Regioselective synthesis of acyclic cis-enediynes via an acid-catalyzed rearrangement of 1,2-dialkynylallyl alcohols. Syntheses, computational calculations, and mechanism

5062

J . Org. Chem. 1999, 64, 5062-5082

Regioselective Syn th esis of Acyclic cis-En ed iyn es via a n

Acid -Ca ta lyzed Rea r r a n gem en t of 1,2-Dia lk yn yla llyl Alcoh ols.

Syn th eses, Com p u ta tion a l Ca lcu la tion s, a n d Mech a n ism ^†

Wei-Min Dai,* J inlong Wu, Kin Chiu Fong, Mavis Yuk Ha Lee, and Chi Wai Lau

Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay,

Kowloon, Hong Kong, China

Received December 21, 1998

A novel synthesis of acyclic cis-enediynes 2 has been established by an acid-catalyzed rearrangement

of 1,2-diyn-2-propen-1-ols 1 possessing a C₃-aryl group in the presence of water, alcohols, or thiols.

Reactivity of allyl alcohols and regio- and cis/trans diastereoselectivity of the allylic migration were

examined. In the presence of (()-10-camphorsulfonic acid (CSA), the parent allyl alcohol 5 and the

C₃-methyl-substituted 9 failed to give enediynes, whereas the C₃-aryl-substituted 12 and 29

underwent the allylic rearrangement to provide predominantly cis-enediynes 16 and 31 at room

temperature or below. Under similar acidic conditions, enediyne alcohol 13 produced 16b and 16d

with the same regio- and cis/trans diastereoselectivity observed for 12. Allyl alcohol 30, an isomer

of 29, also provided enediynes 31c and 32c after a prolonged reaction (90 h) at room temperature

in the presence of CSA and EtOH. These results suggested that the same allylic cations were

obtained from allyl alcohols 12 and 13 or 29 and 30 even though the ease of ionization differed for

each substrate. Involvement of allylic cations in the product-forming step was confirmed by the

finding that chiral allyl alcohols (-)-12 and (-)-18c furnished racemic products. In general, the

p-MeOPh-substituted allyl alcohol 29 gave a better regioselectivity than the Ph-substituted 12. In

the reactions with alcohols, the regioisomeric ratios were 100:0 (31:33) for 29 and ca. 96:4 (16:17)

for 12; the ratios decreased to ca. 90:10 (31:33) for 29 and ca. 70:30 (16:17) for 12 when thiols were

used. The cis/trans diastereoselectivity is higher for allyl alcohol 12 (100% for 16 at 20 °C) compared

to that for 29 (31:32 ) 80:20-94:6 at 0 °C). Computational calculations at the RHF/3-21G level,

carried out on the model compounds and allylic cations, indicated that nucleophilic trapping takes

place preferentially at the C₃carbon to form the thermodynamically much more stable enediynes.

Under the best reaction conditions (1 equiv of CSA and 2 equiv of EtOH in CH₂Cl₂, 20 °C), a number

of acyclic cis-enediynes can be synthesized in three steps from the commercially available

R-bromocinnamaldehyde (10).

In tr od u ction

esperamicin A₁,⁵namenamicin,⁶dynemicin A,⁷kedarcidin

chromophore,⁸C-1027 chromophore,⁹maduropeptin chro-

The naturally occurring enediynes^1,2are a novel class

of antitumor antibiotics that possess a 1,5-diyn-3-ene core

constrained in a 9- or 10-membered ring. At present, the

enediyne antibiotics include the representative structures

(3) Structure of neocarzinostatin chromophore, see: Edo, K.; Mi-

zuyaki, M.; Koide, Y.; Seto, H.; Furihata, K.; Otake, N.; Ishida, N.

Tetrahedron Lett. 1985, 26, 331.

I

of neocarzinostatin chromophore,³calicheamicin γ₁,

I 4

(4) Structure of calicheamicin γ₁, see: Lee, M. D.; Dunne, T. S.;

Siegel, M. M.; Chang, C. C.; Morton, G. O.; Borders, D. B. J . Am. Chem.

Soc. 1987, 109, 3464. Lee, M. D.; Dunne, T. S.; Chang, C. C.; Ellestad,

G. A.; Siegel, M. M.; Morton, G. O.; McGahren, W. J .; Borders, D. B.

J . Am. Chem. Soc. 1987, 109, 3466.

* To whom correspondence should be addressed. Phone: (852) 2358

7365. Fax: (852) 2358 1594. E-mail: chdai@ust.hk.

^†As a result of attachment of the oxygenated substituent (Y ) OH,

OR) at the allylic carbon of enediynes 2, the trisubstituted olefins

possess the E configuration. To be consistent with the nomenclature

of disubstituted enediynes, we use cis and trans designations in the

text. The cis-enediynes have the alkynyl groups on the same side of

the double bond.

(5) Structure of esperamicin A₁, see: Golik, J .; Clardy, J .; Dubay,

G.; Groenewold, G.; Kawaguchi, H.; Konishi, M.; Krishnan, B.; Oh-

kuma, H.; Saitoh, K.; Doyle, T. W. J . Am. Chem. Soc. 1987, 109, 3461.

Golik, J .; Dubay, G.; Groenewold, G.; Kawaguchi, H.; Konishi, M.;

Krishnan, B.; Ohkama, H.; Saitoh, K.; Doyle, T. W. J . Am. Chem. Soc.

1987, 109, 3462.

(1) Selected reviews on chemistry and biology of enediynes, see: (a)

Nicolaou, K. C.; Dai, W.-M. Angew. Chem., Int. Ed. Engl. 1991, 30,

1387. (b) Goldberg, I. H. Acc. Chem. Res. 1991, 24, 191. (c) Lee, M. D.;

Ellestad, G. A.; Borders, D. B. Acc. Chem. Res. 1991, 24, 235. (d)

Nicolaou, K. C.; Smith, A. L. Acc. Chem. Res. 1992, 25, 497. (e)

Nicolaou, K. C.; Smith, A. L.; Yue, E. W. Proc. Natl. Acad. Sci. U.S.A.

1993, 90, 5881. (f) Nicolaou, K. C.; Smith, A. L. In Modern Acetylene

Chemistry; Stang, P. J ., Diederich, F., Eds.; VCH: Weinheim, 1995;

pp 203-283. (g) Lhermitte, H.; Grierson, D. S. Comtemp. Org. Synth.

1996, 3, 41 and 93. (h) Grissom, J . W.; Gunawardena, G. U.; Klingberg,

D.; Huang, D. Tetrahedron 1996, 52, 6453.

(2) (a) Enediynes Antibiotics as Antitumor Agents; Doyle, T. W.,

Borders, D. B., Eds.; Marcel Dekker: New York, 1994. (b) DNA and

RNA Cleavers and Chemotherapy of Cancer and Viral Diseases;

Meunier, B., Ed.; Kluwer Academic Publishers: Dordrecht, 1996; pp

1-73.

(6) Structure of namenamicin, see: McDonald, L. A.; Capson, T. L.;

Krishnamurthy, G.; Ding, W.-D.; Ellestad, G. A.; Bernan, V. S.; Maiese,

W. M.; Lassota, P.; Discafani, C.; Kramer, R. A.; Ireland, C. M. J . Am.

Chem. Soc. 1996, 118, 10898.

(7) Structure of dynemicin A, see: Konishi, M.; Ohkuma, H.;

Matsumoto, K.; Tsuno, T.; Kamei, H.; Miyaki, T.; Oki, T.; Kawaguchi,

H.; VanDuyne, G. D.; Clardy, J . J . Antibiot. 1989, 42, 1449. Konishi,

M.; Ohkuma, H.; Tsuno, T.; Oki, T.; VanDuyne, G. D.; Clardy, J . J .

Am. Chem. Soc. 1990, 112, 3715.

(8) Structure of kedarcidin chromophore, see: Leet, J . E.; Schroeder,

D. R.; Hofstead, S. J .; Golik, J .; Colson, K. L.; Huang, S.; Klohr, S. E.;

Doyle, T. W.; Matson, J . A. J . Am. Chem. Soc. 1992, 114, 7946. Leet,

J . E.; Schroeder, D. R.; Langley, D. R.; Colson, K. L.; Huang, S.; Klohr,

S. E.; Lee, M. S.; Golik, J .; Hofstead, S. J .; Doyle, T. W.; Matson, J . A.

J . Am. Chem. Soc. 1993, 115, 8432. Revised structure, see: Kawata,

S.; Ashizawa, S.; Hirama, M. J . Am. Chem. Soc. 1997, 119, 12012.

Published on Web 06/15/1999

Regioselective Synthesis of Acyclic cis-Enediynes

J . Org. Chem., Vol. 64, No. 14, 1999 5063

mophore,¹⁰and N1999A2.¹¹Since the pioneer contribu-

tions by Bergman,^12a-dMasamune,^12eand Wong,^12fit has

been known that the naturally occurring and synthetic

enediynes can undergo a thermal cycloaromatization to

form 1,4-benzenoid diradical species. The latter causes

DNA strand cleavage through abstraction of hydrogen

atoms from the sugar-phosphate backbone.^1,2,13Synthe-

ses of naturally occurring enediynes and analogues have

been the focus of many research efforts in recent

years.^1a,g,h,14In general, enediynes are prepared by a Pd-

(0)-Cu(I)-mediated cross-coupling reaction of vinyl di-

halides or analogues with terminal acetylenes under the

Sonogashira conditions¹⁵in good to excellent chemical

yields. The geometry of enediynes so prepared is deter-

mined and predictable by that of the vinyl dihalides or

analogues. The most important variation to the Sono-

gashira procedure is the Stille cross-coupling¹⁶of (Z)-1,2-

bis(trimethylstannyl)ethene with iodoalkynes catalyzed

by Pd(0). The latter method is particularly efficient for

construction of cyclic enediynes.¹⁷Alternatively, a num-

ber of methods have been developed to synthesize cis-

enediynes by introducing the double bond into 1,5-diyne

derivatives. These methods include the reductive elimi-

nation,¹⁸the acid-¹⁹or base-induced²⁰elimination of

alcohols, the elimination of diol using the Corey-Winter

reagent,²¹the benzylic oxidation,²²the Norrish Type II

reaction,²³the rearrangement of allyl alcohols,²⁴and the

Diels-Alder and retro-Diels-Alder reactions.²⁵In some

Sch em e 1

of the above-mentioned preparations, control of the cis/

trans diastereoselectivity in the formation of acyclic

enediynes needs further improvement.²³Nevertheless,

these methods provide the chemical basis for enediyne

prodrug²⁶design and synthesis. During our studies on

the formation of enediynes via an allylic rearrangement

conceptually related to the mechanism of action of

maduropeptin chromophore-derived artifacts,¹⁰we have

been successful in conversion of 1,5-diyne derivatives 1

into cis-enediynes

2 via the corresponding allylic

mesylate^24aor the allylic cation intermediate under acidic

conditions.^24b,cIn this article, we disclose a full account

of the acid-catalyzed transformation of 1 into 2 (Scheme

1) with emphases on the substrate structural require-

ment and control of the regio- and cis/trans diastereose-

lectivity.

Resu lts a n d Discu ssion

Syn th esis of En ed iyn es. The parent allyl alcohol 5

was prepared from R-bromoacrolein (3)²⁷as illustrated

in Scheme 2. Addition of the lithium salt of phenyl

propargyl sulfide²⁸(LiCtCCH₂SPh) to 3 gave 2-bromoal-

lyl alcohol 4 in 51% yield. Cross-coupling of 4 with

6-methoxy-1-hexyne in the presence of 5 mol % of Pd-

(PPh₃)₄, 20 mol % of CuI, and 2 equiv of Et₃N in THF

(20 °C, 4 h) afforded 1,2-dialkynylallyl alcohol 5 in 95%

yield. Treatment of 5 with 1 equiv of (()-10-camphor-

sulfonic acid (CSA) and 2 equiv of EtOH in dry CH₂Cl₂

(20 °C, 24 h) did not provide the expected product 6a or

6b. The starting material was recovered (80%). Com-

pound 5 remained unchanged even in the presence of

(9) Structure of C-1027 chromophore, see: Yoshida, K.; Minami, Y.;

Azuma, R.; Sakei, M.; Otani, T. Tetrahedron Lett. 1993, 34, 2637. Iida,

K.; Ishii, T.; Hirama, M.; Otani, T.; Minami, Y.; Yoshida, K. Tetrahe-

dron Lett. 1993, 34, 4079. Iida, K.; Fukuda, S.; Tanaka, T.; Hirama,

M.; Imajo, S.; Ishiguro, M.; Yoshida, K.; Otani, T. Tetrahedron Lett.

1996, 37, 4997.

(10) Structure of maduropeptin chromophore, see: Schroeder, D. R.;

Colson, K. L.; Klohr, S. E.; Zein, N.; Langley, D. R.; Lee, M. S.; Matson,

J . A.; Doyle, T. W. J . Am. Chem. Soc. 1994, 116, 9351.

(11) Structure of N1999A2, see: Ando, T.; Ishii, M.; Kajiura, T.;

Kameyama, T.; Miwa, K.; Sugiura, Y. Tetrahedron Lett. 1998, 39, 6495.

(12) (a) J ones, R. R.; Bergman, R. G. J . Am. Chem. Soc. 1972, 94,

660. (b) Bergman, R. G. Acc. Chem. Res. 1973, 6, 25. (c) Lockhart, T.

P.; Commita, P. B.; Bergman, R. G. J . Am. Chem. Soc. 1981, 103, 4082.

(d) Lockhart, T. P.; Commita, P. B.; Bergman, R. G. J . Am. Chem. Soc.

1981, 103, 4091. (e) Darby, N.; Kim, C. V.; Salaun, J . A.; Shelton, K.

W.; Takada, S.; Masamune, S. J . Chem. Soc., Chem. Commun. 1971,

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217.

(13) (a) Murphy, J . A.; Griffiths, J . Nat. Prod. Rep. 1993, 551. (b)

Pratviel, G. P.; Bernadou, J .; Meunier, B. Angew. Chem., Int. Ed. Engl.

1995, 34, 746. (c) Pogozelski, W. K.; Tullius, T. D. Chem. Rev. 1998,

98, 1089.

(14) Recent Progress in the Chemistry of Enediyne Antibiotics;

Tetrahedron Symposia-in-print No. 53; Doyle, T. W., Kadow, J . F., Eds.;

Tetrahedron 1994, 50, No. 5.

(15) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.

1975, 4467. (b) Sonogashira, K. In Comprehensive Organic Synthesis;

Trost, B. M., Fleming, I., Eds., Pergamon Press: New York, 1991; Vol.

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(16) (a) Stille, J . K. Pure Appl. Chem. 1985, 57, 1771. (b) Stille, J .

K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (c) Mitchell, T. N.

Synthesis 1992, 803.

(20) (a) Audrain, H.; Skrydstrup, T.; Ulibarri, G.; Grierson, D. S.

Synlett 1993, 20. (b) Audrain, H.; Skrydstrup, T.; Ulibarri, G.; Riche,

C.; Chiaroni, A.; Grierson, D. S. Tetrahedron 1994, 50, 1469. (c)

Shibuya, M.; Sakai, Y.; Naoe, Y. Tetrahedron Lett. 1995, 36, 897. (d)

Iida, K.; Hirama, M. J . Am. Chem. Soc. 1995, 117, 8875. (e) Kawata,

S.; Yoshimura, F.; Irie, J .; Ehara, H.; Hirama, M. Synlett 1997, 250.

(f) Wang, J .; De Clercq, P. J . Angew. Chem., Int. Ed. Engl. 1995, 34,

1749. (g) Takahashi, T.; Tanaka, H.; Matsuda, A.; Yamada, H.;

Matsumoto, T.; Sugiura, Y. Tetrahedron Lett. 1996, 37, 2433. (h)

Takahashi, T.; Tanaka, H.; Yamada, H.; Matsumoto, T.; Sugiura, Y.

Angew. Chem., Int. Ed. Engl. 1996, 35, 1835. (i) Takahashi, T.; Tanaka,

H.; Yamada, H.; Matsumoto, T.; Sugiura, Y. Angew. Chem., Int. Ed.

Engl. 1997, 36, 1524.

(21) (a) Semmelhack, M. F.; Gallagher, J . Tetrahedron Lett. 1993,

34, 4121. (b) Semmelhack, M. F.; Gallagher, J . J .; Ding, W.-D.;

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3679. (b) Maier, M. E.; Greiner, B. Liebigs Ann. Chem. 1992, 855.

(23) Nuss, J . M.; Murphy, M. M. Tetrahedron Lett. 1994, 35, 37.

(24) (a) Dai, W.-M.; Fong, K. C.; Danjo, H.; Nishimoto, S. Angew.

Chem., Int. Ed. Engl. 1996, 35, 779. (b) Dai, W.-M.; Fong, K. C.

Tetrahedron Lett. 1996, 37, 8413. (c) Dai, W.-M.; Lee, M. Y. H.

Tetrahedron Lett. 1998, 39, 8149.

(17) (a) Shair, M. D.; Yoon, T.; Danishefsky, S. J . J . Org. Chem.

1994, 59, 3755. (b) Shair, M. D.; Yoon, T.; Chou, T.-C.; Danishefsky,

S. J . Angew. Chem., Int. Ed. Engl. 1994, 33, 2477. (c) Shair, M. D.;

Yoon, T.; Danishefsky, S. J . Angew. Chem., Int. Ed. Engl. 1995, 34,

1721. (d) Shair, M. D.; Yoon, T. Y.; Mosny, K. K.; Chou, T. C.;

Danishefsky, S. J . J . Am. Chem. Soc. 1996, 118, 9509. (e) Takahashi,

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5064 J . Org. Chem., Vol. 64, No. 14, 1999

Dai et al.

Sch em e 2

temperature in the expectation that the phenyl ring could

facilitate ionization of the allyl alcohol. We prepared 1,2-

dialkynylallyl alcohol 12 from the commercially available

R-bromocinnamaldehyde (10)³⁰in two steps as shown in

Scheme 4. The Pd(0)-Cu(I)-catalyzed cross-coupling of

10 with 6-methoxy-1-hexyne under the standard condi-

tions [5 mol % of Pd(PPh₃)₄, 20 mol % of CuI, 2 equiv of

Et₃N, THF, 20 °C, 1 h] furnished eneyne aldehyde 11 in

90% yield. Addition of LiCtCCH₂SPh to 11 (THF, -78

°C, 0.5 h) gave 12 in 79% yield. It was very encouraging

to find that treatment of 12 with 1 equiv of CSA in dry

CH₂Cl₂(20 °C, 16 h) produced the desired cis-enediyne

13 (56%) together with a 34:66 mixture of two isomeric

allyl alcohols 14 and 15 (26% combined yield). We

monitored the conversion of 12 (1 equiv of CSA, CD₂Cl₂,

1

20 °C) by H NMR spectroscopic analysis. The composi-

tions of the reaction mixture against time are plotted in

Figure 1, featuring a gradual decrease of 12 and increases

of the three products 13-15 over the first 3 h. Because

of overlap of the signals of 14 and 15 with others in the

¹H NMR spectra of the reaction mixtures, their ratios

could not be determined separately by the integrations.

After 3 h reaction, an equilibrium mixture of 12:13:

(14+15) in the ratio of 6.5:58.5:35.0 was obtained. These

results indicate that our desired cis-enediyne 13 is

thermodynamically much more stable than 12 and is

formed preferentially during the rearrangement. This is

further supported by the significant difference in the

reaction time of 12 and 13 for acid-catalyzed ionization

to form the same allylic cation in the presence of

nucleophiles (vide infra).

Sch em e 3

The structures of allyl alcohols 12-15 were assigned

according to the chemical shifts of the vinyl and methine

protons and the NOE data as depicted in Figure 2.

