Total synthesis of (+)-ambruticin S

Tetrahedron 59 (2003) 6819–6832

Total synthesis of (1)-ambruticin S

Stephen M. Berberich, Robert J. Cherney, John Colucci, Christine Courillon, Leo S. Geraci,

*

Thomas A. Kirkland, Matthew A. Marx, Matthias F. Schneider and Stephen F. Martin

Department of Chemistry and Biochemistry, The University of Texas, 1 University Station A5300, Austin, TX 78712, USA

Received 21 January 2003; revised 10 March 2003; accepted 10 March 2003

Dedicated to Professor K. C. Nicolaou in recognition of his many contributions to organic chemistry and his receipt of the Tetrahedron Prize

Abstract—A convergent total synthesis of the novel antifungal agent ambruticin S (1) has been completed from the assembly of

intermediates 18, 33 and 52 that served as the respective A-, B-, and C-ring precursors. The ﬁrst generation approach to a potential A-ring

intermediate eventuated in the synthesis of 9a via a route that featured oxidation of the dihydroxy furan 2 and elaboration of the

dihydropyranone 3 derived therefrom. Although 9a served as a precursor of 31E to complete a formal synthesis of 1, there were several

inefﬁciencies associated with the preparation of 9a. A more expedient and efﬁcient route to an A-ring subunit was devised that commenced

with the carbohydrate-derived bisacetonide aldehyde 10 and produced 18 in ﬁve steps and 46% overall yield. The synthesis of the

cyclopropyl sulfone 33 was initiated with the enantioselective cyclopropanation of 19 catalyzed by Rh₂[5(S)-MEPY]₄. Ring opening of the

resultant lactone 20 followed by a series of refunctionalizations gave 33 in a total of seven steps and 46% yield from 19. Coupling of the A-

and B-ring precursors 18 and 33 was then achieved via a modiﬁed Julia coupling followed by deprotection and oxidation to furnish the key

intermediate 35. The dihydropyran core of the C-ring subunit precursor 49 was formed from the ring closing metathesis of the diene 48,

which was prepared in three steps from the known epoxide 45, followed by oxidation. A chelation-controlled addition to the methyl ketone

49 set the stage for a stereoselective [2,3]-Wittig rearrangement that delivered the alcohol 51 that was then transformed in two steps to the

sulfone 52. A traditional Julia coupling of 52 and 35 proceeded with excellent stereoselectivity, and subsequent removal of the various

protecting groups gave ambruticin S (1). The longest linear sequence was 13 steps and proceeded in 4.3% overall yield.

1. Introduction

upon heating at 2408C to give a cycloheptadiene derivative

that showed no biological activity, suggesting that the

divinyl cyclopropane is required for biological activity.⁴

Ambruticin S (1) is a structurally novel antifungal antibiotic

that was isolated from the fermentation extracts of

Polyangium cellulosum var. fulvum in 1977 by researchers

at Warner–Lambert.¹Ambruticin S was initially considered

an interesting lead compound because of its low toxicity

coupled with its oral activity against several systemic fungal

infections.²Following its discovery, a combination of

extensive chemical and spectral analysis was ﬁrst employed

to elucidate the gross structural features of 1. However,

owing to its complexity, it was necessary to determine the

relative stereochemical structure of 1 by X-ray analysis of a

crystalline triformate derivative that was prepared from 1 by

sequential hydride reduction and exhaustive formylation.¹

The absolute conﬁguration of 1 was later established

through the independent synthesis of ozonolysis fragments.³

The presence of a divinyl cyclopropane linking two

hydropyranoid fragments in a natural product was unprece-

dented. It has also been shown that this divinyl cyclo-

propane moiety undergoes a sigmatropic rearrangement

Subsequent to their initial report, Connor’s group at

Warner–Lambert isolated the 5-epi-isomer of 1,⁵and they

prepared a number of synthetic derivatives to explore the

structure activity relationships of ambruticin analogues.⁶

More recently, six natural ambruticins possessing quatern-

ary amines in the place of the C5 hydroxyl group were

isolated from P. cellulosum, and these compounds also

exhibited potent in vivo antifungal activity and low

toxicity.⁷Taken together, the biological studies demonstrate

that the presence of polar functionality at C1, C5 and C6

was critical to the biological activity of the ambruticins. The

mechanism of action of 1 has recently been studied and

appears to involve interference with osmoregulation.⁸

However, the narrow spectrum of antifungal activity

exhibited by ambruticin S and its analogues limited the

clinical utility of these compounds.

The shortcomings of its biological proﬁle notwithstanding,

ambruticin S remains an extremely attractive target for total

synthesis because of its unique structural features. Indeed, a

number of groups have developed synthetic approaches

toward ambruticin S.⁹The ﬁrst total synthesis of 1 was

Keywords: oxygen heterocycles; furan; carbohydrates; enantioselective;

rearrangement; ring closing metathesis; Julia coupling.

*

Corresponding author. Tel.: þ1-512-471-3915; fax: þ1-512-471-4180;

e-mail: sfmartin@mail.utexas.edu

doi:10.1016/S0040-4020(03)00370-3

6820

S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832

reported by Kende in 1990,¹⁰but three additional syntheses

of 1 have recently been independently reported by

ourselves¹¹and the groups of Jacobsen¹²and Lee.¹³

enantioselective reduction of 1-furyl-3-hydroxyacetone¹⁸

using Baker’s yeast,¹⁹this technique proved rather cumber-

some on large scale, and we found that the Sharpless

dihydroxylation of vinyl furan²⁰provided an excellent

alternative route to large quantities of 2.²¹Oxidation of 2

with singlet oxygen then furnished a mixture of anomeric

pyranones 3, which underwent acid-catalyzed cyclization to

give the bicyclic ketal 4 in 61% yield from 2 (Scheme 2).

Subsequent to our developing this approach to 4, Ogasawara

and co-workers published a closely related synthesis of 4

from 2.²²Reduction of 4 by catalytic hydrogenation

followed by reaction of the enolate of the resultant ketone

with PhNTf₂gave 5, reduction of which with Bu₃SnH

provided the bicyclic oleﬁn 6 in 50% overall yield.^23,24The

double bond in 6 was oxidized with m-chloroperbenzoic

acid (MCPBA), and the resulting mixture of a- and

b-epoxides was treated with KOH to give a single

diastereomeric diol that was converted to the dibenzyl

ether 7.²⁵The stereochemical outcome of the epoxide

opening reaction may be attributed to the preference for

hydroxide to attack the epoxide from an axial direction

irrespective of which diastereomeric epoxide was the

substrate.

Our analysis of the challenges posed by ambruticin S led to

the retrosynthetic analysis outlined in Scheme 1 in which

disconnections at the two disubstituted E-oleﬁns are ﬁrst

performed. The three fragments obtained from these

disconnections were an A-ring aldehyde A, a bifunction-

alized B-ring cyclopropane B and a C-ring sulfone C. Each

of these fragments has a similar degree of stereochemical

and functional complexity, thereby endowing the approach

with maximal convergency. We originally envisioned that

the central B ring fragment would be accessible via

methodology we had developed in collaboration with the

Doyle group for the enantioselective synthesis of tri-

substituted cyclopropanes via cyclizations of allylic

diazoacetates in the presence of a chiral rhodium catalyst.¹⁴

There were a number of options for constructing the

hydropyranoid A and C ring subunits. At the outset,

however, we had a particular prejudice for preparing these

fragments from dihydropyranones that would be prepared

via the oxidation of enantiomerically pure furans according

to strategies that have been under extensive development in

our laboratories.^15,16Carbohydrates were also considered as

potential precursors of the A and C rings. Although a

carbohydrate was ultimately chosen as the starting material

for the A ring, the C ring was eventually most readily

prepared by a ring closing metathesis, a transformation that

has gained considerable importance in natural product

synthesis.¹⁷We now report the details of our studies

directed toward the total synthesis of 1.

Scheme 1.

Scheme 2.

2. Results and discussion

2.1. Approaches to the A-ring

With 7 in hand, it remained to install an acetic acid side

chain at C(3) to complete construction of the A-ring

subunit.²⁶Although 7 did react with the trimethylsilyl-

and tert-butyldimethylsilylketene acetals derived from

methyl acetate in the presence of Lewis acids,²⁷the yields

were poor with optimized yields being less than 15%. On

the other hand, reaction of 7 with allyltrimethylsilane in the

presence of TiCl₄provided a mixture (1:4) of the anomeric

C-glycosides 8a,b.^28,29These diastereomers were readily

In our ﬁrst approach to a protected A-ring subunit, we

explored the use of the dihydropyranone 3, which was

prepared by oxidation of the hydroxy furan 2, as a key

intermediate. We had previously shown that various

dihydropyranones thus obtained admirably served as

intermediates in concise syntheses of highly oxygenated

natural products.¹⁶Although we initially prepared 2 by the

S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832

6821

separable and were independently subjected to ozonolysis

followed by oxidation with Br₂in aqueous methanol to

furnish the esters 9a and 9b. Both 9a and 9b gave H and

¹³C NMR spectral data that were consistent with those

reported by Donaldson,³⁰who also showed that 9b could be

readily epimerized to provide exclusively the desired isomer

9a.

trichloroacetimidate and benzyl bromide/silver oxide under

a variety of conditions gave unsatisfactory yields of the

desired dibenzyl ether 14.^34,35Ultimately we found that this

benzylation could be most effectively achieved by reaction

of 13 with benzyl triﬂate that was prepared in situ to furnish

14 in 51% yield.³⁶

1

Heating 14 with NaOMe in MeOH induced a cascade of

reactions involving cleavage of the cyclic carbonate group,

transesteriﬁcation of the ethyl ester, and intramolecular

Michael reaction that led to the formation of 9a. If this

reaction was allowed to proceed for short periods of time,

the C(3) epimeric ester 9b could be observed in the mixture.

However, heating the reaction mixture overnight effected

the complete equilibration of any 9b produced into 9a via a

retro-Michael/Michael process, although these conditions

resulted in signiﬁcant saponiﬁcation of the methyl ester, a

side reaction that was also observed by Donaldson.³⁰Hence,

the acid that was produced during this process was esteriﬁed

in situ by simply adding an excess of TsOH to the cooled

reaction mixture to deliver 9a in 75% overall yield from 14.

The sequence outlined in Scheme 2 provided a successful

entry to the A-ring subunit of ambruticin S, but we were

interested in developing a stereochemically more efﬁcient

route. After considering a number of possibilities, it

occurred to us that the known aldehyde 10 (Scheme 3),

which could be easily synthesized from commercially

available ^L-glucono-1,5-lactone,³¹might be a suitable

starting material. In the event, stereoselective Wittig

oleﬁnation of 10 provided ester 11. The terminal acetonide

moiety was selectively removed by the action of p-TsOH in

aqueous ethanol, and the intermediate diol was reprotected

as a cyclic carbonate.³²The subsequent deprotection of the

internal acetonide of 12 to give 13 proved troublesome, as

the carbonate function was too labile to withstand the

standard acidic conditions required for acetonide cleavage.

Eventually, we discovered that the acetonide group could be

cleanly removed using CuCl₂in acetonitrile to give the diol

13 in good overall yield from 10.³³The instability of the

carbonate to relatively mild acidic conditions served as a

harbinger of the difﬁculties that would follow as we found

that the cyclic carbonate in 13 was incompatible with a

number of standard conditions that are often employed to

prepare O-benzyl ethers. For example, the use of benzyl

ˆ

After we completed this route to 9a, Genet reported a

similar one-pot equilibration and esteriﬁcation procedure

for its preparation.^9kOxidation of the primary alcohol group

in 9a using Dess–Martin periodinane³⁷furnished 15, which

exhibited spectral properties consistent with those pre-

viously reported,^9kin seven steps and 18% overall yield

from 10. This stereoselective synthesis of 9a thus

represented a signiﬁcant improvement over the approach

outlined in Scheme 2 in which 9a was prepared in 11 steps

and 12% overall yield via a sequence that required a

separation of diastereomers.

The route to the A-ring aldehyde 15 summarized in

Scheme 3 was reasonably efﬁcient and was originally

employed to produce the quantities of material that were

needed to explore various model Julia couplings to append

the B ring (vide infra). However, the need to manipulate the

hydroxyl protecting groups was viewed as a serious

drawback to the approach, and so we developed an even

more expeditious synthesis of a suitable A-ring precursor.

