Development of a catalytic enantioselective synthesis of the guanacastepene and heptemerone tricyclic core

Accepted Manuscript

Development of a catalytic enantioselective synthesis of the guanacastepene and

heptemerone tricyclic core

Andrew M. Harned, Brian M. Stoltz

PII:

S0040-4020(19)30213-3

https://doi.org/10.1016/j.tet.2019.02.053

TET 30176

DOI:

Reference:

To appear in: Tetrahedron

Received Date: 12 January 2019

Revised Date: 20 February 2019

Accepted Date: 22 February 2019

Please cite this article as: Harned AM, Stoltz BM, Development of a catalytic enantioselective synthesis

of the guanacastepene and heptemerone tricyclic core, Tetrahedron (2019), doi: https://doi.org/10.1016/

j.tet.2019.02.053.

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Development of a catalytic enantioselective

synthesis of the guanacastepene and

heptemerone tricyclic core

Leave this area blank for abstract info.

Andrew M. Harned^a,b,*and Brian M. Stoltz^a,*

^aThe Warren and Katharine Schlinger Laboratory of Chemistry and Chemical Engineering, California Institute

of Technology, Pasadena, California 91125, United States

^bDepartment of Chemistry & Biochemistry, Texas Tech University, 1204 Boston Ave, Lubbock, Texas 79409,

United States

1

ACCEPTED MANUSCRIPT

Tetrahedron

journal homepage: www.elsevier.com

Development of a catalytic enantioselective synthesis of the guanacastepene and

heptemerone tricyclic core

Andrew M. Harned ^{a,b, *}and Brian M. Stoltz ^{a, *}

^aThe Warren and Katharine Schlinger Laboratory of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125,

United States

^bDepartment of Chemistry & Biochemistry, Texas Tech University, 1204 Boston Ave, Lubbock, Texas 79409, United States

This paper is dedicated to Professor Ryan A. Shenvi on receipt of the Tetrahedron Young Investigator Award.

ARTICLE INFO

ABSTRACT

Article history:

Received

Received in revised form

Accepted

For nearly two decades, synthetic chemists have been fascinated by the structural complexity

and synthetic challenges afforded by the guanacastepene and heptemerone diterpenoids.

Numerous synthetic approaches to these compounds have been reported, but to date the

application of enantioselective catalysis to this problem has not been realized. Herein we report

an enantioselective synthesis of an advanced intermediate corresponding to the tricyclic core

common to the guanacastepenes and heptemerones. Highlights of this work include sequential

Pd-catalyzed decarboxylative allylic alkylation reactions to generate the two all carbon

quaternary stereocenters, the use of ring-closing metathesis to close the A ring in the presence of

a distal allyl sidechain, and a regio- and diastereoselective oxidation of an trienol ether to

introduce oxygenation on the A ring.

Available online

Keywords:

allylic alkylation

Pd catalysis

olefin metathesis

stereoselectivity

natural products

.

2

Tetrahedron

β-ketoester (±)-5 would serve as the source of asymmetry in our

1. Introduction

ACCEPTED MANUSCRIPT

synthesis.

The guanacastepenes are a family of diterpenoids (Figure 1)

originally isolated by Clardy and coworkers from an unidentified

fungus that was found growing on a tree, Daphnopsis americana,

in Costa Rica.¹Various members of the family have displayed

interesting anticancer²and antibacterial³activity. In 2005, Sterner

and co-workers reported the isolation of structurally similar

diterpenoids, the heptemerones, from the mushroom Coprinus

heptemerus.⁴Structurally, the guanacastepenes and heptemerones

are interesting due to their unusual 5-7-6 ring system with a

highly oxidized upper portion and fully saturated lower half. Of

particular note are the two quaternary carbon stereocenters that

have proven to be the one of the biggest synthetic challenges

posed by these targets.

Scheme 1.

2.2. Installation of first stereocenter

Reaction of 1,3-cycloheptanedione (6)¹²with isobutanol under

Dean–Stark conditions in the presence of PPTS produced

vinylogous ester

7

(Scheme 2). Although vinylogous

esterification proceeded smoothly, a significant amount of the

retro-Dieckmann product was obtained if the generated water

was not efficiently removed. This side product could be

eliminated with two simple procedural modifications. First, the

isobutanol should be distilled from CaO. Second, the heating

bath should be preheated before addition of the reaction mixture.

Acylation of

7 with allyl cyanoformate, and subsequent

methylation, gave the required β-ketoester (±)-5. It should be

noted at this point that the absolute configuration of the natural

products requires the use of (R)-t-BuPHOX, which is derived

from the unnatural enantiomer of tert-leucine. Consequently,

much of the subsequent work was carried out with racemic

material obtained by using PPh₃as the ligand. We also used the

more readily available (S)-t-BuPHOX to demonstrate that the

planned enantioselective decarboxylative allylic alkylation could

proceed in good yield and acceptable enantioselectivity [(±)-

5→(S)-4].

Figure 1. Representative members of the guanacastepene and

heptemerone diterpenoids.

Although initial excitement over this family of natural

products has tempered, due to their hemolytic activity,⁵the

synthetic community continues to demonstrate interest in these

molecules.^6,7While there have been several nonasymmetric and

asymmetric total syntheses of these molecules, no catalytic

enantioselective routes have been described in the literature.

When our work on these targets started, our group had recently

disclosed a series of asymmetric Pd-catalyzed decarboxylative

allylic alkylation reactions capable of constructing all-carbon

quaternary stereocenters with high levels of stereocontrol.⁸At the

same time, we had a burgeoning interest in deploying this

technology in natural product synthesis,⁹and believed these

targets would be an ideal challenge for this newly developed

technology. Herein, we describe our enantioselective synthesis of

the tricyclic core common to the guanacastepenes and

heptemerones.

Scheme 2.

2. Results and Discussion

2.1. Synthetic plan

We planned to use keto-acetonide 1 (Scheme 1) as our initial

synthetic target owing to Danishefsky and co-workers’ success in

accessing (±)-guanacastepene A from this intermediate.¹⁰The

acetonide-protected diol would arise through reduction of the

corresponding ketoester. We envisoned that the six-membered

Addition of β-lithiosytrene to vinylogous ester 4 afforded

cyclohepteneone 3 (Scheme 2). In contrast to what is observed

when performing Stork–Danheiser chemistry on six-membered

rings, the intermediate β-hydroxy cycloheptanone was found to

be particularly stable.¹³Fortunately, warming with aqueous HCl

was sufficient to push the elimination toward 3. Attempts were

made to derivatize 3 (e.g. oxime, semicarbazone, various

hydrazones) in order to affect enantioenrichment through

recrystallization; unfortunately none were successful in forming

suitably crystalline products. Fortunately, however, further

transformations would make such enrichment unnecessary.

ring of

1 could be constructed through a Knoevenagel

condensation, after chain elongation of the allyl moiety of 2,

while the isopropyl-substituted cyclopentanone moiety would be

constructed from the cyclopentene portion of 2. The α-quaternary

stereocenter in

2 would be installed by a Pd-catalyzed

decarboxylative allylic alkylation, while the five-membered ring

could be closed by ring-closing metathesis (RCM) of 3. The

styryl moiety in cycloheptenone 3 would be installed by

performing Stork–Danheiser chemistry on vinylogous ester 4.¹¹

Ultimately, an asymmetric decarboxylative allylic alkylation of

3

2.3. Installation of second stereocenter

With this result in hand, ketone (R)-4, of 83% ee, was

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prepared using (R)-t-BuPHOX and advanced to β-ketoester

(R,R/S)-10. Performing the second Pd-catalyzed allylic alkylation

with (R)-t-BuPHOX furnished ketone (R,R)-11 with 9:1

diastereoselectivity. Furthermore, the major diastereomer was

formed with improved levels of enantiopurity (96% ee), in

accordance with the Horeau principle.¹⁹Because both

stereocenters of 11 were formed through catalyst control using

the same antipode of the ligand, we are confident that the major

diastereomer has the desired anti-methyl relationship.

Additionally, subsequent RCM furnished a bicyclic compound

that was diastereometic to 2, vide infra.

Ring-closing metathesis (RCM) with the second-generation

Grubbs catalyst afforded bicyclic dieneone 8, which was acylated

and methylated to give alkylation substrate 9. When screening

ligands to promote the Pd-catalyzed alkylation reaction, we

found that the use of an achiral phosphinooxazoline (PHOX)

ligand or either antipode of t-BuPHOX resulted in the formation

of a single diastereomer of 2 in all cases. Unfortunately,

comparison with later synthetic intermediates revealed this to be

the undesired syn-methyl diastereomer (syn-2).

Scheme 3.

Scheme 4.

Molecular modeling of the enolate intermediate derived from

ketone 9 (enolate A) was performed in order to understand the

high degree of diastereoselectivity observed in this reaction

(Figure 2). This effort revealed that the methyl group of the

previously installed quaternary stereocenter sits in a pseudoaxial

position and effectively blocks the Re face of the enolate. This is

in excellent agreement with related computational work by Houk

that was reported after our experimental work was completed.^14,15

Houk’s work also revealed that steric effects, rather than

torsional effects,¹⁶were primarily responsible for the observed

stereoselectivity.

2.4. Elaboration of the allyl group and Knoevenagel cyclization

With the two quaternary stereocenters in place, our attention

turned to completing the tricyclic ring system (Scheme 5). First,

treating compound 11 with the second-generation Grubbs

catalyst affected the closure of the A ring. Once the initial RCM

reaction was complete, the indicated propenyl boronic ester²⁰was

added to the reaction mixture in order to carry out a cross

metathesis with the remaining allyl group. Undesired cross

metathesis with the liberated styrene was minimized by carefully

monitoring (TLC) the initial RCM. The resulting boronic ester

(12) was not isolated. Instead it was immediately oxidized to

aldehyde 13 with anhydrous²¹Me₃NO.²²A number of other cross

metathesis partners were also examined, but none proved to be as

useful or successful as the coupling with the vinyl boronate.

Re face blocked

O

enolate A

Figure 2. Calculated (B3LYP/6-31+G(d), SMD^THF) structure of

enolate A.

Scheme 5.

Clearly the large amount of substrate control imposed by

enolate A would be difficult to overcome using a bicyclic

scaffold. However, we believed diminished substrate control

might be experienced with a monocyclic enolate.¹⁷To test this

hypothesis, ketone 3 was converted to β-ketoester 10 (Scheme 4).

