Divergent synthesis of 2-C-branched pyranosides and oxepines from 1,2-gem-dibromocyclopropyl carbohydrates

ACCEPTED MANUSCRIPT

Divergent synthesis of 2-C-branched pyranosides and oxepines from 1,2-

gem-dibromocyclopropyl carbohydrates

a

Peter W. Moore , Julia K. Schuster , Russell J. Hewitt, M. Rhia L. Stone, Paul H. Teesdale-

b

a,

Spittle and Joanne E. Harvey ∗

a

School of Chemical and Physical Sciences, Centre for Biodiscovery, Victoria University of Wellington, PO Box 600, Wellington 6140, NEW

ZEALAND

b

School of Biological Sciences, Centre for Biodisovery, Victoria University of Wellington, PO Box 600, Wellington 6140, NEW ZEALAND

ARTICLE INFO

ABSTRACT

Article history:

Received

The ring opening of 1,2-(gem-dibromo)cyclopropyl carbohydrates by two different

modes leads to either 2-C-(bromomethylene)pyranosides (using base) or 2-

Received in revised form

Accepted

Available online

bromooxepines (using silver salts), as shown previously by us for a D-glucal-

derived cyclopropane. The base-promoted ring opening is extended to encompass

additional alcohol, thiol and amine nucleophiles, and diastereoisomeric

cyclopropane precursors. Cross coupling of the 2-C-(bromomethylene)pyranosides

leads to extended 2-C-branched pyranosides. Silver-promoted ring expansion of

the cyclopropyl carbohydrates in the presence of various alcohols is described.

Cross coupling of the resulting benzyl 2-bromooxepines affords 2-C-substituted

oxepines.

Keywords:

gem-Dihalocyclopropanes;

Glycal-derived cyclopropanes;

Modified carbohydrates;

2

-Branched sugars;

2

.

Oxepines

1

. Introduction

Modified carbohydrates provide access to potential mimetics of naturally occurring sugars and

1

,2

represent targets for the development of antivirals, antibacterials and other active agents.

3,4

2,5

2,6

Septanosides (seven-membered-ring sugars), C-branched sugars and C-glycosides are some of

the most important classes of modified carbohydrates. The synthesis of septanosides from oxepines

(

unsaturated oxepanes) allows for the introduction of diversity into the structures through addition to

4

4a

the double bond(s) and cross coupling reactions.

7

,8,9

Cyclopropanes are extremely versatile synthetic intermediates,

as well as being targets in their own

1

0

11,12

right. Oxepines may be obtained, inter alia, by the cyclopropanation of glucals

and ring

4,12,13

expansion.

Alternatively, some cyclopropyl carbohydrates ring open, generally upon treatment

1

2,14,15

with an electrophile, to form C-branched sugars.

We have previously reported the divergent and selective preparation of both highly functionalised

1

6,17

oxepines and C-branched sugars from 1,2-(gem-dibromo)cyclopropyl carbohydrates.

Thus, in the

presence of base, -glucal-derived 1 ring opens to form 2-C-branched pyranosides 2 while, with silver

D

1

6

salts, oxepines 3 are generated (Scheme 1). The mechanism of the base-promoted process is

presently not firmly known: the intermediacy of a cyclopropene is possible, although direct ring

1

8

opening to a dibromomethyl anion is likewise plausible. The ring expansion to oxepines

presumably proceeds through a well-established pathway via an oxonium-stabilised allylic cation that

1

7,18

forms upon silver-promoted bromide abstraction.

Good yields (ca. 70%) of 2-C-branched

16

compounds 2 were reliably obtained, whereas the silver-promoted reactions produced modest yields

∗

Corresponding author. Tel.: +64-4-463-5956; fax: +64-4-463-5237; e-mail: joanne.harvey@vuw.ac.nz

1

ACCEPTED MANUSCRIPT

(

ca. 50%) due to a tendency of the oxepine products to undergo ring contraction to the corresponding

1

7

C-furanosides upon prolonged heating.

SCHEME 1: Divergent Reactions of Cyclopropyl Carbohydrate 1

We now wish to report the optimisation of this chemistry and its extension to other glycals, as well as

the derivatisation of the 2-C-branched and oxepine products through palladium-catalysed cross-

coupling reactions.

2

. Results and Discussion

.1. Synthesis of -Glucal-, D-Galactal- and D-Xylal-derived Cyclopropanes

2

D

Nagarajan et al. have reported the synthesis of 1,2-cyclopropyl carbohydrates from

D

-glucal,

-galactal and -xylal were

prepared from their respective parent aldoses using an adaptation of the method reported by

D-

1

5

galactal,

D-xylal and

D-rhamnal. As part of the present study,

D-glucal,

D

1

9,20

Kozikowski.

As described by Nagarajan, cyclopropanation of the benzylated glycals (4–6) by

2

1

treatment with dibromocarbene under standard phase-transfer conditions (CHBr , 50% aq. NaOH,

phase-transfer catalyst) leads to degradation, also observed in this study. Instead, the modified

Mąkosza method is employed, in which addition of potassium fluoride allows for the use of a lower

3

1

5

2

concentration of sodium hydroxide, decreasing the degradation of substrate and products. Reaction of

1

5

glucal 4 with dibromocarbene under the modified conditions afforded the known cyclopropane 1 in

5% yield, which was accompanied by the previously unreported diastereomeric product 7 in 11%

yield. The isomeric nature of these compounds was evident from the coupling constants of H-2 in the

proton NMR spectrum: in the major product 1, this signal was a doublet of doublets (δ 1.87, J_H₁_,_H₂

.8, J_H₂_,_H₃= 4.9 Hz) whereas the minor isomer 7 displayed a triplet (δ 2.29, J_H₁_,_H₂= J_H₂_,_H₃= 7.9 Hz).

These results are consistent with the modelled dihedral angles for the isomers (see Supporting

7

=

7

15

Information), earlier spectroscopic results and the expectation that dibromocarbene addition from

1

1a,15

the face opposite the C-3 substituent is preferred.

2

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SCHEME 2: Synthesis of Cyclopropyl Carbohydrates

The -galactal- and -xylal-derived cyclopropanes 8 and 9 were likewise prepared according to the

D

1

5

method reported by Nagarajan et al. In the galactose series, 8 was the sole product, as previously

observed. In contrast, dibromocarbene addition to the xylal 6 produced a significant quantity (13%)

of the previously unreported diastereoisomer 10.

2

.2. Synthesis of 2-C-Branched Pyranosides by Cyclopropane Ring Opening

1

6

As we have described previously, the base-promoted ring opening of

D-glucal-derived cyclopropane

1

affords 2-C-branched pyranoside anomers 2 in good yields (Table 1, entries 1–3). The

stereochemistry at the anomeric position was determined by nOe experiments (see Supporting

Information for details). The standard procedure for these reactions is exemplified by the preparation

of allyl glycoside 2c: formation of sodium allyloxide by reaction of allyl alcohol with sodium hydride

in THF is followed by addition of neat cyclopropane 1 and heating the resulting mixture at reflux,

which affords 2c in up to 71% yield (entry 3). During optimisation of this reaction using a range of

temperatures and solvents (entries 4–7), it became evident that slow dissolution of the cyclopropane

upon addition to the reaction mixture was hampering its reactivity. This led to the development of a

modified method whereby the cyclopropane is predissolved and injected as a solution in THF into the

allyloxide solution. A substantial increase in reactivity was thus observed when the reaction was

conducted at 40 °C and the reaction was complete within 10 minutes, as judged by TLC analysis,

resulting in a slightly increased (75%) isolated yield of 2c (entry 6). Any significant increase in the

reaction temperature (such as to 80 °C, achieved in 1,4-dioxane, entry 7) was detrimental to the yield.

There was also a broad trend in anomeric selectivities at different temperatures. Thus, at room

temperature and below, close to a 1:1 ratio of α- and β-isomers was obtained with allyl alcohol

(

2

entries 4 and 5). In comparison, at higher temperatures (40 and 80 °C), the ratio was approximately

:1 in favour of the α-anomer. Interestingly, the bulkier benzyloxide nucleophile reacted at reflux in

THF to form benzyl glycoside 2 with low selectivity and a slight preference for the β-anomer,

opposite to that seen with methoxide and allyloxide under similar conditions. The variation in

anomeric ratios with temperature and size of nucleophile may indicate that a fine balance exists

between a thermodynamic preference for the α-anomer and kinetic favouring of the β-anomer.

3

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TABLE 1: Synthesis of 2-C-Branched Pyranosides by Cyclopropane Ring Opening of 1

a

b

c

Entry NaNu, NuH

Method Product

Yield

71%

63%

71%

70%

73%

75%

49%

76%

52%

d.r.

1

6

1

2

3

4

5

6

7

8

NaOCH , CH OH

NaOBn, BnOH

A

B

C

D

E

2a

2b

2c

2d

2e

2.2:1

1:1.1

2.2:1

1:1.2

1:1.1

2.0:1

1.7:1

1:3.5

1:1

3

NaOAllyl, AllylOH

NaSPh, PhSH

F

G

C

9

NaNEt , NHEt

2

a

Method A: A room temperature solution of the alkoxide, formed from Na (1.5 equiv.) and alcohol (5 equiv.), in THF was

treated with cyclopropane and heated at reflux for 1–4 hours;

Method B: A room temperature solution of the alkoxide, formed from NaH (1.5 equiv.) and alcohol (5 equiv.), in THF was

treated with cyclopropane and heated at reflux for 5 hours;

Method C: A room temperature solution of the alkoxide/amide, formed from NaH (3 equiv.) and alcohol/amine (10 equiv.),

in THF was treated with a room temperature solution of cyclopropane in THF. The reaction was stirred at room temperature

for 14–40 hours;

Method D: A 0 °C solution of the alkoxide, formed from NaH (3 equiv.) and alcohol (10 equiv.), in THF was treated with a

0

°C solution of cyclopropane in THF. The reaction was stirred at room temperature for 40 hours;

Method E: A 40 °C solution of the alkoxide, formed from NaH (3 equiv.) and alcohol (10 equiv.), in THF was treated with a

0 °C solution of cyclopropane in THF. The reaction was stirred at 40 °C for 10 minutes;

4

Method F: A room temperature solution of the alkoxide, formed from NaH (3 equiv.) and alcohol (10 equiv.), in 1,4-dioxane

was treated with cyclopropane and heated at 80 °C for 3 hours;

Method G: A room temperature solution of the sodium thiolate, formed from NaH (3 equiv.) and thiol (10 equiv.), in THF

was treated with a solution of cyclopropane in THF and heated at reflux for 40 hours.

b

Isolated, combined yield of isomers.

c

Isolated ratio of α- and β-anomers. For entries 1–7, this ratio is of the separated isomers; for entries 8 and 9, the ratios are

of the mixture of inseparable isomers.

Reaction of cyclopropane 1 with thiophenol and its conjugate base led to formation of the thiophenyl

glycoside 2d (76%, 1:3.5 α:β), although full conversion required heating at reflux for extended

periods (Table 1, entry 8). A modest yield (52%) of the glycosylamine 2e was obtained from a

similar reaction with diethylamine (entry 9). Glycosylamine 2e was susceptible to hydrolytic

23

degradation under mildly acidic conditions, such that 2-C-formylglycal 11 (13%) and β-bromoenal

2 in equilibrium with its two isomeric hemiacetal congeners 13 (18% combined yield of 12 and 13)

1

were also isolated. By-products 11 and 12 were presumably formed from the initial hydrolysis

products 13 of the acid-labile glycosylamine 2e. Compound 11 has been prepared before in various

2

4

ways and shown to be a useful reactant in a number of applications. Irradiation of the anomeric

proton in 13 caused nOe enhancement of the alkene proton, indicating retention of the E-geometry in

1

2 and 13.

4

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FIGURE 1: By-products Resulting from Hydrolysis of Glycosylamine 2e

The minor D-glucal-derived cyclopropane isomer, 7, was found to produce the same products from

reaction with alkoxides as compound 1, but the rate of reaction was significantly slower. For example,

reaction of 7 with sodium methoxide and methanol in THF did not reach completion after 3 hours at

reflux, producing methyl pyranoside 2a in 48% yield (2.3:1 α:β) together with recovered starting

material 7 (16% yield) (Scheme 3). In contrast, the major cyclopropane isomer 1 had reacted fully

1

6

within 75 minutes under these conditions.

SCHEME 3: Ring Opening of Cyclopropane Isomer 7

To explore this observation more carefully, a competition study was undertaken, in which

approximately equimolar amounts of the isomeric cyclopropanes 1 and 7 (1.05:1.00 ratio,

respectively) were treated with sodium allyloxide (3 equiv.) and allyl alcohol (7 equiv.) in THF at

room temperature and aliquots removed periodically for NMR analysis (Figure 2). The major, α-

orientated, cyclopropane 1 clearly reacted faster than isomer 7. After 4 hours, 1 was completely

consumed, while 7 had barely reacted. The reaction was terminated after 60 hours, after which time

only ca. 20% of 7 had been consumed. Similar rate differences were observed by Nagarajan et al. in

reactions of the non-brominated variants of 1 and 7 with electrophiles, and were attributed to the

1

5

operation of different mechanistic pathways for the isomeric starting materials. Specifically, the

slow but selective production of an α-glycoside from the β-cyclopropane was thought to involve an

S 2-type process, whereas a faster, S 1-like pathway passing through an oxonium ion intermediate

N

1

5

led to mixtures of α- and β-glycosides from the α-cyclopropane. In the gem-dibrominated case

presented here, the production of both anomers from individual reactions of each cyclopropane isomer

indicates that an S 2 mechanism is not operating for 7, yet the slow reaction rate demonstrates

N

similarity with Nagarajan’s results. Reasons for this difference in reaction rates between the major

and minor cyclopropane isomers 1 and 7 are being explored further through mechanistic and

computational studies.

5

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NaOCH CH=CH

OAllyl

H

2

O

BnO

AllylOH

1

+

:

7

THF

BnO Br

(

1.05

1.00)

room temperature

2c

FIGURE 2: NMR-based Kinetic Studies of the Competitive Reaction of a Mixture of Cyclopropane

Isomers 1 + 7 (1:1.05 ratio) with AllylOH and NaOAllyl

D

-Galactal-derived cyclopropane 8 was treated with sodium methoxide in THF and the C-branched

methyl pyranoside 14 was obtained in 65% yield as a mixture favouring the α-anomer (Scheme 4).

SCHEME 4: Galactal-Derived 2-C-Branched Pyranoside 14

6

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2

.3 Cross Coupling of 2-C-Branched Pyranosides

Cross coupling of the 2-C-branched bromoalkenes, prepared through base-mediated ring opening of

glycal-derived cyclopropanes (as described above), was envisaged to produce more complex branched

products representing carbohydrate mimics.

