Studies directed toward the total synthesis of tetronolide 1. An enantioselective synthesis of the octahydronaphthalene unit

Studies directed toward the total synthesis of tetronolide 1. An enantioselective synthesis of the octahydronaphthalene unit

Tchahcdron Pr1nkd Lcrrcrs, Vol32. No 33, pp 40914091. 1991 w40-4039/91 Pcrgamon ,I! Great Hrllaln STUDIES DIRECTED TOWARD THE TOTAL SYNTHESIS...

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Tchahcdron Pr1nkd

Lcrrcrs,

Vol32.

No 33, pp 40914091.

1991

w40-4039/91 Pcrgamon

,I! Great Hrllaln

STUDIES

DIRECTED

TOWARD THE TOTAL SYNTHESIS

AN ENANTIOSELECTIVE

SYNTHESIS

Robert K Boeckman Jr ,+ Thomas

E Barta.

Department

of Chemistry

Unlverslty

of Rochester

Rochester, New York

Summary

An efficfent enanboseieciwe route to the actahydronaphlhabne

couptmg of the two key fragments land The tetrocarcms reLtea‘t0

kljanoiia8

comprise

complex

ofa naturaily-OCCurrIng

of the intramolecular

Diels-Alder

G Nelson

14627

The sequence employs the mtramolecular D/e/s-Aider reaction to

on the trans decalm rmg system, and tncorporates a masked acyfahng agent which should permit 3 as demonstrated by react/on of pentaene

ofantitumor antIbiotIc

ana’ctilbrotlincolia’e,

family 2,3 These structurally SyntheSlS

a group

Scott

UNIT

uaf preseni II) tetronollde (I), the stereochem~calty complex aglycone

common to the telrocarcms, a novel group of anlilumor substances, IS described control the relatrve stereochem/strypresent

and

(

1.

OF TETRONOLIDE

OF THE OCTAHYDRONAPHTHALENE

%3.00+ Press plc

the aglpcone aglycones

member ofthls cycloaddlbon,

4

wth methanol and a mode/ a-hydroxy ester

agents which share a comm0n

umfs of Illanomycin

and’chlbrothncm,

have been the sublect of conslderable Ciass has yet been completed

we chose tetronollde

aglycone,

tetronolide

1 .i

Structurally,

the onl) other known members effort dlrected

toward their preparation,

4 In accord with our Interest In developing

to test the scope of this methodology

ofthrs

We conceived

tetronoltde

IS

natural product although

stereoselective a convergent

no total variants

synthetic

OTBS

OK,



TBOPSO

+

“OMOM P(OlWzHdz

6

7

5

4

strategy (Scheme

I), whose Impl’ementatlon

octahydronapthalene

2 and cyclohexene

4, an enantlomencally

pure precursor

The advantages of 2 was recognzed

required’the

3 subunits of

preparation,

1or

precursors

in enantiomerMy thereof

pure ion,

ano’unlon

oftwo key syntnons comprlsmg

Herein, we descnbe the development

the

of a sultable route to pentaene

of X5x6

of employing

a [4+2] cycloaddltlon

to control the relative

early on, and this strategy has been employed

stereochemistry

by several groups 738 However,

4091

of centers our approach

present

on the decaltn framework

differs slgnlficantly

rn the manner

4092

by which the major fragments will be joined, since in all other studies to dale the major subunits are to be joined in a separate step, whereas we envisioned the coupling process in tandem with the intramolecular [412] cycloaddition.

Thus, the required substrate for construction of 2 becomes

pentaene 4, whose synthesis is outlined below. The requisite pentaene 4 was expected to arise via the sequential corn bination of phosphine oxide 5 and dioxinone phosphonate 6 with an appropriate aldehyde derived from enantiomerically

HOJ.?+MHL MPMOwoH

pure, differentially protected trio1 7 (Scheme 1).

MPMO~,,

c,d

MPMOL

A

%eagentS:

a) NaH, @H3OPhGH$l,

THF, 25%.

NCSIDMS, CH$l2% O’C 0.5h; e) PhpPLi, THF, Preparation of 5 was accomplished

-78*C,

step (Eqn 1) from dioxinone 912

-78”-+

25’C,

lh; c) IAH,

THF, O’C, 5h; d)

lh then [email protected], O’C, 5 mm.

by conversion of E-2-methyl-2-pentene-4-yn-l-01

standard methodology (69% overall) as shown in Scheme 2. 9-l exposure of 8 to fithio diphenylphosphine

lomh then (CH20),,

12h; b) nBuLi. -7Q’C, THF.

