Formal synthesis of berkelic acid: A lesson in α-alkylation chemistry

Article

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Formal Synthesis of Berkelic Acid: A Lesson in α-Alkylation Chemistry

Michael C. McLeod, Zoe E. Wilson, and Margaret A. Brimble*

School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, New Zealand

S

* Supporting Information

ABSTRACT: The full details of our enantioselective formal

synthesis of the biologically active natural product berkelic acid

are described. The insertion of the C-18 methyl group proved

challenging, with three different approaches investigated to

install the correct stereochemistry. Our initial Horner−

Wadsworth−Emmons/oxa-Michael approach to the berkelic

acid core proved unsuccessful upon translation to the natural

product itself. However, addition of a silyl enol ether to an

oxonium ion, followed by a one-pot debenzylation/spiroketal-

isation/thermodynamic equilibration procedure, afforded the tetracyclic structure of the berkelic acid core as a single

diastereoisomer.

INTRODUCTION

■

Extremophiles are organisms that can survive in extreme

conditions and are currently of interest to the synthetic

community due to a number of novel secondary metabolites

that have been isolated from them.¹To date, novel natural

products have been isolated from organisms that inhabit

environments of high and low pH, high and low temperature,

high pressure, and high salt. Berkelic acid (1) was isolated as a

secondary metabolite from a Penicillium species that inhabits

Berkeley Pit Lake in Montana, USA.²This man-made lake was

formed when an abandoned copper mine was flooded, and its

natural product. We envisaged that this objective could be

waters are now both acidic (pH ∼2.5) and contain a number of

accomplished by effecting a Horner−Wadsworth−Emmons/

heavy-metal ions in high concentrations. Berkelic acid (1)

oxa-Michael (HWE/oxa-M) coupling of phosphonate 6 with

displays selective activity against the OVCAR-3 ovarian cancer

lactol 7 to obtain isochroman 5 (Scheme 1). Global debenzyla-

cell line (GI₅₀91 nM) as well as inhibiting caspase-1 (GI₅₀98 μM)

tion of isochroman 5 under acidic conditions should promote

and metalloprotease-3 (GI₅₀1.87 μM).²

spiroketalization, which upon allyl protection of the free acid

Berkelic acid (1) was originally assigned as 2, with the

chirality at the C-22 center unknown. Through total synthesis

and phenol groups would lead to spiroketal 4, an advanced

intermediate in Snider’s total synthesis of berkelic acid (1).⁴

of berkelic acid methyl ester (3), Furstner proposed the

̈

reassignment of the C-18 and C-19 stereocenters.³This

proposal and the absolute stereochemistry were confirmed by

the first total synthesis of berkelic acid by the Snider group,

who tentatively assigned the C-22 center as S.⁴This assignment

was confirmed by further work undertaken by the Snider

group⁵and further supported by a biomimetic total synthesis

This proposed retrosynthetic strategy is based on previous

work reported by our group, where a model tetracyclic core

of berkelic acid was prepared using a similar HWE/oxa-M

method.¹⁰

Lactol 7 could be accessed by reduction of the corresponding

lactone, which could be obtained by hydrogenation and

lactonization of hydroxy ester 8. The chirality of alcohol 8

could be introduced by enantioselective reduction of alkynyl

ketone 9. Phosphonate 6 could be prepared by ring opening of

lactone 10, which is available by reduction and cyclization of

ester 11. The key step of the phosphonate synthesis would be a

syn-selective conjugate addition of pseudoephedrine-derived

amide 13 to the α,β-unsaturated ester 12.

by De Brabander and co-workers.⁶A total synthesis by Furstner

̈

et al.⁷and racemic formal synthesis by Pettus et al.⁸have since

been reported.

We have previously reported an enantioselective formal

synthesis of berkelic acid (1).⁹Herein we report the full results

of our synthetic investigations.

RESULTS AND DISCUSSION

■

Retrosynthesis. We wished to synthesize berkelic acid via

an efficient, modular approach that would be amenable to the

synthesis of analogues to probe the biological activity of the

Received: September 29, 2011

Published: November 11, 2011

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Scheme 1. Original Retrosynthetic Strategy

Synthesis of Lactone 17. The synthesis of alkynyl ketone

9 as the key precursor to lactol 7 commenced with global

benzyl protection of the known benzoic acid 14¹¹(Scheme 2).

with a short reaction time (2 min) resulted in the formation of

alkynyl ketone 9 in a reproducible 88% yield.

With an efficient route to alkynyl ketone 9 established,

attention next turned to the key chiral reduction step (Table 1).

The chiral reduction products were inseparable by HPLC;

hence, they were immediately converted to lactone 17 by

selective reduction of the alkyne moiety with Adam’s catalyst¹²

and lactonization with Amberlyst 15 (R). The two enantiomers

of lactone 17 were readily separable by chiral HPLC (Chiralpak

AD-H).

Scheme 2. Synthesis of Alkynyl Ketone 9

Previous model work by our group had identified (^D)-TarB-

NO₂¹³as the most enantioselective catalyst for the reduction of

a similar substrate.¹⁰However, for the present substrate this

reagent only effected reduction in 28% ee and poor yield

(Table 1, entry 1). After screening several chiral reductants, we

found that the Me-CBS¹⁴reagent provided the highest levels of

enantiocontrol; however, some interesting effects were

observed. When BH₃·SMe₂was employed as the stoichiometric

reductant, a reversal of selectivity was observed upon raising the

temperature of the reaction from −78 °C to −10 °C (entries

2 and 3). This effect was not observed with the use of

catecholborane (entries 4 and 5). To the best of our knowledge,

this temperature-dependent reversal of selectivity in the CBS

reduction has not previously been reported and we can offer no

explanation at this time. After extensive investigation, the

enantioselectivity of the reduction could not be increased

above 82% ee when the reaction was carried out in THF. It has

recently been reported that the enantioselectivity of CBS

reductions of allenyl and alkynyl ketones can be enhanced by

the use of nitroethane as solvent.¹⁵Pleasingly, reduction of 9

with (R)-Me-CBS and catecholborane at −78 °C in nitroethane

resulted in an increase in enantioselectivity to 99% ee (entry 6).

The absolute stereochemistry of the chiral reduction was

determined by conversion to the formal synthesis target 4 (vide

infra). The selectivity displayed by the Me-CBS catalyst (with

the exception of entry 3) is the opposite to that predicted on

the basis of existing chemical literature.¹⁶In this case, the

−CH₂Ar and alkynyl substituents are acting as the small and

Selective saponification of the aliphatic methyl ester was

accomplished by treatment of 15 with lithium hydroxide. An

EDC-mediated coupling of the resultant acid with N,O-

dimethylhydroxylamine hydrochloride afforded the Weinreb

amide 16. Incorporation of the alkynyl chain proved problem-

atic, with low levels of conversion observed at reduced

temperatures and significant degradation resulting from use of

extended reaction times. However, the addition of 4 equiv of

1-pentynylmagnesium bromide to amide 16 at room temperature

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Table 1. Chiral Reduction of Ketone 9

a

entry

cat. (30 mol %)

stoichiometric reductant (1.1 equiv)

temp (°C)

yield (%)

ee (%)

1

2

3

4

5

(^D)-TarB-NO₂

(R)-Me-CBS

NaBH₄

−78 to rt

−78

−10

−78

−10

25

12

67

52

75

59

28

44

BH₃·SMe₂

catecholborane

−82

72

70

b

6

catecholborane

−78

99

a

b

Reactions carried out in THF unless stated. Reaction in EtNO₂with 2 equiv of catecholborane.

large groups, respectively, for the purposes of stereochemical

prediction. The same selectivity has previously been reported

with ketones bearing a −CH₂Ar group.¹⁷

could be obtained. The reason for this disappointing result may

well be due to the fact that a propionyl ephedrine-enolate was

used in the present work, whereas the literature precedent

involved the use of ephedrine-enolates bearing an aryl

substituent.¹⁸An alternative approach to phosphonate 6 was

thus necessitated.

Second-Generation Approach to Phosphonate 6. Our

second-generation retrosynthetic approach to phosphonate 6 is

outlined in Scheme 4. Phosphonate 6 could be obtained by

First-Generation Approach to Phosphonate 6. With a

route to lactone 17 established, the synthesis of phosphonate 6

from lactone 10 was next investigated. A viable synthesis of

lactone 10 was thus required. Pseudoephedrine acetamide

enolates have been shown to undergo syn-selective Michael

addition to a number of α,β-unsaturated esters in the presence

of lithium chloride.¹⁸Pseudoephedrine derivative 13¹⁹was

therefore treated with LiHMDS and lithium chloride, and the

resulting enolate was reacted with Michael acceptor 12 to

afford 11 as an inseparable mixture of rotameric diastereo-

isomers (Scheme 3). To aid analysis of the Michael addition,

Scheme 4. Second-Generation Retrosynthesis of

Phosphonate 6

Scheme 3. Synthesis of Lactone 10

displacement of the chiral auxiliary in 20 with lithiated dimethyl

methylphosphonate. In turn, 20 could be accessed by

manipulation of the allyl chain and selective methylation of

compound 21. The allyl group could be introduced by

conjugate addition to an α,β-unsaturated acyl derivative bearing

the appropriate chiral auxiliary 22.

The preparation of phosphonate 6 initially focused on

conjugate addition of an allyl group to known α,β-unsaturated

N-acyl oxazolidinones 23a−c.²⁰Despite extensive screening of

reaction conditions, cuprate addition of an allyl group

(allylmagnesium bromide, CuBr·SMe₂) was unsuccessful.

Additions without a Lewis acid returned unreacted starting

material, whereas the use of TMSCl or BF₃·OEt₂resulted in

complex mixtures. Attention next turned to the Lewis acid

mediated conjugate addition of allyltrimethylsilane to 23a

(Table 2). Use of BF₃·OEt₂and SnCl₄as Lewis acids returned

unreacted starting material (entries 1 and 2). Use of TiCl₄

(2 equiv) resulted in adduct 24a being isolated in 43% yield,

but with considerable formation of byproduct (entry 3).

Decreasing the amount of TiCl₄resulted in a cleaner

conversion to 24a, albeit in lower yield (entry 4), while 4

adduct 11 was reduced with DIBALH to afford alcohol 18,

which was treated with Amberlyst 15 (R) to promote cyclization.

This procedure resulted in a separable 10:1 mixture of lactones

10 and 19. The relative stereochemistry of the lactone products

was established by analysis of NOE interactions. Chiral HPLC

analysis revealed that the undesired trans lactone 19 was

produced in 96% ee, whereas cis lactone 10 was formed in only

46% ee. After extensive screening of reaction conditions, no

improvement in the enantioselectivity of the Michael addition

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Table 2. Conjugate Addition to α,β-Unsaturated N-Acyl

Oxazolidinones 23a−c

Scheme 5. Literature Precedent for Syn α-Methylation of

β-Substituted N-Acyl Oxazolidinones²⁴

entry

R

Lewis acid

solvent

yield (%)

1

2

3

Ph

Bn

iPr

BF₃·OEt₂

SnCl₄

TiCl₄

CH₂Cl₂

Et₂O

0

43

32

19

0

a

4

b

5

6

7

8

9

MeCN

THF

0

Table 3. Alkylation of N-Acyl Oxazolidinones 24a−c

0

PhMe

0

c

10

CH₂Cl₂

76

24

39

c

11

c

12

a

b

c

1.1 equiv of TiCl₄. 4 equiv of TiCl₄. With allyltributylstannane.

equiv of TiCl₄significantly increased the formation of

byproduct (entry 5). No reaction was observed when other

solvents were used (entries 6−9). The byproducts could not

be isolated but appeared to be the result of benzyl ether

cleavage. We postulated that the trimethylsilyl cation formed

during the conjugate addition could in some way be responsible

for the observed cleavage. To test this hypothesis, the conjugate

addition was repeated using allyltributylstannane. Pleasingly,

adduct 24a formed cleanly and was isolated in 76% yield (entry

10). Conjugate addition of allyltributylstannane to the benzyl

(23b) and isopropyl (23c) oxazolidinones proceeded in lower

yields (entries 11 and 12). The conjugate additions all took

place with excellent selectivity, affording 24a−c as a single

diastereoisomer. The observed facial selectivity was opposite to

that obtained from the corresponding cuprate additions and

was in agreement with that observed for Lewis acid promoted

allylations of similar substrates.^21,22

temp of enolate conversn

dr

entry

R

base

additive formation (°C)

(%)

(anti:syn)

1

2

3

4

5

6

7

Ph LiHMDS

Ph NaHMDS

Bn LiHMDS

iPr LiHMDS

−78

−25

0

LiCl

0

a

LiCl

80 (47)

5:1

6:1

4:1

30

20

50

a

Isolated yield in parentheses.

NaHMDS as base resulted in similar levels of diastereocontrol

with a lower degree of conversion (entry 5). The benzyl and

isopropyl oxazolidinones 24b,c provided 31b,c as a 4:1 mixture

of anti and syn diastereoisomers (entries 6 and 7). It appears

that, in this system, the stereochemistry of the oxazolidinone

directs the facial selectivity of the alkylation.

With allyl adduct 24 in hand, attention next focused on its

α-methylation to provide a precursor to phosphonate 6. Our

proposal for the introduction of an α-methyl group to 24 is

based on a number of literature precedents where alkylation α

to a carbonyl group has been shown to be directed by an

existing chiral center at the β position.²³⁻²⁵For example,

The facial selectivity of the alkylation was determined by

conversion of 31 to cyclic phosphonate 34 (Scheme 6). The

Scheme 6. Stereochemical Proof by Conversion to

Phosphonate 34

́

Fernandez-Zertuche et al. have shown that alkylation of N-acyl

oxazolidinones 25 and 27 proceeded with high diastereocontrol

to afford the syn product, regardless of the chirality of the

auxiliary (Scheme 5).²⁴They rationalized this observation by

the formation of enolate conformers 29 and 30 that minimize

1,3-allylic strain. They argue that the R group provides the

overriding steric influence, directing the methyl group to add

from the opposite face.

Alkylation of 24a was attempted by enolate formation with

LiHMDS in THF for 1 h followed by reaction with methyl

iodide at −25 °C (Table 3). No reaction was observed with

enolate formation at −78 °C, and reaction only occurred by

generating the enolate with lithium chloride (4 equiv) at −25 °C

to afford 31a as a 5:1 mixture of diastereoisomers with the

undesired anti isomer dominating (entries 1−4). Use of

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chiral auxiliary was cleaved by treatment with lithium peroxide

and the resulting carboxylic acid converted to Weinreb amide

32 by HATU-mediated coupling with N,O-dimethylhydroxyl-

amine hydrochloride. Addition of lithiated dimethyl methyl-

phosphonate to 32 afforded 33. Oxidative cleavage of the

terminal olefin with osmium tetroxide and sodium periodate

afforded an aldehyde, which underwent in situ intramolecular

Horner−Wadsworth−Emmons reaction to provide cyclic

phosphonate 34. The trans relationship of the substituents at

C-4 and C-5 was confirmed by the magnitude of the vicinal

coupling constant (J₄₋₅= 11.0 Hz), which was considerably

larger than the corresponding coupling constant for the cis

isomer (J₄₋₅= 4.2 Hz) that had previously been prepared by

our group.²⁶

Table 4. Alkylation of Esters 37a−c

entry substrate

base

solvent conversn (%) dr (syn:anti)

1

2

3

4

5

6

7

8

9

37a

37b

37c

NaHMDS

LiHMDS

KHMDS

THF

PhMe

Et₂O

DME

THF

40

20

50

33

50

30

25

33

81

31

1.3:1

1:2

α-Alkylation to esters has also been shown to be directed by

a β-chiral center. McGarvey and Williams²⁵showed that

reaction of lithium enolate 35 with methyl iodide resulted in a

89:11 mixture of products 36 in favor of the syn diaste-

reoisomer (Scheme 7). They postulate that this outcome is a

NaHMDS

1:1.3

1.2:1

1.3:1

1.5:1

1:1

a

b

c

Scheme 7. Literature Precedent for Syn α-Methylation of

β-Substituted Esters²⁵

d

10

11

NaHMDS

1:4

a

b

c

Reaction at −20 °C. With 4 equiv of LiCl. With 4 equiv of DMPU.

d

With Me₂SO₄as electrophile.

the difference in the chelating abilities of the bulky silyloxy

group used in the present work compared to the substrates

upon which this work is drawn that bear a benzyloxy group.

The relative stereochemistry of products originating from

allyl compound 38a were determined by comparison of the ¹H

NMR resonances with the methyl ester derived from 31. The

stereochemistry of products originating from acetal 37c were

determined by conversion to a compound previously prepared

in our group by addition of dimethyl methylphosphonate.²⁶

The mixture of diastereoisomers obtained from all three

substrates 37a−c were inseparable by chromatography. The

corresponding β-ketophosphonates derived by addition of

lithiated dimethyl methylphosphonate to the alkylation

products were also found to be inseparable.

result of the electrophile approaching the enolate antiperiplanar

to the substituent on the β carbon, thereby providing greater

stabilization of the transition state through hyperconjugation.

In the present work, this β substituent is the −CH₂OBn group,

where the oxygen lone pair can interact with the π system as

shown (inset 1, Scheme 7). This leads to two possible con-

formations, as illustrated by Newman projections along the

C2−C3 bond (inset 2, Scheme 7). Conformer A exhibits

greater steric clashes so that conformer B is favored, leading to

the observed syn methylation.

We proposed that this effect could be extended to our system

to allow access to the desired syn arrangement between the allyl

and methyl groups. To test this hypothesis, methyl esters 37a−c

were prepared from Michael adduct 24a.²⁶The esters 37a−c

were treated with base at −78 °C for 30 min to effect enolate

formation and then reacted with an electrophile at −78 °C for

2 h (Table 4). Diastereoselectivities of 1.3:1 in favor of the

desired syn isomer were observed with ester 37a, independent

of the metal counterion employed (entries 1−3). The choice of

solvent had a profound effect on the reaction, with THF and

DME favoring the syn product and toluene and Et₂O favoring

the anti product (entries 1−6). The use of lithium chloride and

DMPU as additives had a negligible effect on the reaction

(entries 7 and 8). Employing dimethyl sulfate led to a slightly

higher level of diastereocontrol than with methyl iodide

(entries 1 and 9). Alkylation of silyl ether 37b afforded a 1:1

mixture of diastereoisomers, while the use of acetal 37c resulted

in a 4:1 mixture in favor of the anti isomer (entries 10 and 11).