The C-branched methyl pyranoside α-2a was subjected to a Suzuki-Miyaura reaction with methyl

2

5

5c

boronic acid, but only recovered starting material (35%) and the hydrodehalogenated compound 15

30%) were obtained (Scheme 5). More encouragingly, Stille reaction of α-2a with allyl tributyltin

(

afforded the expected skipped diene 16 (52% yield).

SCHEME 5: Cross-Coupling Reactions of 2-C-Branched Pyranoside α-2a

At this stage, it was decided that alternative aglycons should be investigated due to the expected

difficulty in derivatising methyl glycosides for future applications. Therefore, Suzuki-Miyaura cross-

couplings of allyl glycoside β-2c with phenylboronic acid, para-methoxyphenylboronic acid and

potassium thiophen-2-yl trifluoroboronate were explored (Table 2). A series of changes to the base

and palladium (pre)catalyst were examined, which led to moderate product yields (entries 1–3).

Although use of the XantPhos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] ligand in the

palladium-catalysed cross coupling of β-2c with phenylboronic acid provided the product 17b (R =

Ph) in 40% yield, it was inseparable from the reduced material 17a (R = H, 26%) that accompanied it

(

entry 3). Therefore, monodentate catalyst systems with less propensity for hydrodehalogenation

were deemed to be preferable and used in subsequent studies with the other boron reagents. The

cross-couplings with para-methoxyphenylboronic acid were also challenging (entries 4–6), and a new

synthetic protocol was required. In this case, potassium fluoride was found to be a good additive,

providing product 17c in 44% yield. Potassium thiophen-2-yl trifluoroboronate reacted more readily

and provided the product 17d in 57% yield (entry 7). A control reaction containing no boron reagent

provided hydrodebrominated 17a as the only identifiable product (entry 8).

Analysis of the unsuccessful cross-coupling reactions (e.g. Table 2, entries 1 and 4) indicated that loss

of the allyl group had occurred, probably through a competing process of Pd-π-allyl formation,

isomerisation and hydrolysis. While some of the results obtained are encouraging in that, under

certain conditions, the desired cross-coupling is the major process (viz. Table 2, entry 7), the reactivity

of the allyl glycoside seems likely to limit the scope of this chemistry. Therefore, alternative aglycons

will be explored in future work.

7

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TABLE 2: Suzuki-Miyaura Reactions of 2-C-Branched Pyranoside β-2c

a

b

Entry

Boron reagent

PhB(OH)₂

Additive

K CO

Catalyst

t / h Product

Yield

0%

31%

40%

0%

32%

44%

57%

19%

1

2

3

4

5

6

7

Pd dba , PPh

3

Pd(PPh₃)₄

72

20

36

20

48

20

17b

2

3

2

3

K CO

2

t

c

PhB(OH)₂

NaO Bu

K CO

XantPhos, Pd(OAc)₂

Pd dba , PPh

17b+17a

17c

4-MeO-C H B(OH)

6

4

2

3

2

3

4-MeO-C H B(OH)

KF

NEt₃

Pd dba , PPh

Pd dba

3

Pd dba , PPh

17c

6

4

2

3

4-MeO-C H B(OH)

17c

6

4

2

2-Thiophenyl-BF K

17d

3

2

3

d

8

—

K CO

Pd(PPh₃)₄

17a

2

3

a

Typically, a catalyst loading of 10–20 mol% was employed.

Isolated yield.

b

c

This reaction produced a 3:2 mixture of the desired product 17b and the reduced material 17a (R = H); the yield quoted

40%) is the calculated quantity of 17b in the mixture.

(

d

THF was used as solvent.

A Sonogashira reaction between allyl pyranoside α-2c and (trimethylsilyl)acetylene afforded the

conjugated enyne 18 (53%), together with recovered starting material (26%) (Scheme 5).

SCHEME 6: Sonogashira Reaction of 2-C-Branched Pyranoside α-2c

2

.4. Synthesis of 2-Bromooxepines by Cyclopropane Ring Expansion

The ring expansion of cyclopropane 1 to oxepines was shown by us to occur in the presence of silver

1

6,17

salts and either alcohols or an acetate source.

We now wish to report our optimisation studies and

further reactions. Formation of the acetate 3a using silver acetate (1.35 equiv.) in acetic acid caused

16

extensive decomposition at reflux and poor yields of the desired product (Table 3, entry 1), as also

1

5

observed by Nagarajan. We discovered that reducing the temperature to 100 °C was beneficial to

1

6

the results, yielding acetates 3a in 52% yield (entry 2). Any further decrease in reaction

temperature, however, was detrimental to the reaction progress (entries 3 and 4), to the extent that an

experiment carried out at room temperature afforded only starting material after 5 days (entry 5).

Avoiding the use of acetic acid by using a combination of silver acetate (1 equiv.) and sodium acetate

1

6

(

5 equiv.) as the nucleophile source in toluene at 100 °C provided a better yield (65%) (entry 6).

Careful examination of this reaction mixture has also revealed the regioisomeric acetate 19, which

was isolated as a single stereoisomer with undetermined configuration at C3 (14% yield). This

highlights the ambident nature of the extended cation obtained from ring expansion of the

8

ACCEPTED MANUSCRIPT

cyclopropane. Participation of the endocyclic oxygen through an oxonium-containing canonical

structure leads to preferential reaction at C1, yet C3 is evidently also electrophilic.

TABLE 3: Synthesis of 2-Bromooxepines

a

Entry Conditions

Product(s) (Yield, d.r.)

1

2

3

4

5

6

AgOAc (1.9 equiv.), AcOH, 120 °C, 5 h

3a (15%, 1.7:1)

3a (52%, 3.5:1)

3a (37%, 3.4:1), 1 (4%)

3a (27%, 2.9:1), 1 (10%)

1 (100%)

1

6

AgOAc (1.3 equiv.), AcOH, 100 °C, 25 h

AgOAc (1.9 equiv.), AcOH, 90 °C, 36 h

AgOAc (2.1 equiv.), AcOH, 70 °C, 3 days

AgOAc (2.0 equiv.), AcOH, 18 °C, 5 days

AgOAc (1.4 equiv.), NaOAc (5.1 equiv.), toluene,

1

6

b

3a (65%, 4.3:1) , 19 (14%)

1

10ꢀ°C, 28 h

7

8

9

1

NaOAc (5.0 equiv.), toluene, 100 °C, 2 days

AgOAc (1.2 equiv.), toluene, 100 °C, 22 h

AgOAc (1.1 equiv.), AllylOH, 97 °C, 27 h

AgOAc (1.1 equiv.), AllylOH, dark, 97ꢀ°C, 25 h

AgOAc (1.4 equiv.), BnOH (5.0 equiv.), toluene,

3a (18%, 2.1:1)

20 (38%)

3b (51%, 1:1.1) , 3a (4%)

3b (57%, 1:1.4), 3a (21%, 1:1.5)

3c (45%, 1.1:1), 3a (26%, 4.6:1)

1

7

c,17

0

1

00ꢀ°C, 2 days

1

2

3

4

5

AgOCOCF (1.4 equiv.), BnOH (5.0 equiv.), toluene, 3c (56%, 1:1.6)

3

1

00 °C, 2 days

AgNO (1.8 equiv.), PhOH (5.3 equiv.), toluene,

3d (45%, 1:6.7)

3c (15%, 1:4)

3

1

00ꢀ°C, 2 days

AgNO (1.6 equiv.), BnNH (5.0 equiv.), toluene,

3

2

1

00ꢀ°C, 2 days

c

1

AgOAc, Meldrum’s acid, NaH, DMF, 100ꢀ°C

20 (13%), 3a (7%)

a

Yields and anomeric ratios (α:β) are of isolated compounds.

1

b

9 was obtained as a single stereoisomer, the relative configuration of which was not determinable by nOe experiments.

c

By-product 3a was obtained in very small quantities and apparently as a single isomer, the relative configuration of which

was not determined.

In these ring expansion reactions, temperatures of approximately 100 °C were needed for the reactions

1

7

to progress efficiently. Typically, ring expansion of ring-fused halogenated cyclopropanes proceeds

8

with either heating or silver salts, so it seemed prudent, given the high temperatures required for

these transformations, to investigate whether silver salts were actually necessary. Therefore, a

reaction of cyclopropane 1 with sodium acetate was conducted at 100 °C for 2 days in the absence of

silver acetate (Table 3, entry 7). The yield of the product was only 18% (2.1:1α:β), indicating that,

while the reaction is thermally induced, the halophilic silver is beneficial to its efficiency. The role of

the additional acetate provided by the sodium acetate (or acetic acid) was also investigated by

conducting reactions in the presence of AgOAc (1.2 equiv.) as the only acetate source (entry 8). In

this case, none of the acetyl oxepine 3a was isolated, and the only recognisable product was the

bridged bicyclic acetal 20 (38% yield), which was accompanied by benzyl acetate. Thus, the

inclusion of a nucleophilic source other than the stoichiometric silver counterion was deemed

9

ACCEPTED MANUSCRIPT

necessary for these reactions (use of a large excess of silver salt was judged to be uneconomical and

so not explored).

As we have previously reported, the silver-promoted ring expansion of cyclopropyl carbohydrate 1 in

the presence of alcohols provides substituted oxepines, although care is required to avoid prolonged

heating and the liberation of strong acid because these lead to over-reaction to afford C-

1

7,26

furanosides.

Thus, for example, the use of silver nitrate (with a strongly acidic conjugate acid)

1

7

with allyl alcohol provided the oxepine 3b (50% yield) after 1 day but C-furanosides after 3 days.

Similar problems were encountered with silver trifluoroacetate. Therefore, silver acetate was

1

7

employed, despite the concomitant production of small amounts of acetate-substituted oxepine 3a

(

Table 3, entry 9). A slight improvement in the yield of the allyloxy oxepine 3b (57%, 1:1.4 α:β) was

noted upon exclusion of light from the reaction mixture and strict control of the temperature and time

entry 10); as before, the glycosyl acetates 3a were isolated as by-products (21% yield, 1:1.5 α:β).

(

Silver acetate-promoted ring expansion of 1 using benzyl alcohol provided the desired benzyloxy

oxepine 3c (45%, 1.1:1 α:β) and the acetate 3a (26%, 4.6:1 α:β) (entry 11). Modifying the reaction

conditions to employ the less nucleophilic silver trifluoroacetate and monitoring the reaction progress

to avoid over-reaction led to an improved yield of the desired benzyl oxepines 3c (56%, 1:1.6 α:β)

(

entry 12). Reaction of 1 with phenol in the presence of silver nitrate provided the phenyl glycoside

d (45%, 1:6.7 α:β) (entry 13).

3

In our hands, the use of non-oxygen nucleophiles to form alternative C1-substituted 2-bromooxepines

was not fruitful. Thus, for instance, in a reaction of cyclopropane 1 with benzylamine, a small amount

(

15% yield) of benzyl glycoside 3c was the only identifiable product (Table 3, entry 14). This may

have arisen by either hydrolysis of the benzylamine or loss of a benzyl group from the substrate,

followed by interception of the ring expanded oxonium intermediate by the resulting benzyl alcohol.

When the sodium anion of Meldrum’s acid was included in a reaction of cyclopropane 1 with silver

acetate in DMF, only the acetate 3a and bridged bicycle 20 were obtained, albeit in low yields (entry

1

5).

The

D-galactal- and D-xylal-derived cyclopropanes 8 and 9, respectively, underwent ring expansion in

the presence of silver acetate and sodium acetate using the optimised conditions developed for the

glucal-derived compound (Scheme 7). Encouragingly, the galactal-derived cyclopropane provided a

single isomer of the acetylated oxepine 21 in 52% yield. The isolation of only a single acetate isomer

points to the fact that nucleophile attack on the oxonium intermediate is directed by steric factors; in

the galactal series, the top face would be significantly more hindered than the lower face and, thus, 21

was believed to be the α-anomer; this was confirmed by observation of an nOe between the anomeric

proton and the side-chain methylene. This was accompanied by a small quantity of the bridged

bicyclic material 22, likely formed through attack by the pseudo-axial C4 benzyloxy group on the

oxonium ion and subsequent cleavage of the benzyl group. The xylal-derived cyclopropane produced

a 1:1 mixture of acetate isomers in a modest yield. The lack of facial discrimination is again

indicative that approach of the nucleophile is directed by steric effects in the oxonium intermediate.

1

0

ACCEPTED MANUSCRIPT

SCHEME 7: Synthesis of D-Galactal- and D-Xylal-Derived 2-Bromooxepines

2

.5 Cross Coupling of 2-Bromooxepines

Cross coupling reactions of the 2-bromooxepines were expected to produce 2-C-branched oxepines

with potential for conversion to unnatural septanosides. Indeed, Jayaraman and co-workers have

described the synthesis of 2-C-branched septanosides through the use of Suzuki, Sonogashira and

4

a

Heck reactions on oxepines generated from 2-oxyglycal-derived cyclopropanes.

The intramolecular Heck reaction of an allyl-substituted oxepine was expected to produce ring-fused

products, which could conceivably be either pyrano[2,3-b]- or branched furo[2,3-b]oxepines

depending on the regioselectivity of the migratory insertion step. In the event, it was found that allyl

oxepine α-3b selectively provided the furo[2,3-b]oxepine 24, which was isolated in a good yield

(

73%), upon intramolecular Heck reaction using palladium(0) and triethylamine. This unusual

2

7

framework has potential utility in the synthesis of natural product analogues.

SCHEME 8: Intramolecular Heck reaction of oxepine α-3b

As the acetate- and allyl-substituted oxepines, 3a and 3b respectively, were expected to react

unreliably in intermolecular cross-coupling reactions catalysed by palladium due to their multiple

possible reactivities (vide supra), the more robust tetra-O-benzyl oxepine β-3c was used. Suzuki-

Miyaura reactions of this substrate with phenylboronic acid were examined with a view to finding

optimal conditions (Table 4). When the XantPhos [4,5-bis(diphenylphosphino)-9,9-

dimethylxanthene] ligand system was employed, reactions in 1,4-dioxane or toluene at 100 °C led to

poor yields of the desired product 25a (entries 1 and 2) and, in the latter case, substantial amounts of

the hydrodehalogenated by-product 25d. Screening of a range of conditions (entries 3–9) ultimately

revealed that the use of a palladium XantPhos catalyst in the presence of tert-butoxide at reflux (THF)

provided the best results, with the product 25 obtained in 54% yield. These conditions were

replicated for 4-acetyl- and 4-methoxyphenylboronic acids and provided the desired products 26 and

2

7, although a higher temperature (and hence alternative solvent) was required for effective formation

of the latter (entries 11 and 13).