Positions of the double bonds in 12-15 are determined

by the absence or presence of a NOE between the vinyl

and ortho benzene protons. For compounds 12 and 15,

NOEs of 14.5% and 4.0% were observed among the vinyl

and ortho benzene protons, respectively, upon irradiation

at the vinyl proton; a NOE was not detected between the

methine and ortho benzene protons when the methine

proton was irradiated. The small NOE value of 4.0%

between the vinyl and ortho benzene protons in 15 (only

one enantiomer shown) indicates that the benzene ring

is not coplanar with the double bond. This also explains

the NOE (5.8%) between the methine proton and the

other ortho benzene proton in 15. For compounds 13 and

14, NOE values between the vinyl and ortho benzene

protons were not recorded. Instead, NOEs between the

methine and ortho benzene protons were noted (7.2% and

10.9%, respectively) upon irradiation at the methine

proton. These data revealed that the double bond in 13

and 14 is not conjugated with the benzene ring. The cis

relationship of the two alkynyl groups in 13 was un-

equivocally confirmed by a well-established chemical

transformation.^24a

trifluoromethanesulfonic acid [TfOH (1 equiv), EtOH, 20

°C, 24 h]. These results indicate that ionization of 5

cannot take place under the acidic conditions.

The methyl analogue 9 was synthesized from R-bromo-

crotonaldehyde (7)²⁹as shown in Scheme 3. A sequence

different from Scheme 2 was used to introduce the two

alkynyl units into 7. In contrast to 4, a similar cross-

coupling of 3-methyl-2-bromoallyl alcohol, formed from

7 and LiCtCCH₂SPh, failed to provide the desired

product. Therefore, bromination of (E)-crotonaldehyde

(Br₂, CH₂Cl₂, 0 °C) followed by treatment with Et₃N (20

°C, 1 h) afforded R-bromocrotonaldehyde (7) in 72%

overall yield. Cross-coupling of 7 with 6-methoxy-1-

hexyne [5 mol % of Pd(PPh₃)₄, 20 mol % of CuI, 2 equiv

of Et₃N, THF, 20 °C, 5 h] gave eneyne aldehyde 8 in only

10% yield. We attempted to improve efficiency of the

reaction but failed. Addition of LiCtCCH₂SPh to 8 in

THF (-78 °C, 1 h) afforded 1,2-dialkynylallyl alcohol 9

in 62% yield. Unfortunately, treatment of 9 with CSA or

TfOH (1 equiv) in the presence of EtOH (2 equiv) in dry

CH₂Cl₂(20 °C, 24 h) failed to form any product; the

starting allyl alcohol 9 was recovered. At this point, we

realized that a better stabilizing group for the allylic

cation intermediate is required to facilitate the ionization

of 1,2-dialkynylallyl alcohols.

We investigated the acid-catalyzed transformation of

12 and 13 in the presence of nucleophiles such as alcohols

and thiols. Scheme 5 and Table 1 show the results of the

reactions of allyl alcohols 12 and 13 with a number of

alcohols and thiols catalyzed by CSA. It is interesting to

realize that only two regioisomers, 16 and 17, were

formed in these reactions. The major products were

We considered the phenyl analogue 12 as a suitable

substrate for the acid-catalyzed rearrangement at room

(29) Lu¨tjens, H.; Nowotny, S.; Knochel, P. Tetrahedron: Asymmetry

1995, 6, 2675.

(30) Kowalski, C. J .; Weber, A. E.; Fields, K. W. J . Org. Chem. 1982,

47, 5088.

Regioselective Synthesis of Acyclic cis-Enediynes

J . Org. Chem., Vol. 64, No. 14, 1999 5065

Sch em e 4

determined as cis-enediynes 16; trans-enediynes were not

detected in any reaction. The following aspects can be

summarized from Table 1: (a) reactions in alcoholic

solvents are much slower than in CH₂Cl₂(entries 1 and

2 versus entry 3) perhaps as a result of the competition

of solvent molecules for protonation, (b) the regioselec-

tivity of 16:17 is higher for reactions of alcohols (ca. 96:

4) compared with those of thiols (ca. 70:30) regardless of

the bulkiness of the nucleophiles, and (c) enediyne alcohol

13 gave the same products as 12 under the same acidic

conditions (entries 8 and 9 versus entries 3 and 5) after

a prolonged reaction. This last observation suggests that

allyl alcohols 12 and 13 share the same reactive inter-

mediate in the reactions. Moreover, enediyne alcohol 13

is confirmed to be thermodynamically much more stable

than 1,5-diyne alcohol 12.

p-MeOP h -Su bstitu ted Allyl Alcoh ols. The success-

ful transformation of 12 into cis-enediynes 16 prompted

us to synthesize the p-MeOPh-substituted substrate 29

to examine the possibility of effecting the allylic rear-

rangement under milder acidic conditions. 1,2-Dialky-

nylally alcohols 29 and 30 were synthesized from p-anis-

aldehyde (21) according to Scheme 6. The Horner-

Wadsworth-Emmons reaction of trimethyl phosphono-

acetate with 21 (n-BuLi, THF, -78 °C, then 20 °C, 5 h)

afforded R,â-unsaturated ester 22 in quantitative yield.

Addition of Br₂to 22 followed by Et₃N-mediated elimina-

tion of HBr (20 °C, 16 h) produced an inseparable mixture

of R-bromo-R,â-unsaturated esters 23 and 24 in the ratio

We examined the effect of the alkynyl groups in the

allyl alcohols 18a -c^24aon the regioselectivity of the allylic

rearrangement (Table 2). Exposure of 18a -c to CSA and

EtOH in dry CH₂Cl₂at 20 °C gave cis-enediynes 19a -c

in good to excellent yield. The phenylacetylenic group at

C₁of the allyl alcohols enhanced the reactivity and

reduced the reaction time from 93 h for 18a to 45 h for

18b and from 3 h for 12 (Table 1, entry 3) to 2 h for 18c.

Regioselectivity of the allylic rearrangement was also

improved for 18b,c (single isomer formed) versus 94:6

for 18a and 96:4 for 12 (Table 1, entry 3), respectively.

F igu r e 2. NOE experiments for compounds 12-15 measured

on a 400 MHz instrument in CDCl₃at room temperature: (a)

irradiated at the vinyl proton at 6.75 ppm; (b) irradiated at

the methine proton at 4.90 ppm; (c) irradiated at the vinyl

proton at 5.95 ppm; (d) irradiated at the methine proton at

5.17 ppm; (e) irradiated at the vinyl proton at 6.06 ppm; (f)

irradiated at the methine proton at 4.80 ppm for both 14 and

15; (g) irradiated at the vinyl proton at 6.00 ppm; (h) assign-

ment of 5.8% and 10.9% NOE to 14 and 15 is tentative.

F igu r e 1. Conversion of 12 in the presence of 1.0 equiv of

CSA in CD₂Cl₂at 20 °C as monitored by ¹H NMR on a 400

MHz instrument. The relative ratios of 12-15 were obtained

by integrations of the vinyl and methine protons, respectively.

5066 J . Org. Chem., Vol. 64, No. 14, 1999

Dai et al.

Sch em e 5

sequence. It is critical to use THF as the solvent for the

PDC oxidation to obtain the minor aldehyde 28, which

could not be isolated from the same oxidation in CH₂Cl₂.

Fortunately, the isomeric aldehydes 27 and 28 can be

separated by repeated flash column chromatography over

silica gel; however, we used the mixture for the following

reaction. Addition of LiCtCCH₂SPh to 27 and 28 (THF,

-78 °C, 1 h) furnished the allyl alcohols 29 and 30 in

71% and 7% isolated yield, respectively. Compounds 29

and 30 were separated by flash column chromatography

over silica gel, but some mass of the minor isomer 30

was lost during the repeated separation process. NOE

experiments were carried out for compounds 29 and 30

(Figure 3). Irradiation at the vinyl proton (6.73 ppm) of

29 gave 16.5% and 17.2% enhancement of the signals of

the methine proton and the ortho proton of the para-

methoxyphenyl group, respectively. Irradiation at the

methine proton (4.92 ppm) of 29 resulted in 13.3% NOE

for the vinyl proton only. Similar NOE effects between

the methine/vinyl protons and the aryl/vinyl protons were

also observed for compound 30 even though the NOE

effects are stronger than those of compound 15 (Figure

2).

With compounds 29 and 30 in hand, we examined the

allylic rearrangement under different acidic conditions

(Scheme 7 and Table 2). Treatment of 29 with 1 equiv of

CSA in the presence of 2 equiv of EtOH at 20 °C for only

15 min afforded a mixture of 31c and 32c (77:23) in 78%

yield (entry 1). The enhanced reactivity of 29 toward

ionization was further demonstrated in entries 2 and 3.

A weaker acid, CF₃CO₂H, promoted the allylic migration

of 29 to form 31c and 32c (82:18, 68%) after 48 h at 20

°C (entry 2), or a catalytic amount of CSA (0.2 equiv)

completed the same transformation of 29 in 2 h at 20 °C

(entry 3). In the latter reaction, the rearranged cis-

enediyne alcohol 31a (Nu ) OH) was isolated in 15%

yield; this product could be suppressed by using 4 equiv

of EtOH (entry 5). The allylic migration of 29 took place

sluggishly in refluxing formic acid (6 equiv) in the

presence of EtOH (2 equiv), and after 66 h, the formic

acid adducts were isolated in 20% yield (data not listed

in Table 2). Selectivity for the formation of enediynes 31c

and 32c was affected by the acid, the amount of acid,

and the reaction temperature (entries 1-4). To balance

the reaction time and the selectivity, a set of reaction

conditions (0.5 equiv of CSA, 4 equiv of EtOH, 0 °C) was

developed as illustrated in entry 5. From 1,2-dialkynyl-

allyl alcohol 29, cis-enediyne 31c could be isolated in 94:6

ratio and in excellent yield.

Ta ble 1. Syn th esis of En ed iyn es 16^a

entry substrate NuH, t (h)

products (%)

ratio (16:17)

1^b

2^b

3

4

5

6

7

8

9

12

13

MeOH, 48 16a (73); 17a (2)

EtOH, 120 16b (70); 17b (3)

97:3

96:4

67:33

73:27

69:31

EtOH, 3

16b (71); 17b (3)

16c (65); 17c (3)

16d + 17d (79)

16e + 17e (61)

i-PrOH, 4

EtSH, 2.5

t-BuSH, 2

PhSH, 2.5 16f + 17f (54)

EtOH, 48

EtSH, 48

16b (55); 17b^c

16d + 17d (61)

68:32

a

Reactions were performed in CH₂Cl₂in the presence of 1 mole

equiv of CSA (0.16 M) and 2 mole equiv of nucleophile at 20 °C.

The nucleophile was used as solvent. ^cNot isolated.

b

Ta ble 2. Syn th esis of En ed iyn es 19^a

entry

substrate, t (h)

products (%)

ratio (19:20)

1

2

3

18a , 93

18b, 45

18c, 2^b

19a + 20a (70)

19b (82); 20b (0)

19c (65); 20c (0)

94:6

100:0

Reactions of different alcohols (4 equiv) with 29

catalyzed by 0.5 equiv of CSA at 0 °C were compared

(Table 3, entries 5-8). With increasing bulkiness of the

alcohols in the order of MeOH, EtOH, i-PrOH, and

t-BuOH, the reaction time increased accordingly from 3.5

to 7, 9, and 23 h, and the combined yield of enediynes 31

and 32 decreased from 90% to 89%, 77%, and 20%. The

diminished reactivity of t-BuOH due to steric hindrance

resulted in the formation of the dimeric ethers 35 (78%)

as the major products, arising from the addition of the

rearranged allyl alcohol 31a or 32a to the reactive

intermediates. The isolated 35 was a very complex and

inseparable mixture of at least three components that

a

Reactions were performed in the presence of 0.5 mole equiv

b

of CSA (0.043-0.048 M) and 4 mole equiv of EtOH. One mole

equivalent of CSA (0.062 M) and 2 mole equiv of EtOH were used.

of 77:23 (80% combined yield).³¹The mixture of 23 and

24 was used in the cross-coupling reaction with 6-meth-

oxy-1-hexyne [5 mol % of Pd(PPh₃)₄, 20 mol % of CuI, 2

equiv of Et₃N, THF, 20 °C, 22 h] to give eneyne esters

25 and 26 in 86% yield with a similar isomeric ratio of

76:24. Conversion of the ester group in 25 and 26 into

the corresponding formyl group was achieved by the

reduction (DIBAL-H, PhMe, -78 °C, 2 h, 87%) and

oxidation (PDC, 4 Å MS, THF, 20 °C, 4.5 h, 81%)

1

were confirmed by H NMR and MS data. The dimeric

ether 35 was also obtained from the reaction of i-PrOH

(11%, entry 7). Diastereoselectivity among cis- and trans-

enediynes 31b-e and 32b-e varied from 94:6 to 82:18.

(31) (Z)- and (E)-3-(p-Methoxyphenyl)-2-bromo-propenoate, see: Le

Menn, J .-C.; Saarrazin, J .; Tallec, A. Can. J . Chem. 1989, 67, 1332.

Assignment of the (Z) and (E) isomers seems not correct.

Regioselective Synthesis of Acyclic cis-Enediynes

J . Org. Chem., Vol. 64, No. 14, 1999 5067

Sch em e 6

Primary alcohols offered the best cis/trans diastereose-

lectivity (94:6) in favor of cis-enediynes 31b,c. The isomer

33 was not produced in the reactions of alcohols with 29;

but the related isomer 17 was isolated from the same

reactions of allyl alcohol 12 (Table 1). Compounds 31b-e

could not be separated from 32b-e by silica gel column

chromatography, and their structures and ratios were

determined by chemical shifts and integrations of the

vinyl and methine protons.

Thiols gave a much shorter reaction time (2-4 h) than

alcohols in the allylic rearrangement of 29 catalyzed by

CSA (entries 9-12). Variations in the amount of CSA and

EtSH at 0 °C had no visible influence on chemical yield

and product distribution, as shown in entries 9 and 10.

It is interesting to note that the sterically demanding

t-BuSH gave essentially the same result as that of EtSH

(entries 10 and 11); this is a different profile from the

reactions of alcohols. However, more than two products

were isolated from the thiol-associated allylic migration.

In regard to the product distribution, there are two ratios

that need to be mentioned, regioselectivity (31:33) and

cis/trans diastereoselectivity (31:32). Reactions of EtSH,

t-BuSH, and PhSH afforded 92:8, 90:10, and 87:13 ratios

for 31:33, respectively. These values are higher than the

corresponding data obtained from the reactions of EtSH

(67:33), t-BuSH (73:27), and PhSH (69:31) with allyl

alcohol 12 at 20 °C (Table 1). Ratios of enediynes 31 to

32 are 84:16 (EtSH), 80:20 (t-BuSH), and 90:10 (PhSH),

which are lower than the analogous reactions of EtOH

(94:6) and t-BuOH (86:14) with 29. A fourth compound

34h was formed in the reaction of PhSH with 29.

Compounds 31-34 (Nu ) EtS, t-BuS, PhS) are insepa-

rable mixtures whose ratios were measured by the

integrations of their characteristic signals in the ¹H NMR

spectra.

Reaction of allyl alcohol 30 with EtOH was performed

in the presence of 0.5 equiv of CSA and 4 equiv of EtOH

in CH₂Cl₂(Table 3, entry 13). Compound 30 did not show

visible change at 0 °C under the same acidic conditions

used for 29. It suggests that formation of the allylic cation

from 30 is much more difficult. At higher temperature

(20 °C for 90 h), a mixture of 31c and 32c (74:26) was

isolated in 32% yield together with the dimeric ethers

35 (31%). It is interesting to note that compound 34c (Nu

) EtO) was not formed in the reaction of 30, which

provides a piece of evidence for the discussion of isomer-

ization of the allylic cations in the acid-catalyzed allylic

rearrangement (vide infra).

F igu r e 3. NOE experiments for compounds 29 and 30

measured on

a 400 MHz instrument in CDCl₃at room

Kin etic Stu d ies. The acid-catalyzed isomerization of

cis-1-methyl-3-phenylallyl alcohol (36) and trans-1-phen-

yl-3-methylallyl alcohol (37) were reported by Pocker and

Hill (Scheme 8).³²Pseudo-first-order rate constants were

temperature: (a) irradiated at the vinyl proton at 6.73 ppm;

(b) irradiated at the methine proton at 4.92 ppm; (c) irradiated

at the vinyl proton at 6.80 ppm; (d) irradiated at the methine

proton at 5.17 ppm.

5068 J . Org. Chem., Vol. 64, No. 14, 1999

Dai et al.

Sch em e 7

can follow the reaction course on the NMR time scale.

Use of CD₃OD as the cosolvent has two considerations:

(a) methanol is known to slow the reaction (see entry 1,

Table 1) and then allows the kinetic measurements using

the NMR technique; and (b) methanol is a nucleophile

that reacts with the allylic cation to form the allyl ethers.

The disapperance of 12 or 29 was monitored on a 400

MHz NMR instrument by measuring the relative ratios

of the substrate to an acid-stable internal reference

compound, methyl 3,5-dinitrobenzoate, at different reac-

tion times. Figure 4 shows the pseudo-first-order reaction

of 12 in the given acid concentrations at 30, 40, and 55

°C. The slopes of the plots in Figure 4 give the pseudo-

first-order rate constants (k_obs) from which the rate

constants (k) were calculated by the equation k ) k_obs

/

[CSA]. The rate constants (k) and half-lives (t_1/2) for the

conversion of 12 at the given temperatures and acid

concentrations are summarized in Table 4. On the basis

of the rate constants (k) at 30, 40, and 55 °C, an

activation energy (E_a) of 19.1 kcal/mol is estimated from

the Arrhenius equation by the plot of ln k versus 1/T.

Because the p-MeOPh-substituted allyl alcohol 29 is

much more reactive than 12, the kinetic measurements

were performed at further diluted acid concentrations.

Figure 5 shows the pseudo-first-order reactions of 29 at

30, 40, 50, and 60 °C. From these plots and the acid

concentrations [CSA], the rate constants (k) were calcu-

lated and are listed in Table 5. An activation energy (E_a)

of 17.2 kcal/mol is estimated using the Arrhenius equa-

tion. The reduced activation energy for 29 clearly indi-

cates the involvement of a positively charged species in

the rate-determining step.

Rea ction s of Ch ir a l Allyl Alcoh ols. Regioselectivity

of the CSA-catalyzed allylic rearrangement varies re-

markably with different nucleophilic species. In general,

excellent ratios (g 96:4) in favor of enediyne products are

achieved for alcohols. In contrast, thiol nucleophiles give

low regioselectivity (ca. 70:30 for 12 and ca. 90:10 for 29).

We consider that the two reactive intermediates 43 and

44 might be involved in the product-forming step (Scheme

9).³⁵A nucleophile attacks at the protonated allyl alcohol

in either an S_N2 or an S_N2′ fashion to form two regio-

isomers. The same regioisomers can be produced through

nucleophilic trapping at either the R or γ carbon of the

allylic cation. If a chiral substrate is used, we are able to

differentiate these reaction pathways by simply measur-

ing the enantiomeric ratios of the products.