Thus, 11 was heated with H₂SO₄in MeOH to cleave both

acetonides and provide a complex mixture containing the

Scheme 4.

Scheme 3.

6822

S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832

corresponding open-chain tetraol together with tetrahydro-

furans and tetrahydropyrans derived from the acyclic tetraol

via intramolecular Michael addition reactions (Scheme 4).

Precedent suggested that tetrahydrofurans might be kinetic

products,³⁸but on the basis of preliminary molecular

mechanics calculations,³⁹we were seduced into thinking

that the desired tetrahydropyran 16 would be signiﬁcantly

more stable than the tetrahydrofurans. Gratifyingly, 16 was

isolated in 70% overall yield when this mixture was heated

under reﬂux in methanolic NaOMe for 24 h and the

resulting reaction mixture was acidiﬁed with H₂SO₄.

2.2. Synthesis of a B-ring subunit

At the outset of our studies we envisioned that suitable

B-ring subunit precursors would be best accessed via an

enantioselective cyclopropanation using a protocol that we

had developed previously.¹⁴Thus, the known diazoacetate

19 was heated in the presence of Rh₂[5(S)-MEPY]₄to

provide the bicyclic lactone 20 in 80% yield and 92%

enantiomeric excess (Scheme 5).⁴⁰The lactone ring was

opened using morpholine and AlMe₃according to the

Weinreb protocol to give alcohol 21.⁴¹Inasmuch as we

wanted a robust alcohol protecting group to explore various

tactics for coupling the A and B rings (vide infra), the

alcohol 21 was protected as its TIPS ether 22. Base-induced

epimerization of the stereocenter alpha to the carbonyl

group in 22 to give 23 was driven by the conversion of the

more sterically congested all cis-trisubstituted cyclopropane

into a less strained cyclopropane ring in which the

carboxamide group was trans to the other two substituents.

Reduction of the amide moiety to give the requisite primary

alcohol 24 was smoothly effected with the LDA and

borane–ammonia complex reagent reported by Myers.⁴²

Anticipating the union of the A and B subunits via a

standard Julia coupling procedure, the alcohol 24 was

converted into its derived phenyl sulﬁde that was then

oxidized with MCPBA to give the sulfone 25.⁴³

Transformation of 16 into an A-ring aldehyde then

necessitated protection of the two secondary alcohols.

Toward this objective, the primary alcohol of 16 was ﬁrst

selectively protected by reaction with TESCl at 08C;

however, several attempts to benzylate the secondary

alcohols to prepare a precursor of 15 were unsuccessful.

Another protecting group for these hydroxyl groups was

thus indicated. Although we were unable to convert these

alcohols cleanly into their TIPS ethers, the corresponding

TBS ethers were readily formed. Indeed, the entire sequence

of protecting the primary alcohol of 16 and then the two

secondary alcohols with TBS groups could be conveniently

performed in a one-pot procedure to provide ester 17 in

nearly quantitative yield. Selective deprotection of the TES

group with TFA followed by oxidation of the resulting

alcohol provided the A-ring aldehyde 18 in ﬁve steps and

46% overall yield from 10. This yield represented a

signiﬁcant improvement over previous routes to similar

compounds.

2.3. Coupling the A-ring and B-ring subunits

Preliminary experiments directed toward joining the A- and

B-ring subunits 15 and 25 via a classic Julia coupling were

fraught with pitfalls (Scheme 6). For example, when 15 was

treated with the carbanion obtained upon deprotonation of

25 with either n-BuLi or NaHMDS, none of the desired

adduct was obtained. Rather sulfone 25 was isolated

together with an unsaturated aldehyde that appeared to

arise from 15 through deprotonation followed by elimin-

ation of benzyl alkoxide. Some years ago, Lythgoe

discovered a solution to this problem and reported that

magnesium, rather than lithium or sodium, salts of sulfones

added cleanly to highly enolizable aldehydes.⁴⁴We found,

Scheme 5.

Scheme 6.

S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832

6823

however, that direct deprotonation of 25 with EtMgBr was

sluggish, even at elevated temperature, and provided only

about 50% of the deprotonated sulfone as determined by

quenching of the reaction mixture with CD₃OD. On the

other hand, deprotonation of 25 with n-BuLi at 2788C

proceeded quantitatively. The resulting lithiated sulfone

was transmetallated by reaction with ethereal MgBr₂·Et₂O

prepared according to the procedure of Seebach⁴⁵to provide

the corresponding magnesio sulfone,⁴⁶which did react with

the aldehyde 15 to furnish a mixture of diastereomeric

hydroxy sulfones 26, albeit in modest yield.

signiﬁcant quantities of a bisbenzothiazole sulfone, which

was presumably formed through a disproportionation

reaction as described by Kocienski.⁵³However, when a

solution of 15 and 30 in DMF was treated with NaHMDS,

the desired alkene 27 together with its Z-isomer were

obtained. Although these isomers were inseparable, removal

of the TIPS protecting group provided a separable mixture

of the alcohols 31E and 31Z in a 1.4 to 1 ratio. The 31E thus

1

exhibited H NMR spectral characteristics consistent with

those reported by Kende,^10bthus completing a formal total

synthesis of ambruticin S.^11a

Despite this success, converting the diastereomeric hydroxy

sulfones 26 into the desired oleﬁn 27 proved to be

problematic. When 26 was subjected to standard conditions

using sodium amalgam to effect reductive elimination, none

of the desired 27 could be detected in the reaction mixture,

and no other identiﬁable products were isolated. We

speculated that these difﬁculties might be a consequence

of ring opening of the cyclopropyl carbinyl radical that

would be generated upon homolytic scission of the carbon–

sulfur bond. In one attempt to avoid forming this putative

radical intermediate, 26 was transformed into the xanthate

28, but reaction of 28 with Bu₃SnH failed to provide 27.⁴⁷

Falck had encountered similar difﬁculties in related

constructions, and he solved his problem by discovering

that cyclopropyl vinyl sulfones could be reduced by electron

transfer to give the corresponding vinyl cyclopropanes.⁴⁸In

order to explore this tactic as a possible solution to our

dilemma, we converted several model cyclopropyl hydroxy

sulfones into the corresponding vinyl cyclopropanes by

sequential dehydration using either Tf₂O or the Martin

sulfurane⁴⁹and reduction of the resultant vinyl sulfone.

However, we were unable to induce efﬁcient elimination of

26 to the vinyl sulfone 29.

We were, of course, interested in improving the E/Z ratio in

this coupling process. Julia,⁵⁴Kocienski⁵¹and Charette⁵²all

reported that the E/Z ratio in their studies was dependent

upon both the solvent and the counterion employed. In

contrast, we found that changing the solvents (THF, DME,

DMF and Et₂O) as well as the counterions (Na and K) had

little effect upon the E/Z ratio in this reaction. Use of the

phenyl tetrazole sulfone corresponding to 30 as described by

Kocienski also afforded no advantage.⁵¹Although we

brieﬂy examined the possibility of isomerizing the unde-

sired cis-isomer 31Z using iodine, these experiments were

unavailing, and we therefore had to be content with the

result.

Contemporaneous with the successful coupling of 15 with

30, we developed the improved synthesis of the modiﬁed

A-ring precursor 18 that is summarized in Scheme 4. In

planning this approach, ancillary studies suggested that TBS

ethers on the A-ring might not be fully compatible with the

conditions required to remove the TIPS protecting group

from the primary cyclopropyl carbinol in an advanced AB-

ring intermediate. We thus prepared the TBS-protected

benzothiazole sulfone 33 following the procedures pre-

viously developed for the synthesis of 30 (Scheme 8). The

A-ring aldehyde 18 and the sulfone 33 were then coupled

using the previously optimized conditions to give a mixture

(2.6:1) of isomeric E- and Z-alkenes. Although the E/Z ratio

was somewhat higher for this reaction than for the

corresponding coupling of 30 and 15, the overall yield

Given these failures using a phenyl sulfone and the classic

Julia procedure, we turned to modiﬁed Julia coupling

methods in which the anion of either a benzothiazole

sulfone⁵⁰or a phenyl tetrazole sulfone⁵¹is employed as the

reacting nucleophile. Aldehyde adducts derived from both

of these sulfones were known to eliminate spontaneously in

situ, and Charette had exploited such couplings to form

vinyl cyclopropanes.⁵²Toward applying this methodology

to solving the problem in our synthesis, the benzothiazole 30

was ﬁrst prepared from 24 (Scheme 7). The stepwise

procedure of deprotonating 30 followed by adding 15 gave

Scheme 7.

Scheme 8.

6824

S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832

was slightly lower. This mixture of fully protected

geometric isomers was separable, but the chromatography

was tedious. Because the corresponding primary alcohols

were easy to separate, the mixture of alkenes formed from

the Julia coupling was simply treated with aqueous

CF₃CO₂H to selectively remove the TBS group from the

primary alcohol function to give 34E and 34Z. Oxidation of

the primary hydroxyl group of 34E using Dess–Martin

periodinane then furnished the aldehyde 35.³⁷

organometallic species or 41 under a wide variety of

conditions. This inability to add organometallic reagents to

lactone 39 necessitated a dramatic change in our approach to

the C-ring subunit of ambruticin S.

Inasmuch as we were concurrently exploiting ring closing

metathesis (RCM) as a key step in several other projects,⁶¹it

occurred to us that such a construction might constitute a

useful entry to the C-ring. Toward this end, we developed an

improved enantioselective synthesis of the known alcohol

42⁶²in 53% yield and 97% ee by the TADDOL-mediated

addition of Et₂Zn to methacrolein.⁵⁷This alcohol was then

O-alkylated with tert-butyl bromoacetate under phase

transfer conditions, and the enolate derived from the

resulting ester was alkylated with allyl bromide to provide

diene 43 as a mixture (1:1.3) of diastereomers (Scheme 10).

Although small amounts of each diastereomer could be

obtained through careful chromatography, this procedure

would obviously not be amenable to preparing larger

quantities of material. Hence, the mixture was stirred at

room temperature in the presence of Grubbs’ catalyst⁶³to

provide the dihydropyran 44, also as a mixture (1:1.3) of

diastereomers. We had originally anticipated that this

mixture could be equilibrated using base to provide the

desired cis-2,6-disubstituted hydropyran exclusively.

Unfortunately, exposing 44 to a variety of bases in different

solvents simply returned the same ratio of C(18) epimers.

2.4. Synthesis of the C-ring

Our initial approach to the C-ring was based on the

oxidative rearrangement of hydroxy furans that we had

previously exploited in our laboratories.¹⁶We ﬁrst

developed

a

new procedure for preparing the

known enone 36⁵⁵via the singlet oxygen oxidation of

(þ)-1-furyl-1-propanol,⁵⁶which was synthesized by the

TADDOL-mediated addition of Et₂Zn to furfural.⁵⁷Silyla-

tion of 36 provided 37a,b as a mixture (3:1) of anomers

(Scheme 9). In principle, each of these anomers could have

been transformed into the lactone 39; however, because the

ensuing 1,4-reduction of 37b was not clean, they were

separated and 37a was used in subsequent experiments. In

order to avoid epimerization of the stereocenter bearing the

ethyl side chain during conjugate reduction, it was

necessary to add 37a to a solution of ^L-Selectride according

to a protocol developed by Paquette.⁵⁸The intermediate

enolate was trapped as its triﬂate, which was then treated

with Me₂CuLi to deliver the trisubstituted oleﬁn 38.⁵⁹

Removal of the silyl protecting group followed by PCC

oxidation of the resultant lactol provided the lactone 39.

Scheme 10.

Although this study clearly demonstrated the viability of

using a RCM reaction to assemble the C-ring hydropyran

with its trisubstituted double bond, it also revealed the

necessity of correctly establishing the stereocenter at C(18)

prior to ring formation. A different diene was thus required

as a starting material. Toward this goal, the known epoxide

45⁶⁴was converted into its tosylate 46 (Scheme 11). The

ring opening of the epoxide moiety of 46 with 42 in the

presence of BF₃·Et₂O proceeded regioselectively as

expected to give 47,⁶⁵and reduction of the tosylate

with LiAlH₄gave the requisite diene 48 in 65%

overall yield from 46. Heating 48 with Grubbs’ catalyst

followed by oxidation of the intermediate alcohol with

catalytic TPAP provided the methyl ketone 49 as a single

diastereomer.