P(O)Ph,

5

8

to E, E allylic chloride 8 in 4 steps employing

i Chloride 8 was then converted to the required phosphine oxide 5 in 50% yield by

and subsequent oxidation with H&

in CH2Cl2 at O’C. Dioxinone phosphonate 6 was obtained in a single

ua conversion to the lithium enolate with IDA and treatment with diethylchlorophosphite,

followed by oxidation in

situ (H202, CH2Cl2,O”C) to afford a 60% yield of phosphonate 6.13 l)LDA/THF/-76°C then CIP((X;,H,), o&

(1)

-78% + 25% W’W’%Hd,

2) H&‘CH,CI#C

Construction of the enantiomerically in 5 sleps using standard methods to aIdehyde diethylphosphonoacetate

pure trio1 7 was initiated from (R)-(-)-methyl

3.hydroxy-2-methylpropionate

which was converted

in 73% overall yield (Scheme 3). Condensation of aldehyde 10 with the sodium anion of ethyl

afforded the expected E unsaturated ester’11 (97%) which provided allylic alcohol 12 upon reduction with DIBAL-H

(95%). The two remaining stereogenic centers were installed via 3 step sequence involving catalytic asymmetric epoxidationl$ alcohol 13 (88%, 88% de), followed by benzylation,

and treatment of the protected epoxide with lithium dimethylcuprate

to afford epoxy

in Et20 at -45’C to

afford a mixture (7:1) of diastereomeric alcohols 14 and 15 (86% combined from 13). I5 Protection of the remaining alcohol as the methoxymethyl ether then furnished a readily separable mixture of the desired trio1 7 (86%) and its regioisomer 16 (12%).16 Assembly of pentaene 4 from the three major subunits 5-7 was also readily accomplished (Scheme 3). Sequential catalytic debenzylation of 7 (-loo%),

Swem oxidation (90%),t7 and condensation of the resulting aldehyde with the lithium anion derived from 5 at -78’C in THF with

added HMPA smoothly provided, as a single geometric isomer, the E,E,E triene 17 (86%). Repetition of the deprotection, oxidation, olefination sequence on 17 employing instead fluoride to cleave the silyl ether, and the lithium anion derived from 6 in THF with added HMPA delivered exclusively the required Z,E,E,E,E pentaene 4 (53% from 17).‘* With the key pentaene 4 in hand, we were in a position to test whether 4 fulfilled the crucial requirements couplinglcycloaddition

of the intended tandem

assembly of 2 and 3: 1) that the thermally generated acyl ketene undergo efficient intermolecular capture by a suitable 3’

alcohol (ultimately the required cyclohexene synthon 3), and ‘2) that the subsequent cycloaddition proceed with high stereoselectivity correct stereochemica

relationships about the octahydronapthalene

creating the

ring system.lg

To test the essential feasibility of the couplingicycloaddition,

we first examined thermolysis of 4 at

1 IO’?

in the presence of excess

methanol (-100 equiv), which afforded the desired decalin 18 in 54% yield along with 5% of uncharacterized diastereomeric cycloadduct(s)

4093

schwne3a

K&O*CHs abc_

TBDPSOJ__OTs -2% TeDPSOJ+CHO f_ TBDPSOJ/k+Z 10 gG

11 Z=C0,C2HS 12 Z= CH20H

c-p- ““-2.,,, :Bo:Ifl,,oR i lTzL MpMo~,,, HO

7

17

I

OR

15 R-H 16 F&MOM

13

CO&Ho

CH,W

20 aReagents

a)

TBDPSCI, lmldazole (2 equlv)

,25%,5h, b) DIBAL-H

(1 11, A, 10h. e) DIBAL-H, THF, -78’+ 78%

2h, h)[email protected])4

25’C,

(2 equlv), THF, -78’C, 2h.

lh. I) [email protected](O)(CC2H5)2,

(catalflic). (-)DET (catalflic), BuOH,

CH$l2,

-20%

C) TsCI,

DMAP, Py, CH$+,

25’C, 12h, d) KCN, E~oH-H~o

NaH. THF, -78’ + 25’C, lOh, g) DIBAL-H (2 equw), THF, 24h, i) NaH, PhCHpEr, THF, 25’C. 1 h, 1) (CH~)@LI

820, -45’C, 2h, k) CH3GCH2CL EtN(1Pri2, THF. 25’C, 12h, I) H2 (1 atm), PdlC, EtOH, 25’C, lOh, m) (0X1)2,

-

(10 eqw],

DMSO, Et3N, -78’C, lh, n) 5,

~BuLI, THF-HMPA (2 l), -78’C, lh. a) TBAF, THF, 25’lC, 5h, p) 6, n3uL1, THF-HMPA (2 I), -7E°C, 2h, q) A (toluene