We prepared two chiral allyl alcohols (-)-12 and (-)-

18c by asymmetric reduction of ketones 45a ,b using (+)-

DIP-chloride³⁶(Scheme 10). Oxidation of racemic (()-12

to ketone 45a failed with MnO₂. By the use of PCC in

the presence of 4 Å MS (20 °C, 5 h), 45a was obtained

from (()-12 in 51% yield. Oxidation of racemic (()-18c

using MnO₂(20 °C, 1 h) provided ketone 45b in 83%

yield. Reduction of 45a ,b by (+)-DIP-chloride in Et₂O at

-25 °C for 7.5 h followed by the standard workup

procedure³⁷afforded (-)-12 and (-)-18c in good yield and

measured at different HClO₄concentrations in 40%

aqueous dioxane. On the basis of the kinetics, these

authors concluded that formation of allylic cations 36′

and 37′ is the rate-determining step in the acid-catalyzed

allylic rearrangement. Activation energies (E_a) of 23.6^32b

and 18.8^32akcal/mol were obtained for the loss of water

from the protonated allyl alcohols. It is interesting to note

that the rearranged product from both 36 and 37 is trans-

1-methyl-3-phenylallyl alcohol (38), in which conjugation

among the phenyl ring and the double bond is main-

tained. Moreover, a rapid isomerization of the sickle

allylic cation 36′ into the W-type allylic cation 37′ was

proposed, and the rotation barrier³³(36′ f 37′) and

energy difference between 36′ and 37′ were estimated to

be 7.6 and 7.3 kcal/mol, respectively.³⁴

We carried out kinetic studies on the acid-catalyzed

conversion of 3-aryl-1,2-dialkynylallyl alcohols 12 and 29

in a mixed solvent system, i.e., CD₃OD-CDCl₃(1:1).

Because the reaction rate is dependent on acid concen-

tration, by selecting a suitable concentration of CSA we

(35) An ion-neutral complex was proposed for intramolecular race-

mization and regioisomerization of chiral allyl alcohol in the gas phase,

see: (a) Troiani, A.; Gasparrini, F.; Graninetti, F.; Speranza, M. J .

Am. Chem. Soc. 1997, 119, 4525. (b) Troiani, A.; Speranza, M. J . Org.

Chem. 1998, 63, 1012. (c) Speranza, M.; Troiani, A. J . Org. Chem. 1998,

63, 1020.

(36) Brown, H. C.; Ramachandran, P. V. Acc. Chem. Res. 1992, 25,

16. Brown, H. C.; Ramachandran, P. V. Pure Appl. Chem. 1994, 66,

201. Brown, H. C.; Ramachandran, P. V. Organomet. Chem. 1995, 500,

1. Dhar, R. K. Aldrichimica Acta 1994, 27, 43.

(32) (a) Pocker, Y.; Hill, M. J . J . Am. Chem. Soc. 1969, 91, 3243. (b)

Pocker, Y.; Hill, M. J . J . Am. Chem. Soc. 1971, 93, 691.

(33) Isomerization barrier for allylic cations, see: Bollinger, J . M.;

Brinich, J . M.; Olah, G. A. J . Am. Chem. Soc. 1970, 92, 4025.

(34) Izawa, K.; Okuyama, T.; Sakagami, T.; Fueno, T. J . Am. Chem.

Soc. 1973, 95, 6752.

Regioselective Synthesis of Acyclic cis-Enediynes

J . Org. Chem., Vol. 64, No. 14, 1999 5069

Ta ble 3. Syn th esis of En ed iyn es 31 a n d 32 by Acid -Ca ta lyzed Rea r r a n gem en t of 29 a n d 30^a

entry

substrate

acid (equiv)

NuH (equiv)

T (°C), t (h)

products (%)

ratio (31:32:33:34)^b

1

2

3

4

5

6

7

8

9

10

11

12

13

29

30

CSA (1)

EtOH (2)

EtOH (4)

MeOH (4)

i-PrOH (4)

t-BuOH (4)

EtSH (2)

EtSH (4)

t-BuOH (2)

PhSH (2)

EtOH (4)

20, 0.25

20, 48

20, 2

0, 28

0, 7

0, 3.5

0, 9

0, 23

0, 12

0, 3

31c + 32c (78)

77:23:0:0

82:18:0:0

86:14:0:0

95:5:0:0

94:6:0:0

82:18:0:0

86:14:0:0

75:17:8:0

78:15:7:0

74:18:8:0

74:8:11:7

74:26:0:0

CF₃CO₂H (1)

CSA (0.2)

CSA (0.5)^d

CSA (0.5)

CSA (0.2)

CSA (0.5)

31c + 32c (68)

31c + 32c (84); 31a (15)

31c + 32c (74); 31a (3)^c

31c + 32c (89)

31b + 32b (90)

31d + 32d (77); 35 (11)

31e + 32e (20); 35 (78)

31f + 32f + 33f (88)

31g + 32g + 33g (85)

31h + 32h + 33h + 34h (76)

31c + 32c (32); 35 (31)

0, 4

0, 2

20, 90

a

b

d

Reactions were performed in CH₂Cl₂. Determined by ¹H NMR. ^cAlso, 16% of 29 recovered. Final concentration of CSA is 0.03 M.

Ta ble 4. Ra te Con sta n ts (k) a n d Ha lf-Lives (t_1/2) of Allyl

Migr a tion of 12 Ca ta lyzed by CSA in CD₃OD-CDCl₃a t

Va r iou s Tem p er a tu r es As Mea su r ed by ¹H NMR; k )

k

_obs/[CSA]

correlation

coeff

F igu r e 4. CSA-catalyzed conversion of 12 in CDCl₃-CD₃OD

k (s^-1

)

t_1/2(min)

1

T (°C)

[CSA] (M)

(1:1) at 30, 40, and 55 °C, as measured by H NMR on a 400

MHz instrument.

30

40

55

4.38 × 10^-2

4.47 × 10^-2

4.08 × 10^-2

2.15 × 10^-3

6.64 × 10^-3

23.8 × 10^-3

0.995

0.998

128.2

37.0

11.1

Sch em e 8

in >94% ee, respectively. Enantiomeric excess of the

chiral alcohols was determined by HPLC analysis in

comparison with racemic authentic samples using a

Chiralpak AD or AS column. The absolute stereochem-

istry of the chiral alcohols was not determined. Reactions

of (-)-12 and (-)-18c with EtOH and EtSH were then

F igu r e 5. CSA-catalyzed conversion of 29 in CDCl₃-CD₃OD

1

(1:1) at 30, 40, 50, and 60 °C, as measured by H NMR on a

400 MHz instrument.

carried out under the same acidic conditions used for the

racemic substrates. The results are summarized in Table

6. The enantiomeric ratios of products 16b,d , 17b,d , 19c,

(37) Ramachandran, P. V.; Teodorovic, A. V.; Rangaishenvi, M. V.;

Brown, H. C. J . Org. Chem. 1992, 57, 2379.

5070 J . Org. Chem., Vol. 64, No. 14, 1999

Dai et al.

Ta ble 5. Ra te Con sta n ts (k) a n d Ha lf-Lives (t_1/2) of Allyl

Migr a tion of 29 Ca ta lyzed by CSA in CD₃OD-CDCl₃a t

Va r iou s Tem p er a tu r es As Mea su r ed by ¹H NMR; k )

Sch em e 10

k

_obs/[CSA]

T (°C)

[CSA] (M)

k (s^-1

)

correlation coeff

t_1/2(min)

30

40

50

60

4.73 × 10^-4

4.88 × 10^-4

5.16 × 10^-4

4.73 × 10^-4

0.24

0.56

1.13

3.33

0.998

0.997

0.998

0.997

102.2

42.6

19.7

7.3

Sch em e 9

Ta ble 6. En ed iyn es F or m ed fr om Ch ir a l Alcoh ols (-)-12

a n d (-)-18c^a

entry

substrate

NuH, t (h)

products (%)

ratio^c

1

2

3

4

(-)-12

(-)-18c

EtOH, 4

EtSH, 4

EtOH, 2

EtSH, 0.5

16b (64); 17b (4)

16d + 17d (55)

19c (65); 20c (0)

46 + 47 (60)

96:4

70:30

100:0

69:31

a

Reactions were performed in CH₂Cl₂in the presence of 1 mole

46, and 47 were analyzed by HPLC over chiral columns

and all were proved to be in racemic form. These findings

confirm that the regioisomeric products are formed from

the dissociated allylic cation 44. The protonated inter-

mediate 43 is not involved in the product-forming step.

Mech a n istic Con sid er a tion s. With regard to the

structures of the allylic cations, we suggest the possibility

of three species, the W-type allylic cations (48 and 49)

and two kinds of sickle allylic cations (50-53), being

formed from allyl alcohols 12-15, 29, and 30 via acid-

catalyzed ionization (Scheme 11). The U-type allylic

cation is not considered because of its extremely high

instability. The two sickle allylic cations suffer from A^1,3

strain among the substituent and the proton at the R and

γ positions and are less stable than the W-type allylic

cation. Severe A^1,3strain is expected for 52 and 53

between the aryl group and the allylic proton.^32bThis

accounts for the relatively high ratio of 15 to 14 (66:34)

in the equilibrium mixture obtained from the acid-

catalyzed rearrangement given in Scheme 4 and Figure

1. Ionization of 15 to form 52 should be much more

difficult compared to that of 14, and allyl alcohol 15 is

then accumulated in the reaction mixture. Moreover, the

high instability facilitates a rapid isomerization^32b,34of

allylic cation 53 into 49. This explains why compound

34c (formed by attack of a nucleophile at the R position

of 53) is not formed from 30 and EtOH under the acidic

conditions (Scheme 7 and Table 3, entry 13). Acid-

catalyzed ionization of 12 and 13 should form predomi-

equiv of CSA (0.055-0.067 M) and 2 mole equiv of nucleophile at

20 °C. All products were obtained in racemic forms as checked

by HPLC over a chiral column. See Experimental Section for

details. ^cThe regioisomeric ratio of 16b:17b, 16d :17d , 19c:20c,

and 46:47, respectively.

b

nantly the W-type allylic cation 48, although enediyne

alcohol 13 undergoes ionization slower than 12. This is

attributed to the great thermodynamical stability of 13

over 12 (see the ab inito calculations below). Thus, we

assume that it is almost impossible for 13 to form the

much more unstable cation 52 at room temperature,

whereas 12 may give cation 50 as the minor ionization

pathway. A rapid isomerization eventually converts 50

into the W-type allylic cation 48. The above argument is

supported by the fact that both 12 and 13 furnish the

same product mixtures with EtOH and EtSH in the

presence of CSA (Scheme 5 and Table 1). When the

lifetime of allylic cation 51 increases as a result of extra

stabilization (ca. 12 kcal/mol, see the ab inito calculations

below) from the p-MeO group, nucleophilic trapping at

the γ position of 51 is then able to provide trans-

enediynes 32b-h (Scheme 7 and Table 3). Because of the

reduced activation energy for ionization of 29 (1.9 kcal/

mol less than 12), formation of cation 51 could be much

more competitive than formation of 49. However, we can

manipulate the reaction temperature to enhance the

selectivity among the two ionization pathways. Low

temperature favors the route 29 f 49, and higher ratios

Regioselective Synthesis of Acyclic cis-Enediynes

J . Org. Chem., Vol. 64, No. 14, 1999 5071

Sch em e 11

Ta ble 7. Tota l En er gies of th e Most Sta ble Con for m er s

of 54a -f a n d 55a -f Ca lcu la ted a t th e RHF /3-21G Level

(see Supporting Information). We found that 54a is more

stable than 54a ′ and 54a ′′ by 3.03 and 3.96 kcal/mol,

respectively, because of a favorable electrostatic interac-

tion between the oxygen atom and the olefinic proton.

In contrast, the sulfur analogue 54g (structure not

shown) is 0.26 kcal/mol less stable than 54g′ as a result

of the larger van der Waal radius of sulfur (see Support-

ing Information). We noted a similar electrostatic inter-

action in other oxygen-containing systems. For examples,

allyl alcohol 54c is more stable than 54c′ by 1.20 kcal/

mol, and allylic ether 54e is more stable than 54e′ by

3.75 kcal/mol. The hydroxy or methoxy group in 54a -e

and 55a -e is generally out of the allylic plane by ca. 10°,

and the distance between the oxygen atom and the

olefinic proton is within 2.175-2.296 Å. However, allylic

thioether 54f possesses a conformation different from

that of 54e, for example. The sulfur group in 54f is almost

in the perpendicular position relative to the allylic plane

(94.9°). Conformer 54f is 0.77 kcal/mol more stable than

54f′, in which the allylic and olefinic protons are in close

contact (2.208 Å, twisted from the allylic plane by only

4.2°). The most important structural feature of the C₃-

aryl-substituted compounds 54c-f is that the aromatic

ring twists from coplanarity with the double bond by 28-

33° (Figure 6). This conformation avoids the severe van

der Waal interaction among one of the ortho protons in

the aryl group and the C₂-alkynyl unit. However, the

distances of 2.526-2.581 Å for 54c-f are shorter than

those of 55c-f (3.085-3.322 Å). We found that enediynes

55a -f are much more stable than the corresponding

regioisomers 54a -f, perhaps because of the conjugation

of both alkynyl groups with the double bond (Table 7).

When Nu ) OH, the energy difference between 54 and

55 (∆E in kcal/mol) increases in the order of X ) H (2.76)

< X ) Me (4.03) < X ) Ph (5.12) < X ) p-MeOPh (6.64).

We found that this order is parallel to the stability order

of the corresponding allylic cations 56-59 (Figure 7). The

bulkiness of the Nu group has a significant influence on

∆E for C₃-phenyl-substituted compounds: OH (5.12) >

54 (hartrees)^a

55 (hartrees)

∆E (kcal/mol)^b

54a : -341.359 077 7

54b: -380.183 074 1

54c: -569.629 115 1

54d : -682.879 662 5

54e: -608.442 490 5

54f: -929.569 134 0

55a : -341.363 476 7

55b: -380.189 502 8

55c: -569.637 270 5

55d : -682.890 242 0

55e: -608.450 235 1

55f: -929.571 106 5

2.76

4.03

5.12

6.64

4.86

1.24

a

b

One hartree ) 627.5 kcal/mol. Energy difference between 54

and 55. In all cases, enediyne 55 is more stable than 1,5-diyne

54.

of the nucleophilic trapping products 31 and 32 are

obtained at 0 °C compared to the reactions at 20 °C. The

different ionization profiles of allylic alcohols 12 and 29

provide a key to understanding the cis/trans diastereo-

selectivity associated with enediyne formation under the

acid catalysis.

Com p u ta tion a l Ca lcu la tion s. To understand the

substituent effect on reactivity of allyl alcohols and the

origin of regioselectivity observed in the allylic rear-

rangement, we performed ab initio molecular orbital

calculations at the RHF/3-21G level using the Gaussian

94 sets of programs on the model compounds 54a -f and

55a -f and the allylic cations 56-59. The total energies

and geometries of the most stable conformers 54a -f and

55a -f are given in Table 7 and Figure 6. We first

calculated the three conformations 54a , 54a ′, and 54a ′′

5072 J . Org. Chem., Vol. 64, No. 14, 1999

Dai et al.

F igu r e 6. The most stable geometries of 54c-f and 55c-f optimized at the RHF/3-21G level.

F igu r e 7. Total energies, geometries, and Mulliken charge distribution at the R and γ carbons of allylic cations 56-59 optimized

a

b

at the RHF/3-21G level. Total energies in hartrees. Increased stability compared to 56 due to the substituent at the γ carbon in

kcal/mol.

OMe (4.86) . SMe (1.24) (in units of kcal/mol). This

stability order is explained by considering the steric

demand at the Nu-bearing carbon atom. For example,

Ph(MeS)CH- in 55f should suffer from much more

repulsive interaction compared to HCtC(MeS)CH- in

54f. The larger the van der Waal radius of the hetero-

atom is, the more severe the destabilization suffered.

The ab initio calculations on the W-type allylic cations

56-59 show that all structures are planar with a

separation of 2.146-2.321 Å between the allylic protons

Regioselective Synthesis of Acyclic cis-Enediynes

J . Org. Chem., Vol. 64, No. 14, 1999 5073

(Figure 7). Notably, full conjugation with the aromatic

ring is observed in 58 and 59 and is distinguished from

the conformations 54c-f. Much more positive charge is

found at the γ carbon compared to the R carbon in all

cations. Using 56 as the reference, a C₃substituent

greatly enhances the stability of the cation in the

following order: Me (9.63) < Ph (21.95) < p-MeOPh

(33.56) (in units of kcal/mol). Accordingly, the sum of

charge at both R and γ carbons decreases with increasing

cation stability: +0.97659 (56) > +0.89354 (57) >

+0.71407 (58) > +0.60987 (59). The calculated stability

and charge distribution of allylic cations 56-59 provide

the key to understand the reactivity and regioselectivity

observed in the acid-catalyzed allylic rearrangement.

Or igin of Rea ctivity a n d Regioselectivity. As

shown in Schemes 2 and 3, the C₃-unsubstituted and C₃-

methyl allyl alcohols 5 and 9 did not undergo allylic

rearrangement at room temperature in the presence of

a strong acid, such as TfOH. Now, we understand that

these alcohols are difficult to undergo acid-catalyzed

ionization because the corresponding allylic cations can-

not be better stabilized by the C₃substituent. In contrast,

the C₃-arylallyl alcohols 12 and 29 are readily converted

into allylic cations 48 and 49 at room temperature or

below. The calculated substituent effects on the cation

stability given in Figure 7 provide the basis for design of

suitable precursors that can be transformed into ene-

diynes under mild conditions.

The last issue that needs to be addressed is the

regioselectivity observed for nucleophilic trapping of the

W-type allylic cations 48 and 49. Reactions of alcohols

give excellent selectivity (g 94:6) in favor of attack at

the γ position to form enediynes. In contrast, thiols

provide diminished selectivity of ca. 70:30 with cation 48

at 20 °C and ca. 90:10 with cation 49 at 0 °C. We

confirmed that nucleophilic trapping of allylic cations 48

and 49 with thiols is not reversible under the mild acidic

conditions. Change in the ratio was not noted in the

control experiments using a 67:33 mixture of 16d :17d

(1 equiv of CSA, dry CH₂Cl₂, 20 °C, 5 h). Pure isomer

16b was also recovered without change after treatment

with CSA (1 equiv, dry CH₂Cl₂, 20 °C, 5 h). However, a

slow isomerization of the less stable regioisomer 17b into

16b was observed; 17b gave a 1:1 mixture of 16b:17b in

80% recovery after treatment under the same acidic

conditions (1 equiv of CSA, dry CH₂Cl₂, 20 °C, 5 h).

Considering these facts, we believe that the product

ratios given in Tables 1 and 3 for reactions of thiols are

kinetically controlled and the ratios for reactions of

alcohols are partially thermodynamically controlled.

Because the transition state (TS) of the nucleophilic

trapping reaction has partial double bond character, the

path for formation of the more stable regioisomer should

have a better stabilized TS and should take place

preferentially. This argument agrees with the finding

that enediynes 16a -f and 31a -h are the major products

of allylic cations 48 and 49. The diminished selectivity

of thiols is consistent with the smaller energy difference

among thioethers 54f and 55f compared to that of the

oxygen analogues 54e and 55e.

+0.71407 charge at the R and γ positions, and less charge

(+0.60987) is found for 59. The increased stability of 59

allows the nucleophilic trapping TS to have much more

double bond character. Thus, allylic cation 59 demon-

strates an enhanced selectivity for formation of the

thermodynamically stable enediynes. The computational

calculation results agree well with the experimental

observations.

Con clu sion

We have developed a novel synthetic method for the

rearrangement of 3-aryl-1,2-dialkynylallyl alcohols into

cis-enediynes under mild acidic conditions. High regio-

and cis/trans diastereoseletivity is achieved for the reac-

tions carried out in the presence of an alcoholic nucleo-

phile. The allylic rearrangement is confirmed to take

place in a stepwise mechanism. It involves an acid-

catalyzed ionization step to convert the allyl alcohol into

an allylic cation intermediate followed by a nucleophilic

trapping step to form the products. Pocker and Hill³²

reported that formation of the allylic cation is the rate-

determining step for the acid-catalyzed isomerization of

allyl alcohols lacking a C₂substituent. We observed loss

of chirality in the rearrangement of chiral alcohols (-)-

12 and (-)-18c. This confirms that the allylic cation is

the intermediate that produces the final products upon

nucleophilic trapping. Enhanced stability of the allylic

cation by a C₃substituent facilitates the allylic rear-

rangement under mild acidic conditions. This explains

the failure in reactions of C₃-unsubstituted and C₃-methyl

allyl alcohols 5 and 9.