Scheme 9.

We had originally envisioned that addition of an organo-

metallic reagent such as 41⁶⁰to lactone 39 followed by

reduction with Et₃SiH and BF₃·Et₂O would provide the

C-ring subunit 40. Unfortunately, this expectation was

overly optimistic as we obtained at best low yields of

adducts from reactions of 39 with either simple vinyl

With ketone 49 in hand, it remained to append the C-14 to

C-17 segment that would be linked to the AB-ring subunit

35. We reasoned that this goal might be best achieved using

a [2,3]-Wittig rearrangement. Toward this end, addition of

propenylmagnesium bromide to 49 proceeded with

S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832

6825

the aldehyde 35 and the C-ring sulfone 52 (Scheme 12). In

the event, deprotonation of 52 with n-BuLi followed by

addition of 35 provided a mixture of diastereomeric hydroxy

sulfones that was not characterized. Rather, the mixture was

treated directly with Na/Hg to provide 53E/Z as an

inseparable mixture (E/Z<10:1) of isomers in 56%

combined yield.⁷⁰When the TBS protecting groups were

removed with HF·pyridine, the ambruticin S methyl ester

(54) was isolated in 50% overall yield from 52. The 54 thus

1

obtained exhibited H NMR spectral characteristics con-

sistent with those previously reported.^10bSaponiﬁcation of

54 with LiOH delivered synthetic (þ)-ambruticin S (1),

which was identical with an authentic sample of natural

ambruticin S by TLC, ¹H and ¹³C NMR (including HMQC),

MS and optical rotation.

3. Conclusions

A highly convergent synthesis of ambruticin S (1) was

accomplished in 28 total steps with a 4.3% overall yield for

the longest linear sequence, which comprised only 13 steps

from the cyclopropyl lactone 20. The synthesis featured a

catalytic enantioselective cyclopropanation for the prep-

aration of the B-ring precursor of 1. A RCM reaction and a

stereoselective [2,3]-Wittig rearrangement were utilized to

construct the C-ring subunit, whereas the A-ring subunit

was prepared from a carbohydrate. The synthesis also

highlighted a modiﬁed Julia coupling to join the A- and

B-ring fragments and a traditional Julia coupling to

complete the assembly of the skeletal framework.

Scheme 11.

chelation control and with .95% diastereoselectivity to

give the tertiary alcohol 50,⁶⁶which was alkylated with

trimethyltinmethyl iodide⁶⁷to provide an intermediate

stannane. When this stannane was treated with n-BuLi, a

highly diastereoselective (.20:1) [2,3]-Wittig rearrange-

ment ensued to give the homoallylic alcohol 51,⁶⁸which

possessed both the requisite S-conﬁguration at C(15) and the

E-oleﬁn geometry at C(16)–C(17). Transformation of 51

into the sulfone 52 was achieved in 89% overall yield by

sequential reaction with N-thiophenylsuccinimide and

PBu₃, followed by oxidation of the intermediate sulﬁde

with ammonium molybdate/H₂O₂.⁶⁹

4. Experimental

4.1. General

All reagents and solvents were used as received, except as

noted below. Tetrahydrofuran (THF), diethyl ether (Et₂O),

toluene, dimethylformamide (DMF), and methanol (MeOH)

were puriﬁed using solvent columns as described by

Grubbs.⁷¹Dichloromethane (CH₂Cl₂), diisopropylamine,

and triethylamine (NEt₃) were distilled from CaH₂. All

moisture sensitive reactions were performed under a

nitrogen or argon atmosphere in oven dried glassware.

Flash chromatography was performed using Merck silica

gel 60 (230–400 mesh ASTM) according to the Still

protocol.⁷²Percent yields are given for compounds that

The stage was then set for the ﬁnal assembly of the

ambruticin S framework via the Julia coupling between

1

were $95% pure as judged by H NMR spectroscopy. H

and ¹³C NMR spectra were recorded on 300 or 500-MHz

spectrometers in CDCl₃unless otherwise speciﬁed; indi-

vidual peaks are reported as (multiplicity, coupling constant

in Hz, number of hydrogens). Spectral splitting patterns are

designated as: s, singlet; d, doublet; t, triplet; q, quartet; m,

multiplet; comp, complex multiplet; br, broad. Melting

points are uncorrected.

4.1.1. (5S,6R,7S)-5,6;7,8-Diisopropylidene-5,6,7,8-tetra-

hydroxyoct-2-enoic acid, ethyl ester (11). A solution of

aldehyde 10³¹(0.10 g, 0.41 mmol) and carboethoxymethyl-

ene triphenylphosphorane (0.21 g, 0.61 mmol) in THF

(3 mL) was stirred at room temperature for 18 h. The

solvent was removed under reduced pressure, and the

Scheme 12.

6826

S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832

resulting paste was ﬁltered through a plug of silica gel using

Et₂O (75 mL). The ﬁltrate was concentrated under reduced

pressure, and the resulting yellow oil was puriﬁed by ﬂash

chromatography over silica gel eluting with EtOAc/hexanes

(15:85) to provide 110 mg (85%) of 11 as a clear colorless

3.09 (ddd, J¼9.0, 5.0, 2.1 Hz, 1H), 2.56 (dd, J¼15.4,

7.4 Hz, 1H), 2.35 (dd, J¼15.3, 5.8 Hz, 1H), 1.97 (ddd,

J¼12.7, 4.8, 1.8 Hz, 1H), 1.32 (q, J¼12.6 Hz, 1H), 0.93 (t,

J¼8.0 Hz, 9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.54 (q,

J¼8.1 Hz, 6H), 0.07 (s, 3H), 0.06 (s, 9H); ¹³C NMR d

171.5, 81.3, 74.8, 72.8, 71.4, 62.5, 51.5, 40.7, 40.6, 26.4,

26.2, 18.4, 18.1, 6.7, 4.6, 22.8, 22.9, 23.9, 24.7; IR (neat)

2956, 2359, 1748, 1471, 1255 cm²¹; MS (CI) m/z 563.3622

[C₂₇H₅₉O₆Si₃(Mþ1) requires 563.3620] (base), 533, 505,

431, 299.

1

oil: H NMR d 7.04 (dt, J¼15.7, 7.2 Hz, 1H), 5.94 (dt,

J¼15.7, 1.2 Hz, 1H), 4.19 (q, J¼7.1 Hz, 2H), 4.15–3.90

(comp, 4H), 3.57 (t, J¼8.0 Hz, 1H), 2.73 (dddd, J¼16.8,

8.2, 3.4, 1.6 Hz, 1H), 2.50 (dddd, J¼15.3, 8.9, 7.7, 1.6 Hz,

1H), 1.40 (s, 3H), 1.39 (s, 3H), 1.36 (s, 3H), 1.34 (s, 3H),

1.29 (t, J¼7.1 Hz, 3H); ¹³C NMR d 166.3, 144.4, 123.6,

110.0, 109.3, 80.5, 78.8, 77.1, 67.8, 60.2, 35.8, 27.1, 26.9,

26.7, 25.2, 14.2; IR (neat) 2986, 2874, 1746, 1658, 1455,

1372 cm²¹; MS (CI) m/z 315.1809 [C₁₆H₂₇O₆(Mþ1)

requires 315.1808] (base), 275, 257, 217.

4.1.4. [2,3-Bis-O-tert-butyldimethylsilyl-4,6-dideoxy-6-

(methoxycarbonyl)-^D-gluco-b-C-pyranosyl]methanol. A

solution of 17 (36 mg, 0.064 mmol) and triﬂuoroacetic acid

(0.049 mL, 0.64 mmol) in THF (2 mL) and H₂O (0.1 mL)

was stirred for 3 h at room temperature. Saturated aqueous

NaHCO₃(4 mL) and Et₂O (4 mL) were added, and the

layers were separated. The aqueous layer was extracted with

Et₂O (2£2 mL), and the combined organic layers were dried

(MgSO₄) and concentrated under reduced pressure. The

resulting clear oil was puriﬁed by ﬂash chromatography

over silica gel eluting with EtOAc/hexanes (1:4) to provide

23 mg (81%) of alcohol as a clear colorless oil: ¹H NMR d

3.93–3.88 (m, 1H), 3.81 (dd, J¼11.4, 2.8 Hz, 1H), 3.75–

3.69 (m, 1H) 3.72 (s, 3H), 3.60 (dd, J¼11.4, 6.2 Hz, 1H),

3.34 (t, J¼7.8 Hz, 1H), 3.25 (ddd, J¼9.1, 6.2, 2.8 Hz, 1H),

2.58 (dd, J¼15.5, 7.7 Hz, 1H), 2.44 (dd, J¼15.5, 5.3 Hz,

1H), 2.02 (ddd, J¼12.9, 4.8, 1.9 Hz, 1H), 1.58 (br s, 1H),

1.42 (q, J¼12.9 Hz, 1H), 0.92 (s, 9H), 0.91 (s, 9H), 0.12 (s,

3H), 0.11 (s, 6H), 0.10 (s, 3H); ¹³C NMR (CDCl₃,

125 MHz) d 171.1, 80.4, 74.4, 73.2, 71.7, 62.6, 51.7, 40.6,

40.4, 26.3, 26.1, 18.3, 18.0, 22.8, 22.9, 24.1, 24.6; IR

(neat) 3506, 2964, 2353, 2334, 1745, 1467 cm²¹; MS (CI)

m/z 449.2751 [C₂₁H₄₅O₆Si₂(Mþ1) requires 449.2755]

(base), 433, 391, 317, 301.

4.1.2. [4,6-Dideoxy-6-(methoxycarbonyl)-^D-gluco-b-C-

pyranosyl]methanol (16). A solution of H₂SO₄(0.1 M in

MeOH, 0.57 mL) was added to a solution of 11 (90 mg,

0.29 mmol) in anhydrous MeOH (3 mL), and this mixture

was heated under reﬂux for 3 h. The reaction was cooled to

room temperature and the solvent removed in vacuo. The

resultant white solid was redissolved in MeOH (3 mL), and

the solution heated under reﬂux for 3 h; this process was

repeated an additional time. The reaction was then stirred

for 16 h at room temperature, at which time NaOMe (0.5 M

in MeOH, 0.86 mL) was added. This mixture was heated

under reﬂux for an additional 24 h. The solution was then

cooled to room temperature and H₂SO₄(0.1 M in MeOH)

was added until the solution was strongly acidic (pH<1).

The reaction was stirred for 2 h at room temperature, and

saturated aqueous NaHCO₃was added until the mixture was

neutral. The insoluble salts were removed by ﬁltration, and

the ﬁltrate was concentrated under reduced pressure. The

resulting yellow oil was puriﬁed by ﬂash chromatography

over silica gel eluting with MeOH/CH₂Cl₂(1:9) to provide a

white solid. This was recrystallized using EtOAc/hexanes

(2:1) to provide 44 mg (70%) of 16 as a white solid: mp

4.1.5. [2,3-Bis-O-tert-butyldimethylsilyl-4,6-dideoxy-6-

(methoxycarbonyl)-^D-gluco-b-C-pyranosyl] aldehyde

(18). A suspension of alcohol from the preceding experi-

ment (14 mg, 0.031 mmol) and Dess–Martin periodinane

(27 mg, 0.062 mmol) in CH₂Cl₂(0.5 mL) was stirred for 1 h

at room temperature. A solution of 1 M aqueous NaOH

(1 mL) was added, and the layers were separated. The

aqueous layer was extracted with CH₂Cl₂(1£2 mL), and the

combined organic layers were dried (MgSO₄) and concen-

trated under reduced pressure. The resulting clear oil was

puriﬁed by ﬂash chromatography over silica gel eluting with

EtOAc/hexanes (1:4) to provide 13.5 mg (96%) of 18 as a

1

114–1158C; H NMR (CD₃OD) d 3.92–3.77 (comp, 2H),

3.66 (s, 3H), 3.64–3.50 (comp, 2H), 3.17 (d, J¼1.8 Hz, 1H),

3.15 (s, 1H), 2.59 (dd, J¼15.6, 7.7 Hz, 1H), 2.48 (dd,

J¼15.6, 5.5 Hz, 1H), 2.00 (ddd, J¼12.7, 5.1, 1.9 Hz, 1H),

1.33 (q, J¼11.5 Hz, 1H); ¹³C NMR (CD₃OD) d 173.2, 81.6,

73.5, 73.1, 73.0, 62.9, 52.2, 41.1, 39.9; MS (CI) m/z

221.1020 [C₉H₁₇O₆(Mþ1) requires 221.1025], 185 (base),

171, 129.

