Electronic tuning of Fischer carbene complexes in the preparation of bicyclo[3.1.1]heptanones as taxane A-ring synthons

TETRAHEDRON

Pergamon

Tetrahedron 56 (2000) 2183±2194

Electronic Tuning of Fischer Carbene Complexes in the

Preparation of Bicyclo[3.1.1]heptanones as

Taxane A-ring Synthons

,²

*

Weiqin Jiang, Michael J. Fuertes and William D. Wulff

Department of Chemistry, Searle Chemistry Laboratory, The University of Chicago, Chicago, IL 60637, USA

Accepted 7 December 1999

AbstractÐA synthetic route to taxol and other Taxus diterpenes is described which employs as a key step the reaction between a Fischer

carbene complex and a 1,6 enyne to construct 1-substituted-7,7-dimethyl-2-methylenebicyclo[3.1.1]heptan-6-ones. It was found that the

reaction between complex 2 and 7-methyl-3-methylene-6-octen-1-yne (dienyne 30) yielded a mixture of bicyclo[3.1.1]heptanone 35 and

cyclobutenone 36, the latter possibly arising from the migration of the chromium fragment from an electron-rich alkene to a less electron-rich

alkene in the vinyl carbene complex intermediate (i.e. 40±42). On this basis, it was expected that bicycloheptanone yields would increase

with increasing electron de®ciency in the intermediate 40 since this should lead to more competitive CO insertion. This was observed with a

series of electronically modi®ed carbene complexes (45 and 48a±d). The more electron de®cient complexes gave good yields of bicyclo-

Introduction

been heavily scrutinized and of the numerous reported

efforts⁹towards entry into the ABC tricyclic core, six

have culminated successfully into total syntheses of 1.¹⁰

In the past 20 years few natural products have created a

greater impact in the areas of clinical oncology and bio-

medical research than paclitaxel (Taxol^w) 1. Its FDA-

approved use in the treatment of metastatic breast¹and

ovarian cancers²constitutes one of the major breakthroughs

in chemotherapy today; it is currently the number-one

selling anticancer drug in the world.³Taxol, the primary

representative of a new class of compounds called taxoids,

was ®rst isolated from the bark of the Paci®c yew tree,

Taxus brevifolia, in 1969;⁴its complex structure was

elucidated two years later by Wani and collaborators.⁵The

discovery in 1979 by Horwitz and coworkers⁶describing the

unique mechanism by which taxol inhibits cell replication

has since served as an impetus for intense pharmacological

studies aimed at its therapeutic development. They demon-

strated that the cellular target of taxol is tubulin; however, in

contrast to colchicine and the vinca alkaloids which are

known to prevent the assembly of tubulin into micro-

tubules,⁷taxol acts as a promoter of tubulin assembly as

well as an inhibitor of the disassembly process. This novel

overstabilization renders the microtubules dysfunctional in

their role in the formation of mitotic spindles during inter-

phase,⁸leading to cell death. The highly oxygenated

complex structure shared by the Taxus diterpenes thus has

The strategy for the synthesis of taxol upon which we have

recently focused relies on the chromium-mediated intra-

molecular [212] cycloaddition of a vinyl ketene and alkene,

an intermediate that is generated from the reaction between

a Fischer carbene complex¹¹and a 1,6 enyne.¹²The prepara-

tion of cyclobutanones, which have proven to be versatile

synthetic intermediates,¹³through similar intramolecular

cycloadditions involving metal-free ketenes with tethered

ole®ns are well documented.¹⁴In our earlier study on the

stereoselectivity of these metal-mediated cycloadditions,

we reported that the reaction between carbene complex 2

and enyne 3 afforded bicyclo[3.1.1]heptanone 4 in good

yield¹⁵(Scheme 1). The mechanistic pathway is believed

to involve the generation of intermediate 6 via alkyne inser-

tion. This is followed by the migration of a CO ligand into

the carbene ligand to form vinyl ketene complex 7, which

then undergoes a formal [212] cycloaddition with the

tethered alkene to afford 8 and upon hydrolysis, the diketone

Keywords: taxoids; Fischer carbene complexes; cycloadditions; ketenes.

* Corresponding author. E-mail: wulff@cem.msu.edu

²

Current address: Department of Chemistry, Michigan State University,

East Lansing, MI 48864, USA.

PII: S0040-4020(99)01101-1

2184

W. Jiang et al. / Tetrahedron 56 (2000) 2183±2194

Scheme 1.

4. The regiochemistry for the [212] cycloaddition is that

expected given the substitution pattern about the double

bond.¹⁶We therefore envision rapid entry into the carbo-

cyclic core of the taxane family of compounds by utilizing

an appropriately functionalized enyne such as 10 and

carbene complex 9 to construct bicyclo[3.1.1]heptanone

11, a suitable A±C system that can be further manipulated

for subsequent condensation and fragmentation into the

ABC skeleton 14, for example, via acid- (or base-) induced

epoxide-ring cleavage as shown in Scheme 2. In this paper,

we report our initial studies on the evaluation of this overall

strategy which ®nds that the outcome of the reaction of

carbene complexes with 1,6-enynes containing an addi-

tional double-bond is a consequence of the nature of the

enyne.

70% yield. This was followed by deprotection of the terminal

alkyne using AgNO₃/NaI¹⁸as shown in Scheme 3. However,

we were disappointed that the reaction between complex 2

and dienyne 10 did not yield any bicycloheptanone. Instead

an aldehyde tentatively assigned as compound 18 was

obtained as a mixture of isomers in 56% yield. Aldehyde

products of this type have been reported for both metal-

free^14f,19band coordinated vinyl ketenes.^19aAccording to the

mechanism that they proposed, the formation of aldehyde 18

could be accounted for by insertion of the alkyne into the

carbene complex to give the h¹,h³-vinyl carbene complexed

intermediate 19 followed by CO insertion to produce the

ketene complex 22 and ®nally, a 1,5-H migration to give

the aldehyde 18 (Scheme 4). An alternative possible mecha-

nism for the formation of aldehyde 18 is also shown in

Scheme 4. It has been demonstrated by Herndon and Hayford

that an h¹,h³-vinyl carbene complex of the type 19 derived

from a conjugated enyne will undergo rearrangement to an

isomeric h¹,h³-vinyl carbene complex (21) faster than the CO

insertion that gives rise to a vinyl ketene complex.²⁰Based on

a number of observations in the literature,²¹they have

proposed that CO insertion occurs faster from the h¹,h³-

vinyl carbene complexed intermediate in which the

chromium is coordinated to the more electron poor

Results and Discussion

The most obvious choice for an alkyne that would con-

veniently set up the necessary epoxidation in bicyclo-

heptanone 11 is dienyne 10. This compound was

synthesized from the Stille coupling¹⁷between allyl chloride

16 and 1-trimethylstannyl-2-methyl-1-propene to afford 17 in

Scheme 2.

W. Jiang et al. / Tetrahedron 56 (2000) 2183±2194

2185

Scheme 3. (a) 2.2 eq. n-BuLi, 278±08C; 2.2 eq. TMSCl; 1.1 eq. citric acid, MeOH, 08C. (b) PPh₃, CCl₄, THF, re¯ux, 3 h. (c) 3 mol% Pd(PPh₃)₂Cl₂, l-

trimethylstannyl-2-methyl-l-propene, THF, 708C, 14 h. (d) AgNO₃, EtOH/H₂O, rt, 30 min; NaI. (e) CH₃CN, 708C, 3.5 h.

double-bond. In the present case, this would lead to the

expectation that CO-insertion occurs faster in 21 than 19 to

generate ketene complex 24, upon which a [1,5] sigmatropic

hydrogen shift would give aldehyde 18. At this point, it

cannot be determined whether the aldehyde is formed

from one of the vinyl ketene complexes or the other, or

from both, but Harvey has suggested that the [1,5]-

migration should occur faster on a vinyl ketene that

was coordinated to a transition metal.^19a

Given the proposed mechanism for the formation of alde-

hyde 18, we thought that it would be interesting to probe the

reaction between complex 2 and dienyne 28, since the

formation of both bicyclo[3.1.1]heptanone through [212]

Scheme 4.

Scheme 5. (a) NaHMDS, THF, 258C, 30 min; 4-trimethylsilylbut-3-yn-2-one, HMPA, 2788C to 258C, 1 h. (b) AgNO₃, EtOH/H₂O, 258C, 30 min; NaI. (c)

CH₃CN, 708C, 3.5 h.

2186

W. Jiang et al. / Tetrahedron 56 (2000) 2183±2194

Scheme 6.

cycloaddition and an aldehyde via [1,5] hydrogen shift

would be geometrically prevented by the E-con®guration

of the alkene. An intramolecular [212] cycloaddition in

the resulting vinyl ketene complex 25 would produce a

trans-double-bond in a six-membered ring and a [1,5]-

sigmatropic H-shift could not be concerted.

suggests that the strategy for the synthesis of taxol outlined

in Scheme 2 is not viable. A slight modi®cation of the

strategy was suggested by the known isomerization of the

bicyclo[3.1.1]heptanone 33 to chrysanthenone.²³If the same

isomerization could be affected on intermediate 31 then the

strategy would be saved since epoxidation of 32 would

intersect with intermediate 12 in Scheme 2 and the new

retrosynthesis would descend to enyne 30 and carbene

complex 9 (Scheme 6).