The stereochemical outcome of this alkylation may be due to

Third-Generation Approach to Phosphonate 6. The

lack of stereochemical control in the above alkylation reactions

and the coelution of the products by chromatography resulted in

a third route to phosphonate 6 being investigated (Scheme 8).

Scheme 8. Third-Generation Retrosynthesis of Phosphonate 6

Phosphonate 6 could be accessed by ring opening of lactone 39

with dimethyl methylphosphonate. In this route, the methyl

group would be introduced by alkylation of lactone 40, which

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should proceed with high trans selectivity.²⁷Cleavage of the

acetate and oxazolidinone moieties of 41 should provide lactone

40. Finally, silyl ether 41 could be obtained by allylation of α,β-

unsaturated N-acyl oxazolidinone 42, followed by appropriate

functional group manipulation.

The third-generation synthesis of phosphonate 6 commenced

with Horner−Wadsworth−Emmons coupling of the known

phosphonate 43²⁸with aldehyde 44²⁹under Masamune−Roush

conditions³⁰(Scheme 9). TiCl₄-mediated allylation of 42 with

afforded lactol 46, which was opened by dianion formation with

excess KOtBu and trapping as the TBS ether 47 with TBSCl.³²

Attempts to form the analogous benzyl-protected compound 6

were unsuccessful.

Attempted Horner−Wadsworth−Emmons Coupling.

With efficient routes to phosphonate 47 and lactone 17 estab-

lished, the key HWE coupling was investigated (Scheme 10).

Scheme 10. Attempted HWE Coupling

Scheme 9. Synthesis of Phosphonate 47

Lactone 17 was reduced to lactol 7 with DIBALH at −78 °C,

with careful monitoring of the reaction to avoid over-reduction.

The HWE was carried out by deprotonation of lactol 7 followed

by addition of phosphonate 47. Disappointingly, none of the

conditions screened (NaH, THF; K₂CO₃, Et₂O/H₂O; DBU, LiCl,

MeCN, or THF; KOtBu, THF) resulted in any of the desired

product 48 being isolated. We postulate that the lack of reactivity

in this case can be attributed to the lactol−hydroxyaldehyde

equilibrium favoring the unreactive ring-closed form.

Silyl Enol Ether−Oxonium Ion Coupling Strategy. Faced

with this lack of reactivity, we proposed that the two fragments

could be unified by a coupling of a silyl enol ether with an

oxonium ion derived from lactol 7. We therefore prepared silyl

enol ether 51 by addition of methyllithium to lactone 39 to

afford lactol 49, which was opened and trapped as the TBS

ether 50 by treatment with KOtBu and TBSCl (Scheme 11).

Silyl enol ether formation proceeded smoothly by treatment of

Scheme 11. Synthesis of Silyl Enol Ether 51

allyltributylstannane proceeded smoothly to afford 45 as a single

diastereoisomer. The allyl moiety was converted into the TBDPS-

protected alcohol 41 by oxidative cleavage with OsO₄and NaIO₄

in the presence of 2,6-lutidine,³¹reduction of the resulting

aldehyde, and silyl ether formation. It was necessary to perform

the TBDPS protection at concentrations of >0.4 M to avoid

lactonization. The chiral auxiliary and acetate groups were next

cleaved in one pot by reaction with lithium peroxide. The

resulting hydroxyacid underwent lactonization spontaneously, but

the rate of cyclization was significantly enhanced by treatment

with PTSA. Methylation of lactone 40 with NaHMDS and

methyl iodide at −78 °C proceeded with high diastereoselectivity

to afford 39. Lactone 39 has been prepared previously by Snider

and co-workers by conjugate addition of a chiral phosphonamide

anion to 2-butenolide.⁴Comparison of the optical rotation

confirmed the facial selectivity of the conjugate addition to 42.

Addition of lithiated dimethyl methylphosphonate to lactone 39

methyl ketone 50 with TMSOTf and Hunig’s base to afford 51,

which was used without further purification.

Lactol 7 was treated with BF₃·OEt₂to afford oxonium ion

52, which was reacted in situ by addition of silyl enol ether 51

̈

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at −78 °C to afford a diastereomeric mixture of lactols 53

(Scheme 12). Previous studies directed toward the synthesis of

Scheme 13. Oxonium−Silyl Enol Ether Coupling with ent-7

Scheme 12. Completion of Formal Synthesis

CONCLUSIONS

■

In conclusion, a full account of our synthetic efforts culminating

in the successful completion of an enantioselective formal

synthesis of berkelic acid has been described. Our original

retrosynthetic strategy of a HWE/oxa-M cascade reaction

proved unsuccessful, due to poor reactivity of the lactol

coupling partner. This problem was overcome by the use of a

silyl enol ether−oxonium ion coupling to unite the two

fragments. Subsequent one-pot debenzylation, spiroketaliza-

tion, and thermodynamic equilibration resulted in the

formation of the desired spiroketal diastereoisomer. Other

highlights from these synthetic studies include an unusual

selectivity being observed in the CBS reduction of ketone 9,

which also displayed a temperature-dependent reversal of

selectivity using BH₃·SMe₂as the stoichiometric reductant. The

introduction of the methyl substituent on the phosphonate/

silyl enol ether fragment proceeded with incorrect facial

selectivity using acyclic substrates; hence, α-methylation of

lactone 40 was used to obtain the correct stereochemistry. This

route to Snider’s advanced berkelic acid intermediate 4 is highly

scalable and can be readily applied to the synthesis of analogues

by simple reaction of any benzannulated lactols with a range of

silyl enol ethers.

berkelic acid have demonstrated that, upon formation of the

spiroketal moiety, the C-15 and C-17 stereocenters can be

converted to the correct spiroketal configuration by acid-

catalyzed equilibration. The mixture of lactol diastereoisomers

53 was therefore subjected to hydrogenolysis over Pd/C in

the presence of HCl. Under these conditions, debenzylation,

spiroketalization, and thermodynamic equilibration occurred

in one pot to afford spiroketal 54 as a single diastereoisomer

in 58% yield from methyl ketone 50 after purification by

chromatography. To confirm that spiroketal 54 was indeed the

most thermodynamically favored isomer, it was treated with

1

TFA in CDCl₃and the mixture monitored by H NMR over a

period of 3 days. After this period of time, no change in the ¹H

NMR spectrum was observed, suggesting that 54 represents the

most thermodynamically favored diastereoisomer and therefore

contains the same configuration as the natural product. The

formal synthesis of berkelic acid was completed by reaction of

54 with allyl bromide and K₂CO₃to afford 4, whose spectro-

scopic data and optical rotation matched those previously

reported.⁴

EXPERIMENTAL SECTION

■

General Methods. Unless stated, all solvents and reagents were

used as supplied from commercial sources. Tetrahydrofuran was

freshly distilled over sodium. Dichloromethane and diisopropylethyl-

amine were freshly distilled over calcium hydride. Lithium chloride was

dried for >24 h in an oven (110 °C) prior to use. Analytical thin-layer

chromatography (TLC) was performed using Kieselgel F254 0.2 mm

(Merck) silica plates with visualization by ultraviolet irradiation (254

nm) followed by staining with potassium permanganate or vanillin.

Flash chromatography was performed using Kieselgel S 63−100 μm

(Riedel-de-Hahn) silica gel. NMR spectra were recorded at the

frequencies stated. Chemical shifts were referenced to δ 7.26 and 77.0

To confirm unambiguously that we had prepared the correct

spiroketal, and therefore to prove the absolute stereochemistry

of the CBS reduction of ketone 9 (Table 1), we prepared the

opposite enantiomer of lactol 7 by performing the CBS reduc-

tion with (S)-Me-CBS. Treatment of ent-7 with BF₃·OEt₂followed

by silyl enol ether 51 afforded a mixture of lactols 55 (Scheme 13).

The debenzylation−spiroketalization−thermodynamic equilibration

procedure afforded spiroketal 56 as an inseparable 2:1 mixture of

diastereoisomers. Treatment with TFA in CDCl₃resulted in the

mixture slowly equilibrating to a 1:1.5 mixture of the two isomers

after 2 days. This suggests that the two isomers of spiroketal

56 are close in energy and that 56 does not display the same

configuration as the natural product.

1

ppm from chloroform for H and ¹³C, respectively. The multiplicities

of ¹H signals are designated by the following abbreviations: s = singlet;

d = doublet; t = triplet; q = quartet; m = multiplet; br = broad. All

coupling constants J = are reported in hertz. All ¹³C NMR spectra

were acquired using broadband decoupled mode, and assignments

were determined using DEPT sequences. Mass spectra were obtained

by electrospray ionization in positive ion mode. High-performance

liquid chromatography (HPLC) was performed using an analytical

0.46 × 25 cm column with a guard column attached using the

conditions outlined in the relevant experimental procedure.

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The Journal of Organic Chemistry

Article

1-Benzyl 3-Methyl 2,6-Bis(benzyloxy)-4-(2-methoxy-2-

oxoethyl)isophthalate (15). Benzyl bromide (17.1 mL, 144

mmol) was added to a solution of acid 14¹¹(8.17 g, 28.7 mmol)

and potassium carbonate (11.9 g, 86.1 mmol) in acetone (600 mL) at

room temperature under argon. The mixture was heated at reflux for

19 h and then cooled, the solvent removed in vacuo, water (400 mL)

added, and the reaction mixture extracted with ethyl acetate. The

combined organics were dried (MgSO₄) and concentrated in vacuo to

afford a colorless oil. The crude product was purified by

chromatography (silica gel, 3/2 hexanes/ethyl acetate) to afford the

title compound 15 (10.4 g, 65%) as a colorless solid: mp 58.5−59.0 °C;

ν_max(film)/cm⁻¹2953, 1724, 1600, 1295, 1197, 1098, 694; δ_H(400

MHz, CDCl₃) 7.40−7.22 (15H, m), 6.75 (1H, s), 5.30 (2H, s), 5.13

(2H, s), 5.07 (2H, s), 3.79 (3H, s), 3.75 (2H, s), 3.69 (3H, s); δ_C(100

MHz; CDCl₃) 170.5 (C), 166.8 (C), 165.1 (C), 157.2 (C), 155.5 (C),

136.7 (C), 136.6 (C), 135.6 (C), 135.2 (C), 128.4 (CH), 128.3 (CH),

128.2 (CH), 128.0 (CH), 127.9 (CH), 127.8 (CH), 127.6 (CH),

127.0 (CH), 121.0 (C), 118.5 (C), 110.8 (CH), 77.9 (CH₂), 70.5

(CH₂), 67.2 (CH₂), 52.1 (CH₃), 52.0 (CH₃), 39.5 (CH₂); m/z (ESI+)

577 (MNa⁺, 100%); m/z (ESI+) found [M + Na]⁺577.1844, calcd for

solution of pentynylmagnesium bromide was cooled to room

temperature, and a solution of amide 16 (5.52 g, 9.5 mmol) in

tetrahydrofuran (50 mL) was added. The reaction mixture was stirred

at room temperature for 2 min before cooling to 0 °C and addition of

saturated ammonium chloride (100 mL). The reaction mixture was

warmed to room temperature, diluted with water (100 mL), and

extracted with ethyl acetate. The combined organics were washed with

brine, dried (MgSO₄), and concentrated in vacuo to afford a yellow oil.

The crude product was purified by chromatography (silica gel, 4/1

hexanes/ethyl acetate) to afford the title compound 9 (4.92 g, 88%) as

a pale yellow solid: mp 71.0−71.7 °C; ν_max(film)/cm⁻¹2963, 2211,

1722, 1671, 1599, 1301, 1254, 1208, 1179, 1100, 913, 735, 693; δ_H

(400 MHz, CDCl₃) 7.38−7.18 (15H, m), 6.64 (1H, s), 5.25 (2H, s),

5.10 (2H, s), 5.01 (2H, s), 3.90 (2H, s), 3.75 (3H, s), 2.27 (2H, t, J =

7.0), 1.55−1.50 (2H, m), 0.94 (3H, t, J = 7.4); δ_C(100 MHz; CDCl₃)

183.4 (C), 166.8 (C), 165.2 (C), 157.4 (C), 155.8 (C), 136.7 (C),

136.4 (C), 135.7 (C), 135.3 (C), 128.2 (CH), 128.1 (CH), 128.0

(CH), 127.9 (CH), 127.8 (CH), 127.73 (CH), 127.67 (CH), 127.5

(CH), 126.9 (CH), 121.3 (C), 118.9 (C), 111.2 (CH), 96.4 (C), 80.5

(C), 78.1 (CH₂), 70.7 (CH₂), 67.3 (CH₂), 52.2 (CH₃), 50.3 (CH₂),

21.1 (CH₂), 20.9 (CH₂), 13.4 (CH₃); m/z (ESI+) 591 (MH⁺, 80%),

559 ([M − HOCH₃]H⁺, 100); m/z (ESI+) found [M + H]⁺591.2386,

+

C₃₃H₃₀NaO₈577.1833.

1-Benzyl 3-Methyl 2,6-Bis(benzyloxy)-4-(2-(methoxy-

(methyl)amino)-2-oxoethyl)isophthalate (16). Lithium hydroxide

hydrate (1.30 g, 30.6 mmol) was added to a solution of isophthalate 15

(8.50 g, 15.3 mmol) in water (150 mL) and tetrahydrofuran (150 mL)

at 0 °C. The reaction mixture was warmed to room temperature and stirred

for 24 h and then concentrated in vacuo to remove the tetrahydrofuran and

the resulting aqueous solution acidified with 2 M hydrochloric acid and

extracted with ethyl acetate. The combined organics were washed with

water and brine, dried (Na₂SO₄), and concentrated in vacuo to afford

2-(3,5-bis(benzyloxy)-4-(benzyloxycarbonyl)-2-(methoxycarbonyl)-

phenyl)acetic acid (8.27 g, 100%) as a colorless solid: mp <30 °C;

ν_max(film)/cm⁻¹3065, 2951, 1716, 1600, 1300, 1199, 1097, 733,

696; δ_H(400 MHz, CDCl₃) 7.40−7.21 (15H, m), 6.75 (1H, s), 5.28

(2H, s), 5.13 (2H, s), 5.02 (2H, s), 3.77 (3H, s), 3.75 (2H, s); δ_C

(100 MHz; CDCl₃) 175.1 (C), 167.4 (C), 165.1 (C), 157.6 (C),

155.9 (C), 136.6 (C), 136.5 (C), 135.6 (C), 135.2 (C), 128.6 (CH),

128.4 (CH), 128.3 (CH), 128.3 (CH), 128.2 (CH), 128.1 (CH),

128.0 (CH), 127.8 (CH), 127.2 (CH), 120.6 (C), 119.0 (C), 111.1

(CH), 78.1 (CH₂), 70.7 (CH₂), 67.4 (CH₂), 52.5 (CH₃), 14.0 (CH₂);

m/z (ESI+) 563 (MNa⁺, 100%); m/z (ESI+) found [M + Na]⁺

563.1683, calcd for C₃₂H₂₈NaO₈⁺563.1676.

+

calcd for C₃₇H₃₅O₇591.2377.

(R)-Benzyl 6,8-Bis(benzyloxy)-1-oxo-3-pentylisochroman-7-

carboxylate ((R)-17). (R)-Me-CBS (0.10 mL, 1 M in tetrahydrofur-

an, 0.1 mmol) was added to ketone 9 (0.20 g, 0.3 mmol) and the

solvent removed in vacuo. The resulting mixture of solids was placed

under an atmosphere of argon, taken up in nitroethane (1 mL), and

cooled to −78 °C. A solution of catecholborane (72 μL, 0.68 mmol) in

nitroethane (0.5 mL) was added dropwise over 10 min. After 1.3 h at

−78 °C, methanol (0.1 mL) was added and the reaction mixture

warmed to room temperature. Ethyl acetate (20 mL) was added and

the mixture washed with a 2:1 mixture of 1 M sodium hydroxide and

saturated aqueous sodium hydrogen carbonate until the aqueous

layer remained colorless. The organic layer was washed further

with brine, dried (MgSO₄), and concentrated in vacuo. The re-

sultant oil was dissolved in ethyl acetate (5 mL), and platinum

dioxide (15 mg, 0.066 mmol) was added. The reaction mixture was

placed under an atmosphere of hydrogen and stirred at room

temperature for 3 h and then filtered through a pad of silica with

ethyl acetate washings. The solvent was removed in vacuo and the

resultant oil dissolved in dichloromethane (5 mL). Amberlyst 15

(200 mg) was added and the reaction mixture stirred at room

temperature for 13 h. The resin was filtered with dichloromethane

washings, and the filtrate was concentrated in vacuo. The resultant

oil was purified by chromatography (silica gel, 3/2 hexanes/ethyl

acetate) to afford the title compound (R)-17 (110 mg, 59%, 99% ee)

Triethylamine (0.36 mL, 2.6 mmol) was added to a solution of the

above acid (1.07 g, 2.0 mmol), N,O-dimethylhydroxylamine hydro-

chloride (0.25 g, 2.6 mmol), 4-dimethylaminopyridine (0.26 g, 2.8

mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-

chloride (0.47 g, 2.5 mmol) in dichloromethane (12 mL) under argon.