Subjecting ketoester 10 to Pd-catalyzed decarboxylative allylic

alkylation, in the presence of an achiral PHOX ligand, afforded

ketone 11 with a diastereomeric ratio of 2.6:1. Using either

antipode of t-BuPHOX resulted in a dr of 1.3:1. It should be

emphasized that these results were obtained using material

derived from racemic ketone 3. This means that if we were to

observe complete catalyst control, the best possible dr we could

see with (S)- or (R)-t-BuPHOX is 1:1. With this in mind, the

diastereoselectivity afforded by (S)- and (R)-t-BuPHOX was

actually quite encouraging.¹⁸

4

Tetrahedron

Aldehyde 13 was then coupled to ethyl diazoacetate²³to

Scheme 6.

ACCEPTED MANUSCRIPT

furnish β-ketoester 14. To our delight, heating 14 with NaOEt

affected the Knoevenagel cyclization¹⁰needed to produce tricycle

15 representing the complete guanacastepene ring skeleton. It

should be noted the reactions presented in Scheme 3 were not

optimized at this point. Nevertheless, they serve as a useful guide

for how the tricyclic ring system can be constructed.

2.5. Oxygenation of the A-ring.

Having identified a serviceable route to the tricyclic ring

system, we then concerned ourselves with oxidizing the

cyclopentene ring. Considerable effort was expended on this

particularly troublesome task. We investigated a number of

conditions

including

regioselective

epoxidations,

dihydroxylations, and allyic oxidations, but all resulted in either

no reaction or general decomposition of the starting material. Our

prospects for carrying out this necessary transformation seemed

bleak until we located a useful procedure from the literature. Kirk

and Wiles found that α,β-unsaturated ketones could be converted

into γ-hydroxylated ketones by utilizing a two-step procedure

involving extended enol ether formation, followed by m-CPBA

oxidation and hydrolysis.^24,25,26The authors found that solvent

choice was critical to the regioselectivity, as use of CH₂Cl₂or

other anhydrous organic solvents resulted in oxidation at the α-

position. Conversely, the use of aqueous organic solvents (e.g.

THF, dioxane, EtOH) along with slow addition of the oxidant

provided the γ-hydroxy enone in good yields.²⁴

2.6. Multigram synthetic route

Having finally succeeded in identifying conditions to

oxygenate the cyclopentene ring, we then scaled up the route

with enantioenriched material. Our final optimized route to

compound 18 is shown in Scheme 7. Gratifyingly, many of the

steps could be scaled with little problem, but there were a few

last minute optimizations made along the way. The solvent of the

initial decarboxylative allylic alkylation was changed from THF

to toluene. This allowed for the relatively small increase in

selectivity from 83% to 87% ee. Other notable details include the

use of freshly prepared LHMDS for the acylation of 3 and using

Cs₂CO₃, rather than NaH, for the subsequent methylation in order

to improve the impurity profile of these particular

transformations.

Applying these conditions to the present case proved to be

particularly rewarding (Scheme 6). First, an RCM was used to

convert anti-11 into anti-2. Careful monitoring of the reaction

was needed in order to minimize competitive cross metathesis

reactions (homodimer and styrene cross product) involving the

allyl sidechain present in 2. Performing the reaction under an

atmosphere of ethylene further minimized these pathways.

Treating ketone 2 with TBSOTf furnished silyl enol ether 16. To

our delight, oxidation of 16 with m-CPBA in 95% EtOH

smoothly formed alcohol 17 in high yield and as the only

observed isomer. Through experimentation it was found that

magnesium monoperoxyphthalate (MMPP) performed better than

m-CPBA in this oxidation. The secondary alcohol was then

converted to TBS ether 18.

The conversion of 4 to 3 was the one step that did need some

more optimization. While the lithium-halogen exchange of β-

bromostyrene proceeded readily on small scale in THF, the large-

scale reaction proceeded to give products of phenylacetylene

addition (e.g. deprotonation of α-hydrogen, elimination of

bromide, deprotonation of phenylacetylene). Presumably, this

was due to inefficient cooling of the exothermic lithium-halogen

exchange reaction when performed in large volumes of THF.

Changing the solvent to Et₂O alleviated this problem. However,

attempts to heat the mixture of Et₂O with aqueous HCl to affect

elimination of the hydroxyl group were unsuccessful, presumably

due to the two-phase nature of the system. This could be

overcome by first quenching the reaction with 10% HCl followed

by removal of the volatiles under rotary evaporation. THF was

then added and the mixture warmed to 50 ºC. By employing this

procedure, 3 was formed in high yield on multigram scale. By

following this 12-step route, and starting with 5.0 g of

cycloheptanedione, we were able to synthesize 4.5 g of 18 as a

pure, colorless oil.

Scheme 7.

5

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2.7. Generation of tricyclic core

Scheme 9.

With multigram quantities of 18 in hand, we then had a

difficult choice to make. Either we could take the time to

elaborate the five membered ring into the required isopropyl-

containing cyclopentanone, or investigate that problem after

forming the six-membered ring. For better or worse, we chose the

latter.

As the silyl ether at C12 was positioned on the α-face, we first

considered using a Cu-catalyzed coupling reaction with i-

PrMgCl. Similar coupling reactions, albeit not as sterically

crowded as the present example, have been shown to proceed

with net inversion of the initial stereocenter.^30,31If successful, this

would install the C12 isopropyl group with the correct relative

configuration. Conversion of silyl ether 23 into allyl pivalate 24

proceeded smoothly (Scheme 10), but all cross coupling attempts

with this intermediate failed. This is likely due to the presence of

the adjacent quaternary carbon.

Starting with intermediate 18, a cross metathesis reaction was

performed between the allyl group and the indicated vinyl

boronate (Scheme 8). The resulting boronic ester was not

isolated. Instead it was immediately oxidized to aldehyde 19 with

anhydrous Me₃NO. The aldehyde was then coupled to ethyl

diazoacetate²³to furnish β-ketoester 20. Preliminary attempts at

using an alkoxide base (NaOEt) to affect the desired

Knoevenagel ring closure were successful,¹⁰but we found that

using KF as the base²⁷provided higher yields. Notably, the use of

a protic solvent prevented cleavage of the TBS ether. Finally,

stereoselective reduction of the β-ketoester, to give alcohol 22,

was accomplished using a Noyori transfer hydrogenation.²⁸By

relying on reagent control of the newly formed stereocenter, we

were able to address the low diastereoselectivity (~4:1) observed

by Danishefsky,¹⁰Snider,²⁹and Wicha.^7hEster 22 was then

converted into acetonide 23 using standard methods.

In an effort to relieve steric crowding, we decided to convert

silyl ether 23 into a vinyl triflate. First, the silyl ether was cleaved

using TBAF. The more sterically accessible alkene (A ring) was

then hydrogenated under palladium catalysis. Oxidation with

TPAP/NMO³²afforded cyclopentanone 25 in high yield for the

sequence. Formation of the requisite vinyl triflate proceeded

smoothly. To our delight, coupling between the vinyl triflate and

i-PrMgCl proceeded to give triene 26 in high yield, using

catalytic conditions reported by Bäckvall and co-workers.³³

Scheme 8.

Installing oxygenation on the A ring from compound 26, once

again proved taxing. All attempts to isomerize the C12-C13

double bond failed. Preliminary molecular modeling suggested

that the tricyclic ring system adopted a twisted structure, which

does not allow for efficient conjugation in the desired triene.

Consequently, the trisubsubstituted A ring alkene is more

thermodynamically favored.

Scheme 10.

2.8. Attempts to functionalize the A ring

With acetonide 23 in hand, we turned our attention to

functionalizing the A ring (Scheme 9). We thought that the

allylic ether already present in the A ring (A) contained enough

functionality to allow for installation of the C12 isopropyl group

(B). Following that, we planned to access the C14 ketone through

isomerization of a C13-C14 epoxide (B→C→D). In this manner,

and by starting with acetonide 23, we would generate the same

intermediate ketone (1) used by Danishefsky and co-workers in

their synthesis of guanacastepene A.¹⁰This same intermediate

would also be directly applicable to heptemerone G.^7h

In a final attempt to functionalize the A ring, we planned to

employ a Grignard addition/oxidative transposition^34,35sequence

(Scheme 11, box) in order to install the C12 isopropyl and C14

ketone. Our prospects were bolstered by precedent from the

Phillips³⁶and Mander³⁷labs, who performed an analogous

transformation with cyclopentenones. This approach was

evaluated by first converting silyl ether 18 into cyclopentenone

27. Performing nOe experiments on compound 27 confirmed the

site of A-ring oxidation. Treating ketone 27 with i-PrMgBr

1

provided a product, whose H NMR spectrum was deficient by

two alkene protons. This was tentatively assigned as conjugate

6

Tetrahedron

addition product 28. A similar result was obtained when the

chemical shift (δ ppm) (multiplicity, coupling constant (Hz),

integration). The following abbreviations are used to report NMR

data: s = singlet, d = doublet, t = triplet, q = quartet, sept = septet,

br = broad, obsc = obscured, app = apparent. IR spectra were

recorded on a Perkin Elmer Paragon 1000 spectrometer and are

reported in frequency of absorption (cm^-1). High resolution mass

spectra were obtained from the Caltech Mass Spectral Facility.

ACCEPTED MANUSCRIPT

Grignard addition was performed in the presence of CeCl₃.³⁸

After our work was completed, Wicha and co-workers

successfully performed

a

similar 1,2-addition/oxidative

transposition en route to the A ring of guacastepene.^7h,39Notably,

their bicyclic intermediate contained a trans ring fusion between

the A and B rings. This likely enforces a different conformation

that provides a more open approach to the C12 ketone.

4.1. 3-Isobutoxycyclohept-2-enone (7)

Scheme 11.

A 250 mL round-bottom flask fixed with a Dean–Stark trap was

charged with 1,3-cycloheptanedione (6, 5.0054 g, 39.7 mmol)

and toluene (40 mL). Isobutanol (30 mL, 325 mmol, 8.2 equiv)

and PPTS (149.6 mg, 0.595 mmol, 1.5 mol%) were added and

the mixture was then placed in an oil bath pre-heated to 130 °C.

After two hours TLC indicated complete consumption of starting

material. The reaction was cooled and concentrated in vacuo. The

residue was then distilled at 0.6 mmHg, collecting the portion

that distilled at 91–96 °C, to afford the title compound (5.3025 g,

1

73% yield) as a yellow oil. R_F= 0.06 (10:1 Hexane:EtOAc); H

NMR (500 MHz, CDCl₃) δ 5.37 (s, 1H), 3.49 (d, J = 6.6 Hz,

2H), 2.60-2.56 (m, 4H), 2.00 (app sept, J = 6.6 Hz, 1H), 1.88-

1.77 (m, 4H), 0.96 (d, J = 6.8 Hz, 6H); ¹³C NMR (125 MHz,

CDCl₃) δ 202.5, 176.6, 106.0, 75.0, 41.9, 33.1, 27.9, 23.7, 21.5,

19.3; IR (Neat Film NaCl) 2958, 2872, 1646, 1607, 1469, 1237,

1190, 1174 cm^-1; HRMS (EI) m/z calc'd for C₁₁H₁₈O₂[M]^+•:

182.1307; found 182.1310.