The effect of a C₃-aryl group on the ionization of allyl

alcohols has been examined. A diminished activation

energy of ca. 2 kcal/mol is observed for CSA-catalyzed

rearrangement of the p-MeOPh-substituted allyl alcohol

29 compared to the Ph analogue 12 in 50% CD₃OD in

CDCl₃. Stability of the C₃-aryl-substituted allylic cations

accounts for the different ionization profiles of 12 and

29. Alcohols 12 and 29 preferentially form the most stable

W-type allylic cations 48 and 49. A minor ionization

pathway to the sickle allylic cation 51 seems possible for

29; however, it is difficult to form the sickle allylic cation

50 from alcohol 12. This argument is supported by the

fact that trans-enediynes 32 are obtained from 29. The

competitive pathways 29 f 49 and 29 f 51 can be

modulated by temperature, and higher ratios are achieved

at 0 °C in favor of cis-enediynes 31. Nucleophilic attack

at the allylic cations 48 and 49 possibly produces two

regioisomers. We have carried out ab initio molecular

orbital calculations at the RHF/3-21G level on the model

compounds 54 and 55. The results reveal that enediynes

55c-f are much more stable than 1,5-diynes 54c-f,

perhaps as a result of the twisted orientation of the C₃

aryl group in 54c-f. However, the energy difference

between 55c,e,f and 54c,e,f decreases with increasing

bulkiness of the Nu group: OH > MeO . MeS. It

provides the basis for understanding the diminished

regioselectivity in reaction of allylic cations 48 and 49

with thiols. Calculations on the cations 58 and 59 show

that the γ carbon is much more electron-deficient and is

therefore much more reactive toward nucleophiles. En-

hanced stability contributed from the p-MeO group for

cation 49 makes it less reactive toward nucleophiles and

much more regioselective compared to cation 48.

Alternatively, regioselective formation of enediynes can

be discussed according to the charge distribution in the

allylic cations 58 and 59. A hard nucleophile (alcohol)

should favor attack at the γ carbon to form enediynes,

and a soft nucleophile (thiol) should give less preference

to γ attack. However, allylic cation 58 carries a sum of

In summary, an acid-catalyzed allylic rearrangement

of 3-aryl-1,2-dialkynylallyl alcohols into cis-enediynes has

5074 J . Org. Chem., Vol. 64, No. 14, 1999

Dai et al.

been established. We have demonstrated the feasibility

of this methodology for the synthesis of cyclic ene-

diynes.^24b,38Our allylic rearrangement is conceptually

related to the mechanism of action of maduropeptin

chromophore artifacts¹⁰and opens a novel approach to

enediyne prodrug design and synthesis.

drous MgSO₄, filtered, and concentrated under reduced

pressure. The residue was purified by flash column

chromatography (silica gel, 20% EtOAc-hexane) to give

4 (0.563 g, 51%): pale yellow oil; R_f) 0.31 (20% EtOAc-

hexane); IR (neat) 3384, 2228, 1110 cm^-1; ¹H NMR (400

MHz, CDCl₃) δ 7.41 (d, J ) 7.32 Hz, 2 H), 7.28 (t, J )

7.32 Hz, 2 H), 7.22 (d, J ) 7.33 Hz, 1 H), 5.95 (dd, J )

2.45, 0.98 Hz, 1 H), 5.53 (d, J ) 1.95 Hz, 1 H), 4.84 (d, J

) 4.88 Hz, 1 H), 3.62 (d, J ) 1.95 Hz, 2 H), 2.37 (br s, 1

H); ¹³C NMR (100 MHz, CDCl₃) δ 134.7, 132.2, 130.6,

129.0, 127.1, 118.5, 83.2, 80.4, 66.9, 22.9; MS (+CI) m/z

(relative intensity) 284 (M⁺, ⁸¹Br, 100), 282 (M⁺, ⁷⁹Br, 90),

267 (M⁺- OH, ⁸¹Br, 78), 265 (M⁺- OH, ⁷⁹Br, 54); HRMS

(+FAB) calcd for C₁₂H₁₁OS⁸¹Br (M⁺) 283.9694, found

283.9635.

Exp er im en ta l Section

Gen er a l Meth od s. ¹H and ¹³C NMR spectra were

1

recorded in CDCl₃(300 or 400 MHz for H and 75 or 100

MHz for ¹³C) with CDCl₃as the internal reference. IR

spectra were taken on a FT-IR spectrophotometer. Mass

spectra (MS) were measured by CI or FAB method. High-

resolution mass spectra (HRMS) were measured by the

EI or FAB method at Kunming Institute of Botany, The

Chinese Academy of Sciences. Elemental analysis was

performed by the Microanalytic Laboratory of Shanghai

Institute of Organic Chemistry, The Chinese Academy

of Sciences. All reactions were carried out under a

nitrogen atmosphere and monitored by thin-layer chro-

matography on 0.25-mm E. Merck silica gel plates (60

F-254) using UV light or 7% ethanolic phosphomolybdic

acid and heating as the visualizing methods. E. Merck

silica gel (60, particle size 0.040-0.063 mm) was used

for flash column chromatography. Yields refer to chro-

matographically and spectroscopically (¹H NMR) homo-

geneous materials. Phenyl propargyl sulfide was synthe-

sized according to the literature procedure.²⁸Other

reagents were obtained commercially and used as re-

ceived. Room temperature is around 20 °C.

11-Meth oxy-5-m eth ylid en e-1-(p h en ylth io)u n d eca -

2,6-d iyn -4-ol (5). To a suspension of Pd(PPh₃)₄(86.1 mg,

7.45 × 10^-2mmol) and CuI (56.8 mg, 0.298 mmol) in

degassed THF (25 mL) maintained at 0 °C in an ice-

water bath was added a solution of alcohol 4 (0.421 g,

1.49 mmol), 6-methoxy-1-hexyne (0.250 g, 2.24 mmol),

and triethylamine (0.42 mL, 2.98 mmol) in degassed THF

(70 mL) via a syringe. The reaction flask was covered

against light with a sheet of aluminum foil, and the

mixture was stirred at room temperature for 4 h. The

reaction was quenched with saturated aqueous NH₄Cl

(10 × 2 mL) and extracted with EtOAc (30 mL). The

organic layer was washed with brine (30 mL), dried over

anhydrous MgSO₄, filtered, and concentrated in vacuo.

The residue was purified by flash column chromatogra-

phy (silica gel, 20% EtOAc-hexane) to give 5 (0.447 g,

95%): pale yellow oil; R_f) 0.46 (40% EtOAc-hexane);

6-Meth oxy-1-h exyn e. To a suspension of 60% NaH

(1.17 g, 29.3 mmol) in dry THF (40 mL) cooled in an ice-

water bath (0 °C) was added hex-5-yn-1-ol (2.00 g, 19.6

mmol) followed by stirring at room temperature for 30

min. The resultant mixture was cooled back to 0 °C, and

MeI (2.40 mL, 39.2 mmol) was added followed by stirring

at 40 °C for 2 days. The reaction mixture was quenched

by saturated aqueous NH₄Cl (10 mL) and extracted with

ethyl ether (50 mL). The organic layer was washed with

brine (20 mL), dried over anhydrous MgSO₄, filtered, and

concentrated in vacuo. The residue was purified by

distillation to give the product (1.43 g, 65%): colorless

1

IR (neat) 3374, 2224, 1116 cm^-1; H NMR (400 MHz,

CDCl₃) δ 7.47 (d, J ) 7.32 Hz, 2 H), 7.33 (t, J ) 7.32 Hz,

2 H), 7.27 (d, J ) 7.80 Hz, 1 H), 5.53 (s, 1 H), 5.40 (s, 1

H), 4.82 (d, J ) 5.37 Hz, 1 H), 3.69 (d, J ) 1.95 Hz, 2 H),

3.42 (t, J ) 5.86 Hz, 2 H), 3.34 (s, 3 H), 2.39 (s, 1 H),

2.38 (t, J ) 6.84 Hz, 2 H), 1.74-1.61 (m, 4 H); ¹³C NMR

(100 MHz, CDCl₃) δ 135.1, 131.5, 130.3, 128.9, 126.9,

120.6, 93.1, 82.5, 81.8, 76.8, 72.2, 65.2, 58.5, 28.7, 25.2,

23.0, 19.2; MS (+CI) m/z (relative intensity) 332 (M +

NH₄⁺, 100); HRMS (+FAB) calcd for C₁₉H₂₃O₂S (M + H⁺)

315.1419, found 315.1486.

(Z)-R-Br om ocr oton a ld eh yd e (7). To a solution of

trans-crotonaldehyde (5.92 mL, 71.4 mmol) in dry CH₂-

Cl₂(100 mL) cooled in an ice-water bath (0 °C) was

added bromine (3.7 mL, 71.8 mmol) in CH₂Cl₂(4 mL)

followed by stirring at room temperature for 1 h. Tri-

ethylamine (12 mL, 86.1 mmol) was added, and the

mixture was allowed to stir at room temperature for 1

h. The reaction was quenched with saturated aqueous

Na₂S₂O₃(20 mL), and the organic layer was washed with

brine (10 mL), dried over anhydrous MgSO₄, filtered, and

concentrated in vacuo. The residue was purified by

vacuum distillation to give the product 7 (7.76 g, 72%):

bp ) 134-135 °C/∼0.1 mmHg; pale yellow liquid; IR

(neat) 1698, 1624 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 9.21

(s, 1 H), 7.25 (q, J ) 6.84 Hz, 1 H), 2.14 (d, J ) 6.84 Hz,

3 H); ¹³C NMR (100 MHz, CDCl₃) δ 186.0, 150.7, 130.2,

17.9; MS (+CI) m/z (relative intensity) 151 (M + H⁺, ⁸¹Br,

58), 149 (M + H⁺, ⁷⁹Br, 91).

1

liquid; bp ) 120-125 °C; IR (neat) 2118, 1120 cm^-1; H

NMR (400 MHz, CDCl₃) δ 3.40 (t, J ) 6.34 Hz, 2 H), 3.33

(s, 3 H), 2.21 (td, J ) 6.44, 2.44 Hz, 2 H), 1.94 (t, J )

2.44 Hz, 1 H), 1.72-1.59 (m, 4 H); ¹³C NMR (100 MHz,

CDCl₃) δ 84.3, 72.2, 68.4, 58.5, 28.6, 25.1, 18.2; MS (+CI)

m/z (relative intensity) 81 (M⁺- MeO, 100).

2-Br om o-6-(p h en ylth io)h ex-4-yn -1-en -3-ol (4). To

a solution of phenyl propargyl sulfide (0.779 g, 5.26 mmol)

in dry THF (20 mL) cooled in a dry ice-acetone bath (-78

°C) was added n-BuLi (2.5 M in hexanes, 1.91 mL, 4.79

mmol) followed by stirring at the same temperature for

30 min to give the THF solution of PhSCH₂CtCLi. To a

solution of R-bromoacrolein (3)²⁷(0.646 g, 4.79 mmol) in

dry THF (20 mL) in a separate flask cooled at -78 °C

was added the THF solution of PhSCH₂CtCLi prepared

above. The resultant mixture was stirred at the same

temperature for 1 h and quenched with a saturated

aqueous solution of NH₄Cl (40 mL). The reaction mixture

was extracted with EtOAc (30 × 3 mL) and washed with

brine (100 mL). The organic layer was dried over anhy-

(E)-2-Eth yliden e-8-m eth oxyoct-3-yn a l (8). To a sus-

pension of Pd(PPh₃)₄(194.0 mg, 0.17 mmol) and CuI (0.13

g, 0.67 mmol) in degassed THF (30 mL) maintained at 0

°C in an ice-water bath was added a solution of (Z)-R-

bromocrotonaldehyde (7, 0.50 g, 3.36 mmol), 6-methoxy-

(38) Dai, W.-M.; Fong, K. C.; Lau, C. W.; Zhou, L.; Hamahuchi, W.;

Nishimoto, S. J . Org. Chem. 1999, 64, 682.

Regioselective Synthesis of Acyclic cis-Enediynes

J . Org. Chem., Vol. 64, No. 14, 1999 5075

1-hexyne (0.56 g, 5.03 mmol), and triethylamine (0.70

mL, 5.03 mmol) in degassed THF (40 mL) via a syringe.

The reaction flask was covered against light with a sheet

of aluminum foil, and the mixture was stirred at room

temperature for 5 h. The reaction was quenched with

saturated aqueous NH₄Cl (20 mL) and extracted with

EtOAc (60 mL). The organic layer was washed with brine

(20 mL), dried over anhydrous MgSO₄, filtered, and

concentrated in vacuo. The residue was purified by flash

column chromatography (silica gel, 20% EtOAc-hexane)

to give 8 (59.3 mg, 10%): pale yellow oil; R_f) 0.58 (20%

H), 8.08-8.05 (m, 2 H), 7.44-7.42 (m, 3 H), 7.40 (s, 1 H),

3.41 (t, J ) 5.86 Hz, 2 H), 3.32 (s, 3 H), 2.58 (t, J ) 6.59

Hz, 2 H), 1.80-1.70 (m, 4 H); ¹³C NMR (100 MHz, CDCl₃)

δ 191.6, 151.0, 134.1, 131.2, 130.3, 128.6, 123.3, 102.9,

74.5, 72.0, 58.4, 28.7, 25.0, 19.8; MS (+CI) m/z (relative

intensity) 243 (M + H⁺, 100).

(E)-11-Met h oxy-5-p h en ylm et h ylid en e-1-(p h en yl-

th io)u n d eca -2,6-d iyn -4-ol (12). To a solution of alde-

hyde 11 (2.80 g, 11.6 mmol) in dry THF (70 mL) cooled

at -80 °C was added a THF (30 mL) solution of

PhSCH₂CtCLi prepared from phenyl propargyl sulfide

(2.20 g, 15.0 mmol) and n-BuLi (1.44 M in hexanes, 10

mL, 15.0 mmol). The reaction was stirred at the same

temperature for 1 h and quenched with a methanolic

solution of acetic acid (0.9 g of acetic acid in 5 mL MeOH).

The resultant mixture was extracted with EtOAc (50 mL)

and washed with saturated aqueous NaHCO₃(20 mL)

and brine (20 mL). The organic layer was dried over

anhydrous MgSO₄, filtered, and concentrated under

reduced pressure. The residue was purified by flash

column chromatography (silica gel, 10% EtOAc-hexane)

to give 12 (3.50 g, 79%): pale yellow oil; R_f) 0.17 (20%

EtOAc-hexane); IR (neat) 2230, 1700, 1616, 1216 cm^-1

;

¹H NMR (300 MHz, CDCl₃) δ 9.39 (s, 1 H), 6.96 (q, J )

6.98 Hz, 1 H), 3.43 (t, J ) 6.05 Hz, 2 H), 3.35 (s, 3 H),

2.50 (t, J ) 6.62 Hz, 2 H), 2.16 (d, J ) 7.05 Hz, 3 H),

1.77-1.64 (m, 4 H); ¹³C NMR (100 MHz, CDCl₃) δ 190.9,

155.1, 129.7, 100.2, 72.1, 72.0, 58.5, 28.7, 25.2, 19.4, 16.9;

MS (+CI) m/z (relative intensity) 149(M⁺- OMe, 100).

(E)-5-Eth ylid en e-11-m eth oxy-1-(p h en ylth io)u n d e-

ca -2,6-d iyn -4-ol (9). To a solution of phenyl propargyl

sulfide (74.8 mg, 0.51 mmol) in dry THF (3 mL) cooled

in an acetone bath maintained at -80 °C by a chiller was

added n-BuLi (1.6 M in hexanes, 0.35 mL, 0.51 mmol)

followed by stirring at the same temperature for 30 min

to give the THF solution of PhSCH₂CtCLi. To a solution

of aldehyde 8 (70 mg, 0.39 mmol) in dry THF (3 mL) in

a separate flask cooled at -80 °C was added the THF

solution of PhSCH₂CtCLi prepared above. The resultant

mixture was stirred at the same temperature for 1 h and

quenched with a methanolic solution of acetic acid (31

mg of acetic acid in 0.5 mL MeOH). The reaction mixture

was diluted with EtOAc (10 mL) and washed with

saturated aqueous NaHCO₃(2 mL). The organic layer

was washed with brine (2 mL), dried over anhydrous

MgSO₄, filtered, and concentrated under reduced pres-

sure. The residue was purified by flash column chroma-

tography (silica gel, 10% EtOAc-hexane) to give 9 (79.2

mg, 62%): pale yellow oil; R_f) 0.30 (20% EtOAc-

hexane); IR (neat) 3380, 2220, 1116 cm^-1; ¹H NMR (300

MHz, CDCl₃) δ 7.48-7.44 (m, 2 H), 7.34-7.24 (m, 3 H),

6.02 (q, J ) 6.75 Hz, 1 H), 4.77 (d, J ) 6.54 Hz, 1 H),

3.68 (s, 2 H), 3.41 (t, J ) 6.14 Hz, 2 H), 3.33 (s, 3 H),

2.56 (d, J ) 7.08 Hz, 1 H), 2.42 (t, J ) 6.69 Hz, 2 H),

1.83 (d, J ) 6.78 Hz, 3 H), 1.73-1.61 (m, 4 H); ¹³C NMR

(75 MHz, CDCl₃) δ 135.1, 132.7, 130.2, 128.8, 126.8,

124.6, 96.9, 82.2, 75.8, 72.1, 65.4, 58.3, 28.6, 25.3, 22.9,

19.3, 15.7; MS (+CI) m/z (relative intensity) 346 (M +

NH₄⁺, 100).

(E)-8-Met h oxy-2-(p h en ylm et h ylid en e)oct -3-yn a l

(11). To a suspension of Pd(PPh₃)₄(0.27 g, 0.23 mmol)

and CuI (0.18 g, 0.95 mmol) in degassed THF (20 mL)

maintained at 0 °C in an ice-water bath was added a

solution of R-bromocinnamaldehyde (10, 1.02 g, 4.83

mmol), 6-methoxy-1-hexyne (417 mg, 3.72 mmol), and

triethylamine (1.30 mL, 9.30 mmol) in degassed THF (30

mL) via a syringe. The reaction flask was covered against

light by a sheet of aluminum foil, and the mixture was

stirred at room temperature for 2 h. The reaction was

quenched with saturated aqueous NH₄Cl (20 mL) and

extracted with EtOAc (60 mL). The organic layer was

washed with brine (20 mL), dried over anhydrous MgSO₄,

filtered, and concentrated in vacuo. The residue was

purified by flash column chromatography (silica gel, 20%

EtOAc-hexane) to give 11 (811 mg, 90%): pale yellow

oil; R_f) 0.55 (25% EtOAc-hexane); IR (neat) 2250, 1692,

1602, 1116 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 9.53 (s, 1

EtOAc-hexane); IR (neat) 3380, 2218, 1116 cm^-^{1 1}H

;

NMR (400 MHz, CDCl₃) δ 7.76 (d, J ) 6.84 Hz, 2 H),

7.42 (d, J ) 6.83 Hz, 2 H), 7.32-7.15 (m, 6 H), 6.75 (s, 1

H), 4.90 (d, J ) 6.83 Hz, 1 H), 3.66 (s, 2 H), 3.38 (t, J )

6.11 Hz, 2 H), 3.29 (s, 3 H), 2.50 (d, J ) 7.81 Hz, 1 H),

2.45 (t, J ) 6.59 Hz, 2 H), 1.91-1.74 (m, 4 H); ¹³C NMR

(100 MHz, CDCl₃) δ 135.6, 135.1, 133.7, 130.3, 128.9,

128.7, 128.4, 128.1, 126.9, 122.0, 99.5, 82.7, 82.2, 77.6,

72.1, 66.9, 58.5, 28.6, 25.1, 23.1, 19.7; MS (+CI) m/z

(relative intensity) 390 (M⁺, 100). Anal. Calcd for

C₂₅H₂₆O₂S: C, 76.89; H, 6.71. Found: C, 76.78; H, 6.88.

