted with water and

dried with Na₂SO₄. Short column puriﬁcation was performed to

remove Mn species with a solvent systemof EtOAc/petrol(1:1). After

the crude product was dissolved in acetone (0.07 M), Jones reagent

(3.0 M; 3.0 equiv relative to initial 2-alkoxydihydropyran) was

added dropwise. After stirring, the excess of oxidants was quenched

4.8.3. (2R

*

,3S )-4-Methoxybenzyl-4-ethoxy-5-methyl-2-oxo-

*

tetrahydrofuran-5-carboxylate 15b and 4-methoxybenzyl

3-ethoxy-4-oxopentanoate 16b

Prepared by the general MTO oxidation method (conditions E,

0.75 mmol, 1.0 equiv 3t) to afford the title compound 15b (51 mg,

A. Armstrong et al. / Tetrahedron 65 (2009) 4490–4504

4503

by the addition of 2-propanol until the brown colour of the mixture

turned to green. The reaction mixturewas diluted with diethyl ether.

The organic layer was separatedand the aqueous layer was extracted

with diethyl ether. The combined organics were dried, concentrated

and column chromatography gave the lactone product.

(1H, s, OCH), 2.55 (2H, s, CH₂), 1.07–1.89 (10H, m, 5ꢄCH₂in CyHex);

d_C(100 MHz, CDCl₃), 196.2 (C), 175.9 (C), 136.2 (C), 134.2 (CH), 129.1

(2ꢄCH), 128.5 (2ꢄCH), 85.4 (CH), 45.0 (C), 37.3 (CH₂), 36.3, 32.9,

25.2, 23.1, 22.2 (5ꢄCH₂); m/z (CI) 276 (MNH^þ₄, 100%). Found: MNH₄^þ,

276.1588; C₁₆H₁₈O₃requires: MNH^þ₄, 276.1600.

4.9.1. (S)-5-Benzoyl-dihydrofuran-2(3H)-one 7l⁴⁴

4.9.5. (þ)-(S)-5-(4-Methoxybenzoyl)-4,4-dimethyl-dihydrofuran-

2(3H)-one 7p

Prepared by the general procedure (1.35 mmol of 2-alkoxydihy-

dropyran 3w, 0.14 mmol of Jacobsen’s catalyst, 0.28 mmol of pyridine

N-oxide, 4.00 mmol of NaOCl, 4.00 mmol of 3.0 M Jones reagent, 6 h

for epoxidation, 3 h for Jones oxidation) to give lactone (S)-7l as white

crystals (140 mg, 55% over two steps). Mp 79–80 ^ꢁC, ee 38% (HPLC

Prepared by the general procedure (0.53 mmol of 2-alkoxy-

dihydropyran 3aa, 0.05 mmol of Jacobsen’s catalyst, 0.11 mmol of

pyridine N-oxide, 1.59 mmol of NaOCl, 1.59 mmol of 3.0 M Jones

reagent, 6 h for epoxidation, 3 h for Jones oxidation) to give lactone

(S)-7p as a colourless oil (35 mg, 35% over two steps). ee 79% (HPLC

analysis: OD-H column, 254 nm, ﬂow 1.0 mL/min, ⁱPrOH/hexane

20

(5:95), t_m¼37.90 min, t_M¼46.15 min); [

a

]

0.0 (c 0.03, CHCl₃); d_H

analysis: OD column, 254 nm, ﬂow 0.5 mL/min, ⁱPrOH/hexane

D

20

(500 MHz, CDCl₃) 8.02–7.48 (5H, m, Ph), 5.82–5.76 (1H, m, CH₂CH),

2.65–2.44 (4H, m, 2ꢄCH₂); m/z (CI) 208 (MNH^þ₄, 100%), 398. Found:

MNH^þ₄, 208.0972; C₁₁H₁₀O₃requires: MNH^þ₄, 208.0974.