3. Conclusion

We have developed the first catalytic enantioselective route to

the tricyclic core common to the guanacastepene and

heptemerone diterpenoids. Our route relies on sequential Pd-

catalyzed decarboxylative allylic alkylation reactions to generate

the two all carbon quaternary stereocenters with high fidelity. We

have also identified conditions through which oxygenation and

the C12 isopropyl group can be introduced to the A ring.

Although there is still work to be done, particularly on the A ring,

the advanced intermediates we have generated may yet prove

useful; especially when one considers the potential utility of

biocatalysis as a means to perform regioselective C–H oxidation

reactions.⁴⁰

4.2. Allyl 4-isobutoxy-1-methyl-2-oxocyclohept-3-enecarboxylate

(5)

n-Butyllithium (2.12 M in hexane, 15 mL, 31.8 mmol) was added

to a solution of N,N-diisopropylamine (4.4 mL, 31.4 mmol) in

100 mL THF at –78 °C and the solution stirred for 30 min. A

solution of 3-isobutoxycyclohept-2-enone (7, 4.9996 g, 27.43

mmol) in 10 mL THF was added via cannula with a 5 mL THF

rinse. After stirring for 30 min, allyl cyanoformate (3.3677 g,

30.3 mmol) was added. The reaction was kept at –78 °C for 3

hours and then quenched with 50 mL of half saturated aq. NH₄Cl

and allowed to thaw. The mixture was diluted with 50 mL Et₂O

and the aqueous layer washed 3 x 50 mL Et₂O. The combined

organic layers were washed sequentially with water and brine,

dried over MgSO₄, and evaporated in vacuo. The residue was

then dissolved in 60 mL THF and cooled to 0 °C. NaH (60%

dispersion in mineral oil, 1.2218 g, 30.5 mmol) was added in

portions over 10 min. The mixture was stirred cold 20 min, and

then MeI (5 mL, 80.3 mmol) was added. The reaction was then

heated to 50 °C for 1 hour. The reaction was then quenched by

the careful addition of 50 mL of half saturated aq. NH₄Cl. The

mixture was diluted with 50 mL Et₂O and the aqueous layer

washed 3 x 25 mL Et₂O. The combined organic layers were

washed with brine, dried over MgSO₄, and evaporated in vacuo.

Silica gel chromatography (5 x 21 cm, 10:1 hexanes:EtOAc)

afforded the title compound as a pale yellow oil (5.9924 g, 78%

4. Experimental section

Unless otherwise stated, reactions were performed in flame-

dried glassware under an Ar or N₂atmosphere using dry,

deoxygenated solvents. Solvents were dried by passage through

an activated alumina column under argon. Triethylamine,

pyridine, and diisopropylamine were distilled from calcium

hydride immediately prior to use. Isobutanol was distilled from

CaO prior to use. β-bromostyrene was distilled (110 ºC, 20

mmHg) and storred under Ar in a Schlenk flask. Allyl

cyanoformate,⁴¹

TBSOTf,⁴²

and

Ru[(S,S)-Ts-DPEN](p-

cymene)^28awere prepared by known methods. (S)- and (R)-t-Bu-

PHOX was prepared by known methods.⁴³(R)-t-Leucinol was

resolved using a known procedure.⁴⁴Reaction temperatures were

controlled by an IKAmag temperature modulator. Thin-layer

chromatography (TLC) was performed using E. Merck silica gel

60 F254 precoated plates (0.25 mm) and visualized by UV

fluorescence quenching, anisaldehyde, or KMnO₄staining. ICN

Silica gel (particle size 0.032-0.063 mm) was used for flash

chromatography. Analytical chiral HPLC was performed with an

Agilent 1100 Series HPLC utilizing chiralcel AD, OD-H, or OJ

columns (4.6 mm x 25 cm) obtained from Daicel Chemical

Industries, Ltd with visualization at 254 nm. Analytical achiral

GC was performed with an Agilent 6850 GC utilizing a DB-

WAX (30m x 0.25 mm) column (1.0 mL/min carrier gas flow).

Optical rotations were measured with a Jasco P-1010 polarimeter

1

yield). R_F= 0.20 (10:1 Hexane:EtOAc); H NMR (300 MHz,

CDCl₃) δ 5.86 (dddd, J = 5.4, 5.4, 10.5, 16.8 Hz, 1H), 5.40 (s,

1H), 5.29 (dddd, J = 1.5, 1.5, 1.5, 17.1 Hz, 1H), 5.20 (dddd, J =

1.2, 1.2, 1.2, 10.5 Hz, 1H), 4.63 (dddd, J = 1.2, 1.2, 5.7, 13.2 Hz,

1H), 4.56 (dddd, J = 1.2, 1.2, 5.1, 12.9 Hz, 1H), 3.51 (dd, J = 6.6,

9.6 Hz, 1H), 3.46 (dd, J = 6.6, 9.3 Hz, 1H), 2.59 (ddd, J = 4.2,

9.3, 18 Hz, 1H), 2.47-2.36 (m, 2H), 2.04-1.92 (obsc m, 1H), 1.98

(app sept, J = 6.8 Hz, 1H), 1.81 (ddd, J = 4.2, 9.3, 18.9 Hz, 1H),

1.70 (ddd, 4.5, 7.5, 14.4 Hz, 1H), 1.43 (s, 3H), 0.95 (app d, J =

6.6 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 198.8, 173.7, 173.3,

131.7, 118.2, 104.9, 74.6, 65.5, 58.8, 34.1, 33.7, 27.7, 24.0, 21.1,

19.0; IR (Neat Film NaCl) 3084, 2959, 2935, 1733, 1652, 1612,

1

at 589 nm. H and ¹³C NMR spectra were recorded on a Varian

Mercury 300 (at 300 MHz and 75 MHz respectively) or Varian

Unity Inova 500 (at 500 MHz and 125 MHz respectively), and

are reported relative to CDCl₃/CHCl₃(¹H NMR δ 7.26, ¹³C NMR

δ 77.0). Data for ¹H NMR spectra are reported as follows:

7

1

1456, 1383, 1233, 1197, 1170, 1114, 994 cm^-1; HRMS (EI) m/z

Hexane:EtOAc); H NMR (300 MHz, CDCl₃) δ 6.34 (ddd, J =

0.6, 3, 5.4 Hz, 1H), 6.14 (ddd, 1.5, 2.1, 5.4 Hz, 1H), 5.87 (s, 1H),

2.71 (ddddd, J = 0.9, 0.9, 3.6, 6.3, 15 Hz, 1H), 2.59-2.49 (m, 2H),

2.41 (ddd, J = 1.5, 2.7, 18 Hz, 1H), 2.14-1.80 (m, 4H), 1.23 (s,

3H); ¹³C NMR (75 MHz, CDCl₃) δ 204.6, 169.0, 142.6, 134.2,

121.5, 51.4, 46.5, 44.9, 37.7, 29.5, 21.0; IR (Neat Film NaCl)

3059, 2930, 1650, 1615, 1449, 1352, 1261, 968 cm^-1; HRMS m/z

calc'd for C₁₁H₁₄O [M]⁺: 162.1045, found 162.1040.

ACCEPTED MANUSCRIPT

calc'd for C₁₆H₂₄O₄[M]^+•: 280.1675; found 280.1686.

4.3. (R)-7-Allyl-3-isobutoxy-7-methylcyclohept-2-enone ((R)-4)

In a nitrogen filled glove box, a flask was charged with Pd(dm-

dba)₂(568.4 mg, 0.697 mmol, 2 mol%), (R)-tBu-PHOX (334.8

mg, 0.864 mmol, 2.5 mol%), and 200 mL toluene. The mixture

was stirred 30 min, at which time allyl 4-isobutoxy-1-methyl-2-

oxocyclohept-3-enecarboxylate (5, 9.8032 g, 34.97 mmol) was

added with a total of 150 mL toluene. The reaction was then

taken out of the govebox, placed under a stream of argon, and

stirred 60 hrs. The mixture was then evaporated in vacuo. Silica

gel chromatography (5 x 18 cm, 25:1 hexanes:EtOAc) afforded

the title compound as a colorless oil (7.8401 g, 95% yield). R_F=

4.6. (±)-(6R,8aR)-6-Allyl-6,8a-dimethyl-6,7,8,8a-

tetrahydroazulen-5(1H)-one (syn-2)

To s solution of (±)-8a-methyl-6,7,8,8a-tetrahydroazulen-5(1H)-

one (8, 132.9 mg, 0.819 mmol) in 5 mL THF cooled to –78 °C

was added a solution of LHMDS (1.0M in THF, 0.9 mL, 0.9

mmol). The mixture was stirred 30 min and then allyl

cyanoformate (106 mg, 0.954 mmol) was added. After 30 min, 8

mL 50% sat. NH₄Cl was added and the mixture allowed to warm

to ambient temperature. The aqueous layer was extracted with 3 x

10 mL Et₂O, and the combined organic layers dried with MgSO₄

and evaporated in vacuo. The crude residue was then dissolved in

5 mL THF and cooled to 0 °C. NaH (60% dispersion in mineral

oil, 34.8 mg, 0.87 mmol) was added and the mixture stirred 10

min. MeI (140 L, 2.25 mmol) was added and the reaction

warmed to ambient temperature. After 1 hour, the reaction was

quenched by the careful addition of ~5 mL 10% HCl. The

mixture was then diluted with 10 mL H₂O and 10 mL Et₂O. The

aqueous layer was awashed 3 x 10 mL Et₂O. The combined

organic layers were dried with MgSO₄and evaporated in vacuo.

Flash chromatography (2 x 14 cm, 10:1 Hex/EtOAc) afforded β-

ketoester 9 (213.3 mg, 74% yield, 1 diastereomer) as a yellow

oil. R_F= 0.36 (5:1 Hexane:EtOAc); ¹H NMR (300 MHz, CDCl₃)

δ 6.38 (ddd, J = 2.7, 2.7, 5.4 Hz, 1H), 6.15-6.10 (m, 1H), 5.95

(dddd, J = 5.4, 5.4, 10.8, 16.8 Hz, 1H), 5.76 (s, 1H), 5.34 (dddd,

J = 1.5, 1.5, 1.5, 17.4 Hz, 1H), 5.22 (dddd, J = 1.5, 1.5, 1.5, 10.5

Hz, 1H), 4.74-4.62 (m, 2H), 2.81 (ddd, J = 2.7, 14.7, 14.7 Hz,

1H), 2.55 (bd, J = 18 Hz, 1H), 2.41 (ddd, J = 1.5, 3, 18 Hz, 1H),

2.11 (ddd, J = 2.1, 14.1, 14.1 Hz, 1H), 1.81 (ddd, J = 2.7, 6, 14.7

Hz, 1H), 1.70 (ddd, J = 1.8, 5.7, 14.4 Hz, 1H), 1.48 (s, 3H), 1.25

(s, 3H).