4.1.3. [1-O-Triethylsilyl-2,3-bis-O-tert-butyldimethyl-

silyl-4,6-dideoxy-6-(methoxycarbonyl)-^D-gluco-b-C-pyr-

anosyl]methanol (17). To a solution of 16 (50 mg,

0.23 mmol) and 2,6-lutidine (0.29 mL, 2.49 mmol) in

CH₂Cl₂(2.5 mL) at 08C was added TESCl (0.057 mL,

0.34 mmol), and the mixture was stirred for 30 min at 08C.

Freshly distilled TBSOTf (0.21 mL, 0.91 mmol) was then

added, and stirring was continued for another 30 min at 08C.

Saturated aqueous NaHCO₃(2 mL) was added, and the

layers were separated. The aqueous layer was extracted with

CH₂Cl₂(2£2 mL), and the combined organic layers were

dried (MgSO₄) and concentrated under reduced pressure.

The resulting clear oil was puriﬁed by ﬂash chromatography

over silica gel eluting with EtOAc/hexanes (5:95) to provide

1

clear, colorless oil: H NMR d 9.61 (d, J¼1.8 Hz, 1H),

4.01–3.90 (m, 1H), 3.80–3.74 (m, 1H), 3.73 (dd, J¼8.5,

1.9 Hz, 1H) 3.67 (s, 3H), 3.52 (t, J¼8.3 Hz, 1H), 2.67 (dd,

J¼15.8, 7.3 Hz, 1H), 2.44 (dd, J¼15.8, 5.8 Hz, 1H), 2.04

(ddd, J¼13.2, 4.8, 2.5 Hz, 1H), 1.42 (q, J¼12.1 Hz, 1H),

0.88 (s, 9H), 0.86 (s, 9H), 0.08 (s, 6H), 0.07 (s, 3H), 20.04

(s, 3H); ¹³C NMR d 198.4, 171.0, 84.1, 73.4, 72.9, 71.3,

51.7, 40.3, 39.5, 26.2, 25.9, 18.2, 17.9, 23.3, 23.4, 24.4,

24.5; IR (neat) 3473, 2962, 2486, 2334, 1750, 1725 cm²¹

;

MS (CI) m/z 447.2597 [C₂₁H₄₃O₆Si₂(Mþ1) requires

447.2598] (base), 431, 389, 315, 299.

4.1.6. (1R,2S,3R)-2-Hydroxymethyl-3-methyl-1-(mor-

pholino)carbonylcyclopropane (21). To a solution of

morpholine (0.23 mL, 2.7 mmol) in CH₂Cl₂(10 mL) was

1

126 mg (99%) of 17 as a clear colorless oil: H NMR d

3.82–3.61 (comp, 4H), 3.66 (s, 3H), 3.33 (t, J¼8.9 Hz, 1H),

S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832

6827

added AlMe₃(1.3 mL, 2.0 M in hexanes) over 15 min. This

solution was stirred for 15 min, and 20⁴⁰(100 mg,

0.89 mmol) was added. After stirring for 72 h, the reaction

was cooled to 08C, and 1N HCl (10 mL) was slowly added.

The resulting heterogeneous mixture was stirred for 1 h at

room temperature, and then the layers were separated. The

aqueous layer was extracted with CH₂Cl₂(3£10 mL). The

combined organic layers were dried (MgSO₄) and concen-

trated under reduced pressure. The resulting oil was puriﬁed

by ﬂash chromatography over silica gel eluting with EtOAc

solution of i-Pr₂NH (0.10 mL, 0.74 mmol) in THF (2 mL)

at 08C was added n-BuLi (0.55 mL, 1.35 M in hexanes), and

the solution was stirred for 5 min. BH₃·NH₃(26 mg,

0.74 mmol) was added, and the cloudy suspension was

stirred for 15 min at 08C and 15 min at room temperature. A

solution of amide from the preceding experiment (58 mg,

0.19 mmol) in THF (1 mL) was added, and the reaction was

stirred for 90 min at 08C. A solution of 1 M HCl (2 mL) was

then added dropwise until the mixture was neutral. H₂O

(2 mL) and Et₂O (6 mL) were then added, and the layers

were separated. The aqueous layer was extracted with Et₂O

(2£2 mL), and the combined organic layers were dried

(MgSO₄) and concentrated under reduced pressure. The

residue was puriﬁed by ﬂash chromatography over silica gel

eluting with NEt₃/EtOAc/hexanes (2:23:75) to provide

1

to provide 165 mg (93%) of 21 as a clear, colorless oil: H

NMR d 4.07 (br s, 1H), 3.88 (dd, J¼12.0, 6.2 Hz, 1H),

3.80–3.45 (comp, 9H), 1.71 (t, J¼8.8 Hz, 1H), 1.57–1.34

(comp, 2H), 1.05 (d, J¼6.5 Hz, 3H); ¹³C NMR d 169.5,

66.8, 58.7, 46.1, 41.9, 23.1, 22.8, 16.0, 9.4; IR (CHCl₃)

3540–3040, 2965, 2915, 2875, 1625, 1480 cm²¹; MS (CI)

m/z 199.1219 [C₁₀H₁₇NO₃(M) requires 199.1208] (base),

182, 168, 114.

1

37 mg (86%) of 32 as a clear, colorless oil: H NMR d

3.67 (dd, J¼10.9, 6.4 Hz, 1H), 3.56 (dd, J¼10.9, 7.3 Hz,

1H), 3.50 (dd, J¼11.1, 6.7 Hz, 1H), 3.36 (dd, J¼11.1,

7.3 Hz, 1H), 1.72 (br s, 1H), 1.07 (d, J¼6.0 Hz, 3H), 0.95–

0.77 (comp, 2H), 0.86 (s, 9H), 0.73–0.62 (m, 1H), 0.03 (s,

6H); ¹³C NMR d 66.5, 62.3, 27.3, 26.0, 23.8, 18.3, 15.5,

12.7, 25.2; IR (neat) 3356, 2955, 2857, 1472, 1391,

1255 cm²¹; MS (CI) m/z 231.1785 [C₁₂H₂₇O₂Si (Mþ1)

requires 231.1780], 213 (base), 194, 186, 182.

4.1.7. (1R,2S,3R)-3-Methyl-1-(morpholino)carbonyl-2-

(tert-butyldimethylsilyloxy)methylcyclopropane. To

a

solution of 21 (38 mg, 0.19 mmol) and 2,6-lutidine

(0.089 mL, 0.76 mmol) in CH₂Cl₂(2 mL) at 08C was

added freshly distilled TBSOTf (0.066 mL, 0.29 mmol),

and the solution was stirred for 30 min at 08C. Saturated

aqueous NaHCO₃(4 mL) was added, and the layers were

separated. The aqueous layer was extracted with CH₂Cl₂

(2£2 mL), and the combined organic layers were dried

(MgSO₄) and concentrated under reduced pressure to

provide 58 mg (97%) of protected alcohol as a clear,

4.1.10. (1S,2S,3S)-1-[(Benzothiazolo)thio]methyl-2-

methyl-3-(tert-butyldimethylsilyloxy)methyl cyclopro-

pane. A solution of 32 (71 mg, 0.31 mmol), 2-mercapto-

benzothiazole (62 mg, 0.37 mmol), Ph₃P (97 mg,

0.37 mmol), and DEAD (0.058 mL, 0.37 mmol) in THF

(3 mL) was stirred at room temperature for 18 h. The

solvent was removed under reduced pressure, and the

residue was puriﬁed by ﬂash chromatography over silica gel

eluting with CH₂Cl₂/hexanes (1:4) to provide 116 mg (99%)

1

colorless oil that was used without further puriﬁcation: H

NMR d 3.95 (dd, J¼11.5, 5.4 Hz, 1H), 3.79 (dd, J¼11.5,

8.1 Hz, 1H), 3.61–3.38 (comp, 8H), 1.62 (t, J¼9.0 Hz, 1H),

1.41–1.12 (comp, 2H), 1.08 (d, J¼6.2 Hz, 3H), 0.82 (s, 9H),

20.02 (s, 6H); ¹³C NMR d 169.3, 67.0, 59.1, 46.2, 41.8,

26.0, 24.1, 21.1, 18.2, 15.7, 8.3, 25.2; IR (neat) 2953, 2851,

1

of sulﬁde as a clear, colorless oil: H NMR d 7.84 (ddd,

J¼8.1, 1.1, 0.6 Hz, 1H), 7.72 (ddd, J¼8.0, 1.2, 0.6 Hz, 1H),

7.38 (ddd, J¼8.1, 7.3, 1.2 Hz, 1H), 7.26 (ddd, J¼8.4, 7.3,

1.2 Hz, 1H), 3.75 (dd, J¼11.0, 6.0 Hz, 1H), 3.50 (dd, J¼8.1,

11.0 Hz, 1H) 3.35 (dd, J¼12.8, 7.3 Hz, 1H), 3.30 (dd,

J¼12.9, 7.3 Hz, 1H), 1.13–1.05 (m, 1H), 1.08 (d, J¼6.3 Hz,

3H), 1.00–0.93 (m, 1H), 0.87 (s, 9H), 0.85–0.80 (m, 1H),

0.03 (s, 3H), 0.02 (s, 3H); ¹³C NMR d 167.2, 153.4, 135.3,

126.0, 124.1, 120.9, 62.1, 38.6, 26.9, 26.0, 23.4, 18.8, 18.3,

12.6, 25.2, 25.3; IR (neat) 2956, 2928, 2856, 1428, 1428,

1251 cm²¹; MS (CI) m/z 380.1542 [C₁₉H₃₀NOSiS₂(Mþ1)

requires 380.1538] (base), 364, 322, 248, 213.

2364, 1659, 1462 cm²¹

;

MS (CI) m/z 314.2149

[C₁₆H₃₂NO₃Si (Mþ1) requires 314.2151] (base), 298,

256, 182.

4.1.8. (1S,2S,3R)-3-Methyl-1-(morpholino)carbonyl-2-

(tert-butyldimethylsilyloxy)methylcyclopropane (23). To

a solution of preceding cyclopropane amide (159 mg,

0.51 mmol) in THF at 08C was added NaHMDS (0.56 mL,

1.0 M in THF), and the solution was stirred for 90 min at

08C. Saturated aqueous NH₄Cl (2 mL) and Et₂O (4 mL)

were then added, and the layers were separated. The

aqueous layer was extracted with Et₂O (2£2 mL), and the

combined organic layers were dried (MgSO₄) and concen-

trated under reduced pressure. The resulting yellow oil was

puriﬁed by ﬂash chromatography over silica gel eluting with

EtOAc/hexanes (35:65) to provide 146 mg (92%) of

4.1.11. (1S,2S,3S)-1-[(Benzothiazolo)sulfonyl]methyl-2-

methyl-3-(tert-butyldimethylsilyloxy)methylcyclopro-

pane (33). A suspension of sulﬁde from the preceeding

experiment (54 mg, 0.14 mmol), MCPBA (50 mg,

0.29 mmol) and NaHCO₃(60 mg, 0.72 mmol) in CH₂Cl₂

(2 mL) was stirred for 24 h at room temperature. Saturated

aqueous NaHCO₃(2 mL) and Na₂S₂O₃(2 mL) were added

and the layers separated. The aqueous layer was extracted

with CH₂Cl₂(2£2 mL), and the combined organic layers

were dried (MgSO₄) and concentrated under reduced

pressure. The residue was puriﬁed by ﬂash chromatography

over silica gel eluting with EtOAc/hexanes (1:9) to provide

48 mg (82%) of 33 as a white solid: mp 84–868C; ¹H NMR

d 8.20–8.16 (m, 1H), 8.01–7.97 (m, 1H), 7.64–7.52 (comp,

2H), 3.61 (dd, J¼11.0, 5.3 Hz, 1H), 3.54 (dd, J¼14.7,

6.6 Hz, 1H), 3.40 (dd, 14.7, 7.5 Hz, 1H), 3.31 (dd, J¼10.9,

1

epimerized amide as a clear, colorless oil: H NMR d 3.69

(dd, J¼11.0, 4.4 Hz, 1H), 3.68–3.48 (comp, 9H), 1.57–1.52

(comp, 2H), 1.31 (t, J¼4.7 Hz, 1H), 1.08 (d, J¼6.2 Hz, 3H),

0.81 (s, 9H), 20.02 (s, 6H); ¹³C NMR d 171.3, 66.7, 61.0,

45.8, 42.3, 28.1, 25.7, 24.5, 19.4, 18.1, 12.0, 25.4; IR (neat)

2951, 2857, 1647, 1466 cm²¹; MS (CI) m/z 314.2144

[C₁₆H₃₂NO₃Si (Mþ1) requires 314.2151] (base), 298, 256,

182.