The resulting mixture was stirred at room temperature for 3 h and

then washed successively with 1 M hydrochloric acid, brine, saturated

aqueous sodium hydrogen carbonate, and brine. The organic layer was

dried (MgSO₄) and concentrated in vacuo to afford a yellow oil. The

crude product was purified by chromatography (silica gel, 2/3

hexanes/ethyl acetate) to afford the title compound 16 (1.00 g,

20

as a colorless solid: mp 120.5−121.0 °C; [α]_D= −45.7° (c 0.10,

CH₂Cl₂); ν_max(film)/cm⁻¹2931, 1725, 1709, 1601, 1330, 1231, 1188,

1104, 729, 697; δ_H(400 MHz, CDCl₃) 7.48−7.16 (15H, m), 6.56

(1H, s), 5.28−5.11 (6H, m), 4.35−4.26 (1H, m), 3.14−2.74 (2H, m),

2.15−1.25 (8H, m), 0.97−0.85 (3H, m); δ_C(100 MHz; CDCl₃) 165.1

(C), 161.8 (C), 159.5 (C), 159.3 (C), 144.6 (C), 136.7 (C), 135.43

(C), 135.37 (C), 128.8 (CH), 128.7 (CH), 128.4 (CH), 128.2 (CH),

128.1 (CH), 128.0 (CH), 127.0 (CH), 120.0 (C), 112.0 (C), 106.7

(CH), 77.43 (CH₂), 77.36 (CH), 70.6 (CH₂), 67.3 (CH₂), 34.9

(CH₂), 34.5 (CH₂), 31.5 (CH₂), 24.5 (CH₂), 22.5 (CH₂), 14.0 (CH₃);

−1

87%) as a colorless solid: mp 91.0−91.5 °C; ν_max(film)/cm 2949,

1725, 1663, 1600, 1301, 1200, 1096, 730, 696; δ_H(300 MHz, CDCl₃)

7.33−7.20 (15H, m), 6.74 (1H, s), 5.25 (2H, s), 5.11 (2H, s), 5.01

(2H, s), 3.84 (2H, s), 3.74 (3H, s), 3.57 (3H, s), 3.15 (3H, s); δ_C(100

MHz; CDCl₃) 171.0 (C), 167.1 (C), 165.3 (C), 157.1 (C), 155.4 (C),

137.7 (C), 136.8 (C), 135.9 (C), 135.3 (C), 128.5 (CH), 128.3 (CH),

128.2 (CH), 128.0 (CH), 127.92 (CH), 127.86 (CH), 127.8 (CH),

127.7 (CH), 127.1 (CH), 121.3 (C), 118.2 (C), 110.5 (CH), 77.9

(CH₂), 70.5 (CH₂), 67.2 (CH₂), 61.1 (CH₃), 52.1 (CH₃), 37.4 (CH₂),

32.2 (CH₃); m/z (ESI+) 584 (MH⁺, 2%), 552 ([M − HOCH₃]H⁺,

m/z (ESI+) 565 (MH⁺, 2%), 181 (C₁₄H ⁺, 100); m/z (ESI+)

13

+

found [M + H]⁺565.2586, calcd for C₃₆H₃₇O₆565.2585. HPLC:

column, Chiralpak AD-H; mobile phase, hexane/isopropyl alcohol

(65/35 v/v); flow rate, 0.5 mL/min; retention times, 41.8 min

(S), 46.0 min (R).

(E)-Ethyl 4-(Benzyloxy)but-2-enoate (12). Potassium carbonate

(27.3 g, 198 mmol) was added to a solution of triethyl

phosphonoacetate (19.8 mL, 99 mmol) in water (60 mL) at 0 °C.

The reaction mixture was stirred at 0 °C for 15 min, and then a

solution of 2-(benzyloxy)acetaldehyde³³(11.4 g, 76 mmol) in diethyl

ether (60 mL) was added. The biphasic mixture was stirred vigorously

at room temperature for 18 h, and then the aqueous layer was

removed and extracted with ethyl acetate. The combined organics

+

100); m/z (ESI+) found [M + H]⁺584.2284, calcd for C₃₄H₃₄NO₈

584.2279.

1-Benzyl 3-Methyl 2,6-Bis(benzyloxy)-4-(2-oxohept-3-ynyl)-

isophthalate (9). Ethylmagnesium bromide (1 M in tetrahydrofuran,

37.9 mL, 37.9 mmol) was added to pentyne (3.85 mL, 37.9 mmol) at

0 °C under argon, and the mixture was stirred at this temperature for

15 min before heating to 50 °C for a further 2.5 h. The resulting

407

dx.doi.org/10.1021/jo201988m | J. Org. Chem. 2012, 77, 400−416

The Journal of Organic Chemistry

Article

were washed with brine, dried (MgSO₄), and concentrated in vacuo to

afford a yellow oil. The crude product was purified by chromatography

(silica gel, 4/1 hexanes/ethyl acetate) to afford the title compound 12

(6.9 g, 33.5 mmol, 44%) as a colorless oil: δ_H(400 MHz, CDCl₃)

7.36−7.27 (5H, m), 6.99 (1H, dt, J = 15.5, 4.5), 6.14 (1H, dt, J = 15.5,

2.1), 4.56 (2H, s), 4.21 (2H, q, J = 7.2), 4.18−4.16 (2H, m), 1.29 (3H, t,

J = 7.2). The ¹H NMR data closely matched those previously reported.³⁴

(3S,4S)-4-(Benzyloxymethyl)-3-methyltetrahydro-2H-pyran-

2-one (10). LiHMDS (1 M in tetrahydrofuran, 29.0 mL, 29.0 mmol)

was added to a solution of amide 13¹⁹(3.21 g, 14.7 mmol) and lithium

chloride (4.32 g, 101.9 mmol) in tetrahydrofuran (30 mL) at 0 °C

under argon. The reaction mixture was stirred at 0 °C for 30 min

before cooling to −20 °C. α,β-Unsaturated ester 12 (3.00 g, 14.7

mmol) was added and the reaction mixture stirred at −20 °C for

13.5 h. Methanol (6 mL) and saturated aqueous ammonium chloride

(60 mL) were added, and then the reaction mixture was warmed to room

temperature and extracted with ethyl acetate. The combined organics

were washed with water and brine, dried (MgSO₄), and concentrated

in vacuo. The resultant crude oil was partially purified by

chromatography (silica gel, 2/3 hexanes/ethyl acetate) to afford a

yellow oil (4.02 g). This oil was dissolved in dichloromethane (20 mL)

and cooled to −78 °C. DIBALH (1 M in dichloromethane, 36.4 mL,

36.4 mmol) was added and the reaction mixture stirred at −78 °C for

1 h then at 0 °C for a further 1 h. Saturated aqueous Rochelle’s salt (50

mL) was added and the reaction mixture stirred at room temperature

for 15 min before extracting with dichloromethane. The combined

organics were washed with brine, dried (MgSO₄), and concentrated in

vacuo. The resulting oil was dissolved in dichloromethane (40 mL)

and Amberlyst 15 (1.00 g) added. The reaction mixture was heated at

reflux for 10 days without stirring. The resin was filtered, washed with

dichloromethane, and concentrated in vacuo to afford an oil which was

purified by chromatography (silica gel, 1/1 hexanes/ethyl acetate) to

afford the title compound 10 (390 mg, 11%, 46% ee) as a colorless oil

and the (3R,4S) isomer 19 (47 mg, 1%, 96% ee) as a colorless oil. 10:

[α]_D²³= +22.3° (c 0.10, CH₂Cl₂); ν_max(film)/cm⁻¹2975, 1734, 1559,

1457, 1387, 1113, 738, 698, 668; δ_H(400 MHz, CDCl₃) 7.36−7.26

(5H, m), 4.49 (2H, s), 4.42−4.22 (2H, m), 3.46−3.39 (2H, m), 2.80−

2.73 (1H, m), 2.43−2.35 (1H, m), 2.05−1.90 (2H, m), 1.21 (3H, d,

J = 7.0); δ_C(100 MHz; CDCl₃) 175.1 (C), 137.9 (C), 128.4 (CH),

127.6 (CH), 127.85 (CH), 73.3 (CH₂), 70.0 (CH₂), 66.7 (CH₂), 36.1

(CH), 35.3 (CH), 25.4 (CH₂), 12.4 (CH₃); m/z (ESI+) 235 (MH⁺,

3%), 91 (C₆H₅CH⁺, 100); m/z (ESI+) found [M + H]⁺235.1322,

(R)-3-((S)-3-((Benzyloxy)methyl)hex-5-enoyl)-4-phenyloxazolidin-

2-one (24a). Following general procedure A, reaction with

oxazolidinone 23a²⁰(1.0 g, 2.8 mmol) provided the title compound

24a (810 mg, 76%) as a colorless oil: [α]_D= −47.6° (c 0.70,

20

CHCl₃); ν_max(film)/cm⁻¹3032, 2865, 1777, 1703, 1383, 1195; δ_H

(400 MHz, CDCl₃) 7.36−7.23 (10H, m), 5.78−5.68 (1H, m), 5.27

(1H, dd, J = 9.0, 4.0), 5.02−5.00 (1H, m), 4.97 (1H, br s), 4.51 (1H,

dd, J = 9.0, 9.0), 4.39 (2H, s), 4.18 (1H, dd, J = 9.0, 4.0), 3.41 (1H, dd,

J = 9.0, 5.0), 3.33 (1H, dd, J = 9.0, 6.5), 3.03 (1H, dd, J = 16.5, 6.5),

2.96 (1H, dd, J = 16.5, 7.0), 2.40−2.33 (1H, m), 2.20−2.04 (2H, m);

δ_C(100 MHz, CDCl₃) 172.1 (C), 153.7 (C), 139.2 (C), 138.6 (C),

136.1 (CH), 129.1 (CH), 128.6 (CH), 128.3 (CH), 127.6 (CH),

127.5 (CH), 125.9 (CH), 116.9 (CH₂), 72.9 (CH₂), 72.4 (CH₂), 69.9

(CH₂), 57.7 (CH), 37.5 (CH₂), 35.8 (CH₂), 34.9 (CH); m/z (ESI+)

402 (MNa⁺, 100%), 380 (MH⁺, 8), 272 ([M − BnOH]H⁺, 66); m/z

(ESI+) found [M + Na]⁺402.1675, calcd for C₂₃H₂₅NO₄Na⁺

402.1676.

(R)-4-Benzyl-3-((S)-3-((benzyloxy)methyl)hex-5-enoyl)oxazolidin-

2-one (24b). Following general procedure A, reaction with

oxazolidinone 23b²⁰(220 mg, 0.63 mmol) provided the title

20

compound 24b (60 mg, 24%) as a colorless oil: [α]_D= −44.6°

(c 0.70, CHCl₃); ν_max(film)/cm⁻¹2971, 2902, 1777, 1698, 1384,

1205, 1058; δ_H(400 MHz, CDCl₃) 7.33−7.23 (8H, m), 7.17−7.14

(2H, m), 5.84−5.74 (1H, m), 5.10−5.02 (2H, m), 4.55−4.44 (3H, m),

4.07−4.00 (2H, m), 3.53 (1H, dd, J = 9.0, 5.0), 3.42 (1H, dd, J = 9.0,

7.0), 3.22 (1H, dd, J = 13.5, 3.5), 3.06 (1H, dd, J = 16.5, 7.5), 2.94

(1H, dd, J = 16.5, 6.0), 2.56−2.45 (2H, m), 2.27−2.11 (2H); δ_C(100

MHz, CDCl₃) 172.5 (C), 153.5 (C), 138.5 (C), 136.1 (CH), 135.5

(C), 129.4 (CH), 128.9 (CH), 128.3 (CH), 127.8 (CH), 127.6 (CH),

127.2 (CH), 117.0 (CH₂), 73.2 (CH₂), 72.9 (CH₂), 66.1 (CH₂), 55.3

(CH), 37.7 (CH₂), 37.5 (CH₂), 36.1 (CH₂), 35.0 (CH); m/z (ESI+)

432 (MK⁺, 17%), 416 (MNa⁺, 100); m/z (ESI+) found [M + Na]⁺

416.1827, calcd for C₂₄H₂₇NO₄Na⁺416.1832.

(R)-3-((S)-3-((Benzyloxy)methyl)hex-5-enoyl)-4-isopropyloxazoli-

din-2-one (24c). Following general procedure A, reaction with

oxazolidinone 23c²⁰(190 mg, 0.63 mmol) provided the title

20

compound 24c (84 mg, 39%) as a colorless oil: [α]_D= −48.1°

(c 0.70, CHCl₃); ν_max(film)/cm⁻¹2971, 2922, 1778, 1697, 1383,

1195, 1078, 698; δ_H(400 MHz, CDCl₃) 7.33−7.26 (5H, m), 5.82−

5.72 (1H, m), 5.07−5.00 (2H, m), 4.49 (1H, d, J = 12.0), 4.45 (1H, d,

J = 12.0), 4.32−4.29 (1H, m), 4.15−4.08 (2H, m), 3.49 (1H, dd, J =

9.0, 5.0), 3.40 (1H, dd, J = 9.0, 7.0), 2.98 (2H, d, J = 6.8), 2.48−2.38 (1H,

m), 2.35−2.27 (1H, m), 2.25−2.08 (2H, m), 0.87 (3H, d, J = 7.0),

0.82 (3H, d, J = 7.0); δ_C(100 MHz, CDCl₃) 172.5 (C), 154.1 (C),

138.5 (C), 136.1 (CH), 128.3 (CH), 127.7 (CH), 127.5 (CH), 116.9

(CH₂), 73.0 (CH₂), 72.7 (CH₂), 63.2 (CH₂), 58.5 (CH), 37.4 (CH₂),

35.9 (CH₂), 34.9 (CH), 28.4 (CH), 18.0 (CH₃), 14.6 (CH₃); m/z

(ESI+) 368 (MNa⁺, 100%); m/z (ESI+) found [M + Na]⁺368.1840,

calcd for C₂₀H₂₇NO₄Na⁺368.1832.

+

calcd for C₁₄H₁₉O₃235.1329. HPLC: column, Chiralpak IC; mobile

phase, hexane/isopropyl alcohol (65/35 v/v); flow rate, 0.5 mL/min;

23

retention times, 33.3 min (S,S), 35.7 min (R,R). 19: [α]_D= +4.1°

(c 0.57, CH₂Cl₂); ν_max(film)/cm⁻¹2932, 1730, 1454, 1254, 1081, 737,

696; δ_H(400 MHz, CDCl₃) 7.37−7.28 (5H, m), 4.55 (1H, d, J =

12.0), 4.50 (1H, d, J = 12.0) 4.37−4.23 (2H, m), 3.54−3.46 (2H, m),

2.61−2.54 (1H, m), 2.09−1.91 (1H, m), 1.88−1.79 (2H, m), 1.25

(3H, d, J = 6.8); δ_C(75 MHz; CDCl₃) 175.4 (C), 138.0 (C), 128.5

(CH), 127.8 (CH), 127.6 (CH), 73.3 (CH₂), 71.7 (CH₂), 67.0 (CH₂),

38.3 (CH), 36.2 (CH), 26.7 (CH₂), 14.8 (CH₃); m/z (ESI+) 257

(MNa⁺, 100%); m/z (ESI+) found [M + Na]⁺257.1149, calcd for

General Procedure B: Alkylation of N-Acyl Oxazolidinones.

LiHMDS (1.0 M in tetrahydrofuran, 1.3 equiv) was added dropwise

to a solution of the oxazolidinone (1 equiv) and lithium chloride

(4 equiv) in tetrahydrofuran (0.03−0.13 M with respect to the

oxazolidinone) at −78 °C under nitrogen. The reaction mixture was

stirred at −78 °C for 10 min and then at −25 °C for 50 min. Methyl

iodide (5 equiv) was then added, and the reaction mixture was stirred

at −25 °C for a further 6 h and then quenched with saturated aqueous

ammonium chloride, warmed to room temperature, and extracted with

ethyl acetate. The combined organics were dried (Na₂SO₄) and

concentrated in vacuo to afford the crude product.

+

C₁₄H₁₈NaO₃257.1148. HPLC: column, Chiralpak IC; mobile phase,

hexane/isopropyl alcohol (65/35 v/v); flow rate, 0.5 mL/min;

retention times, 32.1 min (3S,4R), 38.9 min (3R,4S).

General Procedure A: Lewis Acid Mediated Allylation. Titanium

tetrachloride (1.0 M in dichloromethane, 2.5 equiv) was added

dropwise over 10 min to a solution of α,β-unsaturated N-acyl

oxazolidinone (1 equiv) in dichloromethane (0.07 M with respect to

the oxazolidinone) at −78 °C under nitrogen. The reaction mixture

was stirred at −78 °C for 15 min. Allyltributylstannane (2 equiv) was

then added, and the resulting deep purple mixture was stirred at −78 °C

for 3 h and then quenched with saturated aqueous ammonium chloride

and warmed to room temperature. The organic layer was removed, and

the aqueous phase was extracted with dichloromethane. The combined

organics were dried (Na₂SO₄) and concentrated in vacuo to afford the

crude product, which was purified by chromatography (silica gel, 100%

hexanes, then 2/1 hexanes/ethyl acetate).

(R)-3-((2R,3S)-3-((Benzyloxy)methyl)-2-methylhex-5-enoyl)-4-

phenyloxazolidin-2-one (31a). Following general procedure B,

reaction with oxazolidinone 24a (750 mg, 2.0 mmol) provided the

title compound 31a (370 mg, 47%) as a colorless oil after purification

21

by chromatography (silica gel, 4/1 hexanes/ethyl acetate): [α]_D

=

−81.9° (c 0.70, CHCl₃); ν_max(film)/cm⁻¹2915, 1778, 1708, 1382,

1199, 1100; δ_H(400 MHz, CDCl₃) 7.37−7.26 (8H, m), 7.19−7.16

(2H, m), 5.86−5.76 (1H, m), 5.07−5.01 (2H, m), 4.97 (1H, dd, J =

8.5, 3.0), 4.43 (1H, d, J = 11.5), 4.39 (1H, d, J = 11.5), 4.21 (1H, dd,

J = 8.5, 8.5), 4.03 (1H, dd, J = 8.5, 3.0), 3.97−3.90 (1H, m), 3.51−3.44

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(2H, m), 2.23−2.12 (3H, m), 1.05 (3H, d, J = 7.0); δ_C(100 MHz,

CDCl₃) 175.7 (C), 153.6 (C), 139.7 (C), 138.6 (C), 136.8 (CH),

129.1 (CH), 128.4 (CH), 128.3 (CH), 127.9 (CH), 127.7 (CH),

125.6 (CH), 116.5 (CH₂), 73.2 (CH₂), 69.8 (CH₂), 69.7 (CH₂), 57.9

(CH), 40.8 (CH), 38.7 (CH), 34.2 (CH₂), 12.9 (CH₃); m/z (ESI+)

416 (MNa⁺, 100%), 394 (MH⁺, 32); m/z (ESI+) found [M + H]⁺

and then a solution of amide 32 (120 mg, 0.41 mmol) in

tetrahydrofuran (2 mL) was added. The reaction mixture was stirred

for a further 4 h at −78 °C and then quenched by addition of saturated

aqueous ammonium chloride (2 mL) and extracted with ethyl acetate.

The combined organics were dried (MgSO₄) and concentrated in

vacuo to afford a colorless oil. The crude product was purified by

chromatography (silica gel, 100% ethyl acetate) to afford the title

+

394.2001, calcd for C₂₄H₂₈NO₄394.2013.