1

ACCEPTED MANUSCRIPT

TABLE 4: Suzuki-Miyaura Reactions of Oxepine β-3c

a

b

Entry

R

Additive

Catalyst

Solvent, Temp.

t / h Product(s) (Yield )

t

1

2

3

4

5

6

7

8

9

Ph-

NaO Bu XantPhos, Pd (dba) 1,4-Dioxane, 100 °C 18 25a (0%)

2

3

t

NaO Bu XantPhos, Pd (dba)

Toluene, 100 °C

THF, 67 °C

Toluene, 100 °C

THF, r.t.

16 25a (23%), 25d (34%)

22 25a (23%)

2

t

NaO Bu XantPhos, Pd (dba)

2

t

NaO Bu XantPhos, Pd(OAc)₂

24 25a (54%)

t

NaO Bu

Pd(PPh ) Cl

2

24 25a (30%), 25d (6%)

20 25a (34%), 25d (2%)

27 25a (0%)

3

2

t

NaO Bu

Pd(dppf)Cl₂

XantPhos, Pd(OAc)₂

Pd(dppf)Cl₂

NEt₃

KF

23 25a (23%)

KF

t

Pd(dppf)Cl₂

23 25a (35%)

10

11

12

13

4-Ac-C H - NaO Bu XantPhos, Pd(OAc)₂

25 25b (14%)

6

4

t

4-Ac-C H - NaO Bu XantPhos, Pd(OAc)₂

THF, 67 °C

Toluene, 100 °C

25 25b (64%), 25d (10%)

25 25c (0%)

6

4

t

4-MeO-C H - NaO Bu XantPhos, Pd(OAc)₂

6

4

t

4-MeO-C H - NaO Bu XantPhos, Pd(OAc)₂

25 25c (38%)

6

4

a

Typically, a catalyst loading of ca. 15 mol% was employed. However, for certain reactions, catalyst loadings of up to 45

mol% were used due to either the need to boost the reactivity or logistical difficulty in weighing out small quantities of pre-

catalyst.

b

Isolated yield.

3

. Conclusion

A number of differentially 2-C-branched pyranosides and oxepines have been prepared through ring

opening and expansion of gem-dibromocyclopropyl carbohydrates, and subsequent cross-coupling

reactions. These products have frameworks that make them attractive as intermediates for the

preparation of glycoconjugate mimics. The conditions explored for the palladium cross-coupling

reactions of 2-bromooxepines and 2-C-(bromomethylene)pyranosides provide the basis for further

research in this area.

4

. Experimental

General procedure for cyclopropanation: The method reported by Nagarajan was followed in

1

5

preparation of the cyclopropanes. Thus, a vigorously stirred solution of the benzylated glycal (1

equiv.) and benzyltriethylammonium chloride (TEBAC) (0.02 – 0.03 equiv.) in bromoform (10 – 25

equiv.) was treated dropwise with a 1:1 w/v solution of potassium fluoride (ca. 50 equiv.) in water

containing sodium hydroxide (ca. 10 equiv.). The biphasic mixture was stirred at room temperature

for 2–3 days before being diluted with water and extracted three times with diethyl ether. The

combined organic fractions were washed with brine, dried (MgSO ), filtered and concentrated.

4

Purification by column chromatography afforded the cyclopropane(s).

1

2

ACCEPTED MANUSCRIPT

1

,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-1,2-C-(dibromomethylene)-

D

-glycero-

D-glucal 4 (2.505 g, 6.01 mmol) and

D

-gulo-hexitol (1)

and 1,5-anhydro-3,4,6-tri-O-benzyl-2-deoxy-1,2-C-(dibromomethylene)-

7) Following the general procedure outlined above, a solution of

D

D-talo-hexitol

(

TEBAC (22 mg, 0.1 mmol) in bromoform (10.0 mL, 114.3 mmol) was treated dropwise with a

solution of sodium hydroxide (2.01 g, 52 mmol) and potassium fluoride (15.1 g, 260 mmol) in water

(

15.0 mL) and stirred vigorously for three days. Column chromatography (14:1 hexanes:ethyl acetate)

1

5

provided known 1 as a white solid (2.644 g, 75%) and 7 as a yellow oil (390 mg, 11%).

Spectroscopic data for 1 replicated those reported previously. 7: R = 0.25 (9:1 hexanes:ethyl

1

5

f

2

1

acetate); [α]_D= -30 (c 1.0, CHCl ); H NMR: (CDCl ) δ 7.50–7.16 (complex m, 15H), 4.92 (d, J =

3

H

1

1.7 Hz, 1H), 4.83 (d, J = 11.1 Hz, 1H), 4.72 (d, J = 11.7 Hz, 1H), 4.67 (d, J = 12.1 Hz, 1H), 4.57 (d,

J = 12.1 Hz, 1H), 4.56 (d, J = 11.1 Hz, 1H), 4.18 (apparent t, J = 7.8 Hz, 1H), 4.08 (d, J = 7.8 Hz,

1

7

1

H), 3.95 (dd, J = 10.3, 7.4 Hz, 1H), 3.77 (dd, J = 11.0, 1.7 Hz, 1H, 1H), 3.68 (dd, J = 11.0, 5.4 Hz,

1

3

H), 3.51 (ddd, J = 10.3, 5.4, 1.7 Hz, 1H), 2.29 (apparent t, J = 7.9 Hz, 1H); C NMR: (CDCl ) δ

3

C

38.3, 138.2, 137.9, 128.7, 128.4, 128.2, 128.1, 128.0, 127.83, 127.79, 127.7, 78.6, 78.5, 76.6, 74.8,

3.7, 71.1, 69.1, 62.8, 33.8, 30.9; IR (Film from CH Cl ): ν 3063, 3030, 2861, 1496, 1454, 1091,

2

+

2

max

+

−

1

79

027, 734, 696 cm ; HRMS: m/z C H O Br Na [M+Na] calcd 609.0252, found 609.0247.

2

8

28

4

2

1

,5-Anhydro-3,4-di-O-benzyl-2-deoxy-1,2-C-(dibromomethylene)-

D-gulo-pentitol (9) and 1,5-

anhydro-3,4-di-O-benzyl-2-deoxy-1,2-C-(dibromomethylene)-

D-talo-pentitol (10) Following the

general procedure outlined above, a solution of xylal 6 (287 mg, 0.97 mmol) and TEBAC (6 mg, 0.03

mmol) in bromoform (2.0 mL, 23 mmol) was treated dropwise with a solution of sodium hydroxide

(

426 mg, 11 mmol) and potassium fluoride (3.2 g, 55 mmol) in water (3.2 mL) and stirred vigorously

1

5

for two days. Column chromatography (9:1 hexanes:ethyl acetate) provided known 9 as a pale-

yellow oil (271 mg, 63%) and 10 as a yellow oil (57 mg, 13%). Spectral data of 9 were consistent

1

5

19

with those reported previously. 10: R = 0.45 (5:1 hexanes:ethyl acetate); [α] = +3 (c 1.0, CHCl₃);

f

D

1

H NMR: (CDCl ) δ 7.49–7.28 (complex m, 10H), 4.91 (d, J = 12.0 Hz, 1H), 4.76 (d, J = 11.5 Hz,

3

H

1

7

H), 4.74 (d, J = 11.5 Hz, 1H), 4.60 (d, J = 11.5 Hz, 1H), 4.09 (app. t, J = 7.9 Hz, 1H), 4.01 (dd, J =

.8, 1.2 Hz, 1H), 3.98 (m, 1H), 3.84 (dd, J = 10.9, 4.8 Hz, 1H), 3.17 (app. t, J = 11.0 Hz, 1H), 2.28

1

3

(

app. t, J = 8.0 Hz, 1H); C NMR: (CDCl ) δ 138.2, 137.9, 128.5, 128.4, 127.94, 127.86, 127.74,

3 C

1

2

27.65, 77.2, 75.9, 73.3, 71.1, 67.2, 63.4, 33.8, 30.8; IR (KBr): ν_m_a_x3087, 3064, 3031, 2979, 2929,

−

1

79

+

873, 1721, 1495, 1454, 1374, 1189, 1094, 1976, 1028, 738, 697 cm ; HRMS: m/z C H O Br Na

2

0

20

3

2

+

[

M+Na] calcd 488.9677, found 488.9673.

Phenyl 3,4,6-tri-O-benzyl-(2E)-2-C-(bromomethylene)-2-deoxy-1-thio-β-

hexopyranoside (β-2d) and phenyl 3,4,6-tri-O-benzyl-(2E)-2-C-(bromomethylene)-2-deoxy-1-

thio-α- -arabino-hexopyranoside (α-2d) Neat thiophenol (175 µL, 1.71 mmol) was treated with

D-arabino-

D

sodium hydride (12 mg, 0.50 mmol). Once the sodium hydride had fully reacted, the solution was

diluted with THF (1.0 mL), then treated with a solution of cyclopropane 1 (105 mg, 0.18 mmol) in

THF (0.7 mL) and heated to reflux. After 40 hours the reaction was cooled, quenched with water (10

mL) and extracted with dichloromethane (3 x 10 mL). The organic fractions were combined, dried,

filtered and concentrated to provide a crude mixture of β-2d and α-2d. Purification by column

chromatography (14:1 hexanes:ethyl acetate) provided a colourless oil consisting of β-2d and α-2d as

1

an inseparable 3.5:1 mixture (81 mg, 76%). R = 0.25 (5:1 hexanes:ethyl acetate); H NMR: (CDCl )

f

3

δ_H7.67–7.16 (complex m, 20H), 7.05 (d, J = 2.2 Hz, 0.22H), 6.81 (d, J = 0.9 Hz, 0.78H), 6.06 (d, J =

2.0 Hz, 0.22H), 5.80 (d, J = 0.9 Hz, 0.78H), 4.82 (d, J = 1.5 Hz, 0.22H), 4.806 (d, J = 1.9 Hz, 0.78H),

4.803 (d, J = 12.1 Hz, 0.78H), 4.67 (d, J = 12.2 Hz, 0.22H), 4.60 (d, J = 12.0 Hz, 0.22H),4.57 (d, J =

11.9 Hz, 0.78H), 4.54 (d, J = 12.1 Hz, 0.78H), 4.52 (d, J = 11.6 Hz, 0.78H), 4.51 (d, J = 10.8 Hz,

0.22H), 4.47 (d, J = 10.8 Hz, 0.22H), 4.46 (d, J = 12.2 Hz, 0.22H), 4.45 (d, J = 12.1 Hz, 0.78H), 4.39

1

3

ACCEPTED MANUSCRIPT

(

d, J = 11.6 Hz, 0.78H), 4.33 (d, J = 11.5 Hz, 0.22H), 4.07 (ddd J = 8.5, 5.0, 3.6 Hz, 0.22H), 3.96 (m,

0

.22H), 3.82 (dd, J = 6.3, 1.9 Hz, 0.78H), 3.79 (dd, J = 6.0, 1.5 Hz, 0.78H), 3.77 (m, 0.78H), 3.70

1

3

(apparent td, J = 6.3, 4.6 Hz, 0.78H), 3.660 (d, J = 5.0 Hz, 0.22H), 3.658 (d, J = 3.6 Hz, 0.22H); C

NMR: (CDCl ) δ 138.4, 138.3, 138.1, 138.0, 137.8, 137.7, 137.5, 137.2, 135.5, 132.8, 131.7, 131.1,

3

C

1

7

2

30.5, 129.4, 129.0, 128.6, 128.55, 128.49, 128.47, 128.46, 128.42, 128.23, 128.21, 128.19, 128.04,

27.99, 127.90, 127.88, 127.8, 127.7, 127.4, 112.9, 112.5, 87.5, 86.2, 79.0, 77.8, 77.6, 75.8, 74.6,

3.4, 73.2, 72.0, 71.8, 71.6, 71.0, 70.9, 70.7, 70.1; IR (Film from CH Cl ): ν 3061, 3031, 2917,

2

max

1

−

864, 2850, 1582, 1496, 1477, 1454, 1439, 1091, 1071, 1027, 738, 696 cm ; HRMS: m/z

79

+

C H O S BrNa [M+Na] calcd 639.1181, found 639.1191. nOe of the major isomer: (CDCl )

34

33

4

3

Irradiation of δ 5.79 (H-1_β_-₂_d) led to enhancement of 6.80 (H-7_β_-₂_d) and 3.69 (H-5_β_-₂_d). This

H

confirmed the β-configuration of the major diastereoisomer.

N,N-Diethyl 3,4,6-tri-O-benzyl-(2E)-2-C-(bromomethylene)-2-deoxy-β-

D-arabino-hexopyranosyl

amine (β-2e) and N,N-diethyl 3,4,6-tri-O-benzyl-(2E)-2-C-(bromomethylene)-2-deoxy-α-

D-

arabino-hexopyranosyl amine (α-2e) Neat diethylamine (0.17 mL, 1.64 mmol) was treated with

sodium hydride (12 mg, 0.50 mmol). Once the sodium hydride had reacted, the solution was diluted

with THF (1.0 mL), then treated with a solution of cyclopropane 1 (101 mg, 0.17 mmol) in THF (0.7

mL). The reaction was stirred at room temperature for 14 hours at which point the reaction was

cooled, quenched with water (10 mL) and extracted with dichloromethane (3 x 10 mL). The organic

fractions were combined, dried, filtered and concentrated to provide a crude mixture of β-2e and α-2e.