Acid -Ca ta lyzed Isom er iza tion of 12. (E)-8-Meth -

oxy-1-p h en yl-2-[4′-p h en ylth io(bu t-2′-yn ylid en e)]oct-

3-yn -1-ol (13), (Z)-8-Meth oxy-1-p h en yl-2-[4′-p h en yl-

th io(bu t-2′-yn ylid en e)]oct-3-yn -1-ol (14), a n d (Z)-11-

Met h oxy-5-p h en ylm et h ylid en e-1-(p h en ylt h io)u n -

d eca -2,6-d iyn -4-ol (15). To a solution of 12 (198 mg, 0.50

mmol) in dry CH₂Cl₂(3 mL) was added CSA (111 mg,

0.50 mmol) followed by stirring at room temperature for

16 h. The reaction mixture was diluted with CH₂Cl₂(5

mL) and washed with saturated aqueous NaHCO₃(2 mL)

and brine (2 mL). The organic layer was dried over

anhydrous MgSO₄, filtered, and concentrated under

reduced pressure. The residue was purified by flash

column chromatography (silica gel, 10% EtOAc-hexane)

to give 13 (111 mg, 56%) and a mixture of 14 and 15 (14:

15 ) 34:66, 52 mg, 26%). 13: pale yellow oil; R_f) 0.32

(20% EtOAc-hexane); IR (neat) 3414, 2208, 1116, 1084

cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J ) 7.32 Hz,

2 H), 7.36-7.18 (m, 8 H), 5.95 (s, 1 H), 5.17 (d, J ) 3.90

Hz, 1 H), 3.80 (d, J ) 1.95 Hz, 2 H), 3.30 (t, J ) 6.10 Hz,

2 H), 3.27 (s, 3 H), 2.33 (s, 1 H), 2.31 (t, J ) 6.35 Hz, 2

H), 1.59-1.51 (m, 4 H); ¹³C NMR (100 MHz, CDCl₃) δ

141.1, 137.6, 135.5, 129.8, 128.9, 128.4, 128.0, 126.6,

113.3, 110.4, 91.8, 81.1, 76.2, 72.1, 58.5, 28.5, 25.0, 23.9,

+

19.5; MS (+CI) m/z (relative intensity) 408 (M + NH₄

,

100). Anal. Calcd for C₂₅H₂₆O₂S: C, 76.89; H, 6.71.

Found: C, 76.81; H, 6.67. 14: colorless oil; R_f) 0.52 (20%

EtOAc-hexane); ¹H NMR (400 MHz, CDCl₃) δ 7.45-7.24

(m, 2 H), 7.32-7.19 (m, 8 H), 6.00 (s, 1 H), 4.80 (s, 1 H),

3.80 (d, J ) 1.95 Hz, 2 H), 3.25 (s, 3 H), 3.24 (t, J ) 6.35

Hz, 2 H), 2.24 (t, J ) 6.60 Hz, 2 H), 1.57-1.42 (m, 4 H).

15: colorless oil; R_f) 0.52 (20% EtOAc-hexane); ¹H

NMR (400 MHz, CDCl₃) δ 7.45-7.42 (m, 2 H), 7.32-7.19

5076 J . Org. Chem., Vol. 64, No. 14, 1999

Dai et al.

(m, 8 H), 6.06 (s, 1 H), 4.80 (s, 1 H), 3.82 (d, J ) 2.44 Hz,

2 H), 3.29 (t, J ) 6.84 Hz, 2 H), 3.27 (s, 3 H), 2.28 (t, J )

6.60 Hz, 2 H), 1.57-1.42 (m, 4 H).

22.0, 19.4. Anal. Calcd for C₂₈H₃₂O₂S: C, 77.74; H, 7.46.

Found: C, 77.87; H, 7.40.

(E)-5-(1′-Eth ylth io-1′-p h en yl)m eth yl-11-m eth oxy-

1-(p h en ylth io)u n d eca -2,6-d iyn -4-en e (16d ). Obtained

as the major component in a 67:33 mixture with 17d .

Pale yellow oil; R_f) 0.42 (10% Et₂O-hexane); IR (neat)

2220, 1118 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.12

(m, 10 H), 5.88 (s, 1 H), 4.47 (s, 1 H), 3.74 (d, J ) 1.96

Hz, 2 H), 3.25 (t, J ) 6.20 Hz, 2 H), 3.22 (s, 3 H), 2.40 (q,

J ) 7.44 Hz, 2 H), 2.29 (t, J ) 6.80 Hz, 2 H), 1.68-1.46

(m, 4 H), 1.14 (t, J ) 7.60 Hz, 3 H); ¹³C NMR (100 MHz,

CDCl₃) δ 139.1, 135.7, 134.1, 129.7, 128.8, 128.6, 128.3,

128.2, 126.6, 114.5, 99.5, 91.4, 81.3, 78.4, 72.1, 58.4, 54.7,

28.5, 26.1, 25.0, 23.8, 19.5, 14.1; MS (+CI) m/z (relative

intensity) 435 (M + H⁺, 100); HRMS (+EI) calcd for

C₂₇H₃₀OS₂(M⁺) 434.1738, found 434.1730.

Acid -Ca ta lyzed Isom er iza tion of 12 or 13 in th e

P r esen ce of Nu cleop h iles. Typ ica l P r oced u r e. (E)-

5-(1′-Eth oxy-1′-p h en yl)m eth yl-11-m eth oxy-1-(p h en -

ylth io)u n deca-2,6-diyn -4-en e (16b) an d (E)-4-Eth oxy-

11-m et h oxy-5-p h en ylm et h ylid en e-1-(p h en ylt h io)-

u n d eca -2,6-d iyn e (17b). To a solution of 12 (0.15 g, 0.38

mmol) and EtOH (44 µL, 0.75 mmol) in dry CH₂Cl₂(2.5

mL) was added CSA (87 mg, 0.39 mmol, 0.16 M). The

mixture was stirred for 3 h at room temperature. The

reaction mixture was diluted with CH₂Cl₂(5 mL) and

washed with saturated aqueous NaHCO₃(2 mL). The

organic layer was dried over anhydrous MgSO₄, filtered,

and concentrated in vacuo. Flash column chromatogra-

phy of the residue over silica gel provided 16b (114 mg,

71%) and 17b (3.0 mg, 3%). The reaction conditions, yield,

and product distribution are summarized in Table 1.

16b: pale yellow oil; R_f) 0.56 (20% EtOAc-hexane); IR

(E)-5-(1′-ter t-Bu tylth io-1′-p h en yl)m eth yl-11-m eth -

oxy-1-(p h en ylth io)u n d eca -2,6-d iyn -4-en e (16e). Ob-

tained as the major component in a 73:27 mixture with

17e. Pale yellow oil; R_f) 0.66 (10% EtOAc-hexane); IR

1

(CDCl₃) 2246, 1116 cm^-1; H NMR (400 MHz, CDCl₃) δ

1

(CDCl₃) 2246, 1114 cm^-1; H NMR (400 MHz, CDCl₃) δ

7.69-7.10 (m, 10 H), 5.92 (s, 1 H), 4.48 (s, 1 H), 3.73 (d,

J ) 2.44 Hz, 2 H), 3.25 (t, J ) 6.35 Hz, 2 H), 3.22 (s, 3

H), 2.30 (t, J ) 6.84 Hz, 2 H), 1.68-1.50 (m, 4 H), 1.23

(s, 9 H); ¹³C NMR (100 MHz, CDCl₃) δ 141.0, 137.5, 134.1,

129.7, 128.9, 128.5, 128.3, 128.2, 126.6, 114.4, 99.4, 91.5,

7.38 (d, J ) 7.33 Hz, 2 H), 7.28-7.11 (m, 8 H), 5.94 (s, 1

H), 4.67 (s, 1 H), 3.74 (d, J ) 1.96 Hz, 2 H), 3.49-3.43

(m, 1 H), 3.40-3.32 (m, 1 H), 3.24 (t, J ) 6.30 Hz, 2 H),

3.22 (s, 3 H), 2.24 (t, J ) 6.59 Hz, 2 H), 1.60-1.40 (m, 4

H), 1.15 (t, J ) 6.25 Hz, 3 H); ¹³C NMR (100 MHz, CDCl₃)

δ 139.9, 136.6, 135.6, 129.7, 128.8, 128.1, 127.7, 127.1,

126.5, 113.0, 99.5, 91.4, 83.3, 81.3, 77.9, 72.1, 64.6, 58.5,

28.5, 25.0, 23.8, 19.4, 15.2; MS (+CI) m/z (relative

intensity) 436 (M + NH₄⁺, 76); HRMS (+EI) calcd for

C₂₇H₃₀O₂S (M⁺) 418.1966, found 418.1945. 17b: pale

yellow oil; R_f) 0.48 (20% EtOAc-hexane); IR (CDCl₃)

2248, 1116 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, J

) 7.20 Hz, 2 H), 7.47-7.44 (m, 2 H), 7.37-7.18 (m, 6 H),

6.83 (s, 1 H), 4.70 (d, J ) 2.00 Hz, 1 H), 3.71 (s, 2 H),

3.60-3.54 (m, 1 H), 3.54-3.48 (m, 1 H), 3.40 (t, J ) 6.00

Hz, 2 H), 3.32 (s, 3 H), 2.48 (t, J ) 6.60 Hz, 2 H), 1.76-

1.60 (m, 4 H), 1.25 and 1.22 (t, J ) 6.84 Hz, 3 H); ¹³C

NMR (100 MHz, CDCl₃) δ 135.8, 135.2, 134.6, 130.3,

128.9, 128.8, 128.3, 128.1, 126.8, 120.1, 98.5, 83.2, 80.6,

81.5, 79.1, 72.2, 58.5, 52.8, 44.6, 31.2, 28.6, 25.1, 23.9,

+

19.5; MS (+CI) m/z (relative intensity) 480 (M + NH₄

100).

,

(E)-11-Meth oxy-5-(1′-ph en yl-1′-ph en ylth io)m eth yl-

1-(p h en ylth io)u n d eca -2,6-d iyn -4-en e (16f). Obtained

as the major component in a 69:31 mixture with 17f. Pale

yellow oil; R_f) 0.29 (10% Et₂O-hexane); IR (neat) 2218,

1

1118 cm^-1; H NMR (400 MHz, CDCl₃) δ 7.49-7.16 (m,

15 H), 5.83 (s, 1 H), 4.84 (s, 1 H), 3.78 (d, J ) 2.44 Hz, 2

H), 3.34 (t, J ) 6.35 Hz, 2 H), 3.29 (s, 3 H), 2.37 (t, J )

6.59 Hz, 2 H), 1.70-1.53 (m, 4 H); ¹³C NMR (100 MHz,

CDCl₃) δ (aromatic carbons cannot be assigned) 115.1,

99.9, 91.7, 81.3, 78.5, 72.2, 58.5, 47.4, 28.8, 25.1, 23.9,

+

19.7; MS (+CI) m/z (relative intensity) 500 (M + NH₄

,

100). Anal. Calcd for C₃₁H₃₀OS₂: C, 77.14; H, 6.26.

Found: C, 76.94; H, 6.07.

78.4, 77.3, 73.6, 72.2, 63.7, 58.5, 28.8, 25.2, 23.1, 19.8,

+

15.1; MS (+CI) m/z (relative intensity) 436 (M + NH₄

100).

,

(E)-4,11-Dim eth oxy-5-ph en ylm eth yliden e-1-(ph en -

ylth io)u n d eca -2,6-d iyn e (17a ). Pale yellow oil; R_f)

(E)-11-Meth oxy-5-(1′-m eth oxy-1′-p h en yl)m eth yl-1-

(p h en ylth io)u n d eca -2,6-d iyn -4-en e (16a ). Pale yellow

oil; R_f) 0.66 (20% EtOAc-hexane); ¹H NMR (400 MHz,

CDCl₃) δ 7.48 (d, J ) 7.32 Hz, 2 H), 7.39-7.22 (m, 8 H),

6.02 (s, 1 H), 4.66 (s, 1 H), 3.85 (s, 2 H), 3.37 (s, 3 H),

3.35 (t, J ) 6.10 Hz, 2 H), 3.32 (s, 3 H), 2.35 (t, J ) 6.59

Hz, 2 H), 1.67-1.52 (m, 4 H); ¹³C NMR (100 MHz, CDCl₃)

δ 139.4, 136.1, 135.6, 129.7, 128.9, 128.2, 127.9, 127.0,

126.6, 113.4, 99.6, 91.5, 85.3, 81.2, 77.7, 72.2, 58.5, 57.0,

28.5, 25.0, 23.8, 19.5.

1

0.63 (20% EtOAc-hexane); H NMR (400 MHz, CDCl₃)

δ 7.74 (d, J ) 6.83 Hz, 2 H), 7.39 (d, J ) 7.80 Hz, 2 H),

7.28-7.11 (m, 6 H), 6.76 (s, 1 H), 4.56 (s, 1 H), 3.66 (s, 2

H), 3.33 (t, J ) 6.10 Hz, 2 H), 3.28 (s, 3 H), 3.25 (s, 3 H),

2.41 (t, J ) 6.84 Hz, 2 H), 1.68-1.61 (m, 4 H).

(E )-4-Isop r op yloxy-11-m e t h oxy-5-p h e n ylm e t h -

ylid en e-1-(p h en ylth io)u n d eca -2,6-d iyn e (17c). Pale

yellow oil; R_f) 0.70 (20% EtOAc-hexane); IR (neat)

2219, 1118, 1076 cm^-1. ¹H NMR (400 MHz, CDCl₃) δ 7.82

(d, J ) 7.20 Hz, 2 H), 7.45 (d, J ) 7.60 Hz, 2 H), 7.34-

7.17 (m, 6 H), 6.84 (s, 1 H), 4.73 (s, 1 H), 3.82 (sept, J )

6.34 Hz, 1 H), 3.70 (d, J ) 2.00 Hz, 2 H), 3.40 (t, J ) 6.2

Hz, 2 H), 3.32 (s, 3 H), 2.47 (t, J ) 6.80 Hz, 2 H), 1.76-

1.65 (m, 4 H), 1.19 (d, J ) 6.35 Hz, 3 H), 1.17 (d, J )

5.86 Hz, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 135.9, 135.2,

134.2, 130.2, 128.9, 128.8, 128.2, 128.0, 126.8, 120.7, 98.3,

82.5, 81.3, 78.6, 72.2, 71.3, 69.9, 58.5, 28.8, 25.2, 23.2,

22.5, 22.0, 19.7.

(E)-5-(1′-Isop r op yloxy-1′-p h en yl)m eth yl-11-m eth -

oxy-1-(p h en ylth io)u n d eca -2,6-d iyn -4-en e (16c). Pale

yellow oil; R_f) 0.73 (20% EtOAc-hexane); IR (neat)

2222, 2174, 1120, cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 7.43

(d, J ) 7.32 Hz, 2 H), 7.71-7.34 (m, 8 H), 6.00 (s, 1 H),

4.85 (s, 1 H), 3.80 (d, J ) 2.45 Hz, 2 H), 3.34 (sept, J )

6.34 Hz, 1 H), 3.31 (t, J ) 6.35 Hz, 2 H), 3.28 (s, 3 H),

2.31 (t, J ) 6.84 Hz, 2 H), 1.64-1.57 (m, 2 H), 1.54-1.48

(m, 2 H), 1.18 (d, J ) 5.86 Hz, 3 H), 1.12 (d, J ) 6.34 Hz,

3 H); ¹³C NMR (100 MHz, CDCl₃) δ 140.3, 137.1, 135.6,

129.6, 128.8, 128.1, 127.6, 127.1, 126.6, 113.0, 99.4, 91.3,

81.3, 80.5, 78.1, 72.1, 69.5, 58.4, 28.5, 25.0, 23.8, 22.2,

(E)-4-Eth ylth io-11-m eth oxy-5-ph en ylm eth yliden e-

1-(p h en ylth io)u n d eca -2,6-d iyn e (17d ). Obtained as

the minor component in a 67:33 mixture with 16d . Pale

yellow oil; R_f) 0.42 (10% Et₂O-hexane); IR (neat) 2220,

Regioselective Synthesis of Acyclic cis-Enediynes

J . Org. Chem., Vol. 64, No. 14, 1999 5077

1118 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 7.69 (d, J ) 7.60

Hz, 2 H), 7.40-7.12 (m, 8 H), 6.70 (s, 1 H), 4.23 (s, 1 H),

3.67 (d, J ) 2.40 Hz, 2 H), 3.32 (t, J ) 6.20 Hz, 2 H,),

3.23 (s, 3 H), 2.60-2.40 (m, 2 H), 2.29 (t, J ) 6.80 Hz, 2

H), 1.68-1.46 (m, 4 H), 1.16 (t, 3 H, J ) 7.60 Hz); ¹³C

NMR (100 MHz, CDCl₃) δ 135.5, 135.2, 134.1, 129.9,

128.9, 128.2, 128.0, 127.4, 126.7, 119.5, 98.0, 82.7, 80.1,

78.9, 72.1, 58.4, 42.4, 28.7, 25.0, 24.8, 23.1, 19.6, 14.1;

MS (+CI) m/z (relative intensity) 435 (M + H⁺, 100);

HRMS (+EI) calcd for C₂₇H₃₀OS₂(M⁺) 434.1738, found

434.1730.

mmol, 48 mM). The mixture was stirred at room tem-

perature for 93 h. The reaction mixture was diluted with

CH₂Cl₂(5 mL) and washed with saturated aqueous

NaHCO₃(2 mL). The organic layer was dried over

anhydrous MgSO₄, filtered, and concentrated in vacuo.

Flash column chromatography of the residue (silica gel,

10% Et₂O-hexane) provided an inseparable mixture of

19a and 20a (19a :20a ) 94:6, 53.9 mg, 70%). 19a : pale

yellow oil; R_f) 0.77 (20% EtOAc in hexane); IR (neat)

2132, 1094, 1072 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 7.39

(d, J ) 7.20 Hz, 2 H), 7.29-7.19 (m, 8 H), 6.09 (s, 1 H),

4.71 (s, 1 H), 3.75 (s, 2 H), 3.53-3.39 (m, 2 H), 1.20 (t, J

) 6.80 Hz, 3 H), 0.18 (s, 9 H); ¹³C NMR (100 MHz, CDCl₃)

δ 139.5, 136.7, 135.4, 130.1, 128.9, 128.2, 127.8, 127.0,

126.7, 114.6, 102.3, 102.1, 94.8, 83.0, 80.3, 64.7, 23.8,

15.2, -0.1; MS (+CI) m/z (relative intensity) 405 (M +

H⁺, 10), 359 (M⁺- EtO, 100).

(E)-4-ter t-Bu t ylt h io-11-m et h oxy-5-p h en ylm et h -

ylid en e-1-(p h en ylth io)u n d eca -5,9-d iyn e (17e). Ob-

tained as the minor component in a 73:27 mixture with

16e. Pale yellow oil; R_f) 0.66 (10% EtOAc-hexane); IR

1

(CDCl₃) 2246, 1116 cm^-1; H NMR (400 MHz, CDCl₃) δ

7.68 (d, J ) 7.32 Hz, 2 H), 7.69-7.10 (m, 8 H), 6.78 (s, 1

H), 4.17 (s, 1 H), 3.66 (d, J ) 1.95 Hz, 2 H), 3.26 (t, J )

6.35 Hz, 2 H), 3.24 (s, 3 H), 2.40 (t, J ) 6.84 Hz, 2 H),

1.68-1.50 (m, 4 H), 1.31 (s, 9 H); ¹³C NMR (100 MHz,

CDCl₃) δ 135.9, 135.6, 135.3, 129.9, 128.8, 128.2, 128.0,

127.1, 126.6, 120.3, 97.8, 82.7, 81.7, 79.3, 72.2, 58.4, 44.7,

40.3, 31.0, 28.8, 23.2, 19.6; MS (+CI) m/z (relative

intensity) 480 (M + NH₄⁺, 100).