21

(R)-4-Benzyl-3-((2R,3S)-3-((benzyloxy)methyl)-2-methylhex-5-

enoyl)oxazolidin-2-one (31b). Following general procedure B,

reaction with oxazolidinone 24b (20 mg, 0.051 mmol) provided an

inseparable 4/1 mixture of diastereoisomers, which were immediately

converted to the corresponding carboxylic acid by cleavage with LiOH/

H₂O₂to determine the facial selectivity of the alkylation. The

diastereomeric ratio of the initial alkylation was determined by integration

of the CH₃group: δ_H,minor1.21 (d, J = 6.8), δ_major1.17 (d, J = 6.8).

(R)-3-((2R,3S)-3-((Benzyloxy)methyl)-2-methylhex-5-enoyl)-4-iso-

propyloxazolidin-2-one (31c). Following general procedure B,

reaction with oxazolidinone 24c (10 mg, 0.029 mmol) provided an

inseparable 4/1 mixture of diastereoisomers, which were immediately

converted to the corresponding carboxylic acid by cleavage with

LiOH/H₂O₂to determine the facial selectivity of the alkylation. The

diastereomeric ratio of the initial alkylation was determined by integration

of the CH₃group: δ_H,minor1.16 (d, J = 6.8), δ_major1.15 (d, J = 6.8).

(2R,3R)-3-((Benzyloxy)methyl)-N-methoxy-N,2-dimethylhex-5-

enamide (32). Aqueous hydrogen peroxide (30%, 280 μL, 2.5 mmol)

was added to a solution of oxazolidinone 31a (195 mg, 0.50 mmol) in

tetrahydrofuran (3 mL) and water (1 mL) at 0 °C. A solution of

lithium hydroxide (42 mg, 0.99 mmol) in water (1 mL) was then

added and the reaction mixture stirred at room temperature for 2 h.

The reaction was quenched by addition of sodium sulfite (300 mg)

in water (3 mL) and then acidified to pH ∼4 with 1 M hydrochloric

acid and extracted with ethyl acetate. The combined organics were

dried (MgSO₄) and concentrated in vacuo to afford a colorless oil.

The crude product was purified by chromatography (silica gel, 2/1

hexanes/ethyl acetate) to afford (2R,3R)-3-benzyloxymethyl-2-methyl-

compound 33 (134 mg, 92%) as a colorless oil: [α]_D= −59.9°

(c 0.73, CHCl₃); ν_max(film)/cm⁻¹2955, 2854, 1709, 1257, 1028; δ_H

(400 MHz, CDCl₃) 7.35−7.25 (5H, m), 5.82−5.71 (1H, m), 5.07−

5.02 (2H, m), 4.40 (1H, d, J = 12.5), 4.37 (1H, d, J = 12.5), 3.76 (3H,

d, J = 11.0), 3.75 (3H, d, J = 11.0), 3.40−3.26 (3H, m), 3.02 (1H, dd,

J = 22.0, 14.5), 2.84 (1H, qd, J = 7.0, 5.0), 2.34−2.28 (1H, m), 2.20−

2.12 (1H, m), 2.07−2.00 (1H, m), 1.04 (3H, d, J = 7.0); δ_C(100 MHz,

CDCl₃) 204.7 (C, d, J = 6.0), 138.1 (C), 136.3 (CH), 128.3 (CH),

127.7 (CH), 127.6 (CH), 117.0 (CH₂), 73.3 (CH₂), 69.5 (CH₂), 53.0

(CH₃, d, J = 6.5), 52.8 (CH₃, d, J = 6.5), 47.9 (CH, d, J = 1.5), 40.4

(CH), 39.6 (CH₂, d, J = 129.5), 34.2 (CH₂), 10.4 (CH₃); m/z (ESI+)

377 (MNa⁺, 100%), 355 (MH⁺, 60), 247 ([M − HOBn]H⁺, 70); m/z

(ESI+) found [M + H]⁺355.1666, calcd for C₁₈H₂₈O₅P⁺355.1669.

Dimethyl ((4S,5R)-4-((Benzyloxy)methyl)-5-methyl-6-oxocyclo-

hex-1-en-1-yl)phosphonate (34). Osmium tetroxide (2.5 wt % in

tBuOH, 32 μL, 0.0031 mmol) was added to a solution of phosphonate

33 (22 mg, 0.062 mmol) and N-methylmorpholine N-oxide (22 mg,

0.19 mmol) in water (1 mL) and acetone (3 mL). The resulting

solution was stirred for 18 h at room temperature, then an additional

aliquot of OsO₄(32 μL, 0.0031 mmol) and NMO (22 mg, 0.19

mmol) were added, and the mixture was stirred for a further 18 h.

A solution of sodium periodate (225 mg, 1.1 mmol) in water (1.5 mL)

was then added and the resulting white precipitate was stirred at room

temperature for 30 min and then filtered with dichloromethane

washings. The filtrate was extracted with dichloromethane, and the

combined organics were washed with saturated aqueous ammonium

chloride, dried (Na₂SO₄), and concentrated in vacuo to afford a

colorless oil. The crude product was purified by chromatography

(silica gel, 100% ethyl acetate) to afford the title compound 34 (7 mg,

33%) as a colorless oil: [α]_D²⁰= +40.8° (c 0.70, CHCl₃); ν_max(film)/

cm⁻¹2956, 2854, 1681, 1249, 1029; δ_H(400 MHz, CDCl₃) 7.86 (1H,

ddd, J = 20.5, 4.5, 3.5), 7.37−7.28 (5H, m), 4.53 (1H, d, J = 12.0), 4.49

(1H, d, J = 12.0), 3.79 (3H, d, J = 11.0), 3.76 (3H, d, J = 11.0), 3.53−

3.47 (2H, m), 2.69−2.65 (2H, m), 2.54 (1H, dq, J = 11.0, 6.5), 2.10−

2.02 (1H, m), 1.15 (3H, d, J = 6.5₃); δ_C(100 MHz, CDCl₃) 198.5 (C,

d, J = 5.0), 162.4 (CH, d, J = 6.0), 138.0 (C), 129.5 (C, d, J = 183.0),

128.5 (CH), 127.8 (CH), 127.6 (CH), 73.4 (CH₂), 70.9 (CH₂), 53.1

(CH₃, d, J = 6.5), 53.0 (CH₃, d, J = 6.5), 43.9 (CH, d, J = 7.1), 40.7

(CH), 30.2 (CH₂, d, J = 16.0), 11.8 (CH₃); m/z (ESI+) 699 (M₂Na⁺,

47%), 361 (MNa⁺, 100), 339 (MH⁺, 48); m/z (ESI+) found [M + H]⁺

339.1356, calcd for C₁₇H₂₄O₅P⁺339.1356.

20

hex-5-enoic acid (124 mg, 100%) as a colorless oil: [α]_D= −15.0°

(c 1.0, CHCl₃); ν_max(film)/cm⁻¹2860, 1701, 1455, 1106; δ_H(400

MHz, CDCl₃) 7.34−7.23 (5H, m), 5.80−5.70 (1H, m), 5.06−5.01

(2H, m), 4.47 (2H, s), 3.47 (1H, dd, J = 9.5, 5.5), 3.44 (1H, dd, J =

9.5, 5.0), 2.67 (1H, qd, J = 7.0, 5.0), 2.23−2.04 (3H, m), 1.12 (3H, d,

J = 7.0); δ_C(100 MHz, CDCl₃) 182.2 (C), 138.3 (C), 136.4 (CH),

128.3 (CH), 127.6 (2 × CH), 116.9 (CH₂), 73.2 (CH₂), 69.7 (CH₂),

40.6 (CH), 40.0 (CH), 33.9 (CH₂), 12.5 (CH₃); m/z (ESI+) 271

(MNa⁺, 100%), 249 (MH⁺, 25); m/z (ESI+) found [M + H]⁺

+

249.1481, calcd for C₁₅H₂₁O₃249.1485.

HATU (335 mg, 0.88 mmol) was added to a solution of the above

acid (109 mg, 0.44 mmol) in DMF (3 mL) at 0 °C under nitrogen.

N,O-Dimethylhydroxylamine hydrochloride (86 mg, 0.88 mmol) was

then added, followed by N-methylmorpholine (97 μL, 0.88 mmol).

The resulting colorless solution was stirred at 0 °C for 18 h and then

diluted with ethyl acetate, washed sequentially with water, 1 M

hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and

brine, dried (MgSO₄), and concentrated in vacuo to afford the title

compound 32 (120 mg, 94%) as a colorless oil, which was used without

Proof of Stereochemistry of Phosphonate 34. The relative

stereochemistry of phosphonate 34 was assigned by comparison of the

spectral data with that of cis-phosphonate 58, prepared from lactone

10 (Scheme 14).

19

further purification: [α]_D= −18.1° (c 1.15, CHCl₃); ν_max(film)/cm⁻¹

Scheme 14. Synthesis of Phosphonate S-2

2972, 2867, 1661, 1110, 996; δ_H(400 MHz, CDCl₃) 7.30−7.17 (5H, m),

5.73−5.62 (1H, m), 4.96−4.89 (2H, m), 4.43 (1H, d, J = 7.5), 4.38 (1H, d,

J = 7.5), 3.77 (3H, s), 3.45 (1H, dd, J = 9.5, 4.0), 3.39 (1H, dd, J = 9.5,

5.0), 3.10 (3H, s), 2.98 (1H, br s), 2.23−2.16 (1H, m), 2.05−1.98 (1H,

m), 1.97−1.89 (1H, m), 1.02 (3H, d, J = 7.0); δ_C(100 MHz, CDCl₃)

177.6 (br, C), 138.7 (C), 137.2 (CH), 128.3 CH), 127.6 (CH), 127.5

(CH), 116.3 (CH₂), 73.1 (CH₂), 69.0 (CH₂), 61.4 (CH₃), 40.8 (CH),

36.0 (CH), 34.6 (CH₂), 32.3 (br, CH₃), 14.5 (CH₃); m/z (ESI+) 314

(MNa⁺, 100%), 292 (MH⁺, 33); m/z (ESI+) found [M + H]⁺292.1906,

calcd for C₁₇H₂₆NO₃⁺292.1907.

Dimethyl (3R,4R)-4-((Benzyloxy)methyl)-3-methyl-2-oxohept-6-

en-1-yl)phosphonate (33). n-Butyllithium (880 μL, 1.23 mmol)

was added to a solution of freshly distilled dimethyl methylphosph-

onate (133 μL, 1.23 mmol) in tetrahydrofuran (3 mL) at −78 °C

under nitrogen. The reaction mixture was stirred at −78 °C for 1 h,

Dimethyl (3S,4R)-4-(Benzyloxymethyl)-3-methyl-2-oxo-6-

(trimethylsilyloxy)hexylphosphonate (57). n-Butyllithium (1.6 M in

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Article

hexanes, 0.99 mL, 1.6 mmol) was added to a solution of dimethyl

methylphosphonate (0.17 mL, 1.6 mmol) in tetrahydrofuran (6 mL)

at −78 °C under argon. The reaction mixture was stirred at −78 °C for

15 min, and then a solution of lactone 10 (370 mg, 1.6 mmol) in

tetrahydrofuran (2 mL) was added. The reaction mixture was stirred at

−78 °C for 30 min, and then lithium diisopropylamine (1 M in

tetrahydrofuran, 1.6 mL, 1.6 mmol) was added. The reaction mixture

was stirred at −78 °C for 1 h, and then trimethylsilyl chloride (400 μL,

3.2 mmol) was added and the reaction mixture was warmed to room

temperature over 14 h. Saturated aqueous ammonium chloride (20

mL) was then added and the reaction mixture extracted with ethyl

acetate. The combined organics were washed with saturated aqueous

sodium bicarbonate, water, and brine, dried (MgSO₄), and

concentrated in vacuo to afford a colorless oil. The crude product

was purified by chromatography (silica gel, 100% ethyl acetate) to

afford the title compound 57 (570 mg, 83%) as a colorless oil: ν_max

(film)/cm⁻¹2956, 1709, 1454, 1250, 1028, 839, 735, 698; δ_H(400

MHz, CDCl₃) 7.27−7.16 (5H, m), 4.42−4.33 (2H, m), 3.66 (3H, d,

J = 11.0), 3.65 (3H, d, J = 11.0), 3.52−3.38 (3H, m), 3.28−3.17 (2H,

m), 2.98−2.89 (2H, m), 2.19−2.11 (1H, m), 1.46−1.26 (2H, m), 0.95

(3H, d, J = 6.8), 0.06−0.00 (9H, m); δ_C(100 MHz; CDCl₃) 205.0 (C,

d, J = 6.2), 137.8 (C), 127.9 (CH), 127.22 (CH), 127.19 (CH), 72.6

(CH₂), 70.7 (CH₂), 60.0 (CH₂), 52.4 (CH₃, d, J = 6.4), 52.3 (CH₃, d,

J = 6.4), 47.6 (CH, d, J = 1.9), 39.5 (CH₂, d, J = 130.0), 36.7 (CH),

30.3 (CH₂), 11.1 (CH₃), −1.0 (CH₃); δ_P(162 MHz, CDCl₃) 23.6;

m/z (ESI+) 453 (MNa⁺, 100%); m/z (ESI+) found [M + Na]⁺453.1840,

calcd for C₂₀H₃₅NaO₆PSi⁺453.1833.

Dimethyl (4S,5S)-4-(Benzyloxymethyl)-5-methyl-6-oxocyclohex-

1-enylphosphonate (58). Dess−Martin periodinane (300 mg, 0.71

mmol) was added to a solution of 57 (150 mg, 0.35 mmol) in

dichloromethane (5 mL) at room temperature. The reaction mixture

was stirred at room temperature for 18 h and then quenched by

addition of water (10 mL) and extracted with dichloromethane. The

combined organics were washed with saturated aqueous sodium

thiosulfate, dried (MgSO₄), and concentrated in vacuo to afford an oil.

The crude product was purified by chromatography (silica gel, 100%

ethyl acetate) to afford the title compound 58 (51 mg, 43%) as a

yellow oil: ν_max(film)/cm⁻¹2957, 1683, 1453, 1375, 1248, 1029, 828,

746; δ_H(400 MHz, CDCl₃) 7.81 (1H, dt, J = 20.8, 4.0), 7.36−7.27

(5H, m), 4.46 (2H, s), 3.78 (3H, d, J = 11.4), 3.71 (3H, d, J = 11.4),

3.48−3.38 (2H, m), 2.75 (1H, dq, J = 7.2, 4.2), 2.69−2.50 (3H, m),

1.09 (3H, d, J = 7.2); δ_C(100 MHz; CDCl₃) 198.6 (C, d, J = 5.2),

161.7 (CH, d, J = 5.9), 137.8 (C), 129.5 (C, d, J = 181.1), 128.4 (CH),

127.7 (CH), 127.6 (CH), 73.3 (CH₂), 69.5 (CH₂), 53.0 (CH₃, d, J =

5.8), 52.8 (CH₃, d, J = 5.8), 43.4 (CH, d, J = 7.2), 38.3 (CH), 28.6 (CH₂,

d, J = 15.7), 10.9 (CH₃); δ_P(162 MHz, CDCl₃) 16.7; m/z (ESI+) 339

(MH⁺, 20%), 233 ([M − BnOH]H⁺, 100), found MNa⁺, 339.1360, calcd

for C₁₇H₂₄O₅P⁺339.1356.

(Trimethylsilyl)diazomethane (2.0 M in diethyl ether, 1.45 mL, 2.9

mmol) was added to a solution of the above acid (575 mg, 2.5 mmol)

in tetrahydrofuran (30 mL) and methanol (10 mL) at room

temperature. The reaction mixture was stirred at room temperature

for 30 min and then concentrated in vacuo to afford a yellow oil. The

crude product was purified by chromatography (silica gel, 6/1

hexanes/ethyl acetate) to afford the title compound 37a (520 mg,

20

84%) as a colorless oil: [α]_D= −1.8° (c 0.70, CHCl₃); ν_max(film)/

cm⁻¹2947, 2857, 1735, 1170, 1101; δ_H(400 MHz, CDCl₃) 7.36−7.26

(5H, m), 5.78−5.69 (1H, m), 5.06−5.01 (2H, m), 4.48 (2H, s), 3.62

(3H, s), 3.44 (1H, dd, J = 9.5, 5.0), 3.36 (1H, dd, J = 9.5, 6.0), 2.42−

2.24 (3H, m), 2.24−2.07 (2H, m); δ_C(100 MHz, CDCl₃) 173.5 (C),

138.5 (C), 135.9 (CH), 128.3 (CH), 127.6 (CH), 127.5 (CH), 117.0

(CH₂), 73.0 (CH₂), 72.4 (CH₂), 51.5 (CH₃), 36.0 (CH₂), 35.8 (CH₂),

35.4 (CH); m/z (ESI+) 271 (MNa⁺, 100%); m/z (ESI+) found [M +

+

Na]⁺271.1303, calcd for C₁₅H₂₀NaO₃271.1305.

(S)-Methyl 3-((Benzyloxy)methyl)-5-((tert-butyldiphenylsilyl)oxy)-

pentanoate (37b). Osmium tetroxide (2.5 wt % in tert-butyl alcohol,

760 μL, 0.075 mmol) was added to a solution of oxazolidinone 24a

(570 mg, 1.5 mmol) and N-methylmorpholine N-oxide (875 mg, 7.5

mmol) in water (10 mL) and acetone (30 mL). The reaction mixture

was stirred for 18 h at room temperature, and then a solution of

sodium periodate (5.4 g, 25.5 mmol) in water (15 mL) was added.

The resulting white precipitate was stirred for 1 h at room temperature

and then filtered with dichloromethane washings. The filtrate was

extracted with dichloromethane, and the combined organics were

washed with saturated aqueous ammonium chloride, dried (Na₂SO₄),

and concentrated in vacuo to afford a black oil. The crude product was

purified by chromatography (silica gel, 1/1 hexanes/ethyl acetate) to

afford (S)-3-((benzyloxy)methyl)-5-oxo-5-((R)-2-oxo-4-phenyloxazo-

25

lidin-3-yl)pentanal (397 mg, 69%) as a colorless oil: [α]_D= −36.4°

(c 0.70, CHCl₃); ν_max(film)/cm⁻¹2861, 1778, 1705, 1385, 1202, 699;

δ_H(400 MHz, CDCl₃) 9.69 (1H, br s), 7.38−7.24 (10H, m), 5.34

(1H, dd, J = 9.0, 4.0), 4.59 (1H, dd, J = 9.0, 9.0), 4.42 (2H, s), 4.23

(1H, dd, J = 9.0, 4.0), 3.43 (1H, dd, J = 9.0, 5.5), 3.38 (1H, dd, J = 9.0,

6.0), 3.07 (1H, dd, J = 17.0, 6.5), 3.02 (1H, dd, J = 17.0, 7.0), 2.85−

2.79 (1H, m), 2.54 (1H, ddd, J = 17.0, 7.0, 2.0), 2.45 (1H, ddd,

J = 17.0, 6.0, 1.5); δ_C(100 MHz, CDCl₃) 201.4 (CH), 171.3 (C),

153.7 (C), 139.0 (C), 138.1 (C), 129.2 (CH), 128.8 (CH), 128.4

(CH), 127.7 (CH), 127.6 (CH), 125.9 (CH), 73.1 (CH₂), 72.4

(CH₂), 70.0 (CH₂), 57.6 (CH), 45.9 (CH₂), 37.2 (CH₂), 30.3 (CH);

m/z (ESI+) 404 (MNa⁺, 100%); m/z (ESI+) found [M + Na]⁺

+

404.1462, calcd for C₂₂H₂₃NNaO₅404.1468.