Compound 28 was synthesized according to Scheme 5. The

phosphonium salt 26 was treated with NaHMDS and the

resulting ylide was allowed to react with 4-trimethylsilyl-

but-3-yn-2-one in the presence of HMPA to give 27 (60:1

E/Z ratio) in fair yield. Removal of the TMS group with

AgNO₃/NaI¹⁸provided 28 in 92% yield. When dienyne 28

was reacted with carbene complex 2, we observed a new

product, cyclobutenone 29, in 70% yield (2:1 E/Z ratio).

Cyclobutenone products have been observed previously

from the reactions of chromium carbene complexes with

alkynes via electrocyclic ring closure of vinyl ketene

complexes,²²and cyclobutenone 29 may have resulted

from ring-closure in the vinyl ketene complex 25.

Dienyne 30 can be conveniently synthesized in 76% yield in

one pot by utilizing Brandsma's method²⁴for generating the

lithiated dianion of isopropenyl acetylene and following that

by the addition of prenyl bromide (Scheme 7). We were

pleased to ®nd that the reaction between 30 and complex

2 (0.01 M in CH₃CN) did result in the formation of the

bicyclo[3.1.1]heptanone 35; however,

a

substantial

amount of cyclobutenone 36 was formed as a side-product.

Attempts to thermally isomerize 36 into 35 by re¯uxing

in toluene were unsuccessful. The E/Z assignment of

the enol ethers were based on Strobel's empirical rule.²⁵

The product distribution is a function of temperature with

the ratio reversing from a predominance of cyclobutenone

The failure of enyne 10 to form bicyclo[3.1.1]heptanone

products upon reaction with Fischer carbene complex 2

Scheme 7.

W. Jiang et al. / Tetrahedron 56 (2000) 2183±2194

2187

Scheme 8.

36 at 1008C to a distribution in favor of the bicyclo[3.1.1]-

heptanone 35 at 458C. The source of the temperature

dependence is not known but it may be related to

solvent displacement of the metal from the vinyl ketene

complexes 43 and 44 at higher temperature where the

metal-free vinyl ketene gives a different distribution of

products.

36 is derived from the isomeric h¹,h³-vinyl ketene complex

44.

The methyloxymethoxy group is more electron withdrawing

than a methoxyl group and thus if the above analysis is

correct, MOM complex 45 (Scheme 9) would be expected

to give a greater proportion of the bicyclo[3.1.1]heptanone

product than the methoxyl complex 2. As can be seen by the

data in Schemes 7 and 9, this expectation was realized as the

ratio of bicycloheptanone to cyclobutenone products was

2.0 for the methoxyl complex 2 and 2.8 for the MOM

complex 45. To further probe this effect, a series of para-

substituted phenoxy complexes of type 48 were prepared

according to the procedure developed by Fischer²⁶as

described in the Experimental section. The data for the reac-

tion of the four complexes 48a±d with enyne 30 are

summarized in Scheme 9. This series of experiments

The mechanistic issues discussed above (Scheme 4) suggest

that the ratio of the bicyclo[3.1.1]heptanone 35 to the cyclo-

butenone 36 could be enhanced by electronic tuning of the

carbene complex. If the electron density in the coordinated

ole®n of intermediate 40 could be decreased, then the rate of

CO-insertion would be enhanced and thus greater pro-

portions of the desired bicycloheptanone product 35 may

be expected, if as indicated in Scheme 8, 35 is derived

from h¹,h³-vinyl ketene complex 43 and the cyclobutenone

Scheme 9.

2188

W. Jiang et al. / Tetrahedron 56 (2000) 2183±2194

Scheme 10.

provides an even better correlation of electron density of the

alkoxy group of the carbene complex with the product

distribution with the highest selectivities for the bicyclo-

heptanone product observed for the electron withdrawing

para-bromo and para-tri¯uoromethyl complexes.

variation of the electronic nature of the carbene complexes

to the point where good yields of the bicyclo[3.1.1]hepta-

none products can be obtained. Finally, the double-bond

isomerization in the bicyclo[3.1.1]heptanone products

could be affected to give endo-methylene derivatives

which are required for the retrosynthetic plan for the

synthesis of members of the taxane family.

The data in Scheme 9 are consistent with the mechanistic

picture presented in Scheme 8 but certainly do not demand

it. Regardless of the mechanism of the reaction, the success

of the phenoxy complexes 48 increases the ¯exibility of the

general strategy to taxol outlined in Scheme 2 since it not

only allows a method of suppressing the formation of cyclo-

butenone side-products, but the phenoxy group is also a true

auxiliary and can easily be removed by hydrolysis of the

enol ether function in the intermediate 11. The tri¯uoro-

methylphenyl complex 48d is relatively sensitive and

while it can be puri®ed by rapid chromatography on silica

gel, losses are incurred during puri®cation. The para-bromo

complex is more stable and would be the complex of choice

in a synthetic application. Attempts to isomerize the cyclo-

butenone 50 to bicycloheptanone 49 by re¯uxing in toluene

were unsuccessful; decomposition of 50 was the only

observation.

Experimental

General information

The atmosphere under which synthetic reagents were

combined was argon. Unless otherwise indicated, all

common reagents and solvents were used as obtained

from commercial suppliers without further puri®cation.

Prior to use, tetrahydrofuran and diethyl ether were distilled

from Na/benzophenone ketyl. Methylene chloride and

carbon tetrachloride were distilled from CaH₂. All of the

above compounds were stored under N₂after distillation.

Hexamethylphosphoramide was distilled under reduced

Ê

pressure onto activated 4 A molecular sieves and stored

under Ar. All other reagents obtained from commercial

suppliers were used as received. Flash chromatography

was carried out using 230±240 mesh silica gel. Routine

¹H NMR spectra were recorded on a Bruker DMX-500

and DRX-400 500 MHz and 400 MHz, respectively,

spectrometer with tetramethylsilane (d 0.0) as an internal

reference. Routine ¹³C NMR spectra were recorded on the

above Bruker instruments at 100 or 125 MHz with the

central peak of the CDCl₃triplet (d 77.0) as an internal

reference. Infrared spectra were recorded on a Nicolet

20SXB FTIR spectrometer. Mass spectral data were

obtained at the Michigan State University Mass Spectro-

metry Facility which is supported, in part, by a grant

(DRR-00480) from the Biotechnology Research

Technology Program, National Center for Research

Resources, National Institutes of Health. Elemental

analyses were performed by Gailbraith Laboratories

Inc., Knoxville, Tennessee.

The success of the reaction of enyne 30 with carbene

complex 2 and 45 in producing bicycloheptanones and the

success of electronic modi®cation of the aryl complex 48 to

enhance the yield of bicycloheptanones were necessary but

not suf®cient for proof of concept of the modi®ed strategy

for the synthesis of taxol outlined in Scheme 6. What yet

remains is the demonstration that an exo to endo isomeriza-

tion can be achieved in molecules of type 31. Any of the

product enol ethers 35, 46 and 49a±d can be hydrolyzed

ef®ciently with aqueous acetic acid to give diketone 51 in

78±90% yield. Subjection of 51 to hydrogen in the presence

of 5% Pd on BaCO₃in ethanol gave the desired endo-isomer

52 in 70% yield (Scheme 10). Thus, this alternate route

which incorporates enyne 30 for providing the endo-cyclic

double bond required for epoxidation and subsequent Grob

fragmentation offers a viable approach to the synthesis of

taxol and other taxane derivatives. The utilization of this

methodology for entry into the ABC ring system of taxol

will be reported in due course.

Allylic chloride 16. cis-3-Methyl-2-penten-4-yn-1-ol

(1.00 g, 10.4 mmol) was dissolved in 15 mL THF and to

this solution was added 11.4 mL 2.0 M nBuLi/pentane

(22.9 mmol) at 2788C. The solution was brought to 08C

and stirred for 20 min, after which time TMSCl (2.48 g,

22.9 mmol) was added slowly. After stirring at room

temperature for 1 h, the temperature was brought down to

08C and the reaction was quenched with sat. aq. NH₄Cl.

Ether (40 mL) was added and after separation of layers,

the organic phase was dried over MgSO₄. Evaporation of

volatiles yielded crude alcohol as a yellow oil, which was

immediately dissolved in 5 mL THF and 10 mL CCl₄. Upon

the addition of 5 g PPh₃, the mixture was heated to re¯ux

Conclusion

We have presented a methodology for the ef®cient prepara-

tion of 1-substituted-7,7-dimethyl-2-methylenebicyclo[3.1.1]-

heptan-6-ones as potential synthons for taxane derivatives.