(E)-4-(1′-Eth oxy-1′-p h en yl)m eth yl-7-p h en ylth io-1-

p h en ylh ep t-1,5-d iyn -3-en e (19b). To a solution of

18b^24a(64.4 mg, 0.17 mmol) and EtOH (40 µL, 0.68 mmol)

in dry CH₂Cl₂(2 mL) was added CSA (19.7 mg, 8.5 ×

10^-2mmol, 43 mM). The mixture was stirred at room

temperature for 45 h. The reaction mixture was diluted

with CH₂Cl₂(5 mL) and washed with saturated aqueous

NaHCO₃(2 mL). The organic layer was dried over

anhydrous MgSO₄, filtered, and concentrated in vacuo.

Flash column chromatography of the residue (silica gel,

10% Et₂O-hexane) provided 19b (56.4 mg, 82%): pale

yellow oil; R_f) 0.80 (20% EtOAc-hexane); IR (neat)

(E)-11-Meth oxy-1,4-d i(ph en ylth io)-5-(ph en ylm eth -

ylid en e)u n d eca -2,6-d iyn e (17f). Obtained as the minor

compounent in a 69:31 mixture with 16f. Pale yellow oil;

R_f) 0.29 (10% Et₂O-hexane); IR (neat) 2218, 1118 cm^-1

;

¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J ) 6.83 Hz, 2 H),

7.49-7.16 (m, 13 H), 6.37 (s, 1 H), 4.49 (s, 1 H), 3.68 (d,

J ) 2.44 Hz, 2 H), 3.40 (t, J ) 6.10 Hz, 2 H), 3.32 (s, 3

H), 2.47 (t, J ) 6.84 Hz, 2 H), 1.76-1.50 (m, 4 H); ¹³C

NMR (100 MHz, CDCl₃) δ (aromatic carbons cannot be

assigned) 119.0, 98.0, 83.4, 80.2, 78.9, 72.2, 58.9, 47.4,

28.6, 25.1, 23.0, 19.5; MS (+CI) m/z (relative intensity)

500 (M + NH₄⁺, 100). Anal. Calcd for C₃₁H₃₀OS₂: C,

77.14; H, 6.26. Found: C, 76.94; H, 6.07.

2194, 1098, 1072 cm^-^{1 1}H NMR (300 MHz, CDCl₃) δ

;

7.48-7.23 (m, 15 H), 6.35 (s, 1 H), 4.84 (s, 1 H), 3.84 (s,

2 H), 3.64-3.47 (m, 2 H), 1.28 (t, J ) 6.96 Hz, 3 H); ¹³C

NMR (75 MHz, CDCl₃) δ 139.7, 135.4, 131.8, 130.0, 128.9,

128.4, 128.3, 128.2, 127.8, 127.0, 126.7, 123.2, 114.9, 96.4,

94.8, 87.2, 83.2, 80.6, 64.7, 23.9, 15.2; MS (+CI) m/z

(relative intensity) 426 (M + NH₄⁺, 24), 363 (M⁺- EtO,

100).

(E)-10-Met h oxy-4-p h en ylm et h ylid en e-1-p h en yl-

d eca -1,5-d iyn -3-ol (18c). To a solution of aldehyde 11

(0.380 g, 1.57 mmol) in dry THF (8 mL) cooled at -80 °C

was added a THF (7 mL) solution of PhCtCLi prepared

from phenylacetylene (0.21 mL, 1.88 mmol) and n-BuLi

(1.6 M in hexanes, 1.1 mL, 1.76 mmol). The reaction was

stirred at the same temperature for 30 min and quenched

with saturated aqueous NH₄Cl. The resultant mixture

was extracted with EtOAc (50 mL) and washed with

brine (20 mL). The organic layer was dried over anhy-

drous MgSO₄, filtered, and concentrated under reduced

pressure. The residue was purified by flash column

chromatography (silica gel, 20% EtOAc-hexane) to give

18c (0.415 g, 80%): pale yellow oil; R_f) 0.18 (20%

(E)-4-(1′-E t h oxy-1′-p h en yl)m et h yl-10-m et h oxy-1-

p h en yld eca -1,5-d iyn -3-en e (19c). To a solution of 18c

(128 mg, 0.37 mmol) and EtOH (44 µL, 0.74 mmol) in

dry CH₂Cl₂(6 mL) was added CSA (86 mg, 0.37 mmol,

62 mM). The mixture was stirred at room temperature

for 2 h. The reaction mixture was diluted with CH₂Cl₂

(10 mL) and washed with saturated aqueous NaHCO₃

(4 mL). The organic layer was dried over anhydrous

MgSO₄, filtered, and concentrated in vacuo. Flash column

chromatography of the residue (silica gel, 20% Et₂O-

hexane) provided 19c (90.3 mg, 65%): pale yellow oil; R_f

) 0.49 (20% EtOAc-hexane); IR (neat) 2220, 1118 cm^-1

;

¹H NMR (400 MHz, CDCl₃) δ 7.45-7.27 (m, 10 H), 6.25

(s, 1 H), 4.82 (s, 1 H), 3.61 (dq, J ) 9.03, 6.84 Hz, 1 H),

3.49 (dq, J ) 9.28, 6.84 Hz, 1 H), 3.30 (t, J ) 5.86 Hz, 2

H), 3.28 (s, 3 H), 2.41 (t, J ) 6.84 Hz, 2 H), 1.68-1.60

(m, 4 H), 1.26 (t, J ) 6.84 Hz, 3 H); ¹³C NMR (100 MHz,

CDCl₃) δ 140.0, 136.4, 131.6, 128.2, 127.8, 127.1, 123.5,

113.4, 100.1, 95.5, 87.5, 83.5, 78.2, 72.1, 64.7, 58.5, 28.5,

25.2, 19.6, 15.2; MS (+CI) m/z (relative intensity) 373

(M⁺+1, 10), 327 (M⁺- EtO, 100); HRMS (+FAB) calcd

for C₂₆H₂₈O₂(M⁺) 372.2089, found 372.2034.

EtOAc-hexane); IR (neat) 3368, 2198, 1118 cm^-^{1 1}H

;

NMR (400 MHz, CDCl₃) δ 7.81 (d, J ) 7.32 Hz, 2 H),

7.42-7.40 (m, 2 H), 7.30-7.19 (m, 6 H), 6.86 (s, 1 H),

5.12 (s, 1 H), 3.33 (t, J ) 5.85 Hz, 2 H), 3.25 (s, 3 H),

2.77 (br s, 1 H), 2.47 (t, J ) 6.35 Hz, 2 H), 1.73-1.61 (m,

4 H); ¹³C NMR (100 MHz, CDCl₃) δ 135.7, 133.7, 131.8,

128.7, 128.5, 128.4, 128.2, 128.1, 122.5, 122.2, 99.5, 87.8,

86.4, 77.7, 72.1, 67.4, 58.5, 28.7, 25.2, 19.7; MS (+FAB)

m/z (relative intensity) 327 (M⁺- OH, 56); HRMS

(+FAB) calcd for C₂₄H₂₄O₂(M⁺) 344.1776, found 344.1775.

Acid -Ca ta lyzed Isom er iza tion of 18a -c. (E)-4-(1′-

Eth oxy-1′-p h en yl)m eth yl-7-p h en ylth io-1-(tr im eth yl-

silyl)h ep t-1,5-d iyn -3-en e (19a ). To a solution of 18a ^24a

(71.7 mg, 0.19 mmol) and EtOH (44 µL, 0.75 mmol) in

dry CH₂Cl₂(2 mL) was added CSA (22.1 mg, 9.5 × 10^-2

Meth yl (E)-4-Meth oxycin n a m a te (22). To a solution

of trimethyl phosphonoacetate (3.93 g, 21.6 mmol) in dry

THF (150 mL) cooled in a dry ice-acetone bath (-78 °C)

was added n-BuLi (1.6 M in hexanes, 14.8 mL, 23.7

mmol) followed by stirring for 30 min. To the resultant

mixture was added p-anisaldehyde (21, 2.89 mL, 23.7

mmol) in dry THF (50 mL) at -78 °C, and the reaction

5078 J . Org. Chem., Vol. 64, No. 14, 1999

Dai et al.

was allowed to warm to room temperature. After 5 h of

stirring at room temperature, the reaction was quenched

with saturated aqueous NH₄Cl (50 mL) and extracted

with EtOAc (60 × 2 mL). The organic layer was washed

with brine (50 mL), dried over anhydrous MgSO₄, filtered,

and concentrated in vacuo. The residue was purified by

flash column chromatography (silica gel, 10% EtOAc-

hexane) to give 22 (4.15 g, 100%): white solid; R_f) 0.41

MHz, CDCl₃) δ 7.37-7.31 (AA′BB′, 2 H), 7.05 (s, 1 H),

6.83-6.77 (AA′BB′, 2 H), 3.81 (s, 3 H), 3.76 (s, 3 H), 3.41

(t, J ) 6.32 Hz, 2 H), 3.34 (s, 3 H), 2.41 (t, J ) 6.60 Hz,

2 H), 1.77-1.65 (m, 4 H); ¹³C NMR (75 MHz, CDCl₃) δ

166.7, 160.2, 142.9, 130.6, 127.2, 114.1, 113.7, 91.8, 78.8,

72.2, 58.5, 55.2, 52.2, 28.7, 25.2, 19.3; MS (+CI) m/z

(relative intensity) 303 (M + H⁺, 56), 271 (M⁺- MeO,

100). Anal. Calcd for C₁₈H₂₂O₄: C, 71.50; H, 7.33;

Found: C, 71.58; H, 7.40. 26: IR (neat) 2218, 1726, 1606,

1178, 1118 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 8.04-7.98

(AA′BB′, 2 H), 7.80 (s, 1 H), 6.95-6.89 (AA′BB′, 2 H),

3.85 (s, 3 H), 3.84 (s, 3 H), 3.43 (t, J ) 6.32 Hz, 2 H),

3.34 (s, 3 H), 2.56 (t, J ) 6.60 Hz, 2 H), 1.77-1.65 (m, 4

H); ¹³C NMR (75 MHz, CDCl₃) δ 167.0, 161.2, 144.3,

132.1, 127.4, 113.8, 110.5, 99.1, 76.8, 72.1, 58.5, 55.3,

52.5, 28.8, 25.1, 19.9; MS (+CI) m/z (relative intensity)

303 (M + H⁺, 56), 271 (M⁺- MeO, 100). Anal. Calcd for

C₁₈H₂₂O₄: C, 71.50; H, 7.33. Found: C, 71.58; H, 7.40.

(E)-8-Meth oxy-2-[(4′-m eth oxyph en yl)m eth yliden e]-

oct-3-yn a l (27) a n d (Z)-8-Meth oxy-2-[(4′-m eth oxy-

p h en yl)m eth ylid en e]oct-3-yn a l (28). To a solution of

25 and 26 prepared above (460.6 mg, 1.53 mmol) in dry

toluene (20 mL) cooled in a dry ice-acetone bath (-78

°C) was added DIBAL-H (1 M in CH₂Cl₂, 3.81 mL, 3.81

mmol) followed by stirring at the same temperature for

1 h. The reaction was quenched by MeOH (3 mL) at -78

°C and stirred for 30 min. Aqueous 5% HCl (35 mL) was

added, and the mixture was stirred at room temperature

for another 40 min. The mixture was extracted with

EtOAc (30 × 2 mL), washed with brine (50 mL), dried

over anhydrous MgSO₄, filtered, and concentrated in

vacuo. The residue was purified by flash column chro-

matography (silica gel, 20% EtOAc-hexane) to give an

inseparable mixture of the alcohols (major:minor ) 71:

29, 365.0 mg, 87%) as a pale yellow oil; R_f) 0.18 (20%

EtOAc-hexane). Ma jor isom er : IR (neat) 3414, 1178,

(10% EtOAc-hexane); IR (Nujol) 1716, 1638, 1176 cm^-1

;

¹H NMR (300 MHz, CDCl₃) δ 7.60 (d, J ) 16.01 Hz, 1

H), 7.51-7.45 (AA′BB′, 2 H), 6.93-6.87 (AA′BB′, 2 H),

6.31 (d, J ) 16.01 Hz, 1 H), 3.84 (s, 3 H), 3.79 (s, 3 H);

¹³C NMR (75 MHz, CDCl₃) δ 167.7, 161.4, 144.5, 129.7,

127.1, 115.2, 114.3, 55.3, 51.3; MS (+CI) m/z (relative

intensity) 193 (M + H⁺, 58).

Meth yl (Z)-R-Br om o-4-m eth oxycin n am ate (23) an d

Meth yl (E)-R-Br om o-4-m eth oxycin n a m a te (24). To a

solution of ester 22 (4.15 g, 21.6 mmol) in dry CH₂Cl₂

(150 mL) cooled in a dry ice-acetone bath (-78 °C) was

added bromine (1.12 mL, 21.6 mmol) in CH₂Cl₂(10 mL)

followed by stirring at -78 °C for 1 h. Triethylamine (3.65

mL, 25.9 mmol) was added, and the mixture was allowed

to stir at room temperature overnight (16 h). The reaction

was quenched with saturated aqueous Na₂S₂O₃(20 mL)

and the organic layer was washed with brine (20 mL),

dried over anhydrous MgSO₄, filtered, and concentrated

in vacuo. The residue was purified by flash column

chromatography (silica gel, 5% EtOAc-hexane) to give

the product 23 and 24 as an inseparable mixture (23:24

) 77:23, 4.66 g, 80%): white solid; R_f) 0.46 (10%

EtOAc-hexane). 23: IR (Nujol) 1720, 1604, 1176 cm^-1

;

¹H NMR (300 MHz, CDCl₃) δ 7.32 (s, 1 H), 7.31-7.25

(AA′BB′, 2 H), 6.89-6.83 (AA′BB′, 2 H), 3.82 (s, 3 H),

3.79 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃) δ 164.9, 160.2,

140.2, 130.1, 127.1, 113.8, 108.5, 55.2, 52.8; MS (+CI)

,

⁸¹Br, 98), 288 (M

+

m/z (relative intensity) 290 (M + NH₄

+ NH₄

,

⁷⁹Br, 100). Anal. Calcd for C₁₁H₁₁BrO₃: C, 48.73;

1116 cm^-^{1 1}H NMR (300 MHz, CDCl₃) δ 7.21-7.15

;

+

H, 4.09. Found: C, 48.64; H, 4.05. 24: IR (Nujol) 1720,

1604, 1176 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 8.19 (s, 1

H), 7.94-7.88 (AA′BB′, 2 H), 6.99-6.93 (AA′BB′, 2 H),

3.89 (s, 3 H), 3.85 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃) δ

(AA′BB′, 2 H), 6.90-6.84 (AA′BB′, 2 H), 6.83 (s, 1 H),

4.32 (s, 2 H), 3.80 (s, 3 H), 3.42 (t, J ) 6.01 Hz, 2 H),

3.34 (s, 3 H), 2.42 (t, J ) 6.61 Hz, 2 H), 1.75-1.62 (m, 4

H); MS (+CI) m/z (relative intensity) 275 (M + H⁺, 50);

257 (M⁺- OH, 100); HRMS (+EI) calcd for C₁₇H₂₂O₃(M⁺)

274.1569, found 274.1579. Min or isom er : IR (neat)

164.9, 160.2, 140.2, 130.1, 127.1, 113.8, 108.5, 55.2, 52.8;

MS (+CI) m/z (relative intensity) 290 (M + NH₄

,

⁸¹Br,

+

98), 288 (M + NH₄

,

⁷⁹Br, 100). Anal. Calcd for C₁₁H₁₁

BrO₃: C, 48.73; H, 4.09. Found: C, 48.64; H, 4.05.

-

3414, 1178, 1116 cm^-^{1 1}H NMR (300 MHz, CDCl₃) δ

;

7.82-7.76 (AA′BB′, 2 H), 6.90-6.84 (AA′BB′, 2 H), 6.62

(s, 1 H), 4.22 (s, 2 H), 3.81 (s, 3 H), 3.42 (t, J ) 6.01 Hz,

2 H), 3.34 (s, 3 H), 2.49 (t, J ) 6.61 Hz, 2 H), 1.75-1.62

(m, 4 H); MS (+CI) m/z (relative intensity) 275 (M + H⁺,

50); 257 (M⁺- OH, 100); HRMS (+EI) calcd for C₁₇H₂₂O₃

(M⁺) 274.1569, found 274.1579.

Meth yl (E)-8-Meth oxy-2-[(4′-m eth oxyph en yl)m eth -

ylid en e]oct-3-yn oa te (25) a n d Meth yl (Z)-8-Meth -

o x y -2-[(4′-m e t h o x y p h e n y l)m e t h y li d e n e ]o c t -3-

yn oa te (26). To a suspension of Pd(PPh₃)₄(124.4 mg,

0.10 mmol) and CuI (61 mg, 0.32 mmol) in degassed THF

(3 mL) maintained at 0 °C in an ice-water bath was

added a solution of the mixture of 23 and 24 prepared

above (541.8 mg, 2.00 mmol), 6-methoxy-1-hexyne (268.8

mg, 2.40 mmol), and triethylamine (0.42 mL, 3.00 mmol)

in degassed THF (4 mL) via a syringe. The reaction flask

was covered against light by a sheet of aluminum foil,

and the mixture was stirred at room temperature for 22

h. The reaction was quenched with saturated aqueous

NH₄Cl (50 mL) and extracted with EtOAc (100 mL). The

organic layer was washed with brine (25 mL), dried over

anhydrous MgSO₄, filtered, and concentrated in vacuo.