4.1.9. (1S,2S,3S)-1-Hydroxymethyl-3-methyl-2-(tert-

butyldimethylsilyloxy)methylcyclopropane (32). To a

6828

S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832

8.3 Hz, 1H), 0.94 (d, J¼5.9 Hz, 3H), 0.98–0.67 (comp, 3H),

0.78 (s, 9H), 20.09 (s, 6H); ¹³C NMR d 166.1, 152.8, 136.7,

127.9, 127.6, 125.3, 122.3, 61.4, 59.2, 25.8, 25.2, 18.1, 17.4,

16.4, 12.1, 25.5; IR (CH₂Cl₂) 2956, 2929, 2856, 1473,

1333, 1270, 1090 cm²¹; MS (CI) m/z 412.1432 [C₁₉H₃₀-

NO₃S₂Si (Mþ1) requires 412.1436], 354, 280 (base), 256.

J¼13.0, 8.2, 4.8 Hz, 1H), 3.65 (s, 3H), 3.53 (dd, J¼11.4,

8.6 Hz, 1H), 3.26 (t, J¼8.4 Hz, 1H), 2.62 (dd, J¼15.7,

6.8 Hz, 1H), 2.39 (dd, J¼15.9, 6.2 Hz, 1H), 2.01 (ddd,

J¼12.8, 4.8, 1.8 Hz, 1H), 1.40 (q, J¼12.6 Hz, 1H),

1.31–1.26 (m, 1H), 1.15 (d, J¼6.4 Hz, 3H), 1.13–1.10

(m, 1H), 1.01–0.96 (m, 1H), 0.89 (s, 9H), 0.83 (s, 9H), 0.08

(s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.02 (s, 3H); ¹³C NMR d

171.3, 138.5, 126.6, 76.9, 76.7, 74.5, 71.5, 61.9, 51.6, 40.7,

40.5, 28.1, 26.3, 26.2, 23.9, 19.8, 18.3, 18.0, 12.3, 22.8,

22.9, 23.5, 24.1; IR (neat) 3444, 2956, 2925, 2883, 2857,

4.1.12. Methyl (8E,10S,11S,12S)-2,3-di-O-tert-butyl-

dimethylsilyl-1,4-dideoxy-1b-[11-methyl-12-hydroxy-

methylcyclopropylethenyl]-^D-glucoheptopyranuronate

(34E) and methyl (8Z, 10S,11S,12S)-2,3-di-O-tert-butyl-

dimethylsilyl-1,4-dideoxy-1b-[11-methyl-12-hydroxy-

methylcyclopropylethenyl]-^D-glucoheptopyranuronate

(34Z). To a solution of aldehyde 18 (35 mg, 0.078 mmol)

and sulfone 33 (48 mg, 0.12 mmol) in DMF (0.5 mL) at

2608C was added a solution of NaHMDS (22 mg,

0.12 mmol) in DMF (1.5 mL). The reaction was stirred for

1 h at 2608C, the cold bath was removed, and the reaction

was stirred at room temperature for 30 min. Saturated

aqueous NH₄Cl (5 mL) and Et₂O (6 mL) were added, and

the layers were separated. The aqueous layer was extracted

with Et₂O (3£4 mL), and the combined organic layers were

dried (MgSO₄) and concentrated under reduced pressure.

The resulting yellow-brown oil was puriﬁed by ﬂash

chromatography over silica gel eluting with EtOAc/NEt₃/

hexanes (4:2:94) to provide 28 mg of the desired adduct as a

clear, colorless oil that was a mixture of inseparable oleﬁn

1732, 1660, 1463 cm²¹

; MS (CI) m/z 529.3380

[C₂₇H₅₃O₆Si₂(Mþ1) requires 529.3381], 511, 379, 265,

243 (base).

4.1.13. Methyl (8E,10S,11S,12S)-2,3-di-O-tert-butyl-

dimethylsilyl-1,4-dideoxy-1b-[11-methyl-12-formyl-

cyclopropylethenyl]-^D-glucoheptopyranuronate (35). A

suspension of 34E (26 mg, 0.049 mmol) and Dess–Martin

periodinane (42 mg, 0.098 mmol) in CH₂Cl₂(1 mL) was

stirred at room temperature for 90 min. A solution of 1 M

aqueous NaOH (2 mL) was added, and the layers were

separated. The aqueous layer was extracted with CH₂Cl₂

(1£2 mL), and the combined organic layers were dried

(MgSO₄) and concentrated under reduced pressure to

provide 24 mg (92%) of 35 as a clear, colorless oil which

1

was used without further puriﬁcation: H NMR d 9.46 (d,

J¼4.6 Hz, 1H), 5.56 (dd, J¼15.3, 7.2 Hz, 1H), 5.19 (ddd,

J¼15.3, 9.0, 0.6 Hz, 1H), 3.82 (dtd, J¼11.6, 6.6, 2.0 Hz,

1H), 3.67–3.61 (m, 1H), 3.65 (s, 3H), 3.49 (dt, J¼8.6,

0.8 Hz, 1H), 3.16 (t, J¼8.4 Hz, 1H), 2.59 (dd, J¼15.5,

6.8 Hz, 1H), 2.38 (dd, J¼15.5, 6.0 Hz, 1H), 2.10 (ddd,

J¼10.8, 6.4, 4.4 Hz, 1H), 1.99 (ddd, J¼13.0, 4.8, 2.0 Hz,

1H), 1.97–1.94 (m, 1H), 1.56–1.51 (m, 1H), 1.38 (q,

J¼12.8 Hz, 1H), 1.26 (d, J¼6.2 Hz, 3H), 0.88 (s, 9H),

0.85 (s, 9H), 0.06 (s, 6H), 0.05 (s, 3H), 0.01 (s, 3H);

¹³C NMR d 199.6, 171.3, 133.5, 129.3, 81.4, 76.5, 74.3,

71.5, 51.7, 40.7, 40.4, 36.5, 32.9, 26.5, 26.3, 26.1, 18.3,

18.0, 12.5, 22.9, 23.0, 23.7, 24.2; IR (neat) 2954, 2929,

1

isomers. Integration of the appropriate signals in the H

NMR spectrum of this mixture revealed the ratio of E- and

Z-isomers to be 2.6:1.

A solution of the mixture of oleﬁns (28 mg, 0.044 mmol)

and triﬂuoroacetic acid (0.034 mL, 0.44 mmol) in THF/H₂O

(1 mL/0.1 mL) was stirred at room temperature for 3 h.

Saturated aqueous NaHCO₃(2 mL) and Et₂O (5 mL) were

added and the layers were separated. The aqueous layer was

extracted with Et₂O (2£2 mL), and the combined organic

layers were dried (MgSO₄) and concentrated under reduced

pressure. The resulting clear oil was puriﬁed by ﬂash

chromatography over silica gel eluting with Et₂O/CH₂Cl₂

(1:9) to ﬁrst provide 6 mg (14%) of the Z-isomer 34Z as a

clear, colorless oil followed by 15 mg (37%) of the

E-isomer 34E as a clear, colorless oil:

2857, 1738, 1698 cm²¹

;

MS (CI) m/z 527.3202

[C₂₇H₅₁O₆Si₂(Mþ1) requires 527.3224], 395, 263, 243

(base).

4.1.14. (2S,3S)-1-p-Toluenesulfoxy-2,3-epoxy-5-hexene

(46). To a solution of alcohol 45⁶⁴(5.0 g, 44 mmol) and

pyridine (6.5 mL, 80 mmol) in CH₂Cl₂(44 mL) at 08C was

added p-toluenesulfonyl chloride (9.6 g, 50 mmol). The

solution was then stirred at room temperature for 16 h,

whereupon H₂O (100 mL) was added. The layers were

separated, and the aqueous layer was extracted with CH₂Cl₂

(2£100 mL). The combined organic layers were dried

(Na₂SO₄) and concentrated under reduced pressure. The

resulting oil was puriﬁed by ﬂash chromatography over

silica gel eluting with Et₂O/hexanes (3:7) to provide 10.0 g

For 34Z. ¹H NMR d 5.38 (dd, J¼15.3, 7.8 Hz, 1H), 5.18 (dd,

J¼15.3, 8.7 Hz, 1H), 3.81 (dtd, J¼11.6, 6.5, 1.8 Hz, 1H),

3.76 (dd, J¼11.5, 6.4 Hz, 1H), 3.65 (s, 3H), 3.64–3.60 (m,

1H), 3.50 (dd, J¼11.5, 8.6 Hz, 1H), 3.49–3.44 (m, 1H),

3.16 (t, J¼8.5 Hz, 1H), 2.61 (dd, J¼15.6, 6.6 Hz, 1H), 2.38

(dd, J¼15.6, 6.5 Hz, 1H), 1.99 (ddd, J¼12.9, 4.8, 1.9 Hz,

1H), 1.38 (q, J¼12.8 Hz, 1H), 1.29–1.23 (m, 1H), 1.22–

1.15 (m, 1H), 1.12 (d, J¼6.0 Hz, 3H), 1.00–0.91 (m, 1H),

0.89 (s, 9H), 0.85 (s, 9H), 0.062 (s, 3H), 0.061 (s, 3H), 0.056

(s, 3H), 0.02 (s, 3H); ¹³C NMR d 171.3, 137.5, 126.6, 82.0,

76.5, 74.3, 71.4, 62.1, 51.7, 40.8, 40.5, 31.6, 27.9, 27.3,

26.3, 26.2, 18.3, 18.0, 12.4, 22.9, 23.0, 23.6, 24.2; IR

(neat) 3432, 2959, 2925, 2880, 1746, 1642 cm²¹; MS (CI)

m/z 529.3355 [C₂₇H₅₃O₆Si₂(Mþ1) requires 529.3381],

511, 379, 265, 243 (base).

1

(85%) of 46 as a clear, colorless oil: H NMR d 7.81 (d,

J¼8.2 Hz, 2H), 7.37 (d, J¼8.0 Hz, 2H), 5.76 (ddt, J¼17.1,

13.2, 6.6 Hz, 1H), 5.17–4.92 (comp, 2H), 4.21 (dd, J¼11.2,

3.2 Hz, 1H), 4.01 (dd, J¼11.2, 5.7 Hz, 1H), 3.01 (ddd, 5.7,

3.9, 2.0 Hz, 1H), 2.90 (td, J¼5.5, 2.0 Hz, 1H), 2.47 (s, 3H),

2.36–2.28 (m, 1H); ¹³C NMR d 145.0, 132.4, 132.0, 129.8,

127.7, 117.9, 69.8, 55.2, 53.8, 35.0, 21.5; IR (neat) 3079,

2981, 2926, 1637, 1598, 1448, 1363, 1190 cm²¹; MS (CI)

m/z 269.0843 [C₁₃H₁₇O₄S (Mþ1) requires 269.0848], 215,

173, 155 (base).