Borane−dimethyl sulfide complex (48 μL, 0.50 mmol) was added

dropwise to a solution of the above aldehyde (174 mg, 0.46 mmol) in

tetrahydrofuran (10 mL) at 0 °C under argon. The reaction mixture

was stirred at 0 °C for 10 min and then quenched by addition of

saturated aqueous ammonium chloride (5 mL) and extracted with

ethyl acetate. The combined organics were dried (Na₂SO₄) and

concentrated in vacuo to afford a colorless oil. The crude product was

purified by chromatography (silica gel, 2/1 hexanes/ethyl acetate)

(S)-Methyl 3-((Benzyloxy)methyl)hex-5-enoate (37a). Aqueous

hydrogen peroxide (30%, 1.5 mL, 13.2 mmol) was added to a solu-

tion of oxazolidinone 24a (1.0 g, 2.6 mmol) in tetrahydrofuran (18 mL)

and water (6 mL) at 0 °C. A solution of lithium hydroxide (220 mg,

5.3 mmol) in water (6 mL) was then added and the reaction mix-

ture stirred at room temperature for 2 h. The reaction mixture was

quenched by addition of sodium sulfite (1.5 g) in water (10 mL) and

then acidified to pH ∼4 with 1 M hydrochloric acid and extracted with

ethyl acetate. The combined organics were dried (MgSO₄) and

concentrated in vacuo to afford a colorless oil. The crude product was

purified by chromatography (silica gel, 2/1 hexanes/ethyl acetate) to

afford (S)-3-((benzyloxy)methyl)hex-5-enoic acid (575 mg, 95%) as a

to afford (R)-3-((S)-3-((benzyloxy)methyl)-5-hydroxypentanoyl)-4-

21

phenyloxazolidin-2-one (176 mg, 100%) as a colorless oil: [α]_D

=

−39.1° (c 0.70, CHCl₃); ν_max(film)/cm⁻¹3430, 2927, 2865, 1777,

1704, 1384, 1201; δ_H(400 MHz, CDCl₃) 7.37−7.24 (10H, m), 5.28

(1H, dd, J = 9.0, 3.5), 4.56 (1H, dd, J = 9.0, 9.0), 4.44 (2H, s), 4.21

(1H, dd, J = 9.0, 3.5), 3.66−3.58 (2H, m), 3.45−3.38 (2H, m), 3.06

(1H, dd, J = 16.5, 7.0), 2.95 (1H, dd, J = 16.5, 6.4), 2.47−2.36 (1H,

m), 1.71−1.49 (2H, m); δ_C(100 MHz, CDCl₃) 172.1 (C), 153.8 (C),

139.1 (C), 138.1 (C), 129.2 (CH), 128.7 (CH), 128.4 (CH), 127.8

(CH), 127.7 (CH), 125.9 (CH), 73.5 (CH₂), 73.2 (CH₂), 70.0 (CH₂),

60.5 (CH₂), 57.7 (CH), 38.2 (CH₂), 35.3 (CH₂), 32.6 (CH); m/z

(ESI+) 406 (MNa⁺, 98%), 366 ([M − H₂O]H⁺], 100); m/z (ESI+)

20

colorless oil: [α]_D= −1.2° (c 0.97, CHCl₃); ν_max(film)/cm⁻¹2912,

2859, 1705, 1101; δ_H(400 MHz, CDCl₃) 7.36−7.26 (5H, m), 5.80−

5.69 (1H, m), 5.08−5.03 (2H, m), 4.51 (1H, d, J = 12.0), 4.48 (1H, d,

J = 12.0), 3.47 (1H, dd, J = 9.5, 5.0), 3.39 (1H, dd, J = 9.5, 6.5), 2.46

(1H, dd, J = 16.0, 7.0), 2.37 (1H, dd, J = 16.0, 6.0), 2.31−2.24 (1H,

m), 2.24−2.07 (2H, m); δ_C(100 MHz, CDCl₃) 179.0 (C), 138.3 (C),

135.7 (CH), 128.4 (CH), 127.58 (CH), 127.56 (CH), 117.3 (CH₂),

73.1 (CH₂), 72.3 (CH₂), 36.1 (CH₂), 35.7 (CH₂), 35.2 (CH); m/z

(ESI+) 257 (MNa⁺, 100%); m/z (ESI+) found [M + Na]⁺257.1143,

+

found [M + Na]⁺406.1628, calcd for C₂₂H₂₅NNaO₅406.1625.

TBDPSCl (76 μL, 0.54 mmol) was added to a solution of the above

alcohol (174 mg, 0.45 mmol), imidazole (62 mg, 0.91 mmol), and

DMAP (5.5 mg, 0.045 mmol) in dichloromethane (5 mL) at room

temperature under argon. The reaction mixture was stirred at room

temperature for 18 h, and then saturated aqueous ammonium chloride

(5 mL) was added. The aqueous layer was extracted with

+

calcd for C₁₄H₁₈NaO₃257.1148.

410

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The Journal of Organic Chemistry

Article

dichloromethane and the combined organics dried (Na₂SO₄) and

concentrated in vacuo to afford a yellow oil. The crude product was

purified by chromatography (silica gel, 9/1 hexanes/ethyl acetate) to

afford (R)-3-((S)-3-((benzyloxy)methyl)-5-((tert-butyldiphenylsilyl)-

oxy)pentanoyl)-4-phenyloxazolidin-2-one (192 mg, 69%) as a pale

oxazolidin-2-one (59; 742 mg, 87%) as a colorless oil, which was used

without further purification: [α]_D= −47.0° (c 0.70, CHCl₃); ν_max

20

(film)/cm⁻¹2883, 1776, 1703, 1200, 698; δ_H(400 MHz, CDCl₃)

7.36−7.22 (10H, m), 5.28 (1H, dd, J = 9.0, 3.5), 4.90 (1H, dd, J = 9.0,

9.0), 4.51 (1H, dd, J = 9.0, 9.0), 4.40 (2H, s), 4.17 (1H, dd, J = 9.0,

3.5), 3.95−3.87 (2H, m), 3.83−3.74 (2H, m), 3.48 (1H, dd, J = 9.0,

5.0), 3.39 (1H, dd, J = 9.0, 6.5), 3.17 (1H, dd, J = 17.0, 6.5), 3.03 (1H,

dd, J = 17.0, 9.0), 2.55−2.48 (1H, m), 1.80 (1H, ddd, J = 14.0, 6.5,

4.5), 1.68 (1H, ddd, J = 14.0, 6.5, 5.5); δ_C(100 MHz, CDCl₃) 171.9

(C), 153.8 (C), 139.3 (C), 138.6 (C), 129.1 (CH), 128.5 (CH), 128.3

(CH), 127.6 (CH), 127.5 (CH), 125.9 (CH), 103.5 (CH), 72.9

(CH₂), 69.9 (CH₂), 64.71 (CH₂), 64.68 (CH₂), 57.6 (CH), 37.9

(CH₂), 35.3 (CH₂), 31.5 (CH); m/z (ESI+) 448 (MNa⁺, 100%), 318

([M − BnOH)]H⁺, 14), 274 ([M − BnOH − C₂H₄O]H⁺, 65); m/z

21

yellow oil: [α]_D= −46.4° (c 0.70, CHCl₃); ν_max(film)/cm⁻¹3073,

3037, 2931, 2857, 1782, 1706, 1110, 702; δ_H(400 MHz, CDCl₃) 7.63

(4H, d, J = 6.0), 7.43−7.21 (16H, m), 5.23 (1H, dd, J = 9.0, 3.5), 4.45

(1H, dd, J = 9.0, 9.0), 4.33 (2H, s), 4.15 (1H, dd, J = 9.0, 3.5), 3.68

(2H, t, J = 6.5), 3.42 (1H, dd, J = 9.0, 5.0), 3.31 (1H, dd, J = 9.0, 7.0),

3.02 (2H, d, J = 6.5), 2.49−2.43 (1H, m), 1.70−1.57 (2H, m), 1.03

(9H, s); δ_C(100 MHz, CDCl₃) 172.0 (C), 153.7 (C), 139.3 (C),

138.6 (C), 135.6 (CH), 133.9 (C), 129.5 (CH), 129.1 (CH), 128.5

(CH), 128.3 (CH), 127.6 (CH), 127.5 (CH), 127.4 (CH), 125.8

(CH), 72.84 (CH₂), 72.75 (CH₂), 69.8 (CH₂), 62.0 (CH₂), 57.7

(CH), 37.9 (CH₂), 34.2 (CH₂), 32.4 (CH), 26.9 (CH₃), 19.2 (C);

m/z (ESI+) 644 (MNa⁺, 77%), 622 (MH⁺, 100), 544 ([M − C₆H₅]⁺,

36), 366 ([M − HOTBDPS]H⁺, 78); m/z (ESI+) found [M + H]⁺

622.2973, calcd for C₃₈H₄₄NO₅Si⁺622.2983.

+

(ESI+) found [M + Na]⁺448.1720, calcd for C₂₄H₂₇NNaO₆

448.1731.

Aqueous hydrogen peroxide (30%, 990 μL, 8.7 mmol) was added to

a solution of the above oxazolidinone (740 mg, 1.74 mmol) in

tetrahydrofuran (18 mL) and water (6 mL) at 0 °C. A solution of

lithium hydroxide (145 mg, 3.5 mmol) in water (6 mL) was then

added, and the reaction mixture was stirred at room temperature for 2

h. The reaction mixture was quenched by addition of sodium sulfite

(1.5 mg) in water (6 mL) and then acidified to pH ∼4 with 1 M

hydrochloric acid and extracted with ethyl acetate. The combined

organics were dried (Na₂SO₄) and concentrated in vacuo to afford a

pale yellow oil. The crude product was purified by chromatography

(silica gel, 1/1 hexanes/ethyl acetate) to afford (S)-3-((1,3-dioxolan-2-

yl)methyl)-4-(benzyloxy)butanoic acid (145 mg, 30%) as a colorless

Aqueous hydrogen peroxide (30%, 170 μL, 1.5 mmol) was added to

a solution of the above oxazolidinone (185 mg, 0.30 mmol) in

tetrahydrofuran (6 mL) and water (2 mL) at 0 °C. A solution of

lithium hydroxide (25 mg, 0.60 mmol) in water (2 mL) was then

added and the reaction mixture stirred at room temperature for 2 h.

The reaction mixture was quenched by addition of sodium sulfite (400

mg) in water (3 mL) and then acidified to pH ∼4 with 1 M

hydrochloric acid and extracted with ethyl acetate. The combined

organics were dried (Na₂SO₄) and concentrated in vacuo to afford a

pale yellow oil. The crude product was purified by chromatography

(silica gel, 2/1 hexanes/ethyl acetate) to afford (S)-3-((benzyloxy)-

methyl)-5-((tert-butyldiphenylsilyl)oxy)pentanoic acid (130 mg, 91%)

20

oil: [α]_D= −7.1° (c 0.70, CHCl₃); ν_max(film)/cm⁻¹3219, 2883,

1705, 1028; δ_H(400 MHz, CDCl₃) 7.34−7.23 (5H, m), 4.92 (1H, t,

J = 5.0), 4.51 (1H, d, J = 12.0), 4.48 (1H, d, J = 12.0), 3.96−3.91 (2H,

m), 3.85−3.79 (2H, m), 3.52 (1H, dd, J = 9.5, 5.0), 3.42 (1H, dd, J =

9.5, 6.0), 2.53−2.51 (2H, m), 2.46−2.40 (1H, m), 1.83 (1H, ddd, J =

14.0, 6.0, 4.5), 1.71 (1H, ddd, J = 14.0, 7.0, 5.0); δ_C(100 MHz,

CDCl₃) 178.6 (C), 138.4 (C), 128.3 (CH), 127.6 (CH), 127.5 (CH),

103.4 (CH), 73.0 (CH₂), 72.7 (CH₂), 64.7 (CH₂), 36.7 (CH₂), 35.2

(CH₂), 31.7 (CH); m/z (ESI+) 303 (MNa⁺, 33%); m/z (ESI+) found

21

as a colorless oil: [α]_D= −5.4° (c 0.70, CHCl₃); ν_max(film)/cm⁻¹

3072, 2931, 2858, 1707, 1111, 701; δ_H(400 MHz, CDCl₃) 7.64 (4H,

d, J = 7.0), 7.43−7.26 (11H, m), 4.48 (1H, d, J = 12.0), 4.44 (1H, d,

J = 12.0), 3.70 (1H, t, J = 6.0), 3.49 (1H, dd, J = 9.0, 4.5), 3.37 (1H,

dd, J = 9.0, 6.5), 2.51 (1H, dd, J = 17.0, 9.0), 2.43−2.39 (2H, m),

1.69−1.61 (2H, m), 1.03 (9H, s); δ_C(100 MHz, CDCl₃) 177.1 (C),

138.2 (C), 135.6 (CH), 133.74 (C), 133.71 (C), 129.6 (CH), 128.4

(CH), 127.7 (CH), 127.6 (2 × CH), 73.1 (CH₂), 72.7 (CH₂), 61.7

(CH₂), 36.7 (CH₂), 34.0 (CH₂), 32.7 (CH), 26.9 (CH₃), 19.2 (C);

m/z (ESI+) 499 (MNa⁺, 100%), 477 (MH⁺, 16), 291 ([M − C₆H₅−

HOBn]H⁺, 22), 221 ([M − HOTBDPS]H⁺, 56); m/z (ESI+) found

[M + H]⁺477.2450, calcd for C₂₉H₃₆O₄Si⁺477.2456.

+

[M + Na]⁺303.1210, calcd for C₁₅H₂₀NaO₅303.1203.

(Trimethylsilyl)diazomethane (2.0 M in diethyl ether, 520 μL, 1.04

mmol) was added to a solution of the above acid (145 mg, 0.52 mmol)

in tetrahydrofuran (5 mL) and methanol (1.7 mL) at room tem-

perature. The reaction mixture was stirred at room temperature for

1 h and then concentrated in vacuo to afford the title compound 37c

(150 mg, 100%) as a yellow oil, which was used without further puri-

fication: [α]_D²⁰= −5.7° (c 0.74, CHCl₃); ν_max(film)/cm⁻¹2954, 2884,

1733, 1088, 1028; δ_H(400 MHz, CDCl₃) 7.29−7.18 (5H, m), 4.85

(1H, t, J = 5.0), 4.42 (2H, s), 3.89−3.85 (2H, m), 3.77−3.73 (2H, m),

3.56 (3H, s), 3.44 (1H, dd, J = 9.0, 5.0), 3.35 (1H, dd, J = 9.0, 6.0),

2.43−2.36 (3H, m), 1.76 (1H, ddd, J = 14.0, 6.0, 4.5), 1.62 (1H, ddd,

J = 14.0, 6.0, 5.0); δ_C(100 MHz, CDCl₃) 173.3 (C), 138.5 (C), 128.3

(CH), 127.6 (CH), 127.5 (CH), 103.4 (CH), 73.0 (CH₂), 72.7

(CH₂), 64.8 (CH₂), 64.7 (CH₂), 51.4 (CH₃), 36.7 (CH₂), 35.4 (CH₂),

32.0 (CH); m/z (ESI+) 317 (MNa⁺, 100%); m/z (ESI+) found

(Trimethylsilyl)diazomethane (2.0 M in diethyl ether, 270 μL, 0.54

mmol) was added to a solution of the above acid (130 mg, 0.27 mmol)

in tetrahydrofuran (9 mL) and methanol (3 mL) at room temperature.

The reaction mixture was stirred at room temperature for 1 h and then

concentrated in vacuo to afford the title compound 37b (133 mg,

100%) as a yellow oil, which was used without further purification:

21

[α]_D= −4.3° (c 0.70, CHCl₃); ν_max(film)/cm⁻¹3072, 2932, 2858,

1737, 1111, 702; δ_H(400 MHz, CDCl₃) 7.65−7.64 (4H, m), 7.43−

7.26 (11H, m), 4.46 (1H, d, J = 13.5), 4.42 (1H, d, J = 13.5), 3.69 (2H,

t, J = 6.5), 3.60 (3H, s), 3.45 (1H, dd, J = 9.0, 4.0), 3.33 (1H, dd, J =

9.0, 5.5), 2.47−2.32 (3H, m), 1.70−1.58 (2H, m), 1.03 (9H, s); δ_C

(100 MHz, CDCl₃) 173.5 (C), 135.6 (CH), 133.8 (C), 129.6 (CH),

128.3 (CH), 127.6 (CH), 127.5 (CH), 127.4 (CH), 73.0 (CH₂), 72.7

(CH₂), 61.8 (CH₂), 51.4 (CH₃), 36.7 (CH₂), 34.1 (CH₂), 32.9 (CH),

26.8 (CH₃), 19.2 (C); m/z (ESI+) 513 (MNa⁺, 100%), 491 (MH⁺,

31), 413 ([M − C₆H₅]⁺, 53), 235 ([M − HOTBDPS]H⁺, 79); m/z

(ESI+) found [M + H]⁺491.2607, calcd for C₃₀H₃₉O₄Si⁺491.2601.