(5:95), t_m¼104.08 min, t_M¼119.72 min); [

a]

þ56.0 (c 0.01, CHCl₃);

D

n_max(CHCl₃)/cm^ꢃ12965–2931 (CH), 1788 (lactone), 1677 (C]O); d_H

(400 MHz, CDCl₃) 8.00 (2H, d, J 9.0, 2ꢄCH in Ph), 7.01 (2H, d, J 9.0,

2ꢄCH in Ph), 5.48 (1H, s, OCH), 3.92 (3H, s, CH₃), 2.62 (1H, d, J 17.0,

CH₂), 2.33 (1H, d, J 17.0, CH₂), 1.40 (3H, s, CCH₃), 1.00 (3H, s, CCH₃);

d_C(100 MHz, CDCl₃), 193.8 (C), 175.9 (C), 164.4 (C), 131.0 (2ꢄCH),

128.8 (C), 114.3 (2ꢄCH), 85.3 (CH), 55.6 (CH₃), 41.8 (CH₂), 40.6 (C),

28.4 (CH₃), 23.5 (CH₃); m/z (CI) 266 (MNH^þ₄, 100%). Found: MNH₄^þ,

266.1403; C₁₄H₁₆O₄requires: MNH^þ₄, 266.1392.

4.9.2. (þ)-(S)-5-Benzoyl-4,4-dimethyl-dihydrofuran-2(3H)-one 7m

Prepared by the general procedure (1.29 mmol of 2-alkoxy-

dihydropyran 3x, 0.13 mmol of Jacobsen’s catalyst, 0.26 mmol of

pyridine N-oxide, 4.0 mmol of NaOCl, 4.0 mmol of 3.0 M Jones re-

agent, 6 h for epoxidation, 3 h for Jones oxidation) to give lactone

(S)-7m as white crystals (140 mg, 49% over two steps). Mp 113–

115 ^ꢁC; ee 58% (HPLC analysis: OD column, 254 nm, ﬂow 0.5 mL/

4.9.6. (þ)-(S)-4,4-Dimethyl-5-(4-methylbenzoyl)-dihydrofuran-

2(3H)-one 7q

i

20

min, 5% PrOH/hexane (5:95), t_M¼53.24 min, t_m¼58.21 min); [

a]

D

þ42.0 (c 0.01, CHCl₃); n_max(CHCl₃)/cm^ꢃ12969 (CH), 2343, 1789

(lactone), 1690 (C]O); d_H(500 MHz, CDCl₃) 7.96 (2H, d, J 8.5, 2ꢄCH

in Ph), 7.67 (1H, dd, J 8.5, 7.5, CH in Ph), 7.55 (2H, d, J 7.5, 2ꢄCH in

Ph), 5.55 (1H, s, OCH), 2.60 (1H, d, J 17.0, CH₂), 2.36 (1H, d, J 17.0,

CH₂), 1.40 (3H, s, CCH₃), 1.00 (3H, s, CCH₃); d_C(100 MHz, CDCl₃)

195.7 (C), 175.7 (C), 135.8 (C), 134.3 (CH), 129.1 (2ꢄCH), 128.6

(2ꢄCH), 85.5 (CH), 41.8 (CH₂), 40.7 (C), 28.3, 23.5 (CH₃, CH₃); m/z

(CI) 236 (MNH₄^þ, 100%). Found: MNH^þ₄, 236.1285; C₁₃H₁₄O₃re-

quires: MNH^þ₄, 236.1287.

Prepared by the general procedure (0.64 mmol of 2-alkoxy-

dihydropyran 3ab, 0.06 mmol of Jacobsen’s catalyst, 0.13 mmol of

pyridine N-oxide, 1.92 mmol of NaOCl, 1.92 mmol of 3.0 M Jones

reagent,15 h for epoxidation,1 h for Jones oxidation) to give lactone

(S)-7q as a white solid (64 mg, 43% over two steps). Mp 157–160 ^ꢁC;

ee 70% (HPLC analysis: OJ column, 254 nm, ﬂow 1.2 mL/min, ⁱPrOH/

20

hexane (2:98), t_m¼33.14 min, t_M¼45.97 min); [

a

]