For 34E. ¹H NMR d 5.27 (t, J¼9.6 Hz, 1H), 5.06 (t,

J¼10.2 Hz, 1H), 3.95 (t, J¼8.8 Hz, 1H), 3.89 (dtd, J¼11.4,

6.8, 1.8 Hz, 1H), 3.79 (dd, J¼11.4, 6.2 Hz, 1H), 3.70 (ddd,

S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832

6829

4.1.15. [2S,3R,3(3R)]-3-(4-Methyl-4-penten-3-oxy)-5-

hexen-2-ol (48). To a solution of epoxide 46 (8.28 g,

30.9 mmol) and alcohol 42⁶²(4.5 g, 45.0 mmol) in CH₂Cl₂

(62 mL) was added BF₃·Et₂O (0.38 mL, 3.0 mmol). After

stirring at room temperature for 16 h, the solvent was

removed under reduced pressure. The resulting paste of 47

was dissolved in Et₂O (50 mL) and added via cannula to a

slurry of LiAlH₄(3.8 g, 100 mmol) in Et₂O (100 mL) at

08C. The mixture was stirred for 3 h at 08C, and then H₂O

(4 mL) was added dropwise. A solution of 6 M aqueous

NaOH (4 mL) and H₂O (8 mL) were added, and the

resulting slurry was stirred for 2 h and then ﬁltered through

a pad of Celite. The pad was washed with Et₂O (2£100 mL)

and the combined organic layers were dried (Na₂SO₄) and

concentrated under reduced pressure. The resulting oil was

puriﬁed by ﬂash chromatography over silica gel eluting with

Et₂O/hexanes (3:7) to provide 4.0 g (65%) of 48 as a clear,

(Na₂SO₄) and concentrated under reduced pressure. The

resulting oil was puriﬁed by ﬂash chromatography over

silica gel eluting with Et₂O/hexanes (1:9) to provide 189 mg

(75%) of 50 as a clear, colorless oil: ¹H NMR d 5.60–5.35

(comp, 3H), 4.08 (br s, 1H), 3.46 (dd, J¼10.7, 3.2 Hz, 1H),

2.64 (br s, 1H), 2.19–2.09 (m, 1H), 1.89 (dd, J¼7.1, 1.1 Hz,

1H), 1.82–1.71 (m, 1H), 1.60 (t, J¼1.1 Hz, 3H), 1.57–1.44

(comp, 2H), 1.29 (s, 3H), 0.90 (t, J¼7.3 Hz, 3H); ¹³C NMR

d 135.0, 134.1, 127.0, 120.6, 79.0, 78.5, 74.9, 25.6, 25.3,

18.8, 14.3, 8.5; IR (neat) 3568, 2967, 2934, 2875, 1719,

1654, 1458, 1375, 1329, 1292, 1116, 1056 cm²¹; MS (CI)

m/z 211.1699 [C₁₃H₂₃O₂(Mþ1) requires 211.1698], 194,

193 (base), 169, 151.

4.1.18. [2R,6R,2(2⁰S,3⁰E)]-2-(1-Hydroxy-2-methyl-3-pen-

ten-4-yl)-5-methyl-6-ethyl-3,6-dihydropyran (51). A sus-

pension of alcohol 50 (0.22 g, 1.1 mmol), 18-crown-6

(0.28 g, 1.1 mmol), and KH (150 mg of 35% dispersion in

mineral oil, 1.3 mmol) in THF (10 mL) was stirred at 08C

for 5 min, whereupon trimethylstannyl methyliodide (3.2 g,

11 mmol) was added. The solution was allowed to warm to

room temperature and stirred for 3 h. H₂O (10 mL) was then

added, and the layers were separated. The aqueous layer was

extracted with Et₂O (4£5 mL), and the combined organic

layers were dried (Na₂SO₄) and concentrated under reduced

pressure. The resulting oil was puriﬁed by ﬂash chroma-

tography over silica gel eluting with Et₂O to provide crude

trimethylstannylmethyl ether that was not puriﬁed but

dissolved in THF (10 mL). The solution was cooled to

2788C, n-BuLi (1.6 M in hexanes, 1.0 mL) was added

slowly, and the reaction was stirred for 2 h at 2788C. The

reaction was then warmed to room temperature, and H₂O

(10 mL) was added. The layers were separated, and the

aqueous layer was extracted with Et₂O (4£5 mL). The

combined organic layers were dried (Na₂SO₄) and concen-

trated under reduced pressure. The resulting oil was puriﬁed

by ﬂash chromatography over silica gel eluting with Et₂O/

hexanes (1:1) to provide 162 mg (70%) of 51 as a clear,

1

colorless oil: H NMR d 5.80 (ddt, J¼17.1, 14.1, 7.1 Hz,

1H), 5.10–4.86 (comp, 4H), 3.96 (dq, J¼6.5, 3.2 Hz, 1H),

3.71 (dd, J¼7.1, 6.8 Hz, 1H), 3.32 (ddd, J¼8.4, 5.2, 3.2 Hz,

1H), 2.40–2.10 (comp, 2H), 2.08 (br s, 1H), 1.66 (d,

J¼0.9 Hz, 3H), 1.66–1.40 (comp, 2H), 1.15 (d, J¼6.5 Hz,

3H), 0.87 (t, J¼7.5 Hz, 3H); ¹³C NMR d 144.6, 135.7,

116.5, 114.1, 84.4, 79.6, 67.2, 33.8, 26.3, 17.5, 16.4, 10.2;

IR (neat) 3474, 2963, 2933, 2874, 1647, 1598, 1458, 1369,

1190 cm²¹; MS (CI) m/z 199.1695 [C₁₂H₂₃O₂(Mþ1)

requires 199.1698], 181, 177, 163, 127, 117, 115, 100

(base).

4.1.16. (2R,6R)-Methyl-(6-ethyl-5-methyl-3,6-dihydro-

solution of 48 (2.0 g,

pyran-2-yl)ketone (49).

A

10.0 mmol) in CH₂Cl₂(100 mL) containing dichlorobis-

(tricyclohexylphosphine)ruthenium benzylidene (0.82 g,

1.0 mmol) was heated under reﬂux for 16 h. The mixture

was cooled, and the solvent was removed under reduced

pressure. The resulting brown oil was puriﬁed by ﬂash

chromatography over silica gel eluting with Et₂O/hexanes

(1:9) to provide the desired dihydropyran as a brown oil.

The crude alcohol thus obtained was dissolved in CH₂Cl₂

1

colorless oil: H NMR d 5.58 (d, J¼4.8 Hz, 1H), 5.23 (d,

˚

(20 mL) containing 4 A molecular sieves (5 g). NMO

J¼9.6 Hz, 1H), 4.11 (br s, 1H), 3.86 (dd, J¼10.5 Hz,

3.0 Hz, 1H), 3.49 (dd, J¼10.5, 6.1 Hz, 1H), 3.38 (dd,

J¼10.2, 7.7 Hz, 1H), 2.73–2.61 (m, 1H), 2.18–2.06 (m,

1H), 1.99–1.88 (m, 1H), 1.84–1.72 (m, 1H), 1.72 (d,

J¼1.1 Hz, 3H), 1.64–1.48 (comp, 2H) 1.61 (d, J¼1.1 Hz,

3H), 0.98 (d, J¼6.8 Hz, 3H), 0.92 (t, J¼7.3 Hz, 3H); ¹³C

NMR d 138.4, 135.1, 127.0, 120.7, 78.0, 77.5, 67.8, 35.0,

30.3, 25.6, 18.9, 16.9, 13.0, 8.3; IR (neat) 3382, 2935, 2854,

1712, 1667, 1453, 1374, 1350, 1266, 1204 cm²¹; MS (CI)

m/z 225.1857 [C₁₄H₂₅O₂(Mþ1) requires 225.1855] (base),

207, 129, 117, 109.

(1.4 g, 12.0 mmol) and TPAP (0.18 g, 0.5 mmol) were

added, and the solution was stirred at room temperature for

2 h. The black solution was then ﬁltered through a pad of

silica gel, and the ﬁltrate was concentrated under reduced

pressure. The resulting yellow oil was puriﬁed by ﬂash

chromatography over silica gel eluting with Et₂O/hexanes

(1:9) to provide 1.0 g (60%) of 49 as a clear, colorless oil:

¹H NMR d 5.57 (br s, 1H), 4.11 (br s, 1H), 3.93 (dd, J¼10.5,

4.6 Hz, 1H), 2.26 (s, 3H), 2.21–2.08 (m, 1H), 1.89–1.76

(m, 1H), 1.62 (d, J¼0.9 Hz, 3H), 1.60–1.40 (comp, 2H),

0.96 (t, J¼7.5 Hz, 3H); ¹³C NMR d 210.0, 135.6, 119.6,

78.8, 78.3, 27.3, 25.7, 25.6, 18.9, 8.6; MS (CI) m/z 169.1229

[C₁₀H₁₇O₂(Mþ1) requires 169.1229].

4.1.17. [2R,6R,2(2⁰R)]-2-[2⁰-Hydroxy-3⁰-penten-2⁰(Z)-yl]-

5-methyl-6-ethyl-3,6-dihydropyran (50). To a solution of

ketone 49 (0.20 g, 1.2 mmol) in THF (10 mL) at 2788C was

slowly added dropwise cis-propenylmagnesium bromide

(1.0 M in THF, 5.0 mL), and the mixture was stirred for 1 h

at 2788C. The reaction was warmed to 08C and poured into

saturated aqueous NH₄Cl (10 mL), and the layers were

separated. The aqueous layer was extracted with Et₂O

(4£5 mL), and the combined organic layers were dried

4.1.19. [2R,6R,2(2⁰S,3⁰E)]-2-(1-Phenylthioxy-2-methyl-3-

penten-4-yl)-5-methyl-6-ethyl-3,6-dihydropyran. To a

solution of N-phenylthiosuccinimide (62 mg, 0.30 mmol)

in C₆H₆(2 mL) was added PBu₃(0.075 mL, 0.30 mmol).

After stirring for 5 min, a solution of alcohol 51 (50 mg,

0.22 mmol) in C₆H₆(1 mL) was added, and the reaction was

stirred for 1 h. The solution was concentrated under reduced

pressure, and the residue was puriﬁed by ﬂash chromato-

graphy over silica gel eluting with Et₂O/hexanes (1:4) to

provide 63 mg (91%) of sulﬁde as a clear, colorless oil: ¹H

NMR d 7.36–7.14 (comp, 5H), 5.58 (d, J¼4.6 Hz, 1H), 5.31

(d, J¼9.1 Hz, 1H), 4.11 (br s, 1H), 3.85 (dd, J¼10.9, 3.2 Hz,

6830

S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832

1H), 2.93 (dd, J¼12.5, 6.6 Hz, 1H), 2.82 (dd, J¼12.3,

7.3 Hz, 1H), 2.76–2.64 (m, 1H), 2.19–2.04 (m, 1H), 2.00–

1.70 (comp, 3H), 1.65–1.50 (comp, 6H), 1.12 (d, J¼6.6 Hz,

3H), 0.92 (t, J¼7.3 Hz, 3H); ¹³C NMR d 137.2, 136.4,

135.0, 129.1, 128.9, 128.7, 125.6, 120.8, 77.8, 77.7, 41.0,

31.9, 30.1, 25.6, 20.1, 18.9, 12.4, 8.2; IR (neat) 2935, 2852,

1576, 1475, 1440, 1084 cm²¹; MS (CI) m/z 317.1945

[C₂₀H₂₉OS (Mþ1) requires 317.1939] (base), 299, 275,

221, 207.

of 53E and its Z-isomer 53Z as a clear, colorless oil. For

1

.53E. H NMR d 5.56–5.53 (m, 1H), 5.41 (dd, J¼15.7,

6.8 Hz, 1H), 5.35 (dd, J¼15.3, 8.0 Hz, 1H), 5.22 (dt, J¼9.0,

1.2 Hz, 1H), 5.17 (dd, J¼15.3, 9.2 Hz, 1H), 5.05 (ddd,

J¼1.2, 8.8, 15.3 Hz, 1H), 4.07 (br s, 1H), 3.81 (dd, J¼11.3,

3.4 Hz, 1H), 3.82–3.77 (m, 1H), 3.67 (m, 1H), 3.65 (s, 3H),

3.47 (t, J¼7.0 Hz, 1H), 3.16 (t, J¼8.4 Hz, 1H), 3.07–3.00

(m, 1H), 2.62 (dd, J¼15.7, 6.4 Hz, 1H), 2.38 (dd, J¼15.5,

6.6 Hz, 1H), 2.12–1.97 (m, 1H), 1.99 (ddd, J¼12.8, 4.8,

1.8 Hz, 1H), 1.89–1.81 (m, 1H), 1.62 (d, J¼1.2 Hz, 3H),

1.57 (br s, 3H), 1.52–1.44 (comp, 2H), 1.43–1.37 (m, 1H),

1.04–0.96 (comp, 2H), 1.03 (d, J¼6.4 Hz, 3H), 1.02 (d,

J¼6.8 Hz, 3H), 0.89–0.85 (m, 3H), 0.88 (s, 9H), 0.86 (s,

9H), 0.06 (s, 6H), 0.05 (s, 3H), 0.02 (s, 3H); ¹³C NMR d

171.3, 138.1, 135.4, 135.0, 129.8, 126.1, 125.3, 121.0, 82.3,

78.1, 77.8, 76.5, 74.3, 71.3, 51.6, 40.8, 40.5, 35.0, 30.9,

30.2, 28.5, 26.3, 26.2, 25.6, 21.2, 20.7, 18.9, 18.3, 18.0,

13.0, 12.1, 8.2, 22.8, 23.0, 23.6, 24.2; IR (CH₂Cl₂) 2958,

2929, 2857, 1763, 1463, 1114, 837 cm²¹; MS (CI) m/z

717.4942 [C₄₁H₇₃O₆Si₂(Mþ1) requires 717.4946] (base),

585, 453, 243 (base).