It was shown that dienyne 10 does not give bicyclo[3.1.1]-

heptanone products but that the isomeric exo-methylene

dienyne 30 gives a mixture of bicyclo[3.1.1]heptanone

and cyclobutenone products. Furthermore, it was shown

that the ratio of these products could be controlled by

W. Jiang et al. / Tetrahedron 56 (2000) 2183±2194

2189

for 3 h. After cooling, 25 mL pentane was added and the

white solids were ®ltered off. The ®ltrate was concentrated

and the resulting yellow oil was subjected to silica gel

chromatography (100% hexanes) to yield 1.165 g (60%

freeze±thaw method (2196/258C, 3 cycles), back-®lled

with argon at room temperature, sealed, and then heated at

708C for 3.5 h. After evaporation of solvent, aldehyde 18

was isolated by NEt₃-treated silica gel chromatography

(10% EtOAc/hexane) and was obtained as a 1.5:1 mixture

of isomers (49 mg, 56% yield). A small amount of the minor

isomer could be obtained pure. The spectral data on the

major isomer was extracted from that of the mixture with

the aid of the data of the minor isomer. The two observed

diastereomers were tentatively assigned as isomeric about

the enol ether. The chemical shift differences of carbons of

the enol ethers of each isomer were too similar to allow for

assignment by Strobel's rule.²⁵Spectral data for 18 (major):

¹H NMR (500 MHz, CDCl₃): d 1.58 (s, 3 H), 1.88 (s, 3 H),

1.90 (s, 3 H), 2.36 (s,3 H), 3.68 (s, 3 H), 5.03 (s, 1 H),6.02 (d,

J11.0 Hz, 1 H), 6.54 (d, J15.3 Hz, 1 H), 6.96 (dd,

J15.2, 11.3 Hz, 1 H), 10.16 (s, 1 H); ¹³C NMR

(100 MHz, CDCl₃): d 13.4, 18.2, 18.9, 26.6, 55.0, 92.5,

126.4, 131.5, 132.0, 141.7, 150.1, 158.3, 191.5, 1 C not

located: IR (NaCl plate, thin ®lm, cm²¹): 2920m, 1753m,

1653s, 1582m, 1436m, 1352m, 1226m, 1170m, 1077m; MS

(EI) m/z (relative intensity): 220 (M¹, 12), 205 (8), 188 (56),

173 (32), 159 (7), 145 (100), 130 (24), 117 (16), 105 (26), 99

(4), 91 (19), 86 (15), 83 (2), 77 (14), 71 (8), 65 (6), 59 (7), 53

(8); HRMS (EI) calcd for C₁₄H₂₀O₂m/z 220.1463, found

220.1463; R_f0.35 (10% EtOAc/hexanes). Spectral data

1

yield) of 16 as a clear oil. Spectral data for 16: H NMR

(500 MHz, CDCl₃): d 0.21 (s, 9 H), 1.90 (s, 3 H), 4.26 (d,

J8.0 Hz, 2 H), 5.84 (m, 1 H); ¹³C NMR (125 MHz,

CDCl₃): d 20.1, 22.8, 42.4, 101.1, 102.1, 123.2, 132.7; IR

(neat, cm²¹): 2960s, 2144m, 1251s, 937s, 840s; HRMS (EI)

calcd for C₉H₁₅³⁵ClSi m/z 186.0632, found 186.0638. Anal.

Calcd for C₉H₁₅ClSi: C, 57.88; H, 8.10. Found: C, 58.16; H,

8.24.

cis-Dienyne 17. A 50 mL ¯ask with a threaded Te¯on

high-vacuum stopcock was charged with 600 mg

(3.2 mmol) 16, 840 mg (3.8 mmol) 1-trimethylstannyl-2-

methyl-1-propene, 67 mg (0.096 mmol) Pd(PPh₃)₂Cl₂, and

25 mL THF. The resulting yellow solution was heated to

808C and stirred for 14 h. The black solution then was

diluted with ether and the organic phase was washed with

10% KF (aq.) followed by brine. After drying the ethereal

layer with MgSO₄and ®ltration, the solvent was stripped to

yield a yellow oil that was subjected to chromatography on

silica gel (100% hexanes), giving 460 mg (70% yield) of 17

1

as a clear oil. Spectral data for 17: H NMR (500 MHz,

CDCl₃): d 0.20 (s, 9 H), 1.67 (s, 3 H), 1.70 (s, 3 H), 1.83

(d, J1.0 Hz, 3 H), 2.96 (d, J7.5 Hz, 2 H), 5.13 (t,

J7.5 Hz, 1 H), 5.64 (tm, J7.5 Hz, 1 H); ¹³C NMR

(125 MHz, CDCl₃): d 0.1, 17.8, 22.7, 25.7, 30.1, 97.4,

104.7, 117.5, 121.4, 132.6, 137.8; IR (neat, cm²¹): 2960s,

2141s, 1249s, 885s, 842s, 760s; MS (EI) m/z (relative inten-

sity) 205 (M¹21, 14), 189 (50), 179 (34), 173 (30), 165

(60), 159 (29), 149 (72), 141 (29), 135 (89), 125 (100), 119

(34), 105 (43); HRMS (EI) calcd for C₁₃H₂₂Si m/z 206.1491,

found 206.1488. Anal. Calcd for C₁₃H₂₂Si: C, 75.65; H,

10.74. Found: C, 75.81; H, 10.90.

1

for 18 (minor): H NMR (500 MHz, CDCl₃): d 1.63 (s, 3

H), 1.88 (s, 3 H), 1.89 (s, 3 H), 2.09 (s,3 H), 3.66 (s, 3 H),

5.05 (s, 1 H), 6.02 (d, J10.9 Hz, 1 H), 6.80 (dd, J14.6,

11.5 Hz, 1 H), 7.13 (d, J14.9 Hz, 1 H), 10.19 (s, 1 H); ¹³C

NMR (100 MHz, CDCl₃): d 13.4, 18.2, 18.4, 26.6, 55.0,

93.7, 126.1, 132.3, 132.5, 141.3, 151.5, 158.1, 190.5, 1 C

not located; R_f0.41 (10% EtOAc/hexanes).

trans-Dienyne 27. To a suspension of 5.0 g (11.8 mmol)

phosphonium bromide 26 (prepared from PPh₃and 5-bromo-

2-methyl-2-pentene in benzene) in 30 mL THF was added

11.8 mL 1.0 M NaHMDS in THF slowly at room tempera-

ture and the resulting yellow mixture was stirred for 30 min.

At 2608C, 4.22 g (23.6 mmol) HMPA was added and

after cooling to 2788C, a solution of 1.65 g (11.8 mmol)

4-trimethylsilyl-but-3-yn-2-one in 2 mL THF was added

dropwise. After 1 h at room temperature, the solvent was

removed under reduced pressure and the residue was taken

up in 100 mL ice water and 100 mL hexane. Following

separation of phases, the aqueous layer was washed with

hexane (3£30 mL) and the combined organic portions

were washed sequentially with 10% HCl (2£100 mL), sat.

aq. NaHCO₃, brine, and ®nally dried over MgSO₄. Filtration

and concentration left a brown oil and white solid (phos-

phine oxide) which was removed by ®ltration over a plug of

Celite with hexanes. After removal of solvent, the product

was puri®ed by distillation (89±998C/2 mmHg) to give 27

as a colorless liquid (1.35 g, 56% yield). The selectivity for

27 over 17 was determined to be $60:1 by ¹H NMR. Spec-

cis-Dienyne 10. To 400 mg (1.9 mmol) of cis-dienyne 17 in

8 mL EtOH was added a solution of 807 mg (4.75 mmol)

AgNO₃in 4 mL H₂O. Another 8 mL of EtOH was then

added and the mixture was stirred vigorously at room

temperature for 30 min. At this time 750 mg (5.0 mmol)

NaI was added slowly followed by the addition of 5 mL

ether. After stirring for 30 min at room temperature the

mixture was diluted with pentane and the organic layer

was washed with brine and then dried over MgSO₄. Filtra-

tion followed by concentration of the organic phase left an

oily residue that was subjected to silica gel chromatography

(100% hexanes) to afford 230 mg (90% yield) of 10 as a

clear oil. Spectral data for 10: ¹H NMR (500 MHz, CDCl₃):

d 1.67 (s, 3 H), 1.72 (s, 3 H), 1.87 (s, 3 H), 2.96 (t, J7.3 Hz,

2 H), 3.11 (s, 1 H), 5.11 (t, J7.3 Hz, 1H), 5.67 (t,

J7.3 Hz, 1 H); ¹³C NMR (125 MHz, CDCl₃): d 17.8,

22.8, 25.6, 29.9, 80.5, 103.2, 116.6, 121.3, 132.8, 138.2;

IR (NaCl plate, thin ®lm, cm²¹): 3296s, 2925s, 2100m,;

MS (EI) m/z (relative intensity) 134 (M¹, 3), 119 (22),

115 (4), 91 (20), 79 (8), 73 (100), 57 (90); HRMS (EI)

calcd for C₁₀H₁₄m/z 134.1095, found 134.1078.