The residue was purified by flash column chromatogra-

phy (silica gel, 5% Et₂O-hexane) to give an inseparable

mixture of 25 and 26 (25:26 ) 76:24, 523.4 mg, 87%):

pale yellow oil; R_f) 0.23 (10% EtOAc-hexane). 25: IR

To a solution of the alcohols prepared above (239.3 mg,

0.87 mmol) in dry THF (20 mL) cooled in an ice-water

bath (0 °C) was added PDC (320 mg, 1.14 mmol) and

some powdered 4 Å molecular sieves followed by stirring

at room temperature for 4.5 h. The reaction mixture was

filtered through a short plug of silica gel with rinsing by

EtOAc. The combined organic layer was concentrated in

vacuo, and the residue was purified by flash column

chromatography (silica gel, 10% EtOAc-hexane) to give

25.3 mg of the starting alcohols (10.6%) and a mixture

of aldehydes (27:28 ) 72:28, 167.4 mg, 81%). Analytic

samples of pure 27 and 28 were obtained by repeated

flash column chromatography. 27: pale yellow oil; R_f)

0.35 (20% EtOAc-hexane); IR (neat) 1686, 1594, 1176,

1

1118 cm^-1; H NMR (300 MHz, CDCl₃) δ 9.49 (s, 1 H),

1

(neat) 2218, 1726, 1606, 1178, 1118 cm^-1; H NMR (300

8.10-8.04 (AA′BB′, 2 H), 7.35 (s, 1 H), 6.98-6.92 (AA′BB′,

Regioselective Synthesis of Acyclic cis-Enediynes

J . Org. Chem., Vol. 64, No. 14, 1999 5079

2 H), 3.86 (s, 3 H), 3.43 (t, J ) 6.03 Hz, 2 H), 3.33 (s, 3

H), 2.59 (t, J ) 6.60 Hz, 2 H), 1.85-1.70 (m, 4 H); ¹³C

NMR (75 MHz, CDCl₃) δ 191.7, 162.0, 151.0, 132.3, 127.1,

120.9, 114.1, 102.1, 74.6, 72.1, 58.5, 55.4, 28.9, 25.2, 19.9;

MS (+CI) m/z (relative intensity) 273 (M + H⁺, 100);

HRMS (+EI) calcd for C₁₇H₂₀O₃(M⁺) 272.1412, found

272.1421. 28: pale yellow oil; R_f) 0.43 (20% EtOAc-

hexane); IR (neat) 1686, 1594, 1176, 1118 cm^-1; ¹H NMR

(300 MHz, CDCl₃) δ 9.81 (s, 1 H), 7.81 (s, 1 H), 7.32-

7.26 (AA′BB′, 2 H), 6.95-6.89 (AA′BB′, 2 H), 3.84 (s, 3

H), 3.40 (t, J ) 5.52 Hz, 2 H), 3.34 (s, 3 H), 2.46 (t, J )

6.70 Hz, 2 H), 1.85-1.70 (m, 4 H); ¹³C NMR (75 MHz,

CDCl₃) δ 191.7, 162.0, 151.0, 132.3, 127.1, 120.9, 114.1,

102.1, 74.6, 72.1, 58.5, 55.4, 28.9, 25.2, 19.9; MS (+CI)

m/z (relative intensity) 273 (M + H⁺, 100); HRMS (+EI)

calcd for C₁₇H₂₀O₃(M⁺) 272.1412, found 272.1421.

with CH₂Cl₂(5 mL) and washed with saturated aqueous

NaHCO₃(2 mL). The organic layer was dried over

anhydrous MgSO₄, filtered, and concentrated in vacuo.

Flash column chromatography of the residue provided

an inseparable mixture of 31c and 32c (31c:32c ) 94:6,

48.4 mg, 89%; entry 5 in Table 3). The reaction condi-

tions, yield, and product distribution are summarized in

Table 3. 31c: pale yellow oil; R_f) 0.57 (20% EtOAc-

hexane); IR (neat) 2220, 2179, 1172, 1116 cm^-1; ¹H NMR

(300 MHz, CDCl₃) δ 7.43-7.39 (m, 2 H), 7.28-7.13 (m, 5

H), 6.83-6.74 (AA′BB′, 2 H), 5.95 (dd, J ) 3.27, 1.14 Hz,

1 H), 4.66 (s, 1 H), 3.78 (d, J ) 2.22 Hz, 2 H), 3.74 (s, 3

H), 3.50-3.36 (m, 2 H), 3.28 (t, J ) 6.15 Hz, 2 H), 3.25

(s, 3 H), 2.28 (t, J ) 6.78 Hz, 2 H), 1.70-1.47 (m, 4 H),

1.16 (t, J ) 7.05 Hz, 3 H); ¹³C NMR (75 MHz, CDCl₃) δ

159.2, 136.8, 132.1, 129.7, 128.9, 128.3, 127.6, 126.6,

113.6, 112.8, 99.4, 91.3, 82.9, 81.3, 78.0, 72.2, 64.5, 58.5,

55.2, 28.5, 25.1, 23.8, 19.5, 15.2; MS (+CI) m/z (relative

intensity) 403 (M⁺- EtO, 100); HRMS (+EI) calcd for

C₂₈H₃₂O₃S (M⁺) 448.2027, found 448.2061.

(E)-8-Meth oxy-1-(4′-m eth oxyp h en yl)-2-[4′-p h en yl-

th io(bu t-2′-yn ylid en e)]oct-3-yn -1-ol (31a ). Pale yellow

oil; R_f) 0.19 (20% EtOAc-hexane); IR (neat) 3402, 2220,

1174, 1116 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 7.41-7.34

(m, 2 H), 7.24-7.10 (m, 5 H), 6.82-6.74 (AA′BB′, 2 H),

5.89 (d, J ) 1.38 Hz, 1 H), 5.08 (d, J ) 3.36 Hz, 1 H),

3.75 (d, J ) 2.13 Hz, 2 H), 3.73 (s, 3 H), 3.25 (t, J ) 5.88

Hz, 2 H), 3.22 (s, 3 H), 2.27 (t, J ) 6.69 Hz, 2 H), 1.61-

1.44 (m, 4 H); MS (+CI) m/z (relative intensity) 421 (M

+ H⁺, 26), 403 (M⁺- OH, 100).

(E)-11-Meth oxy-5-(4′-m eth oxyph en yl)m eth yliden e-

1-(p h en ylth io)u n d eca -2,6-d iyn -4-ol (29) a n d (Z)-11-

Meth oxy-5-(4′-m eth oxyph en yl)m eth yliden e-1-(ph en -

ylth io)u n d eca -2,6-d iyn -4-ol (30). To a solution of the

above prepared mixture of aldehydes 27 and 28 (164.0

mg, 0.60 mmol) in dry THF (4 mL) cooled at -78 °C was

added a THF (3 mL) solution of PhSCH₂CtCLi prepared

from phenyl propargyl sulfide (182.3 mg, 1.23 mmol) and

n-BuLi (1.6 M in hexanes, 0.69 mL, 1.11 mmol). The

reaction was stirred at the same temperature for 1 h and

quenched with saturated aqueous NH₄Cl (5 mL). The

resultant mixture was extracted with EtOAc (10 × 2 mL)

and washed with brine (10 mL). The organic layer was

dried over anhydrous MgSO₄, filtered, and concentrated

under reduced pressure. The residue was purified by

flash column chromatography (silica gel, 15% EtOAc-

hexane) to give 29 (180.3 mg, 71%) and 30 (18.2 mg, 7%).

29: pale yellow oil; R_f) 0.18 (20% EtOAc-hexane); IR

(neat) 3378, 2216, 1178, 1114 cm^-1; ¹H NMR (300 MHz,

CDCl₃) δ 7.80-7.73 (AA′BB′, 2 H), 7.49-7.43 (m, 2 H),

7.31-7.18 (m, 3 H), 6.89-6.83 (AA′BB′, 2 H), 6.73 (s, 1

H), 4.92 (d, J ) 6.21 Hz, 1 H), 3.83 (s, 3 H), 3.70 (d, J )

1.92 Hz, 2 H), 3.42 (t, J ) 5.94 Hz, 2 H), 3.33 (s, 3 H),

2.55 (d, J ) 7.38 Hz, 1 H), 2.49 (t, J ) 6.45 Hz, 2 H),

1.78-1.66 (m, 4 H); ¹³C NMR (75 MHz, CDCl₃) δ 159.7,

135.2, 133.3, 130.2, 130.1, 128.9, 128.4, 126.9, 119.6,

113.5, 98.9, 82.6, 82.3, 77.8, 72.1, 67.0, 58.5, 55.2, 28.8,

25.2, 23.1, 19.7; MS (+CI) m/z (relative intensity) 420

(M⁺, 5), 403 (M⁺- OH, 100); HRMS (+EI) calcd for

C₂₆H₂₈O₃S (M⁺) 420.1759, found 420.1763. 30: pale

yellow oil; R_f) 0.20 (20% EtOAc-hexane); IR (neat)

3400, 2220, 1178, 1114 cm^-1; ¹H NMR (300 MHz, CDCl₃)

δ 7.55-7.44 (m, 2 H), 7.36-7.21 (m, 3 H), 7.20-7.14

(AA′BB′, 2 H), 6.87-6.81 (AA′BB′, 2 H), 6.80 (s, 1 H),

5.17 (d, J ) 9.00 Hz, 1 H), 3.81 (s, 3 H), 3.71 (d, J ) 1.59

Hz, 2 H), 3.42 (t, J ) 5.82 Hz, 2 H), 3.34 (s, 3 H), 2.60 (d,

J ) 9.51 Hz, 1 H), 2.43 (t, J ) 6.81 Hz, 2 H), 1.79-1.58

(m, 4 H); ¹³C NMR (75 MHz, CDCl₃) δ 159.3, 135.2, 130.4,

130.3, 128.9, 127.8, 126.8, 123.6, 113.9, 93.1, 83.0, 81.4,

78.4, 72.2, 60.0, 58.5, 55.3, 28.7, 25.4, 23.1, 19.4; MS (+CI)

m/z (relative intensity) 420 (M⁺, 54), 403 (M⁺- OH, 100).

Acid -Ca ta lyzed Isom er iza tion of 29 in th e P r es-

en ce of Nu cleop h iles. Typ ica l P r oced u r e. (E)-5-[1′-

Eth oxy-1′-(4′′-m eth oxyp h en yl)]m eth yl-11-m eth oxy-

1-(p h en ylt h io)u n d eca -2,6-d iyn -4-en e (31c). To a

solution of alcohol 29 (50.7 mg, 0.12 mmol) and EtOH

(28 µL, 0.48 mmol) in dry CH₂Cl₂(2 mL) cooled in an

ice-water bath (0 °C) was added CSA (14.3 mg, 0.06

mmol, 0.03 M). The mixture was stirred for 7 h at the

same temperature. The reaction mixture was diluted

(E)-11-Meth oxy-5-[1′-m eth oxy-1′-(4′′-m eth oxyph en -

yl)]m eth yl-1-(ph en ylth io)u n deca-2,6-diyn -4-en e (31b).

Obtained as the major component in an inseparable

mixture (31b:32b ) 94:6). 31b: pale yellow oil; R_f) 0.49

(20% EtOAc-hexane); IR (neat) 2229, 1172 cm^-^{1 1}H

;

NMR (300 MHz, CDCl₃) δ 7.40-7.36 (m, 2 H), 7.25-7.13

(m, 5 H), 6.80-6.74 (AA′BB′, 2 H), 5.89 (d, J ) 0.99 Hz,

1 H), 4.51 (s, 1 H), 3.75 (d, J ) 2.19 Hz, 2 H), 3.72 (s, 3

H), 3.27 (t, J ) 7.20 Hz, 2 H), 3.26 (s, 3 H), 2.25 (t, J )

6.78 Hz, 2 H), 1.65-1.45 (m, 4 H); ¹³C NMR (75 MHz,

CDCl₃) δ 159.3, 136.3, 131.6, 129.8, 128.9, 128.3, 127.5,

126.6, 113.6, 113.1, 99.5, 91.4, 84.9, 81.3, 77.8, 72.2, 58.5,

56.8, 55.2, 28.5, 25.1, 23.9, 19.5; MS (+CI) m/z (relative

intensity) 403 (M⁺- MeO, 100); HRMS (+EI) calcd for

C₂₇H₃₀O₃S (M⁺) 434.1916, found 434.1914.

(E )-5-[1′-Isop r op yloxy-1′-(4′′-m e t h oxyp h e n yl)]-

methyl-11-methoxy-1-(phenylthio)undeca-2,6-diyn-4-ene

(31d ). Obtained as the major component in an insepa-

rable mixture (31d :32d ) 82:18). 31d : pale yellow oil;

R_f) 0.62 (20% EtOAc-hexane); IR (neat) 2220, 1172,

1

1120 cm^-1; H NMR (300 MHz, CDCl₃) δ 7.50-7.46 (m,

2 H), 7.35-7.23 (m, 5 H), 6.89-6.81 (AA′BB′, 2 H), 6.02

(d, J ) 1.35 Hz, 1 H), 4.85 (s, 1 H), 3.85 (d, J ) 2.19 Hz,

2 H), 3.81 (s, 3 H), 3.35 (t, J ) 6.12 Hz, 2 H), 3.32 (s, 3

H), 2.35 (t, J ) 6.81 Hz, 2 H), 1.70-1.52 (m, 4 H), 1.21

(d, J ) 6.12 Hz, 3 H), 1.16 (d, J ) 6.09 Hz, 3 H); ¹³C

NMR (75 MHz, CDCl₃) δ 159.1, 137.4, 132.5, 129.7, 128.9,

128.4, 127.6, 126.5, 113.5, 112.7, 99.3, 91.2, 81.4, 80.1,

78.2, 72.2, 69.4, 59.5, 55.2, 28.5, 25.1, 23.8, 22.2, 22.1,

+

19.5; MS (+CI) m/z (relative intensity) 480 (M + NH₄

,

5), 403 (M⁺- i-PrO, 100); HRMS (+EI) calcd for

C₂₉H₃₄O₃S (M⁺) 462.2229, found 462.2226.

(E )-5-[1′-t er t -Bu t yloxy-1′-(4′′-m e t h oxyp h e n yl)]-

methyl-11-methoxy-1-(phenylthio)undeca-2,6-diyn-4-ene

(31e). Obtained as the major component in an insepa-

rable mixture (31e:32e ) 86:14). 31e: pale yellow oil; R_f

5080 J . Org. Chem., Vol. 64, No. 14, 1999

Dai et al.

) 0.69 (20% EtOAc-hexane); IR (neat) 2222, 2179, 1172,

phy of the residue provided an inseparable mixture of

31c and 32c (31c:32c ) 74:26, 17.2 mg, 32%) together

with a mixture of the dimeric ethers 35 (16.5 mg, 31%).

35: pale yellow oil; IR (neat) 2220, 1176, 1116 cm^-1; MS

(+CI) m/z (relative intensity) 823 (M + H⁺, 1), 403 (M⁺

- 419, 100).

1

1118 cm^-1; H NMR (300 MHz, CDCl₃) δ 7.49-7.45 (m,

2 H), 7.34-7.24 (m, 5 H), 6.87-6.81 (AA′BB′, 2 H), 6.06

(d, J ) 1.59 Hz, 1 H), 4.93 (s, 1 H), 3.84 (d, J ) 2.19 Hz,

2 H), 3.81 (s, 3 H), 3.34 (t, J ) 6.09 Hz, 2 H), 3.32 (s, 3

H), 2.34 (t, J ) 6.81 Hz, 2 H), 1.68-1.52 (m, 4 H), 1.20

+

(s, 9 H); MS (+CI) m/z (relative intensity) 494 (M + NH₄

,

Acid -Ca ta lyzed Isom er iza tion of 12 a n d 29 in th e

P r esen ce of Meth yl-d ₃Alcoh ol-d . Typ ica l P r oce-

d u r e. (E)-11-Meth oxy-5-[1′-(tr id eu ter iom eth oxy)-1′-

p h e n ylm e t h y]-1-(p h e n ylt h io)u n d e ca -2,6-d iyn -4-

en e (39) an d (E)-11-Meth oxy-5-(ph en ylm eth yliden e)-

1-p h en ylt h io-4-(t r id eu t er iom et h oxyl)u n d eca -2,6-

d iyn e (40). To a solution of 12 (55.5 mg, 0.14 mmol) and

CD₃OD (11 µL, 0.27 mmol) in dry CH₂Cl₂(1.5 mL) was

added CSA (16.5 mg, 0.07 mmol, 46 mM). The mixture

was stirred for 10.5 h at room temperature. The reaction

mixture was diluted with CH₂Cl₂(3 mL) and washed with

saturated aqueous NaHCO₃(1 mL). The organic layer

was dried over anhydrous MgSO₄, filtered, and concen-

trated in vacuo. Flash column chromatography of the

residue (silica gel, 10% EtOAc-hexane) provided 39 (40.7

mg, 70%) and 40 (5.0 mg, 8.7%). 39: colorless oil; R_f)

4); HRMS (+EI) calcd for C₃₀H₃₆O₃S (M⁺) 476.2386, found

476.2381.

(E)-5-[1′-Eth ylth io-1′-(4′′-m eth oxyp h en yl)]m eth yl-

11-m ethoxy-1-(ph enylthio)undeca-2,6-diyn -4-ene (31f).

Obtained as the major component in an inseparable

mixture (31f:32f:33f ) 78:15:7). 31f: pale yellow oil; R_f

) 0.46 (20% EtOAc-hexane); IR (neat) 2229, 1178, 1118

1

cm^-1; H NMR (300 MHz, CDCl₃) δ 7.49-7.45 (m, 2 H),

7.36-7.30 (m, 5 H), 6.87-6.84 (AA′BB′, 2 H), 5.95 (br s,

1 H), 4.54 (s, 1 H), 3.85 (d, J ) 2.13 Hz, 2 H), 3.81 (s, 3

H), 3.37 (t, J ) 6.06 Hz, 2 H), 3.32 (s, 3 H), 2.51-2.37

(m, 4 H), 1.70-1.58 (m, 4 H), 1.24 (t, J ) 7.35 Hz, 3 H);

¹³C NMR (75 MHz, CDCl₃) δ 158.9, 136.0, 131.2, 129.8,

129.7, 129.3, 129.2, 128.9, 114.3, 113.7, 99.5, 91.4, 81.4,

78.5, 72.2, 58.5, 55.2, 54.1, 28.6, 26.1, 25.1, 23.8, 19.5,

14.2; MS (+CI) m/z (relative intensity) 465 (M + H⁺, 19),

403 (M⁺- EtS, 100); HRMS (+EI) calcd for C₂₆H₂₇O₂S

(M⁺- EtS) 403.1732, found 403.1690.

1

0.65 (20% EtOAc-hexane); H NMR (300 MHz, CDCl₃)

7.50-7.24 (m, 10 H), 6.02 (s, 1 H), 4.66 (s, 1 H), 3.85 (s,

2 H), 3.35 (t, J ) 6.03 Hz, 2 H), 3.32 (s, 3 H), 2.35 (t, J )

6.38 Hz, 2 H), 1.68-1.52 (m, 4 H); ¹³C NMR (100 MHz,

CDCl₃) δ 139.4, 136.1, 135.6, 129.7, 128.9, 128.2, 127.9,

127.0, 126.6, 113.4, 99.6, 91.5, 85.3, 81.2, 77.7, 72.2, 58.5,

57.0, 28.5, 25.0, 23.8, 19.5; MS (+CI) m/z (relative

intensity) 425 (M + NH₄⁺, 100). 40: colorless oil; ¹H NMR

(300 MHz, CDCl₃), δ 7.84 (d, J ) 6.69 Hz), 7.36 (m, 3 H),

6.87 (s, 1 H), 3.90 (s, 1 H), 3.74 (d, J ) 1.89 Hz, 2 H),

3.43 (t, J ) 6.00 Hz, 2 H), 3.32 (s, 3 H), 2.51 (t, J ) 6.38

Hz, 2 H), 1.66-1.29 (m, 4 H).

(E)-5-[1′-ter t-Bu tylth io-1′-(4′′-m eth oxyph en yl)]m eth -

yl-11-m eth oxy-1-(p h en ylth io)u n d eca -2,6-d iyn -4-en e

(31g). Obtained as the major component in an insepa-

rable mixture (31g:32g:33g ) 74:18:8). 31g: pale yellow

oil; R_f) 0.53 (20% EtOAc-hexane); IR (neat) 2229, 1176,

1

1118 cm^-1; H NMR (300 MHz, CDCl₃) δ 7.49-7.45 (m,

2 H), 7.39-7.28 (m, 5 H), 6.85-6.80 (AA′BB′, 2 H), 6.00

(s, 1 H), 4.57 (s, 1 H), 3.84 (d, J ) 2.10 Hz, 2 H), 3.80 (s,

3 H), 3.38 (t, J ) 6.18 Hz, 2 H), 3.33 (s, 3 H), 2.41 (t, J )

6.84 Hz, 2 H), 1.80-1.57 (m, 4 H), 1.33 (s, 9 H); ¹³C NMR

(75 MHz, CDCl₃) δ 158.6, 137.8, 133.0, 130.0, 129.7,

129.0, 128.8, 126.6, 114.1, 113.7, 99.3, 91.4, 81.5, 79.1,

72.2, 58.4, 55.2, 52.2, 44.5, 31.2, 28.6, 25.1, 23.9, 19.5;

MS (+CI) m/z (relative intensity) 510 (M + NH₄⁺, 10),

403 (M⁺- t-BuS, 100); HRMS (+EI) calcd for C₃₀H₃₆O₂S₂

(M⁺) 492.2157, found 492.2136.