110 ‘C (sealed tube), or

xylenes, i30°C (sealed tube)) (Scheme 3) The stereochemrstry of 18 was confirmed wa 300 and 500 MHz NMR spectroscopy with appropnate decoupling 2o This result IS COnSSfenfwith the expectatmn that fhe cyclizatlon

woul’doccur

wourd be Imparted by the C-3 subsntuent wnrcii preferentially bonded InteractIon with the C-8 proton 466~1

nearly excl’uslvel) through an end&chair transttlon state in which the taclal 1318s occupies an equatorral orlenratlon rn the transltion state so as to alleviate a non-

We have also demonstrated the capture of a model 3’ nucleophile in the form of hydroxy ester 19,

which afforded the related decalin 20 (-50%, unoptlmlzed, SO

1 stereoselectivrty) upon thermolysrs of 4 at 13O’C In xylenes m the presence of 1

equlv of 19

t2)

CH,

4094

Our studies have resulted in the development of an enantioselective feasrbility of a tandem couplinglcycloaddition

route to key pentaene synthon 4 and the demonstration

methodolgy for the stereoselective

preparation

following communication details our approach to cyclohexene 3. Application of this methodology

of octahydronaphthalene

subunits for

of the

1. The

to the total synthesis of tetronolide 1 is currently

under investigation.

B.

We are grateful to the National Cancer Institute of the National Institutes of Health for the award of a research grant (CA-

29108) in support of these studies. We thank the Merck Co. for fellowship support awarded to SGN.

References and Notes:

(1) Tamioki, T.; Kasai, M.; Shirahata, K.; Tomita, F. J. Antibiotics. 1982, 35,979. (2) Waitz, J. A.: Horan. A. C.; Kalyanpur, M.; Lee, 8. K.; Loebenberg, D.; Marquer. J. A.; Miller, G.: Patel, M, G. j. Anlibiotics1981.34,

1101.

(3) Keller-Schierlein, W.; Muntwyler, R.; Pache, W.; Zahnet, H. He/v. Ctim. Acfa. 1969, 52, 127. (4) For leading references to prior workon chlorothrlcolide and kljanolide see: (a) Marshall, J. A.; Salovich, J. M.; Shearer, B. G. J. Org. Cbem. 1990,55,2398.

(b)Takeda, K.; Igharashl, Y.; Okazaki, K.; ‘foshii, E.; Yamaguchi, K. J’. Org. Chem. 1990,55,3431.

(c) Roush. W. R.: Kageyama,

M.; Riva, R.: Brown, B. B.; Warmus, J. S.; Moriarity, K. J. d Org. Cbem. 1991, 56, 1192. (5) Taken in part from the Ph. D. dissertation of Thomas E. Barta, University of Rochester, 1987. (6) Boeckman, Jr., R. K.; Bana, T. E. J. Org. Chem. 1985,50,3421. (7) Okumura. K.; Okazaki, K.; Takeda, K.; Yoshii, E. Tefrahedron Leff. 1989,30, 2233. (8) Ireiand, R. t.; Vamey, M. D. J. 0~. Chem 1986, 57,635. (9) Corey, E. J.; Katzenellenbogen, N.; Gilman, N. W.; Roman, A.; Erickson, 8. W. J. Am. Chem. Sot. 1968, 9Q,5618. (10) Corey, E. J.; Kim, C. U.; Takeda, M. Tetrahedron iefl. 1972, 4339. (11) All new substances exhibited satisfactory spectral (NMR, IR, MS) data and microanalytical or high resolution MS data. (12) Sato, M.; Ogasawara, H.:Oi, K.; Kato, T. &em. Pbarm. &ii.

1983, 31, 1896.

(13) Boeckman, Jr., R. K.; Kamenecka, T. M.: Nelson, S. G ; Pruift, J. P.; Baffa, T. E. TeBahedron Left, 1991,32, 0000. (14) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922. (15) Johnson, M. R.; Kishi, Y. Tetrahedron Lett. 1979, 4347. (16) The minor isomers incurred in the asymmetric epoxidation and the subsequent epoxide opening were removed at the protected trio1 stage by chromatography(flash

or prep HPLC] to give 7 as a homogeneous substance.

(17) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978,43, 2480. (18) The dioxinone phosphonate Olefination proceeded in unsatisfactory yields in the absence of HMPA. Yields improved dramatically when a solution of the aldehyde in THF:HMPA(l :l, 1 M overall) was added to the lithiated phosphonate. (t9) Boeckman, Jr., R. K.;Pruitl,J. Ft. J. Am. Chem. Sot. 1989, 117,8286. (20)

DeCOUpling

experiments verified that the C2-C7 coupling constant for the ring junction protons, and the C&7

coupling constant for the CI-

OMOM and adjacent ring junction protons were J=fO.3 Hz and J=8.1 Hz respectively, consistent with frans-diaxial relationships between these protons and thus with ffans- fused decalin 18 (Eqn 2). (21) Marshall, J. A.; Grote, J.; Audia, J. E. J. Am, Chem. Sot.. 1987, 109, 1186.

(Received in USA 26 April 1991)