4.1.20. [2R,6R,2(2⁰S,3E)]-2-(1-Phenylsulfonyl-2-methyl-

3-penten-4-yl)-5-methyl-6-ethyl-3,6-dihydropyran (52).

A solution of ammonium molybdate tetrahydrate (0.12 g,

0.10 mmol) in 30% aqueous H₂O₂(2 mL) was added

dropwise to a solution of the preceding sulﬁde (80 mg,

0.25 mmol) in EtOH (2 mL) at 2108C, and the reaction was

stirred for 30 min. Saturated aqueous NaHCO₃(5 mL) and

Et₂O (5 mL) were added and the layers separated. The

aqueous layer was extracted with Et₂O (3£20 mL), and the

combined organic layers were dried (Na₂SO₄) and concen-

trated under reduced pressure. The resulting oil was puriﬁed

by ﬂash chromatography over silica gel eluting with Et₂O/

hexanes (1:4) to provide 85 mg (98%) of 52 as a clear,

colorless oil: ¹H NMR d 7.90–7.48 (comp, 5H), 5.53–5.46

(m, 1H), 5.13 (d, J¼8.7 Hz, 1H), 4.03–3.95 (m, 1H), 3.67

(dd, J¼10.0, 2.7 Hz, 1H), 3.12–2.96 (comp, 3H), 2.01–1.87

(m, 1H), 1.87–1.65 (m, 1H), 1.56 (d, J¼1.1 Hz, 3H), 1.52

(d, J¼1.1 Hz, 3H), 1.52–1.41 (comp, 2H), 1.12 (d,

J¼6.4 Hz, 3H), 0.84 (t, J¼7.3 Hz, 3H); ¹³C NMR d 139.9,

136.6, 135.0, 133.4, 129.1, 127.8, 127.1, 120.5, 77.8, 77.0,

62.4, 29.9, 27.7, 25.5, 20.8, 18.8, 12.5, 8.3; IR (neat) 3063,

2935, 2848, 1586, 1447, 1374, 1305, 1149, 1085 cm²¹; MS

(CI) m/z 349.1837 [C₂₀H₂₉O₃S (Mþ1) requires 349.1837]

(base), 331, 253, 241.

4.1.22. Methyl 5b,6a-dihydroxypolyangioate (54). A

solution of the preceding mixture of 53E/Z (16 mg,

0.022 mmol) in THF (1 mL) and HF·pyridine (0.2 mL)

was stirred for 16 h at room temperature. Saturated aqueous

NaHCO₃(4 mL) and CH₂Cl₂(4 mL) were added, and the

layers were separated. The aqueous layer was extracted with

CH₂Cl₂(3£2 mL), and the combined organic layers were

dried (MgSO₄) and concentrated under reduced pressure.

The resulting oil was puriﬁed by ﬂash chromatography over

silica gel eluting with EtOAc/hexanes (35:65) followed by

HPLC using two m-porasil columns and eluting with

EtOAc/hexanes (50:50) to provide 9 mg (89%) of 54 as a

clear colorless oil. The ¹H NMR spectrum of 54 was

consistent with that reported.^1,10b¹H NMR (500 MHz,

CDCl₃) d 5.56–5.54 (m, 1H), 5.44 (ddd, J¼15.5, 6.0,

0.6 Hz, 1H), 5.41–5.39 (comp, 2H), 5.23 (dt, J¼8.8, 1.2 Hz,

1H), 5.06 (ddd, J¼15.3, 8.8, 1.4 Hz, 1H), 4.08 (br s, 1H),

3.92–3.87 (m, 1H), 3.70–3.65 (m, 1H), 3.67 (s, 3H),

3.53–3.50 (m, 1H), 3.11 (t, J¼8.8 Hz, 1H), 3.07–3.02

(m, 1H), 2.64 (dd, J¼15.7, 6.8 Hz, 1H), 2.43 (dd, J¼15.7,

6.2 Hz, 1H), 2.33 (br s, 1H), 2.14–2.02 (comp, 2H), 1.91

(br s, 1H), 1.87–1.82 (m, 1H), 1.80–1.72 (m, 1H), 1.62

(d, J¼1.4 Hz, 3H), 1.57 (m, 3H), 1.55–1.40 (comp, 3H),

1.20–1.05 (comp, 2H), 1.04 (comp, 6H), 0.88 (t, J¼7.2 Hz,

3H).

4.1.21. Methyl 5b,6a-di-tert-butyldimethylsilyloxy-

polyangioates (53E/Z). A solution of 1.25 M n-BuLi in

hexanes (0.08 mL, 0.1 mmol) was added to a solution of

sulfone 52 (34 mg, 0.097 mmol) in THF (0.2 mL) at 2788C,

and the resulting solution was stirred for 30 min. A solution

of aldehyde 35 (17 mg, 0.032 mmol) in THF (0.25 mL) was

then added, and the solution was stirred at 2788C for an

additional 2 h. Saturated aqueous NH₄Cl (2 mL) and

CH₂Cl₂(6 mL) were added, and the layers were separated.

The aqueous layer was extracted with CH₂Cl₂(2£2 mL),

and the combined organic layers were dried (MgSO₄) and

concentrated under reduced pressure. The residual oil was

puriﬁed by ﬂash chromatography over silica gel eluting ﬁrst

with CH₂Cl₂/hexanes (1:3) and then with EtOAc/CH₂Cl₂

(1:9) to provide 15 mg of recovered 52 and 31 mg of

hydroxy sulfones as a mixture of diastereomers. The

hydroxy sulfones (31 mg, 0.035 mmol) were dissolved in

MeOH (1.5 mL) containing Na₂HPO₄(0.25 g, 1.8 mmol) at

2308C, and sodium amalgam (1.0 g, 2.1 mmol Na) was

added. The mixture was stirred for 3 h at 2308C, whereupon

saturated aqueous NH₄Cl (10 mL) and CH₂Cl₂(8 mL) were

added. The supernatant was decanted, and the layers were

separated. The aqueous layer was extracted with CH₂Cl₂

(2£2 mL). The combined organic layers were dried

(MgSO₄) and concentrated under reduced pressure, and

the resulting oil was puriﬁed by ﬂash chromatography over

silica gel eluting with PhCH₃/hexanes (1:1) to provide

13 mg (56% from 35) of an inseparable mixture (E/Z<10:1)

4.1.23. Ambruticin S (1). A solution of diol 54 (6 mg,

0.12 mmol) in THF (1 mL) containing 0.3 M aqueous LiOH

(0.21 mL) was stirred for 3.5 h at room temperature. A

solution of 1N HCl (4 mL) and CHCl₃(6 mL) were added,

and the layers were separated. The aqueous layer was

extracted with CHCl₃(3£2 mL), and the combined organic

layers were dried (MgSO₄) and concentrated under reduced

pressure to provide 5 mg (95%) of (þ)-ambruticin S (1) as

an off-white gum. The synthetic sample was identical with

an authentic sample of natural ambruticin S by TLC, ¹H and

¹³C NMR (including HMQC), MS, and optical rotation. ¹H

NMR (CDCl₃) d 5.55 (dd, J¼6.2, 1.6 Hz, 1H), 5.48–5.41

(comp, 3H), 5.23 (dt, J¼8.8, 1.2 Hz, 1H), 5.06 (ddd,

J¼15.3, 8.8, 1.4 Hz, 1H), 4.08 (br s, 1H), 3.92–3.87 (m,

1H), 3.82 (dd, J¼10.6, 3.0 Hz, 1H), 3.69 (ddd, J¼13.7, 8.6,

S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832

6831

1988, 44, 3953–3973. (e) Davidson, A. H.; Eggleton, N.;

Wallace, I. H. J. Chem. Soc., Chem. Commun. 1991, 378–380.

´

(f) Marko, I. E.; Bayston, D. J. Tetrahedron 1994, 50,

5.0 Hz, 1H), 3.56 (dd, J¼9.0, 6.0 Hz, 1H), 3.15 (t,

J¼9.0 Hz, 1H), 3.09–3.03 (m, 1H), 2.65 (dd, J¼16.1,

7.6 Hz, 1H), 2.53 (dd, J¼16.1, 5.0 Hz, 1H), 2.13–2.07

(comp, 2H), 1.89–1.80 (m, 1H), 1.78–1.68 (m, 1H), 1.63

(d, J¼1.2 Hz, 3H), 1.57 (br s, 3H), 1.56–1.45 (comp, 3H),

1.12–1.06 (comp, 2H), 1.05 (br s, 3H), 1.03 (d, J¼7.0 Hz,

3H), 0.88 (t, J¼7.0 Hz, 3H); ¹³C NMR (CDCl₃) d 173.2,

140.1, 135.8, 135.2, 135.1, 129.5, 125.0, 123.3, 120.9, 80.9,

78.0, 77.9, 75.6, 72.0, 71.6, 40.1, 38.0, 35.0, 30.4, 30.2,

29.2, 25.6, 21.7, 21.1, 18.9, 13.0, 12.3, 8.2; MS (CI) m/z

475.3053 [C₂₈H₄₃O₆(Mþ1) requires 475.3060];

[a]_D²²¼þ328 (c 0.11, CHCl₃); {lit.^10bfor synthetic 1,

[a]_D²²¼þ378 (c 0.10, CHCl₃); for natural 1, [a]²_D²¼þ428 (c

0.22, CHCl₃)}.

7141–7156. (g) Nagasawa, T.; Handa, Y.; Onoguchi, Y.;

Ohba, S.; Suzuki, K. Synlett 1995, 739–741. (h) Liu, L.;

´

Donaldson, W. A. Synlett 1996, 103–104. (i) Marko, I. E.;

Bayston, D. J. Synthesis 1996, 297–304. (j) Wakamatsu, H.;

Isono, N.; Mori, M. J. Org. Chem. 1997, 62, 8917–8922.

ˆ

(k) Michelet, V.; Adiey, K.; Bulic, B.; Genet, J.-P.; Dujardin,

G.; Rossignol, S.; Brown, E.; Toupet, L. Eur. J. Org. Chem.

1999, 64, 2885–2892.

10. (a) Kende, A. S.; Fujii, Y.; Mendoza, J. S. J. Am. Chem. Soc.

1990, 112, 9645–9646. (b) Kende, A. S.; Mendoza, J. S.; Fujii,

Y. Tetrahedron 1993, 49, 8015–8038.

11. (a) Kirkland, T. A.; Martin, S. F.; Colucci, J.; Marx, M. A.;

Geraci, L. S. Paper Abstracts; 220th National Meeting of the

American Chemical Society, 2000; American Chemical

Society: Washington, DC, 2000; ORGN-126. (b) Kirkland,

T. A.; Colucci, J.; Geraci, L. S.; Marx, M. A.; Schneider, M.;

Kaelin, D. E., Jr.; Martin, S. F. J. Am. Chem. Soc. 2001, 123,

12432–12433.

Acknowledgements

We thank the National Institutes of Health, the Robert

A. Welch Foundation, Pﬁzer, Inc., Merck Research

Laboratories, and the Alexander von Humboldt Stiftung

for their generous support of this research. M. F. S.

gratefully acknowledges a Feodor-Lynen postdoctoral

fellowship from the Alexander von Humboldt Foundation,

and M. A. M is grateful for an NRSA Postdoctoral

Fellowship from the National Institutes of Health. We also

thank Pﬁzer, Inc. (Ann Arbor Laboratories) for a sample of

natural ambruticin and Professor Andrew Kende

12. Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123,

10772–10773.

13. Lee, E.; Choi, S. J.; Kim, H.; Han, H. O.; Kim, Y. K.; Min,

S. J.; Son, S. H.; Lim, S. M.; Jang, W. S. Angew. Chem. Int. Ed.

2002, 41, 176–178.