Careful purification by column chromatography (5:1 hexanes:ethyl acetate with 3% NEt ) provided a

3

colourless oil consisting of β-2e and α-2e as an inseparable 1:1 mixture (50 mg, 50%), the 2-

2

3

formylglucal 11 (10 mg, 13%) and hemiacetals α-13 and β-13 in equilibrium with aldehyde 12 (16

mg, 18%, 1:3.3:1 ratio α-13:β-13:12). β-2e and α-2e: R = 0.67 (5:1 hexanes:ethyl acetate + 5%

f

1

NEt ); H NMR: (CDCl ) δ 7.38–7.22 (complex m, 15H), 6.83 (d, J = 1.8 Hz, 0.5H), 6.79 (d, J = 1.8

3

H

Hz, 0.5H), 5.17 (d, J = 1.8 Hz, 0.5H), 4.90 (d, J = 1.8 Hz, 0.5H), 4.80 (d, J = 1.7 Hz, 0.5H), 4.72 (d, J

3.6 Hz, 0.5H), 4.69–4.37 (complex m, 6H), 3.89–3.50 (complex m, 4H), 2.86–2.69 (complex m,

=

13

4

1

8

1

7

H), 1.06 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H); C NMR: (CDCl ) δ 140.0, 138.63 (2×C),

3 C

38.62, 138.3, 137.99, 137.95, 137.4, 128.50, 128.47, 128.44, 128.43, 128.40, 128.37, 128.1, 127.97,

27.94, 127.91, 127.86, 127.83, 127.81, 127.80, 127.79, 127.63, 127.61, 127.58, 112.8, 111.7, 91.1,

7.9, 78.9, 78.2, 76.3, 75.7, 75.2, 74.1, 73.4, 73.3, 71.67, 71.66, 71.4, 71.2, 70.8, 69.7, 43.2, 42.6,

4.5, 13.6; IR (Film from CH Cl ): ν 3064, 3030, 2917, 2849, 1605, 1496, 1453, 1091, 1043, 1021,

2

max

79

4

−

1

+

31, 696 cm ; HRMS: m/z C H NO Br [M+H] calcd 580.2069, found 580.2062. 12, α-13 and

3

2

39

1

β-13: R = 0.40 (2:1 hexanes:ethyl acetate); H NMR: (CDCl ) δ 9.48 (s, 0.19H), 7.43 (d, J = 1.7 Hz,

f

3

H

0

.19H), 7.40–7.15 (complex m, 15H), 6.88 (d, J = 1.7 Hz, 0.62H), 6.76 (s, 0.19H), 5.67 (s, 0.62H),

5

4

.46 (d, J = 10.1 Hz, 0.19H), 4.88 (d, J = 4.1 Hz, 0.19H), 4.76 (d, J = 1.7 Hz, 0.62H), 4.74 (s, 0.19H),

.68–4.30 (complex m, 6H), 3.87–3.56 (complex m, 4H), 1.58 (br s, 1H); C NMR: (CDCl ) δ

3 C

1

3

1

7

6

1

89.9, 141.1, 138.6, 138.23, 138.20, 138.1, 137.9, 137.8, 137.6, 137.5, 137.4, 137.3, 137.2, 128.75,

28.70, 128.64, 128.60, 128.58, 128.55, 128.51, 128.49, 128.33, 128.29, 128.23, 128.18, 128.16,

28.12, 128.08, 128.05, 127.99, 127.97, 127.95, 127.9, 127.8, 113.2, 113.1, 96.1, 92.4, 80.0, 78.8,

7.6, 76.5, 75.7, 74.8, 73.9, 73.7, 73.5, 73.4, 72.3, 72.0, 71.8, 71.6, 71.3, 70.9, 70.8, 70.10, 70.05,

9.8; IR (Film from CH Cl ): ν 3048, 3088, 3064, 3031, 2920, 2864, 1725, 1495, 1454, 1090,

2

max

−

1

79

+

072, 1064, 1048, 1029, 732, 697 cm ; HRMS: m/z C H O BrNa [M+Na] calcd 547.1096,

28 29 5

found 547.1105.

Methyl 3,4,6-tri-O-benzyl-(2E)-2-C-(bromomethylene)-2-deoxy-β-

and methyl 3,4,6-tri-O-benzyl-(2E)-2-C-(bromomethylene)-2-deoxy-α-

4) Methanol (100 µL, 2.5 mmol) was treated with metallic sodium (7 mg, 0.3 mmol). Once the

D-lyxo-hexopyranoside (β-14)

D-lyxo-hexopyranoside (α-

1

4

ACCEPTED MANUSCRIPT

sodium had reacted, the solution was diluted with THF (1.7 mL), then treated with cyclopropane 8

(

101 mg, 0.172 mmol) and heated at reflux for 40 minutes. The solution was diluted with water (10

mL), then extracted with dichloromethane (3 x 10 mL). The combined organic fractions were dried,

filtered and concentrated to provide a yellow oil. Upon purification by column chromatography (14:1

hexanes:ethyl acetate), an inseparable mixture of 2-C-substituted sugars α-14 and β-14 was obtained

as a colourless oil (60 mg, 65% combined yield, 3:1 ratio). R 0.10 (14:1 hexanes:ethyl acetate); α-14:

f

1

H NMR: (CDCl ) δ 7.39–7.27 (complex m, 15H), 6.64 (s, 1H), 5.05 (s, 1H), 4.85 (d, J = 11.7 Hz,

3

H

1

H), 4.80 (d, J = 12.2 Hz, 1H), 4.70 (d, J = 3.2 Hz, 1H), 4.61 (d, J = 11.7 Hz, 1H), 4.53 (d, J = 11.7

Hz, 1H), 4.52 (m, 1H), 4.46 (d, J = 12.2 Hz, 1H), 4.17 (m, 1H), 3.88 (apparent t, J = 3.2 Hz, 1H), 3.80

1

3

(

dd, J = 10.4, 7.2 Hz, 1H), 3.68 (dd, J = 10.3, 5.1 Hz, 1H), 3.42 (s, 3H); C NMR: (CDCl ) δ 138.2,

3 C

1

7

38.12, 138.06, 136.9, 128.33, 128.25, 128.2, 127.7, 127.64, 127.59, 127.52, 127.50, 107.5, 100.3,

7.1, 76.4, 73.3, 73.0, 72.5, 72.1, 68.3, 55.5. β-14: (The following NMR data were obtained by

1

subtracting the signals of α-14 from those of the mixture.) H NMR: (CDCl ) δ 7.39–7.27 (complex

3

H

m, 15H), 6.65 (s, 1H), 4.93 (s, 1H), 4.82 (m, 1H), 4.73 (d, J = 12.0 Hz, 1H), 4.68 (d, J = 12.7 Hz, 1H),

.59 (d, J = 12.0 Hz, 1H), 4.48 (d, J = 12.8 Hz, 1H), 4.47 (m, 1H), 4.43 (d, J = 11.0 Hz, 1H), 4.41 (d,

J = 11.7 Hz, 1H), 4.24 (m, 1H), 3.84 (dd, J = 10.7, 2.2 Hz, 1H), 3.72 (dd, J = 5.9, 3.2 Hz, 1H), 3.45 (s,

4

1

3

7

5

H); C NMR: (CDCl ) δ 138.6–137.7, 136.5, 128.5–127.5, 112.8, 101.4, 75.7, 74.5, 73.2, 73.5–

3 C

7

9

+

1.2 (3 x C), 70.5, 55.6. HRMS (α-14 and β-14): m/z C H O BrNa [M+Na] calcd 561.1253, found

61.1250.

2

9

31

5

Methyl 3,4,6-tri-O-benzyl-(2E)-2-C-(but-3-enylidene)-2-deoxy-α-D-arabino-hexopyranoside (16)

A solution of methyl pyranoside α-2a (25 mg, 0.046 mmol) in DMF (1 mL) was treated successively

with allyltributylstannane (18 µL, 0.058 mmol) and palladium tetrakis(triphenylphosphine) (7 mg,

0

.06 mmol), then stirred at 100 °C for one day. The reaction mixture was treated with additional

palladium tetrakis(triphenylphosphine) (7 mg, 0.06 mmol), then stirred for an additional day. The

reaction mixture was diluted with water (10 mL), then extracted with dichloromethane (3 x 10 mL).

The organic fractions were combined, dried and concentrated to provide a yellow oil. This oil was

purified by flash chromatography (9:1 hexanes:ethyl acetate), to provide skipped diene 16 (12 mg,

1

7

1

5

2%) as a colourless oil. R 0.3 (9:1 hexanes:ethyl acetate); [α] −12 (c 0.5 CHCl ); H NMR:

f D 3

(

CDCl ) δ 7.35–7.13 (complex m, 15H), 5.87 (t, J = 7.6 Hz, 1H), 5.80 (ddt, J = 17.1, 10.3, 6.2 Hz,

3 H

1

4

H), 5.06 (s, 1H), 5.05–4.98 (complex m, 2H), 4.68 (d, J = 12.0 Hz, 1H), 4.65 (d, J = 12.0 Hz, 1H),

.63 (d, J = 11.5 Hz, 1H), 4.52 (d, J = 12.2 Hz, 1H), 4.49 (d, J = 12.0 Hz, 1H), 4.48 (partially

obscured m, 1H), 4.40 (d, J = 11.5 Hz, 1H), 3.77 (ddd, J = 9.3, 4.1, 2.9 Hz, 1H), 3.72 (dd, J = 9.4, 4.5

13

Hz, 1H), 3.66–3.68 (complex m, 2H), 3.44 (s, 3H), 2.97 (apparent td, J = 7.0, 1.5 Hz, 2H); C NMR:

(

CDCl ) δ 138.31 (2 x C), 138.0, 136.5, 132.4, 129.9, 128.4, 128.30, 128.28, 127.81, 127.79, 127.64,

3 C

1

27.58, 127.54, 127.50, 115.4, 101.8, 79.7, 77.3, 73.2, 73.0, 71.5, 71.3, 69.4, 54.8, 31.4; IR (KBr):

−

1

+

ν_m_a_x3030, 2920, 1723, 1496, 1453, 1356, 1091, 1067, 1027, 750, 698 cm ; HRMS: m/z C H O Na

32

36

5

+

[

M+Na] calcd 523.2460, found 523.2462.

Allyl 3,4,6-tri-O-benzyl-2-C-(methylene)-2-deoxy-α-D-arabino-hexopyranoside (17a) Compound

β-2c (27 mg, 0.048 mmol) was dissolved in THF (1.0 mL) and the solution degassed for five minutes

by sonication. The solution was then treated with K CO (18 mg, 0.13) and Pd(PPh ) (10 mg, 0.0087

2

3

3 4

mmol, 18 mol% Pd) was added and the solution heated to reflux. After 20 hours the reaction was

cooled, quenched with water (4 mL) and extracted with dichloromethane (3 x 5 mL). The organic

®

fractions were combined, dried, filtered through Celite and concentrated. Purification by column

chromatography (5:1 hexanes:ethyl acetate) provided 17a as colourless oil (4 mg, 19%). R = 0.35

f

1

(

9:1 hexanes:ethyl acetate); H NMR: (CDCl ) δ 7.39–7.14 (complex m, 15H), 5.92 (dddd, J = 17.1,

3

H

1

0.5, 6.1, 5.1 Hz, 1H), 5.30 (partially overlapping dd, J = 2.0, 1.5 Hz, 1H), 5.29 (partially overlapping

1

5

ACCEPTED MANUSCRIPT

apparent dq, J = 17.1, 1.5 Hz, 1H), 5.21 (s, 1H, H-1), 5.19 (apparent dq, J = 10.5, 1.7 Hz, 1H), 5.15

(

apparent t, J = 1.5 Hz, 1H), 4.87 (d, J = 10.8 Hz, 1H), 4.77 (d, J = 11.3 Hz, 1H), 4.71 (d, J = 11.3 Hz,

1

2

9

1

6

H), 4.63 (d, J = 12.2 Hz, 1H), 4.50 (d, J = 12.2 Hz, 1H), 4.49 (d, J = 10.8 Hz, 1H), 4.46 (dt J = 9.0,

.0 Hz, 1H), 4.18 (ddt, J = 12.9, 5.1, 1.5 Hz, 1H), 4.02 (ddt, J = 12.9, 6.1, 1.5 Hz, 1H), 3.97 (ddd, J =

.8, 3.9, 2.0 Hz, 1H), 3.76 (dd, J = 10.8, 3.9 Hz, 1H), 3.67 (dd, J = 10.8, 2.0 Hz, 1H), 3.62 (dd, J = 9.8,

1

3

.0 Hz, 1H); C NMR: (CDCl ) δ 142.4, 138.45, 138.44, 138.3, 134.0, 128.6, 128.49, 128.48, 128.1,

3

C

28.0, 127.9, 127.83, 127.80, 127.75, 117.6, 110.8, 100.7, 81.3, 80.1, 75.2, 73.63, 73.57, 70.9, 68.9,

−

1

7.8; IR (Film from CH Cl ): ν 3032, 2922, 2855, 1496, 1453, 1099, 1065, 1025, 735, 697 cm ;

2

+

2

max

+

HRMS: m/z C H O Na [M+Na] calcd 509.2304, found 509.2304.

3

1

34

5

General Procedure for Suzuki Reactions of 2-Bromomethylene Pyranosides: The chosen

palladium catalyst (ca. 15 mol%) was dissolved in 1,4-dioxane then successively treated with base

(

K CO , K PO ·H O or KF, 3.0 equiv.), an additive (if relevant) and the arylboronic acid or

2 3 3 4 2

aryltrifluoroboronate (2.0 equiv.). The solution was then treated with a pre-mixed solution of allyl

glycoside β-2c (1.0 equiv.) in 1,4-dioxane and heated to reflux. After 20–72 hours the solution was

cooled to room temperature, quenched with water (5 mL) and extracted with dichloromethane (3 x 10

mL). The organic fractions were combined, dried, filtered through Celite® and concentrated. The

crude mixture obtained in this way was purified by flash chromatography.

Allyl 3,4,6-tri-O-benzyl-(2E)-2-C-(phenylmethylidene)-2-deoxy-α-

D-arabino-hexopyranoside

(

17b) Following the general procedure for Suzuki reactions, with Pd(PPh ) (15 mol%), K CO (3.0

3

4

2

3

equiv.) and phenylboronic acid (2.0 equiv.), and flash chromatography (silica gel, 1:9 ethyl

acetate:hexanes), product 17b was prepared as a colourless oil (31%). R 0.35 (5:1 hexanes:ethyl

f

1

acetate); H NMR: (CDCl ) δ 7.42–7.18 (complex m, 20H), 6.83 (d, J = 1.7 Hz, 1H), 6.00 (dddd, J =

3

H

1

=

4

(

7.1, 10.5, 6.4, 5.1 Hz, 1H), 5.56 (s, 1H), 5.32 (apparent dq, J = 17.1, 1.5 Hz 1H), 5.21 (apparent dd, J

10.5, 1.5 Hz 1H), 4.93 (d, J = 10.7 Hz, 1H), 4.83 (d, J = 11.0 Hz, 1H), 4.79 (d, J = 11.0 Hz, 1H),

.613 (d, J = 12.2 Hz, 1H), 4.609 (m, 1H), 4.55 (d, J = 10.7 Hz, 1H), 4.49 (d, J = 12.2 Hz, 1H), 4.20

ddt, J = 12.6, 5.1, 1.3 Hz, 1H), 4.05 (ddt, J = 12.6, 6.4, 1.5 Hz, 1H), 4.01 (ddd, J = 9.5, 3.9, 2.0 Hz,

1

3

1

H), 3.77 (dd, J = 10.5, 3.9 Hz, 1H), 3.72 (m, 1H), 3.67 (dd, J = 10.5, 2.0 Hz, 1H); C NMR:

(

CDCl ) δ 138.5, 138.34, 138.25, 136.3, 135.0, 134.1, 129.0, 128.9, 128.6, 128.53, 128.47, 128.3),

3 C

1

6

28.08, 128.06, 128.0, 127.8, 127.7, 127.4, 124.7, 118.0, 96.2, 81.9, 80.2, 75.3, 74.3, 73.6, 71.5, 68.9,

7.8; IR (Film from CH Cl ): ν 3009, 2997, 2850, 2801, 1423, 1401, 1261, 1100, 1025, 1027, 802,

2

max

−

1

+

97 cm ; HRMS: m/z C H O Na [M+Na] calcd 585.2617, found 585.2623.