þ37.0 (c 0.02,

D

CHCl₃); n_max(CHCl₃)/cm^ꢃ12967–2931 (CH), 2874, 1788 (lactone),

1682 (C]O), 1606; d_H(400 MHz, CDCl₃) 7.86 (2H, d, J 8.0, 2ꢄCH in

Ph), 7.34 (2H, d, J 8.0, 2ꢄCH in Ph), 5.53 (1H, s, OCH), 2.61 (1H, d, J

17.0, CH₂), 2.46 (3H, s, CH₃Ph), 2.34 (1H, d, J 17.0, CH₂), 1.40 (3H, s,

CCH₃), 0.99 (3H, s, CCH₃); d_C(100 MHz, CDCl₃), 195.2 (C), 175.9 (C),

145.5 (C), 133.3 (C), 129.8 (2ꢄCH), 128.7 (2ꢄCH), 85.4 (CH), 41.8

(CH₂), 40.6 (C), 28.4, 23.5, 21.8 (3ꢄCH₃); m/z (CI) 250 (MNH^þ₄, 100%).

Found: MNH^þ₄, 250.1432; C₁₄H₁₆O₃requires: MNH^þ₄, 250.1443.

4.9.3. (þ)-(S)-5-Benzoyl-4,4-diethyl-dihydrofuran-2(3H)-one 7n

Prepared by the general procedure (0.38 mmol of 2-alkoxy-

dihydropyran 3y, 0.04 mmol of Jacobsen’s catalyst, 0.08 mmol of

pyridine N-oxide, 1.14 mmol of NaOCl, 1.14 mmol of 3.0 M Jones

reagent, 6 h for epoxidation, 3 h for Jones oxidation) to give lactone

(S)-7n as a colourless oil (44 mg, 45% over two steps). ee 69% (HPLC

i

analysis: OD-H column, 254 nm, ﬂow 0.5 mL/min, PrOH/hexane

4.9.7. (þ)-(S)-5-(4-Chlorobenzoyl)-4,4-dimethyl-dihydrofuran-

2(3H)-one 7r

20

(2:98), t_M¼49.18 min, t_m¼60.11 min); [

a]

þ47.0 (c 0.01, CHCl₃);

D

n_max(CHCl₃)/cm^ꢃ13444, 2342, 1788 (lactone), 1649 (C]O); d_H

(500 MHz, CDCl₃) 7.96 (2H, d, J 8.5, 2ꢄCH in Ph), 7.68 (1H, dd, J 8.5,

7.5, CH in Ph), 7.55 (2H, d, J 7.5, 2ꢄCH in Ph), 5.71 (1H, s, OCH), 2.63

(1H, d, J 17.0, C(O)CHH), 2.30 (1H, d, J 17.0, C(O)CHH), 1.73–1.80 (1H,

m, CHHCH₃), 1.60–1.68 (1H, m, CHHCH₃), 1.38–1.46 (1H, m,

CHHCH₃), 1.12–1.22 (1H, m, CHHCH₃), 1.09 (3H, s, CH₃), 0.76 (3H, s,

CH₃); d_C(125 MHz, CDCl₃), 196.6 (C), 176.3 (C), 136.0 (C), 134.3 (CH),

129.1 (2ꢄCH), 128.4 (2ꢄCH), 82.2 (CH), 48.0 (C), 38.7 (CH₂), 28.8

(CH₂), 26.2 (CH₂), 9.1 (CH₃), 8.4 (CH₃); m/z (CI) 264 (MNH^þ₄, 100%).

Found: MNH^þ₄, 264.1596; C₁₅H₁₈O₃requires: MNH^þ₄, 264.1600.

Prepared by the general procedure (0.75 mmol of 2-alkoxy-

dihydropyran 3ac, 0.08 mmol of Jacobsen’s catalyst, 0.15 mmol of

pyridine N-oxide, 2.25 mmol of NaOCl, 2.25 mmol of 3.0 M Jones

reagent,15 h for epoxidation,1 h for Jones oxidation) to give lactone

(S)-7r as white crystals (56 mg, 30% over two steps). Mp 155–

158 ^ꢁC; ee 76% (HPLC analysis: OD-H column, 254 nm, ﬂow 0.5 mL/

20

min, ⁱPrOH/hexane (5:95), t_m¼60.54 min, t_M¼74.56 min); [

a]