1

0.36 (10:1 Hexane:EtOAc); H NMR (300 MHz, CDCl₃) δ 5.72

(dddd, J = 7.2, 7.2, 10.8, 15.9 Hz, 1H), 5.31 (s, 1H), 5.05 (br s,

1H), 5.01 (dddd, J = 1.5, 1.5, 2.7, 5.1 Hz, 1H), 3.51 (dd, J = 6.6,

9.3 Hz, 1H), 3.45 (dd, J = 6.6, 9.3 Hz, 1H), 2.50-2.45 (m, 2H),

2.38 (app dd, J = 7.2, 13.5 Hz, 1H), 2.20 (dddd, J = 1.2, 1.2, 7.5,

8.7 Hz, 1H), 1.98 (app sept, J = 6.6 Hz, 1H), 1.89-1.70 (m, 3H),

1.63-1.55 (m, 1H), 1.14 (s, 3H), 0.95 (app d, J = 6.9 Hz, 6H); ¹³

C

NMR (75 MHz, CDCl₃) δ 206.5, 171.1, 134.4, 117.7, 104.8,

74.3, 51.3, 45.2, 35.9, 35.0, 27.8, 25.0, 19.7, 19.1; IR (Neat Film

NaCl) 3075, 2959, 2932, 1614, 1470, 1387, 1213, 1192, 1172,

998, 912 cm^-1; HRMS m/z calc'd for C₁₅H₂₄O₂[M]⁺: 236.1776,

found 236.1775; [α]_D^24.9+61.39 (c 1.055, CH₂Cl₂, 87% ee).

4.4. (R)-4-Allyl-4-methyl-3-styrylcyclohept-2-enone ((R)-3)

β-Bromostyrene (7 mL, 54.57 mmol) was dissolved in 64 mL

Et₂O and cooled to –78 °C. t-BuLi (1.6 M in pentane, 64 mL,

102.4 mmol) was added over 40 min. The mixture was stirred at

–78 °C for 1 hr, at which time (R)-7-allyl-3-isobutoxy-7-

methylcyclohept-2-enone (4, 7.8335 g, 33.14 mmol) in 15 mL

Et₂O was added by cannula with a 5 mL rinse. After 90 min, the

reaction was warmed with an ice bath and stirred for 1 hr. The

reaction was quenched with 10% HCl (100 mL), and the volatiles

removed in vacuo. To the residue was added 100 mL THF. The

mixture was then heated to 50 °C for 12 hrs. After cooling to

room temperature, the mixture was extracted 4 x 100 mL Et₂O.

The combined organic extracts were dried over MgSO₄, and

evaporated in vacuo. Silica gel chromatography (5 x 17 cm, ~700

mL 20:1 hexanes:EtOAc then ~1.6 L 15:1 hexanes:EtOAc)

afforded the title compound as a viscous yellow oil (8.0542 g,

91% yield). R_F= 0.23 (10:1 Hexane:EtOAc); ¹H NMR (300

MHz, CDCl₃) δ 7.45-7.27 (m, 5H), 6.90 (s, 2H), 6.31 (s, 1H),

5.68 (dddd, J = 6.6, 8.1, 10.5, 17.1 Hz, 1H), 5.09-5.01 (m, 2H),

2.66-2.61 (m, 2H), 2.47 (dd, J = 6.6, 14.1 Hz, 1H), 2.14 (dd, J =

8.1, 14.1 Hz, 1H), 1.93-1.80 (m, 3H), 1.70-1.60 (m, 1H), 1.27 (s,

3H); ¹³C NMR (125 MHz, CDCl₃) δ 204.5, 158.3, 136.5, 133.7,

133.1, 129.0, 128.7, 128.3, 126.9, 126.9, 118.3, 46.0, 44.3, 44.2,

38.5, 26.6, 17.4; IR (Neat Film NaCl) 3075, 3026, 2925, 1640,

1582, 1450, 1344, 1250, 1217, 963, 916, 752, 694 cm^-1; HRMS

A flame-dried vial was charged with Pd(dm-dba)₂(4.5 mg,

0.0.00552 mmol, 5 mol%), (S)-tBu-PHOX (2.5 mg, 0.00645

mmol, 5.8 mol%), and 3 mL THF. The mixture is stirred at 25 °C

for 30 min at which time β-ketoester 9 (29 mg, 0.111 mmol)

prepared above was added by syringe. The reaction was stirred at

25 °C for 5.5 hrs. Evaporation in vacuo followed by silica gel

chromatography (3 x 3 cm, 20:1 hexanes:EtOAc) afforded the

title compound as a light yellow oil (20.8 mg, 86% yield, >10:1

1

mixture of diastereomers). R_F= 0.40 (10:1 Hexane:EtOAc); H

NMR (300 MHz, CDCl₃) Major diastereomer: δ 6.26 (ddd, J =

3, 3, 5 Hz, 1H), 6.09 (ddd, J = 1.8, 1.8, 5.4 Hz, 1H), 5.71 (s, 1H),

5.61 (dddd, J = 6.9, 7.5, 10.2, 18 Hz, 1H), 5.06-4.97 (m, 2H),

2.55-2.41 (m, 2H), 2.35 (ddd, J = 1.8, 2.7, 18 Hz, 1H), 2.26-1.93

(m, 3H), 1.70 (app d, J = 5.1 Hz, 1H), 1.64 (app d, J = 5.7 Hz,

1H), 1.12 (s, 3H), 1.07 (s, 3H); Diagnostic peaks of minor

diastereomer: δ 5.74 (s), 1.15 (s), 1.11 (s); ¹³C NMR (75 MHz,

CDCl3) 208.9, 164.5, 141.4, 133.6, 133.3, 119.5, 118.0, 50.9,

50.7, 45.2, 42.2, 34.1, 33.2, 28.8, 23.4; IR (Neat Film NaCl)

3075, 3059, 2961, 2929, 1656, 1625, 1450, 1375, 1220, 1204,

1122, 913 cm^-1.

24.8

m/z calc'd for C₁₉H₂₂O [M]⁺: 266.1671, found 266.1668; [α]_D

+33.70 (c 1.19, CHCl₃, 88% ee).

4.5. (±)-8a-methyl-6,7,8,8a-tetrahydroazulen-5(1H)-one (8)

To a solution of (±)-4-allyl-4-methyl-3-styrylcyclohept-2-enone

(3, 634.g mg, 2.38 mmol) in 80 mL degassed (argon bubbling)

CH₂Cl₂was added the second generation Grubbs catalyst (5.2

mg, 0.00612 mmol, 0.25 mol%). The mixture was then heated to

50 ºC for 50 min and then cooled to ambient temperature. Ethyl

vinyl ether (5 mL) was added and the mixture stirred 30 min.

Evaporation in vacuo, followed by silica gel chromatography (2

cm x 16 cm, 15:1 hexane:EtOAc) afforded the title compound as

a colorless oil (351.3 mg, 91% yield). R_F= 0.17 (10:1

4.7. (5R)-Allyl 5-allyl-1,5-dimethyl-2-oxo-4-styrylcyclohept-3-

enecarboxylate (10)

To a solution of hexamethyldisilazane (10 mL, 47.71 mmol) in

155 mL THF at –78 °C, was added n-butyllithium (2.4 M in

hexane, 19 mL, 45.6 mmol) over 5 min. The mixture was stirred

8

Tetrahedron

30 min and then (R)-4-allyl-4-methyl-3-styrylcyclohept-2-enone

118.1, 118.0, 52.9, 46.2, 45.3, 44.4, 34.3, 29.8, 25.6, 22.8; IR

(Neat Film NaCl) 3076, 3027, 2967, 2931, 1659, 1587, 1449,

1373, 1194, 1147, 1120, 962, 915, 753, 694 cm^-1; FAB⁺HRMS

ACCEPTED MANUSCRIPT

(3, 8.0542 g, 30.24 mmol) in 15 mL THF (precooled to –78 °C)

was added via cannula with a 5 mL rinse. After 30 min, allyl

cyanoformate (4.4772 g, 40.30 mmol) was added quickly. After

10 min, 100 mL of half saturated aq. NH₄Cl was added to the

cold reaction. The layers were separated and the aqueous layer

washed with 3 x 100 mL EtOAc. The combined organic layers

were dried with MgSO₄and evaporated in vacuo. The residue

was then dissolved in 60 mL CH₃CN, and Cs₂CO₃(14.68 g,

45.06 mmol) and MeI (10 mL, 160.28 mmol) were added. The

mixture was then heated to 80 °C. After 4 hrs and 20 min the

reaction was cooled to room temperature and filtered through a

plug of silica gel (5 x 1 cm) which was then rinsed with 3 x 50

mL EtOAc. The filtrate was then evaporated in vacuo. Silica gel

chromatography (5 x 17 cm, 20:1 hexanes:EtOAc) afforded the

title compound as an orange-yellow oil (9.9142 g, 90% yield). ¹H

NMR indicated an ~ 3:1 mixture of diasteromers. R_F= 0.26 (10:1

Hexane:EtOAc); ¹H NMR (500 MHz, CDCl₃) Major

diastereomer: δ 7.44-7.41 (m, 2H), 7.37-7.33 (m, 2H), 7.30-7.26

(m, 1H), 6.91 (d, J = 15.5 Hz, 1H), 6.85 (d, J = 15.5 Hz, 1H),

6.28 (s, 1H), 5.90 (dddd, J = 5.5, 5.5, 11, 22.5 Hz, 1H), 5.68

(dddd, J = 7.5, 7.5, 10.5, 17.5 Hz, 1H), 5.33 (dddd, J = 1.5, 1.5,

1.5, 17.5 Hz, 1H), 5.26-5.21 (m, 1H), 5.09-5.03 (m, 2H), 4.70-

4.56 (m, 2H), 2.44 (dd, J = 7.5, 14.5 Hz, 1H), 2.24 (app dd, J =

8.5, 15 Hz, 1H), 2.18-2.13 (m, 2H), 1.80 (dd, J = 9.5 14 Hz, 1H),

1.54 (dd, J = 8.5 Hz, 15 Hz, 1H), 1.44 (s, 3H), 1.23 (s, 3H),

Minor diastereomer: δ 7.44-7.41 (m, 2H), 7.37-7.33 (m, 2H),

7.30-7.26 (m, 1H), 6.89 (d, J = 16 Hz, 1H), 6.82 (d, J = 15.5 Hz,

1H), 6.31 (s, 1H), 5.89 (dddd, J = 5.5, 5.5, 11.5, 22.5 Hz, 1H),

5.61 (dddd, J = 7, 8.5, 10.5, 17 Hz, 1H), 5.31 (J = 1.5, 1.5, 1.5,

17 Hz, 1H), 5.26-5.21 (m, 1H), 5.06-4.99 (m, 2H), 4.70-4.56 (m,

2H), 2.41-2.34 (obsc m, 1H), 2.11 (obsc dd, J = 8, 14 Hz, 1H),

1.79 (obsc ddd, 2H), 1.66 (ddd, J = 1, 9, 10 Hz, 2H), 1.47 (s, 3H),

1.26 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) Major diastereomer:

δ 202.6, 173.1, 156.9, 136.5, 133.5, 133.3, 131.8, 128.7, 128.4,

128.1, 126.9, 124.6, 118.4, 118.0, 65.6, 60.2, 44.9, 44.5, 34.5,

29.3, 26.3, 23.4, Minor diastereomer: δ 202.2, 172.8, 154.9,

136.5, 133.4, 133.1, 131.7, 128.7, 128.3, 128.0, 126.8, 125,2,

118.4, 118.2, 65.7, 59.8, 46.1, 44.3, 34.1, 28.9, 25.5, 21.8, ; IR

(Neat Film NaCl) 3078, 3025, 2974, 2934, 1735, 1653, 1648,

1584, 1448, 1375, 1221, 1196, 1103, 965, 918 cm^-1; FAB⁺

HRMS m/z calc'd for C₂₄H₂₉O₃[M+H]⁺: 365.2117, found

365.2117.

m/z calc'd for C₂₃H₂₉O [M+H]⁺: 321.2218, found 321.2225;

24.6

[α]_D

+87.18 (c 1.27, CHCl₃, 10:1 dr, anti-Me diastereomer

97% ee).

4.9. (6R,8aR)-6-Allyl-6,8a-dimethyl-6,7,8,8a-tetrahydroazulen-

5(1H)-one (anti-2)

A 3000 mL flask was charged with (4R,7R)-4,7-diallyl-4,7-

dimethyl-3-styrylcyclohept-2-enone (11, 8.1630 g, 25.47 mmol)

and 2000 mL CH₂Cl₂. Argon was bubbled through the solution

using a glass gas dispersion tube for 20 min, at which time

ethylene was bubbled through the mixture for 5 min. The second

generation Grubbs catalyst (434.1 mg, 0.511 mmol, 2 mol%) was

added and ethylene was bubbled through the mixture for 15 min,

followed by flushing the headspace for 15 min. The flask was

then sealed. After 17 hrs, a second portion of the second

generation Grubbs catalyst (112.7 mg, 0.133 mmol, 0.5 mol%)

was added. After 3 hrs, the reaction was quenched by adding 90

mL ethyl vinyl ether and allowed to stir 1.5 hrs. Evaporation in

vacuo, followed by silica gel chromatography (5 cm x 17 cm, 4%

Et₂O in hexane) afforded the title compound as a yellow oil

(5.3386 g, 89% yield with 6% starting material). R_F= 0.40 (10:1

Hexane:EtOAc); ¹H NMR (500 MHz, CDCl₃) Major

diastereomer: δ 6.28 (ddd, J = 3, 3, 5 Hz, 1H), 6.10-6.08 (m,

1H), 5.83 (dddd, J = 6.5, 7.5, 11, 16 Hz, 1H), 5.73 (s, 1H), 5.06-

5.04 (m, 1H), 5.04-5.00 (m, 1H), 2.53-2.46 (m, 2H), 2.35 (ddd, J

= 1.5, 3, 18 Hz, 1H), 2.15 (app dd, J = 8, 13.5 Hz, 1H), 2.13-2.06

(m, 2H), 1.76-1.67 (m, 1H), 1.55-1.47 (m, 1H), 1.15 (s, 3H), 1.11

(s, 3H); Diagnostic peaks of minor diastereomer: δ 5.71 (s),

1.12 (s), 1.07 (s); ¹³C NMR (125 MHz, CDCl₃) δ 208.5, 165.3,

141.7, 135.7, 133.8, 119.9, 117.4, 50.6, 50.0, 45.4, 44.2, 33.3,

32.7, 28.8, 24.7; IR (Neat Film NaCl) 3072, 2966, 2914, 1648,

1625, 1448, 1378, 1225, 1122, 1079, 912 cm^-1; HRMS m/z calc'd

for C₁₅H₂₀O [M]⁺: 216.1514, found 216.1505; [α]_D+12.59 (c

1.165, CHCl₃).

24.9

4.10. (1R,6R,8aS,Z)-6-allyl-1-hydroxy-6,8a-dimethyl-6,7,8,8a-

tetrahydroazulen-5(1H)-one (17)

A

flask was charged with (6R,8aR)-6-allyl-6,8a-dimethyl-

6,7,8,8a-tetrahydroazulen-5(1H)-one (2, 4.4093 g, 20.38 mmol)

and 60 mL CH₂Cl₂. To the ice cooled mixture was added Et₃N

(12 mL, 86.10 mmol) followed by TBSOTf (9.5 mL, 41.36

mmol) over 10 min. The reaction was stirred cold for 10 min and

then allowed to warm to ambient temperature. After 3 hrs the

reaction was cooled with an ice bath and 50 mL sat. NaHCO₃

was added. The mixture was extracted with hexane (3 x 50 mL)

and the combined organic layers dried with Na₂SO₄. Evaporation

in vacuo afforded a yellow residue that was dissolved in 100 mL

95% EtOH and cooled with an ice bath. MMPP (12.6 g, 80%,

20.38 mmol) was added in portions over 1 hour. After stirring a

further 15 min the mixture was evaporated in vacuo to a volume

of 20-30 mL. Water (100 mL) was added and the mixture

extracted with CH₂Cl₂(3 x 100 mL). The combined organic

layers were dried with MgSO₄and evaporated in vacuo. Silica

gel chromatography (3 cm x 18 cm, ~330 mL 5:1 Hex/EtOAc,

then ~600 mL 3:1 Hex/EtOAc) afforded the title compound as a

pale yellow oil (3.9786 g, 84% yield). R_F= 0.10 (5:1

4.8. (4R,7R)-4,7-Diallyl-4,7-dimethyl-3-styrylcyclohept-2-enone

(anti-11)

In a nitrogen filled glove box, a flask was charged with Pd(dm-

dba)₂(440.2 mg, 0.540 mmol, 2 mol%) and (R)-tBu-PHOX

(253.0 mg, 0.653 mmol, 2.4 mol%) and 2500 mL THF. The

mixture is stirred 30 min, at which time (5R)-allyl 5-allyl-1,5-

dimethyl-2-oxo-4-styrylcyclohept-3-enecarboxylate (10, 9.9052

g, 27.18 mmol) was added with a total of 50 mL THF. The

reaction was taken out of the glovebox and stirred at 25 °C for 24

hrs. Evaporation in vacuo followed by silica gel chromatography

(5 x 17 cm, 25:1 hexanes:EtOAc) afforded the title compound as

a light yellow oil (8.163 g, 94% yield, 10:1 mixture of

1

diastereomers). R_F= 0.52 (10:1 Hexane:EtOAc); H NMR (300

MHz, CDCl₃) Major diastereomer: δ 7.45-7.27 (m, 5H), 6.90

(d, J = 15.3 Hz, 1H), 6.82 (d, J = 15.6 Hz, 1H), 6.19 (s, 1H),

5.79-5.54 (m, 2H), 5.08-4.97 (m, 4H), 2.34 (app dd, J = 6.3, 14.1

Hz, 1H), 2.24 (app dd, J = 6.9, 12.9 Hz, 1H), 2.16 (app dd, J =

8.1, 14.1 Hz, 1H), 2.08 (app dd, J = 8.1, 13.8 Hz, 1H), 1.93-1.84

(m, 1H), 1.75-1.66 (m, 1H), 1.56-1.45 (m, 2H), 1.25 (s, 3H), 1.16

(s, 3H); Diagnostic peaks of minor diastereomer: δ 6.20 (s),

1.20 (s), 1.11 (s); 13C NMR (75 MHz, CDCl3) 209.4, 154.8,

136.7, 133.7, 133.7, 132.8, 128.7, 128.3, 128.2, 126.8, 125.2,

1

Hexane:EtOAc); H NMR (500 MHz, CDCl₃) δ 6.35 (dd, J = 2,

5.5 Hz, 1H), 6.31 (d, J = 5 Hz, 1H), 5.83 (dddd, J = 7, 8, 11.5,

11.5 Hz, 1H), 5.82 (s, 1H), 5.07-5.03 (m, 2H), 4.24 (d, J = 2.5

Hz, 1H), 2.49 (dd, J = 6.5, 14 Hz, 1H), 2.29 (m, 1H), 2.20 (dd, J

= 8, 14 Hz, 1H), 2.10 (m, 1H), 1.93 (br s, 1H), 1.64 (app ddd, J =

2, 6.5, 6.5 Hz, 1H), 1.60 (app ddd, J = 2, 6, 6 Hz, 1H), 1.15 (s,

3H), 1.08 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 208.1, 161.6,

9

141.1, 137.4, 135.4, 122.6, 117.6, 84.8, 49.7, 48.1, 43.8, 30.9,

To

a

solution

of

(1R,6R,8aS)-6-allyl-1-(tert-

ACCEPTED MANUSCRIPT

27.6, 27.1, 24.4; IR (Neat Film NaCl) 3401, 3073, 2963, 2915,

butyldimethylsilyloxy)-6,8a-dimethyl-6,7,8,8a-tetrahydroazulen-

5(1H)-one (18, 4.5484 g, 13.12 mmol) in 130 mL degassed

CH₂Cl₂

1631, 1450, 1226, 1089, 1037, 915, 861 cm^-1; HRMS m/z calc'd

23.1

for C₁₅H₂₀O₂[M]⁺: 232.1463, found 232.1467; [α]_D–64.33 (c

was

added

4,4,5,5-tetramethyl-2-vinyl-1,3,2-

1.49, CHCl₃).

dioxaborolane²⁰(10.3126 g, 66.96 mmol, 5 equiv.) followed by

the second generation Hoveyda–Grubbs catalyst (412.5 mg,

0.658 mmol, 5 mol%). The mixture was then heated to reflux for

12 hrs at which time it was cooled and 10 mL ethyl vinyl ether

was added. After stirring for 30 min at ambient temperature, the

reaction mixture was then concentrated in vacuo. The residue

was applied to the top of a 6.5 x 1.5 cm pad of silica gel and

eluted with a total of 600 mL 10:1 Hex/EtOAc. The filtrate was

evaporated in vacuo and the residue dissolved in 130 mL THF.