3

7

38

5

Allyl 3,4,6-tri-O-benzyl-(2E)-2-C-(4′-methoxyphenylmethylidene)-2-deoxy-α-

D-arabino-

hexopyranoside (17c) Following the general procedure for Suzuki reactions, with Pd dba (15

2

3

mol%), KF (3.0 equiv.) and para-methoxyphenylboronic acid (2.0 equiv.), and flash chromatography

silica gel, 1:14 ethyl acetate:hexanes), para-methoxyphenyl-coupled product 17c was prepared. R

(

0

f

1

.35 (9:1 hexanes:ethyl acetate); H NMR: (CDCl ) δ 7.37–7.27 (complex m, 8H), 7.22–7.15

3 H

(

complex m, 6H), 7.12–7.10 (complex m, 2H), 7.00–6.98 (complex m, 2H), 6.72 (m, 2H), 6.03 (dddd,

J = 17.3, 10.5, 6.1, 5.1 Hz, 1H), 5.51 (d, J = 1.7 Hz, 1H), 5.35 (apparent dq, J = 17.3, 1.7 Hz, 1H),

.20 (apparent dq, J = 10.5, 1.5 Hz, 1H), 4.65 (d, J = 12.2 Hz, 1H), 4.63 (br s, 1H), 4.55 (d, J = 12.2

Hz, 1H), 4.47 (d, J = 12.2 Hz, 1H), 4.42 (ddt, J = 13.0, 5.1, 1.5 Hz, 1H), 4.32 (d, J = 11.5 Hz, 1H),

.23 (d, J = 11.5 Hz, 1H), 4.19 (ddt, J = 13.0, 6.1, 1.5 Hz, 1H), 4.09 (d, J = 12.2 Hz, 1H), 3.86 (ddd, J

9.3, 5.4, 2.9 Hz, 1H), 3.81 (s, 3H), 3.74 (dd, J = 9.3, 1.2 Hz, 1H), 3.71 (partially overlapping dd, J =

5

4

=

1

3

1

1.0, 2.9 Hz, 1H), 3.67 (dd, J = 11.0, 5.4 Hz, 1H); C NMR: (CDCl ) δ 159.0, 138.6, 138.1, 137.9,

3 C

34.8, 133.2, 132.8, 130.4, 128.42, 128.41, 128.3, 128.2, 128.0, 127.87, 127.83, 127.60, 127.59,

17.1, 113.6, 98.0, 79.8, 73.2, 72.7, 71.4 (2 x C), 70.0, 69.9, 68.4, 55.4; IR (Film from CH Cl ): ν

max

2

1

6

ACCEPTED MANUSCRIPT

−

1

3

064, 3030, 2907, 2865, 1607, 1510, 1497, 1454, 1249, 1096, 1066, 1029, 735, 698 cm ; HRMS:

+

m/z C H O Na [M+Na] calcd 615.2723, found 615.2725.

38

40

6

Allyl 3,4,6-tri-O-benzyl-(2E)-2-C-(2′-thiophenylmethylidene)-2-deoxy-α-

D-arabino-

hexopyranoside (17d) Following the general procedure for Suzuki reactions, using Pd dba (3 mg,

2

3

0

.003 mmol, 10 mol% Pd), PPh (8 mg, 0.03 mmol), NEt (30 µL, 0.22 mmol), potassium thiophen-2-

3 3

yl trifluoroboronate (26 mg, 0.14 mmol) and allyl glycoside β-2c (35 mg, 0.062 mmol) in 1,4-dioxane

4.5 mL), and heating at reflux for two days afforded a mixture of recovered starting material β-2c

(

and product 17d as a yellow oil. Purification by column chromatography (14:1 hexanes:ethyl acetate)

resulted in the isolation of the title compound 17d as a clear, colourless oil (20 mg, 57%) and

recovered starting material β-2c as a colourless oil (11 mg, 31%). R 0.35 (5:1 hexanes:ethyl acetate);

f

1

H NMR: (CDCl ) δ 7.34–7.25 (complex m, 12H), 7.23 (d, J = 1.7 Hz, 1H), 7.21–7.19 (complex m,

3

H

2

H), 7.16–7.14 (complex m, 2H), 7.00 (dt, J = 3.4, 1.0 Hz, 1H), 6.94 (dd, J = 5.2, 3.4 Hz, 1H), 6.01

(

dddd, J = 17.3, 10.4, 6.1, 5.1 Hz, 1H), 5.50 (d, J = 1.7 Hz, 1H), 5.34 (apparent dq, J = 17.3, 1.7 Hz

1

3

1

2

H), 5.19 (apparent dq, J = 10.4, 1.7 Hz 1H), 5.03 (s, 1H), 4.612 (d, J = 12.2 Hz, 1H), 4.611 (d, J =

2.2 Hz, 1H), 4.54 (d, J = 11.8 Hz, 1H), 4.52 (d, J = 12.2 Hz, 1H), 4.40 (ddt, J = 13.1, 5.1, 1.7 Hz,

H), 4.35 (d, J = 12.2 Hz, 1H), 4.30 (d, J = 11.8 Hz, 1H), 4.34 (ddt, J = 13.1, 6.1, 1.5 Hz, 1H), 3.81–

1

3

.80 (complex m, 2H), 3.67–3.61 (complex m, 2H); C NMR: (CDCl ) δ 138.6, 138.3, 138.1, 137.8,

3

C

34.7, 132.6, 129.9, 128.43, 128.40, 128.35, 128.2, 128.0, 127.9, 127.7, 127.6, 127.1, 126.3, 126.2,

17.1, 97.6, 79.7, 73.8, 73.2, 71.6, 71.4, 70.3, 69.9, 68.5; IR (Film from CH Cl ): ν 3064, 3030,

2

1

2

max

−

906, 2864, 1719, 1672, 1606, 1496, 1454, 1096, 1067, 1027, 735, 697 cm ; HRMS: m/z

+

C H O SNa [M+Na] calcd 591.2181, found 591.2178.

35

36

5

Allyl 3,4,6-tri-O-benzyl-(2E)-2-C-(2′-trimethylsilylethynyl methylidene)-2-deoxy-α-

D-arabino-

hexopyranoside (18) Pd dba (3 mg, 4 mol%) was added to THF (2.0 mL) and the resulting dark red

2

3

coloured solution treated with PPh (3 mg, 0.011 mmol), turning it light yellow in colour. This was

3

followed by successive addition of triethylamine (0.10 mL, 0.72 mmol) and CuI (2 mg, 10 mol%).

The mixture was then treated with a solution of α-2c (42 mg, 0.074 mmol) in THF (1.0 mL). TMSA

(

50 µL, 0.35 mmol) was added and the reaction heated to THF reflux for two days. The reaction was

then diluted with water (4 mL) and then extracted with dichloromethane (3 x 5 mL). The organic

fractions were combined, dried and concentrated to provide a mixture of α-2c and 18. Upon

separation by column chromatography (14:1 hexanes:ethyl acetate), the title compound 18 was

isolated as a yellow oil (23 mg, 53%) together with starting material α-2c as a colourless oil (11 mg,

1

2

5

1

4

6%). 18: R 0.35 (9:1 hexanes:ethyl acetate); H NMR: (CDCl ) δ 7.43–7.22 (complex m, 15H),

f

3

H

.99 (s, 1H), 5.90 (dddd, J = 17.2, 10.6, 5.9, 4.9 Hz, 1H), 5.26 (apparent dq, J = 17.2, 1.5 Hz, 1H),

.15 (apparent dq, J = 10.6, 1.5 Hz, 1H), 5.10 (s, 1H), 4.80 (d, J = 12.1 Hz, 1H), 4.76 (d, J = 3.8 Hz,

H), 4.64 (d, J = 11.8 Hz, 1H), 4.52 (m, 2H), 4.49 (d, J = 11.8 Hz, 1H), 4.47 (d, J = 12.1 Hz, 1H),

.35 (ddt, J = 13.2 Hz, 4.9, 1.5 Hz, 1H), 4.08 (ddt, J = 13.2 Hz, 5.9, 1.5 Hz, 1H), 3.87 (dd, J = 5.1, 3.8

1

3

Hz, 1H), 3.84–3.78 (complex m, 3H), 0.16 (s, 9H); C NMR: (CDCl ) δ 144.4, 138.9, 138.5, 138.0,

3

C

1

9

2

34.3, 128.5, 128.4, 128.3, 128.0, 127.9, 127.85, 127.80, 127.6, 127.5, 117.0, 114.4, 102.7, 100.6,

9.4, 77.1, 75.1, 74.9, 73.4, 72.2, 71.0, 70.8, 68.9, -0.08; IR (Film from CH Cl ): ν 3064, 3031,

2

max

−

1

957, 2917, 2866, 2140, 1496, 1454, 1336, 1250, 1092, 1071, 1028, 845, 735, 697 cm ; HRMS: m/z

+

C H O SiNa [M+Na] calcd 605.2699, found 605.2704.

36

42

5

Benzyl 4,5,7-tri-O-benzyl-2-bromo-2,3-dideoxy-β-

benzyl 4,5,7-tri-O-benzyl-2-bromo-2,3-dideoxy-α-

D

-arabino-hept-2-enoseptanoside (β-3c) and

D-arabino-hept-2-enoseptanoside (α-3c) A

solution of cyclopropane 1 (200 mg, 0.34 mmol) in toluene (3.4 mL) was treated with silver

trifluoroacetate (101 mg, 0.46 mmol), followed by benzyl alcohol (0.18 mL, 1.7 mmol), and stirred in

the dark at 100 °C for 2 days. The suspension was diluted with dichloromethane (20 mL) and filtered

1

7

ACCEPTED MANUSCRIPT

®

through a pad of Celite . After partitioning the eluent with water (20 mL), the aqueous layer was

extracted further with dichloromethane (2 x 20 mL). The organic phases were combined, dried with

magnesium sulfate, filtered and concentrated under reduced pressure to provide a crude mixture of

oxepines 2 and 3 and substrate 1. Upon purification by column chromatography (9:1 hexanes:ethyl

acetate), oxepine β-3c (72 mg, 35%) was isolated as a white solid and oxepine α-3c as a light yellow

1

6

oil (44 mg, 21%) (56% combined yield). β-3c: R 0.3 (9:1 hexanes:ethyl acetate); [α] + 0.9 (c 1.32,

f

D

1

CHCl ); H NMR: (CDCl ) δ 7.39–7.25 (complex m, 18H), 7.17–7.14 (complex m, 2H), 6.33 (dd, J

3

H

=

5.1, 0.7 Hz, 1H), 5.31 (s, 1H), 4.84 (d, J = 12.0 Hz, 1H), 4.67 (d, J = 11.7 Hz, 1H), 4.64 (d, J = 11.2

Hz, 1H), 4.58 (d, J = 11.7 Hz, 1H), 4.57 (d, J = 11.8 Hz, 1H), 4.56 (d, J = 12.0 Hz, 1H), 4.50 (d, J =

1.9 Hz, 1H), 4.44 (d, J = 11.2 Hz, 1H), 4.25 (ddd, J = 8.9, 6.0, 2.5 Hz, 1H), 4.15 (apparent t, J = 5.4

Hz, 1H), 3.74 (dd, J = 9.1, 5.6 Hz, 1H), 3.68 (dd, J = 10.4, 6.0 Hz, 1H), 3.58 (dd, J = 10.5, 2.4 Hz,

1

13

1

H); C NMR: (CDCl ) δ 138.2, 138.1, 138.0, 137.2, 132.2, 128.64, 128.53, 128.51, 128.45, 128.3,

3 C

1

28.05, 128.02, 128.00, 127.9, 127.8, 125.1, 100.1, 80.9, 78.9, 73.8, 73.4, 72.2, 71.7, 70.6, 70.5; IR

–

1

(

Film from CHCl ) v 3065, 3030, 2920, 2865, 1623, 1497, 1455, 1216, 1071, 1027, 749, 697 cm ;

3 max

7

9

+

HRMS: m/z C H O BrNa [M+Na] calcd 637.1566, found 637.1568. α-3c: R 0.28 (9:1

hexanes:ethyl acetate); [α]_D–6.7 (c 0.56 CHCl ); H NMR: (CDCl ) δ 7.39–7.25 (complex m,

3

5

35

5

f

1

6

1

3

H

1

=

(

1

8H), 7.16–7.13 (complex m, 2H), 6.44 (dd, J = 6.9, 1.0 Hz, 1H), 5.12 (d, J = 1.0 Hz, 1H), 4.87 (d, J

11.9 Hz, 1H), 4.73 (d, J = 12.0 Hz, 1H), 4.69 (d, J = 12.0 Hz, 1H), 4.59–4.52 (complex m, 2H), 4.51

d, J = 11.9 Hz, 1H), 4.50 (d, J = 11.2 Hz, 1H), 4.34 (d, J = 11.4 Hz, 1H), 4.10 (dd, J = 7.0, 3.2 Hz,

H), 3.71–3.56 (complex m, 4H); C NMR: (CDCl ) δ 138.3, 138.1, 137.6, 137.2, 132.4, 128.7,

3 C

28.59, 128.57, 128.53, 128.47, 128.42, 128.35, 128.32, 128.18, 128.15, 128.12, 127.07, 128.05,

1

3

27.97, 127.89, 127.79, 102.2, 80.1, 77.5, 75.6, 73.5, 72.9, 71.4, 71.2, 69.8; IR (Film from CHCl )

3

–

1

v_m_a_x3063, 3030, 2917, 2865, 1831, 1636, 1496, 1354, 1359, 1208, 1071, 1026, 735, 696 cm .