(S)-Methyl 3-((1,3-Dioxolan-2-yl)methyl)-4-(benzyloxy)butanoate

(37c). p-Toluenesulfonic acid (187 mg, 0.98 mmol) was added to a

solution of (S)-3-((benzyloxy)methyl)-5-oxo-5-((R)-2-oxo-4-phenyl-

oxazolidin-3-yl)pentanal (750 mg, 2.0 mmol) and ethylene glycol (550

μL, 9.8 mmol) in dichloromethane (30 mL) at room temperature

under argon. Silica (1.5 g) was then added, and the resulting slurry was

stirred at room temperature for 18 h and then filtered with

dichloromethane washings. The filtrate was washed with water and

brine, dried (Na₂SO₄), and concentrated in vacuo to afford (R)-3-

((S)-3-(1,3-dioxolan-2-yl)methyl)-4-(benzyloxy)butanoyl)-4-phenyl-

+

[M + Na]⁺317.1356, calcd for C₁₆H₂₂NaO₅317.1359.

General Procedure C: Alkylation of Methyl Esters. NaHMDS

(1.0 M in tetrahydrofuran, 1.2 equiv) was added dropwise to a solution

of ester 37 (1 equiv) in tetrahydrofuran (0.07−0.10 M with respect to

the ester) at 78 °C under argon. The reaction mixture was stirred at

−78 °C for 30 min and then methyl iodide (3 equiv) was added. The

reaction mixture was stirred for 2 h at −78 °C and then quenched with

saturated aqueous ammonium chloride, warmed to room temperature,

and extracted with ethyl acetate. The combined organics were dried

(Na₂SO₄) and concentrated in vacuo to afford the crude product.

(2S,3S)-Methyl 3-((Benzyloxy)methyl)-2-methylhex-5-enoate

(38a). Following general procedure C, reaction with ester 37a²⁶

(25 mg, 0.10 mmol) provided the title compound 38a as a colorless oil

as an inseparable 1.3:1 mixture of diastereoisomers after purification by

chromatography (silica gel, 5/1 hexanes/ethyl acetate): δ_H(400 MHz,

CDCl₃) 7.37−7.27 (5H, m), 5.79−5.68 (1H, m), 5.05−4.99 (2H, m),

4.45−4.42 (2H, m), 3.61 (3H, s), 3.45−3.34 (2H, m), 2.74−2.62 (1H, m),

411

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2.21−2.02 (3H, m), 1.12 and 1.11 (3H, 2d, J, 6.8, CH₃of syn and anti

diastereoisomers respectively).

dihydrofuran-2(3H)-one (55 mg, 23%) as a colorless oil, which was

used immediately in the next step: δ_H(400 MHz, CDCl₃) 4.90 (1H, t,

J = 4.0), 4.60 (1H, dd, J = 8.5, 8.5), 4.02−3.96 (3H, m), 3.90−3.80

(2H, m), 2.83−2.73 (1H, m), 2.65 (1H, dd, J = 17.0, 8.5), 2.29 (1H,

dd, J = 17.0, 9.5), 1.92 (1H, ddd, J = 14.0, 6.5, 4.0), 1.83 (1H, ddd, J =

14.0, 7.5, 4.5).

(2RS,3S)-Methyl 3-((Benzyloxy)methyl)-5-((tert-butyl-

diphenylsilyl)oxy)-2-methylpentanoate (38b). Following general

procedure C, reaction with ester 37b²⁶(50 mg, 0.10 mmol) provided

the title compound 38b as a colorless oil as an inseparable 1:1 mixture

of diastereoisomers after purification by chromatography (silica gel,

9/1 hexanes/ethyl acetate): δ_H(400 MHz, CDCl₃) 7.66−7.64 (4H, m),

7.43−7.24 (11H, m), 4.46−4.36 (2H, m), 3.71−3.65 (2H, m), 3.59

and 3.57 (3H, 2s), 3.43−3.32 (2H, m), 2.75−2.68 (1H, m), 2.28−

2.25 (1H, m), 1.65−1.40 (2H, m), 1.09 and 1.06 (3H, 2d, J = 7.2),

1.04 (9H, s).

(2R,3S)-Methyl 3-((1,3-Dioxolan-2-yl)methyl)-4-(benzyloxy)-2-

methylbutanoate (38c). Following general procedure C, reaction

with ester 37c²⁶(115 mg, 0.39 mmol) provided the title compound

38c as a colorless oil as an inseparable 4/1 mixture of diastereoisomers

after purification by chromatography (silica gel, 3/1 hexanes/ethyl

acetate): δ_H(400 MHz, CDCl₃) 7.33−7.24 (5H, m), 4.93−4.90 (1H, m),

4.46 (2H, s), 3.96−3.90 (2H, m), 3.84−3.79 (2H, m), 3.61 and 3.60 (3H,

2s, CO₂Me of syn and anti diastereoisomers, respectively), 3.54−3.41

(2H, m), 2.82−3.73 (1H, m), 2.35−2.30 (1H, m), 1.80−1.62 (2H, m),

1.12 and 1.10 (3H, 2d, J = 7.2, CHCH₃of anti and syn diastereoisomers,

respectively).

NaHMDS (1.0 M in tetrahydrofuran, 680 μL, 0.68 mmol) was

added dropwise to a solution of the above lactone (90 mg, 0.52 mmol)

in tetrahydrofuran (5 mL) at −78 °C under argon. The reaction

mixture was stirred for 45 min at −78 °C, and then methyl iodide (100

μL, 1.57 mmol) was added. The reaction mixture was stirred for a

further 3 h at −78 °C and then quenched by addition of saturated

aqueous ammonium chloride (3 mL), warmed to room temperature,

and extracted with ethyl acetate. The combined organics were dried

(Na₂SO₄) and concentrated in vacuo to afford a colorless oil. The

crude product was purified by chromatography (silica gel, 1/1

hexanes/ethyl acetate) to afford the title compound 60 (50 mg,

52%) as a colorless oil: [α]_D²⁰= −17.0° (c 1.20, CHCl₃); ν_max(film)/

cm⁻¹2975, 2888, 1773, 1007; δ_H(400 MHz, CDCl₃) 4.91 (1H, dd, J =

5.0, 3.5), 4.45 (1H, dd, J = 9.5, 7.5), 4.01−3.95 (2H, m), 3.92−3.83

(3H, m), 2.37−2.29 (1H, m), 2.26−2.18 (1H, m), 2.10 (1H, ddd, J =

14.5, 3.5, 3.5), 1.73 (1H, ddd, J = 14.5, 10.0, 5.0), 1.26 (3H, d, J = 7.0);

δ_C(100 MHz, CDCl₃) 179.2 (C), 102.6 (CH), 72.1 (CH₂), 65.1

(CH₂), 64.9 (CH₂), 40.2 (CH), 39.3 (CH), 35.6 (CH₂), 13.5 (CH₃);

m/z (ESI+) 209 (MNa⁺, 100%), 187 (MH⁺, 48), 143 ([M −

C₂H₄O]H⁺, 45); m/z (ESI+) found [M + H]⁺187.0958, calcd for

Stereochemical Proof for Alkylation of 37c. To determine the

stereochemical outcome for the alkylation of 37c, ester 38c was treated

with lithiated dimethyl methylphosphonate and the spectral data of the

resulting β-ketophosphonate compared to that of syn-62, prepared

from oxazolidinone 59 (Scheme 15).

+

C₉H₁₅O₄187.0965.

Dimethyl (((3S,4S)-4-((1,3-Dioxolan-2-yl)methyl)-2-hydroxy-3-

methyltetrahydrofuran-2-yl)methyl)phosphonate (61). nBuLi (1.4 M

in hexanes, 92 μL, 0.13 mmol) was added dropwise to a solution of

dimethyl methylphosphonate (14 μL, 0.13 mmol) in tetrahydrofuran

(1 mL) at −78 °C under argon. The reaction mixture was stirred at

−78 °C for 15 min, and then a solution of lactone 60 (24 mg, 0.13

mmol) in tetrahydrofuran (1 mL) was added. The reaction mixture

was stirred at −78 °C for a further 1 h and then at room temperature

for 1.5 h and was then quenched by addition of saturated aqueous

ammonium chloride (1 mL) and extracted with ethyl acetate. The

combined organics were dried (Na₂SO₄) and concentrated in vacuo to

afford a yellow oil. The crude product was purified by chromatography

(silica gel, 100% ethyl acetate) to afford the title compound 61 (13

Scheme 15. Stereochemical Proof for Alkylation of 37c

20

mg, 32%) as a colorless oil: [α]_D= −36.3° (c 1.10, CHCl₃); ν_max

(film)/cm⁻¹3390, 2957, 2885, 1030; δ_H(400 MHz, CDCl₃) 5.01 (1H,

br s), 4.86 (1H, dd, J = 4.2, 4.2), 4.21 (1H, dd, J = 8.4, 8.4), 3.98−3.92

(2H, m), 3.85−3.80 (5H, m), 3.74 (3H, d, J = 11.0), 3.61 (1H, dd, J =

8.4, 8.4), 2.36−2.25 (2H, m), 2.16−1.94 (2H, m), 1.60−1.46 (2H, m),

1.05 (3H, d, J = 7.0); δ_C(100 MHz, CDCl₃) 103.6 (CH), 102.9 (C, d,

J = 9.0), 72.5 (CH₂), 65.0 (CH₂), 64.9 (CH₂), 53.4 (CH₃, d, J = 6.0),

51.9 (CH₃, d, J = 6.0), 50.0 (CH, d, J = 13.0), 39.3 (CH), 36.8 (CH₂),

33.9 (CH₂, d, J = 134.0), 11.8 (CH₃); m/z (ESI+) 643 (M₂Na⁺, 68%),

333 (MNa⁺, 100), 293 ([M − H₂O]H⁺, 76); m/z (ESI+) found [M +

Na]⁺333.1076, calcd for C₁₂H₂₃NaO₇P⁺333.1074.

Dimethyl ((3S,4S)-4-((1,3-Dioxolan-2-yl)methyl)-5-(benzyloxy)-3-

methyl-2-oxopentyl)phosphonate (syn-62). Potassium tert-butoxide

(22 mg, 0.20 mmol) was added to a solution of lactol 61 (25 mg, 0.081

mmol) in tetrahydrofuran (1.5 mL) at −78 °C under argon. The

resulting yellow suspension was stirred at −78 °C for 15 min and then

benzyl bromide (11 μL, 0.089 mmol) was added. The reaction mixture

was warmed slowly to room temperature over 18 h and then quenched

with saturated aqueous ammonium chloride (2 mL) and extracted

with ethyl acetate. The combined organics were dried (Na₂SO₄) and

concentrated in vacuo to afford a yellow oil. The crude product was

purified by preparative thin-layer chromatography (100% ethyl acetate,

then 9/1 dichloromethane/methanol) to afford the title compound

(3S,4S)-4-((1,3-Dioxolan-2-yl)methyl)-3-methyldihydrofuran-

2(3H)-one (60). A mixture of oxazolidinone 59 (590 mg, 1.39 mol)

and 20% Pd(OH)₂in ethyl acetate (20 mL) was placed under an

atmosphere of hydrogen (balloon), stirred vigorously at room

temperature for 2.5 h, and then filtered through Celite with ethyl

acetate washing and concentrated in vacuo (water bath <30 °C) to

afford a colorless oil. The oil was dissolved in ethyl acetate (20 mL),

and then 0.5 M sodium hydroxide (10 mL) was added. The biphasic

mixture was stirred vigorously at room temperature for 1 h, and then

the organic layer was removed and the aqueous layer extracted with

ethyl acetate. The combined organics were washed with water and

brine, dried (Na₂SO₄), and concentrated in vacuo (water bath <30 °C)

to afford a cream-colored solid. The crude product was purified by

chromatography (silica gel, 95/5 to 90/10 dichloromethane/ethyl

acetate) to afford volatile (S)-4-((1,3-dioxolan-2-yl)methyl)-

20

syn-62 (3 mg, 10%) as a brown oily solid: [α]_D= +28.2° (c 0.38,

CHCl₃); ν_max(film)/cm⁻¹2923, 2853, 1710, 1251, 1029, 748; δ_H(400

MHz, CDCl₃) 7.36−7.28 (5H, m), 4.86 (1H, t, J = 5.0), 4.51 (1H, d,

J = 12.0), 4.45 (1H, d, J = 12.0), 3.95−3.89 (2H, m), 3.83−3.78 (2H,

m), 3.76 (3H, d, J = 11.0), 3.74 (3H, d, J = 11.0), 3.56 (1H, dd, J = 9.5,

5.0), 3.40−3.26 (2H, m), 3.31−2.99 (2H, m), 2.39−2.32 (1H, m),

1.63−1.51 (2H, m), 1.02 (3H, d, J = 7.0); δ_C(100 MHz, CDCl₃)

412

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205.4 (C, d, J = 6.0), 138.2 (C), 128.4 (CH), 127.7 (CH), 127.6

(CH), 103.2 (CH), 73.0 (CH₂), 71.3 (CH₂), 64.9 (CH₂), 64.6 (CH₂),

53.0 (CH₃, d, J = 6.5), 52.9 (CH₃, d, J = 6.5), 47.8 (CH), 39.9 (CH₂,

d, J = 130.0), 36.2 (CH), 31.7 (CH₂), 11.3 (CH₃); m/z (ESI+) 423

(MNa⁺, 100%); m/z (ESI+) found [M + Na]⁺423.1536, calcd for

C₁₉H₂₉NaO₇P⁺423.1543.

(S)-2-(2-tert-Butyldiphenylsilyloxyethyl)-4-oxo-4-((S)-2-oxo-4-

phenyloxazolidin-3-yl)butyl Acetate (41). Osmium tetroxide (2.5%

in tert-butyl alcohol, 4.6 mL, 0.45 mmol) was added to a solution of 45

(7.44 g, 22.5 mmol) and 2,6-lutidine (5.2 mL, 44.9 mmol) in dioxane

(250 mL) and water (100 mL) at room temperature. Sodium

metaperiodate (19.1 g, 89.8 mmol) was then added and the resulting

suspension stirred at room temperature for 2 h. The mixture was

diluted with water (200 mL) and then extracted with dichloromethane.

The combined organics were dried (Na₂SO₄) and concentrated in

vacuo to afford a brown oil, which was used directly in the next step.

An aliquot of aldehyde was purified for characterization by

chromatography (silica gel, 1/1 hexanes/ethyl acetate) to afford (S)-

4-oxo-4-((S)-2-oxo-4-phenyloxazolidin-3-yl)-2-(2-oxoethyl)butyl ace-

Dimethyl ((3R,4S)-4-((1,3-Dioxolan-2-yl)methyl)-5-(benzyloxy)-3-

methyl-2-oxopentyl)phosphonate (anti-62). n-Butyllithium (260 μL,

0.36 mmol) was added dropwise to a solution of dimethyl methyl-

phosphonate (38 μL, 0.36 mmol) in tetrahydrofuran (1 mL) at

−78 °C under argon. The reaction mixture was stirred at −78 °C for

25 min and then a solution of ester 38c (37 mg, 0.12 mmol) in

tetrahydrofuran (2 mL) was added. The reaction mixture was stirred at

20

o

tate as a pale yellow oil: [α]_D= −57.7° (c 1.0, CHCl₃); ν_max

−78 C for 1 h and then at room temperature 2 h and was then

(film)/cm⁻¹2968, 2924, 1776, 1732, 1701, 1233, 1200, 1040; δ_H(400

MHz, CDCl₃) 9.69 (1H, t, J = 1.5), 7.41−7.28 (5H, m), 5.42 (1H, dd,

J = 9.0, 3.5), 4.71 (1H, dd, J = 9.0, 9.0), 4.29 (1H, dd, J = 9.0, 3.5),

4.01 (2H, d, J = 6.0), 3.11 (1H, dd, J = 17.5, 6.0), 2.99 (1H, dd, J =

17.5, 7.0), 2.90−2.85 (1H, m), 2.53 (1H, ddd, J = 17.5, 7.0, 1.5), 2.46

(1H, ddd, J = 17.5, 6.5, 1.5), 1.99 (3H, s); δ_C(100 MHz, CDCl₃)

200.4 (CH), 170.9 (C), 170.8 (C), 153.7 (C), 138.9 (C), 129.3 (CH),

128.9 (CH), 125.9 (CH), 70.1 (CH₂), 66.1 (CH₂), 57.7 (CH), 45.4

(CH₂), 36.9 (CH₂), 28.8 (CH), 20.7 (CH₃); m/z (ESI+) 372 (MK⁺,

100%), 356 (MNa⁺, 35); m/z (ESI+) found [M + Na]⁺356.1114,

calcd for C₁₇H₁₉NO₆Na⁺356.1105.

quenched with saturated aqueous ammonium chloride (2 mL) and

extracted with ethyl acetate. The combined organics were dried

(Na₂SO₄) and concentrated in vacuo to afford a yellow oil. The crude

product was purified by chromatography (silica gel, 100% ethyl

acetate) to afford the title compound 62 as an inseparable 4/1 mixture

1

of anti and syn diastereoisomers. The H and ¹³C data for the minor

syn isomer matched those obtained above. Data for anti-62: δ_H(400

MHz, CDCl₃) 7.34−7.25 (5H, m), 4.92 (1H, t, J = 5.0), 4.41 (1H, d,

J = 11.0), 4.38 (1H, d, J = 11.0), 3.97−3.88 (2H, m), 3.83−3.79 (2H,

m), 3.77 (3H, d, J = 11.5), 3.74 (3H, d, J = 11.5), 3.45 (1H, dd, J = 9.5,

5.0), 3.40−3.26 (2H, m), 3.03 (1H, dd, J = 22.0, 14.5), 2.94−2.89

(1H, m), 2.52−2.45 (1H, m), 1.77−1.63 (2H, m), 1.06 (3H, d, J =

7.0); δ_C(100 MHz, CDCl₃) 204.3 (C, d, J = 6.1), 138.1 (C), 128.3

(CH), 127.7 (CH), 127.6 (CH), 103.4 (CH), 73.2 (CH₂), 70.0

(CH₂), 64.78 (CH₂), 64.76 (CH₂), 53.0 (CH₃, d, J = 6.5), 52.7 (CH₃,

d, J = 6.5), 48.6 (CH), 39.5 (CH₂, d, J = 130.0), 36.6 (CH), 33.7

(CH₂), 10.6 (CH₃).