1

tral data for 27: H NMR (500 MHz, CDCl₃): d 0.17 (s, 9

H), 1.61 (s, 3 H), 1.68 (s, 3 H), 1.79 (d, J1.0 Hz, 3 H), 2.75

(d, J9.2 Hz, 2 H), 5.07 (t, J9.0 Hz, 1 H), 5.88 (tm,

J9.0 Hz, 1 H); ¹³C NMR (100 MHz, CDCl₃): d 0.1,

17.0, 17.7, 25.6, 27.5, 89.9, 108.5, 117.4, 121.0, 132.7,

138.0; IR (NaCl, thin ®lm, cm²¹): 2962m, 2142m, 1249m,

842s, 760m; MS (EI) m/z (relative intensity) 206 (M¹,14),

189 (24), 179 (9), 173 (8), 163 (14),149 (28), 132 (15), 125

Aldehyde 18. A 200 mL ¯ask with a threaded Te¯on high-

vaccuum stopcock was charged with 100 mg (0.4 mmol)

carbene complex 2,²⁷59 mg (0.44 mmol) dienyne 10, and

80 mL CH₃CN. The solution was deoxygenated by the

2190

W. Jiang et al. / Tetrahedron 56 (2000) 2183±2194

(14), 109 (9), 97 (32), 91 (13), 83 (28), 73 (100), 59 (70), 53

(9): HRMS (EI) calcd for C₁₃H₂₂Si m/z 206.1491, found

206.1493. Anal. Calcd for C₁₃H₂₂Si: C, 75.65; H, 10.74.

Found: C, 76.04; H, 10.81.

(s, 3 H), 2.28-2.34 (m, 2 H), 3.37 (t, J7.1 Hz, 1 H), 3.57 (s,

3 H), 4.82 (s, 1 H), 5.12 (t, J7.1 Hz, 1 H); ¹³C NMR

(100 MHz, CDCl₃): d 14.3, 17.9, 19.2, 25.9, 28.1, 55.3,

62.8, 87.8 (enol ether), 122.3, 133.6, 143.7, 161.3, 169.0

(enol ether), 191.0; IR (NaCl plate, thin ®lm, cm²¹):

2928w, 1749s, 1656m, 1239s, 1135s; MS (EI) m/z (relative

intensity) 220 (M¹, 20), 204 (18), 177 (35), 161 (75), 123

(49), 91 (56), 69 (100); HRMS (EI) calcd for C₁₄H₂₀O₂m/z

220.1463, found 220.1471. Spectral data for 29Z: ¹H NMR

(500 MHz, CDCl₃): d 1.58 (s, 3 H), 1.66 (s, 3 H), 1.93 (s, 3

H), 2.18 (s, 3 H), 2.29-2.35 (m, 2 H), 3.33 (t, J6.3 Hz, 1

H), 3.67 (s, 3 H), 4.78 (s, 1 H), 5.12 (t, J5.7 Hz, 1 H); ¹³C

NMR (100 MHz, CDCl₃): d 16.6, 18.2, 18.4, 26.4, 28.2,

55.9, 63.3, 93.7 (enol ether), 121.4, 133.7, 141.7, 157.1,

170.0 (enol ether), 193.0; IR (NaCl plate, thin ®lm,

cm²¹): 2967m, 2915m, 1753s, 1653s, 1437m, 1352m,

1088s; MS (EI) m/z (relative intensity) 220 (M¹,15), 204

(42), 179 (75), 161 (55), 137 (100), 125 (42), 109 (49), 89

(28), 80 (20), 69 (38); HRMS (EI) calcd for C₁₄H₂₀O₂m/z

220.1463, found 220.1515.

Assignment of the stereochemistry of dienynes 17 and 27

The stereochemistry expected from the Wittig reaction of a

non-stabilized ylide is that with the larger carbonyl sub-

stituent cis to the ylide derived group.²⁸Thus, the product

from the Wittig reaction would be expected to have an

E-con®guration as in 27. This is supported by the ¹H

NMR shifts of the conjugated enyne vinyl hydrogens in

17 and 27 (d5.64 and 5.88 ppm, respectively) which

were found to correlate with those shifts in the com-

mercially available compounds 53 and 54. Additionally,

this assignment is consistent with the NOE experiments

on 17 and 27 which are summarized below.

Dienyne 30. To 4.32 mL (45 mmol) of isopropenyl acetyl-

ene in 60 mL THF was added at 2788C 51 mL (100 mmol)

1.96 M nBuLi/hexanes followed by freshly prepared KOtBu

[from 4.38 g (109 mmol) KH and 7.41 g (100 mmol)

tBuOH] in 80 mL THF. The yellow mixture was stirred

for 30 min before warming to 08C for 15 min. The reaction

was then brought down to 2308C and a solution of 8.69 g

(100 mmol) LiBr in 40 mL THF was added slowly. After

20 min the yellow-orange solution was cooled to 2788C and

5.23 mL (45 mmol) of prenyl bromide was added dropwise

over 10 min. The mixture was allowed to warm to room

temperature and after 1 h, 75 mL sat. aq. NH₄Cl and

150 mL pentane was added. The organic phase was

separated and washed sequentially with water and brine.

Drying with MgSO₄, ®ltration, and concentration left the

crude dienyne which was further puri®ed by distillation

(95±988C, 80 mmHg) to yield 6.04 g 30 as a clear oil in

76% yield. Spectral data for 30: ¹H NMR (500 MHz,

CDCl₃): d 1.62 (s, 3 H), 1.69 (s, 3 H), 2.20 (m, 4 H),

2.89 (s, 1 H), 5.10 (m, 1 H), 5.29 (s, 1 H), 5.41 (s, 1 H);

¹³C NMR (100 MHz, CDCl₃): d 17.7, 25.6, 26.6, 37.1, 76.8,

84.1, 122.8, 123.1, 130.5, 132.3; IR (NaCl plate, thin

®lm, cm²¹): 3297s, 2968s, 2916s, 1611m, 1449m, 1376m;

MS (EI) m/z (relative intensity) 133 (M¹21, 14), 109

(17), 95 (22), 87 (40), 73 (100), 67 (16), 57 (61), 43 (49);

HRMS (EI) calcd for C₁₀H₁₄m/z 134.1096, found

134.1100.

trans-Dienyne 28. The same deprotection procedure for the

preparation of 10 was used to furnish 28 as a clear oil from

27 in 92% yield. Spectral data for 28: ¹H NMR (500 MHz,

CDCl₃): d 1.64 (s, 3 H), 1.71 (s, 3 H), 1.83 (s, 3 H), 2.75 (m,

3 H), 5.07 (t, J5.0 Hz, 1 H), 5.89 (t, J5.7 Hz, 1 H); ¹³C

NMR (100 MHz, CDCl₃): d 17.3,18.0, 26.0, 28.0, 74.2,

87.2, 117.3, 121.5, 133.2, 138.6; IR (NaCl plate, thin ®lm,

cm²¹): 3311s, 3294s, 2972s, 2916s, 1448m, 1377m; MS

(EI) m/z (relative intensity) 134 (M¹,14), 133 (M¹21,

45), 119 (80), 91 (100), 79 (58), 69 (50); HRMS (EI)

calcd for C₁₀H₁₄m/z 134.1095, found 134.1087.

Cyclobutenone 29. A 100 mL ¯ask with a threaded Te¯on

high-vacuum stopcock was charged with 108.2 mg

(0.433 mmol) carbene complex 2, 87 mg (0.649 mmol)

dienyne 28, and 100 mL CH₃CN (0.00433 M in 16). The

solution was deoxygenated by the freeze±thaw method

(2196/258C, 3 cycles), back-®lled with argon at room

temperature, sealed, and then heated at 708C for 3.5 h.

After evaporation of solvent, the cyclobutenones 29 were

isolated by column chromatography on NEt₃-treated silica

gel (10% EtOAc/hexane). The E-isomer was isolated

(R_f0.22) as a pale yellow oil in 56% yield (53.1 mg) and

the Z-isomer (R_f0.19) as a pale yellow oil in 26% yield

(25.0 mg). The assignment of the stereochemistry was made

by the difference in chemical shift of the enol ether carbons

by the method of Strobel.²⁵A reaction at 0.01 M gave a 70%

yield (E/Z2.0:1) and a reaction at 0.1 M gave 65% yield

Reaction between carbene complex 2 and dienyne 30

A 100 mL ¯ask with a threaded Te¯on high-vacuum stop-

cock was charged with 125 mg (0.5 mmol) carbene complex

2, 74 mg (0.55 mmol) dienyne 30, and 50 mL CH₃CN. The

solution was deoxygenated by the freeze±thaw method

(2196/258C, 3 cycles), back-®lled with argon at room

temperature, sealed, and then heated at 708C for 3.5 h.