D

þ25.0 (c 0.01, CHCl₃); n_max(CHCl₃)/cm^ꢃ12963 (CH), 2874, 1789

(lactone), 1690 (C]O); d_H(400 MHz, CDCl₃) 7.92 (2H, d, J 8.5, 2ꢄCH

in Ph), 7.53 (2H, d, J 8.5, 2ꢄCH in Ph), 5.46 (1H, s, OCH), 2.59 (1H, d, J

17.0, CH₂), 2.38 (1H, d, J 17.0, CH₂),1.45 (3H, s, CH₃),1.00 (3H, s, CH₃);

d_C(100 MHz, CDCl₃), 194.7 (C), 175.4 (C), 141.0 (C), 134.1 (C), 130.0

(2ꢄCH), 129.5 (2ꢄCH), 85.6 (CH), 41.9 (CH₂), 40.8 (C), 28.2, 23.5

(2ꢄCH₃); m/z (CI) 270 (MNH^þ₄, 100%). Found: MNH^þ₄, 270.0893;

C₁₃H₁₃O₃Cl requires: MNH^þ₄, 270.0897.

4.9.4. (þ)-(S)-1-Benzoyl-2-oxa-spiro[4,5]decan-3-one 7o

Prepared by the general procedure (1.10 mmol of 2-alkoxy-

dihydropyran 3z, 0.11 mmol of Jacobsen’s catalyst, 0.22 mmol of

pyridine N-oxide, 3.30 mmol of NaOCl, 3.30 mmol of 3.0 M Jones

reagent, 6 h for epoxidation, 3 h for Jones oxidation) to give lactone

(S)-7o as a colourless oil (120 mg, 40% over two steps). ee 80%

4.9.8. (þ)-(S)-4,4-Dimethyl-5-(4-nitrobenzoyl)-dihydrofuran-

2(3H)-one 7s

Prepared by the general procedure (0.32 mmol of 2-alkoxy-

dihydropyran 3ad, 0.03 mmol of Jacobsen’s catalyst, 0.06 mmol of

pyridine N-oxide, 1.00 mmol of NaOCl, 1.00 mmol of 3.0 M Jones

reagent, 15 h for epoxidation, 3 h for Jones oxidation) to give

i

(HPLC analysis: OD column, 254 nm, ﬂow 0.5 mL/min, PrOH/hex-

20

ane (5:95), t_m¼57.82 min, t_M¼79.09 min); [

a

]

þ29.2 (c 0.01,

D

CHCl₃); n_max(CHCl₃)/cm^ꢃ13434, 2931 (CH), 2338, 1787 (lactone),

1685 (C]O); d_H(400 MHz, CDCl₃) 7.94 (2H, d, J 9.0, 2ꢄCH in Ph),

7.65 (1H, dd, J 9.0, 7.5, CH in Ph), 7.53 (2H, d, J 7.5, 2ꢄCH in Ph), 5.53

4504

A. Armstrong et al. / Tetrahedron 65 (2009) 4490–4504

8. Crandall, J. K.; Batal, D. J.; Sebesta, D. P.; Lin, F. J. Org. Chem. 1991, 56, 1153–1166.

9. Burke, S. D.; Danheiser, R. L. Handbook of Reagents for Organic Synthesis[2]

Oxidizing and Reducing Agents; John Wiley & Sons: New York, NY, 1999.

10. Yang, D.; Wong, M. K.; Yip, Y. C. J. Org. Chem. 1995, 60, 3887–3889.

11. Otsuka, K.; Zenibaya.Y; Itoh, M.; Totsuka, A. Agric. Biol. Chem. 1974, 38, 485–

490.

12. (a) Jefford, C. W.; Sledeski, A. W.; Boukouvalas, J. Helv. Chim. Acta 1989, 72,

1362–1370; (b) Rojo, J.; Garcia, M.; Carretero, J. C. Tetrahedron 1993, 49, 9787–

9800.

13. Moret, E.; Schlosser, M. Tetrahedron Lett. 1984, 25, 4491–4494.

14. Gademann, K.; Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2002, 41,

3059–3061.