Anhydrous Me₃NO²¹(5.03 g, 66.97 mmol) was added and the

mixture heated to reflux for 10 hrs. To the cooled reaction

mixture was added 50 mL H₂O and the mixture was allowed to

stir ~15 min. Brine (50 mL) was added and the layers separated.

The organic layer was washed with 50 mL brine, and the

combined aqueous layers washed with EtOAc (3 x 100 mL). The

combined organic layers were dried with MgSO₄and

concentrated in vacuo. Silica gel chromatography (5 x 15 cm,

~600 mL 7:1 Hex/EtOAc then ~450 mL 6:1 Hex/EtOAc)

afforded the title compound (3.7336 g, 78%) as a yellow oil. R_F=

0.3 (5:1 Hexane:EtOAc); ¹H NMR (500 MHz, CDCl₃) δ 9.79 (dd,

J = 1.5, 1.5 Hz, 1H), 6.22 (d, J = 5.5 Hz, 1H), 6.20 (dd, J = 2.5,

5.5 Hz, 1H), 5.76 (s, 1H), 4.23 (d, J = 2.5 Hz, 1H), 2.53 (m, 1H),

2.47 (m, 1H), 2.36 (ddd, J = 2, 14.5, 14.5 Hz, 1H), 2.10 (ddd, J =

2.5, 14.5, 14.5 Hz, 1H), 2.02 (ddd, J = 6.5, 9.5, 14.5 Hz, 1H),

1.72 (ddd, J = 6, 9.5, 14 Hz, 1H), 1.54 (ddd, J = 2, 6, 14.5 Hz,

1H), 1.46 (ddd, J = 2, 5.5, 14.5 Hz, 1H), 1.17 (s, 3H), 1.06 (s,

3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); ¹³C NMR (125

MHz, CDCl₃) δ 207.9, 202.7, 162.6, 141.9, 136.1, 121.8, 85.0,

49.5, 48.3, 39.8, 31.6, 31.2, 27.8, 27.4, 25.8, 24.8, 18.2, –4.3,

–4.8; IR (Neat Film NaCl) 3059, 2956, 2928, 1725, 1654, 1636,

1472, 1451, 1382, 1361, 1250, 1095, 1062, 936, 870, 837, 775

cm^-1; HRMS m/z calc'd for C₂₁H₃₄O₃Si [M]⁺: 362.2277, found

362.2260; [α]_D^23.3–127.87 (c 2.305, CHCl₃).

4.11. (1R,6R,8aS)-6-Allyl-1-(tert-butyldimethylsilyloxy)-6,8a-

dimethyl-6,7,8,8a-tetrahydroazulen-5(1H)-one (18)

A solution of (1R,6R,8aS,Z)-6-allyl-1-hydroxy-6,8a-dimethyl-

6,7,8,8a-tetrahydroazulen-5(1H)-one (17, 3.9786 g, 17.13 mmol)

in 84 mL CH₂Cl₂was cooled to –78 °C. To this mixture was

added 2,6-lutidine (8 mL, 68.68 mmol, 4 equiv.), followed by

TBSOTf (5.9 mL, 25.69 mmol, 1.5 equiv.) over ~5 min. The

reaction was stirred cold for 45 min and then quenched by adding

100 mL sat. NaHCO₃. The mixture was allowed to thaw and the

layers separated. The aqueous layer was washed with EtOAc (3 x

100 mL) and the combined organic layers dried with MgSO₄.

Evaporation in vacuo, followed by silica gel chromatography (5

cm x 15 cm, 35:1 pet. ether:EtOAc) afforded the title compound

as a colorless oil (4.5484 g, 77% yield). R_F= 0.17 (20:1

1

Hexane:EtOAc); H NMR (500 MHz, CDCl₃) δ 6.23 (d, J = 5.5

Hz, 1H), 6.19 (dd, J = 2.5, 5 Hz, 1H), 5.84 (dddd, J = 7, 8, 12.5,

12.5 Hz, 1H), 5.78 (s, 1H), 5.06-5.01 (m, 2H), 4.23 (d, J = 2.5

Hz, 1H), 2.48 (dd, J = 7, 13.5 Hz, 1H), 2.31 (ddd, J = 2.5, 14.5,

14.5 Hz, 1H), 2.20 (dd, J = 8, 14 Hz, 1H), 2.04 (ddd, J = 2, 15,

15 Hz, 1H), 1.59 (ddd, J = 2, 5.5, 14.5 Hz, 1H), 1.46 (ddd, J = 2,

5.5, 14.5 Hz, 1H), 1.15 (s, 3H), 1.06 (s, 3H), 0.90 (s, 9H), 0.09 (s,

3H), 0.08 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 208.3, 162.4,

141.6, 136.2, 135.6, 122.0, 117.4, 85.1, 49.7, 48.4, 43.8, 31.0,

27.9, 27.6, 25.8, 24.4, 18.3, –4.3, –4.7; IR (Neat Film NaCl)

3073, 2957, 2929, 1656, 1637, 1472, 1258, 1096, 1067, 872, 837,

775 cm^-1; HRMS m/z calc'd for C₂₁H₃₄O₂Si [M]⁺: 346.2328,

found 346.2326; [α]_D^23.1–149.36 (c 1.56, CHCl₃).

4.12. (6R,8aS)-6-Allyl-6,8a-dimethyl-6,7,8,8a-

tetrahydroazulene-1,5-dione (27)

A vial was charged with a mixture of (1R,6R,8aS)-6-allyl-1-(tert-

butyldimethylsilyloxy)-6,8a-dimethyl-6,7,8,8a-tetrahydroazulen-

4.14. Ethyl 5-((1R,6R,8aS,Z)-1-(tert-butyldimethylsilyloxy)-6,8a-

dimethyl-5-oxo-1,5,6,7,8,8a-hexahydroazulen-6-yl)-3-

oxopentanoate (20)

5(1H)-one

and

(6R,8aR)-6-allyl-6,8a-dimethyl-6,7,8,8a-

tetrahydroazulen-5(1H)-one (20.3 mg) and 0.3 mL THF. TBAF

(1.0M in THF, 50 L, 0.050 mmol) was added and the mixture

stirred 15 min. The volatiles were removed in vacuo and the

residue taken up in EtOAc and filtered through a plug of silica

gel, rinsing with EtOAc. Evaporation in vacuo gave a residue that

was dissolved in 0.3 mL CH₂Cl₂. Dess–Martin periodinane (19.6

mg, 0.0462 mmol) was added. After 40 min, isopropanol was

added and the mixture evaporated in vacuo. Flash

chromatography (0.7 cm x 7 cm, 10:1 Hex/EtOAc) afforded the

title compound as a colorless oil (8 mg): R_F= 0.11 (10:1

A

250 mL round-bottom flask was charged with 3-

((1R,6R,8aS,Z)-1-(tert-butyldimethylsilyloxy)-6,8a-dimethyl-5-

oxo-1,5,6,7,8,8a-hexahydroazulen-6-yl)propanal (19, 3.7336 g,

10.30 mmol) and 100 mL CH₂Cl₂. Anhydrous SnCl₂(195.4 mg,

1.031 mmol) was added, followed by ethyl diazoacetate (1.1946

g, 10.47 mmol) over ~ 5 min. The reaction was stirred 1.5 hrs at

ambient temperature and a further portion of ethyl diazoacetate

(210 L, 2.00 mmol) was added. After stirring another 1.5 hrs,

the reaction was concentrated in vacuo, and the residue subjected

to silica gel chromatography (3 cm x 31 cm, 7:1 Hex:EtOAc) to

afford the title compound as a viscous yellow oil (4.0558 g, 88%

yield). R_F= 0.28 (5:1 Hexane:EtOAc); Major keto tautomer:

¹H NMR (500 MHz, CDCl₃) δ 6.23 (d, J = 6 Hz, 1H), 6.20 (dd, J

= 2.5, 5.5 Hz, 1H), 5.75 (s, 1H), 4.23 (d, J = 2.5 Hz, 1H), 4.19

(app q, J = 7.5 Hz, 2H), 3.48 (s, 1.6H), 2.64 (m, 1H), 2.62 (m,

1H), 2.36 (ddd, J = 2, 14.5, 14.5 Hz, 1H), 2.09 (ddd, J = 2, 14.5,

14.5 Hz, 1H), 1.97 (ddd, J = 6.5, 8.5, 14 Hz, 1H), 1.71 (ddd, J =

6, 9.5, 14 Hz, 1H), 1.54 (ddd, J = 2.5, 6, 15 Hz, 1H), 1.46 (ddd, J

= 2, 6, 15 Hz, 1H), 1.27 (dd, J = 7, 7 Hz, 3H), 1.17 (s, 3H), 1.06

(s, 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); ¹³C NMR (125

MHz, CDCl₃) δ 208.0, 203.1, 167.4, 162.5, 141.9, 136.1, 121.9,

85.0, 61.3, 49.5, 49.2, 48.3, 38.9, 33.1, 31.2, 27.8, 27.4, 25.8,

24.8, 18.2, 14.1, –4.3, –4.7; IR (Neat Film NaCl) 3054, 2956,

2929, 1744, 1718, 1653, 1636, 1472, 1449, 1367, 1318, 1258,

1165, 1095, 1071, 936, 869, 837, 802, 775 cm^-1; HRMS m/z

1

Hexane:EtOAc); H NMR (300 MHz, CDCl₃) δ 7.69 (d, J = 5.7

Hz, 1H), 6.37 (d, J = 5.4 Hz, 1H), 6.00 (s, 1H), 5.83 (dddd, J =

7.2, 7.2, 10.5, 14.7 Hz, 1H), 5.12-5.02 (m, 2H), 2.40 (app dd, J =

7.2, 14.1 Hz, 1H), 2.29 (app dd, J = 7.2, 13.5 Hz, 1H), 2.05 (ddd,

J = 2.4, 14.7, 14.7 Hz, 1H), 1.92 (ddd, J = 3.3, 5.1, 14.7 Hz, 1H),

1.77 (obsc ddd, J = 2.4, 18.3 Hz, 1H), 1.67 (ddd, J = 2.7, 5.1,

14.7 Hz, 1H), 1.13 (s, 3H), 1.09 (s, 3H); ¹³C NMR (75 MHz,

CDCl₃) δ 209.4, 207.8, 155.8, 152.8, 134.7, 134.1, 125.2, 118.2,

50.8, 48.9, 43.3, 32.2, 26.8, 22.6, 22.0; IR (Neat Film NaCl)

3071, 2973, 2932, 1713, 1675, 1550, 1448, 1379, 1345, 1227,

1090, 1073, 917, 866, 627 cm^-1; HRMS m/z calc'd for C₁₅H₁₈O₂

23.5

[M]⁺: 230.1307, found 230.1302; [α]_D

+46.28 (c 0.40,

CH₂Cl₂).