Phenyl 4,5,7-tri-O-benzyl-2-bromo-2,3-dideoxy-β-

phenyl 4,5,7-tri-O-benzyl-2-bromo-2,3-dideoxy-α-

D

-arabino-hept-2-enoseptanoside (β-3d) and

D-arabino-hept-2-enoseptanoside (α-3d) A

solution of cyclopropane 1 (101 mg, 0.172 mmol) in toluene (1.7 mL) was treated with silver nitrate

53 mg, 0.31 mmol) and phenol (86 mg, 0.91 mmol), then stirred at 100 °C for two days. The solution

(

was diluted with water (10 mL), then extracted with dichloromethane (3 x 10 mL), then the organic

fractions were combined, dried, filtered and concentrated to provide a yellow oil. Upon separation by

column chromatography (14:1 hexanes:ethyl acetate), an inseparable mixture of oxepines β-3d and α-

3

d (6.7:1 ratio) was obtained as a colourless oil (46 mg, 45%). The NMR data quoted are only of the

1

major oxepine, β-3d, except where otherwise noted. R 0.55 (5:1 hexanes:ethyl acetate); H NMR:

f

(

CDCl ) δ 7.36–7.12 (complex m, 19H), 7.03 (t, J = 7.3 Hz, 1H), 6.45 (d, J = 5.4 Hz, 1H), 5.91 (s,

3 H

1

H), 4.72 (d, J = 12.0 Hz, 1H), 4.67–4.62 (complex m, 2H), 4.51–4.46 (complex m, 2H), 4.40 (d, J =

1.9 Hz, 1H), 4.29 (ddd, J = 8.6, 4.6, 2.9 Hz, 1H), 4.25 (t, J = 5.5 Hz, 1H), 3.92 (dd, J = 8.6, 5.5 Hz,

H), 3.68 (dd, J = 10.7, 4.6 Hz, 1H), 3.45 (dd, J = 10.6, 2.6 Hz, 1H) [the following key resonances

1

3

were observed for the minor isomer, α-3d: 6.51 (d, J = 7.1 Hz, 1H), 5.64 (s, 1H)]; C NMR: (CDCl )

3

δ_C157.2, 138.0, 137.9, 137.8, 133.1, 129.5, 128.5, 128.4, 128.3, 127.92, 127.90, 127.8, 127.7, 127.5,

1

2

23.8, 122.6, 116.8, 99.8, 80.2, 78.7, 73.7, 73.2, 72.4, 72.1, 70.0; IR (KBr): v 3077, 3060, 3030,

max

−

1

912, 2862, 1590, 1495, 1454, 1363, 1222, 1102, 1070, 1028, 736, 697 cm ; HRMS: m/z

79

+

C H O BrNa [M+Na] calcd 623.1409, found 623.1405.

34

33

5

3

-O-Acetyl-1,6-anhydro-4,5,7-tri-O-benzyl-2-bromo-2-deoxy-

solution of cyclopropane 1 (102 mg, 0.173 mmol) in toluene (1.7 mL) was treated with silver acetate

41 mg, 0.24 mmol) and sodium acetate (72 mg, 0.88 mmol), then stirred at reflux for 28 hours. The

D-arabino-hept-1-enitol (19) A

(

solution was filtered through a pad of silica, eluting further with dichloromethane (40 mL), then the

organic fractions were combined, dried, filtered and concentrated to provide acolourless oil. Upon

1

8

ACCEPTED MANUSCRIPT

purification by column chromatography (14:1 hexanes:ethyl acetate), 3-acetyl oxepine 19 (14 mg,

1

4%) was obtained, in addition to oxepine 3a (4.3:1 ratio of α- and β-isomers, 64 mg, 65%). The

1

6

18

spectral data for 3a matched those reported previously. R 0.4 (5:1 hexanes:ethyl acetate); [α] +78

f

D

1

(

c 0.5 CHCl ); H NMR: (CDCl ) δ 7.43–7.06 (complex m, 15H), 6.94 (s, 1H), 5.63 (d, J = 5.9 Hz,

3 3 H

1

H), 4.69 (d, J = 12.2 Hz, 1H), 4.62 (d, J = 12.5 Hz, 1H), 4.58 (d, J = 12.2 Hz, 1H), 4.50 (d, J = 12.2

Hz, 1H), 4.45 (dd, J = 10.5, 4.6 Hz, 1H), 4.16 (d, J = 10.7 Hz, 1H), 4.14 (d, J = 5.9 Hz, 1H), 4.07 (d, J

1

3

=

10.7 Hz, 1H), 3.73 (d, J = 10.2 Hz, 1H), 3.66–3.60 (complex m, 2H), 1.89 (s, 3H); C NMR:

(

CDCl ) δ 170.6, 151.8, 137.9, 137.5, 137.0, 128.5, 128.4, 128.3, 128.21, 128.20, 128.1, 128.0,

3

C

1

2

27.8, 127.7, 99.4, 84.1, 78.8, 75.6, 75.3, 73.4, 72.5, 72.2, 69.8, 20.9; IR (KBr): ν 3065, 3027,

max

−

1

79

+

928, 2871, 1739, 1454, 1367, 1223, 1072, 1025, 750, 698 cm ; HRMS: m/z C H O BrNa

3

0

31

6

+

[

M+Na] calcd 589.1202, found 589.1198.

1

,7-Anhydro-4,5-di-O-benzyl-2-bromo-2,3-dideoxy-β-

solution of cyclopropane 1 (106 mg, 0.180 mmol) in toluene (1.7 mL) was treated with silver acetate

35 mg, 0.21 mmol), then stirred at 100 °C for 22 hours. The solution was diluted with water (10 mL),

D-arabino-hept-2-enoseptanose (20) A

(

extracted with dichloromethane (3 x 10 mL), then the organic fractions were combined, dried, filtered

and concentrated to provide a yellow oil. Upon purification by column chromatography (9:1

hexanes:ethyl acetate), bicyclic sugar 20 (30 mg, 38%) was obtained as a colourless oil. R 0.35 (9:1

f

2

0

1

hexanes:ethyl acetate); [α] −22 (c 0.4 CHCl ); H NMR: (CDCl ) δ 7.40–7.27 (complex m, 10H),

D

3

H

6

.20 (dd, J = 2.2, 1.2 Hz, 1H), 5.66 (s, 1H), 4.79 (d, J = 11.7 Hz, 1H), 4.73 (d, J = 11.5 Hz, 1H), 4.68

(

1

d, J = 11.5 Hz, 1H), 4.61 (d, J = 11.7 Hz, 1H), 4.60 (m, 1H), 4.48 (dd, J = 8.0, 5.5 Hz, 1H), 4.13

1

3

apparent t, J = 8.1 Hz, 1H), 3.63 (d, J = 8.5 Hz, 1H), 3.55 (dd, J = 8.4, 5.5 Hz, 1H); C NMR:

CDCl ) δ 137.9, 137.7, 134.1, 128.49, 128.47 (CH, Bn), 127.9 (CH, Bn), 127.84 (CH, Bn), 127.82

3

C

CH, Bn), 118.8 (C, C-2), 104.2 (CH, C-1), 88.7 (CH, C-5), 78.6 (CH, C-4), 77.8 (CH, C-6), 73.5

CH , PhCH ), 73.3 (CH , PhCH ), 66.4 (CH , C-7); IR (KBr): ν 3063, 3031, 2928, 2862, 1725,

2

max

−

1

639, 1601, 1539, 1496, 1453, 1349, 1272, 1210, 1091, 1027, 933, 865, 737, 698 cm ; HRMS: m/z

79

+

C H O BrNa [M+Na] calcd 439.0521, found 439.0515.

21

4

Acetyl 4,5,7-tri-O-benzyl-2-bromo-2,3-dideoxy-α-

anhydro-4,7-di-O-benzyl-2-bromo-2,3-dideoxy-β-

D

-lyxo-hept-2-enoseptanoside (21) and 1,6-

D-lyxo-hept-2-enopyranose (22) A solution of

cyclopropane 8 (103 mg, 0.175 mmol) in toluene (1.7 mL) was treated with silver acetate (42 mg,

.25 mmol) and sodium acetate (71 mg, 0.86 mmol), then stirred at 100 °C for two days. The solution

0

was diluted with dichloromethane (10 mL), filtered through a pad of silica, then eluted further with

dichloromethane (30 mL). The organic fractions were combined, dried, filtered and concentrated to

provide a yellow oil. Upon purification by column chromatography (14:1 hexanes:ethyl acetate),

acetyl oxepine 21 (51 mg, 52%) and bicyclic sugar 22 (7 mg, 7%) were obtained as colourless oils.

18

1

2

1: R 0.4 (5:1 hexanes:ethyl acetate); [α] −25 (c 2.0 CHCl ); H NMR: (CDCl ) δ 7.34–7.24

f D 3 3 H

(

complex m, 15H), 6.44 (s, 1H), 6.38 (s, 1H), 4.80 (d, J = 12.0 Hz, 1H), 4.64 (d, J = 12.0 Hz, 1H),

4

1

.54 (d, J = 11.2 Hz, 1H), 4.49 (d, J = 11.7 Hz, 1H), 4.46–4.40 (complex m, 2H), 4.38 (d, J = 11.7 Hz,

1

3

H), 4.11 (m, 1H), 4.09 (m, 1H), 3.68 (apparent d, J = 6.3 Hz, 2H), 2.08 (s, 3H); C NMR: (CDCl )

3

δ_C168.8, 138.2, 138.0, 137.4, 134.4, 128.6, 128.4, 128.3, 128.00, 127.95, 127.9, 127.7, 127.62,

1

27.61, 119.9, 91.6, 80.4, 77.0, 75.4, 73.6, 73.2, 71.9, 67.5, 20.9; IR (KBr): ν 3063, 3030, 2870,

max

−

1

79

+

775, 1604, 1496, 1454, 1370, 1219, 1061, 1027, 752, 698 cm ; HRMS: m/z C H O BrNa

3

0

31

6

+

[

M+Na] calcd 589.1202, found 589.1199. The α-anomeric stereochemistry was determined by NOE

spectroscopy: irradiation of H-1 (δ 6.44) caused enhancement of the signal for the side-chain proton,

H-7 (δ 3.68), on the top face (the spectrum is shown in the Supporting Information). 22: R 0.5 (5:1

f

1

8

1

hexanes:ethyl acetate); [α] −69 (c 0.3 CHCl ); H NMR: (CDCl ) δ 7.40–7.24 (complex m, 10H),

D

3

H

6

.10 (d, J = 3.5 Hz, 1H), 5.51 (s, 1H), 4.64 (s, 2H), 4.61 (m, 1H), 4.56 (s, 2H), 3.79 (m, 1H), 3.63 (d, J

1

9

ACCEPTED MANUSCRIPT

1

3

=

4.6 Hz, 1H), 3.58 (dd, J = 9.6, 5.2 Hz, 1H), 3.43 (dd, J = 9.4, 7.5 Hz, 1H); C NMR: (CDCl ) δ

3 C

1

7

9

37.6, 137.5, 128.6, 128.5, 128.0, 127.9, 127.8, 127.6, 126.3, 123.9, 101.4, 76.5, 74.0, 73.8, 73.6,

0.8, 70.2; IR (KBr): ν 3029, 2917, 2866, 1756, 1630, 1496, 1454, 1261, 1217, 1105, 1064, 1026,

max

−

1

79

+

20, 737, 698 cm ; HRMS: m/z C H O BrNa [M+Na] calcd 439.0521, found 439.0516.

2

1

21

4

Acetyl 4,5-di-O-benzyl-2-bromo-2,3-dideoxy-β-

O-benzyl-2-bromo-2,3-dideoxy-α- -threo-hex-2-enoseptanoside (23) Cyclopropane 9 (95 mg,

.20 mmol) in toluene (2.1 mL) was treated with silver acetate (53 mg, 0.32 mmol) and sodium

D-threo-hex-2-enoseptanoside and acetyl 4,5-di-

D

0

acetate (89 mg, 1.1 mmol), then stirred at 100 °C for two days. The solution was filtered through a

pad of silica, then eluted further with diethyl ether (100 mL). The organic fractions were combined,

dried, filtered and concentrated to provide a mixture of oxepines as a yellow oil. Upon purification by

column chromatography (14:1 hexanes:ethyl acetate), oxepine 23 (41 mg, 45%) was obtained as an

inseparable mixture of isomers (1:1 ratio) and as a colourless oil. R 0.5 (5:1 hexanes:ethyl acetate);

f

1

H NMR: (CDCl ) δ 7.35–7.28 (complex m, 10H), 6.55 (apparent t, J = 1.7 Hz, 0.5H), 6.40 (dd, J =

3

H

3

4

.0, 1.5 Hz, 0.5H), 6.38 (d, J = 3.4 Hz, 0.5H), 6.18 (d, J = 1.7 Hz, 0.5H), 4.72–4.60 (complex m,

.5H), 4.53 (ddd, J = 7.6, 3.4, 1.5 Hz, 0.5H), 4.25 (dd, J = 13.8, 5.0 Hz, 0.5H), 4.03 (m, 0.5H), 3.88

(

td, J = 4.7, 1.5 Hz, 0.5H), 3.85 (d, J = 13.9 Hz, 0.5H), 3.83–3.78 (complex m, 1H), 2.15 (s, 1.5H),

1

3

2

1

7

1

4

.13 (s, 1.5H); C NMR: (CDCl ) δ 169.1, 138.1, 137.9, 137.7, 137.6, 137.5, 136.5, 128.5, 128.41,

3 C

28.38, 127.9, 127.79, 127.78, 127.68, 127.67, 119.2, 118.5, 95.6, 94.3, 82.7, 80.3, 80.0, 79.2, 73.1,

3.0, 72.8, 72.4, 66.0, 65.3, 20.8; IR (KBr): ν_m_a_x3061, 3030, 2939, 2880, 1755, 1640, 1496, 1454,

−

1

79

+

370, 1273, 1218, 1092, 997, 946, 738, 698 cm ; HRMS: m/z C H O BrNa [M+Na] calcd

2

23

5

69.0627, found 469.0630.

2

-(Benzyloxymethyl)-3,4-dibenzyloxy-6-methylene-3,4,7,8a-tetrahydro2H-furo-[2,3-b]oxepine

(

24) A solution of oxepine β-3b (20 mg, 0.035 mmol) in tetrahydrofuran (1 mL) was treated with

tetrakis(triphenylphosphine)palladium (4 mg, 0.004 mmol) and triethylamine (0.0075 mL, 0.054

mmol), then stirred at reflux for 24 hours. The suspension was diluted with dichloromethane (5 mL),

®

filtered through a pad of Celite and washed with water (5 mL). The aqueous phase was extracted

further with dichloromethane (3 x 5 mL), then, upon combination, the organic phase was dried with

magnesium sulfate, filtered and concentrated under reduced pressure to provide a yellow oil.