15. Lohman, G. J. S.; Seeberger, P. H. J. Org. Chem. 2003, 68, 7541–7543.

16. Soldaini, G.; Cardona, F.; Goti, A. Org. Lett. 2005, 7, 725–728.

17. Beebe, T. R.; Adkins, R. L.; Belcher, A. I.; Choy, T.; Fuller, A. E.; Morgan, V. L.;

Sencherey, B. B.; Russell, L. J.; Yates, S. W. J. Org. Chem. 1982, 47, 3006–3008.

18. Donohoe, T. J.; Stevenson, C. A.; Helliwell, M.; Irshad, R.; Ladduwahetty, T.

Tetrahedron: Asymmetry 1999, 10, 1315–1322.

lactone (S)-7s as a colourless oil (54 mg, 64% over two steps). ee 46%

(HPLC analysis: OD-H column, 254 nm, ﬂow 1.5 mL/min, PrOH/

i

20

hexane (10:90), t_m¼35.79 min, t_M¼43.31 min); [

a

]

þ14.0 (c 0.01,

D

CHCl₃); n_max(CHCl₃)/cm^ꢃ12980 (CH), 2939, 1790 (lactone), 1698

(C]O), 1603; d_H(400 MHz, CDCl₃) 8.39 (2H, d, J 9.0, 2ꢄCH in Ph),

8.15 (2H, d, J 9.0, 2ꢄCH in Ph), 5.44 (1H, s, OCH), 2.57 (1H, d, J 17.0,

CH₂), 2.43 (1H, d, J 17.0, CH₂), 1.44 (3H, s, CCH₃), 1.02 (3H, s, CCH₃);

d_C(100 MHz, CDCl₃), 195.1 (C), 174.9 (C), 150.8 (C), 140.2 (C), 129.8

(2ꢄCH), 124.2 (2ꢄCH), 86.2 (CH), 42.0 (CH₂), 41.1 (C), 27.9, 23.4

(2ꢄCH₃); m/z (CI) 250 (MNH^þ₄, 100%). Found: MNH^þ₄, 281.1141;

C₁₃H₁₃NO₅requires: MNH^þ₄, 281.1137.

4.9.9. (þ)-(S)-5-(2-Naphthoyl)-4,4-dimethyl-dihydrofuran-2(3H)-

one 7t

19. (a) Shi, Y. Acc. Chem. Res. 2004, 37, 488–496; (b) Yang, D. Acc. Chem. Res. 2004,

37, 497–505.

20. (a) Armstrong, A.; Ahmed, G.; Dominguez-Fernandez, B.; Hayter, B. R.; Wailes,

J. S. J. Org. Chem. 2002, 67, 8610–8617; (b) Armstrong, A.; Tsuchiya, T. Tetrahe-

dron 2006, 62, 257–263.

Prepared by the general procedure (0.71 mmol of 2-alkoxy-

dihydropyran 3ae, 0.07 mmol of Jacobsen’s catalyst, 0.14 mmol of

pyridine N-oxide, 2.13 mmol of NaOCl, 2.13 mmol of 3.0 M Jones

reagent,15 h for epoxidation,1 h for Jones oxidation) to give lactone

(S)-7t as a colourless oil (78 mg, 41% over two steps). ee 71% (HPLC

21. Zhu, Y. M.; Tu, Y.; Yu, H. W.; Shi, Y. Tetrahedron Lett. 1998, 39, 7819–7822.

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23. Brandes, B. D.; Jacobsen, E. N. J. Org. Chem. 1994, 59, 4378–4380.

24. Jacobsen, E. N.; Zhang, W.; Guler, M. L. J. Am. Chem. Soc. 1991, 113, 6703–6704.

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4323–4334.

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27. Takano, D.; Nagamitsu, T.; Ui, H.; Shiomi, K.; Yamaguchi, Y.; Masuma, R.;

Kuwajima, I.; Omura, S. Tetrahedron Lett. 2001, 42, 3017–3020.