4.13. 3-((1R,6R,8aS,Z)-1-(tert-Butyldimethylsilyloxy)-6,8a-

dimethyl-5-oxo-1,5,6,7,8,8a-hexahydroazulen-6-yl)propanal (19)

10

Tetrahedron

calc'd for C₂₅H₄₀O₅Si [M]⁺: 448.2645, found 448.2631; [α]_D

122.05 (c 0.870, CHCl₃).

–

Ester 22 (1.3934 g, 3.22 mmol) was dissolved in 30 mL THF and

23.4

ACCEPTED MANUSCRIPT

cooled to 0 °C. Red-Al (~3.5 M solution in toluene, 3.6 mL, 12.6

mmol) was added slowly over 5 min. The mixture was allowed to

stir cold for 1 hr. The reaction was quenched by the careful

addition of EtOH (15 mL). The mixture was then warmed to

ambient temperature and Na₂SO₄•10 H₂O (15 g) was added. After

stirring vigorously for 1 hour, the mixture was filtered through a

fritted glass funnel and the salts rinsed with EtOAc(3 x 50 mL).

Evaporation in vacuo gave a residue that was subjected to flash

chromatography (3 x 18 cm, 2:1 Hex/EtOAc) to afford a diol

product (960.2 mg, 76% yield). R_F= 0.16 (2:1 Hexane:EtOAc);

¹H NMR (300 MHz, CDCl₃) δ 6.18 (d, J = 5.4 Hz, 1H), 5.95 (s,

1H), 5.92 (dd, J = 2.1, 5.4 Hz, 1H), 4.40-4.32 (m, 2H), 4.28-4.20

(m, 2H), 2.40 (bs, 1H), 2.15-1.65 (m, 5H), 1.60 (bs, 1H), 1.55-

1.22 (m, 3H), 0.99 (s, 3H), 0.97 (s, 3H), 0.89 (s, 9H), 0.07 (s,

6H); IR (Neat Film NaCl) 3352, 3054, 2953, 2929, 1650, 1472,

1463, 1450, 1362, 1256, 1092, 1059, 1005, 870, 836, 774 cm^-1;

FAB⁺HRMS m/z calc'd for C₂₃H₃₇O₃Si [(M+H)-H₂]⁺: 389.2512,

found 389.2509. Note: due to conformational instability, we

were unable to obtain a suitable ¹³C NMR spectrum.

4.15. Knoevenagel cyclization (preparation of compound 21)

To

a

solution

of

ethyl

5-((1R,6R,8aS,Z)-1-(tert-

butyldimethylsilyloxy)-6,8a-dimethyl-5-oxo-1,5,6,7,8,8a-

hexahydroazulen-6-yl)-3-oxopentanoate (20, 2.3213 g, 5.17

mmol, 1 equiv) in 52 mL EtOH was added KF (337.9 mg, 0.280

mmol, 1.1 equiv). The mixture was then heated to 80 °C for 10

hrs, at which time TLC analysis (twice developed in 10:1

Hex/EtOAc) indicated no SM was present. The reaction was then

cooled and evaporated in vacuo. The residue was directly applied

to a column of silica (3 x 22 cm) and eluted with 10:1

Hex/EtOAc. Unclean fractions were chromatographed again (2 x

18 cm silica gel) to afford compound 21 (1.6580 g, 74%) as a

yellow oil that solidified on standing. R_F

= 0.29 (5:1

1

Hexane:EtOAc); H NMR (500 MHz, CDCl₃) δ 6.19 (d, J = 5.5

Hz, 1H), 6.13 (dd, J = 2, 5 Hz, 1H), 6.00 (s, 1H), 4.30 (dq, J = 7,

13.5 Hz, 1H), 4.23 (dq, J = 7, 13.5 Hz, 1H), 4.22 (obsc d, J = 3.5

Hz, 1H), 2.64 (m, 1H), 2.62 (m, 1H), 2.27 (app br t, J = 13.5 Hz,

1H), 2.10 (br s, 1H), 2.01 (m, 1H), 1.81 (ddd, J = 5.5, 5.5, 11 Hz,

1H), 1.62 (ddd, J = 2, 7, 15 Hz, 1H), 1.37 (ddd, J = 2, 7, 15.5 Hz,

1H), 1.27 (dd, J = 7, 7 Hz, 3H), 1.22 (s, 3H), 1.05 (s, 3H), 0.89

(s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ

195.2, 167.3, 162.1 (br), 161.4 (br), 140.1, 136.6, 132.6, 117.6

(br), 85.2, 61.0, 48.2, 37.6 (br), 36.5, 33.6, 27.2, 27.1 (br), 25.8,

25.8, 24.6 (br), 18.2, 14.1, –4.3, –4.7; IR (Neat Film NaCl) 3054,

2955, 2928, 1734, 1671, 1617, 1472, 1451, 1367, 1321, 1229,

1136, 1093, 1071, 1031, 872, 836, 774 cm^-1; FAB⁺HRMS m/z

calc'd for C₂₅H₃₉O₄Si [M+H]⁺: 431.2618, found 431.2614;

[α]_D^23.4–909.69 (c 1.945, CHCl₃).

The isolated diol was dissolved in 25 mL CH₂Cl₂and cooled

to 0 °C. PPTS (30.3 mg, 0.121 mmol, 5 mol%) was added,

followed by 2,2-dimethoxypropane (6 mL, 48.80 mmol, 20

equiv). After stirring cold for 1 hour, the reaction mixture was

evaporated in vacuo and the residue subjected to flash

chromatography (3 x 25 cm, 25:1 Hex/EtOAc) to afford

acetonide 23 (552.8 mg, 52% yield) as a white solid. R_F= 0.32

(20:1 Hexane:EtOAc); ¹H NMR (500 MHz, CDCl₃) δ 6.15 (d, J =

5.5 Hz, 1H), 5.88 (dd, J = 2.5, 5.5 Hz, 1H), 5.69 (s, 1H), 4.35

(dddd, J = 1.5, 3.5, 3.5, 7.5 Hz, 1H), 4.29 (d, J = 15.5 Hz, 1H),

4.26 (d, J = 2.5 Hz, 1H), 4.13 (ddd, J = 2, 2, 16 Hz, 1H), 2.24

(ddd, J = 3, 14.5, 14.5 Hz, 1H), 2.00 (ddd, J = 3, 14, 14 Hz, 1H),

1.84 (dddd, J = 3.5, 3.5, 7, 12.5 Hz, 1H), 1.71 (dddd, J = 6, 10.5,

10.5, 10.5 Hz, 1H), 1.60-1.52 (m, 2H), 1.43 (s, 3H), 1.38 (obsc

ddd, J = 3, 4.5, 13.5 Hz, 1H), 1.35 (s, 3H), 1.29 (ddd, J = 3, 5, 15

Hz, 1H), 0.97 (s, 3H), 0.96 (s, 3H), 0.89 (s, 9H), 0.07 (s, 6H); ¹³C

NMR (125 MHz, CDCl₃) δ 153.5, 135.6, 135.5, 134.9, 133.1,

117.8, 99.5, 86.4, 67.8, 60.5, 46.7, 38.6, 36.9, 36.0, 26.9, 25.9,

25.9, 25.3, 25.0, 24.4, 23.8, 18.3, –4.4, –4.7; IR (Neat Film NaCl)

3054, 2951, 2930, 1472, 1378, 1250, 1224, 1092, 1064, 866, 835,

774 cm^-1; FAB⁺HRMS m/z calc'd for C₂₆H₄₁O₃Si [(M+H)-H₂]⁺:

429.2825, found 429.2805; [α]_D^24.9–514.23 (c 1.54, CHCl₃).

4.16. Diastereoselective reduction of β-ketoester 21

A solution of Knoevenagel product 21 (1.6173 g, 3.76 mmol) in

40 mL isopropanol, was degassed by bubbling argon through the

mixture for 30 min. Ru[(S,S)-Ts-DPEN](p-cymene) (112.9 mg,

0.188 mmol, 5 mol%) was then added. The mixture was stirred at

ambient temperature for 24 hrs and then evaporated in vacuo.

After silica gel chromatography (3 x 24 cm, 7:1 Hex/EtOAc), any

fractions containing unreacted starting material were pooled and

collected away from the reaction product. This residue (461.8

mg) containing ketoester 21 was then dissolved in 11 mL

isopropanol and degassed as above. Ru[(S,S)-Ts-DPEN](p-

cymene) (7.2 mg, 0.0120 mmol) was then added. The mixture

was stirred at ambient temperature for 36 hrs and then evaporated

in vacuo. After silica gel chromatography (2 x 17 cm, 7:1

Hex/EtOAc), any fractions containing unreacted starting material

were pooled and subjected to one further silica gel column (2 x

17 cm, 7:1 Hex/EtOAc). The final product (22) was isolated as a

4.18. Conversion to pivalate 24

Compound 23 (30.5 mg, 0.708 mmol) was dissolved in 0.2 mL

THF and TBAF (1.0 M in THF, 150 L, 0.150 mmol) was added

at ambient temperature. The reaction was allowed to stir at

ambient temperature 2.5 hrs at which time it was filtered through

a plug of silica gel, eluted with EtOAc, and evaporated in vacuo.