Purification by column chromatography (5:1 hexanes:ethyl acetate) provided the desired product 24

1

9

as a pale-yellow solid (13 mg, 73% yield). R 0.3 (5:1 hexanes:ethyl acetate); m.p. 78–81 °C; [α]

-

D

f

1

2

6

1

3

1

7

1

(c 0.4 CHCl ); H NMR: (CDCl ) δ 7.73–7.69 (complex m, 2H), 7.43–7.12 (complex m, 13H),

.19 (dd, J = 3.5, 1.6 Hz, 1H), 5.50 (d, J = 1.7 Hz, 1H), 5.39 (apparent t, J = 2.3 Hz, 1H), 4.94 (br. s,

H), 4.91 (d, J = 10.5 Hz, 1H), 4.78 (dt, J = 12.7, 2.4 Hz, 1H), 4.75 (d, J = 11.8 Hz, 1H), 4.70 (d, J =

1.7 Hz, 1H), 4.62 (d, J = 12.2 Hz, 1H), 4.54–4.50 (complex m, 3H), 4.41 (dd, J = 9.1, 3.5 Hz, 1H),

.94 (dd, J = 10.0, 3.9 Hz, 1H), 3.90 (ddd, J = 8.7, 3.9, 2.1 Hz, 1H), 3.77 (dd, J = 10.0, 2.0 Hz, 1H),

.63 (apparent t, J = 9.0 Hz, 1H); C NMR: (CDCl ) δ 141.4, 141.2, 138.3, 138.2, 138.1, 135.2,

28.4, 128.3, 127.99, 127.97, 127.9, 127.7, 127.60, 127.56, 125.0, 105.2, 103.3, 82.5, 80.7, 76.1, 75.3,

3.6, 73.2, 72.7, 70.7; IR (KBr): v 3063, 3030, 2918, 2866, 1723, 1604, 1496, 1453, 1359, 1091,

3

H

1

3

C

max

−

1

+

072, 1027, 750, 697 cm ; HRMS: m/z C H O Na [M+Na] calcd 507.2147, found 507.2148.

3

1

32

5

General Procedure for Suzuki Cross-Coupling Reactions of Oxepines: A solution of oxepine β-3c

1.0 equiv.) in tetrahydrofuran was treated with the arylboronic acid (ca. 2.0 equiv.), 4,5-

bis(diphenylphosphino)-9,9-dimethylxanthene (ca. 20 mol%), a base (usually sodium tert-butoxide)

6 mg, 0.06 mmol) and palladium acetate (ca. 15 mol%), then heated at reflux (for ca. 24 h). The

(

®

suspension was diluted with dichloromethane, filtered through a pad of Celite and washed with

water. The aqueous phase was extracted further with dichloromethane. The combined organic phases

2

0

ACCEPTED MANUSCRIPT

were dried (MgSO ), filtered and concentrated under reduced pressure. The resulting mixture was

4

purified by column chromatography (9:1 hexanes:ethyl acetate).

Benzyl 4,5,7-tri-O-benzyl-2-phenyl-2,3-dideoxy-β-D-arabino-hept-2-enoseptanoside (25a) Using

the general procedure for cross couplings with oxepine β-3c (13 mg, 0.021 mmol), phenylboronic acid

(

5 mg, 0.04 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3 mg, 0.005 mmol), sodium

tert-butoxide (6 mg, 0.06 mmol) and palladium acetate (1 mg, 0.0045 mmol) in tetrahydrofuran (1

mL) and heating at reflux for 24 hours, gave the desired product 25a as a colourless oil (7 mg, 54%

1

6

1

yield). R 0.3 (9:1 hexanes:ethyl acetate); [α]_D+1.9 (c 0.18, CHCl ); H NMR: (CDCl ) δ 7.37–

f

3

H

7

1

.16 (complex m, 25H), 5.99 (d, J = 4.1 Hz, 1H), 5.62 (s, 1H), 4.83 (d, J = 11.9 Hz, 1H), 4.79 (d, J =

1.0 Hz, 1H), 4.75 (d, J = 11.7 Hz, 1H), 4.67 (d, J = 11.7 Hz, 1H), 4.61 (d, J = 12.0 Hz, 1H), 4.59

(

partially obscured d, J = 12.0 Hz, 1H), 4.58 (d, J = 11.7 Hz, 1H), 4.53 (d, J = 10.7 Hz, 1H), 4.48 (dd,

J = 6.4, 4.4 Hz, 1H), 4.40 (ddd, J = 9.3, 5.9, 2.3 Hz, 1H), 3.83–3.79 (complex m, 2H), 3.70 (dd, J =

1

3

1

2

6

0.3, 2.3 Hz, 1H); C NMR: (CDCl ) δ 142.2, 140.8, 138.5, 138.4, 138.3, 137.4, 129.7, 128.54,

3 C

27.50, 128.48, 128.41, 128.39, 128.26, 128.12, 128.0, 127.98, 127.82, 127.79, 127.70, 127.45,

26.93, 99.2, 80.3, 79.8, 74.2, 73.5, 72.5, 71.8, 71.0, 70.1, 66.0; IR (film from chloroform) v 3030,

918, 2850, 1496, 1454, 1095, 1026, 735, 697 cm ; HRMS: m/z C H O Na [M+Na] calcd

35.2773, found 635.2779.

max

-1

+

4

1

40

5

Benzyl 4,5,7-tri-O-benzyl-2-(4-acetylphenyl)-2,3-dideoxy-β-

D-arabino-hept-2-enoseptanoside

(

25b) and benzyl 4,5,7-tri-O-benzyl-2,3-dideoxy-β- -arabino-hept-2-enoseptanoside (25d) Using

D

the general procedure for cross couplings with oxepine β-3c (70 mg, 0.12 mmol), p-

acetylphenylboronic acid (38.5 mg, 0.23 mmol), 4.5-bis(diphenylphosphino)-9,9-dimethylxanthene

(

17 mg, 0.029 mmol), sodium tert-butoxide (34 mg, 0.35 mmol) and palladium acetate (4 mg, 0.018

mmol) in THF (1.3 mL) and stirring the reaction for 25 hours at 62 °C provided the expected product

2

8

2

=

5b as a colourless oil (47 mg, 64% yield) and the dehydrohalogenated compound 25d (7 mg, 10%).

1

6

1

5b: R 0.26 (5:1 hexanes:ethyl acetate); [α] + 0.7 (c 0.61, CHCl ) H NMR: (CDCl ) δ 7.85 (d, J

f

D

3

H

8.3 Hz, 2H), 7.38–7.16 (complex m, 22H), 6.05 (d, J = 4.4 Hz, 1H), 5.63 (s, 1H), 4.83 (d, J = 12 Hz,

H), 4.78 (d, J = 10.9 Hz, 1H), 4.74 (d, J = 12 Hz, 1H), 4.68 (d, J = 11.7 Hz, 1H), 4.61 (d, J = 12.2

Hz, 1H), 4.59 (d, J = 11.7 Hz, 1H), 4.57 (d, J = 12.2 Hz, 1H), 4.52 (d, J = 11.3 Hz, 1H), 4.48 (dd, J =

1

6

1

.3, 4.4 Hz, 1H), 4.38 (ddd, J = 8.3, 5.6, 1.9 Hz, 1H), 3.82 (partially obscured dd, J = 10.5, 5.4 Hz,

H), 3.80 (dd, J = 8.1, 6.6 Hz, 1H), 3.70 (dd, J = 10.4, 2.1 Hz, 1H), 2.61 (s, 3H); C NMR: (CDCl )

13

3

δ_C197.9, 145.4, 141.6, 138.4, 138.22, 138.21, 137.1, 136.0, 131.5, 128.57, 128.55, 128.52, 128.49,

1

7

1

28.47, 128.4, 128.2, 128.02, 127.98, 127.9, 127.8, 127.0, 98.6, 80.2, 79.5, 74.2, 73.5, 72.7, 72.0,

0.9, 70.0, 26.8; IR (film from CHCl ) v 3063, 3031, 2917, 2864, 1682, 1603, 1497, 1398, 1359,

3

max

-1

+

072, 1027, 749, 698 cm ; HRMS: m/z C H O Na [M+Na] calcd 677.2879, found 677.2886. 25d:

43

42

6

1

6

1

R 0.29 (9:1 hexanes:ethyl acetate); [α]_D+5.5 (c 0.42, CHCl ); H NMR: (CDCl ) δ 7.34–7.23

f

3

H

(

complex m, 18H), 7.16–7.14 (complex m, 2H), 5.89 (dd, J = 12.0, 5.6 Hz, 1H), 5.75 (dd, J = 12.1,

1

.6 Hz, 1H), 5.43 (s, 1H), 4.87 (d, J = 11.9 Hz, 1H), 4.67 (d, J = 12.2 Hz, 1H), 4.57 (d, J = 12.1 Hz,

H), 4.56 (d, J = 10.7 Hz, 1H), 4.54 (d, J = 10.9 Hz, 1H), 4.51 (d, J = 11.7 Hz, 1H), 4.48 (d, J = 12.1

Hz, 1H), 4.35 (d, J = 11.2 Hz, 1H), 4.18–4.11 (complex m, 2H), 3.75 (dd, J = 9.2, 3.9 Hz, 1H), 3.68

1

3

(

dd, J = 10.5, 6.1 Hz, 1H), 3.59 (dd, J = 10.5, 1.9 Hz, 1H); C NMR: (CDCl ) δ 138.5, 138.4, 138.2,

3 C

1

7

38.1, 132.6, 129.3, 128.72, 128.69, 128.63, 128.61, 128.57, 128.55, 128.53, 128.51, 128.48, 128.44,

28.16, 128.05, 128.03, 128.0, 127.87, 127.93, 127.87, 127.83, 127.66, 98.2, 81.7, 76.1, 73.3, 73.1,

1.9, 71.4, 71.0, 69.5; IR (film from CHCl ): v 3063, 3030, 2863, 1496, 1454, 1097, 1039, 734, 696

3

max

-

1

+

cm ; HRMS: m/z C H O Na [M+Na] calcd 559.2460, found 559.2462.

3

5

36

5

Benzyl 4,5,7-tri-O-benzyl-2-(4-methoxyphenyl)-2,3-dideoxy-β-

D-arabino-hept-2-enoseptanoside

(

25c) Using the general procedure for cross couplings with oxepine β-3c (70 mg, 0.12 mmol), p-

2

1

ACCEPTED MANUSCRIPT

methoxyphenylboronic acid (35 mg, 0.23 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

(

17 mg, 0.03 mmol), sodium tert-butoxide (34 mg, 0.35 mmol) and palladium acetate (12 mg, 0.053

mmol) in toluene (1.7 mL) and heating at 100 °C for 25 h provided product 25c (27.6 mg) as a

1

6

1

colourless oil (38% yield). R 0.31 (9:1 hexanes:ethyl acetate); [α]_D+1.3 (c 1.25, CHCl ); H NMR:

f

3

(

CDCl ) δ 7.37–7.26 (complex m, 16H), 7.22-7.18 (complex m, 4H), 7.13 (m, 2H), 6.79 (m, 2H),

3 H

5

.91 (d, J = 4.5 Hz, 1H), 5.58 (s, 1H), 4.83 (d, J = 11.8 Hz, 1H), 4.78 (d, J = 11.2 Hz, 1H), 4.74 (d, J

=

11.9 Hz, 1H), 4.66 (d, J = 11.9 Hz, 1H), 4.60 (d, J = 12.2, 1H), 4.59 (d, J = 11.9 Hz, 1H), 4.55 (d, J

12.2 Hz, 1H), 4.52 (d, J = 11.0 Hz, 1H), 4.46 (dd, J = 6.6, 4.3 Hz, 1H), 4.38 (ddd, J = 8.6, 5.6, 2.2

Hz, 1H), 3.81 (s, 3H), 3.81 (partially obscured m, 1H), 3.78 (dd, J = 8.9, 6.6 Hz, 1H), 3.69 (dd, J =

1

3

1

0.4, 2.4 Hz, 1H); C NMR: (CDCl ) δ 159.1, 141.6, 138.6, 138.4, 138.3, 137.4, 133.3, 128.53,

3 C

1

28.5, 128.47, 128.4, 129.11, 128.09, 127.99, 127.97, 127.83, 127.8, 127.77, 127.7, 113.6, 99.3, 80.4,

7

9.8, 74.1, 73.5, 72.4, 71.7, 71.0, 70.0, 55.4; IR (film from CHCl ) v 3063, 3030, 2917, 2862, 1607,

3

max

-1

+

1

511, 1454, 1247, 1102, 1027, 735, 697 cm ; HRMS: m/z C H O Na [M+Na] calcd 665.2879,

42 42 6

found 665.2880.

Acknowledgements

The authors gratefully acknowledge funding from the Cancer Society of New Zealand (PhD

Scholarship, RJH), Victoria University of Wellington for a Victoria Masters by Thesis Scholarship

(

PWM) and a Faculty of Science Summer Research Scholarship (MRLS). We thank John Spencer

VUW) and Richard Taylor (University of York) for helpful discussions and Yinrong Lu (IRL), A.

Jonathan Singh, John Ryan, Ian Vorster, Claire Turner, Mark Bartlett, Dylan Davies, Jacqui Kane-

Barber, Peter Clark (VUW) for help with mass spectrometry, NMR spectroscopy and practical advice.

Supporting Information Available: General experimental information, procedures for reactions,

analysis of NMR coupling constants for cyclopropane isomers 1 and 7, full characterisation for all

1

new compounds, assignment of NMR data for all compounds, H NMR spectra for all new

compounds.

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2

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3

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(

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ACCEPTED MANUSCRIPT

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8. See Harvey, J. E.; Hewitt, R. J.; Moore, P. W.; Somarathne, K. K. Pure Appl. Chem. 2014,

accepted, and references cited therein for a discussion of plausible mechanistic pathways.

1

2

9. Kozikowski, A. P.; Lee, J. J. Org. Chem. 1990, 55, 863–870.

0. See Supporting Information for full details of starting material synthesis.

1. Mąkosza, M.; Wawrzyniewicz, Tetrahedron Lett. 1969, 10, 4659–4662.

2

3

ACCEPTED MANUSCRIPT

2

7

2. Fedoryński, M.; Mąkosza, M. J. Organomet. Chem. 1973, 51, 89–91.

3. Ramesh, N. G.; Balasubramanian, K. K. Tetrahedron Lett. 1991, 32, 3875–3878.

4. For a recent review and selected examples, see (a) Ramesh, N. G. Eur. J. Org. Chem. 2014, 689–

07. (b) Sagar, R.; Park, J.; Koh, M.; Park, S. B. J. Org. Chem. 2009, 74, 2171–2174. (c) Rawal, G.

K.; Rani, S.; Kumari, N.; Vankar, Y. D. J. Org. Chem. 2009, 74, 5349–5355. (d) Maiti, D. K.; Halder,

S.; Pandit, P.; Chatterjee, N.; De Joarder, D.; Pramanik, N.; Saima, Y.; Patra, A.; Maiti, P. K. J. Org.