28. Riahi, A.; Henin, F.; Muzart, J. Tetrahedron Lett. 1999, 40, 2303–2306.

29. Perez, I.; Sestelo, J. P.; Sarandeses, L. A. J. Am. Chem. Soc. 2001, 123, 4155–4160.

30. Trahanovsky, W. S.; Emeis, S. L. J. Am. Chem. Soc. 1975, 97, 3773–3777.

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33. (a) Bhattacharyya, S.; Mukherjee, D. Synth. Commun. 1981, 11, 993–998; (b)

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34. Kasturi, T. R.; Parvathi, S. J. Chem. Soc., Perkin Trans. 1 1980, 448–456.

35. Bates, F. X.; Donnelly, J. A.; Keegan, J. R. Tetrahedron 1991, 47, 4991–5000.

36. Noecker, L. A.; Martino, J. A.; Foley, P. J.; Rush, D. M.; Giuliano, R. M.; Villani, F. J.

Tetrahedron: Asymmetry 1998, 9, 203–212.

i

analysis: AD-H column, 254 nm, ﬂow 1.8 mL/min, PrOH/hexane

20

(4:96), t_m¼64.66 min, t_M¼69.32 min); [

a]

þ31.0 (c 0.01, CHCl₃);

D

n_max(CHCl₃)/cm^ꢃ12962–2926 (CH), 1788 (lactone), 1681 (C]O),

1627; d_H(400 MHz, CDCl₃) 8.48 (1H, s, CH in NapH), 7.93–8.04 (4H,

m, 4ꢄCH in Naph), 7.62–7.71 (2H, 2ꢄCH in Naph), 5.71 (1H, s, OCH),

2.66 (1H, d, J 17.0, CH₂), 2.39 (1H, d, J 17.0, CH₂), 1.46 (3H, s, CH₃),

1.03 (3H, s, CH₃); d_C(100 MHz, CDCl₃), 195.6 (C), 175.8 (C), 136.0 (C),

133.2 (C), 132.4 (C), 130.7 (CH), 129.8 (CH), 129.3 (CH), 129.2 (CH),

127.9 (CH), 127.3 (CH), 123.7 (CH), 85.5 (CH), 41.9 (CH₂), 40.8 (C),

28.4, 23.6 (2ꢄCH₃); m/z (CI) 286 (MNH^þ₄, 100%). Found: MNH₄^þ,

286.1437; C₁₇H₁₆O₃requires: MNH^þ₄, 286.1443.

References and notes

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38. Wada, E.; Pei, W.; Yasuoka, H.; Chin, U.; Kanemasa, S. Tetrahedron 1996, 52,

1205–1220.

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1988, 53, 3843–3845.

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dere, B. Tetrahedron: Asymmetry 1993, 4, 1711–1754; (c) Wolfe, J. P.; Hay, M. B.

Tetrahedron 2007, 63, 261–290.

3. Hall, S. S.; Chernoff, H. C. Chem. Ind. (London) 1970, 896–897.

4. (a) Ireland, R. E.; Habich, D. Tetrahedron Lett. 1980, 21, 1389–1392; (b) Ireland, R.

E.; Habich, D. Chem. Ber. 1981, 114, 1418–1427.

5. McRae, K. J.; Rizzacasa, M. A. J. Org. Chem. 1997, 62, 1196–1197.

6. Armstrong, A.; Cumming, G. R.; Pike, K. Chem. Commun. 2004, 812–813.

7. (a) Danishefsky, S.; Bednarski, M. Tetrahedron Lett. 1984, 25, 721–724; (b)

Bednarski, M.; Danishefsky, S. J. Am. Chem. Soc. 1983, 105, 3716–3717.

44. Hargreaves, J.; Park, J.; Ghisalberti, E. L.; Sivasithamparam, K.; Skelton, B. W.;

White, A. H. Aust. J. Chem. 2002, 55, 625–627.

Article Doi

Oxidative rearrangement of 2-alkoxy-3,4-dihydro-2H-pyrans: stereocontrolled synthesis of 4,5-cis-disubstituted tetrahydrofuranones including whisky and cognac lactones and crobarbatic acid

DOI: 10.1016/j.tet.2009.04.013

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