The residue was then dissolved in 0.3 mL pyridine and

trimethylacetyl chloride (50 L, 0.406 mmol) was added. The

mixture was then heated to 50 ºC for 30 min. The cooled reaction

mixture was then applied to a column of silica (3 x 2 cm) and

eluted with 20:1 Hex/EtOAc to afford pivalate ester 24 (24.7 mg,

87%) as a white solid. R_F= 0.33 (10:1 Hexane:EtOAc); ¹H NMR

(500 MHz, CDCl₃) δ 6.29 (d, J = 6 Hz, 1H), 5.90 (dd, J = 2.5, 5

Hz, 1H), 5.77 (s, 1H), 5.33 (d, J = 2.5 Hz, 1H), 4.35 (ddd, J = 1,

5.5, 9 Hz, 1H), 4.29 (d, J = 15.5 Hz, 1H), 4.13 (ddd, J = 2, 2, 16

Hz, 1H), 2.24 (ddd, J = 2.5, 13.5, 13.5 Hz, 1H), 1.95 (ddd, J = 3,

14, 14 Hz, 1H), 1.85 (dddd, J = 3.5, 3.5, 6.5, 13 Hz, 1H), 1.70

(m, 1H), 1.6-1.55 (m, 2H), 1.43 (s, 3H), 1.39-1.23 (m, 2H), 1.35

(s, 3H), 1.19 (s, 9H), 1.08 (s, 3H), 0.98 (s, 3H); ¹³C NMR (125

MHz, CDCl₃) δ 178.2, 152.6, 138.5, 134.2, 134.1, 131.4, 118.8,

99.7, 86.8, 67.7, 60.4, 46.2, 39.0, 38.5, 36.7, 36.0, 27.2, 26.8,

26.1, 25.2, 24.9, 23.9, 23.8; IR (Neat Film NaCl) 3049, 2980,

brown viscous oil (1.3934 g, 86%). R_F

= 0.26 (5:1

1

Hexane:EtOAc); H NMR (500 MHz, CDCl₃, 50 ºC) δ 6.21 (s,

1H), 6.20 (d, J = 5.5 Hz, 1H), 5.95 (dd, J = 2.5, 5.5 Hz, 1H), 4.54

(br d, J = 3.5 Hz, 1H), 4.24 (dq, J = 7, 13.5 Hz, 1H), 4.20 (obsc

d, J = 2.5 Hz, 1H), 4.19 (dq, J = 7, 13.5 Hz, 1H), 2.59 (bs, 1H),

2.12 (app t, J = 13 Hz, 1H), 1.95-1.85 (m, 4 H), 1.58 (ddd, J = 2,

7.5, 14.5 Hz, 1H), 1.39-1.37 (obsc m, 1H), 1.33 (ddd, J = 2, 7.5,

15 Hz, 1H), 1.27 (dd, J = 7, 7 Hz, 3H), 1.05 (s, 3H), 1.00 (s, 3H),

0.90 (s, 9H), 0.082 (s, 3H), 0.076 (s, 3H); IR (Neat Film NaCl)

3435, 3054, 2951, 2929, 1700, 1472, 1366, 1257, 1216, 1089,

1073, 873, 835, 773 cm^-1; HRMS m/z calc'd for C₂₅H₄₀O₄Si [M]⁺:

23.4

432.2696, found 432.2716; [α]_D

–707.61 (c 0.620, CHCl₃).

Note: due to conformational instability, we were unable to obtain

a suitable ¹³C NMR spectrum.

4.17. Conversion to acetonide 23

11

2938, 1724, 1455, 1379, 1279, 1224, 1152, 1093, 1028, 976, 865

cm^-1; HRMS m/z calc'd for C₂₅H₃₆O₄[M]⁺: 400.2614, found

400.2610; [α]_D^23.7–533.13 (c 1.185, CHCl₃).

was added and the suspension allowed to warm to ambient

ACCEPTED MANUSCRIPT

temperature. After evaporation in vacuo, the solid mixture was

subjected to flash chromatography (2 x 12 cm, 5% Et₂O in

petroleum ether) to afford a vinyl triflate (36 mg, 59% yield) as a

colorless oil. R_F= 0.2 (20:1 Hexane:EtOAc); ¹H NMR (300

MHz, C₆D₆) δ 5.33 (bs, 1H), 5.22 (dd, J = 2.4, 2.4 Hz, 1H), 4.31-

4.21 (m, 1H), 4.18-4.06 (m, 2H), 2.59 (ddd, J = 2.4, 2.4, 20.7 Hz,

1H), 2.49 (ddd, 2.4, 2.4, 20.7 Hz, 1H), 1.96 (ddd, J = 3.3. 13.8,

13.8 Hz, 1H), 1.80-1.68 (m, 2H), 1.62 (ddd, J = 3, 13.8, 13.8 Hz,

1H), 1.45-1.12 (m, XH), 1.40 (s, 3H), 1.36 (s, 3H), 1.05 (s, 3H),

0.96 (ddd, J = 3, 4.2, 14.4 Hz, 1H), 0.81 (s, 3H).

4.19. Conversion to cyclopentanone 25

Compound 23 (262 mg, 0.608 mmol) was dissolved in 5 mL

THF and cooled with an ice bath. TBAF (1.0M in THF, 2.4 mL,

2.4 mmol) was added dropwise and the ice bath was removed.

After stirring at ambient temperature for 2 hours, the volatiles

were evaporated in vacuo to leave a viscous orange residue

which was applied to a 3 x 2 cm plug of silica gel and eluted with

3:1 Hex/EtOAc (~350 mL total). Evaporation in vacuo provided

a residue that was dissolved in 3 mL EtOAc and cooled with an

ice bath. Pd/C was added (5 wt% Pd, 65.4 mg, 0.0307 mmol Pd,

5 mol%). The atmosphere was evacuated three times, filling with

H₂(balloon) each time. The reaction was stirred at 0 °C for 2.5

hours, with monitoring by TLC (AgNO₃treated silica plates, 5:1

Hex/EtOAc). Once complete, the reaction was filtered through a

3 x 1 cm plug of silica gel and rinsed with ~65 mL EtOAc.

Evaporation in vacuo afforded a residue that was dissolved in 3

mL CH₂Cl₂. To the solution was added 413.2 mg 4Å molecular

sieves, NMO (110.8 mg, 0.946 mg, 1.5 equiv), and then TPAP

(10.6 mg, 0.0302 mmol, 5 mol%). The reaction was allowed to

stir 40 min and was then filtered through a 3 x 1 cm plug of silica

gel which was rinsed with ~50 mL EtOAc. Evaporation in vacuo,

followed by silica gel chromatography (2 x 12 cm, 10% Et₂O in

petroleum ether) afforded cyclopentatnone 25 (174 mg, 90% over

three steps) as a viscous colorless oil. R_F= 0.16 (10:1

The vinyl triflate prepared above was evaporated twice from

benzene. CuI (1.8 mg, 0.00945 mg, 12 mol%) and THF (0.65

mL) were added under an atmosphere of argon and the

suspension cooled to –15 °C. i-PrMgCl (1.91 M in THF, 0.13

mL, 0.248 mmol, 3.1 equiv) was added quickly and the reaction

turned from blue to green to yellow brown. The reaction mixture

was kept between –20 and –15 °C for 2.5 hrs and then warmed

with an ice bath and silica gel added. After evaporation in vacuo,

the solid mixture was subjected to flash chromatography (3 x 2

cm, 5% Et₂O in petroleum ether) to afford compound 26 (23.5

mg, 85%, contaminated with ~10% reduction product) as a

1

colorless oil. R_F= 0.43 (20:1 Hexane:EtOAc); H NMR (300

MHz, CDCl₃) δ 5.62 (bs, 1H), 5.37 (dd, J = 2.4, 2.4 Hz, 1H),

4.39-4.31 (m, 1H), 4.26 (d, J = 15 Hz, 1H), 4.16 (ddd, J = 1.5,

1.5, 15 Hz, 1H), 2.59 (ddd, J = 2.1, 2.1, 21.6 Hz, 1H), 2.49 (ddd,

2,1, 2.1, 21 Hz, 1H), 2.28 (ddd, J = 3.3, 13.2, 13.2 Hz, 1H), 2.14

(app pent, J = 6.9 Hz, 1H), 1.90-1.79 (m, 1H), 1.79-1.57 (m, 3H),

1.57-1.50 (m, 2H), 1.44 (s, 3H), 1.37 (s, 3H), 1.09 (s, 3H), 1.06

(d, J = 6.6 Hz, 3H), 1.04 (d, J = 6.6 Hz, 3H), 0.99 (s, 3H); ¹³C

NMR (125 MHz, CDCl₃) δ 159.4, 150.9, 134.9, 130.9, 117.9,

117.6, 99.4, 67.7, 60.5, 52.8, 38.3, 37.8, 37.3, 35.9, 30.6, 26.8,

25.5, 25.4, 25.3, 25.0, 24.9, 23.6, 21.4; IR (Neat Film NaCl)

3044, 2956, 2935, 1651, 1455, 1377, 1223, 1091, 863, 755 cm^-1;

HRMS m/z calc'd for C₂₃H₃₃O₂[(M+H)-H₂]⁺: 341.2481, found

341.2489; [α]_D^24.4–169.01 (c 0.075, CHCl₃).

1

Hexane:EtOAc), 0.36 (5:1 Hex:EtOAc); H NMR (500 MHz,

CDCl₃) δ 5.78 (s, 1H), 4.40-4.30 (m, 1H), 4.27 (d, J = 15 Hz,

1H), 4.14 (ddd, J = 2, 2, 15 Hz, 1H), 2.71-2.58 (m, 2H), 2.52

(ddd, J = 4.5, 9.5, 18 Hz, 1H), 2.42 (ddd, J = 10, 10, 18 Hz, 1H),

2.24 (ddd, J = 2.5, 13.5, 13.5 Hz, 1H), 1.89-1.83 (m, 1H), 1.74-

1.66 (m, 2H), 1.61 (ddd, J = 3.5, 5, 14 Hz, 1 H), 1.57-1.50 (m,

2H), 1.43 (s, 3H), 1.39-1.34 (obsc m, 1H), 1.36 (s, 3H), 1.07 (s,

3H), 0.98 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 222.2, 146.3,

133.8, 132.4, 120.5, 99.5, 67.4, 60.5, 51.5, 37.9, 36.7, 36.7, 36.1,

28.4, 26.9, 26.5, 25.3, 25.2, 23.5, 20.0; IR (Neat Film NaCl)

2982, 2937, 1743, 1445, 1378, 1224, 1090, 1026, 863 cm^-1;

HRMS m/z calc'd for C₂₀H₂₈O₃[M]⁺: 316.2039, found 316.2030;

[α]_D^25.2–91.95 (c 0.695, CHCl₃).

Acknowledgments

We thank the NIH-NIGMS (R01GM080269 and postdoctoral

fellowship F32GM073332 to A.M.H.), Amgen, the Gordon and

Betty Moore Foundation, and Caltech for financial support.

4.20. Installation of isopropyl (preparation of compound 26)

A solution of ketone 25 (42.9 mg, 0.136 mmol, evaporated twice

from benzene) dissolved in 0.5 mL THF and cooled to –78 °C

was added via teflon cannula to a solution of KHMDS (37.2 mg,

0.186 mmol) in 0.6 mL THF at –78 °C with a 0.5 mL rinse. The

mixture was stirred 30 min and then added, via Teflon cannula,

to a solution of PhNTf₂(70 mg, 0.196 mmol, evaporated twice

from benzene) in 1 mL THF at –78 °C. After 50 min, silica gel

Supplementary Material

Supplementary material includes selected spectra of new

synthetic compounds.

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Article Doi

Development of a catalytic enantioselective synthesis of the guanacastepene and heptemerone tricyclic core

DOI: 10.1016/j.tet.2019.02.053

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