After evaporation of solvent, products were isolated as

colorless oils by silica gel chromatography (5% EtOAc/

hexane) in the following amounts: 40 mg (36%) bicyclo-

heptanone 35E, 67 mg (61%) cyclobutenones 36E and

36Z in a 1.4:1 ratio, respectively. When the reaction was

performed at 458C for 48 h, the product distribution was

1

(E/Z2.7:1). Spectral data for 29E: H NMR (500 MHz,

CDCl₃): d 1.62 (s, 3 H), 1.70 (s, 3 H), 2.12 (s, 3 H), 2.13

W. Jiang et al. / Tetrahedron 56 (2000) 2183±2194

2191

69 mg (63%) 35E, 34 mg (31%) 36E and 36Z in a 2:1 ratio,

respectively. When the reaction was performed at 1008C for

2 h, the product distribution was 19% yield 35E and a 68%

yield of 36E. Careful chromatography can provide a pure

sample of 36Z. The spectral data for 35E and 36Z were

obtained on pure compounds and the spectral data for 36E

was extracted from that of a mixture of 36E and 36Z. The

assignment of the stereochemistry of the isomers of 36 was

made by the difference in chemical shift of the enol ether

carbons by the method of Strobel.²⁵Since 35 was only

obtained as the one isomer it could not be assigned by

Strobel's rule. Compound 35 was assumed to have the

same stereochemistry as the products 49a±d. Spectral data

for 35E: ¹H NMR (500 MHz, CDCl₃): d 1.08 (s, 3 H), 1.09

(s, 3 H), 1.73 (s, 3 H), 2.05±2.20 (m, 2 H), 2.28±2.37 (m, 1

H), 2.46 (dd, J16.5, 8.0 Hz, 1 H), 2.68 (dd, J4.8, 1.5 Hz,

1 H), 3.55 (s, 3 H), 4.23 (s, 1 H), 4.80 (m, 1 H), 4.87 (m, 1

H); ¹³C NMR (100 MHz, CDCl₃): d 17.9, 19.2, 24.6, 25.1,

27.4, 29.7, 54.5, 63.0, 76.1, 89.7, 109.3, 150.4, 156.6, 210.2;

IR (NaCl plate, thin ®lm, cm²¹): 2953s, 1777s, 1657s,

1228s; MS (EI) m/z (relative intensity) 220 (M¹, 45), 205

(20), 192 (95), 177 (100), 161 (34), 145 (75), 135 (45), 110

(30), 105 (45), 91 (40), 77 (25), 69 (25), 59 (20), 55 (2);

domethylene]pentacarbonyl chromium²⁷in 20 mL CH₂Cl₂

was slowly added 0.80 g (6.5 mmol) freshly distilled acetyl

bromide at 2788C. After the deep red solution was stirred

for 2 h, a 20 mL THF solution of the corresponding sodium

phenoxide (prepared by reacting 6.5 mmol NaH with

6.5 mmol of para-substituted phenol) was added over

15 min and the mixture was slowly warmed to 2108C

over 1 h. After 2 h at this temperature, the solvent was

removed under reduced pressure and 50 mL nitrogen-

purged pentane was added. The solids were ®ltered through

Celite and after concentration of the ®ltrate, the orange±red

oil was ¯ashed through a short pad of NEt₃-treated silica gel

using 1:1 hexane/CH₂Cl₂as eluent. Removal of solvent left

complexes 48a±d as an orange±red oil which solidi®ed

upon cooling. Yields ranged from 20 to 60% and depended

on the quickness of puri®cation. They were often taken on to

the next reaction immediately. Spectral data for 48a: red

1

solid; H NMR (500 MHz, CDCl₃): d 3.10 (s, 3 H), 3.84

(s, 3 H), 6.98 (m, 4 H); ¹³C NMR (125 MHz, CDCl₃): d

49.3, 55.7, 115.1, 121.9, 152.4, 158.7, 215.7, 224.0, 363.9;

IR (NaCl, thin ®lm, cm²¹): 2064s, 1938brs, 1502s, 1251m,

1210s, 1099m; HRMS (EI) calcd for C₁₄H₁₀O₇Cr 341.9832,

found 341.9833: Anal. Calcd for C₁₄H₁₀O₇Cr: C, 49.13; H,

2.94. Found: C, 49.05; H, 3.07. Spectral data for 48b: orange

solid, ¹H NMR (500 MHz, CDCl₃): d 3.11 (s, 3 H), 7.08 (d,

J7.8 Hz, 2 H), 7.39 (t, J7.4 Hz, 1 H), 7.49 (t, J7.8 Hz,

2 H); ¹³C NMR (125 MHz, CDCl₃): d 49.3 121.2, 127.5,

130.2, 158.4, 215.6, 223.9, 363.3; IR (NaCl, thin ®lm,

cm²¹): 2065s, 1944brs, 1485m, 1211s, 1106m; HRMS

(EI) calcd for C₁₃H₈O₆Cr 311.9726, found 311.9724:

Anal. Calcd for C₁₃H₈O₆Cr: C, 50.01; H, 2.58. Found: C,

1

R_f0.31 (10% EtOAc/hexanes). Spectral data for 36E: H

NMR (500 MHz, CDCl₃): d 1.63 (s, 3 H), 1.70 (s, 3 H), 2.15

(s, 3 H), 2.90 (q, J7.5 Hz, 2 H), 2.58 (t, J7.5 Hz, 2 H),

3.11 (s, 2 H), 3.56 (s, 3 H), 4.85 (s, 1 H), 5.11 (m, 1 H); ¹³C

NMR (100 MHz, CDCl₃): d 17.8, 19.0, 24.8, 25.7, 29.7,

49.2, 54.9, 87.4 (enol ether), 122.8, 133.1, 143.4, 160.9

(enol ether), 167.2, 187.4; R_f0.26 (10% EtOAc/hexanes).

Spectral data for 36Z: ¹H NMR (500 MHz, CDCl₃): d 1.64

(s, 3 H), 1.70 (s, 3 H), 1.96 (s, 3 H), 2.27 (q, J7.5 Hz, 2 H),

2.68 (t, J7.5 Hz, 2 H), 3.10 (s, 2 H), 3.68 (s, 3 H), 4.80 (s, 1

H), 5.11 (m, 1 H); ¹³C NMR (100 MHz, CDCl₃): d 17.7,

17.5, 25.1, 25.6, 31.1, 49.6, 55.2, 93.2 (enol ether), 123.2,

132.6, 141.6, 156.3 (enol ether), 168.2, 188.5; IR (NaCl

plate, thin ®lm, cm²¹): 2965m, 2916m, 1757s, 1653m,

1658m, 1378w, 1358w, 1224m, 1085m; MS (EI) m/z (rela-

tive intensity) 220 (M¹, 55), 205 (20), 189 (20), 179 (30),

163 (15), 145 (22), 135 (22), 123 (20), 117 (10), 109 (30), 89

(65), 84 (63), 69 (100), 77 (15), 65 (10), 59 (24), 55 (27), 49

(15); R_f0.12 (10% EtOAc/hexanes).

1

49.84; H, 2.66. Spectral data for 48c: orange±red oil, H

NMR (500 MHz, CDCl₃): d 3.12 (s, 3 H), 6.98 (d,

J8.0 Hz, 2 H), 7.60 (t, J8.0 Hz, 2 H); ¹³C NMR

(125 MHz, CDCl₃): d 49.4, 118.8, 123.0, 133.2, 157.2,

215.4, 223.5, 363.9; IR (NaCl, thin ®lm, cm²¹): 2066s,

1948brs, 1484s, 1200s, 1012m. Spectral data for 48d::

orange±red oil, ¹H NMR (400 MHz, CDCl₃): d 3.15 (s, 3 H),

7.25 (d, J8.5 Hz, 2 H), 7.78 (d, J8.5 Hz, 2 H); IR (NaCl,

thin ®lm, cm²¹): 2058s, 1950brs, 1317s, 1185s, 1124m, 1059s.

Reaction between complexes 45 and 48a±d and dienyne

30

Carbene complex 45. To a solution of 1.0 g (3.2 mmol) of

tetramethylammonium

[(methyl)oxidomethylene]penta-

A 100 mL ¯ask with a threaded Te¯on high-vacuum stop-

cock was charged with 125 mg (0.5 mmol) carbene

complex, 74 mg (0.55 mmol) dienyne 30, and 50 mL

CH₃CN. The solution was deoxygenated by the freeze±

thaw method (2196/258C, 3 cycles), back-®lled with

argon at room temperature, sealed, and then heated at

458C for 48 h. After evaporation of solvent, the

bicyclo[3.1.1]heptanone and cyclobutenone products were

isolated by silica gel chromatography (5±10% EtOAc/

hexane) in the yields shown below. While the products 49

and 50 could be separated, the E and Z isomers could not be

easily separated. Pure samples of the E-isomers of 49a±d

and [Z-isomers] 50a±d could be obtained by careful chro-

matography. The spectral data of their corresponding

isomers were obtained by extraction from the spectral data

obtained from a mixture of E and Z isomers with the aid of

the authentic spectral data of one pure isomer. Compounds

46 and 47 were each formed as only one isomer and could

be separated. The stereochemistry was assigned by the

carbonyl chromium²⁷in 15 mL CH₂Cl₂was added 0.44 g

(3.5 mmol) of MOMBr at rt. The resulting orange solution

was stirred for 30 min after which time 5 mL sat. aq.