Borane−dimethyl sulfide complex (2.35 mL, 24.8 mmol) was added

dropwise over 5 min to a solution of the above crude aldehyde in

tetrahydrofuran (250 mL) at 0 °C under nitrogen. The reaction

mixture was stirred at 0 °C for 10 min and then quenched carefully

with saturated aqueous ammonium chloride (50 mL) and extracted

with ethyl acetate. The combined organics were dried (Na₂SO₄) and

concentrated in vacuo to afford a black oil. The crude product was

purified by chromatography (silica gel, 1/3 hexanes/ethyl acetate) to

(S,E)-4-Oxo-4-(2-oxo-4-phenyloxazolidin-3-yl)but-2-en-1-yl Ace-

tate (42). Diisopropylethylamine (9.8 mL, 56 mmol) was added to

a solution of phosphonate 43²⁸(1.91 g, 5.6 mmol) and lithium

chloride (360 mg, 8.4 mmol) in tetrahydrofuran (40 mL) at room

temperature under nitrogen. The solution was stirred at room tem-

perature for 20 min, and then a solution of aldehyde 44²⁹(1.24 g,

11.2 mmol) in tetrahydrofuran (20 mL) was added. The resulting

yellow solution was stirred at room temperature for 18 h and then

quenched with 1 M hydrochloric acid (30 mL) and extracted with

ethyl acetate. The combined organics were dried (Na₂SO₄) and

concentrated in vacuo to afford a brown oil. The crude product was

purified by chromatography (silica gel, 1/1 hexanes/ethyl acetate

to afford the title compound 42 (700 mg, 43%) as a colorless oil.

[α]_D²⁰= −78.4° (c 0.70, CHCl₃); ν_max(film)/cm⁻¹3035, 2987, 2929,

1775, 1743, 1689, 1337, 1223, 1199; δ_H(400 MHz, CDCl₃) 7.47 (1H,

dt, J = 15.5, 2.0), 7.41−7.30 (5H, m), 7.03 (1H, dt, J = 15.5, 4.5), 5.49

(1H, dd, J = 9.0, 4.0), 4.78 (2H, dd, J = 4.5, 2.0), 4.72 (1H, dd, J = 9.0,

9.0), 4.31 (1H, dd, J = 9.0, 4.0), 2.14 (3H, s); δ_C(100 MHz, CDCl₃)

170.4 (C), 163.8 (C), 153.6 (C), 143.4 (CH), 138.8 (C), 129.2 (CH),

128.8 (CH), 126.0 (CH), 120.8 (CH), 70.0 (CH₂), 62.9 (CH₂), 57.7

(CH), 20.7 (CH₃); m/z (ESI+) 312 (MNa⁺, 100%); m/z (ESI+)

found [M + Na]⁺312.0842, calcd for C₁₅H₁₅NO₅Na⁺312.0842.

(S)-2-(2-Oxo-2-((S)-2-oxo-4-phenyloxazolidin-3-yl)ethyl)pent-4-

en-1-yl Acetate (45). Following general procedure A, reaction with

oxazolidinone 42 (8.54 g, 29.5 mmol) provided the title compound 45

afford (S)-2-(2-hydroxyethyl)-4-oxo-4-((S)-2-oxo-4-phenyloxazolidin-

20

3-yl)butyl acetate (6.59 g, 87% over 2 steps) as a yellow oil: [α]_D

=

−55.7° (c 0.70, CHCl₃); ν_max(film)/cm⁻¹3457, 2924, 1775, 1732,

1704, 1385, 1234, 1200; δ_H(400 MHz, CDCl₃) 7.42−7.29 (5H, m),

5.43 (1H, dd, J = 9.0, 3.5), 4.71 (1H, dd, J = 9.0, 9.0), 4.29 (1H, dd, J =

9.0, 3.5), 4.07 (1H, dd, J = 11.0, 5.0), 3.96 (1H, dd, J = 11.0, 6.0), 3.65

(2H, t, J = 6.0), 3.03 (2H, br d, J = 6.5), 2.48−2.42 (1H, m), 1.98 (3H, s),

1.71−1.46 (2H, m); δ_C(100 MHz, CDCl₃) 171.8 (C), 171.0 (C),

153.7 (C), 138.9 (C), 129.2 (CH), 128.9 (CH), 126.0 (CH), 70.1

(CH₂), 66.7 (CH₂), 60.2 (CH₂), 57.7 (CH), 37.6 (CH₂), 34.3 (CH₂),

30.8 (CH), 20.8 (CH₃); m/z (ESI+) 358 (MNa⁺, 100%), 318 ([M −

H₂O]H⁺, 54); m/z (ESI+) found [M + Na]⁺358.1264, calcd for

C₁₇H₂₁NO₆Na⁺358.1261.

Imidazole (1.61 g, 23.6 mmol) was added to a solution of the above

alcohol (6.59 g, 19.7 mmol), DMAP (240 mg, 1.97 mmol), and

TBDPSCl (5.5 mL, 39.3 mmol) in dichloromethane (50 mL) at room

temperature under nitrogen. The reaction mixture was stirred at room

temperature for 18 h. Saturated aqueous ammonium chloride (30 mL)

was added, and the organic layer was removed. The aqueous layer was

extracted with dichloromethane, and then the combined organics were

dried (Na₂SO₄) and concentrated in vacuo to afford a brown oil. The

crude product was purified by chromatography (silica gel, 3/1

hexanes/ethyl acetate) to afford the title compound 41 (9.63 g,

20

85%) as a pale yellow oil: [α]_D= −33.3° (c 0.70, CHCl₃); ν_max

20

(film)/cm⁻¹2931, 2858, 1781, 1737, 1706, 1385, 1236, 1192, 1107,

703; δ_H(400 MHz, CDCl₃) 7.66−7.62 (4H, m), 7.42−7.27 (11H, m),

5.37 (1H, dd, J = 9.0, 3.5), 4.64 (1H, dd, J = 9.0, 9.0), 4.25 (1H, dd, J =

9.0, 3.5), 4.05 (1H, dd, J = 11.0, 5.0), 3.90 (1H, dd, J = 11.0, 6.0), 3.68

(2H, t, J = 6.5), 3.07 (1H, dd, J = 17.5, 7.0), 2.94 (1H, dd, J = 17.5,

6.5), 2.54−2.46 (1H, m), 1.91 (3H, s), 1.68−1.53 (2H, m), 1.03

(9H, s); δ_C(100 MHz, CDCl₃) 171.4 (C), 171.0 (C), 153.7 (C), 139.1

(C), 135.6 (CH), 133.7 (C), 129.6 (CH), 129.2 (CH), 128.8 (CH),

127.7 (CH), 125.9 (CH), 70.0 (CH₂), 66.5 (CH₂), 61.7 (CH₂), 57.7

(CH), 37.3 (CH₂), 33.8 (CH₂), 31.1 (CH), 26.9 (CH₃), 20.8 (CH₃),

19.1 (C); m/z (ESI+) 596 (MNa⁺, 100%), 496 ([M − C₆H₅]⁺, 19); m/z

(ESI+) found [M + Na]⁺596.2428, calcd for C₃₃H₃₉NNaO₆Si⁺

596.2439.

(7.56 g, 77%) as a pale yellow oil: [α]_D= −45.1° (c 0.70, CHCl₃);

ν_max(film)/cm⁻¹2978, 2919, 1779, 1735, 1704, 1383, 1237, 1195; δ_H

(400 MHz, CDCl₃) 7.41−7.29 (5H, m), 5.76−5.66 (1H, m), 5.42

(1H, dd, J = 9.0, 4.0), 5.04 (1H, br s), 5.02−4.99 (1H, m), 4.69 (1H,

dd, J = 9.0, 9.0), 4.28 (1H, dd, J = 9.0, 4.0), 4.06 (1H, dd, J = 11.0,

5.0), 3.88 (1H, dd, J = 11.0, 6.5), 3.04 (1H, dd, J = 17.5, 6.5), 2.95

(1H, dd, J = 17.5, 6.5), 2.42−2.35 (1H, m), 2.16−2.03 (2H, m), 1.94

(3H, s); δ_C(100 MHz, CDCl₃) 171.4 (C), 171.0 (C), 153.7 (C),

139.1 (C), 135.3 (CH), 129.2 (CH), 128.8 (CH), 125.9 (CH), 117.4

(CH₂), 70.0 (CH₂), 66.1 (CH₂), 57.7 (CH), 36.9 (CH₂), 35.4 (CH₂),

33.4 (CH), 20.8 (CH₃); m/z (ESI+) 354 (MNa⁺, 100%), 272 ([M −

HOAc]H⁺, 77); m/z (ESI+) found [M + Na]⁺354.1307, calcd for

C₁₈H₂₁NO₅Na⁺354.1312.

413

dx.doi.org/10.1021/jo201988m | J. Org. Chem. 2012, 77, 400−416

The Journal of Organic Chemistry

Article

(4S)-4-(2-tert-Butyldiphenylsilyloxyethyl)dihydrofuran-2(3H)-one

(40). A solution of lithium hydroxide (2.82 g, 67.2 mmol) in water

(50 mL) was added to a solution of protected diol 41 (9.63 g, 16.8

mmol) and 30% aqueous hydrogen peroxide solution (19.0 mL, 168

mmol) in tetrahydrofuran (150 mL) and water (50 mL) at 0 °C. The

reaction mixture was warmed to room temperature and stirred for

2 h and then quenched by addition of sodium sulfite (7.5 g) in water

(20 mL). The mixture was acidified to ∼pH 4 with 2 M hydrochloric

acid and then extracted with ethyl acetate. The combined organics

were dried (Na₂SO₄) and concentrated in vacuo to afford a pale yellow

oil. The crude product was dissolved in toluene (300 mL) and p-

toluenesulfonic acid (640 mg, 3.36 mmol) added. The reaction

mixture was stirred at room temperature for 2 h and then diluted with

ethyl acetate (300 mL), washed with water and brine, dried (Na₂SO₄),

and concentrated in vacuo to afford a colorless oily solid. The crude

product was purified by chromatography (silica gel, 1/1 hexanes/ethyl

acetate) to afford the title compound 40 (6.03 g, 97%) as a pale yellow

oil. The auxiliary could be isolated by flushing the column with 100%

ethyl acetate to afford a colorless crystalline solid (2.30 g, 77%). Data

for lactone 40: [α]_D²¹= +4.7° (c 0.70, CHCl₃); ν_max(film)/cm⁻¹2931,

2858, 1775, 1168, 1106, 1090, 703; δ_H(400 MHz, CDCl₃) 7.63 (4H,

d, J = 7.0), 7.46−7.38 (6H, m), 4.42 (1H, dd, J = 8.5, 8.5), 3.94 (1H,

dd, J = 8.5, 8.5), 3.72−3.66 (2H, m), 2.77−2.69 (1H, m), 2.57 (1H,

dd, J = 17.0, 8.5), 2.17 (1H, dd, J = 17.0, 9.0), 1.75−1.65 (2H, m), 1.05

(9H, s); δ_C(100 MHz, CDCl₃) 177.1 (C), 135.5 (CH), 133.3 (C),

129.9 (CH), 127.8 (CH), 73.5 (CH₂), 61.9 (CH₂), 35.6 (CH₂), 34.6

(CH₂), 33.5 (CH), 26.9 (CH₃), 19.1 (C); m/z (ESI+) 391 (MNa⁺,

2.23−2.15 (1H, m), 2.00 (1H, dd, J = 18.0, 15.0), 1.84−1.76 (1H, m),

1.50−1.42 (2H, m), 1.04 (9H, s), 1.02 (3H, d, J = 7.0); δ_C(100 MHz,

CDCl₃) 135.6 (CH), 133.7 (C), 129.6 (CH), 127.7 (CH), 103.1 (C,

d, J = 9.0), 72.6 (CH₂), 63.2 (CH₂), 53.3 (CH₃, d, J = 6.0), 52.0 (CH₃,

d, J = 6.5), 50.1 (CH), 41.7 (CH), 35.8 (CH₂), 33.9 (CH₂, d, J = 134),

26.8 (CH₃), 19.1 (C), 12.0 (CH₃); m/z (ESI+) 529 (MNa⁺, 100%);

m/z (ESI+) found [M + Na]⁺529.2129, calcd for C₂₆H₃₉O₆PSiNa⁺

529.2146.

(3S,4S)-Dimethyl 4-tert-Butyldimethylsilyloxymethyl-6-tert-butyl-

diphenylsilyloxy-3-methyl-2-oxohexylphosphonate (47). Potassium

tert-butoxide (800 mg, 7.11 mmol) was added to a solution of lactol 46

(900 mg, 1.78 mmol) in tetrahydrofuran (50 mL) at −78 °C under

argon. The reaction mixture was stirred at −78 °C for 15 min, and

then TBSCl (1.61 g, 10.7 mmol) was added. The reaction mixture was

warmed to room temperature, stirred for 18 h, and then quenched by

addition of saturated aqueous ammonium chloride (20 mL). The

biphasic mixture was stirred vigorously for 15 min and then extracted

with ethyl acetate. The combined organics were dried (Na₂SO₄) and

concentrated in vacuo to afford a colorless oil. The crude product was

purified by chromatography (silica gel, 1/1 hexanes/ethyl acetate)

to afford the title compound 47 (930 mg, 83%) as a colorless oil:

20

[α]_D= +31.1° (c 1.1, CHCl₃); ν_max(film)/cm⁻¹2954, 2930, 2857,

1711, 1256, 1031, 836, 702; δ_H(400 MHz, CDCl₃) 7.66−7.63 (4H,

m), 7.45−7.36 (6H, m), 3.77 (3H, d, J = 11.0), 3.75 (3H, d, J = 11.0),

3.65−3.61 (3H, m), 3.39−3.26 (2H, m), 3.04−2.93 (2H, m), 2.15−

2.07 (1H, m), 1.54−1.46 (1H, m), 1.38−1.26 (1H, m), 1.04 (9H, s),

0.99 (3H, d, J = 7.0), 0.88 (9H, s), 0.02 (3H, s), 0.01 (3H, s); δ_C(100

MHz, CDCl₃) 205.7 (C, d, J = 6.0), 135.5 (CH), 133.7 (C), 129.6

(CH), 127.7 (CH), 63.5 (CH₂), 62.0 (CH₂), 53.0 (CH₃, d, J = 6.5),

52.8 (CH₃, d, J = 6.5), 47.4 (CH), 39.9 (CH₂, d, J = 130), 39.1 (CH),

29.9 (CH₂), 26.9 (CH₃), 25.9 (CH₃), 19.2 (C), 18.2 (C), 10.8 (CH₃),

−5.5 (CH₃), −5.6 (CH₃); m/z (ESI+) 643 (MNa⁺, 100%); m/z (ESI+)

found [M + Na]⁺643.2977, calcd for C₃₂H₅₃O₆PSi₂Na⁺643.3011.

(3R)-Benzyl 6,8-Bis(benzyloxy)-1-hydroxy-3-pentylisochroman-7-

carboxylate ((R)-7). DIBALH (1 M in toluene, 2.55 mL, 2.55 mmol)

was added dropwise to a solution of lactone (R)-17 (720 mg, 1.28

mmol) in dichloromethane (10 mL) at −78 °C under argon. The

reaction mixture was stirred at −78 °C for 1 h and then quenched with

methanol (1 mL) and saturated aqueous Rochelles’ salt (10 mL) and

stirred at room temperature for 3 h. The mixture was extracted with

dichloromethane and the combined organics dried (Na₂SO₄) and

concentrated in vacuo to afford a colorless solid. The crude product

was purified by chromatography (silica gel, 3/1 hexanes/ethyl acetate)

to afford the title compound (R)-17 (631 mg, 87%) as a colorless oil:

[α]_D²¹= −29.6° (c 0.28, CH₂Cl₂); ν_max(film)/cm⁻¹3493, 2928, 1720,

1606, 1378, 1261, 1163, 1093, 1015, 733, 695; δ_H(400 MHz, CDCl₃)

7.38−7.22 (15H, m), 6.52 (1H, s), 6.14 (1H, d, J = 3.6), 5.31 (2H, s),

5.18 (1H, d, J = 10.8), 5.10 (2H, s), 4.99 (1H, d, J = 10.8), 4.29−4.23

(1H, m), 2.86 (1H, d, J = 3.6), 2.68−2.57 (2H, m), 1.70−1.26 (8H,

m), 0.96−0.91 (3H, m); δ_C(100 MHz, CDCl₃) 166.1 (C), 156.2 (C),

154.8 (C), 138.7 (C), 137.3 (C), 136.4 (C), 135.5 (C), 128.5 (CH),

128.4 (CH), 128.1 (CH), 127.93 (CH), 127.90 (CH), 127.6 (CH),

127.1 (CH), 122.1 (C), 118.8 (C), 108.0 (CH), 88.6 (CH), 77.2

(CH), 70.5 (CH₂), 67.3 (CH₂), 66.2 (CH₂), 35.4 (CH₂), 34.2 (CH₂),

31.8 (CH₂), 25.0 (CH₂), 22.6 (CH₂), 14.0 (CH₃); m/z (ESI+) 589

(MNa⁺, 65%), 389 ([M − C₅H₁₀− OBn]⁺, 100); m/z (ESI+) found

+

41%), 386 (MNH₄, 13), 291 ([M − C₆H₅]⁺, 100); m/z (ESI+) found

[M + Na]⁺391.1690, calcd for C₂₂H₂₈O₃SiNa⁺391.1700.