Chem. 2009, 74, 8086–8097.

2

5. For a discourse of hydrodehalogenation, see Mukhopadhyay, S.; Rothenburg, G.; Gitis, D.;

Baidossi, M.; Ponde, D. E.; Sasson, Y. J. Chem. Soc., Perkin Trans. 2 2000, 1809–1812.

6. Interestingly, Jayaraman and co-workers have recently demonstrated that 2-oxyglycal-derived

2

cyclopropanes have less tendency to undergo this type of ring contraction: Dey, S.; Jayaraman, N.

Carbohydr. Res. 2014, 389, 66–71.

2

7. Several complex natural products contain embedded furo[2,3-b]oxepine ring systems, including

azadirachtin: (a) Veitch, G. E.; Pinto, A.; Boyer, A.; Beckmann, E.; Anderson, J. C.; Ley, S. V. Org.

Lett. 2008, 10, 569–572; dysoxyhainanin A: (b) He, X.-F.; Wang, X.-N.; Gan, L.-S.; Yin, S.; Dong,

L.; Yue, J.-M. Org. Lett. 2008, 10, 4327–4330; and fabianane: (c) Brown, G. D. J. Nat. Prod. 1994,

5

7, 328–330.

2

8. Compound 25d has been prepared previously in a mixture with its anomer and partially

characterised: Ovaa, H.; Leeuwenburgh, M. A.; Overkleeft, H. S.; van der Marel, G. A.; van Boom, J.

H. Tetrahedron Lett. 1998, 39, 3025-3028.

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4

ACCEPTED MANUSCRIPT

Supporting Information for

Divergent Synthesis of 2-C-Branched Pyranosides and Oxepines

from 1,2-gem-Dihalocyclopropyl Carbohydrates

Peter W. Moore, Julia K. Schuster, Russell J. Hewitt, M. Rhia L. Stone, Paul H. Teesdale-Spittle and

Joanne E. Harvey*

Contents

General Experimental ..................................................................................................................4

Synthesis of Per-O-benzyl Glucals 4, 5 and 6 .................................................................................4

Tri-O-acetyl-D-glucal (S4) ..........................................................................................................5

D-Glucal ...................................................................................................................................6

Tri-O-benzyl-D-glucal (4) ...........................................................................................................6

D-Galactal ................................................................................................................................7

Tri-O-benzyl-D-galactal (5) ........................................................................................................7

Di-O-acetyl-D-xylal (S6).............................................................................................................8

Di-O-benzyl-D-xylal (6)..............................................................................................................9

Synthesis of Cyclopropyl Carbohydrates .......................................................................................9

General procedure for cyclopropanation...................................................................................9

1

,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-1,2-C-(dibromomethylene)-

and 1,5-anhydro-3,4,6-tri-O-benzyl-2-deoxy-1,2-C-(dibromomethylene)-

7).......................................................................................................................................... 10

Analysis of NMR coupling constants in cyclopropane diastereomers 1 and 7............................ 11

,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-1,2-C-(dibromomethylene)- -glycero-L-manno-hexitol

8).......................................................................................................................................... 12

,5-Anhydro-3,4-di-O-benzyl-2-deoxy-1,2-C-(dibromomethylene)- -gulo-pentitol (9) and 1,5-

anhydro-3,4-di-O-benzyl-2-deoxy-1,2-C-(dibromomethylene)- -talo-pentitol (10).................... 13

D

-glycero-

D

-gulo-hexitol (1)

D-glycero-

D-talo-hexitol

(

1

D

(

1

D

Synthesis of 2-C-Branched pyranosides....................................................................................... 13

General procedures for cyclopropyl ring opening .................................................................... 13

Allyl 3,4,6-tri-O-benzyl-(2E)-2-C-(bromomethylene)-2-deoxy-β-

and allyl 3,4,6-tri-O-benzyl-(2E)-2-C-(bromomethylene)-2-deoxy-α-

c) ......................................................................................................................................... 15

Phenyl 3,4,6-tri-O-benzyl-(2E)-2-C-(bromomethylene)-2-deoxy-1-thio-β- -arabino-

hexopyranoside (β-2d) and phenyl 3,4,6-tri-O-benzyl-(2E)-2-C-(bromomethylene)-2-deoxy-1-

D-arabino-hexopyranoside (β-2c)

D-arabino-hexopyranoside (α-

2

D

thio-α-D-arabino-hexopyranoside (α-2d)................................................................................. 17

1

ACCEPTED MANUSCRIPT

N,N-Diethyl 3,4,6-tri-O-benzyl-(2E)-2-C-(bromomethylene)-2-deoxy-β-D-arabino-hexopyranosyl

amine (β-2e) and N,N-diethyl 3,4,6-tri-O-benzyl-(2E)-2-C-(bromomethylene)-2-deoxy- α-D-

arabino-hexopyranosyl amine (α-2e) ...................................................................................... 18

9

1

,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-C-2-formyl-

,4,6-Tri-O-benzyl-(2E)-2-C-(bromomethylene)-2-deoxy-β-

-arabino-hexopyranose (α-13 ) and 3,4,6-

-arabino-hexose (12)................................. 19

Methyl 3,4,6-tri-O-benzyl-(2E)-2-C-(bromomethylene)-2-deoxy-β- -lyxo-hexopyranoside (β-14)

and methyl 3,4,6-tri-O-benzyl-(2E)-2-C-(bromomethylene)-2-deoxy-α- -lyxo-hexopyranoside (α-

4)......................................................................................................................................... 19

Cross-coupling Reactions of 2-C-Branched Pyranosides ............................................................... 20

Methyl 3,4,6-tri-O-benzyl-2-deoxy-2-C-(methylene)-α- -arabino-hexopyranoside (15)............. 20

Methyl 3,4,6-tri-O-benzyl-(2E)-2-C-(but-3-enylidene)-2-deoxy-α- -arabino-hexopyranoside (16)

............................................................................................................................................. 21

Allyl 3,4,6-tri-O-benzyl-(2E)-2-C-(2’-trimethylsilylethynyl methylidene)-2-deoxy-α- -arabino-

D

-arabino-hex-1-enitol (11) ..................... 18

3

D

-arabino-hexopyranose (β-13 ), 3,4,6-

tri-O-benzyl-(2E)-2-C-(bromomethylene)-2-deoxy-α-

D

tri-O-benzyl-(2E)-2-C-(bromomethylene)-2-deoxy-

D

1

D

.

D

hexopyranoside (18)............................................................................................................... 24

General Procedure for Suzuki Reactions of 2-Bromomethylene Pyranosides ............................ 22

Allyl 3,4,6-tri-O-benzyl-2-C-(methylene)-2-deoxy-α-

Allyl 3,4,6-tri-O-benzyl-(2E)-2-C-(phenylmethylidene)-2-deoxy-α-

17b)...................................................................................................................................... 23

Allyl 3,4,6-tri-O-benzyl-(2E)-2-C-(4’-methoxyphenylmethylidene)-2-deoxy-α- -arabino-

hexopyranoside (17c) ............................................................................................................. 23

Allyl 3,4,6-tri-O-benzyl-(2E)-2-C-(2’-thiophenylmethylidene)-2-deoxy-α- -arabino-

D-arabino-hexopyranoside (17a) ............... 22

D-arabino-hexopyranoside

(

D

hexopyranoside (17d)............................................................................................................. 24

Synthesis of Oxepines ................................................................................................................ 25

Allyl 4,5,7–tri–O–benzyl–2–bromo–2,3–dideoxy–β-

Allyl 4,5,7–tri–O–benzyl–2–bromo–2,3–dideoxy–α–

and Acetyl 4,5,7–tri–O–benzyl–2–bromo–2,3–dideoxy–β-

a) and Acetyl 4,5,7–tri–O–benzyl–2–bromo–2,3–dideoxy–α–D–arabino–hept–2–

D

-arabino-hept–2–enoseptanoside (β-3b) and

-arabino-hept–2–enoseptanoside (α-3b)

–arabino–hept–2–enoseptanoside (β-

D

3

enoseptanoside (α-3a)............................................................................................................ 25

Benzyl 4,5,7–tri–O–benzyl–2–bromo–2,3–dideoxy–β–D–arabino–hept–2–enoseptanoside (β-3c)

and benzyl 4,5,7–tri–O–benzyl–2–bromo–2,3–dideoxy–α–D–arabino–hept–2–enoseptanoside

(

α-3c)..................................................................................................................................... 27

Phenyl 4,5,7-tri-O-benzyl-2-bromo-2,3-dideoxy-β- -arabino-hept-2-enoseptanoside (β-3d) and

phenyl 4,5,7-tri-O-benzyl-2-bromo-2,3-dideoxy-α- -arabino-hept-2-enoseptanoside (α-3d) .... 28

-O-Acetyl-1,6-anhydro-4,5,7-tri-O-benzyl-2-bromo-2-deoxy- -arabino-hept-1-enitol (19)....... 29

,7-Anhydro-4,5-di-O-benzyl-2-bromo-2,3-dideoxy-β- -arabino-hept-2-enoseptanose (20)...... 29

D

3

1

D

Acetyl 4,5,7-tri-O-benzyl-2-bromo-2,3-dideoxy-α-D-lyxo-hept-2-enoseptanoside (21) and 1,6-

anhydro-4,7-di-O-benzyl-2-bromo-2,3-dideoxy-β-D-lyxo-hept-2-enopyranose (22) ................... 30

2

ACCEPTED MANUSCRIPT

Acetyl 4,5-di-O-benzyl-2-bromo-2,3-dideoxy-β-D-threo-hex-2-enoseptanoside and acetyl 4,5-di-

O-benzyl-2-bromo-2,3-dideoxy-α-

D-threo-hex-2-enoseptanoside (23)..................................... 31

Cross-coupling reactions of Oxepines ......................................................................................... 32

-(Benzyloxymethyl)-3,4-dibenzyloxy-6-methylene-3,4,7,8a-tetrahydro2H-furo-[2,3-b]oxepine

24)........................................................................................................................................ 32

General Procedure for Suzuki Cross-Coupling Reactions of Oxepines ....................................... 33

Benzyl 4,5,7-tri-O-benzyl-2-phenyl-2,3-dideoxy-β- -arabino-hept-2-enoseptanoside (25a)....... 33

Benzyl 4,5,7-tri-O-benzyl-2-(4-acetylphenyl)-2,3-dideoxy-β- -arabino-hept-2-enoseptanoside

25b) and Benzyl 4,5,7-tri-O-benzyl-2,3-dideoxy-β- -arabino-hept-2-enoseptanoside (25d)...... 34

Benzyl 4,5,7-tri–O–benzyl–2–(4–methoxyphenyl)–2,3–dideoxy–β– –arabino–hept–2 –

2

(

D

(

D

enoseptanoside (25c) ............................................................................................................. 35

H NMR Spectra of New Compounds .......................................................................................... 36

1

References................................................................................................................................. 48

3

ACCEPTED MANUSCRIPT

General Experimental

Unless otherwise stated, the following conditions apply. All reactions were performed

under argon (zero grade) or oxygen-free nitrogen in vacuum-dried glassware using dry solvents and

standard syringe techniques. Tetrahydrofuran (THF) was freshly distilled in the presence of sodium

benzophenone ketyl radical ion. Dichloromethane (CH Cl ), and diethylamine (Et NH) were distilled

2

in the presence of calcium hydride. Methanol (MeOH), allyl alcohol (AllylOH), 1,4-dioxane and

toluene were distilled in the presence of sodium. Acetic anhydride was used as received. Anhydrous

N,N-dimethylformamide (DMF) and methanol-d were purchased from Aldrich Chemical Company

and were used without further purification. Chloroform and bromoform were both used as received

(

with small amounts of ethanol as stabiliser). Sodium hydride (NaH) was obtained as a 60% (w/w)

dispersion in paraffin oil and was used as obtained, unless otherwise stated. n-BuLi (n-butyllithium)

−

1

was obtained as a 1.6 molL solution in hexanes, unless otherwise stated. Potassium fluoride

dehydrate was crystallised from a super-saturated aqueous solution of potassium fluoride. All other

reagents were used as obtained or distilled prior to use if necessary.

Reaction progress was monitored using aluminium-backed thin layer chromatography (TLC) plates

pre-coated with silica UV254 and visualised by UV fluorescence quenching (254 nm) and/or

anisaldehyde dip. Purification of products via flash chromatography was conducted using a column

filled with Silica Zeoprep 60 (40-63 microns) as the matrix, obtained from Pure Science Ltd (NZ), with

1

13

solvent systems as indicated. H and C NMR spectra were recorded on a Varian Unity Inova 500

1

13

(

operating at 500 MHz for H and 125 MHz for C) spectrometer, NOESY spectra were recorded on

1

either a Varian Unity Inova 300 (300 MHz for H) or on a Varian Direct Drive instrument equipped

1

with an inverse-detected triple resonance HCN probe operating at 25 °C (600 MHz for H). All

chemical shifts (δ) were referenced to solvent peaks as follows. Proton NMR spectra were

1

referenced to residual CHCl : H, 7.26 ppm or C H D: H, 7.16 ppm. Carbon spectra were referenced

3

6 5

13

to CDCl : C, 77.16 ppm or C D : C, 128.06 ppm). Melting points were determined using a

3

6 6

Gallenkamp melting point apparatus and are uncorrected. Optical rotations were measured on

either an Autopol II polarimeter from Rudolph Research Analytical or a Perkin–Elmer Polarimeter at

the sodium D-line. Infrared spectra were obtained on a Brucker Tensor 27 spectrometer or a Perkin–

Elmer Spectrum One FT-IR spectrometer. High-resolution mass spectrometry (HRMS) was performed

on a Waters Q-TOF PremierTM Tandem Mass Spectrometer operating in ESI mode. The structure of

each compound is presented, together with a corresponding method of preparation and

spectroscopic data.

Synthesis of Per-O-benzyl Glucals 4, 5 and 6

Per-O-benzylated D-glucal (4), D-galactal (5) and D-xylal (6) were prepared from their respective

1

parent carbohydrates S1–S3 using an adaptation of the method reported by Kozikowski. The

1

syntheses of the per-O-acetyl glycals S4–S6 were performed in the established manner. Acetate

deprotection was performed using either triethylamine in aqueous methanol or sodium methoxide

1

in methanol instead of ammonia in methanol as described before. In this way,

D-glucal was

4

Article Doi

Divergent synthesis of 2-C-branched pyranosides and oxepines from 1,2-gem-dibromocyclopropyl carbohydrates

DOI: 10.1016/j.tet.2014.06.069

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Authors:

Article abstract of DOI:10.1016/j.tet.2014.06.069

Full text of DOI:10.1016/j.tet.2014.06.069

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