NaHCO₃was added. The organic phase was separated,

dried with MgSO₄, ®ltered, and concentrated to leave an

oil that was subjected to silica gel chromatography (100%

hexane) to yield 760 mg (85% yield) of 45 as a dark orange

1

oil. Spectral data for 45: H NMR (500 MHz, CDCl₃): d

3.10 (s, 3 H), 3.68 (s, 3 H), 5.89 (s, 2 H); ¹³C NMR

(100 MHz, CDCl₃): d 48.7, 58.4, 103.5, 216.1, 223.4,

359.1; IR (NaCl, thin ®lm, cm²¹): 2065s, 1951brs, 651s;

MS (EI) m/z (relative intensity) 280 (M¹, 100), 252 (75),

224 (44), 196 (34), 168 (30), 151 (14), 140 (61), 123 (16),

110 (12), 95 (16), 80 (18), 63 (8), 52 (35), 45 (24); HRMS

(EI) calcd for C₉H₈O₇Cr m/z 279.9675, found 279.9678.

Phenoxy carbene complexes 48a±d. To a solution of

2.00 g (6.5 mmol) of tetramethylammonium [(methyl)oxi-

2192

W. Jiang et al. / Tetrahedron 56 (2000) 2183±2194

difference in chemical shift of the enol ether carbons accord-

ing to Strobel's rule.²⁵The bicycloheptanones and the

cyclobutenone 47 were formed as predominately the E

isomer while the cyclobutenones 50a and 50c were formed

as predominately the Z isomer. Cyclobutenones 50b and

50d could not be assigned by Strobel's rule and the major

isomer was assumed to be Z in each case.

(125 MHz, CDCl₃): d 18.0, 18.1, 24.6, 25.4, 26.6, 36.5,

55.6, 63.3, 76.7, 103.3 (enol ether), 109.5, 114.3, 120.3,

148.7 (enol ether), 149.1, 149.3, 155.3, 210.6.

Cyclobutenone 50aZ. 23% yield, spectral data for 50aZ:

¹H NMR (500 MHz, CDCl₃): d 1.56 (s, 3 H), 1.65 (s, 3 H),

1.82 (s, 3 H), 2.21 (q, J7.5 Hz, 2 H), 2.69 (t, J7.5 Hz, 2

H), 3.11 (s, 2 H), 3.79, (s, 3 H), 5.02 (m, 1 H), 5.23 (s, 1 H),

6.83 (d, J9.0 Hz, 2 H), 6.91 (d, J9.0 Hz, 2 H); ¹³C NMR

(125 MHz, CDCl₃): d(17.7, 18.6, 25.1, 25.6, 31.4, 50.0,

55.6, 99.4 (enol ether), 114.6, 119.7, 123.0, 133.4, 140.7,

148.9, 153.6 (enol ether), 155.7, 170.6, 188.2; IR (NaCl,

thin ®lm, cm²¹) 2965m, 1765s, 1455m, 1215m; MS (EI)

m/z (relative intensity) 312 (M¹, 22), 269 (15), 227 (7),

215 (11), 201 (23), 189 (100), 173 (61), 161 (19), 147

(70), 135 (78), 124 (95), 109 (62), 91 (25), 84 (20), 69

(22), 55 (11), 49 (19); HRMS (EI) calcd for C₂₀H₂₄O₃m/z

312.1725, found 312.1738: Anal. Calcd for C₂₀H₂₄O₃: C,

76.89; H, 7.74. Found: C, 76.54; H, 7.97.

Bicycloheptanone 46. 62% yield, E-isomer only, pale

yellow oil, R_f0.46 (10% EtOAc/hexanes). Spectral data

1

for 46E: H NMR (500 MHz, CDCl₃): d 1.05 (s, 3 H),

1.08 (s, 3 H), 1.75 (s, 3 H), 2.01±2.19 (m, 2 H), 2.27±

2.37 (J16.5, 10.0, 2.5, 2.5 Hz, 1 H), 2.44±2.49 (dd,

J16.3, 8.0 Hz, 1 H), 2.66±2.68 (dd, 1 H), 3.42 (s, 3 H),

4.54 (s, 1 H), 4.80 (m, 1 H), 4.87 (m, 1 H), 4.95 (dd, J29.3,

6.5 Hz, 2 H); ¹³C NMR (125 MHz, CDCl₃): d 17.7, 18.8,

24.5, 25.0, 27.4, 29.7, 55.8, 62.9, 76.1, 93.4, 95.0, 109.2,

150.3, 155.3, 209.9; IR (NaCl, thin ®lm, cm²¹): 2952s,

1776s, 1650m, 1222w, 1178w, 1150m, 1048s; MS (EI)

m/z (relative intensity) 250 (M¹, 2), 218 (5), 205 (8), 188

(7), 177 (38), 159 (6), 147 (10), 133 (8), 119 (8), 105 (12),

91 (14), 79 (8), 69 (16), 61 (18), 55 (8), 45 (100); HRMS

(EI) calcd for C₁₅H₂₂O₃m/z 250.1596, found 250.1588:

Anal. Calcd for C₁₅H₂₂O₃: C, 71.97; H, 8.86. Found: C,

71.98; H, 8.86.

Cyclobutenone 50aE. 11% yield, spectral data for 50aE:

¹H NMR (500 MHz, CDCl₃): d 1.57 (s, 3 H), 1.66 (s, 3 H),

2.19 (q, J8.0 Hz, 2 H), 2.31 (s, 3 H), 2.43 (t, J8.0 Hz, 2

H), 3.09 (s, 2 H), 3.81, (s, 3 H), 4.86 (s, 1 H), 5.02 (m, 1 H),

6.86 (d, J9.0 Hz, 2 H), 6.92 (d, J9.0 Hz, 2 H); ¹³C NMR

(125 MHz, CDCl₃): d(17.7, 18.4, 24.7, 25.6, 29.7, 49.3,

55.7, 94.4 (enol ether), 114.6, 121.9, 122.7, 133.8, 140.7,

148.9, 156.3, 160.6 (enol ether), 168.5, 187.1.

Cyclobutenone 47. 22% yield, E-isomer only, R_f0.26

1

(10% EtOAc/hexanes). Spectral data for 47E: H NMR

(500 MHz, CDCl₃): d 1.65 (s, 3 H), 1.71 (s, 3 H), 2.01 (s,

3 H), 2.30 (m, 2 H), 2.70 (m, 2 H), 3.12 (s, 2 H), 3.45 (s, 3

H), 4.91 (s, 1 H), 4.99 (s, 2 H), 5.10 (brs, 1 H); ¹³C NMR

(125 MHz, CDCl₃): d 17.7, 18.7, 24.7, 25.6, 29.6, 49.1,

58.4, 91.6, 108.2, 122.7, 133.0, 143.1, 157.8, 168.2, 187.0;

IR (NaCl, thin ®lm, cm²¹): 2925m, 1759s, 1152m, 1041m;

MS (EI) m/z (relative intensity) 250 (M¹, 4), 218 (5), 205

(8), 191 (4), 177 (32), 163 (15), 147 (16), 135 (32), 121

(20), 105 (30), 93 (44), 79 (20), 69 (34), 55 (23), 45

(100); HRMS (EI) calcd for C₁₅H₂₂O₃m/z 250.1596,

found 250.1590.

Bicycloheptanone 49bE. 47% yield, spectral data for

49bE: H NMR (500 MHz, CDCl₃): d 1.01 (s, 3 H), 1.03

1

(s, 3 H), 1.88 (s, 3 H), 2.06±2.20 (m, 2 H), 2.30±2.40 (m, 1

H), 2.47 (dd, J16.3, 7.5 Hz, 1 H), 2.69 (dd, J5.0, 1.5 Hz,

1 H), 4.75 (s, 1 H), 4.88 (m, 1 H), 4.93 (m, 1 H), 7.00 (d,

J7.5 Hz, 2 H), 7.04 (t, J7.5 Hz, 1 H), 7.31 (t, J7.5 Hz,

2 H); ¹³C NMR (125 MHz, CDCl₃): d(17.5, 17.8, 24.5, 24.9,

27.3, 34.9, 62.8, 75.8, 104.1 (enol ether), 109.4, 118.6,

122.6, 129.4, 149.8, 155.4, 156.2 (enol ether), 208.9; IR

(NaCl, thin ®lm, cm²¹): 2947w, 1766s, 1591m, 1481s,

1217s, 1165m; MS (EI) m/z (relative intensity) 282 (M¹,

9), 254 (30), 239 (37), 211 (35), 188 (93), 173 (22), 161

(92), 146 (100), 131 (56), 119 (90), 105 (65), 91 (55), 77

(43), 69 (30), 55 (26); HRMS (EI) calcd for C₁₉H₂₂O₂m/z

282.1620, found 282.1613: Anal. Calcd for C₁₉H₂₂O₂: C,

80.81; H, 7.85. Found: C, 80.76; H, 7.96.