(3S,4S)-4-(2-tert-Butyldiphenylsilyloxyethyl)-3-methyldihydrofur-

an-2(3H)-one (39). NaHMDS (1 M in THF, 9.0 mL, 8.95 mmol) was

added dropwise over 10 min to a solution of lactone 40 (3.0 g, 8.14

mmol) in THF (120 mL) at −78 °C under argon. The reaction

mixture was stirred at −78 °C for 1 h, and then methyl iodide (1.5 mL,

24.4 mmol) was added. The reaction mixture was stirred at −78 °C for

a further 3 h and then quenched with saturated aqueous ammonium

chloride (30 mL), warmed to room temperature, and extracted with

ethyl acetate. The combined organics were dried (Na₂SO₄) and

concentrated in vacuo to afford a brown oil. The crude product was

purified by chromatography (silica gel, 9/1 hexanes/ethyl acetate) to

20

afford the title compound 39 (2.36 g, 76%) as a pale yellow oil: [α]_D

= −13.4° (c 0.70, CHCl₃) (lit.⁴[α]_D²²= −15.5° (c 2.73, CHCl₃)); δ_H

(400 MHz, CDCl₃) 7.65−7.63 (4H, m), 7.47−7.37 (6H, m), 4.43

(1H, dd, J = 9.0, 7.5), 3.85 (1H, dd, J = 9.0, 9.0), 3.72−3.67 (2H, m),

2.33−2.15 (2H, m), 1.89−1.81 (1H, m), 1.65−1.56 (1H, m), 1.23

(3H, d, J = 7.0), 1.05 (9H, s); δ_C(100 MHz, CDCl₃) 179.6 (C), 135.5

(CH), 133.2 (C), 129.9 (CH), 127.8 (CH), 72.1 (CH₂), 62.1 (CH₂),

42.0 (CH), 40.4 (CH), 34.7 (CH₂), 26.9 (CH₃), 19.1 (C), 13.8 (CH₃);

m/z (ESI+) found [M + Na]⁺405.1869, calcd for C₂₃H₃₀O₃SiNa⁺

405.1856. The spectroscopic data closely matched thosepreviously

reported.⁴

Dimethyl ((3S,4S)-4-(2-tert-Butyldiphenylsilyloxyethyl)-2-

hydroxy-3-methyltetrahydrofuran-2-yl)methylphosphonate (46).

n-Butyllithium (1.6 M in hexanes, 2.45 mL, 3.92 mmol) was added

dropwise to a solution of dimethyl methylphosphonate (420 μL, 3.92

mmol) in tetrahydrofuran (10 mL) at −78 °C under argon. The

reaction mixture was stirred at −78 °C for 20 min, and then a solution

of lactone 39 (1.0 g, 2.61 mmol) in tetrahydrofuran (10 mL) was

added. The resulting yellow solution was stirred at −78 °C for 2 h and

then quenched by addition of saturated aqueous ammonium chloride

(10 mL) and warmed to room temperature. The reaction mixture was

extracted with ethyl acetate. The combined organics were washed with

water and brine, dried (Na₂SO₄), and concentrated in vacuo to afford a

yellow oil. The crude product was purified by chromatography (silica

gel, 100% ethyl acetate) to afford the title compound 46 (912 mg,

69%) as a colorless oil: [α]_D²¹= −27.3° (c 0.70, CHCl₃); ν_max(film)/

cm⁻¹3391, 2956, 2932, 2857, 1030, 701; δ_H(400 MHz, CDCl₃)

7.66−7.63 (4H, m), 7.45−7.36 (6H, m), 5.00 (1H, s), 4.21 (1H, dd,

J = 8.5, 8.5), 3.84 (3H, d, J = 11.0), 3.74 (3H, d, J = 11.0), 3.67−3.61

(2H, m), 3.57 (1H, dd, J = 8.5, 8.5), 2.31 (1H, dd, J = 18.0, 15.0),

+

[M + Na]⁺589.2568, calcd for C₃₆H₃₈NaO₆589.2561.

(3S,4S)-4-(2-tert-butyldiphenylsilyloxyethyl)-2,3-dimethyltetrahy-

drofuran-2-ol (49). Methyllithium (1.6 M in diethyl ether, 1.8 mL,

2.88 mmol) was added dropwise to a solution of lactone 39 (1.0 g,

2.61 mmol) in tetrahydrofuran (30 mL) at −78 °C under argon. The

reaction mixture was stirred for 3 h at −78 °C, and then quenched

with saturated aqueous ammonium chloride (10 mL), warmed to

room temperature, and extracted with ethyl acetate. The combined

organics were dried (Na₂SO₄) and concentratred in vacuo to afford a

colorless oil, which was used directly in the next step. An aliquot of

aldehyde was purified for characterization by chromatography (silica

gel, 3/1 hexanes/ethyl acetate) to afford the title compound 49 as a

colorless oil: [α]_D¹⁹= −30.9° (c 0.70, CHCl₃); ν_max(film)/cm⁻¹3401,

2931, 2858, 1105, 1089, 700; δ_H(400 MHz, CDCl₃) 7.66−7.63 (4H, m),

414

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The Journal of Organic Chemistry

Article

7.44−7.36 (6H, m), 4.11 (1H, dd, J = 8.5, 8.5), 3.68−3.63 (2H, m), 3.48

(1H, dd, J = 8.5, 8.5), 2.18−2.10 (1H, m), 1.88−1.80 (1H, m), 1.53−

1.41 (2H, m), 1.43 (3H, s), 1.04 (9H, s), 1.01 (3H, d, J = 7.0); δ_C

(100 MHz, CDCl₃) 135.6 (CH), 133.7 (C), 129.6 (CH), 127.8

(CH), 72.4 (CH₂), 63.2 (CH₂), 48.5 (CH), 42.1 (CH), 35.5 (CH₂),

26.8 (CH₃), 25.5 (CH₃), 19.1 (C), 12.1 (CH₃); m/z (ESI+) 421

(MNa⁺, 35%), 381 ([M − H₂O]H⁺, 22), 269 ([M − (C₆H₅)₂]Na⁺,

100), 247 ([M − (C₆H₅)₂]H⁺, 54); m/z (ESI+) found [M + Na]⁺

421.2145, calcd for C₂₄H₃₄O₃SiNa⁺421.2169.

(CH₂), 35.3 (CH₂), 34.4 (2 × CH₂), 31.8 (CH₂), 26.8 (CH₃), 25.0

(CH₂), 22.6 (CH₂), 19.1 (C), 14.0 (CH₃), 12.0 (CH₃); m/z (ESI+)

found [M + Na]⁺681.3178, calcd for C₃₉H₅₀O₇SiNa⁺681.3218.

Snider’s Allyl Ester 4. The compound was prepared from acid 54

by the method reported in the literature:⁴[α]_D= −63.1° (c 0.50,

20

CHCl₃) (lit.⁴[α]_D= −60.0° (c 2.31, CHCl₃)); δ_H(400 MHz,

22

CDCl₃) 7.67−7.64 (4H, m), 7.45−7.38 (6H, m), 6.23 (1H, s), 6.01−

5.92 (2H, m), 5.36 (1H, ddd, J = 17.4, 3.2, 1.6), 5.32 (1H, ddd, 17.4,

2.8, 1.6), 5.22 (1H, ddd, J, 10.4, 2.8, 1.6), 5.14 (1H, ddd, J = 10.4, 2.8,

1.6), 4.82−4.68 (3H, m), 4.51 (2H, ddd, J = 4.8, 1.6, 1.6), 4.20 (1H,

dd, J = 8.6, 8.6), 3.85−3.78 (1H, m), 3.70−3.62 (2H, m), 3.61 (1H,

dd, J = 8.6, 8.6), 2.74 (1H, dd, J = 16.8, 4.0), 2.60 (1H, dd, J = 16.8,

10.8), 2.29−2.19 (1H, m), 2.14 (1H, dd, J = 12.2, 5.4), 1.96 (1H, dd,

J = 12.2, 12.2), 1.88−1.81 (1H, m), 1.71−1.62 (2H, m), 1.54−1.25

(8H, m), 1.05 (9H, s), 1.00 (3H, d, J = 6.8), 0.90 (3H, t, J = 6.8); δ_C

(400 MHz, CDCl₃) 165.6 (C), 155.6 (C), 149.1 (C), 135.9 (C), 135.6

(CH), 133.64 (C), 133.61 (C), 133.0 (CH), 132.4 (CH), 129.7 (CH),

127.7 (CH), 118.1 (CH₂), 117.1 (CH₂), 114.7 (C), 109.7 (C), 108.8

(C), 104.4 (CH), 75.4 (CH), 73.4 (CH₂), 69.5 (CH₂), 68.2 (CH),

65.6 (CH₂), 63.3 (CH₂), 49.0 (CH), 41.4 (CH), 36.4 (CH₂), 35.7

(CH₂), 34.6 (CH₂), 34.5 (CH₂), 31.8 (CH₂), 26.9 (CH₃), 25.2 (CH₂),

22.6 (CH₂), 19.1 (C), 14.1 (CH₃), 11.7 (CH₃). The spectroscopic

data closely matched those previously reported.⁴

(3S,4S)-4-tert-Butyldimethylsilyloxymethyl-6-tert-butyldiphenylsi-

lyloxy-3-methylhexan-2-one (50). TBSCl (787 mg, 5.22 mmol) was

added to a solution of crude lactol 49 (∼2.61 mmol) and imidazole

(888 mg, 13.1 mmol) in dimethylformamide (20 mL) at room

temperature under argon. The reaction mixture was stirred at room

temperature for 4 h then diluted with diethyl ether, washed with water

and brine, dried (Na₂SO₄), and concentrated in vacuo to afford a pale

yellow oil. The crude product was purified by chromatography (silica

gel, 9/1 hexanes/ethyl acetate) to afford the title compound 50 (1.11

20

g, 83% over two steps) as a colorless oil: [α]_D= +16.8° (c 0.70,

CHCl₃); ν_max(film)/cm⁻¹2955, 2930, 2857, 1710, 1105, 1084, 835,

700; δ_H(400 MHz, CDCl₃) 7.66−7.63 (4H, m), 7.44−7.35 (6H, m),

3.66−3.60 (3H, m), 3.55 (1H, dd, J = 10.0, 8.0), 2.87−2.79 (1H, m),

2.22−2.16 (1H, m), 2.13 (3H, s), 1.54−1.46 (1H, m), 1.37−1.29 (1H,

m), 1.04 (9H, s), 0.95 (3H, d, J = 7.0), 0.87 (9H, s), 0.01 (3H, s,

SiCH₃), 0.00 (3H, s, SiCH₃); δ_C(100 MHz, CDCl₃) 212.6 (C), 135.6

(CH), 133.8 (C), 129.6 (CH), 127.7 (CH), 63.6 (CH₂), 62.1 (CH₂),

47.1 (CH), 39.0 (CH), 30.0 (CH₂), 28.7 (C), 26.9 (CH₃), 25.9 (CH₃),

19.2 (C), 18.2 (C), 10.9 (CH₃), −5.5 (CH₃), −5.6 (CH₃); m/z (ESI+)

535 (MNa⁺, 100%), 381 ([M − TBSOH]H⁺, 55); m/z (ESI+) found

[M + Na]⁺535.3027, calcd for C₃₀H₄₈O₃Si₂Na⁺535.3034.

ASSOCIATED CONTENT

■

S

* Supporting Information

Figures giving ¹H and ¹³C NMR spectra for all new

compounds. This material is available free of charge via the

Internet at http://pubs.acs.org.

(3S,4S)-4-tert-Butyldimethylsilyloxymethyl-6-tert-butyldiphenylsi-

lyloxy-3-methyl-2-trimethylsilyloxyhex-1-ene (51). TMSOTf (26 μL,

0.15 mmol) was added to a solution of methyl ketone 50 (50 mg,

0.097 mmol) and diisopropylethylamine (51 μL, 0.29 mmol) in

dichloromethane (1.5 mL) at 0 °C under argon. The reaction mixture

was stirred at 0 °C for 1.5 h and then diluted with dichloromethane,

washed with water, dried (Na₂SO₄), and concentrated in vacuo (water

bath <30 °C) to afford 51 (78 mg) as a colorless oil, which was used

directly in the next step.

AUTHOR INFORMATION

Corresponding Author

*E-mail: m.brimble@auckland.ac.nz.

■

ACKNOWLEDGMENTS

Financial assistance from the Royal Society of New Zealand

Marsden Fund is gratefully acknowledged.

■

Snider’s Acid 54. Boron trifluoride diethyl etherate (16 μL, 0.13

mmol) was added dropwise to a solution of lactol 7 (66 mg, 0.12

mmol) in dichloromethane (1.5 mL) at −78 °C under argon. The

resulting yellow solution was stirred at −78 °C for 5 min and then at

0 °C for 10 min and then recooled to −78 °C and a solution of crude

silyl enol ether 51 (78 mg) in dichloromethane (1.5 mL) added. The

resulting yellow solution was stirred at −78 °C for 30 min and then

quenched with saturated aqueous sodium hydrogen carbonate (2 mL),

warmed to room temperature, and extracted with dichloromethane.

The combined organics were dried (Na₂SO₄) and concentrated to

afford lactol 53 (130 mg) as a pale yellow oil, which was used in the

next step without further purification. A mixture of crude lactol 53,

10% Pd/C (25 mg), 2 M hydrochloric acid (3 drops), methanol

(3 mL), and ethyl acetate (3 mL) was placed under a balloon of hydrogen

and stirred vigorously at room temperature for 4 h and then filtered

through Celite with methanol washings and concentrated in vacuo to

afford a yellow oil (85 mg). The crude product was purified by

chromatography (silica gel, 19/1 hexane/ethyl acetate with 1.5% acetic

acid) to afford the acid 54 (37 mg, 58% from methyl ketone 50) as a

REFERENCES

■

(1) Wilson, Z. E.; Brimble, M. A. Nat. Prod. Rep. 2009, 26, 44.

(2) Stierle, A. S.; Stierle, D. B.; Kelly, K. J. Org. Chem. 2006, 71, 5357.

(3) Buchgraber, P.; Snaddon, T. N.; Wirtz, C.; Mynott, R.; Goddard,

R.; Furstner, A. Angew. Chem., Int. Ed. 2008, 47, 8450.

(4) Wu, X.; Zhou, J.; Snider, B. B. Angew. Chem., Int. Ed. 2009, 48,

1283.

(5) Wu, X.; Zhou, J.; Snider, B. B. J. Org. Chem. 2009, 74, 6245.

(6) Bender, C. F.; Yoshimoto, F. K.; Paradise, C. L.; De Brabander,

J. K. J. Am. Chem. Soc. 2009, 131, 11350.

(7) Snaddon, T. N.; Buchgraber, P.; Schulthoff, S.; Wirtz, C.; Mynott,

R.; Furstner, A. Chem. Eur. J. 2010, 16, 12133.

(8) Wenderski, T. A.; Marsini, M. A.; Pettus, T. R. R. Org. Lett. 2011,

13, 118.

(9) McLeod, M. C.; Wilson, Z. E.; Brimble, M. A. Org. Lett. 2011, 13,

5382.

(10) Wilson, Z. E.; Brimble, M. A. Org. Biomol. Chem. 2010, 8, 1284.

(11) Buechi, G.; Leung, J. C. J. Org. Chem. 1986, 51, 4813.

(12) Differing reactivities were observed, depending on the batch of

PtO₂used. Aldrich PtO₂·H₂O gold label (cat. no. 22,905-9) resulted in

significant hydrogenolysis of the benzyl groups, while that obtained

from Strem (cat. no. 7-1890) selectively reduced the alkyne group with

no observed debenzylation.

(13) Suri, J. T.; Truong, V.; Hernandez, A.; Congdon, J.; Bakthan, S.

Tetrahedron Lett. 2002, 43, 3649.

(14) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,

20

colorless solid: mp 105−107 °C (hexane); [α]_D= −60.3° (c 0.70,

CHCl₃); ν_max(film)/cm⁻¹3238, 2956, 2931, 2858, 1695, 1429, 1111,

1074, 702; δ_H(400 MHz, CDCl₃) 11.86 (1H, s), 11.17 (1H, br s),

7.67−7.64 (4H, m), 7.45−7.38 (6H, m), 6.45 (1H, s), 4.80 (1H, dd,

J = 12.0, 5.4), 4.28 (1H, dd, J = 8.7, 8.7), 3.87−3.80 (1H, m), 3.76 (1H,

dd, J = 8.7, 8.7), 3.73−3.69 (2H, m), 2.81 (1H, dd, J = 17.7, 4.1), 2.63

(1H, dd, J = 17.7, 10.8), 2.30−2.21 (2H, m), 2.09 (1H, dd, J = 12.2,

12.2), 1.95−1.85 (2H, m), 1.68−1.33 (7H, m), 1.11 (3H, d, J = 6.9),

1.06 (9H, s), 0.91 (3H, t, J = 6.9); δ_C(100 MHz, CDCl₃) 170.6 (C),

162.6 (C), 149.9 (C), 142.2 (C), 135.5 (CH), 133.4 (C), 129.8 (CH),

127.8 (CH), 112.5 (C), 112.2 (C), 110.4 (CH), 98.7 (C), 75.2 (CH),

74.2 (CH₂), 67.4 (CH), 62.8 (CH₂), 48.8 (CH), 41.9 (CH), 36.3

109, 5551.

(15) Yu, C.-M.; Kim, C.; Kweon, J.-H. Chem. Commun. 2004, 2494.

(16) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.

415

dx.doi.org/10.1021/jo201988m | J. Org. Chem. 2012, 77, 400−416

The Journal of Organic Chemistry

Article

(17) Gooding, O. W.; Bansal, R. P. Synth. Commun. 1995, 25, 1155.

(18) Smitrovich, J. H.; DiMichele, L.; Qu, C.; Boice, G. N.; Nelson,

T. D.; Huffman, M. A.; Murry, J. J. Org. Chem. 2004, 69, 1903.

(19) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky,

D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.

(20) Henderson, J. R.; Parvez, M.; Keay, B. A. Org. Lett. 2009, 11,

3178.

(21) Williams, D. R.; Mullins, R. J.; Miller, N. A. Chem. Commun.

2003, 2220.

(22) Wilding, E. E.; Gregg, J. J.; Mullins, R. J. Synlett 2010, 793.

(23) Nakamura, S.; Kikuchi, F.; Hashimoto, S. Tetrahedron:

Asymmetry 2008, 19, 1059.

́ ́

(24) Fernandez-Zertuche, M.; Robledo-Perez, R.; Meza-Avina, M. E.;

Ordonez-Palacios, M. Tetrahedron Lett. 2002, 43, 3777.

(25) McGarvey, G. J.; Williams, J. M. J. Am. Chem. Soc. 1985, 107,

1435.

(26) See the Supporting Information.

(27) Sibi, M. P.; Johnson, M. D.; Punniyamurthy, T. Can. J. Chem.

2001, 79, 1546.

(28) Romo, D.; Rzasa, R. M.; Shea, H. A.; Park, K.; Langenhan, J. M.;

Sun, L.; Akhiezer, A.; Liu, J. O. J. Am. Chem. Soc. 1998, 120, 12237.

(29) Brzezinski, L. J.; Rafel, S.; Leahy, J. W. Tetrahedron 1997, 53,

16423.

(30) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;

Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,

2183.

(31) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6,

3217.

(32) Ditrich, K.; Hoffmann, R. W. Tetrahedron Lett. 1985, 26, 6325.

(33) Nicolaou, K. C.; Patron, A. P.; Ajito, K.; Richter, P. K.; Khatuya,

H.; Bertinato, P.; Miller, R. A.; Tomaszewski, M. J. Chem. Eur. J. 1996,

2, 847.

(34) Han, H.; Cho, C.-W.; Janda, K. D. Chem. Eur. J. 1999, 5, 1565.

416

dx.doi.org/10.1021/jo201988m | J. Org. Chem. 2012, 77, 400−416

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