(E)-11-Meth oxy-5-[1′-(tr id eu ter iom eth oxy)-1′-(4′′-

m eth oxyp h en yl)m eth yl]-1-(p h en ylth io)u n d eca -2,6-

d iyn -4-en e (41). Obtained as the major component in

an inseparable mixture (41:42 ) 75:25). 41: pale yellow

oil; R_f) 0.43 (20% EtOAc-hexane); IR (neat) 2202, 1172,

1118 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, J ) 7.33

Hz, 2 H), 7.31-7.20 (m, 5 H), 6.88-6.83 (AA′BB′, 2 H),

5.97 (S, 1 H), 4.59 (s, 1 H), 3.83 (d, J ) 1.95 Hz, 2 H),

3.80 (s, 3 H), 3.32 (t, J ) 5.86 Hz, 2 H), 2.33 (t, J ) 6.83

Hz, 2 H), 1.68-1.49 (m, 4 H); ¹³C NMR (100 MHz, CDCl₃)

δ 159.3 136.3, 131.6, 129.7, 128.9, 128.3, 127.5, 126.6,

113.8, 113.1, 99.5, 91.4, 84.8, 81.2, 77.8, 72.2, 58.5, 55.2,

28.6, 25.1, 23.8, 19.5; MS (+CI) m/z (relative intensity)

437 (M⁺, 7), 403 (M⁺- OMe-d₃, 100).

(Z)-11-Meth oxy-5-[1′-(tr id eu ter iom eth oxy)-1′-(4′′-

m eth oxyp h en yl)m eth yl]-1-(p h en ylth io)u n d eca -2,6-

d iyn -4-en e (42). Obtained as the minor component in

an inseparable mixture (41:42 ) 75:25). 42: pale yellow

oil; R_f) 0.43 (20% EtOAc-hexane); IR (neat) 2202, 1172,

1118 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, J ) 7.33

Hz, 2 H), 7.31-7.20 (m, 5 H), 6.82-6.79 (AA′BB′, 2 H),

5.82 (S, 1 H), 5.18 (s, 1 H), 3.88 (d, J ) 1.95 Hz, 2 H),

3.79 (s, 3 H), 3.35 (t, J ) 5.86 Hz, 2 H), 2.34 (t, J ) 6.83

Hz, 2 H), 1.68-1.49 (m, 4 H); ¹³C NMR (100 MHz, CDCl₃)

δ 159.1 137.8, 1315.6, 134.9, 129.8, 129.0, 128.5, 126.9,

115.3, 113.5, 96.9, 95.0, 80.6, 79.8, 78.1, 72.1, 58.5, 55.2,

28.5, 25.0, 23.7, 19.4; MS (+CI) m/z (relative intensity)

437 (M⁺, 7), 403 (M⁺- OMe-d₃, 100).

(E)-11-Met h oxy-5-[1′-p h en ylt h io-1′-(4′′-m et h oxy-

p h en yl)]m et h yl-1-(p h en ylt h io)u n d eca -2,6-d iyn -4-

en e (31h ). Obtained as the major component in an

inseparable mixture (31h :32h :33h :34h ) 74:8:11:7).

31h : pale yellow oil; R_f) 0.45 (20% EtOAc-hexane); IR

(neat) 2220, 1176, 1116 cm^-1; ¹H NMR (300 MHz, CDCl₃)

δ 7.50-7.43 (m, 2 H), 7.40-7.25 (m, 10 H), 6.90-6.82

(AA′BB′, 2 H), 5.86 (s, 1 H), 4.86 (s, 1 H), 3.83 (d, J )

2.16 Hz, 2 H), 3.82 (s, 3 H), 3.38 (t, J ) 6.06 Hz, 2 H),

3.33 (s, 3 H), 2.41 (t, J ) 6.78 Hz, 2 H), 1.72-1.61 (m, 4

H); ¹³C NMR (75 MHz, CDCl₃) δ 159.1, 135.4, 134.7,

131.9, 131.3, 130.2, 129.4, 128.9, 128.7, 128.5, 127.0,

126.6, 114.9, 113.8, 99.8, 91.6, 81.3, 78.6, 72.2, 58.5, 58.2,

55.2, 28.6, 25.1, 23.9, 19.6; MS (+CI) m/z (relative

intensity) 513 (M + H⁺, 32), 403 (M⁺- PhS, 100); HRMS

(+EI) calcd for C₃₂H₃₂O₂S₂(M⁺) 512.1844, found 512.1855.

Acid -Ca ta lyzed Isom er iza tion of 30 in th e P r es-

en ce of Eth a n ol. To a solution of alcohol 30 (50.7 mg,

0.12 mmol) and EtOH (28 µL, 0.48 mmol) in dry CH₂Cl₂

(2 mL) was added CSA (14.3 mg, 0.06 mmol, 0.03 M).

The mixture was stirred for 90 h at room temperature.

The reaction mixture was diluted with CH₂Cl₂(5 mL) and

washed with saturated aqueous NaHCO₃(2 mL). The

organic layer was dried over anhydrous MgSO₄, filtered,

and concentrated in vacuo. Flash column chromatogra-

Oxid a tion of Allyl Alcoh ol 12. (E)-11-Meth oxy-5-

p h en ylm eth ylid en e-1-(p h en ylth io)u n d eca -2,6-d iyn -

4-on e (45a ). To a solution of alcohol 12 (0.597 g, 1.53

mmol) and powdered 4 Å molecular sieves in dry CH₂Cl₂

Regioselective Synthesis of Acyclic cis-Enediynes

J . Org. Chem., Vol. 64, No. 14, 1999 5081

(50 mL) cooled at 0 °C in an ice-water bath was added

PCC (495 mg, 2.30 mmol) followed by stirring at room

temperature for 5 h. The reaction mixture was diluted

with Et₂O (50 mL) and filtered through a short plug of

silica gel with rinsing by Et₂O. The combined organic

layer was concentrated in vacuo, and the residue was

purified by flash column chromatography (silica gel, 20%

EtOAc-hexane) to give 45a (300 mg, 51%): yellow oil;

R_f) 0.26 (20% EtOAc-hexane); IR (neat) 2224, 1638,

1594, 1118 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 7.97-7.93

(m, 2 H), 7.83 (s, 1 H), 7.54-7.22 (m, 8 H), 3.84 (s, 2 H),

3.41 (t, J ) 5.82 Hz, 2 H), 3.32 (s, 3 H), 2.56 (t, J ) 6.57

Hz, 2 H), 1.78-1.69 (m, 4 H); ¹³C NMR (75 MHz, CDCl₃)

δ 176.8, 147.9, 134.2, 134.1, 131.1, 130.7, 130.6, 129.2,

128.5, 127.5, 122.6, 102.7, 91.2, 80.7, 75.3, 72.1. 58.5,

28.8, 25.0, 23.2, 19.9; MS (+CI) m/z (relative intensity)

389 (M + H⁺, 100); HRMS (+FAB) calcd for C₂₅H₂₅O₂S

(M + H⁺) 389.1575, found 389.1506.

detector at 254 nm; t_R) 20.1 min for (-)-18c and t_R

)

17.8 min for the other enantiomer. The absolute stereo-

chemistry of (-)-18c is not determined.

Acid -Ca ta lyzed Isom er iza tion of (-)-12 a n d (-)-

18c in th e P r esen ce of Eth a n ol or Eth a n eth iol.

Typ ica l P r oced u r e. (E)-4-(1′-Eth ylth io-1′-p h en yl)-

m eth yl-10-m eth oxy-1-ph en yldeca-1,5-diyn -3-en e (46)

a n d

(E)-3-E t h ylt h io-10-m et h oxy-4-p h en ylm et h -

ylid en e-1-p h en yld eca -1,5-d iyn e (47). To a solution of

(-)-18c (46 mg, 0.134 mmol) and EtSH (20 µL, 0.27

mmol) in dry CH₂Cl₂(2 mL) was added CSA (31 mg, 13.4

× 10^-2mmol, 67 mM). The mixture was stirred at room

temperature for 30 min. The reaction mixture was diluted

with CH₂Cl₂(5 mL) and washed with saturated aqueous

NaHCO₃(2 mL). The organic layer was dried over

anhydrous MgSO₄, filtered, and concentrated in vacuo.

Flash column chromatography of the residue (silica gel,

20% EtOAc-hexane) provided an inseparable mixture of

46 and 47 (46:47 ) 69:31, 60 mg, 60%). 46: pale yellow

oil; R_f) 0.49 (20% EtOAc-hexane); IR (neat) 2200, 1118

cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 7.50-7.27 (m, 10 H),

6.21 (s, 1 H), 4.65 (s, 1 H), 3.33 (t, J ) 5.86 Hz, 2 H),

3.29 (s, 3 H), 2.54 (q, J ) 7.35 Hz, 2 H), 2.47 (t, J ) 7.47

Hz, 2 H), 1.77-1.61 (m, 4 H), 1.27 (t, J ) 7.32 Hz, 3 H);

¹³C NMR (75 MHz, CDCl₃) δ 139.2, 135.5, 131.7, 128.4,

128.2, 127.5, 123.4, 114.8, 100.1, 95.6, 87.6, 78.7, 77.2,

72.1, 58.5, 54.9, 28.6, 26.2, 25.2, 19.6, 14.2; MS (+CI) m/z

(relative intensity) 327 (M⁺- EtS, 100); HRMS (+FAB)

calcd for C₂₆H₂₈OS (M⁺) 388.1861, found 388.1806. 47:

pale yellow oil; R_f) 0.49 (20% EtOAc-hexane); IR (neat)

2200, 1118 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 7.88 (d, J

) 7.14 Hz, 2 H), 7.50-7.27 (m, 8 H), 6.96 (s, 1 H), 4.58

(s, 1 H), 3.40 (t, J ) 5.85 Hz, 2 H), 3.33 (s, 3 H), 2.88-

2.65 (m, 2 H), 2.54 (t, J ) 6.60 Hz, 2 H), 1.77-1.61 (m,

4 H), 1.35 (t, J ) 7.35 Hz, 3 H); ¹³C NMR (75 MHz, CDCl₃)

δ 137.0, 134.5, 131.6, 128.4, 128.3, 127.7, 123.0, 116.0,

101.0, 97.0, 86.9, 79.0, 74.0, 72.0, 64.3, 47.0, 41.8, 28.5,

25.1, 19.5, 14.4; MS (+CI) m/z (relative intensity) 327 (M⁺

- EtS, 100).

Table 6 summaries the results of reactions of chiral

alcohols (-)-12 and (-)-18c with EtOH and EtSH. The

products 16b,d , 17b,d , 19c, 46, and 47 given in Table 6

were proved to be racemic mixtures as analyzed by HPLC

using chiral columns as specified below.

For compound 16b: two Chiralpak AD columns eluted

with hexane-2-propanol (99:1) at 0.6 mL/min using UV

detector at 254 nm; t_R) 24.1 and 29.5 min for the two

enantiomers.

For compound 17b: two Chiralcel OD columns eluted

with hexane-2-propanol (99:1) at 1 mL/min using UV

detector at 254 nm; t_R) 24.1 and 25.1 min for the two

enantiomers.

For compounds 16d and 17d : two Chiralpak AD

columns eluted with hexane-2-propanol (99:1) at 0.8 mL/

min using UV detector at 254 nm; t_R) 39.2 and 42.5

min for the two enantiomers of 17d . Chiralcel OD column

eluted with hexane-2-propanol (99:1) at 1 mL/min using

UV detector at 254 nm; t_R) 12.7 and 17.1 min for the

two enantiomers of 16d .

Oxid a tion of Allyl Alcoh ol 18c. (E)-10-Meth oxy-

4-p h en ylm et h ylid en e-1-p h en yld eca -1,5-d iyn -3-on e

(45b). To a solution of alcohol 18c (130 mg, 0.38 mmol)

in dry THF (5 mL) was added MnO₂(657 mg, 5.67 mmol)

followed by stirring at room temperature for 1 h. The

reaction mixture was diluted with EtOAc (10 mL) and

filtered through a short plug of silica gel with rinsing by

EtOAc. The combined organic layer was concentrated in

vacuo, and the residue was purified by flash column

chromatography (silica gel, 20% EtOAc-hexane) to give

45b (107 mg, 83%): yellow oil; R_f) 0.32 (20% EtOAc-

hexane); IR (neat) 2200, 1634, 1490, 1174, 1118 cm^-1

;

¹H NMR (400 MHz, CDCl₃) δ 8.12-8.10 (m, 2 H), 8.07

(s, 1 H), 7.65-7.63 (m, 2 H), 7.48-7.39 (m, 6 H), 3.41 (t,

J ) 6.34 Hz, 2 H), 3.32 (s, 3 H), 2.62 (t, J ) 6.83 Hz, 2

H), 1.78-1.75 (m, 4 H); ¹³C NMR (100 MHz, CDCl₃) δ

177.1, 146.9, 134.4, 132.9, 131.1, 130.7, 130.4, 128.6,

128.5, 122.7, 120.3, 102.5, 93.7, 86.7, 75.9, 72.1. 58.5,

28.9, 25.1, 19.9; MS (+CI) m/z (relative intensity) 343 (M

+ H⁺, 100).

Red u ction of Keton es 45a ,b. Typ ica l P r oced u r e.

(-)-(E)-11-Met h oxy-5-p h en ylm et h ylid en e-1-(p h en -

ylth io)u n d eca -2,6-d iyn -4-ol (12). To a solution of (+)-

DIP-chloride (331 mg, 1.03 mmol) in dry Et₂O (2 mL)

cooled at -20 °C was added a solution of 45a (334 mg,

0.86 mmol) in dry Et₂O (8 mL). The resultant mixture

was stirred at the same temperature for 7.5 h. Excess

acetaldehyde (∼1.5 mL) was then added to the reaction

mixture, and stirring was continued for another 4 h at

room temperature. The reaction was quenched with 2 N

NaOH (20 mL) and stirred for 3 h at room temperature.

The reaction mixture was extracted with Et₂O (20 × 3

mL). The organic layer was washed with brine, dried over

anhydrous MgSO₄, filtered, and concentrated in vacuo.

Flash column chromatography of the residue (silica gel,

30% EtOAc-hexane) provided (-)-12 (200 mg, 60%):

[R]²⁰-27.6° (c ) 1.02, CHCl₃); 94.3% ee determined by

D

HPLC over Chiralpak AD column eluted with hexane-

2-propanol (95:5) at 1 mL/min using UV detector at 254

nm; t_R) 32.5 min for (-)-12 and t_R) 26.3 min for the

other enantiomer. The absolute stereochemistry of (-)-

12 is not determined.

For compound 19c: Chiralpak AD column eluted with

hexane-2-propanol (95:5) at 1 mL/min using UV detector

at 254 nm; t_R) 4.5 and 6.4 min for the two enantiomers.

For compounds 46 and 47: two Chiralpak AD columns

eluted with hexane-2-propanol (99:1) at 0.6 mL/min

using UV detector at 254 nm; t_R) 23.8 and 24.6 min for

(-)-(E)-10-Meth oxy-4-p h en ylm eth ylid en e-1-p h en -

yld eca -1,5-d iyn -3-ol (18c). Obtained in 69% yield from

the (+)-DIP-chloride reduction of ketone 45b as described

for 45a . 18c: [R]²⁰-16.4° (c ) 1.03, CHCl₃); 94.4% ee

D

determined by HPLC over Chiralpak AS column eluted

with hexane-2-propanol (95:5) at 1 mL/min using UV

5082 J . Org. Chem., Vol. 64, No. 14, 1999

Dai et al.

the two enantiomers of 47; t_R) 27.4 and 35.3 min for

the two enantiomers of 46.

f, 55a -f, and 56-59. Calculation results for 54g and

other less stable conformations are found in the Sup-

Kin etic Mea su r em en t. Conversion of 12 in CD₂Cl₂

in the presence of 1.0 equiv of CSA at 20 °C was

monitored by H NMR on a 400 MHz instrument. The

porting Information. Substituent effect (∆∆E ) ∆E_ref

∆E_subst) on the stability of allylic cations 57-59 are

obtained by the difference in the energy gap (∆E_subst

-

1

)

relative integration values for compounds 12 (at 5.0 ppm),

13 (at 5.2 ppm), and the mixture of 14 and 15 (at 4.8

ppm) in the ¹H NMR spectrum were recorded at the

specified reaction time and were plotted against the time

shown in Figure 1.

between the cations 57-59 and the most stable confor-

mation of the allylic alcohols 54b-d , respectively, com-

pared to that (∆E_ref) of 56 and 54a . The data are given

in Figure 7.

Ack n ow led gm en t. This work was supported by the

UGC Competitive Earmarked Research Grants

[HKUST212/93E and HKUST590/95P] from the Re-

search Grants Council of the Hong Kong Special Ad-

ministrative Region, China. Financial support from the

Department of Chemistry, HKUST is also acknowl-

edged.

Conversion of alcohols 12 and 29 in CDCl₃-CD₃OD

(1:1 v/v) in the presence of CSA at the indicated temper-

1

ature was monitored by H NMR on a 400 MHz instru-

ment. Methyl 3,5-dinitrobenzoate was used as the inter-

nal reference compound. At the given temperature and

CSA concentration, the relative integration values of the

substrate (at ca. 6.80 ppm for both 12 and 29) to methyl

1

3,5-dinitrobenzoate (at 9.10 ppm) in the H NMR spec-

Su p p or tin g In for m a tion Ava ila ble: Z-Matrixes and

total energies for 54a -g, 55a -f, 56-59, and related species

and copies of ¹H and ¹³C NMR spectra of products. This

material is available free of charge via the Internet at

http://pubs.acs.org.

trum were recorded at the specified reaction time. These

data were used to construct the plots shown in Figures

4 and 5. The rate constants and half-lives were calculated

from the slopes of the plots in Figures 4 and 5 and listed

in Tables 4 and 5. Activation energies were estimated

from the Arrhenius equation by the plot of ln k versus

1/T for both 12 and 29.

Com p u ta tion a l Ca lcu la tion s. The ab initio molec-

ular orbit calculations were performed using the Gauss-

ian 94³⁹sets of programs. The geometries of the examined

structures were optimized at the RHF/3-21G level of

theory. Table 7 and Figures 6 and 7 list the total energies

and geometries of the most stable conformations of 54a -

J O982476V

(39) Gaussian 94, Revision D. 3; Frisch, M. J .; Trucks, G. W.;

Schlegel, H. B.; Gill, P. M. W.; J ohnson, B. G.; Robb, M. A.; Cheeseman,

J . R.; Keith, T. A.; Petersson, G. A.; Montgomery, J . A.; Raghavachari,

K.; Al-Laham, M. A.; Zakrzewski, V. G.; Ortiz, J . V.; Foresman, J . B.;

Cioslowski, J .; Stefanov, B. B.; Nanayakkara, A.; Challacombe, M.;

Peng, C. Y.; Ayala, P. Y.; Chen, W.; Wong, M. W.; Andres, J . L.;

Replogle, E. S.; Gomperts, R.; Martin, R. L.; Fox, D. J .; Binkley, J . S.;

Defrees, D. J .; Baker, J .; Stewart, J . P.; Head-Gordon, M.; Gonzalez,

C.; Pople, J . A.; Gaussian, Inc.: Pittsburgh, PA, 1995.

Article Doi

Regioselective synthesis of acyclic cis-enediynes via an acid-catalyzed rearrangement of 1,2-dialkynylallyl alcohols. Syntheses, computational calculations, and mechanism

DOI: 10.1021/jo982476v

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Article abstract of DOI:10.1021/jo982476v

Full text of DOI:10.1021/jo982476v

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