Bicycloheptanone 49aE. 32% yield, spectral data for 49aE:

¹H NMR (500 MHz, CDCl₃): d 0.98 (s, 6 H), 1.87 (s, 3 H),

2.03±2.20 (m, 2 H), 2.27±2.39 (m, 1 H), 2.46 (dd, J14.5,

7.8 Hz, 1 H), 2.66 (dd, J5.0, 2.5 Hz, 1 H), 3.79 (s, 3 H),

4.51 (s, 1 H), 4.84 (m, 1 H), 4.90 (m, 1 H), 6.84, (d,

J9.0 Hz, 2 H), 6.94 (d, J9.0 Hz, 2 H); ¹³C NMR

(125 MHz, CDCl₃): d(17.6, 18.2, 24.5, 25.0, 27.4, 34.9,

55.6, 62.9, 75.9, 100.3 (enol ether), 109.3, 114.6, 120.7,

149.3, 150.0, 155.5, 157.0 (enol ether), 209.4; IR (NaCl,

thin ®lm, cm²¹): 2947w, 1766s, 1504s, 1214s; MS (EI)

m/z (relative intensity) 312 (M¹, 7), 284 (4), 269 (11),

241 (15), 227 (5), 199 (5), 188 (51), 173 (15), 161 (96),

145 (32), 124 (27), 105 (19), 91 (16), 84 (100), 77 (9), 65

(5), 49 (92); HRMS (EI) calcd for C₂₀H₂₄O₃m/z 312.1725,

found 312.1725: Anal. Calcd for C₂₀H₂₄O₃: C, 76.89; H,

7.74. Found: C, 76.70; H, 8.11.

Bicycloheptanone 49bZ. 24% yield, spectral data for 49bZ:

¹H NMR (500 MHz, CDCl₃): d 1.13 (s, 3 H), 1.16 (s, 3 H),

1.88 (s, 3 H), 2.06±2.20 (m, 2 H), 2.25±2.35 (m, 1 H), 2.42

(dd, J16.3, 7.5 Hz, 1 H), 2.67 (dd, J5.0, 1.5 Hz, 1 H),

4.87 (m, 1 H), 4.88 (s, 1 H), 4.97 (m, 1 H), 6.94 (d,

J7.5 Hz, 2 H), 7.04 (t, J7.5 Hz, 1 H), 7.29 (t,

J7.5 Hz, 2 H); ¹³C NMR (125 MHz, CDCl₃): d(17.8,

18.0, 24.5, 25.3, 26.5, 36.6, 63.3, 76.8, 105.1, 109.5 (enol

ether), 118.9, 122.5, 129.2, 148.9 (enol ether), 149.3, 155.0,

210.3.

Bicycloheptanone 49aZ. 16% yield, spectral data for 49aZ:

¹H NMR (500 MHz, CDCl₃): d 1.14 (s, 3 H), 1.16 (s, 3 H),

1.82 (s, 3 H), 2.03±2.20 (m, 2 H), 2.27±2.39 (m, 1 H), 2.44

(dd, J15.0, 8.0 Hz, 1 H), 2.66 (dd, J5.0, 2.5 Hz, 1 H),

3.78 (s, 3 H), 4.76 (s, 1 H), 4.89 (m, 1 H), 4.97 (m, 1 H), 6.82

(d, J9.0 Hz, 2 H), 6.89 (d, J9.0 Hz, 2 H); ¹³C NMR

Cyclobutenone 50bE. 5% yield, spectral data for 50bE: ¹H

NMR (500 MHz, CDCl₃): d 1.55 (s, 3 H), 1.64 (s, 3 H), 1.88

(s, 3 H), 2.20 (q, J7.3 Hz, 2 H), 2.67 (t, J7.3 Hz, 2 H),

3.09 (s, 2 H), 5.00 (m, 1 H), 5.34 (s, 1 H), 6.96 (d, J7.5 Hz,

2 H), 7.06 (t, J7.5 Hz, 1 H), 7.31 (d, J7.5 Hz, 2 H); ¹³C

NMR (125 MHz, CDCl₃): d(17.7, 18.7, 25.1, 25.6, 31.3,

W. Jiang et al. / Tetrahedron 56 (2000) 2183±2194

2193

50.0, 101.1, 118.1, 122.9, 123.0, 129.5, 132.8, 140.6, 152.7,

155.3, 171.1, 188.0; IR (NaCl, thin ®lm, cm²¹): 3054s,

2986m, 1756s, 1490s, 1422s, 1220s; MS (EI) m/z (relative

intensity) 282 (M¹, 7), 267 (2), 256 (2), 240 (3), 213 (5),

189 (100), 171 (25), 161 (15), 147 (54), 131 (12), 119 (18),

105 (17), 94 (42), 84 (6), 77 (15), 55 (8); HRMS (EI) calcd

for C₁₉H₂₂O₂m/z 282.1620, found 282.1624: Anal. Calcd

for C₁₉H₂₂O₂: C, 80.81; H, 7.85. Found: C, 80.53; H, 7.98.

(s, 3 H), 1.87 (s, 3 H), 2.10-2.22 (m, 2 H), 2.33-2.41 (m, 1

H), 2.49 (dd, J16.2, 7.6 Hz, 1 H), 2.72 (dd, J5.0, 1.5 Hz,

1 H), 4.87 (d, J2.1 Hz, 1 H), 4.93 (s, 1 H), 4.96 (s, 1 H),

7.07 (d, J8.5 Hz, 2 H), 7.56 (d, J8.5 Hz, 2 H); ¹³C NMR

(125 MHz, CDCl₃) d 17.6, 17.7, 24.5, 24.9, 27.4, 35.0, 63.0,

75.8, 107.4 (enol ether), 109.5, 117.6, 124.3 (q,

J_CF269.6 Hz), 124.4 (q, J_CF32.5 Hz), 127.0 (q,

J_CF3.8 Hz), 149.6, 154.3, 159.4 (enol ether), 208.3; IR

(NaCl, thin ®lm, cm²¹): 2957brm, 1755s, 1631s, 1619s,

1325s, 1242s, 1168s, 1107s, 1066s; HRMS (EI) calcd for

C₂₀H₂₁O₂F₃m/z 350.1494, found 350.1509. Anal. Calcd for

C₂₀H₂₁O₂F₃: C, 68.55; H, 6.04. Found: C, 68.50; H, 6.14.

Cyclobutenone 50bZ. 11% yield, spectral data for 50bZ:

¹H NMR (500 MHz, CDCl₃): d 1.57 (s, 3 H), 1.66 (s, 3 H),

2.20 (q, J7.5 Hz, 2 H), 2.32 (s, 3 H), 2.46 (t, J7.5 Hz, 2

H), 3.11 (s, 2 H), 5.02 (m, 1 H), 5.02 (s, 1 H), 6.99 (d,

J7.5 Hz, 2 H), 7.13 (t, J7.5 Hz, 1 H), 7.34 (t,

J7.0 Hz, 2 H).

Bicycloheptanone 49dZ. 22% yield, spectral data for 49dZ:

¹H NMR (500 MHz, CDCl₃) d 1.10 (s, 3 H), 1.14 (s, 3 H),

1.92 (s, 3 H), 2.06±2.12 (m, 2 H), 2.25±2.35 (m, 1 H), 2.41

(dd, J16.2, 7.6 Hz, 1 H), 2.67 (dd, J5.0, 1.5 Hz, 1 H),

4.86 (m, 1 H), 4.88 (m, 1 H), 4.98 (s, 1 H), 7.01 (d,

J8.5 Hz, 2 H), 7.55 (d, J8.5 Hz, 2 H); ¹³C NMR

(125 MHz, CDCl₃) d 17.8, 17.9, 24.5, 25.4, 26.6, 36.4,

63.3, 76.8, 107.8 (enol ether), 109.5, 118.3, 124.4 (q,

J_CF269.6 Hz), 124.5 (q, J_CF32.5 Hz), 126.7 (q,

J_CF3.8 Hz), 148.7 (enol ether), 149.0, 157.9, 209.2.

Cyclobutenone 50dE. 3% yield, spectral data for 50cE: ¹H

NMR (500 MHz, CDCl₃): d (1.57 (s, 3 H), 1.65 (s, 3 H),

1.93 (s, 3 H), 2.21 (q, J7.2 Hz, 2 H), 2.63 (t, J7.2 Hz, 2

H), 3.08 (s, 2 H), 4.99 (m, 1 H), 5.48 (s, 1 H), 7.02 (d,

J8.5 Hz, 2 H), 7.56 (d, J8.5 Hz, 2 H); HRMS (EI)

calcd for C₂₀H₂₁O₂F₃m/z 350.1494, found 350.1501.

Bicycloheptanone 49cE. 46% yield, spectral data for 49cE:

¹H NMR (500 MHz, CDCl₃): d 1.01 (s, 3 H), 1.02 (s, 3 H),

1.85 (s, 3 H), 2.08±2.20 (m, 2 H), 2.30±2.40 (m, 1 H), 2.47

(dd, J16.3, 8.0 Hz, 1 H), 2.69 (dd, J5.0, 1.5 Hz, 1 H),

4.75 (s, 1 H), 4.84 (m, 1 H), 4.92 (m, 1 H), 6.89 (d,

J8.5 Hz, 2 H), 7.40 (d, J8.5 Hz, 2 H); ¹³C NMR (125

MHz, CDCl₃): d 17.6, 17.8, 24.5, 24.9, 27.4, 34.9, 62.9,

75.8, 104.7 (enol ether), 109.4, 115.1, 120.3, 132.4, 149.7,

155.3, 155.4 (enol ether), 208.7; IR (NaCl, thin ®lm, cm²¹):

2954s, 1772s, 1483s, 1265s, 1226s; HRMS (EI) calcd for

C₁₉H₂₁O₂⁷⁹Br m/z 360.0725, found 360.0747. HRMS (EI)

calcd for C₁₉H₂₁O₂⁸¹Br m/z 362.0706, found 362.0696.