14. (a) Doyle, M. P.; Pieters, R. J.; Martin, S. F.; Austin, R. E.;

Oalmann, C. J.; Mu¨ller, P. J. Am. Chem. Soc. 1991, 113,

1423–1424. (b) Doyle, M. P.; Austin, R. E.; Bailey, S. A.;

Dwyer, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Kwan, M. M. Y.;

Liras, S.; Oalmann, C. J.; Pieters, R. J.; Protopopova, M. N.;

Raab, C. E.; Roos, G. H. P.; Zhou, Q.-L.; Martin, S. F. J. Am.

Chem. Soc. 1995, 117, 5763–5775.

1

(University of Rochester) for providing us with H NMR

spectra of ambruticin and an advanced intermediate in his

synthesis. We are also most grateful to Dr David E. Kaelin,

Jr. for invaluable assistance in characterizing advanced

intermediates and synthetic ambruticin S.

15. Achmatowicz, O., Jr.; Bukowski, P.; Szechner, B.; Zwierz-

chowska, Z.; Zamojski, A. Tetrahedron 1971, 27, 1973–1996.

16. For example, see: (a) Martin, S. F.; Gluchowski, C.; Campbell,

C. L.; Chapman, R. C. J. Org. Chem. 1984, 49, 2512–2513.

(b) Martin, S. F.; Guinn, D. E. J. Org. Chem. 1987, 52,

5588–5593. (c) Martin, S. F.; Zinke, P. W. J. Org. Chem.

1991, 56, 6600–6606. (d) Martin, S. F.; Dodge, J. A.; Burgess,

L. E.; Limberakis, C.; Hartmann, M. Tetrahedron 1996, 52,

3229–3246. (e) Martin, S. F.; Lee, W.-C.; Pacofsky, G. J.;

Gist, R. P.; Mulhern, T. A. J. Am. Chem. Soc. 1994, 116,

4674–4688. (f) Martin, S. F.; Hida, T.; Kym, P. R.; Loft, M.;

Hodgson, A. J. Am. Chem. Soc. 1997, 119, 3193–3194.

(g) Martin, S. F.; Limberakis, C.; Burgess, L. E.; Hartmann,

M. Tetrahedron 1999, 55, 3561–3572.

References

1. Connor, D. T.; Greenough, R. C.; von Strandtmann, M. J. Org.

Chem. 1977, 42, 3664–3669.

2. (a) Shadomy, S.; Utz, C.; White, S. Antimicrob. Agents

Chemother. 1978, 14, 95–98. (b) Levine, H. B.; Ringel, S. M.;

Cobb, J. M. Chest 1978, 73, 202–206.

3. Just, G.; Potvin, P. Can. J. Chem. 1980, 58, 2173–2177.

4. Connor, D. T.; Klutchko, S.; von Strandtmann, M. J. Antibiot.

1979, 32, 368–378.

5. Connor, D. T.; von Strandtmann, M. J. Org. Chem. 1978, 43,

4606–4607.

17. For reviews of RCM in synthesis, see: (a) Schuster, M.;

Blechert, S. Angew. Chem. Int. Ed. Engl. 1997, 36,

2037–2056. (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998,

54, 4413–4450. (c) Wright, D. L. Curr. Org. Chem. 1999, 3,

211–240. (d) Fu¨rstner, A. Angew. Chem. Int. Ed. 2000, 39,

3012–3043.

6. (a) Connor, D. T.; von Strandtmann, M. J. Med. Chem. 1979,

22, 1055–1059. (b) Connor, D. T.; von Strandtmann, M.

J. Med. Chem. 1979, 22, 1144–1147.

¨

7. Hoﬂe, G.; Steinmetz, H.; Gerth, K.; Reichenbach, H. Liebigs

Ann. Chem. 1991, 941–945.

18. Miller, R. E.; Cantor, S. M. J. Am. Chem. Soc. 1952, 74,

5236–5237.

8. Knauth, P.; Reichenbach, H. J. Antibiot. 2000, 53,

1182–1190.

19. Bucciarelli, M.; Forni, A.; Moretti, I.; Torre, G. Synthesis

1983, 897–899.

9. For selected synthetic studies toward ambruticin S, see:

(a) Barnes, N. J.; Davidson, A. H.; Hughes, L. R.; Procter, G.

J. Chem. Soc., Chem. Commun. 1985, 1292–1294. (b) Sinay,

P. Bioorganic Heterocycles 1986: Synthesis, Mechanism and

Bioactivity; Elsevier: Amsterdam, 1986; pp 59–70. (c) Burke,

S. D.; Armistead, D. M.; Schoenen, F. J.; Fevig, J. M.

Tetrahedron 1986, 42, 2787–2801. (d) Proctor, G.; Russell,

A. T.; Murphy, P. J.; Tan, T. S.; Mather, A. N. Tetrahedron

20. Arekion, J.; Delmas, M.; Gaset, A. Biomass 1983, 3, 59–65.

21. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.

Rev. 1994, 94, 2483–2547.

22. Taniguchi, T.; Nakamura, K.; Ogasawara, K. Synlett 1996,

971–972.

23. Compound 6 has been previously prepared in racemic form.

6832

S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832

See: Murray, T. P.; Williams, C. S.; Brown, R. K. J. Org.

Chem. 1971, 36, 1311–1314.

48. Falck, J. R.; Mekonnen, B.; Yu, J.; Lai, J.-Y. J. Am. Chem. Soc.

1996, 118, 6096–6097.

24. Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108,

3033–3040.

49. Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93,

4327–4329.

25. The enantiomerically pure epoxide and diol prepared in this

sequence gave ¹H NMR spectral data consistent with those

previously reported for racemic materials. See: Murray, T. P.;

Singh, U. P.; Brown, R. K. Can. J. Chem. 1971, 49,

2132–2138.

50. Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron

Lett. 1991, 32, 1175–1178.

51. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.

Synlett 1998, 26–29.

52. Charette, A. B.; Lebel, H. J. Am. Chem. Soc. 1996, 118,

10327–10328.

26. Numbering of all intermediates corresponds to ambruticin S

numbering.

53. Kocienski, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000,

365–366.

27. Saigo, K.; Osaki, M.; Mukaiyama, T. Chem. Lett. 1976,

769–770.

54. (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Chim.

Soc. Fr. 1993, 130, 336–357. (b) Baudin, J. B.; Hareau, G.;

Julia, S. A.; Lorne, R.; Ruel, O. Bull. Chim. Soc. Fr. 1993, 130,

856–878.

28. (a) Hosomi, A.; Endo, M.; Sakurai, H. Chem. Lett. 1976,

941–942. (b) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem.

Soc. 1982, 104, 4976–4978.

29. For a related route to 8b, see Ref. 30.

55. Kuo, Y.-H.; Shih, K.-S. Heterocycles 1990, 31, 1941–1949.

56. Soai, K.; Kawase, Y.; Niwa, S. Heterocycles 1989, 29,

2219–2223.

30. Liu, L.; Donaldson, W. A. Synlett 1996, 103–104.

31. Regeling, H.; Chittenden, G. J. F. Recl. Trav. Chim. Pays-Bas

1989, 108, 330–334.

57. Seebach, D.; Plattner, D. A.; Beck, A. K.; Wang, Y. M.;

Hunziker, D. Helv. Chim. Acta 1992, 75, 2171–2209, and

references therein.

32. Burk, R. M.; Roof, M. B. Tetrahedron Lett. 1993, 34,

395–398.

33. Saravanan, P.; Chandrasekhar, M.; Anand, R. V.; Singh, V. K.

Tetrahedron Lett. 1998, 39, 3091–3092.

58. Paquette, L. A.; Liang, S.; Wang, H.-L. J. Org. Chem. 1996,

61, 3268–3279.

34. (a) Iversen, T.; Bundle, D. R. J. Chem. Soc., Chem. Commun.

1981, 1240–1241. (b) Widner, U. Synthesis 1987, 568–570.

(c) Eckenberg, P.; Groth, U.; Huhn, T.; Richter, N.; Schmeck,

C. Tetrahedron 1993, 49, 1619–1624.

59. McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1980, 21,

4313–4316.

60. Compound 41 was prepared by slight modiﬁcation of a

procedure Schreiber employed for making the corresponding

phenylsulﬁde. See: Romo, D.; Johnson, D. D.; Plamondon, L.;

Miwa, T.; Schreiber, S. L. J. Org. Chem. 1992, 57,

5060–5063.

35. For an example, see: Martin, S. F.; Rueger, H.; Williamass

spectrumon, S. A.; Grzejszczak, S. J. Am. Chem. Soc. 1987,

109, 6124–6134.

36. (a) Lemieux, R. U.; Kondo, T. Carbohydr. Res. 1974, 35,

C4–C6. (b) Fleming, I.; Leslie, C. P. J. Chem. Soc., Perkin

Trans. 1 1996, 1197–1203.

61. See Neipp, C. E.; Martin, S. F. Tetrahedron Lett. 2002, 43,

1779–1782, and references therein.

62. (a) Overman, L. E.; Lin, N.-H. J. Org. Chem. 1985, 50,

3669–3670. (b) Andersen, M. W.; Hildebrant, B.; Dahmann,

G.; Hoffmann, R. W. Chem. Ber. 1991, 124, 2127–2139.

63. Schwab, P. E.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.

1996, 118, 100–110.

37. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.

38. Rokach, J.; Lau, C.-K.; Zamboni, R.; Guindon, Y.

Tetrahedron Lett. 1981, 22, 2763–2766.

39. Molecular mechanics calculations were performed using

MM2 in Spartan.

64. Raiﬁeld, Y. E.; Nikitenko, A. A.; Arshava, B. M.; Mikerin,

I. E.; Zilberg, L. L.; Vid, G. Y.; Lang, J. r.; S, A.; Lee, V. J.

Tetrahedron 1994, 50, 8603–8616.

40. Martin, S. F.; Dorsey, G. O.; Gane, T.; Hillier, M. C.; Kessler,

H.; Bhat, T. N.; Munshi, S.; Gulnik, S. V.; Topol, I. A. J. Med.

Chem. 1998, 41, 1581–1597.

65. Brandes, A.; Eggert, U.; Hoffmann, H. M. R. Synlett 1994,

745–747.

41. Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982,

12, 989–993.

66. Davidson, A. H.; Wallace, I. H. J. Chem. Soc., Chem.

Commun. 1986, 1759–1760, and references therein.

67. Seyferth, D.; Andrews, S. B. J. Organomet. Chem. 1971, 30,

151–166.

42. Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky,

D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496–6511.

43. Ager, D. J. J. Chem. Soc., Perkin Trans. 1 1986, 195–203.

44. Kocienski, P. J.; Lythgoe, B.; Ruston, S. J. Chem. Soc., Perkin

Trans. 1 1978, 829–834.

68. For a review, see: Mikami, K.; Nakai, T. Synthesis 1991,

594–604.

45. Pohmakotr, M.; Geiss, K.-H.; Seebach, D. Chem. Ber. 1979,

112, 1420–1439. Use of commercial anhydrous MgBr₂or

MgBr₂·Et₂O resulted in no addition of the sulfone anion to 15,

presumably because of the presence of an adventitious proton

source in the commercial reagents.

69. Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org. Chem.

1962, 28, 1140–1142.

70. The E/Z ratio was determined by integration of the signal for a

vinyl proton of the minor Z-diastereomer that was centered at d

4.89.

46. (a) Eisch, J. J.; Galle, J. E. J. Org. Chem. 1979, 44,

3279–3280. (b) Ashwell, M.; Jackson, R. F. W. J. Chem.

Soc., Chem. Commun. 1988, 645–647.

71. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen,

R. K.; Timmers, F. J. Organometallics 1996, 15, 1518–1520.

72. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.

47. Lythgoe, B.; Waterhouse, I. Tetrahedron Lett. 1977, 18,

4223–4226.

Article Doi

Total synthesis of (+)-ambruticin S

DOI: 10.1016/S0040-4020(03)00370-3

Source and publish data:

Authors:

Article abstract of DOI:10.1016/S0040-4020(03)00370-3

Full text of DOI:10.1016/S0040-4020(03)00370-3

Products guided by the article

R&D Labs maybe for 616895-64-8

Relevant to this article

Hot Product