Bicycloheptanone 49cZ. 23% yield, spectral data for 49cZ:

¹H NMR (500 MHz, CDCl₃): d 1.10 (s, 3 H), 1.13 (s, 3 H),

1.87 (s, 3 H), 2.02-2.20 (m, 2 H), 2.25-2.35 (m, 1 H), 2.40

(dd, J16.3, 8.0 Hz, 1 H), 2.66 (dd, J5.0, 1.5 Hz, 1 H),

4.75 (s, 1 H), 4.84 (m, 1 H), 4.92 (m, 1 H), 6.89 (d,

J8.5 Hz, 2 H), 7.40 (d, J8.5 Hz, 2 H); ¹³C NMR

(125 MHz, CDCl₃): d 17.8, 17.9, 24.5, 25.3, 26.6, 36.4,

63.3, 76.7, 106.2 (enol ether), 109.5, 115.0, 120.4, 132.2,

148.9 (enol ether), 149.0, 154.2, 209.7.

Diketone 51. Enol ether 49 (0.2 mmol) was dissolved in

10 mL ether, 1.5 mL acetic acid, and 1.5 mL H₂O. The

mixture was stirred at room temperature and monitored by

TLC for completion of reaction (4±12 h). Upon completion

of reaction, sat. aq. NaHCO₃was added and the product was

extracted with CH₂Cl₂. After drying with Na₂SO₄, ®ltration,

and concentration, the crude diketone 51 was further puri-

®ed by subjection to silica gel chromatography (25%

EtOAc/hexanes) to give a colorless oil. Yields varied from

78±90%. Spectral data for 51: R_f0.15 (10% EtOAc/

Cyclobutenone 50cZ. 6% yield, spectral data for 50cZ: ¹H

NMR (500 MHz, CDCl₃): d 1.57 (s, 3 H), 1.66 (s, 3 H), 1.88

(s, 3 H), 2.21 (q, J7.1 Hz, 2 H), 2.64 (t, J7.4 Hz, 2 H),

3.09 (s, 2 H), 5.00 (m, 1 H), 5.34 (s, 1 H), 6.84 (d, J9.0 Hz,

2 H), 7.40 (d, J9.0 Hz, 2 H); ¹³C NMR (125 MHz, CDCl₃):

d 17.7, 18.6, 25.0, 25.6, 31.1, 50.0, 102.2 (enol ether),

115.3, 119.5, 122.8, 132.5, 133.0, 140.4, 152.1 (enol

ether), 154.6, 171.3, 187.4; IR (NaCl, thin ®lm, cm²¹):

2914s, 1755s, 1671s, 1585s, 1482s, 1220s; HRMS (EI)

calcd for C₁₉H₂₁O₂⁷⁹Br m/z 360.0725, found 360.0715.

HRMS (EI) calcd for C₁₉H₂₁O₂⁸¹Br m/z 362.0706, found

362.0717.

1

hexanes), H NMR (500 MHz, CDCl₃): d 1.05 (s, 3 H),

1.12 (s, 3 H), 2.08±2.23 (m, 2 H), 2.19 (s, 3 H), 2.29±

2.36 (dddd, J16.5, 10.0, 2.5, 2.5 Hz, 1 H), 2.38±2.43

(dd, J16.0, 8.0 Hz, 1 H), 2.68 (dd, J5.0, 1.5 Hz, 1 H),

2.69 (dd, J53.0, 17.5 Hz, 2 H), 4.52 (d, J2.5 Hz, 1 H),

4.88 (d, J2.5 Hz, 1 H); ¹³C NMR (125 MHz, CDCl₃): d

17.8, 24.1, 24.5, 28.3, 30.1, 34.9, 41.0, 63.2, 73.5, 108.3,

149.6, 206.5, 209.2; IR (NaCl, thin ®lm, cm²¹): 2953m,

1771s, 1722m, 1361m; MS (EI) m/z (relative intensity)

206 (M¹, 10), 192 (12), 178 (36), 163 (29), 135 (95), 121

(60), 105 (75), 91 (100), 79 (74), 55 (55); HRMS (EI) calcd

for C₁₃H₁₈O₂m/z 206.1307, found 206.1312.

Cyclobutenone 50cE. 3% yield, spectral data for 50cE: ¹H

NMR (500 MHz, CDCl₃): d 1.58 (s, 3 H), 1.67 (s, 3 H), 2.21

(q, J8.0 Hz, 2 H), 2.31 (s, 3 H), 2.47 (t, J7.0 Hz, 2 H),

3.12 (s, 2 H), 5.03 (s, 1 H), 5.03 (m, 1 H), 6.88 (d, J9.0 Hz,

2 H), 7.44 (d, J9.0 Hz, 2 H); ¹³C NMR (125 MHz, CDCl₃):

d 17.7, 18.2, 24.7, 25.6, 29.8, 49.5, 97.3 (enol ether), 116.7,

122.1, 122.5, 132.7, 133.3, 142.0, 150.9 (enol ether), 154.3,

169.8, 186.8.

Isomerization of 51 to diketone 52. To a solution of

100 mg (0.49 mmol) diketone 51 in 15 mL absolute EtOH

was added 400 mg 5% Pd on BaCO₃. Under an atmosphere

of hydrogen, the mixture was stirred for 4 h at room

temperature. The solvent then was evaporated and the

resulting residue was subjected to silica gel chromatography

(10% EtOAc/hexanes) to yield 52 a clear oil in 70% yield.

1

Bicycloheptanone 49dE. 43% yield, spectral data for

49dE: H NMR (500 MHz, CDCl₃): d 1.04 (s, 3 H), 1.06

Spectral data for 52: R_f0.15 (10% EtOAc/hexanes), H

1

NMR (500 MHz, CDCl₃): d 1.05 (s, 3 H), 1.36 (s, 3 H),

2194

W. Jiang et al. / Tetrahedron 56 (2000) 2183±2194

2755±2756. (c) Wender, P. A.; Badham, N. F.; Conway, S. P.;

Floreancig, P. E.; Glass, T. E.; Houze, J. B.; Krauss, N. E.; Lee,

D.; Marquess, D. G.; McGrane, P. L.; Meng, W.; Natchus, M. G.;

Shuker, A. J.; Sutton, J. C.; Taylor, R. E. J. Am. Chem. Soc. 1997,

119, 2757±2758. (d) Mukaiyama, T.; Shiina, I.; Iwadare, H.;

Saitoh, M.; Nishimura, T.; Ohkawa, N.; Sakoh, H.; Nishimura,

K.; Tani, Y.; Hasegawa, M.; Yamada, K.; Saitoh, K. Chem. Eur.

J. 1999, 5, 121. (e) Morihara, K.; Hara, R.; Kawahara, S.;

Nishimori, T.; Nakamura, N.; Kusama, H.; Kuwajima, I. J. Am.

Chem. Soc. 1998, 120, 12980.

1.64 (s, 3 H), 2.19 (s, 3 H), 2.60 (m, 3 H), 2.68 (d,

J19.2 Hz, 1 H), 2.93 (d, J19.2 Hz, 1 H), 5.45 (m, 1

H); ¹³C NMR (100 MHz, CDCl₃): d 15.3, 19.9, 24.7, 28.0,

31.1, 33.6, 42.4, 63.7, 67.7, 121.2, 140.0, 206.4, 206.8; IR

(NaCl, thin ®lm, cm²¹): 2950s, 1771s, 1710s, 1366m,

1165s; MS (EI) m/z (relative intensity) 206 (M¹, 40), 189

(11), 178 (12), 163 (30), 145 (25), 135 (80), 121 (100), 105

(70), 93 (80), 77 (55), 69 (55), 57 (60); HRMS (EI) calcd for

C₁₃H₁₈O₂m/z 206.1307, found 206.1310.

11. For reviews on the chemistry of Fischer carbene complexes,

È

see: (a) Dotz, K. H. In Organometallics in Organic Synthesis:

Acknowledgements

Aspects of a Modern Interdisciplinary Field; tom Dieck, H., de

Meijere, A., Eds.; 1988. (b) Wulff, W. D. In Comprehensive

Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon

Press: New York, 1991; Vol. 5, pp 1065±1113.

This work was supported by a grant from the National

Institutes of Health (PHS-GM 33589).

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Article Doi

Electronic tuning of Fischer carbene complexes in the preparation of bicyclo[3.1.1]heptanones as taxane A-ring synthons

DOI: 10.1016/S0040-4020(99)01101-1

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